Measuring institutional community engagement: Adding value to academic health systems.

Beyond medical schools' historical focus on pillar missions including clinical care, education, and research, several medical schools now include community engagement (CE) as a mission. However, most academic health systems (AHSs) lack the tools to provide metrics, evaluation, and standardization for quantifying progress and contributions of the CE mission. Several nationwide initiatives, such as that driven by the Institute of Medicine recommending advances in CE metrics at institutions receiving Clinical and Translational Science Awards, have encouraged the research and development of systematic metrics for CE, but more progress is needed. The CE components practical model provides a foundation for analyzing and evaluating different types of CE activities at AHSs through five components: research, education, community outreach and community service, policy and advocacy, and clinical care. At the Medical College of Wisconsin (MCW), an annual survey administered to faculty and staff assessed the types and number of CE activities from the prior year. Survey results were combined to create a CE report for departments across the institution and inform MCW leadership. Insights gathered from the survey have contributed to next steps in CE tracking and evaluation, including the development of a CE dashboard to track CE activities in real time. The dashboard provides resources for how individuals can advance the CE mission through their work and guide CE at the institutional level.

Defining and Measuring Community Engagement and Community-Engaged Research: Clinical and Translational Science Institutional Practices.

BACKGROUND: The institutions that comprise the Clinical and Translational Science Award (CTSA) consortium and the National Center for Advancing Translational Sciences continue to explore and develop community-engaged research strategies and to study the role of community academic partnerships in advancing the science of community engagement. OBJECTIVES: To explore CTSA institutions in relation to an Institute of Medicine recommendation that community engagement occur in all stages of translational research and be defined and evaluated consistently. METHODS: A sequential multimethods study starting with an online pilot survey followed by survey respondents and site informant interviews. A revised survey was sent to the community engagement and evaluation leads at each CTSA institution, requesting a single institutional response about the definitions, indicators, and metrics of community engagement and community-engaged research. RESULTS: A plurality of CTSA institutions selected the definition of community engagement from the Principles of Community Engagement. Although claiming unique institutional priorities create barriers to developing shared metrics, responses indicate an overall lack of attention to the development and deployment of metrics to assess community engagement in and contributions to research. CONCLUSIONS: Although definitions of community engagement differ among CTSAs, there seem to be more similarities than differences in the indicators and measures tracked and reported on across all definitions, perhaps owing to commonalities among program infrastructures and goals. Metrics will likely need to be specific to translational research stages. The assessment of community engagement within translational science will require increased institutional commitment.

Patient vs. Community Engagement: Emerging Issues.

BACKGROUND: The value proposition of including patients at each step of the research process is that patient perspectives and preferences can have a positive impact on both the science and the outcomes of comparative effectiveness research. How to accomplish engagement and the extent to which approaches to community engagement inform strategies for effective patient engagement need to be examined to address conducting and accelerating comparative effectiveness research. OBJECTIVES: To examine how various perspectives and diverse training lead investigators and patients to conflicting positions on how best to advance patient engagement. RESEARCH DESIGN: Qualitative methods were used to collect perspectives and models of engagement from a diverse group of patients, researchers and clinicians. The project culminated with a workshop involving these stakeholders. The workshop used a novel approach, combining World Café and Future Search techniques, to compare and contrast aspects of patient engagement and community engagement. SUBJECTS: Participants included patients, researchers, and clinicians. MEASURES: Group and workshop discussions provided the consensus on topics related to patient and community engagement. RESULTS: Participants developed and refined a framework that compares and contrasts features associated with patient and community engagement. CONCLUSIONS: Although patient and community engagement may share a similar approach to engagement based on trust and mutual benefit, there may be distinctive aspects that require a unique lexicon, strategies, tactics, and activities.

Science Cafés: Transforming citizens to scientific citizens-What influences participants' perceived change in health and scientific literacy?

INTRODUCTION: Science Cafés facilitated by the Clinical and Translational Science Institute of Southeast Wisconsin seek to increase health and scientific literacy through informal conversation between researchers and community members. The goal was to understand what factors have the greatest influence on attendees' perceived changes in health and science literacy levels (PCHSL) to increase impact. METHODS: Previous research established the evaluation used in the Science Cafés to measure PCHSL. In this study, comparisons were made between (1) 2 different approaches to Science Cafés (Genomics Science Cafés or Health Science Cafés) and (2) regression models to show which factors best predicted PCHSL. RESULTS: The approach of the Genomics Science Cafés series to Science Cafés showed a larger impact on PCHSL. Regression models suggest SES and education significantly contributes to PCHSL. CONCLUSIONS: Insights for program development to have greater impact on PCHSL were identified. Continuing to optimize dissemination of research findings to the public is essential for improving community health and well-being.

Towards a practical model for community engagement: Advancing the art and science in academic health centers.

INTRODUCTION: Community engagement (CE) has become more prevalent among academic health centers (AHCs), with significant diversity in practices and language. The array of approaches to CE contributes to confusion among practitioners. METHODS: We have reviewed multiple models of CE utilized by AHCs, Clinical and Translational Science Awards, and higher education institutions overall. Taking these models into consideration, we propose a comprehensive model of CE that encompasses a broader spectrum of activities and programs. RESULTS: The CE Components Practical Model includes 5 components: Community Outreach and Service, Education, Clinical Care, Research, and Policy and Advocacy. The components are supported by the foundational elements within administrative functions and infrastructure. CONCLUSIONS: This model will accomplish the following: (1) reduce confusion about CE; (2) provide a broader understanding of CE; and (3) increase the ability of CE practitioners to interact with each other through this common reference and engage in advancing CE scholarship.

A Social Network Analysis of 140 Community-Academic Partnerships for Health: Examining the Healthier Wisconsin Partnership Program.

INTRODUCTION: Social Network Analysis (SNA) provides an important, underutilized approach to evaluating Community Academic Partnerships for Health (CAPHs). This study examines administrative data from 140 CAPHs funded by the Healthier Wisconsin Partnership Program (HWPP). METHODS: Funder data was normalized to maximize number of interconnections between funded projects and 318 non-redundant community partner organizations in a dual mode analysis, examining the period from 2003-2013.Two strategic planning periods, 2003-2008 vs. 2009-2014, allowed temporal comparison. RESULTS: Connectivity of the network was largely unchanged over time, with most projects and partner organizations connected to a single large component in both time periods. Inter-partner ties formed in HWPP projects were transient. Most community partners were only involved in projects during one strategic time period. Community organizations participating in both time periods were involved in significantly more projects during the first time period than partners participating in the first time period only (Cohen's d = 0.93). DISCUSSION: This approach represents a significant step toward using objective (non-survey) data for large clusters of health partnerships and has implications for translational science in community settings. Considerations for government, funders, and communities are offered. Examining partnerships within health priority areas, orphaned projects, and faculty ties to these networks are areas for future research.

Science cafés: engaging scientists and community through health and science dialogue.

Engagement of the community through informal dialogue with researchers and physicians around health and science topics is an important avenue to build understanding and affect health and science literacy. Science Cafés are one model for this casual interchange; however the impact of this approach remains under researched. The Community Engagement Key Function of the Clinical and Translational Science Institute of Southeast Wisconsin hosted a series of Science Cafés in which topics were collaboratively decided upon by input from the community. Topics ranged from Personalized Medicine to Alzheimer's and Dementia to BioMedical Innovation. A systematic evaluation of the impact of Science Cafés on attendees' self-confidence related to five health and scientific literacy concepts showed statistically significant increases across all items (Mean differences between mean retrospective pre-scores and post-scores, one tailed, paired samples t-test, n=141, p<.0001 for all items). The internal consistency of the five health and scientific literacy items was excellent (n=126, α=0.87). Thematic analysis of attendees' comments provides more nuance about positive experience and suggestions for possible improvements. The evaluation provides important evidence supporting the effectiveness of brief, casual dialogue as a way to increase the public's self-rated confidence in health and science topics.

Syntrophin isoforms play specific functional roles in the α1D-adrenergic receptor/DAPC signalosome.

α(1D)-Adrenergic receptors, key regulators of cardiovascular system function, are organized as a multi-protein complex in the plasma membrane. Using a Type-I PDZ-binding motif in their distal C-terminal domain, α(1D)-ARs associate with syntrophins and dystrophin-associated protein complex (DAPC) members utrophin, dystrobrevin and α-catulin. Three of the five syntrophin isoforms (α, ß(1) and ß(2)) interact with α(1D)-ARs and our previous studies suggest multiple isoforms are required for proper α(1D)-AR function in vivo. This study determined the contribution of each specific syntrophin isoform to α(1D)-AR function. Radioligand binding experiments reveal α-syntrophin enhances α(1D)-AR binding site density, while phosphoinositol and ERK1/2 signaling assays indicate ß(2)-syntrophin augments full and partial agonist efficacy for coupling to downstream signaling mechanisms. The results of this study provide clear evidence that the cytosolic components within the α(1D)-AR/DAPC signalosome significantly alter the pharmacological properties of α(1)-AR ligands in vitro.

The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder precipitated by exposure to extreme traumatic stress. Yet, most individuals exposed to traumatic stress do not develop PTSD and may be considered psychologically resilient. The neural circuits involved in susceptibility or resiliency to PTSD remain unclear, but clinical evidence implicates changes in the noradrenergic system. METHODS: An animal model of PTSD called Traumatic Experience with Reminders of Stress (TERS) was developed by exposing C57BL/6 mice to a single shock (2 mA, 10 sec) followed by exposure to six contextual 1-minute reminders of the shock over a 25-day period. Acoustic startle response (ASR) testing before the shock and after the last reminder allowed experimenters to separate the shocked mice into two cohorts: mice that developed a greatly increased ASR (TERS-susceptible mice) and mice that did not (TERS-resilient mice). RESULTS: Aggressive and social behavioral correlates of PTSD increased in TERS-susceptible mice but not in TERS-resilient mice or control mice. Characterization of c-Fos expression in stress-related brain regions revealed that TERS-susceptible and TERS-resilient mice displayed divergent brain activation following swim stress compared with control mice. Pharmacological activation of noradrenergic inhibitory autoreceptors or blockade of postsynaptic α(1)-adrenoreceptors normalized ASR, aggression, and social interaction in TERS-susceptible mice. The TERS-resilient, but not TERS-susceptible, mice showed a trend toward decreased behavioral responsiveness to noradrenergic autoreceptor blockade compared with control mice. CONCLUSIONS: These data implicate the noradrenergic system as a possible site of pathological and perhaps also adaptive plasticity in response to traumatic stress.

Differential regulation of GPR54 transcription by specificity protein-1 and partial estrogen response element in mouse pituitary cells.

Precise spatial and temporal expression of the recently identified G-protein coupled receptor GPR54 is critical for proper reproductive function and metastasis suppression. However, regulatory factors that control GPR54 expression remain unknown. Thus, the identification of these cis-acting DNA elements can provide insight into the role of GPR54 in reproduction and cancer. Using luciferase reporter, electrophoretic mobility shift, and chromatin immunoprecipitation assays, we demonstrate that three SP1 sites and a partial estrogen response element modulate mouse GPR54 (mGPR54) promoter activity. Supporting experiments show transcription factor SP1 binds directly to the mGPR54 promoter region and activates gene expression. In conclusion, these novel findings now identify factors that regulate activity of the mGPR54 promoter, and these factors are highly conserved across multiple mammalian species.

Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-protein-coupled receptor function.

The G-protein-coupled receptor (GPCR) GPR54 is essential for the development and maintenance of reproductive function in mammals. A point mutation (L148S) in the second intracellular loop (IL2) of GPR54 causes idiopathic hypogonadotropic hypogonadism, a disorder characterized by delayed puberty and infertility. Here, we characterize the molecular mechanism by which the L148S mutation causes disease and address the role of IL2 in Class A GPCR function. Biochemical, immunocytochemical, and pharmacological analysis demonstrates that the mutation does not affect the expression, ligand binding properties, or protein interaction network of GPR54. In contrast, diverse GPR54 functional responses are markedly inhibited by the L148S mutation. Importantly, the leucine residue at this position is highly conserved among class A GPCRs. Indeed, mutating the corresponding leucine of the alpha(1A)-AR recapitulates the effects observed with L148S GPR54, suggesting the critical importance of this hydrophobic IL2 residue for Class A GPCR functional coupling. Interestingly, co-immunoprecipitation studies indicate that L148S does not hinder the association of Galpha subunits with GPR54. However, fluorescence resonance energy transfer analysis strongly suggests that L148S impairs the ligand-induced catalytic activation of Galpha. Combining our data with a predictive Class A GPCR/Galpha model suggests that IL2 domains contain a conserved hydrophobic motif that, upon agonist stimulation, might stabilize the switch II region of Galpha. Such an interaction could promote opening of switch II of Galpha to facilitate GDP-GTP exchange and coupling to downstream signaling responses. Importantly, mutations that disrupt this key hydrophobic interface can manifest as human disease.

Blood pressure is regulated by an alpha1D-adrenergic receptor/dystrophin signalosome.

Hypertension is a cardiovascular disease associated with increased plasma catecholamines, overactivation of the sympathetic nervous system, and increased vascular tone and total peripheral resistance. A key regulator of sympathetic nervous system function is the alpha(1D)-adrenergic receptor (AR), which belongs to the adrenergic family of G-protein-coupled receptors (GPCRs). Endogenous catecholamines norepinephrine and epinephrine activate alpha(1D)-ARs on vascular smooth muscle to stimulate vasoconstriction, which increases total peripheral resistance and mean arterial pressure. Indeed, alpha(1D)-AR KO mice display a hypotensive phenotype and are resistant to salt-induced hypertension. Unfortunately, little information exists about how this important GPCR functions because of an inability to obtain functional expression in vitro. Here, we identified the dystrophin proteins, syntrophin, dystrobrevin, and utrophin as essential GPCR-interacting proteins for alpha(1D)-ARs. We found that dystrophins complex with alpha(1D)-AR both in vitro and in vivo to ensure proper functional expression. More importantly, we demonstrate that knock-out of multiple syntrophin isoforms results in the complete loss of alpha(1D)-AR function in mouse aortic smooth muscle cells and abrogation of alpha(1D)-AR-mediated increases in blood pressure. Our findings demonstrate that syntrophin and utrophin associate with alpha(1D)-ARs to create a functional signalosome, which is essential for alpha(1D)-AR regulation of vascular tone and blood pressure.

Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase.

Norbinaltorphimine (NorBNI), guanidinonaltrindole, and atrans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) piperidine (JDTic) are selective kappa opioid receptor (KOR) antagonists having very long durations of action in vivo despite binding non-covalently in vitro and having only moderately high affinities. Consistent with this, we found that antagonist treatment significantly reduced the subsequent analgesic response of mice to the KOR agonist U50,488 in the tail-withdrawal assay for 14-21 days. Receptor protection assays were designed to distinguish between possible explanations for this anomalous effect, and we found that mice pretreated with the readily reversible opioid antagonists naloxone or buprenorphine before norBNI responded strongly in the tail-flick analgesia assay to a subsequent challenge with U50,488 1 week later. Protection by a rapidly cleared reagent indicates that norBNI did not persist at the site of action. In vitro binding of [(3)H]U69,593 to KOR showed that K(d) and Bmax values were not significantly affected by prior in vivo norBNI exposure, indicating that the agonist binding site was intact. Consistent with the concept that the long-lasting effects might be caused by a functional disruption of KOR signaling, both norBNI and JDTic were found to stimulate c-Jun N-terminal kinase (JNK) phosphorylation in HEK293 cells expressing KOR-GFP but not in untransfected cells. Similarly, norBNI increased phospho-JNK in both the striatum and spinal cord in wild type mice but not in KOR knock-out mice. Pretreatment of mice with the JNK inhibitor SP600125 before norBNI attenuated the long acting antagonism. Together, these results suggest that the long duration KOR antagonists disrupt KOR signaling by activating JNK.

A single spacer nucleotide determines the specificities of two mRNA regulatory proteins.

Regulation of messenger RNA is crucial in many contexts, including development, memory and cell growth. The 3' untranslated region is a rich repository of regulatory elements that bind proteins and microRNAs. Here we focus on PUF proteins, an important family of mRNA regulatory proteins crucial in stem-cell proliferation, pattern formation and synaptic plasticity. We show that two Caenorhabditis elegans PUF proteins, FBF and PUF-8, differ in RNA-binding specificity. FBF requires the presence of a single 'extra' nucleotide in the middle of an eight-nucleotide site, whereas PUF-8 requires its absence. A discrete protein segment is responsible for the difference. We propose that a structural distortion in the central region of FBF imposes the requirement for the additional nucleotide and that this mode of PUF specificity may be common. We suggest that new specificities can be designed and selected using the PUF scaffold.