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1.  Shortening the Work Preference Inventory for use with Physician Scientists: WPI-10 
The Work Preference Inventory (WPI) is a four-factor, 30-item measure that assesses work motivation. Used to help individuals choose appropriate career paths, its length contributes to response burden, especially when combined with other measures. We aimed to develop a shortened, valid and reliable version of the WPI. Trainees at the University of Pittsburgh’s Institute for Clinical Research Education completed the 30-item WPI between 2007 and 2012. We conducted exploratory and confirmatory factor analyses to reduce the number of items. Of the 402 eligible trainees, 371 (92%) provided data for the exploratory factor analysis (EFA), and 134 of the eligible 144 trainees (93%) provided data for the confirmatory factor analysis (CFA). EFA revealed four factors that were roughly equivalent to those of the original. CFA used the 3 items with the highest loadings on each factor, with two items removed due to low loadings and R-squareds, resulting in a 10-item scale. Cronbach’s alpha for each of the 4 factors ranged from 0.68 to 0.76. Factors in the WPI-10 were strongly and significantly associated with factors in the original WPI, indicating strong validity of the shortened measure. The WPI-10 shows evidence for similar validity and reliability as the original instrument while reducing respondent burden.
PMCID: PMC4090299  PMID: 24405561
Clinical research training; clinical research; work motivation; WPI
3.  Tracking the pharmaceutical pipeline: Clinical trials and global disease burden 
Aggregate data about pharmaceutical research and development (R&D) tend to examine Phase III trials. Hence, there are few published data about investigational drugs in earlier phases of clinical development that might fail. It is also unclear how well R&D corresponds to disease burden. We track the pharmaceutical pipeline using data from industry publications that provide otherwise unreported information about industry-sponsored clinical trials. The sample includes 2477 unique drug entities in 4182 clinical trials. The majority of drugs targeted neoplasms (26.20%), neurological diseases/diseases of the sense organs (13.48%), infectious and parasitic diseases (10.5%), and endocrine, metabolic, nutrition, and immunity disorders (9.45%). Less than 6% of drugs targeted diseases of the circulatory system, which represent the most prevalent causes of global mortality. Detailing the pharmaceutical pipeline, our findings suggest that pharmaceutical development does not adequately address global disease burden. Future research on the under-reported details of phase I and II clinical trials is needed to understand how the industry operates and how its resource-allocation matches global health concerns.
PMCID: PMC4134709  PMID: 24816032
4.  Engaging the Underserved: A Process Model to Mobilize Rural Community Health Coalitions as Partners in Translational Research 
Community engagement (CE) and community-engaged research (CEnR) are increasingly recognized as critical elements in research translation. Process models to develop CEnR partnerships in rural and underserved communities are needed.
Academic partners transformed four established Community Health Improvement Partnerships (CHIPs) into Community Health Improvement and Research Partnerships (CHIRPs). The intervention consisted of three elements: an academic-community kick-off/orientation meeting, delivery of eight research training modules to CHIRP members, and local community-based participatory research (CBPR) pilot studies addressing childhood obesity. We conducted a mixed methods analysis of pre/post surveys, interviews, session evaluations, observational field notes, and attendance logs to evaluate intervention effectiveness and acceptability.
Forty-nine community members participated; most (78.7%) attended five or more research training sessions. Session quality and usefulness was high. Community members reported significant increases in their confidence for participating in all phases of research (e.g., formulating research questions, selecting research methods, writing manuscripts). All CHIRP groups successfully conducted CBPR pilot studies.
The CHIRP process builds on existing infrastructure in academic and community settings to foster CEnR. Brief research training and pilot studies around community-identified health needs can enhance individual and organizational capacity to address health disparities in rural and underserved communities.
PMCID: PMC4134739  PMID: 24837826
6.  A Distributed Model: Redefining a Robust Research Subject Advocacy Program at the Harvard Clinical and Translational Science Center 
The Harvard Clinical and Translational Science Center (“Harvard Catalyst”) Research Subject Advocacy (RSA) Program has reengineered subject advocacy, distributing the delivery of advocacy functions through a multiinstitutional, central platform rather than vesting these roles and responsibilities in a single individual functioning as a subject advocate. The program is processoriented and output-driven, drawing on the strengths of participating institutions to engage local stakeholders both in the protection of research subjects and and in advocacy for subjects’ rights. The program engages stakeholder communities in the collaborative development and distributed delivery of accessible and applicable educational programming and resources. The Harvard Catalyst RSA Program identifies, develops, and supports the sharing and distribution of expertise, education, and resources for the benefit of all institutions, with a particular focus on the front-line: research subjects, researchers, research coordinators, and research nurses.
PMCID: PMC4219549  PMID: 24841488
8.  Imprinting Status of GαS, NESP55, and XLαs in Cell Cultures Derived from Human Embryonic Germ Cells: GNAS Imprinting in Human Embryonic Germ Cells 
GNAS is a complex gene that through use of alternative first exons encodes signaling proteins Gαs and XLαs plus neurosecretory protein NESP55. Tissue-specific expression of these proteins is regulated through reciprocal genomic imprinting in fully differentiated and developed tissue. Mutations in GNAS account for several human disorders, including McCune–Albright syndrome and Albright hereditary osteodystrophy, and further knowledge of GNAS imprinting may provide insights into variable phenotypes of these disorders. We therefore analyzed expression of Gαs, NESP55, and XLαs prior to tissue differentiation in cell cultures derived from human primordial germ cells. We found that the expression of Gαs was biallelic (maternal allele: 52.6% ± 2.5%; paternal allele: 47.2% ± 2.5%; p = 0.07), whereas NESP55 was expressed preferentially from the maternal allele (maternal allele: 81.9% ± 10%; paternal allele: 18.1% ± 10%; p = 0.002) and XLαs was preferentially expressed from the paternal allele (maternal allele: 2.7% ± 0.3%; paternal allele: 97.3% ± 0.3%;p = 0.007). These results demonstrate that imprinting of NESP55 occurs very early in development, although complete imprinting appears to take place later than 5–11 weeks postfertilization, and that imprinting of XLαs occurs very early postfertilization. By contrast, imprinting of Gαs most likely occurs after 11 weeks postfertilization and after tissue differentiation.
PMCID: PMC4434047  PMID: 20443919
imprinting; Albright hereditary osteodystrophy; pseudohypoparathyroidism; GNAS; Gαs; NESP55; XLαs; embryonic germ cells; embryoid body-derived cells
9.  The Influence of the Brain-Derived Nuerotrophic Factor Val66Met Genotype and HMG-CoA Reductase Inhibitors on Insulin Resistance in the Schizophrenia and Bipolar Populations 
The Brain-derived Neurotrophic Factor (BNDF) Val66Met variant and HMG-COA reductase inhibitors (statins) have been implicated in insulin resistance and diabetes risk. We sought to determine the effect of the BDNF Met variant and statin use on insulin resistance in schizophrenia and bipolar disorder using the homeostasis model assessment of insulin resistance (HOMA-IR).
A cross-sectional design was used and patients with diabetes or receiving medications affecting glucose regulation were excluded. Associations between insulin resistance and genotype were analyzed by ANOVA and regression analysis. Subjects were grouped by BDNF genotype as well as statin use.
252 subjects with a mean age of 44 years were included. The group was 53% male and 59% had a schizophrenia diagnosis; 78% and 19% were receiving atypical antipsychotics(AAPs) and statin medications, respectively. Analysis showed schizophrenia subjects with the BDNF met allele as well as schizophrenia subjects with the BDNF met allele and statin combination had significantly higher HOMA-IR values compared to the other groups (p=0.046 and p=0.016, respectively).
These results suggest that in the metabolically high-risk population of schizophrenia the BDNF met allele alone and in combination with statin medications is associated with higher insulin resistance values. This was not seen in the bipolar population. Further validation of these associations remains necessary.
PMCID: PMC4426971  PMID: 23253673
10.  β2-adrenergic receptor promoter haplotype influences spirometric response during an acute asthma exacerbation 
Genetic variants in the β2-adrenergic receptor (ADRB2) coding block have been associated with different parameters of asthma severity, but there is no consensus on which variants are most important. Our objective was to determine whether genetic variants in the 5′- or 3′-flanking regions of ADRB2 impact response to therapy. DNA was obtained initially from 72 adults hospitalized for an asthma exacerbation. We sequenced a 5000 bp region of the ADRB2 gene that spanned the flanking regions and identified 31 single nucleotide polymorphisms (SNPs). Non-responders to asthma therapy were defined as patients whose FEV1 worsened by >10% at 24 h after admission. We then evaluated the relationship between the 19 common SNPs and response to asthma-specific therapy during acute disease exacerbations. Our results showed a significant association between non-responders and a haplotype of 5 promoter SNPs in nearly complete linkage disequilibrium. Analysis of promoter and coding block polymorphisms in an extended cohort of 99 patients confirmed that promoter haplotype was the genetic component most strongly associated with asthmatic non-responders, which was statistically significant among whites (p < 0.05). Identification of this promoter haplotype may provide an alternate explanation for the variation in asthma responses observed with ADRB2 coding block polymorphisms.
PMCID: PMC4416213  PMID: 20443840
11.  The Relevancy of Community-Based Methods: Using Diet within Native American and Alaska Native Adult Populations as an Example 
The rates of obesity, diabetes, and heart disease in Native Americans and Alaska Natives far exceed that of the general US population. There are many postulating reasons for these excessive rates including the transition from a traditional to a contemporary diet. Although information on the dietary intakes of Native American and Alaska Native communities are limited, there seems to be a consensus that the Native American and Alaska Native diet is high in total fat, saturated fat, cholesterol, and sodium. Further information on the diet needs to be attained so that dietary interventions can effectively be implemented in these communities. An approach that is community based is proposed as the best solution to understanding the Native diet and developing culturally tailored interventions to sustainably improve diet.
PMCID: PMC4407991  PMID: 22686210
community-based participatory research; Native Americans; Alaskan Natives; dietary intake; chronic diseases; obesity
12.  Sex Modulates Intestinal Transformation by the Tumor-Suppressor GCC 
Background and Aims
Ovarian hormones oppose colorectal cancer, although mechanisms remain undefined. Similarly, the most commonly lost gene products in intestinal neoplasia include guanylin and uroguanylin, paracrine hormones for guanylyl cyclase C (GCC), which recently emerged as a tumor suppressor. However, the molecular intersection between intestinal paracrine and systemic sex hormones opposing intestinal neoplasia has not been explored.
Intestinal tumorigenesis was quantified in wild type (Gcc+/+) and GCC-deficient (Gcc−/−) mice carrying mutations in adenomatous polyposis coli (Apc) (ApcMin/+) or exposed to the carcinogen azoxymethane (AOM). Proliferation of epithelial cells was examined employing cell cycle markers.
Deletion of Gcc increased tumor multiplicity and growth in colons and small intestines, respectively, of ApcMin/+ mice. While changes in multiplicity and growth increased tumor burden, females exhibited approximately 60% (p = 0.040) of the burden in males. Similarly, female Gcc−/− mice treated with AOM exhibited approximately 40% (p = 0.048) of the burden in males. Moreover, Gcc deletion promoted epithelial cell proliferation, quantified by increases in β-catenin, cMyc, cyclin D1, and phosphorylated retinoblastoma protein (pRb), in males but not females.
There is a previously unappreciated interaction between sex and GCC signaling restricting crypt cell proliferation. Thus, the invariable loss of guanylin and uroguanylin resulting in tumorigenesis is mitigated in females by hormonal components of the ovarian axis. In the context of the universal overexpression of GCC by tumors, these observations highlight the combination of GCC paracrine and ovarian hormones for targeted prevention and therapy of colorectal cancer.
PMCID: PMC4406767  PMID: 20443837
colon cancer; sex; guanylyl cyclase C; proliferation; hormone deficiency; prevention; therapy
To determine how grant funds are shared between academic institutions and community partners in community-based participatory research (CBPR).
Review of all 62 investigator-initiated R01 CBPR grants funded by the National Institutes of Health from January 2005 to August 2012. Using pre-specified criteria, two reviewers independently categorized each budget item as being for an academic institution or a community partner. A third reviewer helped resolve any discrepancies.
Among 49 evaluable grants, 68% of all grant funds were for academic institutions and 30% were for community partners. For 2% of funds, it was unclear whether they were for academic institutions or for community partners. Community partners' share of funds was highest in the categories of other direct costs (62%) and other personnel (48%) and lowest in the categories of equipment (1%) and indirect costs (7%).
A majority of CBPR grant funds are allocated to academic institutions. In order to enhance the share that community partners receive, funders may wish to specify a minimum proportion of grant funds that should be allocated to community partners in CBPR projects.
PMCID: PMC4006285  PMID: 24655929
15.  The CTSA Consortium’s CATCHR (Catalog of Assets for Translational and Clinical Health Research) 
The 61 CTSA Consortium sites are home to valuable programs and infrastructure supporting translational science and all are charged with ensuring that such investments translate quickly to improved clinical care. CATCHR (Catalog of Assets for Translational and Clinical Health Research) is the Consortium’s effort to collect and make available information on programs and resources to maximize efficiency and facilitate collaborations. By capturing information on a broad range of assets supporting the entire clinical and translational research spectrum, CATCHR aims to provide the necessary infrastructure and processes to establish and maintain an open-access, searchable database of consortium resources to support multi-site clinical and translational research studies. Data is collected using rigorous, defined methods, with the resulting information made visible through an integrated, searchable web-based tool. Additional easy to use web tools assist resource owners in validating and updating resource information over time. In this article, we discuss the design and scope of the project, data collection methods, current results, and future plans for development and sustainability. With increasing pressure on research programs to avoid redundancy, CATCHR aims to make available information on programs and core facilities to maximize efficient use of resources.
PMCID: PMC4006289  PMID: 24456567
17.  People United to Sustain Health (PUSH): A Community-Based Participatory Research Study 
The prevention of weight gain to address the obesity epidemic rather than weight loss involves promoting small changes in food choices and physical activity. People United to Sustain Health (PUSH) was designed to increase fruit and vegetable consumption, physical activity, and food security to prevent weight gain in rural adults. Forty-nine participants were randomized into a treatment group which received access to a “Rolling Store,” nutrition education and physical activity, and a control group which received family coping classes. Forty-one (84%) of participants completed the study. At the end of 6 months, weight for all participants was maintained from baseline to completion with no significant differences between the groups. The mean fruit consumption over 6 months for the treatment group increased and was significantly greater than change in the control group (p = 0.01). This CBPR study was considered successful because weight gain was prevented.
PMCID: PMC4006294  PMID: 24405579
Weight maintenance; Healthy Eating
18.  An Update from the United States National Heart, Lung, and Blood Institute-funded Production Assistance for Cellular Therapies (PACT) Program: A Decade of Cell Therapy 
Recognizing the challenges faced by researchers and clinicians working in the field of cellular therapy, the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, established the Production Assistance for Cellular Therapies (PACT) program in 2003 and expanded it in 2010. The PACT program provides both clinical product manufacturing support that furthers the mission of NHLBI in the areas of cardiac, lung, and blood diseases and broad support of translational development across all disease areas to serve the entire cell therapy community. The program also provides access to expertise in project management, regulatory affairs, and quality assurance and control. Education initiatives include webinars, cell processing facility-hosted workshops, national workshops, and active participation and leadership within the cell therapy community through collaboration with other cell therapy organizations and academia. So far, over 650 PACT-manufactured cell therapy products have been administered in 32 clinical trials for a range of illnesses and diseases such as acute myocardial infarction, sickle cell disease, and graft-versus-host disease.
PMCID: PMC4006308  PMID: 24655892
cellular therapy; GMP; cell engineering; cell and tissue therapy
19.  Public Interest in Medical Research Participation: Differences by Volunteer Status and Study Type 
We assessed national levels of public interest in medical research participation (MRP) and factors associated with interest as a healthy volunteer; as a diagnosed volunteer; and in seven study types.
Cross-sectional, web-based survey of the US population in June 2012. Descriptive statistics estimated interest in MRP and multivariable logistic regression determined associations between respondent-level predictors and interest in MRP.
Of 2,668 respondents (response rate=61%), 41% were interested in MRP as healthy volunteers and 60% as diagnosed volunteers. Respondents with some college (OR=1.54, 1.09–2.19) or higher education (OR=1.86, 1.29–2.70) had higher adjusted odds of interest as healthy volunteers. Non-Hispanic black race (OR=0.56, 0.37–0.86) and education below high school (OR=0.57, 0.35–0.92) were associated with lower adjusted odds of interest as diagnosed volunteers. Non-Hispanic black race was associated with lower odds of interest in medication trials as diagnosed volunteers (OR=0.61, 0.40–0.93).
We found high levels of interest in MRP that contrast with low levels of prior research participation. Interest is higher in medical research involving noninvasive designs. Comparatively lower levels of interest in MRP among non-Hispanic blacks and those with less education raise concerns about disparities in future study enrollment.
PMCID: PMC4012324  PMID: 24456538
research participation; non-Hispanic black; Hispanic; drugs; devices; vaccines; clinical trial behavior; mental health; nutrition; volunteer
In vitro, C-reactive protein (CRP) impairs endothelial progenitor cell (EPC) function; however, the influence of CRP on EPCs in vivo is unclear. We determined whether EPC function is impaired in adults with elevated plasma CRP concentrations, independent of other risk factors. EPCs were harvested from 75 adults (43 males, 32 females): 25 with low CRP (< 1.0 mg/L); 25 with moderate CRP (1.0–3.0 mg/L); and 25 with high CRP (> 3.0 mg/L). The capacity of EPCs to form colonies (colony assay), migrate (Boyden chamber), release angiogenic growth factor (ELISA) and resist apoptosis (active caspase-3) was determined. There were no significant differences between the CRP groups in EPC colony formation (CFU), migration (AU) or the ability to release vascular endothelial growth factor (VEGF; pg/mL): low (13±3 CFU; 1255±100 AU; 126±24 pg/mL); moderate (11±3 CFU; 1137±85 AU; 97±14 pg/mL); and high (13±4 CFU; 1071±80 AU; 119±22 pg/mL) CRP. Staurosporine-stimulated activation of caspase-3 was also similar between the low (2.3±0.2 ng/mL), moderate (2.1±0.3 ng/mL), and high (2.2±0.2 ng/mL) CRP groups. These results indicate that elevations in plasma CRP are not associated with impaired EPC function. EPC dysfunction may not play a role in CRP-related cardiovascular risk.
PMCID: PMC4113468  PMID: 24422709
22.  Hypertrophy-Associated Polymorphisms Ascertained in a Founder Cohort Applied to Heart Failure Risk and Mortality 
A three-stage approach was undertaken using genome-wide, case-control, and case-only association studies to identify genetic variants associated with heart failure mortality. In an Amish founder population (n = 851), cardiac hypertrophy, a trait integral to the adaptive response to failure, was found to be heritable (h2 = 0.28, p = 0.0002) and GWAS revealed 21 candidate hypertrophy SNPs. In a case (n = 1,610)-control (n = 463) study in unrelated Caucasians, one of the SNPs associated with hypertrophy (rs2207418, p = 8 × 10−6), was associated with heart failure, RR = 1.85(1.25–2.73, p = 0.0019). In heart failure cases rs2207418 was associated with increased mortality, HR = 1.51(1.20–1.97, p = 0.0004). There was consistency between studies, with the GG allele being associated with increased ventricular mass (~13 g/m2) in the Amish, heart failure risk, and heart failure mortality. This SNP is in a gene desert of chromosome 20p12. Five genes are within 2.0 mbp of rs2207418 but with low LD between their SNPs and rs2207418. A region near this SNP is highly conserved in multiple vertebrates (lod score = 1,208). This conservation and the internal consistency across studies suggests that this region has biologic importance in heart failure, potentially acting as an enhancer or repressor element. rs2207418 may be useful for predicting a more progressive form of heart failure that may require aggressive therapy.
PMCID: PMC4373555  PMID: 21348951
genetics; heart failure; hypertrophy; mortality; signal transduction
23.  NIH Career Development Awards in Clinical and Translational Science Award Institutions: Distinguishing Characteristics of Top Performing Sites 
To identify and disseminate the organizational characteristics of “top performing” National Institute of Health (NIH) Clinical and Translational Science Awards (CTSA) institutions in regards to career development, using the number of new K awards received per year to rank institutions and comparing these with non-CTSA institutions.
The authors analyzed the organizational characteristics of all 61 CTSA institutions from 2006 to 2013 using the American Association of Medical Colleges Organizational Characteristics Database and K Award funding details using NIH RePORT.
Five of the “top 10 performing” institutions are in the western region, and six out of the ten are public schools. Three of the “top 10 performing” institutions receive most of their K awards through two funding mechanisms—the K08 (mentored clinical scientist research award) and K23 (mentored patient-oriented research career development awards). Notably, these three institutions lack a KL2 program.
The CTSA network of institutions is committed to developing the next generation of physician scientists in order to meet the pressing health needs of society. Educators and evaluators within this network may need to provide training to junior investigators beyond the traditional KL2 programs in order to advance their career development as physician scientists and clinical translational researchers.
PMCID: PMC4361077  PMID: 25044058
translational research; evaluation; CTSA
24.  Community Member and Faith Leader Perspectives on the Process of Building Trusting Relationships Between Communities and Researchers 
In the first phase of this research, we conducted, audio-recorded, and transcribed seven focus groups with more than 50 English- or Spanish-speaking women of childbearing age. Qualitative analysis revealed the following themes: 1) expectation that participation would involve relationships based on trust that is built over time and impacted by cultural factors; 2) perceived characteristics of research staff that would help facilitate the development of trusting relationships; 3) perceptions about the location of the visits that may affect trust; 4) perceptions of a research study and trust for the institution conducting the study may affect trust; 5) connecting the study to larger communities, including faith communities, could affect trust and willingness to participate. In the second phase of this research, we conducted, recorded, transcribed, and analyzed interviews with leaders from diverse faith communities to explore the potential for research partnerships between researchers and faith communities. In addition to confirming themes identified in focus groups, faith leaders described an openness to research partnerships between the university and faith communities and considerations for the formation of these partnerships. Faith leaders noted the importance of finding common ground with researchers, establishing and maintaining trusting relationships, and committing to open, bidirectional communication.
PMCID: PMC4358802  PMID: 24405695
25.  A Capacity Building Program to Promote CBPR Partnerships Between Academic Researchers and Community Members 
Community-based participatory research (CBPR) adds community perspectives to research and aids translational research aims. There is a need for increased capacity in CBPR but few models exist for how to support the development of community/university partnerships
Evaluate an approach to promote nascent CBPR partnerships.
Design was a mixed-methods evaluation utilizing interviews, process notes, and open and closed ended survey questions. We trained ten community scholars, matched them with prepared researchers to form seven partnerships, and supported their developing partnerships. Sequential mixed-methods analysis assessed research and partnership processes and identified integrated themes.
Four of seven partnerships were funded within 15 months; all self-reported their partnerships as successful. Themes were: 1) Motivators contributed to partnership development and resiliency; 2) Partners took on responsibilities that utilized individuals' strengths; 3) Partners grappled with communication, decision-making, and power-dynamics; and 4) Community-university infrastructure was essential to partnership development.
This program for developing nascent partnerships between academicians and community members may guide others in increasing capacity for CBPR.
PMCID: PMC4313536  PMID: 22212224
community-based participatory research; translational research

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