BACKGROUNDPatients and healthcare stakeholders are increasingly becoming engaged in the planning and conduct of biomedical research. However, limited research characterizes this process or its impact.OBJECTIVEWe aimed to characterize patient and stakeholder engagement in the 50 Pilot Projects funded by the Patient-Centered Outcomes Research Institute (PCORI), and identify early contributions and lessons learned.DESIGNA self-report instrument was completed by researchers between 6 and 12 months following project initiation.PARTICIPANTSForty-seven principal investigators or their designees (94 % response rate) participated in the study.MAIN MEASURES Self-report of types of stakeholders engaged, stages and levels of engagement, facilitators and barriers to engagement, lessons learned, and contributions from engagement were measured.KEY RESULTSMost (83 %) reported engaging more than one stakeholder in their project. Among those, the most commonly reported groups were patients (90 %), clinicians (87 %), health system representatives (44 %), caregivers (41 %), and advocacy organizations (41 %). Stakeholders were commonly involved in topic solicitation, question development, study design, and data collection. Many projects engaged stakeholders in data analysis, results interpretation, and dissemination. Commonly reported contributions included changes to project methods, outcomes or goals; improvement of measurement tools; and interpretation of qualitative data. Investigators often identified communication and shared leadership strategies as “critically important” facilitators (53 and 44 % respectively); lack of stakeholder time was the most commonly reported challenge (46 %). Most challenges were only partially resolved. Early lessons learned included the importance of continuous and genuine partnerships, strategic selection of stakeholders, and accommodation of stakeholders’ practical needs.CONCLUSIONSPCORI Pilot Projects investigators report engaging a variety of stakeholders across many stages of research, with specific changes to their research attributed to engagement. This study identifies early lessons and barriers that should be addressed to facilitate engagement. While this research suggests potential impact of stakeholder engagement, systematic characterization and evaluation of engagement at multiple stages of research is needed to build the evidence base.Electronic supplementary materialThe online version of this article (doi:10.1007/s11606-015-3450-z) contains supplementary material, which is available to authorized users.

PurposeTo provide an overview of PCORI’s approach to engagement in research.MethodsThe Patient-Centered Outcomes Research Institute (PCORI) was established in 2010 to fund patient-centered comparative effectiveness research. Requirements for research funding from PCORI include meaningful engagement of patients and other stakeholders in the research. PCORI’s approach to engagement in research is guided by a conceptual model of patient-centered outcomes research (PCOR), that provides a structure for understanding engagement in research.ResultsTo understand and improve engagement in research PCORI is learning from awardees and other stakeholders. Those efforts are described along with PCORI’s capacity building and guidance to awardees via the Engagement Rubric. PCORI’s unique model of engaging patients and other stakeholders in merit review of funding applications is also described. Additional support for learning about engagement in research is provided through specific research funding and through PCORI’s major infrastructure initiative, PCORnet.ConclusionPCORI requires engagement of stakeholders in the research it funds. In addition PCORI engages stakeholders in activities including review of funding applications and establishment of CER research infrastructure through PCORnet. The comprehensive approach to engagement is being evaluated to help guide the field toward promising practices in research engagement.

Background The medical research enterprise depends on public recognition of its societal value. In light of evidence indicating public mistrust, especially among minorities, inadequate enrollment and diversity of research participants, and poor uptake of findings, medical research appears to fall short of sufficient public regard. Community engagement in medical research, with special attention to minority communities, may help to remedy this shortfall by demonstrating respect for communities in practical ways. Approach We provide three case examples that illustrate how specific approaches to community-engaged research can build trust between researchers and communities, encourage participation among under-represented groups, and enhance the relevance and uptake of research findings. Discussion A common attribute of the specific approaches discussed here is that they enable researchers to demonstrate respect by recognizing community values and interests. The demonstration of respect for communities has intrinsic ethical importance. Conclusion Two potential outgrowths of demonstrating respect specifically through community engagement are (1) the production of research that is more relevant to the community and (2) the mitigation of asymmetry in the researcher-community relationship. We summarize practical resources available to researchers who seek to incorporate community engagement in their research.

a composite variable that captures an employee's links to people and the organization, perceived job fit, and the sacrifices inherent in job change, has become an increasingly popular variable in turnover research. Analyses of survey data from a national sample of 143 retail pharmacists indicated a significant negative relationship between participants' job embeddedness and their intentions to leave. Job embeddedness was also found to be positively related to perceived organizational support and job satisfaction; regression analyses found that it accounted for significant variance in intentions to leave beyond that explained by these 2 established turnover antecedents. Results also suggest that organizations' proactive efforts to increase job embeddedness mitigated pharmacists' intentions to leave. Implications for health care managers and pharmacist employers are discussed.

Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α-subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and β subunits separately (TSD α + β) injected at high (1.3 × 10 vector genomes) or low (4.2 × 10 vector genomes) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all adeno-associated virus-treated sheep. Postmortem evaluation showed superior HexA and vector genome distribution in the brain of TSD α + β sheep compared to TSD α sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formation after treatment with both vectors (TSD α + β), and ganglioside clearance was most widespread in the TSD α + β high-dose sheep. Microglial activation and proliferation in TSD sheep-most prominent in the cerebrum-were attenuated after gene therapy. This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.

Our findings on the nature and impacts of engagement have importance not only for practical questions researchers, funders, and patients might raise, but also for several ethical considerations regarding patient engagement related to why patients are engaged, the kinds of patients engaged, when patients are engaged, and how patients are engaged. We discuss our findings in consideration of the main ethical issues they imply, including ethical rationales for engagement, justice-related concerns, and ethical concerns arising from when and how patients are engaged. As efforts to engage patients increase, this discussion provides insights that researchers, funders, and patients may find valuable.

The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are fatal lysosomal storage disorders caused by mutations in the HEXA and HEXB genes, respectively. These mutations cause dysfunction of the lysosomal enzyme b-N-acetylhexosaminidase A (HexA) and accumulation of GM2 ganglioside (GM2) with ensuing neurodegeneration, and death by 5 years of age. Until recently, the most successful therapy was achieved by intracranial co-delivery of monocistronic adenoassociated viral (AAV) vectors encoding Hex alpha and betasubunits in animal models of SD. The blood-brain barrier crossing properties of AAV9 enables systemic gene therapy; however, the requirement of co-delivery of two monocistronic AAV vectors to overexpress the heterodimeric HexA protein has prevented the use of this approach. To address this need, we developed multiple AAV constructs encoding simultaneously HEXA and HEXB using AAV9 and AAV-PHP.B and tested their therapeutic efficacy in 4-to 6-week-old SD mice after systemic administration. Survival and biochemical outcomes revealed superiority of the AAV vector design using a bidirectional CBA promoter with equivalent dose-dependent outcomes for both capsids. AAV-treated mice performed normally in tests of motor function, CNS GM2 ganglioside levels were significantly reduced, and survival increased by >4-fold with some animals surviving past 2 years of age.

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline b-galactosidase (b-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where b-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and b-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.