Author Correction: Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Specification of hematopoietic stem cells in mammalian embryos: a rare or frequent event?

Hematopoietic stem cells (HSCs) are the blood-forming stem cells thought to be responsible for supporting the blood system throughout life. Transplantability has long been the flagship assay used to define and characterize HSCs throughout ontogeny. However, it has recently become clear that many cells emerge during ontogeny that lack transplantability yet nevertheless are fated to ultimately contribute to the adult HSC pool. Here, we explore recent advances in understanding the numbers and kinetics of cells that emerge during development to support lifelong hematopoiesis; these advances are made possible by new technologies allowing interrogation of lifelong blood potential without embryo perturbation or transplantation. Illuminating the dynamics of these cells during normal development informs efforts to better understand the origins of hematologic disease and engineer HSCs from differentiating pluripotent stem cells.

Dementia-Inclusive Choices for Exercise Toolkit: Impact on the Knowledge, Perspectives, and Practices of Exercise Providers.

Physical activity improves the well-being of persons living with dementia but few exercise programs include them. The Dementia-Inclusive Choices for Exercise (DICE) toolkit aims to improve exercise providers' understanding of dementia and ability to support persons living with dementia in physical activity. We evaluated the co-designed DICE toolkit with exercise providers using a mixed-methods approach comprising pre/post questionnaires and interviews and reflection diaries. Among 16 participants, self-efficacy for exercise delivery to persons living with dementia and both knowledge and attitudes toward dementia significantly improved. Thematic analysis suggested participants (a) had a deeper understanding of the variability of dementia, (b) were planning for equitable access for persons living with dementia, (c) planned to promote social connection through exercise, and (d) were optimistic for future engagement with persons living with dementia. The DICE toolkit may improve exercise providers' knowledge and confidence to plan proactively to support persons living with dementia in programs and services.

ARID5B influences B-cell development and function in mouse.

There is growing evidence for an inherited basis of susceptibility to childhood acute lymphoblastic leukemia. Genomewide association studies by us and others have identified non-coding acute lymphoblastic leukemia risk variants at the ARID5B gene locus, but the molecular mechanisms linking ARID5B to normal and malignant hematopoiesis remain largely unknown. Using a Vav1-driven transgenic mouse model, we characterized the role of Arid5b in hematopoiesis in vivo. Arid5b overexpression resulted in a dramatic reduction in the proportion of circulating B cells, immature, and mature Bcell fractions in the peripheral blood and the bone marrow, and also a decrease of follicular B cells in the spleen. There were significant defects in B-cell activation upon Arid5b overexpression in vitro with hyperactivation of B-cell receptor signaling at baseline. In addition, increased mitochondrial oxygen consumption rate of naïve or stimulated B cells of Arid5b-overexpressing mice was observed, compared to the rate of wild-type counterparts. Taken together, our results indicate that ARID5B may play an important role in B-cell development and function.

Development and evaluation of the Rural and Northern Community Focused Model of COPD Care (RaNCoM).

BACKGROUND: The prevalence of COPD continues to rise. To address the challenges to provide high quality COPD care in rural and northern communities, leaders in one rural and northern community in Western Canada sought to change the culture of COPD screening and care. Recognizing effective assessment, diagnosis, and treatment for patients with COPD are crucial to improve outcomes, a program was developed between 2012 and 2021 to enhance primary care for COPD patients. METHODS: A process evaluation was undertaken to assess program development, implementation, mechanisms of impact, and context of COPD program. Qualitative thematic analysis of stakeholder interviews (n = 11) and a document review (n = 60; ~ 500 pages) of key clinic documents was conducted. RESULTS: We describe five phases of the COPD program's development (Survive; Reorganize and Stabilize; Assess and Respond; Build and Refine; and Sustain and Share), highlighting areas of innovation. Outreach and localizing resources improved access to the program. Acquiring secured physician compensation, capturing quality data, and improving patient and provider self-efficacy built the capacity of the system and stakeholders within it. Finally, relationships were forged through building an integrated facility, collaborative networking, and patient engagement. Key elements of program implementation included the resources (infrastructure, software, operational) required to ensure operation. CONCLUSION: Team-based care and service integration enhanced care capacity and the health network. Focused use of infrastructure and resources supported the people in the care system. Upholding a shared value of relationship is critical to deliver robust and sustainable rural healthcare. Quality improvement requires investment in rural community healthcare resources.

Qualities of the dying experience of persons who access medical assistance in dying: A scoping review.

Defining a "good death" is complex and grounded in diverse cultural, social, and personal factors. Although there is a significant body of literature exploring the broad concepts of death and dying, there is a dearth in literature that has explored what constitutes a good death for persons undergoing assisted dying such as Medical Assistance in Dying (MAiD). In this scoping review of 19 articles, we explore dying experiences and what a good death entails for people accessing MAiD. Understanding personal values and ideas about positive dying experiences can guide patients, care partners, and clinicians in their preparation toward, and facilitation of, a good death experience particularly among persons who access MAiD.

GPRASP proteins are critical negative regulators of hematopoietic stem cell transplantation.

Hematopoietic stem cell (HSC) transplantation (HSCT) is often exploited to treat hematologic disease. Donor HSCs must survive, proliferate, and differentiate in the damaged environment of the reconstituting niche. Illuminating molecular mechanisms regulating the activity of transplanted HSCs will inform efforts to improve HSCT. Here, we report that G-protein-coupled receptor-associated sorting proteins (GPRASPs) function as negative regulators of HSCT. Silencing of Gprasp1 or Gprasp2 increased the survival, quiescence, migration, niche retention, and hematopoietic repopulating activity of hematopoietic stem and progenitor cells (HSPCs) posttransplant. We further show that GPRASP1 and GPRASP2 promote the degradation of CXCR4, a master regulator of HSC function during transplantation. CXCR4 accumulates in Gprasp-deficient HSPCs, boosting their function posttransplant. Thus, GPRASPs negatively regulate CXCR4 stability in HSCs. Our work reveals GPRASP proteins as negative regulators of HSCT and CXCR4 activity. Disruption of GPRASP/CXCR4 interactions could be exploited in the future to enhance the efficiency of HSCT.

Progress towards enhanced access and use of technology during the COVID-19 pandemic: A need to be mindful of the continued digital divide for many rural and northern communities.

The COVID-19 pandemic produced unprecedented adoption and deployment of technology in rural and northern areas; however, this expansion widened the digital divide for many. Evidence shows that older adults' use of technology has increased. Coupled with an increasing number of available technologies to enhance healthcare delivery, social engagement, meaningful activities, and support to carers, we are at a crossroads for change. Emerging strategies used by organizations to promote technology and support efforts to bridge and close the digital divide are discussed. In a post-pandemic society, policy-makers can play a critical role to ensure that improvements, efficiency gains, and lessons learned are fully leveraged to reap the benefits of technology use by older adults, care partners, and the healthcare system. Recommendations are given for policy-makers to capitalize on this opportunity to narrow the digital divide for those in rural and northern communities.

The global clonal complexity of the murine blood system declines throughout life and after serial transplantation.

Although many recent studies describe the emergence and prevalence of "clonal hematopoiesis of indeterminate potential" in aged human populations, a systematic analysis of the numbers of clones supporting steady-state hematopoiesis throughout mammalian life is lacking. Previous efforts relied on transplantation of "barcoded" hematopoietic stem cells (HSCs) to track the contribution of HSC clones to reconstituted blood. However, ex vivo manipulation and transplantation alter HSC function and thus may not reflect the biology of steady-state hematopoiesis. Using a noninvasive in vivo color-labeling system, we report the first comprehensive analysis of the changing global clonal complexity of steady-state hematopoiesis during the natural murine lifespan. We observed that the number of clones (ie, clonal complexity) supporting the major blood and bone marrow hematopoietic compartments decline with age by ∼30% and ∼60%, respectively. Aging dramatically reduced HSC in vivo-repopulating activity and lymphoid potential while increasing functional heterogeneity. Continuous challenge of the hematopoietic system by serial transplantation provoked the clonal collapse of both young and aged hematopoietic systems. Whole-exome sequencing of serially transplanted aged and young hematopoietic clones confirmed oligoclonal hematopoiesis and revealed mutations in at least 27 genes, including nonsense, missense, and deletion mutations in Bcl11b, Hist1h2ac, Npy2r, Notch3, Ptprr, and Top2b.

A Cross-Sectoral Comparison of Prevalence and Predictors of Symptoms of Depression Over Time Among Older Adults in Ontario, Canada.

OBJECTIVES: Late-life depression, a common mental health issue, poses a significant burden of illness globally. We investigated factors associated with symptoms of depression among older adults across 3 health sectors in Ontario, Canada. METHOD: Electronic health assessment data on older adults aged 60 years+ in home care (HC; N = 359 217), long-term care (LTC; N = 125 496), and palliative care (PC; N = 29 934) were examined. Change in symptoms of depression, measured using the interRAI Depression Rating Scale (DRS), over time was examined, including predictors of the development of depression. RESULTS: At baseline, symptoms of depression were observed in 19.1% (HC), 24.2% (LTC), and 11.9% (PC). This increased to 20.6% (HC), 33.8% (LTC), and 13.2% (PC) at follow-up. For most older adults, DRS scores remained the same across sectors over time. Three independent variables emerged consistently across sectors as the main risk and protective factors for symptoms of depression. CONCLUSION: Although variations in the risk and protective factors for late-life depression were demonstrated across each sector, some commonalities emerged including unmanaged pain, symptoms of depression at baseline, social connectedness, and activity.

Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids that enhance HSPC engraftment. The pro-haematopoietic effects of EETs were conserved in the developing zebrafish embryo, where 11,12-EET promoted HSPC specification by activating a unique activator protein 1 (AP-1) and runx1 transcription program autonomous to the haemogenic endothelium. This effect required the activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, specifically PI(3)Kγ. In adult HSPCs, 11,12-EET induced transcriptional programs, including AP-1 activation, which modulate several cellular processes, such as migration, to promote engraftment. Furthermore, we demonstrate that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study establishes a new method to explore the molecular mechanisms of HSPC engraftment, and discovers a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.

Hospice care providers experiences of grappling with medical assistance in dying in a hospice setting: a qualitative descriptive study.

BACKGROUND: Rapid implementation of Medical Assistance in Dying (MAiD) across care settings has challenged providers and organizations, including hospices, to develop and implement new modes of practice. The aim of this study was to examine the effects that legalization of MAiD has had on hospice care provider roles within the non-provider context. METHODS: Eight in-depth semi-structured interviews were conducted and a qualitative descriptive approach used to examine hospice care providers experiences in a small western Canadian city. In the study context, patients who choose MAiD are cared for until immediately prior to the procedure when they are transferred off-site to undergo MAiD. Inductive and thematic analyses were undertaken. RESULTS: Participants experienced practical, philosophical, and professional challenges. Despite the overwhelming desire to support patient autonomy and decision-making, some interpreted patient choice for MAiD as rejection of the natural death experience at the hospice. Patient choice for MAiD initiated a new and different pathway of end-of-life care. While participants felt uncertain how best to support patients undergoing MAiD, they shared mixed optimism on how their care provider roles were evolving as their level of experience broadened. While implementation of MAiD was rapid, the introduction of practical and professional supports has remained slow to materialize, leaving many providers to navigate their own personal and professional positions and practices. CONCLUSION: Care providers require a multi-faceted range of clinical, legal, and logistical supports at the practice, organizational, and health system levels, to facilitate care delivery to those requesting and undergoing MAiD and to promote coordinated and holistic patient-centered care. The different pathway for those who chose MAiD may lead care providers to struggle with relational challenges and interpersonal unease. Further research may address how to support those undergoing MAiD within the hospice context.

Professional experiences of formal healthcare providers in the provision of medical assistance in dying (MAiD): A scoping review.

OBJECTIVE: This scoping review describes the existing literature which examines the breadth of healthcare providers' (HCP's) experiences with the provision of medical assistance in dying (MAiD). METHOD: This study employed a scoping review methodology: (1) identify research articles, (2) identify relevant studies, (3) select studies based on inclusion/exclusion criteria, (4) chart the data, and (5) summarize the results. RESULTS: In total, 30 papers were identified pertaining to HCP's experiences of providing MAiD. Fifty-three percent of the papers were from Europe (n = 16) and 40% of studies were from the USA or Canada (n = 12). The most common participant populations were physicians (n = 17) and nurses (n = 12). This scoping review found that HCPs experienced a variety of emotional responses to providing or providing support to MAiD. Some HCPs experienced positive emotions through helping patients at the end of the patient's life. Still other HCPs experienced very intense and negative emotions such as immense internal moral conflict. HCPs from various professions were involved in various aspects of MAiD provision such as responding to initial requests for MAiD, supporting patients and families, nursing support during MAiD, and the administration of medications to end of life. SIGNIFICANCE OF RESULTS: This review consolidates many of the experiences of HCPs in relation to the provision of MAiD. Specifically, this review elucidates many of the emotions that HCPs experience through participation in MAiD. In addition to describing the emotional experiences, this review highlights some of the roles that HCPs participate in with relation to MAiD. Finally, this review accentuates the importance of team supports and self-care for all team members in the provision of MAiD regardless of their degree of involvement.

Factors associated with teletrauma utilization in rural areas: a review of the literature.

INTRODUCTION: Trauma patients residing in rural areas face increased challenges to accessing timely and appropriate health services as a result of large geographic distances and limited resource availability. Virtual trauma supports, coined 'teletrauma', are one solution offered to address gaps in rural trauma care. Teletrauma represents a new and innovative solution to addressing health system gaps and optimizing patient care within rural settings. Here, the authors synthesize the empirical evidence on teletrauma research. METHODS: A review of literature, with no date limiters, was guided by Arksey and O'Malley's (2005) scoping review methodology. The aim of the review was to provide an overview of the current landscape of teletrauma research while identifying factors associated with utilization. RESULTS: Following a systematic search of key health databases, 1484 articles were initially identified, of which 28 met the inclusion criteria and were included for final analysis. From the review of the literature, the benefits of teletrauma for rural and remote areas were well-recognized. Several factors were found to be significantly associated with teletrauma utilization, including younger patient age, penetrating injury, and higher injury or illness severity. Lack of access to resources and clinician characteristics were also identified as reasons that sites adopted teletrauma services. CONCLUSION: By identifying factors associated with teletrauma utilization, teletrauma programs may be used more judiciously and effectively in rural areas as a means of enhancing access to definitive trauma care in rural areas. Gaps in current knowledge were also identified, along with recommendations for future research.

Nfix Promotes Survival of Immature Hematopoietic Cells via Regulation of c-Mpl.

Hematopoietic stem and progenitor cells (HSPCs) are necessary for life-long blood production and replenishment of the hematopoietic system during stress. We recently reported that nuclear factor I/X (Nfix) promotes HSPC survival post-transplant. Here, we report that ectopic expression of Nfix in primary mouse HSPCs extends their ex vivo culture from about 20 to 40 days. HSPCs overexpressing Nfix display hypersensitivity to supportive cytokines and reduced apoptosis when subjected to cytokine deprivation relative to controls. Ectopic Nfix resulted in elevated levels of c-Mpl transcripts and cell surface protein on primary murine HSPCs as well as increased phosphorylation of STAT5, which is known to be activated down-stream of c-MPL. Blocking c-MPL signaling by removal of thrombopoietin or addition of a c-MPL neutralizing antibody negated the antiapoptotic effect of Nfix overexpression on cultured HSPCs. Furthermore, NFIX was capable of binding to and transcriptionally activating a proximal c-Mpl promoter fragment. In sum, these data suggest that NFIX-mediated upregulation of c-Mpl transcription can protect primitive hematopoietic cells from stress ex vivo. Stem Cells 2018;36:943-950.

Hospice use and one-year survivorship of residents in long-term care facilities in Canada: a cohort study.

BACKGROUND: Hospice care is designed for persons in the final phase of a terminal illness. However, hospice care is not used appropriately. Some persons who do not meet the hospice eligibility receive hospice care, while many persons who may have benefitted from hospice care do not receive it. This study aimed to examine the characteristics of, and one-year survivorship among, residents who received hospice care versus those who did not in long-term care facilities (LTCFs) in Canada. METHODS: This retrospective cohort study used linked health administrative data from the Canadian Continuing Reporting System (CCRS) and the Discharge Abstract Database (DAD). All persons who resided in a LTCF and who had a Resident Assessment Instrument Minimum Data Set Version 2.0 (RAI-MDS 2.0) assessment in the CCRS database between Jan. 1st, 2015 and Dec 31st, 2015 were included in this study (N = 185,715). Death records were linked up to Dec 31th, 2016. Univariate, bivariate and multivariate analyses were performed. RESULTS: The reported hospice care rate in LTCFs is critically low (less than 3%), despite one in five residents dying within 3 months of the assessment. Residents who received hospice care and died within 1 year were found to have more severe and complex health conditions than other residents. Compared to those who did not receive hospice care but died within 1 year, residents who received hospice care and were alive 1 year following the assessment were younger (a mean age of 79.4 [+ 13.5] years vs. 86.5 [+ 9.2] years), more likely to live in an urban LTCF (93.2% vs. 82.6%), had a higher percentage of having a diagnosis of cancer (50.7% vs. 12.9%), had a lower percentage of having a diagnosis of dementia (30.2% vs. 54.5%), and exhibited more severe acute clinical conditions. CONCLUSIONS: The actual use of hospice care among LTCF residents is very poor in Canada. Several factors emerged as potential barriers to hospice use in the LTCF population including ageism, rurality, and a diagnosis of dementia. Improved understanding of hospice use and one-year survivorship may help LTCFs administrators, hospice care providers, and policy makers to improve hospice accessibility in this target group.

Community perspectives of end-of-life preparedness.

While death is a universal human experience, the process of planning for death can be difficult and may be avoided altogether. To understand community perspectives of end-of-life preparedness, we undertook a multimethod study exploring the experiences of 25 community members and 10 stakeholders engaged in end-of-life planning. In addition, card sorting activities and focused discussions with 97 older adults were undertaken to highlight perspectives and needs. Data were analyzed using descriptive statistics and qualitative description. Overall, the participants perceived many benefits to being end-of-life prepared, however, few community members had engaged in formal planning. Key barriers include concerns about the accessibility and accuracy of information, discomfort when engaging in end-of-life conversations, and perceptions about the cost associated with engaging in formal legal or financial preparations. Areas for further research include the need for studies that capture the cultural dimensions of end-of-life planning and explores the implementation and evaluation of community-based interventions to improve preparedness.

Medical assistance in dying: A political issue for nurses and nursing in Canada.

Death and dying are natural phenomena embedded within complex political, cultural and social systems. Nurses often practice at the forefront of this process and have a fundamental role in caring for both patients and those close to them during the process of dying and following death. While nursing has a rich tradition in advancing the palliative and end-of-life care movement, new modes of care for patients with serious and irremediable medical conditions arise when assisted death is legalized in a particular jurisdiction. In early 2015, the Supreme Court of Canada released its landmark decision Carter v. Canada (Attorney General) ('Carter'), which legalized physician-assisted suicide in particular clinical situations. The new law provided the broad national framework for Medical Assistance in Dying (MAiD) in Canada but, once the law was passed, provincial and territorial governments and health professional regulatory bodies each had to undertake a process of developing policies, procedures and processes to guide MAiD-related practice specific to their jurisdiction. In this paper, we begin to examine the political ramifications and professional tensions arising from MAiD for nurses and nursing, focusing specifically upon the impacts for registered nurses. We identify how variations in the provincial and territorial literature and regulatory guidelines across Canada have given rise to role confusion and uncertainty among some registered nurses and how this may potentially impact patient care. We then continue to highlight the need for greater political activism among nurses to foster greater clarity in nursing roles in MAiD and to advocate for improved supports for patients and those close to them.