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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.

Introduction: Canada’s health systems remain fragmented, an issue further exacerbated by the COVID-19 pandemic. Evidence-informed system transformation towards better integrated care can ensure our health systems and policies are oriented towards achieving the Quadruple Aim and health equity. The Canadian Institutes of Health Research – Institute of Health Services and Policy Research (CIHR-IHSPR) is developing a large-scale research funding initiative Transforming Health with Integrated Care (THINC) to address challenges with implementation, evaluation, and scale of evidence-informed integrated care policies and interventions. This study reports on the process and outcomes of an evidence-informed, community-engaged approach to designing the THINC research funding initiative.Aims and Methods: We aimed to meaningfully engage with patients, providers, researchers, and decision-makers from the health services and policy research community. Participants were identified from the literature, Institute’s network, and referrals. We conducted a retrospective analysis of relevant funded research, an environmental scan (2011-2021), and a series of engagements (June - November 2021): semi-structured interviews (n=14), a workshop at the 1st North American Conference on Integrated Care, and three focus groups (n=~8-10 participants per group) among prioritized population groups. Descriptive (quantitative) and thematic (qualitative) analyses were used to identify themes essential for successful integrated care, research investment priorities, and funding design elements. Key Findings: Preliminary findings suggest several elements essential to integrating care, however with a critical need for a better understanding of how to implement and adapt promising interventions and policies for equitable uptake across diverse contexts. Stakeholder engagements identified a common interest in prioritizing research and assessment of impact within integrated care and the need for community-based and community-led solutions. Patients identified the need for patient-led research and strategies for meaningful engagement; providers expressed the need for improving access, data infrastructure and team-based care models for better integration of care; and distinct priorities, needs and challenges were identified among rural and remote communities. There was common agreement across key informants and focus groups about the importance of partnerships among researchers, practitioners, decision-makers and patients/communities. Conclusions: Transformative integrated care remains a priority for patients, providers, researchers, and decision-makers alike to achieve the Quadruple Aim and health equity for all Canadians. Future research investments are needed to support equitable scale and spread of interventions and policies with the greatest potential for transformative impact.Implications for applicability/transferability, sustainability, and limitations: By co-creating and mobilizing knowledge related to the development of this large, pan-Canadian research initiative, we as a federal research funding agency contribute towards learning health systems. Challenges with developing a large strategic research initiative within a short time frame included limited time and resources.

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.

DNA replication initiates from multiple genomic locations called replication origins. In metazoa, DNA sequence elements involved in origin specification remain elusive. Here, we examine pluripotent, primary, differentiating, and immortalized human cells, and demonstrate that a class of origins, termed core origins, is shared by different cell types and host ~80% of all DNA replication initiation events in any cell population. We detect a shared G-rich DNA sequence signature that coincides with most core origins in both human and mouse genomes. Transcription and G-rich elements can independently associate with replication origin activity. Computational algorithms show that core origins can be predicted, based solely on DNA sequence patterns but not on consensus motifs. Our results demonstrate that, despite an attributed stochasticity, core origins are chosen from a limited pool of genomic regions. Immortalization through oncogenic gene expression, but not normal cellular differentiation, results in increased stochastic firing from heterochromatin and decreased origin density at TAD borders., In metazoan the DNA sequence elements characterizing origin specification are unknown. By generating and analysing 19 SNS-seq datasets from different human cell types, the authors reveal a class and features of Core origins of replication which can be predicted by an algorithm.

Objective— Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion. Approach and Results— We previously showed that both low shear stress and DAPT ( N -[ N -(3,5-difluorophenacetyl)-L-alanyl]- S -phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion. Conclusions— This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.

Objective- Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion. Approach and Results- We previously showed that both low shear stress and DAPT ( N-[ N-(3,5-difluorophenacetyl)-L-alanyl]- S-phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion. Conclusions- This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.

Erythro-myeloid progenitors (EMPs) were recently described to arise from the yolk sac endothelium, just prior to vascular remodeling, and are the source of adult/post-natal tissue resident macrophages. Questions remain, however, concerning whether EMPs differentiate directly from the endothelium or merely pass through. We provide the first evidence in vivo that EMPs can emerge directly from endothelial cells (ECs) and demonstrate a role for these cells in vascular development. We find that EMPs express most EC markers but late EMPs and EMP-derived cells do not take up acetylated low-density lipoprotein (AcLDL), as ECs do. When the endothelium is labelled with AcLDL before EMPs differentiate, EMPs and EMP-derived cells arise that are AcLDL+. If AcLDL is injected after the onset of EMP differentiation, however, the majority of EMP-derived cells are not double labelled. We find that cell division precedes entry of EMPs into circulation, and that blood flow facilitates the transition of EMPs from the endothelium into circulation in a nitric oxide-dependent manner. In gain-of-function studies, we inject the CSF1-Fc ligand in embryos and found that this increases the number of CSF1R+ cells, which localize to the venous plexus and significantly disrupt venous remodeling. This is the first study to definitively establish that EMPs arise from the endothelium in vivo and show a role for early myeloid cells in vascular development.

BRIL is a bone-specific membrane protein that is involved in osteogenesis imperfecta type V.Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation.Regulation of Bril involves trans-acting factors integrating at conserved promoter elements and epigenetic modifications.Identification of the mechanisms governing Bril transcription is important to understand its role in skeletal biology. Bril encodes a small membrane protein present in osteoblasts. In humans, a single recurrent mutation in the 5'-UTR of BRIL causes osteogenesis imperfecta type V. The exact function of BRIL and the mechanism by which it contributes to disease are still unknown. The goal of the current study was to characterize the mechanisms governing Bril transcription in humans, rats, and mice. In the three species, as detected by luciferase reporter assays in UMR106 cells, we found that most of the base-line regulatory activity was localized within ∼250 bp upstream of the coding ATG. Co-transfection experiments indicated that Sp1 and Sp3 were potent inducers of the promoter activity, through the binding of several GC-rich boxes. Osterix was a weak activator but acted cooperatively with Sp1 and GLI2 to synergistically induce the BRIL promoter. GLI2, a mediator of hedgehog signaling pathway, was also a potent activator of BRIL through a single GLI binding site. Correspondingly, agonists of the hedgehog pathway (purmorphamine and Indian hedgehog) in MC3T3 osteoblasts led to increased BRIL levels. The BRIL promoter activity was also found to be negatively modulated through two different mechanisms. First, the ZFP354C zinc finger protein repressed basal and Sp1-induced activity. Second, CpG methylation of the promoter region correlated with an inactive state and prevented Sp1 activation. The data provide the very first analyses of the cis- and trans-acting factors regulating Bril transcription. They revealed key roles for the Sp members and GLI2 that possibly cooperate to activate Bril when the promoter becomes demethylated.

BRIL (bone-restricted IFITM-like), is a short transmembrane protein expressed almost exclusively in osteoblasts. Although much is known about its bone-restricted gene expression pattern and protein biochemical and topological features, little information is available for BRIL physiological function. Two autosomal dominant forms of osteogenesis imperfecta (OI) are caused by distinct, but recurrent mutations in the BRIL gene. Yet, the underlying mechanisms by which those mutations lead to OI are still poorly understood. A previous report indicated that BRIL knockout (KO) mice had bone deformities, shortened long bones, and reproductive problems. Here we generated and systematically analyzed the skeletal phenotype of a new global Bril KO/LacZ knockin mouse model. KO mice reproduced and thrived normally up to 12 month of age. The skeletal phenotype of KO and WT littermates was assessed at embryonic (E13.5 to E18.5) and postnatal (2 days, 3 weeks, 3 months and 8 months) time-points. Embryos from E13.5 through to E18.5 showed significant X-Gal staining in all skeletal elements without any apparent patterning anomalies. Although bone deformities were never observed at any postnatal ages, minor and transient differences were noted in terms of bone length and static uCT parameters, but not systematically across all ages and genders. These changes, however, were not accompanied by significant alteration in bone material properties as assessed by a 3-point bending test. In addition, no changes were detected in circulating serum markers of bone turnover (P1NP, CTX-I, and osteocalcin). Gene expression monitoring also revealed no major impact of the loss of BRIL. Further, when mice were challenged with a surgically-induced fracture in tibia, bones repaired equally well in the KO mice as compared to WT. Finally, we showed that BRIL C-terminus is not a bona fide binding site for calcium. In conclusion, our in depth analysis suggest that skeletal patterning, bone mass accrual and remodeling in mice proceeded independent of BRIL.

While the surgical procedure of distraction osteogenesis (DO) is very successful in the treatment of orthopedic conditions, its major limitation of slow bone formation in the distracted gap has prompted numerous attempts to understand and accelerate this slow bone formation. Interestingly, WNT/FZD signaling has been identified as a critical pathway in mediating bone formation and regeneration but has not yet been studied in the context of DO. The objective of this study was to determine the spatial and temporal localization of endogenous WNT signaling proteins at various times of bone formation in a wild-type mouse model of DO. In this study, the DO protocol performed on mice consisted of three phases: latency (5 days), distraction (12 days), and consolidation (34 days). Our immunohistochemical findings of distracted bone specimens show an increased expression of WNT ligands (WNT4 and WNT10A), receptors (FZD1 and 2, LRP5 and 6), β-catenin, and pathway antagonizers (DKK1; CTBP1 and 2; sFRP1, 2, and 4) during the distraction phase, which were then down-regulated during consolidation. This is the first published report to show an activation of the WNT pathway in DO and could help identify WNT as a potential therapeutic target in accelerating bone regeneration during DO.

Objective— The H2.0-like homeobox transcription factor (HLX) plays an essential role in visceral organogenesis in mice and has been shown to regulate angiogenic sprouting in vitro and in zebrafish embryos. We therefore examined the role of HLX in vascular development in mouse and avian embryos. Approach and Results— In situ hybridization showed that Hlx is expressed in a subset of sprouting blood vessels in postnatal mouse retinas and embryos. Hlx expression was conserved in quail embryos and upregulated in blood vessels at the onset of circulation. In vitro assays showed that Hlx is dynamically regulated by growth factors and shear stress alterations. Proangiogenic vascular endothelial growth factor induces Hlx expression in cultured endothelial cells, whereas signals that induce stalk cell identity lead to a reduction in Hlx expression. HLX was also downregulated in embryos in which flow was ablated, whereas injection of a starch solution, which increases blood viscosity and therefore shear stress, causes an upregulation in HLX. HLX knockdown in vitro resulted in a reduction in tip cell marker expression and in reduced angiogenic sprouting, but Hlx −/− embryos showed no defect in vascular sprouting at E8.5, E9.5, or E11.5 in vivo. Vascular remodeling of the capillary plexus was altered in Hlx −/− embryos, with a modestly enlarged venous plexus and reduction of the arterial plexus. Conclusions— Our findings indicate not only that Hlx regulates sprouting in vitro, but that its role in sprouting is nonessential in vivo. We find HLX is regulated by shear stress and a subtle defect in vascular remodeling is present in knockout embryos.

Children with musculoskeletal conditions experience muscle weakness, difficulty walking and limitations in physical activities. Standard treatment includes physiotherapy, casting, and surgery. The use of botulinum toxins appears as a promising treatment on its own, but usually as an adjunct to other treatment modalities and as an alternative to surgery. The objectives were to establish the evidence on the effectiveness, safety and functional outcome of BTX-A in children with musculoskeletal conditions. A literature search using five electronic databases identified 24 studies that met our inclusion criteria. Two randomized clinical trials were included; most studies were case studies with small sample sizes and no control group. Improvements in gait pattern, function, range of motion, reduction of co-contractions, and avoidance of surgical procedures were found following BTX-A injections. Adverse events were not reported in 10 studies, minor adverse events were reported in 13 children and there were no severe adverse events. Additional doses appear safe. BTX-A is a promising treatment adjunct in improving functional outcomes in children with musculoskeletal conditions. Future studies including larger samples, longer follow-up periods and a comparison group are required to provide evidence on the effectiveness and safety of this drug in children with musculoskeletal conditions.