Objectives Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality.Methods By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32 415 adults with a cancer diagnosis at Vanderbilt and 79 258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index.Results Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR.Conclusions EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data.

The regulation of protein synthesis is vital for a host of cell biological processes, but investigating roles for protein synthesis have been hindered by the inability to selectively interfere with it. To inhibit protein synthesis with spatial and temporal control, we have developed a photo-releasable anisomycin compound, N-([6-bromo-7-hydroxycoumarin-4-yl]methyloxycarbonyl)anisomycin (Bhc-Aniso), that can be removed through exposure to UV light. The area of protein synthesis inhibition can be restricted to a small light-exposed region or, potentially, the volume of two-photon excitation if a pulsed IR laser is the light source. We have tested the compound's effectiveness with an in vitro protein-translation system, CHO cells, HEK293 cells, and neurons. The photo-released anisomycin can inhibit protein synthesis in a spatially restricted manner, which will enable the specific inhibition of protein synthesis in subsets of cells with temporal and spatial precision.

Background Underrepresentation of minorities within academic surgery is an ever present problem with a profound impact on healthcare. The factors influencing surgery residents to pursue an academic career have yet to be formally investigated. We sought to elucidate these factors, with a focus on minority status. Methods A web-based questionnaire was sent to all administered to all ACGME-accredited general surgery programs in the United States. The main outcome was the decision to pursue a fully academic versus non-academic career. Multivariable logistic regression was used to identify characteristics impacting career choice. Results Of the 3,726 residents who received the survey, a total of 1,217 residents completed it – a response rate of 33%. Forty-seven percent planned to pursue non-academic careers, 35% academic careers, and 18% were undecided. There was no association between underrepresented minority status and academic career choice (Odds Ratio = 1.0, 95% Confidence Interval 0.6 – 1.6). Among all residents, research during training (OR=4.0, 95% CI 2.7-5.9), mentorship (OR=2.1, 95% CI 1.6-2.9), and attending a residency program requiring research (OR=2.3, 95% CI 1.5-3.4) were factors associated with choosing an academic career. When the analysis was performed among only senior residents (i.e., 4th and 5th year residents), a debt burden >$150,000 was associated with choosing a non-academic career (OR=0.4, 95% CI 0.1-0.9). Conclusions Underrepresented minority status is not associated with career choice. Intentional recruitment of minorities into research-oriented training programs, increased mentorship and research support among current minority residents, and improved financial options for minorities may increase the number choosing an academic surgical career.

Von Hippel-Lindau disease is a heritable syndrome that confers an increased risk of developing various benign and malignant tumors to those with a germline mutation of the tumor suppressor gene. We present a case of a male patient who initially presented at age 9 with headaches, fevers, and fatigue. He was found to have a left pheochromocytoma which was successfully managed with open total adrenalectomy. He presented again at age 18 with a second pheochromocytoma in the right adrenal gland. DNA analysis revealed a de novo Val84Leu mutation in the Von Hippel-Lindau gene, not seen in either parent. The challenge presented was that of balancing the obvious benefits of cortical- sparing adrenalectomy with the risk of tumor recurrence in spared tissue. Ultimately, management consisted of a robot-assisted laparoscopic partial right adrenalectomy with successful preservation of adrenocortical function.

Background In this study, we examine the relationship between level of education of patients and five year mortality following major lower extremity amputation. Methods We retrospectively reviewed the records of all patients who underwent above- or below-knee amputation at the Nashville VA by the vascular surgery service between January 2000 and August 2006. Formal level of education of the study patients was recorded. Outcomes were compared between those patients who had completed high school and those who had not. Bivariate analysis using chi-square and student's t-test, and multivariable logistic regression were performed. Results Five year mortality for patients who completed high school was lower than those who had not completed high school (62.6% vs. 84.3%; p = 0.001), even after adjusting for important clinical factors (Odds Ratio of death = 0.377, 95% CI 0.164 – 0.868 p=0.022). Conclusions Patients with less education have increased long term mortality following lower extremity amputation.

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