Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:There has been no prospective, community-based study to track changes in adenoma detection by individual physicians over time and to determine the effectiveness of targeted educational interventions. METHODS:We prospectively collected information on 47,253 screening colonoscopies in average-risk individuals 50 years and older performed by a community-based practice in the Twin Cities of Minnesota. During a period of 3 years, 5 specific interventions were implemented; each was designed to improve adenoma detection rates. Controlling for patient-related and procedure-related factors, rates of adenoma detection and 3-year trends for individual physicians were plotted, and intraclass correlation coefficients were calculated. Generalized estimating equations were used to identify factors associated with detection of adenomas and polyps. RESULTS:At least 1 polyp and 1 adenoma were found in 36% and 22% of examinations, respectively. Adenoma detection rates by endoscopists ranged from 10%-39%. There was no significant improvement during the study period despite planned, systematic interventions. Factors associated with adenoma detection included age of the patient (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.02-1.02), male sex (OR, 1.53; 95% CI, 1.34-1.74), and adequate preparation quality (OR, 2.26; 95% CI, 1.64-3.12). CONCLUSIONS:The detection of adenomas by individual physicians during a 3-year period varied and did not appear to change between individual endoscopists, despite planned, systematic interventions. This indicates that other targeted interventions might be required to improve adenoma detection rates among experienced, community gastroenterologists.

OBJECTIVE:Vitamin D supplementation may be required for certain subgroups in the United States in whom status and intake are inadequate, but the impact of various doses, and whether calcium administration jointly or independently influences vitamin D metabolite levels, is unclear. METHODS:In a pilot chemoprevention trial of biomarkers of risk for colorectal adenoma, we measured the impact of vitamin D supplementation and/or calcium supplementation on plasma vitamin D metabolite concentrations. Ninety-two adult men and women living in the southeastern United States were randomized to 800 IU vitamin D(3), 2000 mg elemental calcium, both, or placebo daily for 6 months. We examined vitamin D status at baseline and postintervention and compared the change in plasma 25-hydroxyvitamin D (25(OH)D) and 1,25(OH)(2)D levels by intervention group using general linear models. RESULTS:Eighty-two percent of the study population had insufficient plasma 25(OH)D concentrations (<75 nmol/L) at baseline, with the lowest levels observed among African American participants. Vitamin D supplements, with or without calcium supplementation, raised plasma 25(OH)D concentrations, on average, by 25 to 26 nmol/L. Half of the study participants were classified as having sufficient 25(OH)D status after 6 months of 800 IU of vitamin D(3) daily. Calcium alone did not influence 25(OH)D concentrations. CONCLUSION/CONCLUSIONS:In this southeastern U.S. population, half of the study participants receiving 800 IU vitamin D(3) daily had blood 25(OH)D concentrations of <or=75 nmol/L after a 6-month intervention period, supporting higher vitamin D dose requirements estimated by some groups. More research is needed to identify the optimal vitamin D dose to improve 25(OH)D status in various at-risk populations.

To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop "treatable" phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months. Overall expression and distributions of p21(waf1/cip1) (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P = 0.03), 242% (P = 0.005), and 25% (P = 0.47), respectively, along the full lengths of colorectal crypts after 6 months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P = 0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may "normalize" the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms.

BACKGROUND:Left atrial thrombus (LAT) is frequently present in patients with cerebral ischemic events (CIE) who are in atrial fibrillation. The prevalence and predictor of LAT in patients who are in sinus rhythm (SR) is unclear. OBJECTIVE:To determine the prevalence and identify predictors of LAT formation in patients with CIE who are in SR. METHODS:Consecutive patients with CIE who are in SR were evaluated by transesophageal echocardiography (TEE) from July 2000 to August 2001. Patient demographics including cerebrovascular risk factors were recorded. RESULTS:LAT was present in 5.5%. Left ventricular systolic dysfunction (LVSD) was present in 25 (10%). Patients' mean age was 59 +/- 14 years and 119 (50%) were male. In the univariate analysis, LAT was associated with LVSD (odds ratio [OR] 9.24, 95% confidence interval [CI] 2.8; 10.3) and male patients (OR 4.56, 95% CI: 1.6, 12.6) who had coronary artery disease (OR 3.4, 95% CI: 1.3, 8.4). In the multivariate analysis, LVSD (OR 10.6, CI 2.2-51.6) strongly predicted the development of LAT. CONCLUSIONS:LAT is not uncommon in patients CIE, who are in sinus rhythm, especially those with poor left ventricular functions. TEE should be considered in patients with CIE and LVSD for early detection and treatment of LAT.

We systematically reviewed the literature on the extent to which population characteristics or clinical features predict groups of individuals likely to develop advanced liver disease or die from chronic infection with hepatitis B virus (HBV). We searched Medline to include studies with reported cirrhosis, liver failure, liver cancer, or death outcomes after at least 1 year of follow-up from the measurement of predictive factors (age, age at infection, geographic location, race/ethnicity, sex, positive family history, presence of coinfections, HBV viral level, change in hepatitis B e antigen [HBeAg] status, genotype, HBV mutations, nonalcoholic fatty liver disease, alcohol consumption, liver enzymes, and liver biopsy finding). Evidence from 41 included articles suggested that cirrhosis, higher HBV viral level, and male sex were consistently associated with significantly increased risk of death and liver cancer. Evidence about the role of HBV genotype, HBeAg status, age and duration of infection, coinfections with hepatitis C virus, human immunodeficiency virus, hepatitis delta virus, and alanine aminotransferase levels were limited and inconsistent, but were deemed promising to identify patients at higher risk of clinical outcomes. Adults with chronic hepatitis B had increased risk for poorer health outcomes compared to the general population; however, the magnitude of risk varied greatly depending on baseline patient and disease characteristics, and typically clinical outcomes required many years to become manifest. Many adults with chronic hepatitis B had low absolute risks of clinical outcomes and likely would not benefit from immediate treatment. Baseline patient and disease characteristics provide important information about the risk of clinical outcomes and should be incorporated into monitoring or treatment decisions.

OBJECTIVES/OBJECTIVE:The aim of this study was to examine the potential cost-effectiveness of calcium chemoprevention post-polypectomy as a substitute or adjunct for surveillance. METHODS:We constructed a Markov model of post-polypectomy adenoma recurrence and colorectal cancer (CRC) development, calibrated to data from prospective chemoprevention trials of fiber, calcium, antioxidants, and aspirin. We modeled four scenarios for 50-year-old patients immediately after polypectomy: (i) natural history with no further intervention; (ii) elemental calcium 1,200 mg/day from age 50-80; (iii) surveillance colonoscopy from age 50-80 every 5 years, or 3 years for large adenoma; (iv) calcium + surveillance. Patients were followed up until age 100 or death. RESULTS:Calcium was cost-effective compared to natural history ($49,900/life-year gained). However, surveillance was significantly more effective than calcium (18.729 versus 18.654 life-years/patient; 76 percent versus 14 percent reduction in CRC incidence) at an incremental cost of $15,900/life-year gained. Calcium + surveillance yielded a very small benefit (0.0003 incremental life-years/patient) compared with surveillance alone, at a substantial incremental cost of $3,090,000/life-year gained. CONCLUSION/CONCLUSIONS:Post-polypectomy calcium chemoprevention is unlikely to be a reasonable substitute for surveillance. It may be cost-effective in patients unwilling or unable to undergo surveillance.

To further clarify and/or develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans, understand the mechanisms by which these agents reduce risk for the disease, and develop "treatable" biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D3, alone and in combination on markers of apoptosis, in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D3, alone or in combination, versus placebo over 6 months. Overall expression and colorectal crypt distributions of Bcl-2 (an apoptosis inhibitor) and Bax (an apoptosis promoter) in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, Bax expression along the full lengths of crypts increased 56% (P = 0.02) in the vitamin D group and 33% in both the calcium (P = 0.31) and calcium plus vitamin D (P = 0.36) groups relative to the placebo group. The vitamin D treatment effect was more pronounced in the upper 40%, or differentiation zone, of crypts (80%; P = 0.01). There were no statistically significant treatment effects on Bcl-2 expression. Overall, these preliminary results suggest that calcium and vitamin D, individually or together, may enhance apoptosis in the normal human colorectal epithelium, and the strongest treatment effects may be vitamin D related and in the upper sections of the colorectal crypts.

BACKGROUND:Chronic hepatitis B infection can lead to liver failure, hepatocellular carcinoma, and death. PURPOSE/OBJECTIVE:To evaluate the effectiveness of antiviral therapy for adults with chronic hepatitis B infection. DATA SOURCES/METHODS:Randomized, controlled trials (RCTs) of interferon (alpha2b and pegylated alpha2a), lamivudine, adefovir, entecavir, and telbivudine published from 1990 to 2008. STUDY SELECTION/METHODS:Randomized, controlled clinical trials of adults with chronic hepatitis B published in English after 1989 that reported death; incidence of hepatocellular carcinoma or liver failure; prevalence and incidence of cirrhosis; presence or seroconversion of hepatitis B e antigen (HBeAg) or surface antigen (HBsAg), viral load of hepatitis B virus DNA; aspartate aminotransferase and alanine aminotransferase (ALT) levels; or fibrosis scores after therapy with interferon-alpha2b, pegylated interferon-alpha2a, lamivudine, adefovir, entecavir, and telbivudine. DATA EXTRACTION/METHODS:Data extracted with standard protocols to calculate risk difference for clinical outcomes, viral load, HBeAg and HBsAg, ALT, histologic scores, and adverse events. DATA SYNTHESIS/RESULTS:In 16 RCTs (4431 patients), drug treatment did not improve clinical outcomes of chronic hepatitis B infection, but the trials were underpowered. In 60 RCTs that examined intermediate outcomes, no single treatment improved all intermediate outcomes. Low-quality evidence suggested HBsAg clearance after interferon-alpha2b (2 RCTs; 211 patients). Moderate-quality evidence suggested ALT normalization at follow-up after treatment with adefovir (2 RCTs; 600 patients) and HBeAg loss with lamivudine (2 RCTs; 318 patients). With interferon-alpha2b, moderate-quality evidence suggested HBeAg loss (3 RCTs; 351 patients), seroconversion (2 RCTs; 304 patients), and ALT normalization (2 RCTs; 131 patients). Pegylated interferon-alpha2a versus lamivudine improved HBeAg seroconversion (1 RCT; 814 patients) and ALT normalization (2 RCTs; 905 patients) off treatment. Pegylated interferon-alpha2a combined with lamivudine versus lamivudine improved HBeAg loss (1 RCT; 543 patients) and ALT normalization (2 RCTs; 905 patients). Adverse events during antiretroviral therapy occurred in more than 50% of patients but were not associated with increased treatment discontinuation. However, most studies excluded patients with hepatic or renal insufficiency or other serious comorbid conditions. LIMITATION/CONCLUSIONS:Marked heterogeneity in study samples, interventions, and measured outcomes preclude definitive conclusions. CONCLUSION/CONCLUSIONS:Evidence was insufficient to assess treatment effect on clinical outcomes or determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. Future research is needed to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection.