Compassionate Machines: The Ethics of "Artificial Empathy" in Cancer Care.

This Viewpoint discusses the ethics of artificial intelligence­generated compassion in cancer care and outlines 4 main points of concern.

Single-genome analysis reveals a heterogeneous association of the herpes simplex virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts.

The fate of herpesvirus genomes following entry into different cell types is thought to regulate the outcome of infection. For the Herpes simplex virus 1 (HSV-1), latent infection of neurons is characterized by association with repressive heterochromatin marked with Polycomb silencing-associated lysine 27 methylation on histone H3 (H3K27me). However, whether H3K27 methylation plays a role in repressing lytic gene expression in non-neuronal cells is unclear. To address this gap in knowledge, and with consideration that the fate of the viral genome and outcome of HSV-1 infection could be heterogeneous, we developed an assay to quantify the abundance of histone modifications within single viral genome foci of infected fibroblasts. Using this approach, combined with bulk epigenetic techniques, we were unable to detect any role for H3K27me3 during HSV-1 lytic infection of fibroblasts. By contrast, we could detect the lesser studied H3K27me2 on a subpopulation of viral genomes, which was consistent with a role for H3K27 demethylases in promoting lytic gene expression. In addition, viral genomes co-localized with the H3K27me2 reader protein PHF20L1, and this association was enhanced by inhibition of the H3K27 demethylases UTX and JMJD3. Notably, targeting of H3K27me2 to viral genomes was enhanced following infection with a transcriptionally defective virus in the absence of Promyelocytic leukemia nuclear bodies. Collectively, these studies implicate a role for H3K27me2 in fibroblast-associated HSV genome silencing in a manner dependent on genome sub-nuclear localization and transcriptional activity. IMPORTANCE: Investigating the potential mechanisms of gene silencing for DNA viruses in different cell types is important to understand the differential outcomes of infection, particularly for viruses like herpesviruses that can undergo distinct types of infection in different cell types. In addition, investigating chromatin association with viral genomes informs on the mechanisms of epigenetic regulation of DNA processes. However, there is a growing appreciation for heterogeneity in the outcome of infection at the single cell, and even single viral genome, level. Here we describe a novel assay for quantifying viral genome foci with chromatin proteins and show that a portion of genomes are targeted for silencing by H3K27me2 and associate with the reader protein PHF20L1. This study raises important questions regarding the mechanism of H3K27me2-specific targeting to viral genomes, the contribution of epigenetic heterogeneity to herpesvirus infection, and the role of PHF20L1 in regulating the outcome of DNA virus infection.

Single-genome analysis reveals heterogeneous association of the Herpes Simplex Virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts.

The fate of herpesvirus genomes following entry into different cell types is thought to regulate the outcome of infection. For the Herpes simplex virus 1 (HSV-1), latent infection of neurons is characterized by association with repressive heterochromatin marked with Polycomb silencing-associated lysine 27 methylation on histone H3 (H3K27me). However, whether H3K27 methylation plays a role in repressing lytic gene expression in non-neuronal cells is unclear. To address this gap in knowledge, and with consideration that the fate of the viral genome and outcome of HSV-1 infection could be heterogeneous, we developed an assay to quantify the abundance of histone modifications within single viral genome foci of infected fibroblasts. Using this approach, combined with bulk epigenetic techniques, we were unable to detect any role for H3K27me3 during HSV-1 lytic infection of fibroblasts. In contrast, we could detect the lesser studied H3K27me2 on a subpopulation of viral genomes, which was consistent with a role for H3K27 demethylases in promoting lytic gene expression. This was consistent with a role for H3K27 demethylases in promoting lytic gene expression. In addition, viral genomes co-localized with the H3K27me2 reader protein PHF20L1, and this association was enhanced by inhibition of the H3K27 demethylases UTX and JMJD3. Notably, targeting of H3K27me2 to viral genomes was enhanced following infection with a transcriptionally defective virus in the absence of Promyelocytic leukemia nuclear bodies. Collectively, these studies implicate a role for H3K27me2 in fibroblast-associated HSV genome silencing in a manner dependent on genome sub-nuclear localization and transcriptional activity.

The GenoVA study: Equitable implementation of a pragmatic randomized trial of polygenic-risk scoring in primary care.

Polygenic risk scores (PRSs) hold promise for disease risk assessment and prevention. The Genomic Medicine at Veterans Affairs (GenoVA) Study is addressing three main challenges to the clinical implementation of PRSs in preventive care: defining and determining their clinical utility, implementing them in time-constrained primary care settings, and countering their potential to exacerbate healthcare disparities. The study processes used to test patients, report their PRS results to them and their primary care providers (PCPs), and promote the use of those results in clinical decision-making are modeled on common practices in primary care. The following diseases were chosen for their prevalence and familiarity to PCPs: coronary artery disease; type 2 diabetes; atrial fibrillation; and breast, colorectal, and prostate cancers. A randomized clinical trial (RCT) design and primary outcome of time-to-new-diagnosis of a target disease bring methodological rigor to the question of the clinical utility of PRS implementation. The study's pragmatic RCT design enhances its relevance to how PRS might reasonably be implemented in primary care. Steps the study has taken to promote health equity include the thoughtful handling of genetic ancestry in PRS construction and reporting and enhanced recruitment strategies to address underrepresentation in research participation. To date, enhanced recruitment efforts have been both necessary and successful: participants of underrepresented race and ethnicity groups have been less likely to enroll in the study than expected but ultimately achieved proportional representation through targeted efforts. The GenoVA Study experience to date offers insights for evaluating the clinical utility of equitable PRS implementation in adult primary care.

Palliative Care in Survivors of Critical Illness: A Qualitative Study of Post-Intensive Care Unit Program Clinicians.

Background: Survivors of critical illness experience high rates of serious health-related suffering. The delivery of palliative care may assist in decreasing this burden for survivors and their families. Objectives: To understand beliefs, attitudes, and experiences of post-intensive care unit (ICU) program clinicians regarding palliative care and explore barriers and facilitators to incorporating palliative care into critical illness survivorship care. Design: Qualitative inquiry using semistructured interviews and framework analysis. Results were mapped using the Consolidated Framework for Implementation Research. Setting/Subjects: We interviewed 29 international members (United States, United Kingdom, Canada) of the Critical and Acute Illness Recovery Organization post-ICU clinic collaborative. Results: All interprofessional clinicians described components of palliative care as essential to post-ICU clinic practice, including symptom management, patient/family support, facilitation of goal-concordant care, expectation management and anticipatory guidance, spiritual support, and discussion of future health care wishes and advance care planning. Facilitators promoting palliative care strategies were clinician level, including first-hand experience, perceived value, and a positive attitude regarding palliative care. Clinician-level barriers were reciprocals and included insufficient palliative care knowledge, lack of self-efficacy, and a perceived need to protect ICU survivors from interventions the clinician felt may adversely affect recovery or change the care trajectory. System-level barriers included time constraints, cost, and lack of specialty palliative care services. Conclusion: Palliative care may be an essential element of post-ICU clinic care. Implementation efforts focused on tailoring strategies to improve post-ICU program clinicians' palliative care knowledge and self-efficacy could be a key to enhanced care delivery for survivors of critical illness.

Living in human-modified landscapes narrows the dietary niche of a specialised mammalian scavenger.

Anthropogenic impacts on carnivores can be complex, posing numerous threats to many species, yet also benefits to those able to exploit certain resources. This balancing act is particularly precarious for those adapters that exploit dietary resources provided by humans, but still require other resources only available in native habitat. Here we measure the dietary niche of one such species, the Tasmanian devil (Sarcophilus harrisii), a specialised mammalian scavenger, across an anthropogenic habitat gradient stretching from cleared pasture to undisturbed rainforest. Populations inhabiting areas of greater disturbance showed restricted dietary niches, suggesting that all individuals fed on similar food items, even within regenerated native forest. Populations in undisturbed rainforest habitats had comparatively broad diets and showed evidence of niche partitioning by body size, which may reduce intraspecific competition. Despite the potential benefits of reliable access to high-quality food items in anthropogenically-modified habitats, the constrained niches we observed may be harmful, indicating altered behaviours and potentially increasing the rate of fights between individuals over food. This is of particular concern for a species at risk of extinction due to a deadly cancer primarily transmitted through aggressive interactions. The lack of diversity in devil diets within regenerated native forest compared to those in old-growth rainforest also indicates the conservation value of the latter for both the devil and the species which they consume.

Examining the needs of survivors of critical illness through the lens of palliative care: A qualitative study of survivor experiences.

OBJECTIVE: To examine the needs of adult survivors of critical illness through a lens of palliative care. RESEARCH METHODOLOGY: A qualitative study of adult survivors of critical illness using semi-structured interviews and framework analysis. SETTING: Participants were recruited from the post-intensive care unit clinic of a mid-Atlantic academic medical center in the United States. FINDINGS: Seventeen survivors of critical illness aged 34-80 (median, 66) participated in the study. The majority of patients were female (64.7 %, n = 11) with a median length of index ICU stay of 12 days (interquartile range [IQR] 8-19). Interviews were conducted February to March 2021 and occurred a median of 20 months following the index intensive care stay (range, 13-33 months). We identified six key themes which align with palliative care principles: 1) persistent symptom burden; 2) critical illness as a life-altering experience; 3) spiritual changes and significance; 4) interpreting/managing the survivor experience; 5) feelings of loss and burden; and 6) social support needs. CONCLUSION: Our findings suggest that palliative care components such as symptom management, goals of care discussions, care coordination, and spiritual and social support may assist in the assessment and treatment of survivors of critical illness.

Development of a clinical polygenic risk score assay and reporting workflow.

Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. For the ongoing Veterans Affairs Genomic Medicine at Veterans Affairs (GenoVA) Study we developed a clinical genotype array-based assay for six published PRS. We used data from 36,423 Mass General Brigham Biobank participants and adjustment for population structure to replicate known PRS-disease associations and published PRS thresholds for a disease odds ratio (OR) of 2 (ranging from 1.75 (95% CI: 1.57-1.95) for type 2 diabetes to 2.38 (95% CI: 2.07-2.73) for breast cancer). After confirming the high performance and robustness of the pipeline for use as a clinical assay for individual patients, we analyzed the first 227 prospective samples from the GenoVA Study and found that the frequency of PRS corresponding to published OR > 2 ranged from 13/227 (5.7%) for colorectal cancer to 23/150 (15.3%) for prostate cancer. In addition to the PRS laboratory report, we developed physician- and patient-oriented informational materials to support decision-making about PRS results. Our work illustrates the generalizable development of a clinical PRS assay for multiple conditions and the technical, reporting and clinical workflow challenges for implementing PRS information in the clinic.

Conflicts of interest in oncology expanded access studies.

Expanded access is a treatment use of investigational drugs, biologicals or medical devices outside of clinical trials. The purpose of our study was to assess self-reported conflicts of interest (COIs) in oncology expanded access studies. One hundred fifty-eight oncology expanded access studies published from 2013 through 2020 were included. The pharmaceutical industry funded either completely or in part 94 studies (59.49%). The authors disclosed mostly financial COIs, while the number of the reported nonfinancial conflicts was relatively small (3528 and 57 COIs, respectively). The number of articles in which at least one author had a financial COI was 118 (74.68%). The most common financial COI types included advisory board membership/consulting (1471 COIs; 41.7%), followed by honoraria (570 COIs; 16.16%) and research funding (441 COIs; 12.5%). Logistic regression was performed to identify predictors of disclosing financial COIs and positive study's conclusions. On univariate analysis, financial COIs were more likely to occur in studies with at least one center located in the United States (odds ratio [OR], 5.62; 95% confidence interval [CI], 1.57-35.98; P = .02). We also found that positive conclusions about the studied treatments were less likely in studies without industry funding (OR, 0.26; CI, 0.08-0.77; P = .01). Most of the research on COIs in oncology performed to date focused on other types of studies, especially clinical trials. To our knowledge, our study is the first to evaluate COIs in oncology expanded access studies.

The care of older cancer patients in the United Kingdom.

The ageing population poses new challenges globally. Cancer care for older patients is one of these challenges, and it has a significant impact on societies. In the United Kingdom (UK), as the number of older cancer patients increases, the management of this group has become part of daily practice for most oncology teams in every geographical area. Older cancer patients are at a higher risk of both under- and over-treatment. Therefore, the assessment of a patient's biological age and effective organ functional reserve becomes paramount. This may then guide treatment decisions by better estimating a prognosis and the risk-to-benefit ratio of a given therapy to anticipate and mitigate against potential toxicities/difficulties. Moreover, older cancer patients are often affected by geriatric syndromes and other issues that impact their overall health, function and quality of life. Comprehensive geriatric assessments offer an opportunity to identify and address health problems which may then optimise one's fitness and well-being. Whilst it is widely accepted that older cancer patients may benefit from such an approach, resources are often scarce, and access to dedicated services and research remains limited to specific centres across the UK. The aim of this project is to map the current services and projects in the UK to learn from each other and shape the future direction of care of older patients with cancer.

Chronic microfiber exposure in adult Japanese medaka (Oryzias latipes).

Microplastic fibers (MFs) pollute aquatic habitats globally via sewage release, stormwater runoff, or atmospheric deposition. Of the synthetic MFs, polyester (PES) and polypropylene (PP) are the most common. Field studies show that fish ingest large quantities of MFs. However, few laboratory studies have addressed host responses, particularly at the organ and tissue levels. Adult Japanese medaka (Oryzias latipes), a laboratory model fish, were exposed to aqueous concentrations of PES or PP MFs (10,000 MFs/L) for 21 days. Medaka egested 1,367 ± 819 PES MFs (0.1 ± 0.04 mg) and 157 ± 105 PP MFs (1.4 ± 0.06 mg) per 24 hrs, with PP egestion increasing over time. Exposure did not result in changes in body condition, gonadosomatic- or hepatosomatic indices. PES exposure resulted in no reproductive changes, but females exposed to PP MFs produced more eggs over time. MF exposure did not affect embryonic mortality, development, or hatching. Scanning electron microscopy (SEM) of gills revealed denuding of epithelium on arches, fusion of primary lamellae, and increased mucus. Histologic sections revealed aneurysms in secondary lamellae, epithelial lifting, and swellings of inner opercular membrane that altered morphology of rostral most gill lamellae. SEM and histochemical analyses showed increased mucous cells and secretions on epithelium of foregut; however, overt abrasions with sloughing of cells were absent. For these reasons, increased focus at the tissue and cell levels proved necessary to appreciate toxicity associated with MFs.

Treatment of tobacco dependence in UK hospitals: an observational study.

Over a million smokers are admitted to hospitals in the UK each year. The extent to which tobacco dependence is identified and addressed in this population is unclear. Data on 14,750 patients from 146 hospitals collected for the British Thoracic Society smoking cessation audit were analysed to determine smoking prevalence, attempts to ask smokers about quitting, and referrals to smoking cessation services. Associations with hospital organisational factors were assessed by logistic regression. Overall hospital smoking prevalence was 25%. Only 28% of smokers were asked whether they would like to quit, and only one in 13 smokers was referred for treatment of tobacco dependence. There was a higher chance of smokers being asked about quitting in organisations with smoke-free sites, dedicated smoking cessation practitioners, regular staff training, and availability of advanced pharmacotherapy. Treatment of tobacco dependence in smokers attending UK hospitals is poor and could be associated with organisational factors.

[Pituitary apoplexy in a young woman].

Pituitary apoplexy occurs when a preexisting pituitary adenoma undergoes acute haemorrhage, infarct or both. The patho-genesis is not fully understood but macroadenomas and prolactinomas have been reported as being predisposed to apoplexy. Only a few cases are described in the paediatric population. We present a 17-year-old woman with secondary amenorrhoea, headache and blurred vision. An MRI showed a pituitary apoplexy in a preexisting macroadenoma. The majority of milder cases resolve spontaneously. Close monitoring of the pituitary function is important to detect pituitary insufficiency witch may need long-term hormone replacement therapy.