Developing AHRQ's Feasibility Assessment Criteria for Wide-Scale Implementation of Patient-Centered Outcomes Research Findings.

BACKGROUND: The Agency for Healthcare Research and Quality's (AHRQ) Patient-Centered Outcomes Research (PCOR) Dissemination and Implementation (D&I) Initiative identifies and prioritizes PCOR findings that could improve health care if widely implemented. To inform PCOR implementation investments, AHRQ sought to assess feasibility of widely implementing impactful PCOR findings with good strength of evidence in clinical practice. OBJECTIVE: To develop criteria to assess the feasibility of widely implementing nominated PCOR findings. METHODS: We reviewed literature and interviewed thirteen D&I experts to identify factors affecting feasibility of implementing PCOR findings. We grouped similar factors into themes. Fourteen technical expert panel (TEP) members discussed the face-validity and relative merits of the themes and additional factors, applied themes to fictional case studies, and prioritized themes for assessing feasibility. We developed criteria and guiding questions with a 3-point Likert scale. Seven D&I experts pilot-tested the criteria using sample nominations of PCOR findings. Experts represented diverse views of implementation from federal and state government agencies, research institutions, and quality improvement and advocacy organizations. KEY RESULTS: We developed a set of three essential criteria for AHRQ to assess feasibility of widely implementing PCOR findings to be widely implementable: (1) acceptability to the implementers; (2) generalizability, adaptability, and ease of implementing with fidelity; and (3) alignment with external policies and incentives. Two supplemental criteria, (1) the presence of a plan or toolkit supporting implementation, or (2) evidence supporting implementation outside the research setting, can enhance reviewers' confidence in the intervention's feasibility. Each criterion includes "guiding questions" to parse out specific components that could be more readily assessed. CONCLUSIONS: The criteria and guiding questions are a valuable tool for informing AHRQ's investment decisions regarding implementing PCOR findings. Although developed for AHRQ's needs, the criteria may help other funders and health care organizations determine the feasibility of implementing evidence-based practices.

Generalized shared decision making approaches and patient problems. Adapting AHRQ's SHARE Approach for Purposeful SDM.

OBJECTIVE: Generalized shared decision making (SDM) describes the involvement of patients in choosing options. However, there are many situations in which patients and clinicians make decisions together that don't focus on choosing between options, e.g. problem-solving dialysis and insulin use while traveling. Poor uptake associated with clinicians' perception that SDM doesn't apply to clinical situations they face may reflect the lack of adaptation of generalized SDM approaches to patients' problems. The Purposeful SDM schema published in 2019 identifies problems for which different kinds of SDM are appropriate. METHODS: The U.S. Agency for Healthcare Research and Quality developed SHARE as a generalized SDM approach. We sought to adapt SHARE to the different problems that patients face using a matrix to relate SHARE steps and Purposeful SDM modes and describe changes in generalized concepts and practices of SDM across these modes. RESULTS: Many SHARE communicative behaviors applied across modes, although the meaning of SDM terms and practices, e.g. patients involved as problem solvers versus experts, varied substantially. CONCLUSION: Aspects of SHARE require adaptation to different patient problems. PRACTICE IMPLICATIONS: SDM in education, practice, and tools may be supported by adapting generalized SDM approaches to patients' problems.

Prioritizing Evidence-based Interventions for Dissemination and Implementation Investments: AHRQ's Model and Experience.

BACKGROUND: The Agency for Healthcare Research and Quality (AHRQ) is mandated to implement patient-centered outcomes research (PCOR) to promote safer, higher quality care. With this goal, we developed a process to identify which evidence-based PCOR interventions merit investment in implementation. We present our process and experience to date. MATERIALS AND METHODS: AHRQ developed and applied a systematic, transparent, and stakeholder-driven process to identify, evaluate, and prioritize PCOR interventions for broad dissemination and implementation. AHRQ encouraged public nominations, and assessed them against criteria for quality of evidence, potential impact, and feasibility of successful implementation. Nominations with sufficient evidence, impact, and feasibility were considered for funding. RESULTS: Between June 2016 and June 2018, AHRQ received 35 nominations from researchers, nonprofit corporations, and federal agencies. Topics covered diverse settings, populations, and clinical areas. Twenty-eight unique PCOR interventions met minimum criteria; 16 of those had moderate to high evidence/impact and were assessed for feasibility. Fourteen topics either duplicated other efforts or lacked evidence on implementation feasibility. Two topics were prioritized for funding (cardiac rehabilitation after myocardial infarction and screening/treatment for unhealthy alcohol use). CONCLUSIONS: AHRQ developed replicable criteria, and a transparent and stakeholder-driven framework that attracted a diverse array of nominations. We identified 2 evidence-based practice interventions to improve care with sufficient evidence, impact, and feasibility to justify an AHRQ investment to scale up practice. Other funders, health systems or institutions could use or modify this process to guide prioritization for implementation.

EvidenceNOW: Balancing Primary Care Implementation and Implementation Research.

The mission of the Agency for Healthcare Research and Quality (AHRQ) is to generate knowledge about how America's health care delivery system can provide high-quality care, and to ensure that health care professionals and systems understand and use this evidence. In 2015 AHRQ invested in the largest primary care research project in its history. EvidenceNOW is a $112 million effort to disseminate and implement patient-centered outcomes research evidence in more than 1,500 primary care practices and to study how quality-improvement support can build the capacity of primary care practices to understand and apply evidence.EvidenceNOW comprises 7 implementation research grants, each funded to provide external quality-improvement support to primary care practices to implement evidence-based cardiovascular care and to conduct rigorous internal evaluations of their work. An independent, external evaluator was funded to conduct an overarching evaluation using harmonized outcome measures and pooled data. The design of EvidenceNOW required resolving tensions between implementation and implementation research goals.EvidenceNOW is poised to develop a blueprint for how stakeholders can invest in strengthening the primary care delivery system and to offer a variety of resources and tools to improve the capacity of primary care to deliver evidence-based care. Federal agencies must maximize the value of research investments to show improvements in the lives and health of Americans and the timeliness of research results. Understanding the process and decisions of a federal agency in designing a large clinical practice transformation initiative may provide researchers, policy makers, and clinicians with insights into future implementation research, as well as improve responsiveness to funding announcements and the implementation of evidence in routine clinical care.

Learning Collaboratives: Insights And A New Taxonomy From AHRQ's Two Decades Of Experience.

Learning collaboratives are increasingly used as mechanisms to support and hasten the diffusion and implementation of innovation, clinical evidence, and effective models of care. Factors contributing to the collaboratives' success or failure are poorly understood. The Agency for Healthcare Research and Quality (AHRQ) has sponsored collaboratives for nearly two decades to support improvements in health care quality and value by accelerating the diffusion and implementation of innovation. We examined AHRQ's experience with these collaboratives to characterize their attributes, identify factors that might contribute to their success or failure, and assess the challenges they encountered. Building on the literature and insights from AHRQ's experience, we propose a taxonomy that can offer guidance to decision makers and funders about the factors they should consider in developing collaboratives and planning their evaluation, as well as to researchers who seek to conduct research that will ultimately help decision makers make better investments in diffusing innovation and evidence.

Joint requirement for Rac and ERK activities underlies the mid-G1 phase induction of cyclin D1 and S phase entry in both epithelial and mesenchymal cells.

Cyclin D1 gene induction is a key event in G1 phase progression. Our previous studies indicated that signaling to cyclin D1 is cell type-dependent because the timing of cyclin D1 gene expression in MCF10A mammary epithelial cells and mesenchymal cells such as fibroblasts and vascular smooth muscle cells is very different, with epithelial cells first expressing cyclin D1 in early rather than mid-G1 phase. In this report, we induced a mesenchymal phenotype in MCF10A cells by long-term exposure to TGF-beta and used the control and transitioned cells to examine cell type specificity of the signaling pathways that regulate cyclin D1 gene expression. We show that early-G1 phase cyclin D1 gene expression in MCF10A cells is under the control of Rac, whereas mid-G1 phase cyclin D1 induction requires parallel signaling from Rac and ERK, both in the control and transitioned cells. This combined requirement for Rac and ERK signaling is associated with an increased requirement for intracellular tension, Rb phosphorylation, and S phase entry. A similar co-regulation of cyclin D1 mRNA by Rac and ERK is seen in primary mesenchymal cells. Overall, our results reveal two mechanistically distinct phases of Rac-dependent cyclin D1 expression and emphasize that the acquisition of Rac/ERK co-dependence is required for the mid-G1 phase induction of cyclin D1 associated with S phase entry.

Rac-dependent cyclin D1 gene expression regulated by cadherin- and integrin-mediated adhesion.

Integrin-mediated adhesion to substratum is required for cyclin D1 induction in mesenchymal cells, but we show here that the induction of cyclin D1 persists despite blockade of ECM-integrin signaling in MCF10A mammary epithelial cells. E-cadherin-mediated cell-cell adhesion also supports cyclin D1 induction in these cells, and the combined inhibition of both E-cadherin and integrin adhesion is required to prevent the expression of cyclin D1 mRNA and protein. Our previous studies described a pro-proliferative effect of E-cadherin in MCF10A cells, mediated by Rac, and we now show that Rac is required for cyclin D1 mRNA induction by both E-cadherin and integrin engagement. The levels of p21Cip1 and p27Kip1, Cdk inhibitors that are also targets of integrin signaling, are not affected by E-cadherin-mediated cell-cell adhesion. Finally, we show that the increased expression of cyclin D1 mRNA associated with E-cadherin-dependent cell-cell adhesion is causally linked to an increased entry into S phase. Our results identify Rac signaling to cyclin D1 as a crucial pro-proliferative effect of E-cadherin-mediated cell-cell adhesion.

Phorbol ester-induced G1 phase arrest selectively mediated by protein kinase Cdelta-dependent induction of p21.

Although protein kinase C (PKC) has been widely implicated in the positive and negative control of proliferation, the underlying cell cycle mechanisms regulated by individual PKC isozymes are only partially understood. In this report, we show that PKCdelta mediates phorbol ester-induced G1 arrest in lung adenocarcinoma cells and establish an essential role for this novel PKC in controlling the expression of the cell cycle inhibitor p21. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) in early G1 phase impaired progression of lung adenocarcinoma cells into S phase, an effect that was completely abolished by specific depletion of PKCdelta, but not PKCalpha. Although the PKC effect was unrelated to the inhibition of cyclin D1 expression, PKC activation significantly up-regulated p21 and down-regulated Rb hyperphosphorylation and cyclin A expression. Elevations in p21 mRNA and protein by PMA were mediated by PKCdelta but not PKCalpha. Studies using luciferase reporters also revealed an essential role for PKCdelta in the PMA-induced inhibition of Rb-dependent cyclin A promoter activity. Finally, we showed that the cell cycle inhibitory effect of PKCdelta is greatly attenuated by RNA interference-mediated knock-down of p21. Our results identify a novel link between PKCdelta and G1 arrest via p21 up-regulation and highlight the complexities in the downstream effectors of PKC isozymes in the context of cell cycle progression and proliferation.

Regulation of growth factor signaling and cell cycle progression by cell adhesion and adhesion-dependent changes in cellular tension.

The proliferation of most non-transformed cell types requires cell adhesion and cellular tension as well as exposure to mitogenic growth factors. Integrins and cadherins provide the adhesion signals, which ultimately allow for the cytoskeletal changes that control cellular tension. This review discusses the roles of integrins, cadherins, and the actin cytoskeleton as mediators of the mechanical tension critical for growth factor-dependent signaling and cell cycle progression.