Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.

Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.

"We are not the person we will be when these things happen:" Reflections on personhood from an ethnography of neuropalliative care.

Neuropalliative care developed to address the needs of patients living with life-limiting neurologic disease. One critical consideration is that disease-related changes to cognition, communication, and function challenge illness experiences and care practices. We conducted an ethnography to understand neuropalliative care as a phenomenon; how it was experienced, provided, conceptualized. Personhood served as our conceptual framework; with its long philosophical history and important place in nursing theory, we examined the extent to which it captured neuropalliative experiences and concerns. Personhood contextualized complex losses, aligning the impact of functional and relational changes. Cognition, communication, and functional alterations stretched conceptions of personhood, insinuating it can be relational, fluid, adaptive. Although normative conceptions of personhood guided research and decision-making, ethical considerations suggested personhood could be transformed, remade. We consider the implications of our findings through three themes. First, we examine how literature on illness experience fails to integrate the realities of people living with and dying from neurologic disease; we counter this by interrogating the concept of experience. Second, we turn to Ricoeur's work on recognition to illuminate relational conceptions of personhood to inform care practices. Finally, we reflect on how personhood can bridge the gap left by functional changes, enhance relational engagement, and promote dignity at the end of life.

ISGylation is induced in neurons by demyelination driving ISG15-dependent microglial activation.

The causes of grey matter pathology and diffuse neuron injury in MS remain incompletely understood. Axonal stress signals arising from white matter lesions has been suggested to play a role in initiating this diffuse grey matter pathology. Therefore, to identify the most upstream transcriptional responses in neurons arising from demyelinated axons, we analyzed the transcriptome of actively translating neuronal transcripts in mouse models of demyelinating disease. Among the most upregulated genes, we identified transcripts associated with the ISGylation pathway. ISGylation refers to the covalent attachment of the ubiquitin-like molecule interferon stimulated gene (ISG) 15 to lysine residues on substrates targeted by E1 ISG15-activating enzyme, E2 ISG15-conjugating enzymes and E3 ISG15-protein ligases. We further confirmed that ISG15 expression is increased in MS cortical and deep gray matter. Upon investigating the functional impact of neuronal ISG15 upregulation, we noted that ISG15 expression was associated changes in neuronal extracellular vesicle protein and miRNA cargo. Specifically, extracellular vesicle-associated miRNAs were skewed toward increased frequency of proinflammatory and neurotoxic miRNAs and decreased frequency of anti-inflammatory and neuroprotective miRNAs. Furthermore, we found that ISG15 directly activated microglia in a CD11b-dependent manner and that microglial activation was potentiated by treatment with EVs from neurons expressing ISG15. Further study of the role of ISG15 and ISGylation in neurons in MS and neurodegenerative diseases is warranted.

Is progress being made on Canada's palliative care framework and action plan? A survey of stakeholder perspectives.

BACKGROUND: The legalization of Medical Assistance in Dying in Canada in 2016 provided new impetus for improving palliative care. This commitment to improvement included the development of a National Palliative Care Framework and Action Plan. The purpose of this study was to understand the progress made in palliative care since 2016 from the perspective of persons working and volunteering in palliative care and compare geographic differences. METHODS: A digital survey was developed from goals identified in Canada's Palliative Care Framework and Action Plan and administered online using Qualtrics. Participants were recruited through national palliative care organizations. The survey included both quantitative survey items designed to evaluate improvements across 5 domains and 29 items and included open-ended questions about impacts, innovations, and ongoing challenges. Descriptive statistics were generated for survey domains, items, and demographic variables. Geographic differences were compared using Independent-Samples Kruskal-Wallis test. Qualitative data was analyzed inductively into themes. RESULTS: One hundred fifty surveys met inclusion criteria and were analysed. Overall, the most improvement was reported in palliative care education and the least improvement was reported in support for family caregivers. Items on which respondents reported the most improvement included healthcare provider education in palliative care, advance care planning, and use of technology. Items on which respondents reported the least improvement were respite for family caregivers, access to bereavement services, and in-home support for family caregivers. Notably, rural participants reported more statistically significant improvements in the domains of education, access, and research and data collection than their urban counterparts. However, rural participants reported less improvement in places to die when home is not preferable. The COVID-19 pandemic was a significant contributor to these perceived improvements and ongoing challenges. CONCLUSION: Canada's Framework and Action Plan sets out a roadmap for improving palliative care in Canada. Participants in this survey noted significant improvements in key areas, a notable accomplishment amidst the effects of the COVID-19 pandemic. Some improvements were a result of greater use of distance technology. Further leveraging these improvements will make an important contribution to solving some of the rural and remote palliative care issues that have arisen from Canada's unique geography.

Blowing the whistle during the first wave of COVID-19: A case study of Quebec nurses.

The experiences of nurses who blew the whistle during the COVID-19 pandemic have exposed gaps and revealed an urgent need to revisit our understanding of whistleblowing. AIM: The aim was to develop a better understanding of whistleblowing during a pandemic by using the experiences and lessons learned of Quebec nurses who blew the whistle during the first wave of COVID-19 as a case study. More specifically, to explore why and how nurses blew the whistle, what types of wrongdoing triggered their decision to do so and how context shaped the whistleblowing process as well as its consequences (including perceived consequences). DESIGN: The study followed a single-case study design with three embedded units of analysis. METHODS: We used content analysis to analyse 83 news stories and 597 forms posted on a whistleblowing online platform. We also conducted 15 semi-structured interviews with nurses and analysed this data using a thematic analysis approach. Finally, we triangulated the findings. RESULTS: We identified five themes across the case study. (1) During the first wave of COVID-19, Quebec nurses experienced a shifting sense of loyalty and relationship to workplace culture. (2) They witnessed exceedingly high numbers of intersecting wrongdoings amplified by mismanagement and long-standing issues. (3) They reported a lack of trust and transparency; thus, a need for external whistleblowing. (4) They used whistleblowing to reclaim their rights (notably, the right to speak) and build collective solidarity. (5) Finally, they saw whistleblowing as an act of moral courage in the face of a system in crisis. Together, these themes elucidate why and how nurse whistleblowing is different in pandemic times. CONCLUSION: Our findings offer a more nuanced understanding of nurse whistleblowing and address important gaps in knowledge. They also highlight the need to rethink external whistleblowing, develop whistleblowing tools and advocate for whistleblowing protection. IMPACT: In many ways, the COVID-19 pandemic has challenged our foundational understanding of whistleblowing and, as a result, it has limited the usefulness of existing literature on the topic for reasons that will be brought to light in this paper. We believe that studying the uniqueness of whistleblowing during a pandemic can address this gap by describing why and how health care workers blow the whistle during a pandemic and situating this experience within a broader social, political, organizational context.

A novel k-mer set memory (KSM) motif representation improves regulatory variant prediction.

The representation and discovery of transcription factor (TF) sequence binding specificities is critical for understanding gene regulatory networks and interpreting the impact of disease-associated noncoding genetic variants. We present a novel TF binding motif representation, the k-mer set memory (KSM), which consists of a set of aligned k-mers that are overrepresented at TF binding sites, and a new method called KMAC for de novo discovery of KSMs. We find that KSMs more accurately predict in vivo binding sites than position weight matrix (PWM) models and other more complex motif models across a large set of ChIP-seq experiments. Furthermore, KSMs outperform PWMs and more complex motif models in predicting in vitro binding sites. KMAC also identifies correct motifs in more experiments than five state-of-the-art motif discovery methods. In addition, KSM-derived features outperform both PWM and deep learning model derived sequence features in predicting differential regulatory activities of expression quantitative trait loci (eQTL) alleles. Finally, we have applied KMAC to 1600 ENCODE TF ChIP-seq data sets and created a public resource of KSM and PWM motifs. We expect that the KSM representation and KMAC method will be valuable in characterizing TF binding specificities and in interpreting the effects of noncoding genetic variations.

Assessing the spread of the novel coronavirus in the absence of mass testing.

BACKGROUND: Assessing why the spread of the COVID-19 virus slowed down in many countries in March through to May of 2020 is of great significance. The relative role of restrictions on behaviour ("lockdowns") and of a natural slowing for other reasons is difficult to assess when mass testing was not widely done. This paper assesses the evolution of the spread of the COVID-19 virus over this period when there was no data on test results for a large, random sample of the population. METHOD: We estimate a version of the susceptible-infected-recovered model applied to data on the numbers who were tested positive in several countries over the period when the virus spread very fast and then its spread slowed sharply. Up to the end of April 2020, test data came from non-random samples of populations who were overwhelmingly those who displayed symptoms. Using data from a period when the criteria used for testing (which was that people had clear symptoms) was relatively consistent is important in drawing out the message from test results. We use this data to assess two things: how large might be the group of those infected who were not recorded and how effective were lockdown measures in slowing the spread of the infection. RESULTS: We find that to match data on daily new cases of the virus, the estimated model favours high values for the number of people infected but not recorded. CONCLUSIONS: Our findings suggest that the infection may have spread far enough in many countries by April 2020 to have been a significant factor behind the fall in measured new cases. Government restrictions on behaviour-lockdowns-were only one factor behind slowing in the spread of the virus.

Navigating medical assistance in dying from Bill C-14 to Bill C-7: a qualitative study.

BACKGROUND: Even as healthcare providers and systems were settling into the processes required for Medical Assistance in Dying (MAID) under Bill C-14, new legislation was introduced (Bill C-7) that extended assisted death to persons whose natural death is not reasonably foreseeable. The purpose of this paper is to describe the experiences of nurses and nurse practitioners with the implementation and ongoing development of this transition. METHODS: This qualitative longitudinal descriptive study gathered data through semi-structured telephone interviews with nurses from across Canada; cross sectional data from 2020 to 2021 is reported here. The study received ethical approval and all participants provided written consent. FINDINGS: Participants included nurses (n = 34) and nurse practitioners (n = 16) with significant experience with MAID. Participants described how MAID had transitioned from a new, secretive, and anxiety-producing procedure to one that was increasingly visible and normalized, although this normalization did not necessarily mitigate the emotional impact. MAID was becoming more accessible, and participants were learning to trust the process. However, the work was becoming increasingly complex, labour intensive, and often poorly remunerated. Although many participants described a degree of integration between MAID and palliative care services, there remained ongoing tensions around equitable access to both. Participants described an evolving gestalt of determining persons' eligibility for MAID that required a high degree of clinical judgement. Deeming someone ineligible was intensely stressful for all involved and so participants had learned to be resourceful in avoiding this possibility. The required 10-day waiting period was difficult emotionally, particularly if persons worried about losing capacity to give final consent. The implementation of C-7 was perceived to be particularly challenging due to the nature of the population that would seek MAID and the resultant complexity of trying to address the origins of their suffering within a resource-strapped system. CONCLUSIONS: Significant social and system calibration must occur to accommodate assisted death as an end-of-life option. The transition to offering MAID for those whose natural death is not reasonably foreseeable will require intensive navigation of a sometimes siloed and inaccessible system. High quality MAID care should be both relational and dialogical and those who provide such care require expert communication skills and knowledge of the healthcare system.

What's suffering got to do with it? A qualitative study of suffering in the context of Medical Assistance in Dying (MAID).

BACKGROUND: Intolerable suffering is a common eligibility requirement for persons requesting assisted death, and although suffering has received philosophic attention for millennia, only recently has it been the focus of empirical inquiry. Robust theoretical knowledge about suffering is critically important as modern healthcare provides persons with different options at end-of-life to relieve suffering. The purpose of this paper is to present findings specific to the understanding and application of suffering in the context of MAID from nurses' perspectives. METHODS: A longitudinal qualitative descriptive study using semi-structured telephone interviews. Inductive analysis was used to construct a thematic account. The study received ethical approval and all participants provided written consent. RESULTS: Fifty nurses and nurse practitioners from across Canada were interviewed. Participants described the suffering of dying and provided insights into the difficulties of treating existential suffering and the iatrogenic suffering patients experienced from long contact with the healthcare system. They shared perceptions of the suffering that leads to a request for MAID that included the unknown of dying, a desire for predictability, and the loss of dignity. Eliciting the suffering story was an essential part of nursing practice. Knowledge of the story allowed participants to find the balance between believing that suffering is whatever the persons says it is, while making sure that the MAID procedure was for the right person, for the right reason, at the right time. Participants perceived that the MAID process itself caused suffering that resulted from the complexity of decision-making, the chances of being deemed ineligible, and the heighted work of the tasks of dying. CONCLUSIONS: Healthcare providers involved in MAID must be critically reflective about the suffering histories they bring to the clinical encounter, particularly iatrogenic suffering. Further, eliciting the suffering stories of persons requesting MAID requires a high degree of skill; those involved in the assessment process must have the time and competency to do this important role well. The nature of suffering that patients and family encounter as they enter the contemplation, assessment, and provision of MAID requires further research to understand it better and develop best practices.

Moral identity and palliative sedation: A systematic review of normative nursing literature.

BACKGROUND: In the last two decades, nursing authors have published ethical analyses of palliative sedation-an end-of-life care practice that also receives significant attention in the broader medical and bioethics literature. This nursing literature is important, because it contributes to disciplinary understandings about nursing values and responsibilities in end-of-life care. RESEARCH AIM: The purpose of this project is to review existing nursing ethics literature about palliative sedation, and to analyze how nurses' moral identities are portrayed within this literature. RESEARCH DESIGN: We reviewed discussion papers, written by nurses about the ethics of palliative sedation, which were cited in MEDLINE, CINAHL, Nursing and Allied Health, or Philosopher's Index (search date March 2018). Twenty-one papers met selection criteria. We performed a comprehensive review and analysis (using the Qualitative Analysis Guide of Leuven), of the values, responsibilities, and relationships reflected in authors' portrayal of the nursing role. FINDINGS: Two different tones are apparent in the extant nursing ethics literature. One is educational, while the other is critically reflective. Irrespective of tone, all authors agree on the alleviation of suffering as a fundamental nursing responsibility. However, they differ in their analysis of this responsibility in relation to other values in end-of-life care, including those that depend on consciousness. Finally, authors emphasize the importance of subjective and experience-based understandings of palliative sedation, which they argue as depending on nurses' proximity to patients and families in end-of-life care. DISCUSSION AND CONCLUSION: Based on our findings, we develop three recommendations for future writing by nurses about palliative sedation. These relate to the responsibility of recognizing how consciousness might matter in (some) peoples' moral experiences of death and dying, to the importance of moral reflectiveness in nursing practice, and to the value of a relational approach in conceptualizing the nursing ethics of palliative sedation.

Of dilemmas and tensions: a qualitative study of palliative care physicians' positions regarding voluntary active euthanasia in Quebec, Canada.

OBJECTIVES: In 2015, the Province of Quebec, Canada passed a law that allowed voluntary active euthanasia (VAE). Palliative care stakeholders in Canada have been largely opposed to euthanasia, yet there is little research about their views. The research question guiding this study was the following: How do palliative care physicians in Quebec position themselves regarding the practice of VAE in the context of the new provincial legislation? METHODS: We used interpretive description, an inductive methodology to answer research questions about clinical practice. A total of 18 palliative care physicians participated in semistructured interviews at two university-affiliated hospitals in Quebec. RESULTS: Participants positioned themselves in opposition to euthanasia. Their justifications were framed within their professional commitment to not hasten death, which sat in tension with the value of patients' autonomy to choose how to die. Participants described VAE as unacceptable if it impeded opportunities to evaluate and alleviate suffering. Further, they contested government rhetoric that positioned VAE as a way to improve end-of-life care. Participants felt that VAE would diminish the potential of palliative care to relieve suffering. Dilemmas were apparent in their narratives, about reconciling respect for patient autonomy with broader palliative care values, and the value of accompanying and not abandoning patients who make requests for VAE while being committed to neither prolonging nor hastening death. CONCLUSIONS: This study provides insight into nuanced positions of experienced palliative care physicians in Quebec and confirms expected tensions between an important stakeholder and the practice of VAE as guided by the new legislation.

Dead on the table: A theoretical expansion of the vicarious trauma that operating room clinicians experience when their patients die.

The practice of operating room (OR) clinicians - nurses, surgeons, and anesthetists - is fundamentally about preserving life. Some patients, however, die in the OR. Clinicians are therefore vulnerable to moral and emotional trauma. In this paper, we discuss three forces that shape clinicians' moral and emotional experiences in OR care: biomedical values, normative death discourse, and socially (un)sanctioned grief. We suggest how each of these forces increases clinicians' vulnerability to feel traumatized when their patients die. We hope this discussion will stimulate clinicians and researchers to engage with social and cultural determinants of clinicians' experiences when patients die.

Relational ethics of delirium care: Findings from a hospice ethnography.

Delirium, a common syndrome in terminally ill people, presents specific challenges to a good death in end-of-life care. This paper examines the relational engagement between hospice nurses and their patients in a context of end-of-life delirium. Ethnographic fieldwork spanning 15 months was conducted at a freestanding residential hospice in eastern Canada. A shared value system was apparent within the nursing community of hospice; patients' comfort and dignity were deemed most at stake and therefore commanded nurses' primary attention. This overarching commitment to comfort and dignity shaped all of nursing practice in this hospice, including practices related to end-of-life delirium. The findings of this study elaborate the ways in which hospice nurses interpreted and responded to the discomfort of their patients in delirium, as well as the efforts they made to understand their patients' subjective experiences and to connect with them in supportive ways. In addition to what is already known about clinical assessment and treatment of delirium in palliative care settings, the findings of this study offer points of reflection for nurses anywhere who are contending with the relational challenges that delirium presents in end-of-life care.

Nurses' moral experiences of assisted death: A meta-synthesis of qualitative research.

BACKGROUND:: Legislative changes are resulting in assisted death as an option for people at the end of life. Although nurses' experiences and perspectives are underrepresented within broader ethical discourses about assisted death, there is a small but significant body of literature examining nurses' experiences of caring for people who request this option. AIM:: To synthesize what has been learned about nurses' experiences of caring for patients who request assisted death and to highlight what is morally at stake for nurses who undertake this type of care. DESIGN:: Qualitative meta-synthesis. METHODS:: Six databases were searched: CINAHL, Medline, EMBASE, Joanna Briggs Institute, PsycINFO, and Web of Science. The search was completed on 22 October 2014 and updated in February 2016. Of 879 articles identified from the database searches, 16 articles were deemed relevant based on inclusion criteria. Following quality appraisal, 14 studies were retained for analysis and synthesis. RESULTS:: The moral experience of the nurse is (1) defined by a profound sense of responsibility, (2) shaped by contextual forces that nurses navigate in everyday end-of-life care practice, and (3) sustained by intra-team moral and emotional support. DISCUSSION:: The findings of this synthesis support the view that nurses are moral agents who are deeply invested in the moral integrity of end-of-life care involving assisted death. The findings further demonstrate that to fully appreciate the ethics of assisted death from a nursing standpoint, it is necessary to understand the broader constraints on nurses' moral agency that operate in everyday end-of-life care. ETHICAL CONSIDERATIONS:: Research ethics board approval was not required for this synthesis of previously published literature. CONCLUSION:: In order to understand how to enact ethical practice in the area of assisted death, the moral experiences of nurses should be investigated and foregrounded.

Forensic nursing and the palliative approach to care: an empirical nursing ethics analysis.

BACKGROUND: A movement is underway to promote a palliative approach to care in all contexts where people age and live with life-limiting conditions, including psychiatric settings. Forensic psychiatry nursing-a subfield of mental health nursing- focuses on individuals who are in conflict with the criminal justice system. We know little about the values of nurses working in forensic psychiatry, and how these values might influence a palliative approach to care for frail and aging patients. METHOD: Interviews with four nurses working on one of two forensic units of a university-affiliated mental health hospital in an urban area of eastern Canada. FINDINGS: Three specific values were found to guide forensic nurses in their care of aging patients that are commensurate with a palliative approach: hope, inclusivity, and quality of life. CONCLUSION: When we started this project, we wondered whether the culture of forensic nursing practice was antithetical to the values of a palliative approach. Instead, we found several parallels between forensic nurses' moral identities and palliative philosophy. These findings have implications for how we think about the palliative approach in contexts not typically associated with palliative care, but in which patients will increasingly age and die.

Engaging with patients who desire death: Interpretation, presence, and constraint.

Canadian end-of-life care is changing. Given recent legislative changes concerning assisted death (euthanasia and assisted suicide), it is vital to examine the perspectives of nurses regarding their care of patients who want to die. This qualitative descriptive study reports findings from interviews with 11 oncology nurses about their experiences of engaging with patients who desire death. Findings provide important insights about how oncology nurses interpret patients' desire-for-death and enact therapeutic presence with these patients. Findings further speak to contextual forces that constrain therapeutic engagement. Interviews were conducted before laws changed in Canada, generating insights that are relevant now more than ever, as increasing numbers of patients will contemplate and receive assisted death in the new landscape of Canadian end-of-life care.

Individual long-term albuminuria exposure during angiotensin receptor blocker therapy is the optimal predictor for renal outcome.

BACKGROUND: Albuminuria reduction due to angiotensin receptor blockers (ARBs) predicts subsequent renoprotection. Relating the initial albuminuria reduction to subsequent renoprotection assumes that the initial ARB-induced albuminuria reduction remains stable during follow-up. The aim of this study was to assess individual albuminuria fluctuations after the initial ARB response and to determine whether taking individual albuminuria fluctuations into account improves renal outcome prediction. METHODS: Patients with diabetes and nephropathy treated with losartan or irbesartan in the RENAAL and IDNT trials were included. Patients with >30% reduction in albuminuria 3 months after ARB initiation were stratified by the subsequent change in albuminuria until Month 12 in enhanced responders (>50% albuminuria reduction), sustained responders (between 20 and 50% reduction), and response escapers (<20% reduction). Predictive performance of the individual albuminuria exposure until Month 3 was compared with the exposure over the first 12 months using receiver operating characteristics (ROC) curves. RESULTS: Following ARB initiation, 388 (36.3%) patients showed an >30% reduction in albuminuria. Among these patients, the albuminuria level further decreased in 174 (44.8%), remained stable in 123 (31.7%), and increased in 91 (23.5%) patients. Similar albuminuria fluctuations were observed in patients with <30% albuminuria reduction. Renal risk prediction improved when using the albuminuria exposure during the first 12 months versus the initial Month 3 change [ROC difference: 0.78 (95% CI 0.75-0.82) versus 0.68 (0.64-0.72); P < 0.0001]. CONCLUSIONS: Following the initial response to ARBs, a large within-patient albuminuria variability is observed. Hence, incorporating multiple albuminuria measurements over time in risk algorithms may be more appropriate to monitor treatment effects and quantify renal risk.

Delirium as letting go: An ethnographic analysis of hospice care and family moral experience.

BACKGROUND: Delirium is extremely common in dying patients and appears to be a major threat to the family's moral experience of a good death in end-of-life care. AIM: To illustrate one of the ways in which hospice caregivers conceptualize end-of-life delirium and the significance of this conceptualization for the relationships that they form with patients' families in the hospice setting. DESIGN: Ethnography. SETTING/PARTICIPANTS: Ethnographic fieldwork was conducted at a nine-bed, freestanding residential hospice, located in a suburban community of Eastern Canada. Data collection methods included 15 months of participant observation, 28 semi-structured audio-recorded interviews with hospice caregivers, and document analysis. RESULTS: Hospice caregivers draw on a culturally established framework of normal dying to help families come to terms with clinical end-of-life phenomena, including delirium. By offering explanations about delirium as a natural feature of the dying process, hospice caregivers strive to protect for families the integrity of the good death ideal. CONCLUSION: Within hospice culture, there is usefulness to deemphasizing delirium as a pathological neuropsychiatric complication, in favor of acknowledging delirious changes as signs of normal dying. This has implications for how we understand the role of nurses and other caregivers with respect to delirium assessment and care, which to date has focused largely on practices of screening and management.