Concentration dependence of human and mouse aryl hydrocarbon receptor responsiveness to polychlorinated biphenyl exposures: Implications for aroclor mixtures.

1. Aryl hydrocarbon receptor (AhR) ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs), are endocrine disrupting chemicals associated with nonalcoholic fatty liver disease. This study documents the species-specific differences between mouse (high affinity mAhR) and human AhR (hAhR) activation by PCB congeners and Aroclor mixtures. 2. AhR activation by TCDD or PCBs 77, 81, 114, 114, 126, and 169 was measured using luciferase reporter constructs transfected into either Hepa1c1c7 mouse or HepG2 human liver cell lines. The EC50 values were lower in Hepa1c1c7 cells than HepG2 cells for all compounds tested except PCB 81. The results for TCDD and PCB 126 were validated in primary human and mouse hepatocytes by measuring CYP1A1 gene transcript levels. 3. Because humans are exposed to PCB mixtures, several mixtures (Aroclors 1254; 1260; and 1260 + 0.1% PCB126 each at 10 µg/ml) were then tested. Neither Aroclor 1254 nor Aroclor 1260 increased luciferase activity by the transfected AhR reporter construct. The Aroclor 1260 + 0.1% PCB 126 mixture induced mAhR-mediated transactivation, but not hAhR activation in cell lines. 4. In summary, significant concentration-dependent differences exist between human and mouse AhR activation by PCBs. Relative effect potencies differed, in some cases, from published toxic equivalency factors.

Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.

AIMS: Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. MATERIALS & METHODS: We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). RESULTS: Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40-0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. CONCLUSION: A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.

Lower visual acuity predicts worse utility values among patients with type 2 diabetes.

OBJECTIVE: We estimated the quality of life impact of vision loss in a community-based population with diabetes. DESIGN AND METHODS: We randomly surveyed 4,000 members of a large health maintenance organization with type 2 diabetes to assess quality of life using the EQ-5D instrument. Visual acuity was obtained by automated text processing of clinical notes recorded during the two years preceding subjects' surveys. Natural language processing was used to collect data from electronic medical records and to read clinical notes to determine the stage of retinopathy. Linear regression was used to model quality of life scores. RESULTS: Of the 4,000 surveys sent, approximately 55% of patients responded. Patients with > or = 20/20 acuity reported the highest mean utility (mean = 0.82), which declined as the visual angle doubled to 20/40 (mean = 0.75), and then doubled again to < or = 20/80 (mean = 0.71). Perfect utility (1.0) was reported by 28% of the sample. Only 7% of patients suffered visual impairment (< or = 20/40), and lower levels of visual acuity rarely occurred. Compared with patients with > or = 20/20 acuity, the first doubling of the visual angle (20/40) lowered utility by three points (95% confidence interval [CI], -0.05 to -0.01), and the second doubling of the visual angle (< or = 20/80) lowered utility by six points (95%CI, -0.10 to -0.02). CONCLUSIONS: This study aimed to estimate disutility associated with visual loss in patients with diabetes using a community-based sample and controlled for many characteristics associated with quality of life. We found a smaller utility decrement compared to other studies, suggesting that visual acuity's impact on the quality of life for patients with diabetes in the community setting differs from more selected populations.

A survey of factors affecting clinician acceptance of clinical decision support.

BACKGROUND: Real-time clinical decision support (CDS) integrated into clinicians' workflow has the potential to profoundly affect the cost, quality, and safety of health care delivery. Recent reports have identified a surprisingly low acceptance rate for different types of CDS. We hypothesized that factors affecting CDS system acceptance could be categorized as relating to differences in patients, physicians, CDS-type, or environmental characteristics. METHODS: We conducted a survey of all adult primary care physicians (PCPs, n = 225) within our group model Health Maintenance Organization (HMO) to identify factors that affect their acceptance of CDS. We defined clinical decision support broadly as "clinical information" that is either provided to you or accessible by you, from the clinical workstation (e.g., enhanced flow sheet displays, health maintenance reminders, alternative medication suggestions, order sets, alerts, and access to any internet-based information resources). RESULTS: 110 surveys were returned (49%). There were no differences in the age, gender, or years of service between those who returned the survey and the entire adult PCP population. Overall, clinicians stated that the CDS provided "helps them take better care of their patients" (3.6 on scale of 1:Never-5:Always), "is worth the time it takes" (3.5), and "reminds them of something they've forgotten" (3.2). There was no difference in the perceived acceptance rate of alerts based on their type (i.e., cost, safety, health maintenance). When asked about specific patient characteristics that would make the clinicians "more", "equally" or "less" likely to accept alerts: 41% stated that they were more (8% stated "less") likely to accept alerts on elderly patients (> 65 yrs); 38% were more (14% stated less) likely to accept alerts on patients with more than 5 current medications; and 38% were more (20% stated less) likely to accept alerts on patients with more than 5 chronic clinical conditions. Interestingly, 80% said they were less likely to accept alerts when they were behind schedule and 84% of clinicians admitted to being at least 20 minutes behind schedule "some", "most", or "all of the time". CONCLUSION: Even though a majority of our clinical decision support suggestions are not explicitly followed, clinicians feel they are of benefit and would be even more beneficial if they had more time available to address them.