What Is Possible If We Focus on Where Healthcare Is Going Instead of Where Medicine Has Been.

As Canadian leaders of the world's largest virtual care organization, we bring a national and a global perspective to our response to Falk's (2022) paper on virtual care in Canada in this issue. With more than 20 years of experience enabling virtual care and more than 90 million people accessing our virtual care services and tools in more than 170 countries, across more than 600 health systems and more than 70 clinical use cases, we have already done or witnessed first-hand many of the changes that Falk anticipates Canadians will contend with as we expand channels to and modalities of care beyond the incumbent monochannel of in-person, physician-mediated service delivery. In this essay, we respond to Falk's (2022) paper in three ways: (1) we disagree with the definition of virtual care; (2) we agree with - and expand on - the analysis and ideas; and (3) we reveal two gaps in Falk's analysis that will or should be at the forefront of the Canadian discourse. That is, we disagree with the narrow framing of virtual care, we agree with the locks and keys (and suggest, from experience, other ways to think about the keys) and we table important gaps that are notably missing from the debate.

Targeting improved patient outcomes using innovative product listing agreements: a survey of Canadian and international key opinion leaders.

OBJECTIVES: To address the uncertainty associated with procuring pharmaceutical products, product listing agreements (PLAs) are increasingly being used to support responsible funding decisions in Canada and elsewhere. These agreements typically involve financial-based rebating initiatives or, less frequently, outcome-based contracts. A qualitative survey was conducted to improve the understanding of outcome-based and more innovative PLAs (IPLAs) based on input from Canadian and international key opinion leaders in the areas of drug manufacturing and reimbursement. METHODS: Results from a structured literature review were used to inform survey development. Potential participants were invited via email to partake in the survey, which was conducted over phone or in person. Responses were compiled anonymously for review and reporting. RESULTS: Twenty-one individuals participated in the survey, including health technology assessment (HTA) key opinion leaders (38%), pharmaceutical industry chief executive officers/vice presidents (29%), ex-payers (19%), and current payers/drug plan managers/HTA (14%). The participants suggested that ~80%-95% of Canadian PLAs are financial-based rather than outcomes-based. They indicated that IPLAs offer important benefits to patients, payers, and manufacturers; however, several challenges limit their use (eg, administrative burden, lack of agreed-upon endpoint). They noted that IPLAs are useful in rapidly evolving therapeutic areas and those associated with high unmet need, a quantifiable endpoint, and/or robust data systems. The Canadian Agency for Drugs and Technologies in Health, the pan-Canadian Pharmaceutical Alliance, and other arms-length organizations could play important roles in identifying uncertainty and endpoints and brokering pan-Canadian PLAs. Industry should work collaboratively with payers to identify uncertainty and develop innovative mechanisms to address it. CONCLUSION: The survey results indicated that while challenging, use of IPLAs may be associated with various benefits. Collaboration among stakeholders remains key: Canadian agencies could play an important role in the success of these agreements, while industry should be proactive in offering solutions that will help improve outcomes across the entire health care system.

Intracellular segregation of phosphatidylinositol-3,4,5-trisphosphate by insulin-dependent actin remodeling in L6 skeletal muscle cells.

Insulin stimulates glucose uptake by recruiting glucose transporter 4 (GLUT4) from an intracellular pool to the cell surface through a mechanism that is dependent on phosphatidylinositol (PI) 3-kinase (PI3-K) and cortical actin remodeling. Here we test the hypothesis that insulin-dependent actin filament remodeling determines the location of insulin signaling molecules. It has been shown previously that insulin treatment of L6 myotubes leads to a rapid rearrangement of actin filaments into submembrane structures where the p85 regulatory subunit of PI3-K and organelles containing GLUT4, VAMP2, and the insulin-regulated aminopeptidase (IRAP) colocalize. We now report that insulin receptor substrate-1 and the p110alpha catalytic subunit of PI3-K (but not p110beta) also colocalize with the actin structures. Akt-1 was also found in the remodeled actin structures, unlike another PI3-K effector, atypical protein kinase C lambda. Transiently transfected green fluorescent protein (GFP)-tagged pleckstrin homology (PH) domains of general receptor for phosphoinositides-1 (GRP1) or Akt (ligands of phosphatidylinositol-3,4,5-trisphosphate [PI-3,4,5-P(3)]) migrated to the periphery of the live cells; in fixed cells, they were detected in the insulin-induced actin structures. These results suggest that PI-3,4,5-P(3) is generated on membranes located within the actin mesh. Actin remodeling and GLUT4 externalization were blocked in cells highly expressing GFP-PH-GRP1, suggesting that PI-3,4,5-P(3) is required for both phenomena. We propose that PI-3,4,5-P(3) leads to actin remodeling, which in turn segregates p85alpha and p110alpha, thus localizing PI-3,4,5-P(3) production on membranes trapped by the actin mesh. Insulin-stimulated actin remodeling may spatially coordinate the localized generation of PI-3,4,5-P(3) and recruitment of Akt, ultimately leading to GLUT4 insertion at the plasma membrane.

Exercise- and insulin-stimulated muscle glucose transport: distinct mechanisms of regulation.

In mammals, skeletal muscle is the primary target for the stimulation of glucose transport by a variety of activators. These include the hormone insulin and stimuli which increase energy demand such as exercise, hypoxia, and challenges to the oxidative chain. While it is known that both stimuli rapidly elevate glucose uptake into muscle by signalling the translocation of glucose transporters from intracellular stores to the plasma membrane, there are numerous contrasts between energy stressors and insulin in their mechanisms of glucose transport activation. Exercise and insulin recruit distinct intracellular pools of glucose transporters in skeletal muscle and the maximal effects of contraction and insulin are additive. Activation of phosphatidylinositol 3-kinase (PI3-K) is utilized by insulin to induce glucose transporter translocation, but does not participate in the responses to exercise or hypoxia. These findings suggest that energy stressors utilize different mechanisms from insulin to increase glucose influx; however, how these factors elicit their response is not clear. This review will summarize our current knowledge of these alternative pathways of glucose transport regulation. Emphasis is placed on the use of the mitochondrial uncoupler dinitrophenol to investigate mediators of this alternative signalling pathway in L6 muscle cells, a line used to characterize physiological responses in muscle such as glucose transport.