Feasibility of connecting regional research programs to national multisite trials emanating from the CTSA Trial Innovation Network.

A collaborative research model was developed and tested to enable regional healthcare systems to join multisite clinical trials emanating from the Clinical and Translational Science Award (CTSA) Trial Innovation Network (TIN) by the Institute of Translational Health Sciences at the University of Washington and the Northwest Participant and Clinical Interactions (NW PCI) Network. The NW PCI is a collaborative group of regional research programs located at medical centers, healthcare systems, and universities across Washington, Wyoming, Alaska, Montana, and Idaho. This article describes the purpose, development, barriers, and initial experience with feasibility assessment for TIN-supported studies in the NW PCI. The tools and processes of the NW PCI Network were adapted to enable network sites to assess studies for clinical relevance and feasibility. Seven of seventeen TIN-supported studies were reviewed for consideration; three of which resulted in successful completion of study documentation for site selection by NW PCI sites. The NW PCI/TIN model can be adapted by other CTSAs to increase involvement of regional research programs in national multisite clinical research studies. Barriers to expanding TIN-supported trials to regional networks include short timelines for study document submissions, insufficient site reimbursement rates, and non-feasible study designs.

Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People.

Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites. Only the CYP2D6 variation was significantly associated with concentrations of endoxifen (P = 0.0008) and 4-hydroxytamoxifen (P = 0.0074), tamoxifen's principal active metabolites, as well as key metabolic ratios. The CYP2D6 was also the most significant predictor of active metabolites and metabolic ratios in a multivariate regression model, including all four genes as predictors, with minor roles for other CYP genes. In AIAN populations, CYP2D6 is the largest contributor to tamoxifen bioactivation, illustrating the importance of validating pharmacogenetic testing for therapy optimization in an understudied population.

The Northwest Participant and Clinical Interactions Network: Increasing opportunities for patients to participate in research across the Northwestern United States.

INTRODUCTION: The Institute of Translational Health Sciences (ITHS) promotes and supports translational research collaboration between clinicians, communities, and investigators across the five-state Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) region. The ITHS has developed a collaborative regional clinical research network, the Northwest Participant & Clinical Interactions Network (NW PCI), involving 12 diverse clinical health systems and academic institutions. METHODS: This descriptive article details NW PCI's development, infrastructure and governance, tools, characteristics, and initial outcomes. RESULTS: Regional NW PCI sites are conducting largely industry-sponsored studies; they are interested in including more grant-funded research. Regional NW PCI sites had over 1,240 open studies involving over 6700 patients in 2016. NW PCI trials are largely industry-sponsored; NW PCI sites are interested in including more grant-funded research. In its first three years, the NW PCI Coordinating Center facilitated regional sites' participation in 34 new grant and contract applications across diverse topics. CONCLUSION: The NW PCI model supports the goals of the developing CTSA Trial Innovation Network by increasing access to cutting-edge research across the Northwestern U.S., by supporting investigators seeking diverse populations, including those with rare diseases, for their research studies, and by providing settings to test implementation and dissemination of effective interventions.

Partnership with the Confederated Salish and Kootenai Tribes: Establishing an Advisory Committee for Pharmacogenetic Research.

BACKGROUND: Inclusion of American Indian and Alaska Native (AI/AN) populations in pharmacogenetic research is key if the benefits of pharmacogenetic testing are to reach these communities. Community-based participatory research (CBPR) offers a model to engage these communities in pharmacogenetics. OBJECTIVES: An academic-community partnership between the University of Montana (UM) and the Confederated Salish and Kootenai Tribes (CSKT) was established to engage the community as partners and advisors in pharmacogenetic research. METHODS: A community advisory committee, the Community Pharmacogenetics Advisory Council (CPAC), was established to ensure community involvement in the research process. To promote bidirectional learning, researchers gave workshops and presentations about pharmacogenetic research to increase research capacity and CPAC members trained researchers in cultural competencies. As part of our commitment to a sustainable relationship, we conducted a self-assessment of the partnership, which included surveys and interviews with CPAC members and researchers. RESULTS: Academic and community participants agree that the partnership has promoted a bidirectional exchange of knowledge. Interviews showed positive feedback from the perspectives of both the CPAC and researchers. CPAC members discussed their trust in and support of the partnership, as well as having learned more about research processes and pharmacogenetics. Researchers discussed their appreciation of CPAC involvement in the project and guidance the group provided in understanding the CSKT community and culture. DISCUSSION: We have created an academic-community partnership to ensure CSKT community input and to share decision making about pharmacogenetic research. Our CBPR approach may be a model for engaging AI/AN people, and other underserved populations, in genetic research.

Psychological stress preceding idiopathic ventricular fibrillation.

OBJECTIVE: Emotional stress is well established as a trigger of sudden death in the context of coronary heart disease (CHD), but its role in patients experiencing cardiac arrest with apparently normal hearts is unknown. This study sought to determine the role of psychosocial stress as a precipitant of cardiac arrest in patients with apparently normal hearts, so-called idiopathic ventricular fibrillation (IVF). METHODS: We interviewed 25 IVF survivors (12 men, 13 women) and 25 matched comparison patients regarding life events during the 6 months and 24 hours preceding the cardiac event. The comparison group consisted of patients with an acute myocardial infarction or angina pectoris requiring angioplasty but without cardiac arrest. Judges independently rated written summaries of these interviews for psychosocial stress at each time point on a three-point scale (low, moderate, severe). RESULTS: During the 6 months before the cardiac event, 20 patients sustaining IVF had severe/moderate stress and five had low stress, whereas 10 comparison patients had severe/moderate stress and 15 had low stress (Fisher exact p = .008). During the preceding 24 hours, nine patients with IVF had severe/moderate stress and 16 had low stress, whereas two comparison patients had severe/moderate stress and 22 had low stress (Fisher exact p = .04) (one silent myocardial infarction could not be precisely dated). CONCLUSION: These data suggest that psychosocial stress is playing a role in otherwise unexplained cardiac arrest.

Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses?

Anecdotal and published case reports suggest that some patients taking selective serotonin reuptake inhibitors (SSRI) experience diminution in emotional responsiveness. This study aims to define the individual components of emotion disturbed in these patients. Fifteen patients reporting SSRI-induced sexual dysfunction completed the Laukes Emotional Intensity Scale (LEIS), a questionnaire about various emotions. Compared to controls, patients reported significantly (p<0.05) less ability to cry, irritation, care about others' feelings, sadness, erotic dreaming, creativity, surprise, anger, expression of their feelings, worry over things or situations, sexual pleasure, and interest in sex. Total score on the LEIS did not correlate with total score on the Hamilton Depression Rating Scale. In our sample, 80% of patients with SSRI-induced sexual dysfunction also describe clinically significant blunting of several emotions. Emotional blunting may be an under-appreciated side-effect of SSRIs that may contribute to treatment non-compliance and/or reduced quality of life.