Understanding the training, mentorship, and professional development priorities of early career embedded researchers.

INTRODUCTION: Health systems are constantly evolving in response to existing and emerging health challenges and are increasingly adopting the Quintuple Aim to guide transformation and improvement efforts. Addressing health challenges and achieving the Quintuple Aim (enhancing patient experience, improving healthcare provider experience, promoting population health, optimising the value of healthcare services, and advancing health equity) may be enhanced with the use of a Learning Health Systems approach that fosters the real-time use of data and evidence to inform improvement efforts and harnesses embedded researchers to co-produce timely, relevant evidence to address priorities. Training programs have emerged to build embedded research capacity within health system organisations and have focused predominantly on the postdoctoral career stage, with little attention paid to the early career researcher (ECR) stage. The objective of this study was to understand ECR training and mentorship needs in the embedded research context to inform the creation new or adaptation of existing programs to build embedded ECR capacity. METHODS: This study used a qualitative approach to garner insight from embedded and applied scholars and health systems leaders in Canada from various professional backgrounds and at various career stages using a combination of focus group discussions, key informant interviews, and an online survey. Thematic content analysis was used to examine the responses of study participants within the interview themes. RESULTS: Twenty-six (26) participants were included in the study. Results were organised according to four key themes: (1) key competencies and skills needed by embedded ECRs; (2) additional training and capacity development needs; (3) training delivery approaches; and (4) enablers and challenges faced by embedded ECRs. Results highlight the importance of supporting ECRs to develop their leadership and organisational management capabilities; their knowledge of and ability to use research approaches that are well-suited to real-world, complex, evolving environments; and their opportunities to learn with and from each other and mentors. Results underscore the perceived importance of context, including being embedded in a supportive environment that values research and evidence and of academic incentives that recognise and value real-world research impact. The challenges of responding to shifting organisational and system priorities were identified. Additional insights from health systems leaders were also highlighted. CONCLUSION: This study identified the multifaceted needs of embedded ECRs and the challenges they face within healthcare systems. Designing new programs or tailoring existing ones to address these needs would build their capacity, foster career progression, and ensure their impact as leaders of evidence-informed health system improvement which is crucial for achieving the Quintuple Aim.

Trustworthy Evidence to Support Quality Digital Healthcare Policy for Underserved Communities: What Needs to Happen to Translate Evidence into Policy?

In this paper, we explore what is needed to generate quality research to guide evidence-informed digital health policy and call the Canadian community of patients, clinicians, policy (decision) makers and researchers to action in setting digital health research priorities for supporting underserved communities. Using specific examples, we describe how evidence is produced and implemented to guide digital health policy. We study how research environments must change to reflect and include the communities for whom the policy is intended. Our goal is to guide how future evidence reaches policy makers to help them shape healthcare services and how these services are delivered to underserved communities in Canada. Understanding the pathways through which evidence can make a difference to equitable and sustainable digital health policy is vital for guiding the types of research that attract priority resources.

IL-8 production in response to cigarette smoke is decreased in epithelial cells from COPD patients.

Cigarette smoke is the principal cause of chronic obstructive pulmonary disease (COPD), a disorder characterized by airway inflammation. As epithelial cells are the first line of defense against foreign material, the response of normal epithelial cells to smoke has been extensively studied. However, little is known about how epithelial cells derived from COPD patients respond to ongoing smoke exposure. This study was aimed at comparing the intracellular response of normal human bronchial/tracheal epithelial cells (NHBE) and COPD-diseased human bronchial/tracheal epithelial cells (DHBE) to cigarette smoke. NHBE and DHBE cells were treated with cigarette smoke condensate (CSC) for 24 h. IL-8 production was measured by ELISA and western blot was used to measure TLR4 expression. Cells were pretreated with CLI-095, a TLR4 inhibitor, or the signaling pathway inhibitors PD184352, Helenalin, or PI-103, which inhibit the ERK1/2, NF-κB and PI3K pathways, respectively. NHBE cells increased IL-8 production in a dose-dependent manner in response to CSC while DHBE cells did not show any significant difference and had a much lower production of IL-8 in response to CSC compared to NHBE cells. There was no change in TLR4 expression with CSC exposure. CLI-095 and PD184352 attenuated IL-8 secretion, indicating that CSC-induced inflammation is both TLR4- and ERK1/2-dependent. These results demonstrate that NHBE and DHBE cells differentially respond to cigarette smoke. DHBE cells exhibit a dampened IL-8 release, indicating that COPD is associated with a reduced capacity of airway epithelial cells to respond to foreign material.

IL-17A and IL-17F expression in B lymphocytes.

BACKGROUND: Recent evidence suggests that cells other than Th-17 lymphocytes express interleukin (IL)-17A and IL-17F and contribute to the production of these cytokines in immunologically mediated diseases. B lymphocytes are known to be an important source of cytokines in chronic inflammatory diseases. We therefore investigated the potential of human B lymphocytes to produce IL-17A and IL-17F. METHODS: Highly purified B cells were obtained using a multiple-step separation procedure which included rosette depletion, adherence depletion, CD3+ cell magnetic activated depletion and CD19+ magnetic activated positive cell selection. In these CD19+ B cell fractions, CD3+/CD4+ and CD14+ cells were negligible (<0.2%), and CD8 and CD161 mRNAs were undetectable. The CD19+/CD20+ B cells were stimulated with IL-4, interferon-γ, IL-6, IL-23 and transforming growth factor (TGF)-ß, and the expression of IL-17A and IL-17F in response to stimulation was determined by quantitative reverse transcription (RT)-PCR, Western blot, immunocytochemistry and ELISA. RESULTS: Evidence of expression of IL-17A and IL-17F in purified B cells was obtained using RT-PCR, flow cytometry, immunofluorescence microscopy, Western immunoblotting and ELISA. Stimulation of B cells with IL-6, IL-23 or TGF-ß upregulated the expression of both IL-17A and F cytokines. CONCLUSIONS: These novel findings provide evidence that cytokine-stimulated B lymphocytes could be a significant source of IL-17A and IL-17F and support the notion that these cells actively participate in immune responses via alternative mechanisms in addition to the classic release of antibodies.

Accelerating Health System Transformation through Research to Achieve the Quadruple Aim and Health Equity.

The Canadian Institutes of Health Research - Institute of Health Services and Policy Research's (IHSPR's) Strategic Plan 2021-2026: Accelerate Health Care System Transformation through Research to Achieve the Quadruple Aim and Health Equity for All (CIHR IHSPR 2021) outlines the Institute's key priority areas for investment and activity over the next five years. IHSPR used an evidence-informed strategic planning process that was pan-Canadian in scope and designed to elicit the health services and policy research priorities of decision makers, providers, researchers, patients, communities and the public. This paper outlines IHSPR's four key strategic priorities for supporting and optimizing research in transforming Canada's healthcare delivery systems over the next five years.

From Strategy to Implementation: Optimizing the Contribution of Health Services and Policy Research to Equitable Healthcare System Transformation.

The Canadian Institutes of Health Research - Institute of Health Services and Policy Research's (IHSPR) Strategic Plan 2021-2026 (CIHR IHSPR 2021) aims to accelerate healthcare system transformation to achieve the Quadruple Aim and health equity through research. This special issue features a collection of commentaries from academic and health system leaders who were invited to respond to IHSPR's strategic plan and share insights regarding the opportunities the plan presents and areas where more attention may be needed. The present paper features a response from the IHSPR team and outlines the next steps regarding implementation. IHSPR is deeply grateful to the commentary authors for their insight, advice and recommendations, which will help to inform the implementation of the plan.

CD8 positive T cells express IL-17 in patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible chronic inflammatory disease of the lung. The nature of the immune reaction in COPD raises the possibility that IL-17 and related cytokines may contribute to this disorder. This study analyzed the expression of IL-17A and IL-17F as well as the phenotype of cells producing them in bronchial biopsies from COPD patients. METHODS: Bronchoscopic biopsies of the airway were obtained from 16 COPD subjects (GOLD stage 1-4) and 15 control subjects. Paraffin sections were used for the investigation of IL-17A and IL-17F expression in the airways by immunohistochemistry, and frozen sections were used for the immunofluorescence double staining of IL-17A or IL-17F paired with CD4 or CD8. In order to confirm the expression of IL-17A and IL-17F at the mRNA level, a quantitative RT-PCR was performed on the total mRNA extracted from entire section or CD8 positive cells selected by laser capture microdissection. RESULTS: IL-17F immunoreactivity was significantly higher in the bronchial biopsies of COPD patients compared to control subjects (P < 0.0001). In the submucosa, the absolute number of both IL-17A and IL-17F positive cells was higher in COPD patients (P < 0.0001). After adjusting for the total number of cells in the submucosa, we still found that more cells were positive for both IL-17A (P < 0.0001) and IL-17F (P < 0.0001) in COPD patients compared to controls. The mRNA expression of IL-17A and IL-17F in airways of COPD patients was confirmed by RT-PCR. The expression of IL-17A and IL-17F was co-localized with not only CD4 but also CD8, which was further confirmed by RT-PCR on laser capture microdissection selected CD8 positive cells. CONCLUSION: These findings support the notion that Th17 cytokines could play important roles in the pathogenesis of COPD, raising the possibility of using this mechanism as the basis for novel therapeutic approaches.

Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8(+) T cells in chronic obstructive pulmonary disease.

BACKGROUND: Cigarette smoke is a major risk factor for chronic obstructive pulmonary disease (COPD), an inflammatory lung disorder. COPD is characterized by an increase in CD8(+) T cells within the central and peripheral airways. We hypothesized that the CD8(+) T cells in COPD patients have increased Toll-like receptor (TLR) expression compared to control subjects due to the exposure of cigarette smoke in the airways. METHODS: Endobronchial biopsies and peripheral blood were obtained from COPD patients and control subjects. TLR4 and TLR9 expression was assessed by immunostaining of lung tissue and flow cytometry of the peripheral blood. CD8(+) T cells isolated from peripheral blood were treated with or without cigarette smoke condensate (CSC) as well as TLR4 and TLR9 inhibitors. PCR and western blotting were used to determine TLR4 and TLR9 expression, while cytokine secretion from these cells was detected using electrochemiluminescence technology. RESULTS: No difference was observed in the overall expression of TLR4 and TLR9 in the lung tissue and peripheral blood of COPD patients compared to control subjects. However, COPD patients had increased TLR4 and TLR9 expression on lung CD8(+) T cells. Exposure of CD8(+) T cells to CSC resulted in an increase of TLR4 and TLR9 protein expression. CSC exposure also caused the activation of CD8(+) T cells, resulting in the production of IL-1ß, IL-6, IL-10, IL-12p70, TNFα and IFNγ. Furthermore, inhibition of TLR4 or TLR9 significantly attenuated the production of TNFα and IL-10. CONCLUSIONS: Our results demonstrate increased expression of TLR4 and TLR9 on lung CD8(+) T cells in COPD. CD8(+) T cells exposed to CSC increased TLR4 and TLR9 levels and increased cytokine production. These results provide a new perspective on the role of CD8(+) T cells in COPD.

Informing Canada's Health System Response to COVID-19: Priorities for Health Services and Policy Research.

To inform Canada's research response to COVID-19, the Canadian Institutes of Health Research's Institute of Health Services and Policy Research (IHSPR) conducted a rapid-cycle priority identification process. Seven COVID-19 priorities for health services and policy research were identified: system adaptation and organization of care; resource allocation decision-making and ethics; rapid synthesis and comparative policy analysis of the COVID-19 response and outcomes; healthcare workforce; virtual care; long-term consequences of the pandemic; and public and patient engagement. Three additional cross-cutting themes were identified: supporting the health of Indigenous Peoples and vulnerable populations, data and digital infrastructure, and learning health systems and knowledge platforms. IHSPR hopes these research priorities will contribute to the broader ecosystem for collective research investment and action.

Rewarding Success: Changing the Paradigm of How Research Is Rewarded.

International health system comparisons reveal that Canada ranks poorly in several measures when assessed against comparable countries, despite the fact that billions of dollars are spent on the Canadian healthcare system every year. Canada is among one of the highest spenders on health care, yet value for our investment is not always clear. To sustain Canadian health care, it is essential that innovations and process transformations that improve health outcomes and value for our investment are implemented in the health system. Following the movement of other organizations that are experimenting with innovative models of funding, the Canadian Institutes of Health Research partnered with four Canadian provinces to pilot the Rewarding Success Initiative. This initiative rewards and incentivizes research teams to develop effective partnerships with health system payers and, together, implement innovative solutions in the health system that will enhance value-based care, health system sustainability and health outcomes.

Health services and policy research in the first decade at the Canadian Institutes of Health Research.

BACKGROUND: Health services and policy research is the innovation engine of a health care system. In 2000, the Canadian Institutes of Health Research (CIHR) was formed to foster the growth of all sciences that could improve health care. We evaluated trends in health services and policy research funding, in addition to determinants of funding success. METHODS: All applications submitted to CIHR strategic and open operating grant competitions between 2001 and 2011 were included in our analysis. Age, sex, size of research team, critical mass, season, year and research discipline were retrieved from application information. A cohort of 4725 applicants successfully funded between 2001 and 2005 were followed for 5 years to evaluate predictors of continuous funding. Multivariate generalized estimating equation logistic regression was used to estimate predictors of funding success and sustained funding. RESULTS: Between 2001 and 2011, 80 163 applications were submitted to open and strategic grant competitions. Over time, grant applications increased from 327 to 1137 per year, and annual funding increased from $12.6 to $48.0 million. Grant applications from young male researchers were more likely to be funded than those from female researchers (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.01-1.95), as were applications from larger research teams and institutions with a large critical mass. Only 24.0% of scientists whose first funded grant was in health services and policy research had sustained 5-year funding, compared with 52.8% of biomedical scientists (OR 0.34, 95% CI 0.24-0.49). INTERPRETATION: The CIHR has successfully increased the amount of health services and policy research in Canada. To enhance conditions for success, researchers should be encouraged to work in teams, request longer duration grants, resubmit unsuccessful applications and affiliate themselves with institutions with a greater critical mass.