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Cooper A.L.,Brown University | Trivedi A.N.,Brown University | Trivedi A.N.,Research Enhancement Award Program
New England Journal of Medicine | Year: 2012

BACKGROUND: Because Medicare Advantage plans must pay for covered services, they may design insurance benefits to appeal to healthier beneficiaries. METHODS:We identified 11 Medicare Advantage plans that offered new fitness-membership benefits in 2004 or 2005 and matched these plans to 11 Medicare Advantage control plans that did not offer coverage for fitness memberships. Using a difference-in- differences approach, we compared the self-reported health status of persons who enrolled after the fitness benefit was added to the plan with the self-reported health status of persons entering the same plan before the fitness benefit was offered. RESULTS:The proportion of enrollees reporting excellent or very good health was 6.1 percentage points higher (95% confidence interval [CI], 2.6 to 9.7) among the 755 new enrollees in plans that added fitness benefits than among the 4097 earlier enrollees. The proportion of new enrollees reporting activity limitation was 10.4 percentage points lower (95% CI, 6.6 to 14.3) and the proportion reporting difficulty walking was 8.1 percentage points lower (95% CI, 4.4 to 11.7), as compared with earlier enrollees. Within control plans, the differences between the 1154 new enrollees and the 3910 earlier enrollees were 1.5 percentage points or less for each measure. The adjusted differences between the fitness-benefit plans and the control plans were 4.7 percentage points higher for general health (95% CI, 0.2 to 9.2), 9.2 percentage points lower for activity limitation (95% CI, 5.1 to 13.3), and 7.4 percentage points lower for difficulty walking (95% CI, 4.5 to 10.4). These differences persisted at 2 years for activity limitation and difficulty walking. CONCLUSIONS: Medicare Advantage plans offering coverage for fitness memberships may attract and retain a healthier subgroup of the Medicare population. (Funded by the National Institute on Aging.) Copyright © 2012 Massachusetts Medical Society.

Ioannou G.N.,Research Enhancement Award Program | Haigh W.G.,Research Enhancement Award Program | Thorning D.,University of Washington | Savard C.,Research Enhancement Award Program
Journal of Lipid Research | Year: 2013

We sought to determine whether hepatic cholesterol crystals are present in patients or mice with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH), and whether their presence or distribution correlates with the presence of NASH as compared with simple steatosis. We identified, by filipin staining, free cholesterol within hepatocyte lipid droplets in patients with NASH and in C57BL/6J mice that developed NASH following a highfat high-cholesterol diet. Under polarized light these lipid droplets exhibited strong birefringence suggesting that some of the cholesterol was present in the form of crystals. Activated Kupffer cells aggregated around dead hepatocytes that included strongly birefringent cholesterol crystals, forming "crown-like structures" similar to those recently described in infl amed visceral adipose tissue. These Kupffer cells appeared to process the lipid of dead hepatocytes turning it into activated lipid-laden "foam cells" with numerous small cholesterol-containing droplets. In contrast, hepatocyte lipid droplets in patients and mice with simple steatosis did not exhibit cholesterol crystals and their Kupffer cells did not form crown-like structures or transform into foam cells. Our results suggest that cholesterol crystallization within hepatocyte lipid droplets and aggregation and activation of Kupffer cells in crown-like structures around such droplets represent an important, novel mechanism for progression of simple steatosis to NASH. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.

Berry K.,University of Washington | Ioannou G.N.,University of Washington | Ioannou G.N.,Research Enhancement Award Program
American Journal of Transplantation | Year: 2012

We aimed to estimate the survival benefit derived from transplantation in patients with stage II hepatocellular carcinoma (HCC) and Child's A cirrhosis, defined as the mean lifetime with transplantation minus the mean lifetime with treatments other than transplantation. We calculated the posttransplantation survival of all adult, first-time, deceased-donor, liver transplant recipients in the United States since the introduction of the Model for End-Stage Liver Disease based priority system in February 2002 (n = 36 791). We estimated the posttreatment survival of patients with Child's A cirrhosis and stage II HCC treated by radiofrequency ablation (RFA) ± transarterial chemoembolization (TACE) or surgical resection by conducting a systematic review of the medical literature. In patients with Child's A cirrhosis and stage II HCC, the estimated median survival benefit of liver transplantation compared to RFA ± TACE was 1.5 months at 3 years (range -3.5 to 5.6) and 5.7 months at 5 years (range 0.7-11.4), whereas compared to surgical resection it was 0.7 months at 3 years (range -2.9 to 3) and 2.8 months at 5 years (range -4.4 to 5.7). Liver transplantation in patients with stage II HCC and Child's A cirrhosis results in a very low survival benefit and may not constitute optimal use of scarce liver donor organs. Liver transplantation in patients with stage II hepatocellular carcinoma and Child's A cirrhosis results in a very low survival benefit and may not constitute optimal use of scarce liver donor organs. © copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

Ausk K.J.,University of Washington | Boyko E.J.,University of Washington | Ioannou G.N.,University of Washington | Ioannou G.N.,Research Enhancement Award Program
Diabetes Care | Year: 2010

OBJECTIVE - Insulin resistance is a suspected causative factor in a wide variety of diseases. We aimed to determine whether insulin resistance, estimated by the homeostasis model assessment for insulin resistance (HOMA-IR), is associated with all-cause or disease-specific mortality among nondiabetic persons in the U.S. RESEARCH DESIGN AND METHODS - We determined the association between HOMA-IR and death certificate - based mortality among 5,511 nondiabetic, adult participants of the third U.S. National Health and Nutrition Examination Survey (1988-1994) during up to 12 years of follow-up, after adjustment for potential confounders (age, sex, BMI, waist-to-hip ratio, alcohol consumption, race/ethnicity, educational attainment, smoking status, physical activity, C-reactive protein, systolic and diastolic blood pressure, plasma total and HDL cholesterol, and triglycerides). RESULTS - HOMA-IR was significantly associated with all-cause mortality (adjusted hazard ratio 1.16 [95% CI 1.01-1.3], comparing successive quartiles of HOMA-IR in a linear model and 1.64 [1.1-2.5], comparing the top [HOMA-IR >2.8] to the bottom [HOMA-IR ≤1.4] quartile). HOMA-IR was significantly associated with all-cause mortality only in subjects with BMI <25.2 kg/m2 (the median value) but not in subjects with BMI ≥25.2 kg/m2. Subjects in the second, third, and fourth quartile of HOMA-IR appeared to have higher cardiovascular mortality than subjects in the lowest quartile of HOMA-IR. HOMA-IR was not associated with cancer-related mortality. CONCLUSIONS - HOMA-IR is associated with all-cause mortality in the nondiabetic U.S. population but only among persons with normal BMI. HOMA-IR is a readily available measure that can be used in the future to predict mortality in clinical or epidemiological settings. © 2010 by the American Diabetes Association.

Trivedi A.N.,Brown University | Trivedi A.N.,Research Enhancement Award Program | Moloo H.,Brown University | Mor V.,Brown University
New England Journal of Medicine | Year: 2010

BACKGROUND: When copayments for ambulatory care are increased, elderly patients may forgo important outpatient care, leading to increased use of hospital care. METHODS: We compared longitudinal changes in the use of outpatient and inpatient care between enrollees in Medicare plans that increased copayments for ambulatory care and enrollees in matched control plans - similar plans that made no changes in these copayments. The study population included 899,060 beneficiaries enrolled in 36 Medicare plans during the period from 2001 through 2006. RESULTS: In plans that increased copayments for ambulatory care, mean copayments nearly doubled for both primary care ($7.38 to $14.38) and specialty care ($12.66 to $22.05). In control plans, mean copayments for primary care and specialty care remained unchanged at $8.33 and $11.38, respectively. In the year after the rise in copayments, plans that increased cost sharing had 19.8 fewer annual outpatient visits per 100 enrollees (95% confidence interval [CI], 16.6 to 23.1), 2.2 additional annual hospital admissions per 100 enrollees (95% CI, 1.8 to 2.6), 13.4 more annual inpatient days per 100 enrollees (95% CI, 10.2 to 16.6), and an increase of 0.7 percentage points in the proportion of enrollees who were hospitalized (95% CI, 0.51 to 0.95), as compared with concurrent trends in control plans. These estimates were consistent among a cohort of continuously enrolled beneficiaries. The effects of increases in copayments for ambulatory care were magnified among enrollees living in areas of lower income and education and among enrollees who had hypertension, diabetes, or a history of myocardial infarction. CONCLUSIONS: Raising cost sharing for ambulatory care among elderly patients may have adverse health consequences and may increase total spending on health care. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Savard C.,Research Enhancement Award Program | Savard C.,University of Washington | Tartaglione E.V.,Research Enhancement Award Program | Kuver R.,University of Washington | And 8 more authors.
Hepatology | Year: 2013

The majority of patients with nonalcoholic fatty liver disease (NAFLD) have "simple steatosis," which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10%-30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction. Conclusion: Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice. (HEPATOLOGY 2013) © 2012 American Association for the Study of Liver Diseases.

Ioannou G.N.,University of Washington | Ioannou G.N.,Research Enhancement Award Program
American Journal of Gastroenterology | Year: 2010

Objectives: Cholelithiasis and fatty liver disease share some important risk factors, such as central obesity, insulin resistance, and diabetes. We sought to determine whether persons with cholelithiasis or a history of cholecystectomy were more likely to have elevated serum liver enzymes or to develop cirrhosis.Methods: We used cohort data from the first National Health and Nutrition Examination Survey (NHANES), to determine whether persons with a self-reported history of cholecystectomy at baseline (n=466) had a higher incidence of hospitalization or death due to cirrhosis than persons without a history of cholecystectomy (n=8,691) during up to 21 years of follow-up. We also used cross-sectional data from the third NHANES conducted between the years 1988 and 1994 to determine whether persons with cholelithiasis (n=833) or previous cholecystectomy (n=709), as determined by ultrasonography, were more likely to have elevated serum alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) than persons without cholecystectomy or cholelithiasis (n=8,027).Results: Persons with previous cholecystectomy were two times more likely to be hospitalized for or die of cirrhosis (adjusted hazard ratio 2.1, 95% confidence interval (CI) 1.1-4.0) and were more likely to have elevated serum ALT (adjusted odds ratio 1.8, 95% CI 1.3-2.5) or GGT (adjusted odds ratio 1.7, 95% CI 1.1-2.6) than persons without cholecystectomy. We did not identify an independent association between cholelithiasis and serum ALT or GGT levels.Conclusions: Cholecystectomy is a predictor of the development cirrhosis and is associated with elevated serum liver enzymes. Cholelithiasis is not independently associated with serum liver enzyme levels; whether cholelithiasis is associated with the development of cirrhosis remains to be determined. © 2010 by the American College of Gastroenterology.

Afzali A.,University of Washington | Afzali A.,Research Enhancement Award Program | Berry K.,University of Washington | Ioannou G.N.,University of Washington | Ioannou G.N.,Research Enhancement Award Program
Liver Transplantation | Year: 2012

Because of the ongoing epidemics of obesity and diabetes, nonalcoholic steatohepatitis (NASH) may become a leading indication for liver transplantation. There are concerns about the posttransplant survival of patients with NASH because of associated cardiovascular and metabolic risk factors. We aimed to determine recent trends in the proportion of patients undergoing transplantation for NASH-related cirrhosis in the United States and to estimate their posttransplant survival. We used data provided by the United Network for Organ Sharing for first-time adult cadaveric liver transplants performed in the United States between January 1, 1997 and October 31, 2010 (n = 53,738). The proportion of liver transplants performed for NASH-related cirrhosis increased dramatically from 1.2% in 1997-2003 to 7.4% in 2010 when NASH was the fourth most common indication for transplantation. The posttransplant survival of patients with NASH (n = 1810) at 1 (87.6%), 3 (82.2%), and 5 years (76.7%) was superior to the survival of patients with hepatocellular carcinoma, hepatitis C virus, alcoholic liver disease, acute hepatic necrosis, hemochromatosis, or cryptogenic liver disease and was inferior to the survival of only 4 groups of patients (those with primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, or hepatitis B virus). In conclusion, NASH-related cirrhosis is increasing rapidly as an indication for liver transplantation in the United States and is associated with excellent posttransplant survival. Copyright © 2011 American Association for the Study of Liver Diseases.

Qato D.M.,Brown University | Trivedi A.N.,Brown University | Trivedi A.N.,Research Enhancement Award Program
Journal of General Internal Medicine | Year: 2013

BACKGROUND: Since 2005, the Centers for Medicare and Medicaid Services (CMS) has required all Medicare Advantage (MA) plans to report prescribing rates of high risk medications (HRM). OBJECTIVE: To determine predictors of receipt of HRMs, as defined by the National Committee for Quality Assurance's "Drugs to Avoid in the Elderly" quality indicator, in a national sample of MA enrollees. DESIGN AND PARTICIPANTS: Retrospective analysis of Healthcare Effectiveness Data and Information Set (HEDIS) data for 6,204,824 enrollees, aged 65 years or older, enrolled in 415 MA plans in 2009. To identify predictors of HRM use, we fit generalized linear models and modeled outcomes on the risk-difference scale. MAIN OUTCOME MEASURES: Receipt or non-receipt of one or two HRMs. KEY RESULTS: Approximately 21 % of MA enrollees received at least one HRM and 4.8 % received at least two. In fully adjusted models, females had a 10.6 (95 % CI: 10.0-11.2) higher percentage point rate of receipt than males, and residence in any of the Southern United States divisions was associated with a greater than 10 percentage point higher rate, as compared with the reference New England division. Higher rates were also observed among enrollees with low personal income (6.5 percentage points, 95 % CI: 5.5-7.5), relative to those without low income and those residing in areas in the lowest quintile of socioeconomic status (2.7 points, 95 % CI: 1.9-3.4) relative to persons residing in the highest quintile. Enrollees ≥ 85 years old, black enrollees, and other minority groups were less likely to receive these medications. Over 38 % of MA enrollees residing in the hospital referral region of Albany, Georgia received at least one HRM, a rate four times higher than the referral region with the lowest rate (Mason City, Iowa). CONCLUSIONS: Use of HRMs among MA enrollees varies widely by geographic region. Persons living in the Southern region of the U.S.; whites, women, and persons of low personal income and socioeconomic status are more likely to receive HRMs. © 2012 Society of General Internal Medicine.

Patel N.,Research Enhancement Award Program
Journal of the American Heart Association | Year: 2012

Insulin resistance, characterized by hyperinsulinemia and normal or elevated serum glucose, is an established precursor to diabetes and cardiovascular disease. Despite fasting serum C-peptide levels being an accurate and stable marker of endogenous insulin production used in patients with diabetes, it is unknown whether C-peptide could serve as a marker of insulin resistance and predict outcomes in patients without diabetes. This is a retrospective cohort study using data from the NHANES-3 (1988-1994) survey with mortality follow-up through December 31, 2006. Participants included 5153 subjects, 40 to 74 years of age with fasting glucose ≥ 70 mg/dL, without diabetes by history or laboratory testing. Receiver-operating-curve analysis compared fasting C-peptide against known insulin resistance measures such as fasting plasma glucose, serum insulin, HOMA-IR, quantitative-insulin-sensitivity-check-index, and metabolic syndrome for the prediction of cardiovascular and overall death. Subjects were then stratified by quartiles of C-peptide levels. Cox proportional-hazards modeling compared hazards of cardiovascular and overall death amongst C-peptide quartiles and adjusted for potential confounders of cardiovascular and diabetes risk. Fasting serum C-peptide levels predicted cardiovascular and overall death better than other studied measures (AUC=0.62 and 0.60 respectively vs the rest, with AUC ≤ 0.58 and ≤ 0.57 respectively, P<0.001). When compared with the lowest C-peptide quartile, subjects in the highest quartile had significantly higher adjusted hazard ratios (HR) of cardiovascular death (HR=1.60, 95%CI 1.07 to 2.39) and overall mortality (HR=1.72, 95%CI 1.34 to 2.21) after controlling for confounders. C-peptide levels significantly related to hazards of cardiovascular and overall death in nondiabetic adults and was a better predictor of these outcomes than serum insulin and/or glucose derived measures.

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