Karin Esposito

Defining translational research: Implications for training

Because translational research is not clearly defined, developers of translational research programs are struggling to articulate specific program objectives, delineate the knowledge and skills (competencies) that trainees are expected to develop, create an appropriate curriculum, and track outcomes to assess whether program objectives and competency requirements are being met. Members of the Evaluation Committee of the Association for Clinical Research Training (ACRT) reviewed current definitions of translational research and proposed an operational definition to use in the educational framework. In this article, the authors posit that translational research fosters the multidirectional and multidisciplinary integration of basic research, patient-oriented research, and population-based research, with the long-term aim of improving the health of the public. The authors argue that the approach to designing and evaluating the success of translational training programs must therefore be flexible enough to accommodate the needs of individual institutions and individual trainees within the institutions but that it must also be rigorous enough to document that the program is meeting its short-, intermediate-, and long-term objectives and that its trainees are meeting preestablished competency requirements. A logic model is proposed for the evaluation of translational research programs.

Leptin Replacement Improves Cognitive Development

Background Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown. Objective To evaluate the effect of leptin on neurocognitive development. Methodology A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children. Principal Findings Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia. Conclusions We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system. Trial Registration ClinicalTrials.gov NCT00659828

Evaluation of dream content in combat-related PTSD

Nightmares that replicate traumatic events are among the criteria that define posttraumatic stress disorder (PTSD); however, there has been limited systematic assessment of the content of dreams in PTSD. A PTSD dream rating instrument was developed to ope rationalize features attributed to dreams associated with combat-related PTSD that incorporated dimensions from the dream content analysis literature, and its reliability was assessed. Then the instrument was used to characterize dream reports in 18 Vietnam combat veterans diagnosed with PTSD. Approximately half of the groups target dreams contained features characteristic of combat, and all but 3 (17%) were moderately to highly threatening. Fifty-three percent were set at least partially in the present and 79% contained distorted elements. We therefore conclude that target dreams of combat veterans with PTSD vary with regard to replication of trauma and elements normally associated with dreaming, but typically are threatening.

Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients

Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptins effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m(2); female, 42 yr old, BMI 25.1 kg/m(2); female, 46 yr old, BMI 31.7 kg/m(2)) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2-4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 +/- 3.27 vs. 8.16 +/- 2.77 mg.kg(-1).min(-1), P = 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) = 0.57 and P = 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity.

Predictors of response in depression.

Conflicting or sparse data on predictors of treatment response in depression have resulted in lack of clear guidelines in choosing antidepressant treatment. Critical to treatment outcome are accurate diagnosis and adequate treatment. Other data easy to obtain, such as age, gender, and marital status, have failed to be consistent predictors; more elaborate studies, such as receptor analysis or neuroimaging, are not yet accessible to most clinicians or economically feasible; however, they offer hope for the future, when more biologically based diagnostic distinctions may come to guide treatment choices.

Phosphodiesterase genes and antidepressant treatment response: A review

Depression results in a tremendous burden to individuals suffering from the disorder and to the global health economy. Available pharmacologic treatments for depression target monoamine levels and monoamine receptors. However, delayed onset of effect, partial or inadequate treatment response, and side-effects are significant limitations of current therapies. The search for a better understanding of mechanisms of depression and for new treatment targets has turned attention to intracellular mediators. Phosphodiesterases (PDEs) are enzymes that break down the intracellular second messenger mononucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Recent data from animal and human studies indicate that PDEs may play a role in depression and in related stress conditions. PDE genes have been linked directly to depression and to other genes associated with psychiatric disorders.

Elevated stress-hemoconcentration in major depression is normalized by antidepressant treatment: secondary analysis from a randomized, double-blind clinical trial and relevance to cardiovascular disease risk.

Background Major depressive disorder (MDD) is an independent risk factor for cardiovascular disease (CVD); the presence of MDD symptoms in patients with CVD is associated with a higher incidence of cardiac complications following acute myocardial infarction (MI). Stress-hemoconcentration, a result of psychological stress that might be a risk factor for the pathogenesis of CVD, has been studied in stress-challenge paradigms but has not been systematically studied in MDD. Methods Secondary analysis of stress hemoconcentration was performed on data from controls and subjects with mild to moderate MDD participating in an ongoing pharmacogenetic study of antidepressant treatment response to desipramine or fluoxetine. Hematologic and hemorheologic measures of stress-hemoconcentration included blood cell counts, hematocrit, hemoglobin, total serum protein, and albumin, and whole blood viscosity. Findings Subjects with mild to moderate MDD had significantly increased hemorheologic measures of stress-hemoconcentration and blood viscosity when compared to controls; these measures were correlated with depression severity. Measures of stress-hemoconcentration improved significantly after 8 weeks of antidepressant treatment. Improvements in white blood cell count, red blood cell measures and plasma volume were correlated with decreased severity of depression. Conclusions Our secondary data analyses support that stress-hemoconcentration, possibly caused by decrements in plasma volume during psychological stress, is present in Mexican-American subjects with mild to moderate MDD at non-challenged baseline conditions. We also found that after antidepressant treatment hemorheologic measures of stress-hemoconcentration are improved and are correlated with improvement of depressive symptoms. These findings suggest that antidepressant treatment may have a positive impact in CVD by ameliorating increased blood viscosity. Physicians should be aware of the potential impact of measures of hemoconcentration and consider the implications for cardiovascular risk in depressed patients.

Implementing an Entrustable Professional Activities Framework in Undergraduate Medical Education: Early Lessons From the Aamc Core Entrustable Professional Activities for Entering Residency Pilot

In 2014, the Association of American Medical Colleges (AAMC) published a list of 13 Core Entrustable Professional Activities for Entering Residency (Core EPAs) that medical school graduates might be expected to perform, without direct supervision, on the first day of residency. Soon after, the AAMC commissioned a five-year pilot with 10 medical schools across the United States, seeking to implement the Core EPA framework to improve the transition from undergraduate to graduate medical education. In this article, the pilot team presents the organizational structure and early results of collaborative efforts to provide guidance to other institutions planning to implement the Core EPA framework. They describe the aims, timeline, and organization of the pilot as well as findings to date regarding the concepts of entrustment, assessment, curriculum development, and faculty development. On the basis of their experiences over the first two years of the pilot, the authors offer a set of guiding principles for institutions intending to implement the Core EPA framework. They also discuss the impact of the pilot, its limitations, and next steps, as well as how the pilot team is engaging the broader medical education community. They encourage ongoing communication across institutions to capitalize on the expertise of educators to tackle challenges related to the implementation of this novel approach and to generate common national standards for entrustment. The Core EPA pilot aims to better prepare medical school graduates for their professional duties at the beginning of residency with the ultimate goal of improving patient care.

Genethics 2.0: Phenotypes, Genotypes, and the Challenge of Databases Generated by Personal Genome Testing

Page, G. P., George, V., Go, R. C., Page, P. Z., and Allison, D. B. 2003. “Are we there yet?”: Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits. American Journal of Human Genetics 73(4): 711–719. Pearson, T. A., and Manolio, T. A. 2008. How to interpret a genomewide association study. Journal of the American Medical Association 299(11): 1335.

Socially Accountable Medical Education: An Innovative Approach at Florida International University Herbert Wertheim College of Medicine

Problem Despite medical advances, health disparities persist, resulting in medicine’s renewed emphasis on the social determinants of health and calls for reform in medical education. Approach The Green Family Foundation Neighborhood Health Education Learning Program (NeighborhoodHELP) at Herbert Wertheim College of Medicine provides a platform for the school’s community-focused mission. NeighborhoodHELP emphasizes social accountability and interprofessional education while providing evidence-based, patient- and household-centered care. NeighborhoodHELP is a required, longitudinal service–learning outreach program in which each medical student is assigned a household in a medically underserved community. Students, teamed with learners from other professional schools, provide social and clinical services to their household for three years. Here the authors describe the program’s engagement approach, logistics, and educational goals and structure. Outcomes During the first six years of NeighborhoodHELP (September 2010–August 2016), 1,470 interprofessional students conducted 7,452 visits to 848 households with, collectively, 2,252 members. From August 2012, when mobile health centers were added to the program, through August 2016, students saw a total of 1,021 household members through 7,207 mobile health center visits. Throughout this time, households received a variety of free health and social services (e.g., legal aid, tutoring). Compared with peers from other schools, graduating medical students reported more experience with clinical interprofessional education and health disparities. Surveyed residency program directors rated graduates highly for their cultural sensitivity, teamwork, and accountability. Next Steps Faculty and administrators are focusing on social accountability curriculum integration, systems for assessing and tracking relevant educational and household outcomes, and policy analysis.