As part of the Clinical and Translational Science Institute pre-doctoral TL1 training program at the Pennsylvania State University, a multidisciplinary team of pre-doctoral trainees representing the Chemistry, Neurosurgery, Nutritional Sciences, and Public Health Sciences departments were introduced to the NIH-sponsored Informatics for Integrating Biology and the Bedside (i2b2) database to test the following student-generated hypothesis: children with iron deficiency anemia (IDA) are at increased risk of attention deficit-hyperactivity disorder (ADHD). Children aged 4–12 and 4–17 were categorized into IDA and control groups. De-identified medical records from the Penn State Milton S. Hershey Medical Center (HMC) and the Virginia Commonwealth University Medical Center (VCUMC) were used for the analysis. Overall, ADHD prevalence at each institution was lower than 2011 state estimates. There was a significant association between IDA and ADHD in the 4–17 age group for all children (OR: 1.902 [95% CI: 1.363–2.656]), Caucasian children (OR: 1.802 [95% CI: 1.133–2.864]), and African-American children (OR: 1.865 [95% CI: 1.152–3.021]). Clinical and Translational Science Award (CTSA) infrastructure is particularly useful for trainees to answer de novo scientific questions with minimal additional training and technical expertise. Moreover, projects can be expanded by collaborating within the CTSA network.
Serum levels of hepcidin-25, a peptide hormone that reduces blood iron content, are elevated when patients with cystic fibrosis (CF) develop pulmonary exacerbation (PEx). Because hepcidin-25 is unavailable as a clinical laboratory test, we questioned whether a onetime serum iron level was associated with the subsequent number of days until PEx, as defined by the need to receive systemic antibiotics (ABX) for health deterioration.
Clinical, biochemical, and microbiological parameters were simultaneously checked in 54 adults with CF. Charts were reviewed to determine when they first experienced a PEx after these parameters were assessed. Time to ABX was compared in subgroups with and without specific attributes. Multivariate linear regression was used to identify parameters that significantly explained variation in time to ABX.
In univariate analyses, time to ABX was significantly shorter in subjects with Aspergillus-positive sputum cultures and CF-related diabetes (CFRD). Multivariate linear regression models demonstrated that shorter time to ABX was associated with younger age, lower serum iron level, and Aspergillus sputum culture positivity.
Serum iron, age, and Aspergillus sputum culture positivity are factors associated with shorter time to subsequent PEx in CF adults.
cystic fibrosis; exacerbation; iron; age; Aspergillus
This paper is the third in a five-part series on the clinical and translation science educational pipeline, and it focuses on strategies for enhancing graduate research education to improve skills for interdisciplinary team science. Although some of the most cutting edge science takes place at the borders between disciplines, it is widely perceived that advancements in clinical and translational science are hindered by the “siloed” efforts of researchers who are comfortable working in their separate domains, and reluctant to stray from their own discipline when conducting research. Without appropriate preparation for career success as members and leaders of interdisciplinary teams, talented scientists may choose to remain siloed or to leave careers in clinical and translational science all together, weakening the pipeline and depleting the future biomedical research workforce. To address this threat, it is critical to begin at what is perhaps the most formative moment for academics: graduate training. This paper focuses on designs for graduate education, and contrasts the methods and outcomes from traditional educational approaches with those skills perceived as essential for the workforce of the future, including the capacity for research collaboration that crosses disciplinary boundaries.
Clinical and translational research; education; pipeline; workforce; career development
Under-recruitment into clinical trials is a common and costly problem that undermines medical research. To better understand barriers to recruitment into clinical trials in our region, we conducted a multi-method descriptive study. We initially surveyed investigators who had conducted or were currently conducting studies that utilized an adult or pediatric clinical research center (n = 92). We then conducted focus groups and key informant interviews with investigators, coordinators, and other stakeholders in clinical and translational research (n = 32 individuals). Only 41% of respondents reported that they had or were successfully meeting recruitment goals and 24% of the closed studies actually met their targeted recruitment goals. Varied reasons were identified for poor recruitment but there was not a single investigator or study “phenotype” that predicted enrollment outcome. Investigators commonly recruited from their own practice or clinic, and 29% used a manual electronic medical record search. The majority of investigators would utilize a service that provides recruitment advice, including feasibility assessment and consultation, easier access to the electronic health record and assistance with institutional review board and other regulatory requirements. Our findings suggest potential benefits providing assistance across a range of services that can be individualized to the varied needs of clinical and translational investigators.
Critical interdisciplinary research skills include effective communication with diverse disciplines and cultivating collaborative relationships. Acquiring these skills during graduate education may foster future interdisciplinary research quality and productivity.
The project aim was to develop and evaluate an interactive Toolbox workshop approach within an inter-professional graduate level course to enhance student learning and skill in interdisciplinary research. We sought to examine the student experience of integrating the Toolbox workshop in modular format over the duration of a 14 week course.
The Toolbox Health Sciences Instrument includes six modules that were introduced in a 110-minute dialogue session during the first class and then integrated into the course in a series of six individual workshops in three phases over the course of the semester.
Seventeen students participated; the majority were nursing students. Three measures were used to assess project outcomes: pre-post intervention Toolbox survey, competency self-assessment and a post-course survey. All measures indicated the objectives were met by a change in survey responses, improved competencies and favorable experience of the Toolbox modular intervention.
Our experience indicates that incorporating this Toolbox modular approach into research curricula can enhance individual level scientific capacity, future interdisciplinary research project success, and ultimately impact on practice and policy.
Competencies in Master of Science Clinical Research programs are becoming increasingly common. However, students and programs can only benefit fully from competency-based education if students’ competence is formally assessed. Prior to a summative assessment, students must have at least one formative, formal assessment to be sure they are developing competence appropriate for their stage of training. This paper describes the Comprehensive Competency Review (CCR), a milestone for MS students in Clinical Research at the University of Pittsburgh’s Institute for Clinical Research Education. The CCR involves metacognitive reflection of the student’s learning as a whole, written evidence of each competency, a narrative explaining the choice of evidence for demonstrating competencies, and a meeting in which two faculty members review the evidence and solicit further oral evidence of competence. CCRs allow for individualized feedback at the midpoint in degree programs, providing students with confidence that they will have the means and strategies to develop competence in all areas by the summative assessment of competence at their thesis defense. CCRs have also provided programmatic insight on the need for curricular revisions and additions. These benefits outweigh the time cost on the part of students and faculty in the CCR process.
There is growing appreciation that process improvement holds promise for improving the quality and efficiency across the translational research continuum but frameworks for such programs are not often described. The purpose of this paper is to present a framework and case examples of a Research Process Improvement Program implemented at Tufts CTSI. To promote research process improvement, we developed online training seminars, workshops, and in-person consultation models to describe core process improvement principles and methods, demonstrate the use of improvement tools, and illustrate the application of these methods in case examples. We implemented these methods, as well as relational coordination theory, with junior researchers, pilot funding awardees, our CTRC, and CTSI resource and service providers. The program focuses on capacity building to address common process problems and quality gaps that threaten the efficient, timely and successful completion of clinical and translational studies.
Achieving timely accrual into clinical research studies remains a challenge for clinical translational research. We developed an evaluation measure, the Accrual Index (AI), normalized for sample size and study duration, using data from the protocol and study management databases. We applied the AI retrospectively and prospectively to assess its utility.
Accrual Target, Predicted Time to Accrual Completion (PTAC), evaluable subjects, dates of recruitment initiation, analysis and completion were defined. AI is (% Accrual Target accrued / % PTAC elapsed). Changes to recruitment practices were described, and data extracted from study management databases.
December 2014 (or final) AI was analyzed for 101 studies initiating recruitment from 2007-2014. Median AI was ≥1 for protocols initiating recruitment in 2011, 2013 and 2014. The AI varied widely for studies pre-2013. Studies with AI >4 utilized convenience samples for recruitment. Data-justified PTAC was refined in in 2013-14 after which the AI range narrowed. Protocol characteristics were not associated with study AI.
Protocol AI reflects the relative agreement between accrual feasibility assessment (PTAC), and accrual performance, and is affected by recruitment practices. The AI may be useful in, managing accountability, modeling accrual, allocating recruitment resources and testing innovations in recruitment practices.
The complex, dynamic nature of health systems requires dissemination, implementation and improvement (DII) sciences to effectively translate emerging knowledge into practice. Although they hold great promise for informing multi-sector policies and system-level changes, these methods are often not strategically used by public health.
Objectives and Methods
More than 120 stakeholders from Southern California, including the community, federal and local government, university, and health services were convened to identify key priorities and opportunities for public health departments and Clinical and Translational Science Awards programs (CTSAs) to advance DII sciences in population health.
Participants identified challenges (mismatch of practice realities with narrowly-focused research questions; lack of iterative learning) and solutions (using methods that fit the dynamic nature of the real world; aligning theories of change across sectors) for applying DII science research to public health problems. Pragmatic steps that public health and CTSAs can take to facilitate DII science research include: employing appropriate study designs; training scientists and practicing professionals in these methods; securing resources to advance this work; and supporting team science to solve complex-systems issues.
Public health and CTSAs represent a unique model of practice for advancing DII research in population health. The partnership can inform policy and program development in local communities.
population health; public health strategies; translational research; community engagement; dissemination; implementation; improvement sciences
Research projects in translational science are increasingly complex and require interdisciplinary collaborations. In the context of training translational researchers, this suggests that multiple mentors may be needed in different content areas. This study explored mentoring structure as it relates to perceived mentoring effectiveness and other characteristics of masters-level trainees in clinical-translational research training programs.
A cross-sectional online survey of recent graduates of clinical research master’s program was conducted. Of 73 surveys distributed, 56.2% (n=41) complete responses were analyzed. Trainees were overwhelmingly positive about participation in their master’s programs and the impact it had on their professional development. Overall the majority (≥75%) of trainees perceived they had effective mentoring in terms of developing skills needed for conducting clinical-translational research. Fewer trainees perceived effective mentoring in career development and work-life balance. In all 15 areas of mentoring effectiveness assessed, higher rates of perceived mentor effectiveness was seen among trainees with ≥2 mentors compared to those with solo mentoring. In addition, trainees with ≥2 mentors perceived having effective mentoring in more mentoring aspects (median 14.0; IQR:12.0–15.0) than trainees with solo mentoring (10.5; IQR:8.0–14.5).
Results from this survey suggest having ≥2 mentors may be beneficial in fulfilling trainee expectations for mentoring in clinical-translational training.
Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long-standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with five-year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett's esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett's esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review article, we critically examined the current animal models of Barrett's esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett's carcinogenesis.
Barrett's Esophagus; Esophageal Adenocarcinoma; animal models; surgical model; genetic model
This article describes how a new regional campus of an academic health center engaged in a community-based participatory research (CBPR) process to set a community-driven research agenda to address health disparities. The campus is situated among growing Marshallese and Hispanic populations that face significant health disparities. In 2013, with support from the Translational Research Institute, the University of Arkansas for Medical Sciences Northwest began building its research capacity in the region with the goal of developing a community-driven research agenda for the campus. While many researchers engage in some form of community-engaged research, using a CBPR process to set the research agenda for an entire campus is unique. Utilizing multiple levels of engagement, three research areas were chosen by the community: 1) chronic disease management and prevention; 2) obesity and physical activity; and 3) access to culturally appropriate healthcare. In only 18 months, the CBPR collaboration had dramatic results. Ten grants and five scholarly articles were collaboratively written and 25 community publications and presentations were disseminated. Nine research projects and health programs were initiated. In addition, many interprofessional educational and service learning objectives were aligned with the community-driven agenda resulting in practical action to address the needs identified.
Recent developments in the study of health and social networks have focused on linkages between health outcomes and naturally-occurring social relations, such as friendship or kinship. Based on findings in this area, a new generation of health behavior intervention programs have been implemented that rely on the formation of new social relations among program participants. However, little is known about the qualities of these de novo social relations. We examined the social networks of 59 participants within a randomized controlled trial of an intervention designed to prevent excessive gestational weight gain. We employed exponential random graph modeling techniques to analyze supportive relationships formed between participants in the intervention arm, to detect unique effects of program participation on the likelihood of forming ties. Program participation had a positive effect on the likelihood of forming supportive social relations, however, in this particular timeframe we did not detect any additional effect of such relations on the health behaviors or outcomes of interest. Our findings raise two critical questions: do short-term group-level programs reliably lead to the formation of new social relations among participants; and do these relations have a unique effect on health outcomes relative to standard methods of health behavior intervention?
Social networks; behavior; health intervention
Practice-Based Research Networks (PBRNs) promote the conduct of research in real-world settings by engaging primary care clinicians as champion research collaborators. Card studies are brief surveys administered to patients or clinicians at the point of care. The objective of this paper is to describe the design and evaluation of a card study methodology that the WWAMI region Practice and Research Network (WPRN) used to develop research partnerships across multiple member sites.
We used a collaborative model to develop, implement and disseminate the results of a network-wide card study to assess patient preferences for weight loss in primary care. After the card study data collection was completed, we conducted individual and focus group interviews and a brief survey of participating practice champions.
Increased research engagement and personal and professional development were the primary motivators for participating in the development of the card study. Increasing research activity at practices and learning information about patients were motivators for implementing the study. Their participation resulted in champions reporting increased confidence in collaborating on research projects as well as the development of new clinical services for patients.
This collaborative model positively influenced research capacity in the WPRN and may be a useful strategy for helping PBRNs conduct translational research.
Radial artery catheterization has become a preferred route over femoral artery catheterization, in order to monitor the blood pressure of hemodynamically unstable patients or for repeated sampling of arterial blood gases. While the incidence of catheter-related infection is lower in the radial artery than the femoral artery, infection remains a major issue that requires attention. In this review of the literature, we discuss infectious complications of radial artery catheterization, with a focus on various risk factors and establishing the most common causative agents. We also critically review the role of the innate immune system involving Toll-like receptors (TLRs) in host-defense, with the goal of establishing a common pathway used by the innate immune system via TLRs to combat the pathogens that most commonly cause infection in radial artery catheterization. If this pathway can be therapeutically manipulated to preemptively attack pathogenic agents, immunomodulation may be an option in reducing the incidence of infection in this procedure.
Arterial catheterization; Innate immunity; Radial artery; Toll-like receptors
lung function; sensitizers; biological monitoring; respiratory; health surveillance
Hypoplastic left heart syndrome (HLHS) is a heterogeneous, lethal combination of congenital malformations characterized by severe underdevelopment of left heart structures, resulting in a univentricular circulation. The genetic determinants of this disorder are largely unknown. Evidence of copy number variants (CNVs) contributing to the genetic etiology of HLHS and other congenital heart defects has been mounting. However, the functional effects of such CNVs have not been examined, particularly in cases where the variant of interest is found in only a single patient.
METHODS AND RESULTS
Whole-genome SNP microarrays were employed to detect CNVs in two patient cohorts (N = 70 total) predominantly diagnosed with some form of nonsyndromic HLHS. We discovered 16 rare or private variants adjacent to or overlapping 20 genes associated with cardiovascular or premature lethality phenotypes in mouse knockout models. We evaluated the impact of selected variants on the expression of nine of these genes through quantitative PCR on cDNA derived from patient heart tissue. Four genes displayed significantly altered expression in patients with an overlapping or proximal CNV verses patients without such CNVs.
Rare and private genomic imbalances perturb transcription of genes that potentially affect cardiogenesis in a subset of nonsyndromic HLHS patients.
Epigenomic processes are believed to play a pivotal role for the effect of environmental exposures in early life to modify disease risk throughout the lifespan. Offspring of women with hypertensive complications of pregnancy (HTNPREG) have an increased risk of developing systemic and pulmonary vascular dysfunction in adulthood. In this preliminary report, we sought to determine whether epigenetic modifications of genes involved in the regulation of vascular function were present in HTNPREG offspring. We contrasted DNA methylation and gene expression patterns of peripheral blood mononuclear cells obtained from young male offspring of HTNPREG (n=5) to those of normotensive controls (n=19). In HTNPREG offspring we identified six differentially methylated regions (DMRs) including three genes (SMOC2, ARID1B and CTRHC1) relevant to vascular function. The transcriptional activity of ARID1B and CTRCH1 was inversely related to methylation status. HTNPREG offspring had higher systolic pulmonary artery pressure (sPPA) vs. controls. Our findings demonstrate that epigenetic marks are altered in offspring of HTNPREG with a modest elevation of sPPA and introduce novel epigenomic targets for further study. On the basis of these findings we speculate that epigenomic mechanisms may be involved in mediating the effect of HTNPREG to raise the risk of vascular disease later in life.
epigenetics; preeclampsia; gestational hypertension; developmental programming
Pain is a hallmark of almost all bodily ailments and can be modulated by agents, including analgesics and anesthetics that suppress pain signals in the central nervous system. Defects in the modulatory systems, including the endogenous pain-inhibitory pathways, are a major factor in the initiation and chronicity of pain. Thus, pain modulation is particularly applicable to the practice of medicine. This review summarizes the existing literature on pain modulation. Here, we critically reviewed the literature from PubMed on pain modulation published primarily within last 5 years in high impact journals. Specifically, we have discussed important anatomical landmarks of pain modulation and outlined the endogenous networks and underlying mechanisms of clinically relevant pain modulatory methods. The Gate Control Theory is briefly presented with discussion on the capacity of pain modulation to cause both hyper- and hypoalgesia. An emphasis has been given to highlight key areas in pain research that, because of unanswered questions or therapeutic potential, merit additional scientific scrutiny. The information presented in this article would be helpful in developing novel therapies, metrics, and interventions for improved patient management.
Pain Modulation; Gate control theory; Opioids; Inhibitory amino acids; Cannabinoids; Electroanalgesia; Periaqueductal Gray; Rostral Ventromedial Medulla
To develop the next generation of translational investigators, New York University School of Medicine (NYUSOM) and the NYU-NYC Health and Hospitals Corporation Clinical and Translational Science Institute (NYU-HHC CTSI) developed the Masters of Science in Clinical Investigation dual-degree (MD/MSCI) program. This five-year program dedicates one year to coursework and biomedical research, followed by a medical school/research overlap year, to prepare students for academic research careers. This article details the MD/MSCI program's curriculum and approach to mentorship, describes the research/professional interests of students, and reports student productivity. In the first four years of the program (2010-2014) 20 students were matriculated; 7 (35%) were women, and 12 (60%) research projects were in surgical specialties. To date, 14 students have applied to residency, and half pursued surgical residency programs. Our students have produced 68 accepted abstracts, 15 abstracts in submission, 38 accepted papers and 24 papers in submission. Despite the time-limited nature of this program, additional training in research design and implementation has promoted a high level of productivity. We conclude that dual-degree training in medicine and translational research is feasible for medical students and allows for meaningful participation in valuable projects. Follow-up is warranted to evaluate the academic trajectory of these students.
This article reports core competencies for dissemination and implementation (D&I) grant application writing and provides tips for writing a successful proposal.
Two related phases were used to collect the data: a card sorting process among D&I researchers and an expert review among a smaller set of researchers. Card sorting was completed by 123 respondents. In the second phase, a series of grant application writing tips were developed based on the combined 170 years of grant review experience of the writing team.
The card sorting resulted in 12 core competencies for D&I grant application writing that covered the main sections in a grant application to the US National Institutes of Health: a) specific aims that provide clear rationale, objectives, and an overview of the research plan; significance that frames and justifies the importance of a D&I question; c) innovation that articulates novel products and new knowledge; and d) approach that uses a relevant D&I model, addresses measurement and the D&I context, and includes an analysis plan well-tied to the aims and measures.
Writing a successful D&I grant application is a skill that can be learned with experience and attention to the core competencies articulated in this article.
dissemination and implementation research; grant writing; research; grant review; translational research
The contributions of Academic Medical Centers (AMCs) to biomedical innovation have been difficult to measure because of the challenges involved in tracing knowledge flows from their origin to their uses.
The authors examined patent citation linkages between AMC research funded by the National Institutes of Health (NIH) and patents. In prospective analyses, they examine the extent to which articles resulting from NIH grants to AMCs awarded between 1990 and 1995 were cited in drug and medical patents. The authors then examine the extent to which these patents are associated with marketed drugs. In retrospective analyses, they examine the share of drugs approved between 2000 and 2009 that have citation links to NIH-funded AMC research.
The prospective analyses show over a third of AMC grants resulted in publications that were cited in patents. Most the patents are drug and biotechnology patents, and are assigned to private firms. Patents citing NIH-funded AMC publications were associated with 106 new FDA approved drugs, half of which are new molecular entities and a quarter of which are priority NMEs. The retrospective analyses showed that about half of the new molecular entities approved over the 2000–2009 period had citations links to NIH-funded AMC research.
There are strong links between articles from NIH-funded AMC research and private sector medical patenting, including drugs. More research is needed to better understand the types of links the citations represent and their implications for public policy.
To help maximize the real-world applicability of available interventions in clinical and community healthcare practice, there has been greater emphasis over the last two decades on engaging local communities in health-related research. While there have been numerous successful community-academic partnered collaborations, there continues to be a need to articulate the common barriers experienced during the evolution of these partnerships, and to provide a roadmap for best practices that engage health care providers, patients, families, caregivers, community leaders, healthcare systems, public agencies and academic medical centers. To this end, this article presents a summary of a forum discussion from the 2014 Southern California Dissemination, Implementation and Improvement (DII) Science Symposium, sponsored by the University of California Los Angeles (UCLA) Clinical Translational Science Institute (CTSI), University of Southern California (USC) CTSI, and Kaiser Permanente. During this forum, a diverse group of individuals representing multiple constituencies identified four key barriers to success in community-partnered participatory research (CPPR) and discussed consensus recommendations to enhance the development, implementation, and dissemination of community health-related research. In addition, this group identified several ways in which the over 60 NIH funded Clinical and Translational Science Institutes across the country could engage communities and researchers to advance DII science.
community-partnered participatory research; community-based participatory research; community engagement; translational research; implementation science
Much of Dissemination, Implementation and Improvement (DII) science is conducted by social scientists, health care practitioners, and biomedical researchers. While each of these groups has its own venues for sharing methods and findings, forums that bring together the diverse DII science workforce provide important opportunities for cross-disciplinary collaboration and learning. In particular, such forums are uniquely positioned to foster the sharing of three important components of research. First: they allow the sharing of conceptual frameworks for DII science that focus on the use and spread of innovations. Second: they provide an opportunity to share strategies for initiating and governing DII research, including approaches for eliciting and incorporating the research priorities of patients, study participants, and health care practitioners and decision-makers. Third: they allow the sharing of outcome measures well-suited to the goals of DII science, thereby helping to validate these outcomes in diverse contexts, improving the comparability of findings across settings, and elevating the study of the implementation process itself.
Dissemination; Implementation; Improvement; Outcomes; Collaboration; Research; Diffusion; Framework; Governance; Workforce