Citations

Abstract 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.

Blood oxygen level-dependent (BOLD) MRI data of kidney, while indicative of tissue oxygenation level (Po2), is in fact influenced by multiple confounding factors, such as R2, perfusion, oxygen permeability, and hematocrit. We aim to explore the feasibility of extracting tissue Po2 from renal BOLD data. A method of two steps was proposed: first, a Monte Carlo simulation to estimate blood oxygen saturation (SHb) from BOLD signals, and second, an oxygen transit model to convert SHb to tissue Po2. The proposed method was calibrated and validated with 20 pigs (12 before and after furosemide injection) in which BOLD-derived tissue Po2 was compared with microprobe-measured values. The method was then applied to nine healthy human subjects (age: 25.7 ± 3.0 yr) in whom BOLD was performed before and after furosemide. For the 12 pigs before furosemide injection, the proposed model estimated renal tissue Po2 with errors of 2.3 ± 5.2 mmHg (5.8 ± 13.4%) in cortex and −0.1 ± 4.5 mmHg (1.7 ± 18.1%) in medulla, compared with microprobe measurements. After injection of furosemide, the estimation errors were 6.9 ± 3.9 mmHg (14.2 ± 8.4%) for cortex and 2.6 ± 4.0 mmHg (7.7 ± 11.5%) for medulla. In the human subjects, BOLD-derived medullary Po2 increased from 16.0 ± 4.9 mmHg (SHb: 31 ± 11%) at baseline to 26.2 ± 3.1 mmHg (SHb: 53 ± 6%) at 5 min after furosemide injection, while cortical Po2 did not change significantly at ∼58 mmHg (SHb: 92 ± 1%). Our proposed method, validated with a porcine model, appears promising for estimating tissue Po2 from renal BOLD MRI data in human subjects.

AbstractBackground and ObjectivesPrevious studies have established the relationship between tobacco use and pain severity among patients suffering from chronic pain. Unfortunately, many physicians feel underprepared to counsel patients on smoking cessation. The purpose of this study was to identify the attitudes, beliefs, and practices of pain medicine fellowship directors in regard to tobacco control interventions and trainee education.MethodsProgram directors of ACGME‐accredited pain medicine fellowships were surveyed via a web‐based form to assess current practices in tobacco intervention and to gauge interest in incorporating tobacco control into their current fellowship training curriculum.ResultsOf the respondents, the majority indicated that they frequently asking their patients about tobacco use and advise them to quit. In addition, most agreed that presenting tobacco control is a responsibility of pain physicians. However, few consistently provided any assistance with quitting. Finally, the majority of program directors felt that pain medicine fellowships should include tobacco control training and were interested in incorporating an educational module about smoking and pain into their training program.ConclusionsThis survey of pain medicine fellowship program directors indicates that although smoking cessation interventions are not being consistently applied in academic pain practices, there is a strong interest in doing so. Furthermore, the majority of program directors recognized the importance of incorporating tobacco control training into pain medicine fellowships. This recognition may provide an opportunity to develop a web‐based training module that could be easily incorporated into the upcoming milestones in pain medicine training.

Objective To present the first age‐stratified assessment of outcomes after holmium laser enucleation of the prostate ( HoLEP ) for the treatment of lower urinary tract symptoms resulting from prostate enlargement. Patients and Methods We retrospectively analysed and compared the morbidity, and the peri‐operative and functional outcomes of patients aged 50–59, 60–69, 70–79 and ≥80 years. Complications at 30 days were stratified using the C lavien system. Functional outcomes were assessed using the I nternational P rostate S ymptom S core ( IPSS ), maximum urinary flow rate ( Q max ), post‐void residual urine volume ( PVR ) and urinary continence. Results A total of 311 patients underwent HoLEP for obstructive voiding symptoms from A ugust 2007 to J une 2011, of whom 22 patients were aged 50–59 years, 91 were aged 60–69 years, 153 were aged 70–79 years, and 45 were aged ≥80 years. The overall morbidity rates were similar among the age groups (20, 24.4, 21.6 and 22.1% for groups 1, 2, 3 and 4, respectively), as were the incidence of significant complications ( C lavien grade ≥ III ), change in serum haemoglobin level, and length of hospital stay. Patients ≥80 years did have a longer catheterization time (3.4 days) than patients aged 50–59 years (1.68 days). By 1 year there were no significant differences in urinary continence, IPSS , Q max , or PVR among the age groups. Conclusions Overall morbidity, hospital stay, and 1‐year functional outcomes of HoLEP were similar among all age groups. This study shows that HoLEP is a safe and effective treatment for benign prostatic hyperplasia regardless of age.

Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-β-induced CCL2 upregulation. Based on these observations, we conclude that p38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.