A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo.

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to cardiovascular disease, PCSK9 has attracted intense interest as a therapeutic target. Despite this interest, an orally bioavailable small-molecule inhibitor of PCSK9 with extensive lipid-lowering activity is yet to enter the clinic. We report herein the discovery of NYX-PCSK9i, an orally bioavailable small-molecule inhibitor of PCSK9 with significant cholesterol-lowering activity in hyperlipidemic APOE∗3-Leiden.CETP mice. NYX-PCSK9i emerged from a medicinal chemistry campaign demonstrating potent disruption of the PCSK9-LDLR interaction in vitro and functional protection of the LDLR of human lymphocytes from PCSK9-directed degradation ex vivo. APOE∗3-Leiden.CETP mice orally treated with NYX-PCSK9i demonstrated a dose-dependent decrease in plasma total cholesterol of up to 57%, while its combination with atorvastatin additively suppressed plasma total cholesterol levels. Importantly, the majority of cholesterol lowering by NYX-PCSK9i was in non-HDL fractions. A concomitant increase in total plasma PCSK9 levels and significant increase in hepatic LDLR protein expression strongly indicated on-target function by NYX-PCSK9i. Determinations of hepatic lipid and fecal cholesterol content demonstrated depletion of liver cholesteryl esters and promotion of fecal cholesterol elimination with NYX-PCSK9i treatment. All measured in vivo biomarkers of health indicate that NYX-PCSK9i has a good safety profile. NYX-PCSK9i is a potential new therapy for hypercholesterolemia with the capacity to further enhance the lipid-lowering activities of statins.

Optimizing the integration of family caregivers in the delivery of person-centered care: evaluation of an educational program for the healthcare workforce.

BACKGROUND: While family caregivers provide 70-90% of care for people living in the community and assist with 10-30% of the care in congregate living, most healthcare providers do not meaningfully involve family caregivers as partners in care. Recent research recommends that the healthcare workforce receive competency-based education to identify, assess, support, and partner with family caregivers across the care trajectory. OBJECTIVE: This paper reports a mixed-methods evaluation of a person-centered competency-based education program on Caregiver-Centered Care for the healthcare workforce. METHODS: This foundational education was designed for all healthcare providers and trainees who work with family caregivers and is offered free online (caregivercare.ca). Healthcare providers from five healthcare settings (primary, acute, home, supportive living, long-term care) and trainees in medicine, nursing, and allied health were recruited via email and social media. We used the Kirkpatrick-Barr health workforce training evaluation framework to evaluate the education program, measuring various healthcare providers' learner satisfaction with the content (Level 1), pre-post changes in knowledge and confidence when working with family caregivers (Level 2), and changes in behaviors in practice (Level 3). RESULTS: Participants were primarily healthcare employees (68.9%) and trainees (21.7%) and represented 5 healthcare settings. Evaluation of the first 161 learners completing the program indicated that on a 5-point Likert scale, the majority were satisfied with the overall quality of the education (Mean(M) = 4.69; SD = .60). Paired T-tests indicated that out of a score of 50, post-education changes in knowledge and confidence to work with family caregivers was significantly higher than pre-education scores (pre M = 38.90, SD = 6.90; post M = 46.60, SD = 4.10; t(150) = - 16.75, p < .0001). Qualitative results derived from open responses echoed the quantitative findings in satisfaction with the education delivery as well as improvements in learners' knowledge and confidence. CONCLUSION: Health workforce education to provide person-centered care to all family caregivers is an innovative approach to addressing the current inconsistent system of supports for family caregivers. The education program evaluated here was effective at increasing self-reported knowledge and confidence to work with family caregivers.

Tailored, Community-Based Programs for People Living With Dementia and Their Family Caregiver.

People living with dementia (PLWD) have voiced a desire to remain in their home environment as long as possible; unfortunately, there is limited integrated person-and family-centered community support. To examine the need for tailored supports for PLWD and their family caregivers (caregiving dyad), a meeting was conducted in Spring 2020. Thirty key provincial stakeholders with diversity in geographic location, employer and/or organization, range of roles, and family representatives participated in the meeting. Stakeholders identified a series of gaps, including: (a) systemic gaps; (b) gaps between communities of practice; (c) underserved populations; (d) program content and delivery gaps; and (e) PLWD and family caregiver support gaps. With input from stakeholders, we highlighted the need for consistent resources for the caregiving dyad that are flexible, timely, and accessible, which are embedded in the community and led by qualified and trained staff. [Journal of Gerontological Nursing, 48(4), 26-32.].

Person-centered care for family caregivers of people living with dementia: Co-designing an education program for the healthcare workforce.

BACKGROUND: Recent research recommends the healthcare workforce receive competency-based education to identify, assess, support and partner with family-caregivers [FCGs} across the care trajectory.[1 2] Although the risk of FCG anxiety, burden, and loneliness to FCG's wellbeing is widely documented, typically education has been targeted towards FCG's to increase their care skills rather to educate healthcare providers to support FCG's caregiving and wellbeing.[3] OBJECTIVES: We will present the co-design process used to create a competency-based education program for the healthcare workforce that ensures a person-centered focus on FCGs and introduce our Health Workforce Caregiver-Centered Care Education focused on dementia. Co-design is the act of creating with stakeholders to ensure the results meet their needs and are usable. PROJECT DESCRIPTION: We began by coining the concept "caregiver-centered care," defining it as: a collaborative working relationship between families and healthcare providers aimed at supporting FCGs in their caregiving role, decisions about services, care management, and advocacy [4 5] . From this definition, and working with multi-level interdisciplinary stakeholders we designed[6] and validated[7] a Caregiver-Centered Care Competency Framework in a Modified Delphi Process. Stakeholders (n= 101) including FCGs, health providers, policy makers, community organizations, research team, script writer, and educational designers then used effective practices for dementia education for the health workforce [8-11] to co-design the first or 'foundational' level of a Caregiver Centered Care education program. RESULTS: Teaching and learning resources include six competency-aligned educational modules with videos and interactive exercises that encourage reflection. With the COVID-19 pandemic, we moved the education online (caregivercare.ca). In the first two months online, November 9, 2020-January 9, 2021, 352 healthcare providers completed the education. To date, learners' qualitative evaluations have been positive, "Very good information for professionals working with caregivers; especially relevant to homecare, geriatricians, allied health, and others working within the Seniors' Health realm. Engaging format that really evokes empathy for caregivers." DISCUSSION: We continue to use mixed methods to evaluate the Caregiver-Centered Care Education, for acceptability and effectiveness, in five care contexts (primary, acute, home, supportive living, long-term care). CONCLUSION: We expect that our education will support caregiver-centered care in all settings providing dementia-related care.

Acute changes in nerve excitability following oxaliplatin treatment in mice.

Oxaliplatin chemotherapy produces acute changes in peripheral nerve excitability in humans by modulating voltage-gated Na+ channel activity. However, there are few animal studies of oxaliplatin-induced neuropathy that demonstrate similar changes in excitability. In the present study, we measured the excitability of motor and sensory caudal nerve in C57BL/6 mice after oxaliplatin injections either systemically (intraperitoneal) or locally (intramuscular at the base of the tail). As opposed to intraperitoneal administration of oxaliplatin, a single intramuscular injection of oxaliplatin produced changes in both motor and sensory axons. In motor axons, oxaliplatin caused a greater change in response to long-lasting depolarization and an upward shift in the recovery cycle, particularly at 24 h [depolarizing threshold electrotonus (TEd) 10-20 ms, P = 0.0095; TEd 90-100 ms, P = 0.0056) and 48 h (TEd 10-20 ms, P = 0.02; TEd 90-100 ms, P = 0.04) posttreatment. Oxaliplatin treatment also stimulated the production of afterdischarges in motor axons. These changes were transient and showed dose dependence. Mathematical modeling demonstrated that these changes could be accounted for by slowing inactivation of voltage-gated Na+ channels by 73.3% and reducing fast K+ conductance by 47% in motor axons. In sensory axons, oxaliplatin caused an increase in threshold, a reduction in peak amplitude, and greater threshold changes to strong hyperpolarizing currents on days 4 and 8. Thus, local administration of oxaliplatin produced clinically relevant changes in nerve excitability in mice and may provide an alternative approach for the study of acute oxaliplatin-induced neurotoxicity.NEW & NOTEWORTHY We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.

A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove.

Proprotein convertase (PC) subtilisin kexin type 9 (PCSK9) inhibits the clearance of low density lipoprotein (LDL) cholesterol from plasma by directly interacting with the LDL receptor (LDLR). As the interaction promotes elevated plasma LDL cholesterol levels and a predisposition to cardiovascular disease (CVD), it has attracted much interest as a therapeutic target. While anti-PCSK9 monoclonal antibodies have been successful in the treatment of hypercholesteremia by decreasing CVD risk, their high cost and a requirement for injection have prohibited widespread use. The advent of an orally bioavailable small molecule inhibitor of the PCSK9-LDLR interaction is an attractive alternative, however efforts have been tempered as the binding interface is unfavourable for binding by small organic molecules. Despite its challenging nature, we report herein the discovery of compound 3f as a small molecule inhibitor of PCSK9. The kinase inhibitor nilotinib emerged from a computational screen that was applied to identify compounds that may bind to a cryptic groove within PCSK9 and proximal to the LDLR-binding interface. A subsequent in vitro PCSK9-LDLR binding assay established that nilotinib was a bona fide but modest inhibitor of the interaction (IC50 = 9.8 µM). Through multiple rounds of medicinal chemistry, 3f emerged as a lead-like molecule by demonstrating disruption of the PCSK9-LDLR interaction at nanomolar levels in vitro (IC50 = 537 nM) with no inhibitory activity (IC50 > 10 µM) against a small panel of kinases. Compound 3f restored LDL uptake by liver cells at sub-micromolar levels and demonstrated excellent bioavailability when delivered subcutaneously in mice. Most significantly, compound 3f lowered total cholesterol levels in the plasma of wild-type mice, thereby providing proof-of-concept that the notion of a small molecule inhibitor against PCSK9 is therapeutically viable.

A mixed-method evaluation of a volunteer navigation intervention for older persons living with chronic illness (Nav-CARE): findings from a knowledge translation study.

BACKGROUND: Volunteer navigation is an innovative way to help older persons get connected to resources in their community that they may not know about or have difficulty accessing. Nav-CARE is an intervention in which volunteers, who are trained in navigation, provide services for older persons living at home with chronic illness to improve their quality of life. The goal of this study was to evaluate the impact of Nav-CARE on volunteers, older persons, and family participating across eight Canadian sites. METHODS: Nav-CARE was implemented using a knowledge translation approach in eight sites using a 12- or 18-month intervention period. A mixed method evaluation was used to understand the outcomes upon older person engagement; volunteer self-efficacy; and older person, family, and volunteer quality of life and satisfaction with the intervention. RESULTS: Older persons and family were highly satisfied with the intervention, citing benefits of social connection and support, help with negotiating the social aspects of healthcare, access to cost-effective resources, and family respite. They were less satisfied with the practical help available for transportation and errands. Older persons self-reported knowledge of the services available to them and confidence in making decisions about their healthcare showed statistically significant improvements (P < .05) over 12-18 months. Volunteers reported satisfaction with their role, particularly as it related to building relationships over time, and good self-efficacy. Volunteer attrition was a result of not recruiting older persons in a timely manner. There was no statistically significant improvement in quality of life for older persons, family or volunteers from baseline to study completion. CONCLUSIONS: Findings from this study support a developing body of evidence showing the contributions volunteers make to enhanced older person and family well-being in the context of chronic illness. Statistically significant improvements were documented in aspects of client engagement. However, there were no statistically significant improvements in quality of life scores even though qualitative data illustrated very specific positive outcomes of the intervention. Similar findings in other volunteer-led intervention studies raise the question of whether there is a need for targeted volunteer-sensitive outcome measures.

Commentary: Identifying the Underpinnings of "Care That Honours Seniors" in Alberta.

It is no surprise that seniors' care is an important focus across Canada. Seniors are the fastest growing age group in Canada, and it is not uncommon for this population to have high comorbidity rates, functional impairments and a significant risk of decline. It is essential to support the public in remaining healthy as they age and identify what is truly important to them.

Establishing Effective Resident and Family Councils: A Pilot Project to Increase Family and Resident Engagement in Alberta's Continuing Care Sites.

Resident and family councils aim to improve resident and family satisfaction, but guidelines for councils are scarce. This project developed a toolkit and tested its ability, along with networking meetings, to promote successful councils. Nine continuing care sites participated with residents, family and staff from each site who received the toolkit, completed surveys, attended meetings and participated in post-pilot interviews. Participants found that the toolkit helped improve council function and, with the networking meetings, increased participation. All sites found the toolkit and networking meetings to be valuable resources and had a strong desire to have them available in the future.

A metasynthesis study of family caregivers' transition experiences caring for community-dwelling persons with advanced cancer at the end of life.

BACKGROUND: Family caregivers (broadly defined as family and friends) experience multiple concurrent transitions when caring for a person with advanced cancer. AIMS: To (a) explore the transition experience of family caregivers caring for persons with advanced cancer living in the community, (b) describe potential triggers for transitions, (c) identify what influences this experience, and (d) develop a conceptual framework of their transition experience. DESIGN: Sandelowski and Barroso's methodology for synthesizing qualitative research included (a) a comprehensive search of empirical literature, (b) quality appraisal of qualitative studies, (c) classification of studies, and (d) synthesis of the findings. DATA SOURCES: Literature was sourced from six electronic data bases. Inclusion criteria were as follows: (a) published qualitative studies (and mixed-method designs) of the caregiving experience of family caregivers of community-living persons with advanced cancer at the end of life, (b) participants (caregivers and care recipients) of 18 years of age and above, (c) studies published in English in any country, and (d) studies published between 2004 and 2014. RESULTS: A total of 72 studies were included in the metasynthesis. Family caregivers experience a "life transition" whereby their lives are permanently altered. The participants described the process of redefining normal which consisted of coming to terms with their situation and connecting with others. Outcomes of these processes were as follows: (a) maintaining a sense of personhood, (b) reframing hope, (c) maintaining self-efficacy, (d) finding meaning, and (e) preparing for the death of their care recipient. CONCLUSION: The findings provide a framework to guide the development of supportive programs and future research.

Physician education on decision-making capacity assessment: Current state and future directions.

OBJECTIVE: To examine FPs' training needs for conducting decision-making capacity assessments (DMCAs) and to determine how training materials, based on a DMCA model, can be adapted for use by FPs. DESIGN: A scoping review of the literature and qualitative research methodology (focus groups and structured interviews). SETTING: Edmonton, Alta. PARTICIPANTS: Nine FPs, who practised in various settings, who chose to attend a focus group on DMCAs. METHODS: A scoping review of the literature to examine the current status of physician education regarding assessment of decision-making capacity, and a focus group and interviews with FPs to ascertain the educational needs of FPs in this area. MAIN FINDINGS: Based on the scoping review of the literature, 4 main themes emerged: increasing saliency of DMCAs owing to an aging population, suboptimal DMCA training for physicians, inconsistent approaches to DMCA, and tension between autonomy and protection. The findings of the focus groups and interviews indicate that, while FPs working as independent practitioners or with interprofessional teams are motivated to engage in DMCAs and use the DMCA model for those assessments, several factors impede their conducting DMCAs. The most notable barriers were a lack of education, isolation from interprofessional teams, uneasiness around managing conflict with families, fear of liability, and concerns regarding remuneration. CONCLUSION: This pilot study has helped to inform ways to better train and support FPs in conducting DMCAs. Family physicians are well positioned, with proper training, to effectively conduct DMCAs. To engage FPs in the process, however, the barriers should be addressed.

Managing Responsive Behaviours: A Wicked Problem Addressed through a Grassroots Approach.

Challenging responsive behaviours, such as aggression, wandering and social inappropriateness, exhibited by persons with neurological, mental health or developmental disorders are of increasing concern across Canada. These behaviours can cause distress or catastrophic outcomes for the person, others in care, caregivers and healthcare providers, and result in extensive resource utilization. The objective of this paper is to discuss the role and impact of a unique, grassroots provincial initiative aimed at networking among healthcare providers, decision-makers and caregivers across government ministries and service-provider agencies. This collaboration provides a model for informing service provision and policy development across multiple stakeholders.

Diagnosis and management of dementia in primary care: exploratory study.

OBJECTIVE: To assess the current identification and management of patients with dementia in a primary care setting; to determine the accuracy of identification of dementia by primary care physicians; to examine reasons (triggers) for referral of patients with suspected dementia to the geriatric assessment team (GAT) from the primary care setting; and to compare indices of identification and management of dementia between the GAT and primary care network (PCN) physicians and between the GAT and community care (CC). DESIGN: Retrospective chart review and comparisons, based on quality indicators of dementia care as specified in the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, were conducted from matching charts obtained from 3 groups of health care providers. SETTING: Semirural region in the province of Alberta involving a PCN, CC, and a GAT. PARTICIPANTS: One hundred patients who had been assessed by the GAT randomly selected from among those diagnosed with dementia or mild cognitive impairment by the GAT. MAIN OUTCOME MEASURES: Diagnosis of dementia and indications of high-quality dementia care listed in PCN, CC, and GAT charts. RESULTS: Only 59% of the patients diagnosed with dementia by the GAT had a documented diagnosis of dementia in their PCN charts. None of the 12 patients diagnosed with mild cognitive impairment by the GAT had been diagnosed by the PCN. Memory decline was the most common reason for referral to the GAT. There were statistically significant differences between the PCN and the GAT on all quality indicators of dementia, with underuse of diagnostic and functional assessment tools and lack of attention to wandering, driving, medicolegal, and caregiver issues, and underuse of community supports in the PCN. There was higher congruence between CC and the GAT on assessment and care indices. CONCLUSION: Dementia care remains a challenge in primary care. Within our primary care setting, there are opportunities for synergistic collaboration among the health care professionals from the PCN, CC, and the GAT. Currently they exist as individual entities in the system. An integrated model of care is required in order to build capacity to meet the needs of an aging population.

Family physicians' preferences for education to support family caregivers: a sequential mixed methods study.

BACKGROUND: One in four Canadians is a family caregiver. Family caregivers (carers, care-partners) are relatives or chosen family, friends, or neighbors who provide 75 to 90% of the care for people with physical or mental illness, disabilities, or frailty living in community homes and assist with 15 to 30% of the care in congregate care. However, a recent (2022) Statistics Canada population health study reports 44% of family caregivers are distressed. Family physicians and primary care teams are well-positioned to support family caregivers; yet, family caregiver needs assessments tend to be ad hoc and their most common needs remain unmet. Research recommends training healthcare professionals to enhance their knowledge and skills to support family caregivers. METHODS: The objective of this sequential mixed methods research, a survey followed by qualitative interviews, was to explore family physicians' desire and preferences for education about supporting family caregivers. 85 family physicians completed the online survey and eight took part in the interviews. Results from the survey and interviews were compared, contrasted, and interpreted together. RESULTS: Primary care physicians expressed a desire to be better equipped to assess and support FCGs' needs. Even though most physicians (61%) were very/confident about addressing family caregivers' needs, 72% were highly/interested in education to support family caregivers of their patients. Topics with the most interest were assessing family caregivers needs in an organized way, assisting family caregivers to access resources, and address system and practice barriers to support family caregivers. The overarching theme running through the interviews was physicians hope for education to help change the patient-focused culture to inclusion of FCGs. The three themes reflect physicians' conviction about including family caregivers in patient care: We need to take care of their caregivers, Practice and system barriers thwart including family caregivers, and Practical education might help. CONCLUSIONS: This study of family physicians' preferences for education to support family caregivers will inform the development of education about supporting family caregivers for family physicians and trainees.

Family Involvement Training for Staff and Family Caregivers: Case Report on Program Design and Mixed Methods Evaluation.

The COVID-19 pandemic underscored the imperative for meaningful family involvement in long-term care, aligning with policy and safety standards while enhancing outcomes for caregivers, residents, and staff. The objectives of this article are as follows: (1) a case study report on implementing a family involvement intervention designed to facilitate the formal and safe engagement of family caregivers in resident care and (2) the pilot evaluation of the intervention. We used Knapp's six-step implementation science model to guide and describe intervention development to provide insight for others planning family involvement projects. We employed sequential mixed methods, including surveys with quantitative and qualitative questions before and after program implementation for providers, and surveys and interviews with family caregivers a year after. We used the Mann-Whitney U test (p < 0.05) to assess differences in health providers' perceptions pre- and post-education. Families and staff perceived that the Family Involvement Program was important for improving the quality of care, residents' quality of life and family/staff relationships. Providers' perceptions of the program's positive impact on residents' quality of life (p = 0.020) and quality of care (p = 0.010), along with their satisfaction with working relationships with families (p = 0.039), improved significantly after the program. Qualitative data confirmed improvements in family-staff relationships. In conclusion, we documented the design of this family involvement initiative to encourage family caregivers and staff to work together in residents' care. Youville's Family Involvement Program gives families and family caregivers an explicit role as partners in long-term care. The mixed methods pilot evaluation documented improvements in staff and family relationships.

Double-duty caregivers enduring COVID-19 pandemic to endemic: "It's just wearing me down".

The COVID-19 pandemic has considerably strained health care providers and family caregivers. Double-duty caregivers give unpaid care at home and are employed as care providers. This sequential mixed-method study, a survey followed by qualitative interviews, aimed to comprehensively understand the experiences of these Canadian double-duty caregivers amidst the pandemic and the transition to the endemic phase. The multi-section survey included standardized assessments such as the Double-duty Caregiver Scale and the State Anxiety Scale, along with demographic, employment-related, and care work questions. Data analysis employed descriptive and linear regression modeling statistics, and content analysis of the qualitative data. Out of the 415 respondents, the majority were female (92.5%) and married (77.3%), with 54.9% aged 35 to 54 years and 29.2% 55 to 64 years. 68.9% reported mental health decline over the past year, while 60.7% noted physical health deteriorated. 75.9% of participants self-rated their anxiety as moderate to high. The final regression model explained 36.8% of the variance in participants' anxiety levels. Factors contributing to lower anxiety included more personal supports, awareness of limits, younger age, and fewer weekly employment hours. Increased anxiety was linked to poorer self-rated health, and both perceptions and consequences of blurred boundaries. The eighteen interviewees highlighted the stress of managing additional work and home care during the pandemic. They highlighted the difficulty navigating systems and coordinating care. Double-duty caregivers form a significant portion of the healthcare workforce. Despite the spotlight on care and caregiving during the COVID-19 pandemic, the vital contributions and well-being of double-duty caregivers and family caregivers have remained unnoticed. Prioritizing their welfare is crucial for health systems as they make up the largest care workforce, particularly evident during the ongoing healthcare workforce shortage.

Characteristics of Patients Receiving Complex Case Management in an Acute Care Hospital.

BACKGROUND: Improving transitions in care is a major focus of health care planning. In the research team's prior intervention study, the length of stay (LOS) was reduced when patients at high risk for readmission were identified early in their acute care stay and received complex management. OBJECTIVE: This study will describe the characteristics of patients receiving complex case management in an urban acute care hospital. PRIMARY PRACTICE SETTING: Acute care hospital. METHODOLOGY AND SAMPLE: This was a retrospective chart review of patients in a previous quality assurance study. A random selection of patients who previously underwent high-risk screening using the LACE (Length of stay; Acuity of the admission; Comorbidity of the patient; Emergency department use) index and received complex case management (the intervention group) were reviewed. The charts of a random selection of patients from the previous comparison group were also reviewed. Patient characteristics were collected and compared using descriptive statistics. RESULTS: In the intervention group, more patients had their family physicians (FPs) documented (93.1% [81/87] vs. 89.2% [66/74]). More patients in the intervention group (89.7% [77/87] vs. 85.1% [63/74]) lived at home prior to admission. More patients in the intervention group had a family caregiver involved (44.8% [39/87] vs. 41.9% [31/74]). At discharge, more patients in the intervention group (87.1% [74/85]) were discharged home compared with the comparison group (78.4% [58/74]). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: (1) Having an identified FP, living at home, and having family caregiver(s) characterized those with lower LOS and discharged home. (2) Case management, risk screening, and discharge planning improve patient outcomes. (3) This study identified the importance of having a FP and engaged family caregivers in improving care outcomes.

Three Perspectives on the Experience of Support for Family Caregivers in First Nations Communities.

There is a dearth of research on how family caregivers are supported in First Nations. We interviewed family caregivers, health and community providers, and leaders in two Alberta First Nations Communities about their experiences of care and support for the family caregivers in their communities. We employed a qualitative, collaborative participatory action research methodology. We drew on Etuaptmumk, the Mi'kmaw understanding of being in the world is the gift of multiple perspectives. Participants in this research included family caregivers (n = 6), health and community providers (n = 14), and healthcare and community leaders (n = 6). The overarching caregiving theme is the "Hierarchy of challenge". Six themes capture the challenges faced by family caregivers: (one) "Caregiving is a demanding job": yet "No one in a sense is taking care of them"; (two) difficult navigation: "I am unable to access that"; (three) delayed assessments and treatment "And I don't know how they're being missed"; (four) disconnected health records: "It's kind of on you to follow up"; (five) racism, "It's treated differently"; and, (six) social determinants of health, "A lot of these factors have been developing for the longest time". This study provides evidence that family caregivers' need to care for and to maintain their own wellbeing is not top of mind in policy or programs in these First Nations communities. As we advocate for support for Canadian family caregivers, we need to ensure that Indigenous family caregivers are also recognized in policy and programs.

Supporting First Nations Family Caregivers and Providers: Family Caregivers', Health and Community Providers', and Leaders' Recommendations.

Family caregivers and care providers are increasingly becoming more distressed and reaching a breaking point within current systems of care. First Nations family caregivers and the health and community providers employed in First Nations communities have to cope with colonial, discriminatory practices that have caused intergenerational trauma and a myriad of siloed, disconnected, and difficult-to-navigate federal-, provincial/territorial-, and community-level policies and programs. Indigenous participants in Alberta's Health Advisory Councils described Indigenous family caregivers as having more difficulty accessing support than other Alberta caregivers. In this article, we report on family caregivers', providers', and leaders' recommendations to support First Nations family caregivers and the health and community providers employed in First Nations. We used participatory action research methods in which we drew on Etuaptmumk (the understanding that being in the world is the gift of multiple perspectives) and that Indigenous and non-Indigenous views are complementary. Participants were from two First Nation communities in Alberta and included family caregivers (n = 6), health and community providers (n = 14), and healthcare and community leaders (n = 6). Participants advised that family caregivers needed four types of support: (1) recognize the family caregivers' role and work; (2) enhance navigation and timely access to services, (3) improve home care support and respite, and (4) provide culturally safe care. Participants had four recommendations to support providers: (1) support community providers' health and wellbeing; (2) recruit and retain health and community providers; (3) improve orientation for new providers; and (4) offer providers a comprehensive grounding in cultural awareness. While creating a program or department for family caregivers may be tempting to address caregivers' immediate needs, improving the health of First Nations family caregivers requires a population-based public health approach that focuses on meaningful holistic system change to support family caregivers.

TRPC Channels Activated by G Protein-Coupled Receptors Drive Ca2+ Dysregulation Leading to Secondary Brain Injury in the Mouse Model.

Canonical transient receptor potential (TRPC) non-selective cation channels, particularly those assembled with TRPC3, TRPC6, and TRPC7 subunits, are coupled to Gαq-type G protein-coupled receptors for the major classes of excitatory neurotransmitters. Sustained activation of this TRPC channel-based pathophysiological signaling hub in neurons and glia likely contributes to prodigious excitotoxicity-driven secondary brain injury expansion. This was investigated in mouse models with selective Trpc gene knockout (KO). In adult cerebellar brain slices, application of glutamate and the class I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine to Purkinje neurons expressing the GCaMP5g Ca2+ reporter demonstrated that the majority of the Ca2+ loading in the molecular layer dendritic arbors was attributable to the TRPC3 effector channels (Trpc3KO compared with wildtype (WT)). This Ca2+ dysregulation was associated with glutamate excitotoxicity causing progressive disruption of the Purkinje cell dendrites (significantly abated in a GAD67-GFP-Trpc3KO reporter brain slice model). Contribution of the Gαq-coupled TRPC channels to secondary brain injury was evaluated in a dual photothrombotic focal ischemic injury model targeting cerebellar and cerebral cortex regions, comparing day 4 post-injury in WT mice, Trpc3KO, and Trpc1/3/6/7 quadruple knockout (TrpcQKO), with immediate 2-h (primary) brain injury. Neuroprotection to secondary brain injury was afforded in both brain regions by Trpc3KO and TrpcQKO models, with the TrpcQKO showing greatest neuroprotection. These findings demonstrate the contribution of the Gαq-coupled TRPC effector mechanism to excitotoxicity-based secondary brain injury expansion, which is a primary driver for mortality and morbidity in stroke, traumatic brain injury, and epilepsy.