Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275-520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.

Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis.

UNLABELLED:  Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. MATERIAL AND METHODS: This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. RESULTS: Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. CONCLUSIONS: Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.

Weekend Admission for Acute Cholangitis Does Not Adversely Impact Clinical or Endoscopic Outcomes.

BACKGROUND: Acute cholangitis (AC) requires prompt diagnosis and treatment for optimal management. AIMS: To examine whether a putative "weekend effect" impact outcomes of patients hospitalized for AC. METHODS: We conducted a retrospective study of patients admitted with AC between 2009 and 2012. After excluding those not meeting Tokyo consensus criteria for AC, the cohort was categorized into weekend (Saturday-Sunday) and weekday (Monday-Friday) hospital admission and endoscopic retrograde cholangiography (ERC) groups. Primary outcome was length of stay (LOS); secondary outcomes included ERC performance, organ failure, and mortality. Groups were compared with Chi-square and t tests; predictors of LOS were assessed with linear regression. RESULTS: The cohort consisted of 181 patients (mean age 63.1 years, 62.4 % male). Choledocholithiasis was the most common etiology of AC (29.4 %). Fifty-two patients (28.7 %) were admitted on a weekend and 129 (71.3 %) on a weekday. One hundred forty-one patients (78 %) underwent ERC, of which 120 (85 %) were on a weekday. There were no significant differences in baseline characteristics, LOS, proportion undergoing ERC, time to ERC, organ failure, or mortality between weekend and weekday admission groups. Similarly, there were no significant differences between weekend and weekday ERC groups. In multivariate analyses, international normalized ratio (p < 0.01) and intensive care unit triage (p < 0.01) were independent predictors of LOS, whereas weekend admission (p = 0.23) and weekend ERC (p = 0.74) were not. CONCLUSIONS: Weekend admission and weekend ERC do not negatively impact outcomes of patients hospitalized with acute cholangitis at a tertiary care center. Further studies, particularly in centers with less weekend resources or staffing, are indicated.

Initial external validation of REGRESS in public health graduate students.

Linear regression is typically taught as a second and potentially last required (bio)statistics course for Public Health and Clinical and Translational Science students. There has been much research on the attitudes of students toward basic biostatistics, but there has not been much assessing students' understanding of critical regression topics. The REGRESS (REsearch on Global Regression Expectations in StatisticS) quiz developed at Mayo Clinic utilizes 27 questions to assess understanding for simple and multiple linear regression. We performed an initial external validation of this tool with 117 University of Michigan public health students. We compare the results of pre- and postcourse quiz scores from the Michigan cohort to scores of Mayo medical students and professional statisticians. University of Michigan students performed higher than Mayo students on the precourse quiz due to previous related coursework, but did not perform as high postcourse indicating the need for course modification. In the Michigan cohort, REGRESS scores improved by a mean (standard deviation) of 4.6 (3.4), p < 0.0001. Our results support the use of the REGRESS quiz as a learning tool for students and an evaluation tool to identify topics for curricular improvement for teachers, while we highlight future directions of research.

Technetium-labeled erythrocyte scintigraphy in acute gastrointestinal bleeding.

PURPOSE: Optimal management of acute gastrointestinal (GI) bleeding requires accurate localization of the bleeding source. The role of technetium-labeled erythrocyte scintigraphy (tagged red blood cell (TRBC) scan) in evaluating acute GI bleeding has been controversial, though recent literature suggests that it is a reliable tool and may be used as a first-line diagnostic test. We evaluated our recent experience with and the clinical outcomes of the TRBC scan in patients presenting with acute GI bleeding. METHODS: A retrospective study of 100 consecutive TRBC scans performed between April 2006 and January 2009 was conducted. Medical records of each corresponding patient were queried for pertinent data. Twenty TRBC scans performed for occult GI bleeding or >48 h after hospital admission were excluded. RESULTS: Of the 80 TRBC scans, 29 (36%) were positive and 51 (64%) were negative for bleeding. Eight (10%) were incorrect positive (leading to five incorrect operations), 12 (15%) true positive, 9 (11%) unconfirmed positive, 17 (21%) false negative, and 34 (43%) unconfirmed negative. The cause of bleeding was confirmed in 31 cases, of which the scan result was incorrect positive in 2 (7%), true positive in 12 (39%), and false negative in 17 (55%). CONCLUSIONS: TRBC scans have low positive yield as well as high incorrect positive and high false negative rates in patients with acute GI bleeding. Further research is needed to improve scan technique, refine patient selection, and determine in what setting TRBC scanning may be more clinically useful.

Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study.

OBJECTIVES: The significance of nonalcoholic fatty liver disease (NAFLD) among patients with diabetes is unknown. We sought to determine whether a diagnosis of NAFLD influenced mortality among a community-based cohort of patients with type II diabetes mellitus. METHODS: A total of 337 residents of Olmsted County, Minnesota with diabetes mellitus diagnosed between 1980 and 2000 were identified using the Rochester Epidemiology Project and the Mayo Laboratory Information System, and followed for 10.9 + or - 5.2 years (range 0.1-25). Survival was analyzed using Cox proportional hazards modeling, with NAFLD treated as a time-dependent covariate. RESULTS: Among the 337 residents, 116 were diagnosed with NAFLD 0.9 + or - 4.6 years after diabetes diagnosis. Patients with NAFLD were younger, and more likely to be female and obese. Overall, 99/337 (29%) patients died. In multivariate analysis to adjust for confounders, overall mortality was significantly associated with a diagnosis of NAFLD (hazard ratio (HR) 2.2; 95% confidence interval (CI) 1.1, 4.2; P=0.03), presence of ischemic heart disease (HR 2.3; 95% CI 1.2, 4.4), and duration of diabetes (HR per 1 year, 1.1; 95% CI 1.03, 1.2). The most common causes of death in the NAFLD cohort were malignancy (33% of deaths), liver-related complications (19% of deaths), and ischemic heart disease (19% of deaths). In adjusted multivariate models, NAFLD was borderline associated with an increased risk of dying from malignancy (HR 2.3; 95% CI 0.9, 5.9; P=0.09) and not from cardiovascular disease (HR 0.9; 95% CI 0.3, 2.4; P=0.81). CONCLUSIONS: The diagnosis of NAFLD is associated with an increased risk of overall death among patients with diabetes mellitus.

The Mayo Dysphagia Questionnaire-30: documentation of reliability and validity of a tool for interventional trials in adults with esophageal disease.

The aim of this study was to develop the Mayo Dysphagia Questionnaire-30 Day (MDQ-30), a tool to measure esophageal dysphagia, by adapting items from validated instruments for use in clinical trials, and assess its feasibility, reproducibility, and concurrent validity. Outpatients referred to endoscopy for dysphagia or seen in a specialty clinic were recruited. Feasibility testing was done to identify problematic items. Reproducibility was measured by test-retest format. Concurrent validity reflects agreement between information gathered in a structured interview versus the patients' written responses. The MDQ-30, a 28-item instrument, took 10 min (range = 5-30 min) to complete. Four hundred thirty-one outpatients [210 (49%) men; mean age = 61 years] participated. Overall, most concurrent validity kappa values for dysphagia were very good to excellent with a median of 0.78 (min 0.28, max 0.95). The majority of reproducibility kappa values for dysphagia were moderate to excellent with a median kappa value of 0.66 (min 0.07, max 1.0). Overall, concurrent validity and reproducibility kappa values for gastroesophageal reflux disease (GERD) symptoms were 0.81 (95% CI = 0.72, 0.91) and 0.66 (95% CI = 0.55, 0.77), respectively. Individual item percent agreement was generally very good to excellent. Internal consistency was excellent. We conclude that the MDQ-30 is an easy-to-complete tool to evaluate reliably dysphagia symptoms over the last 30 days.

Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis.

UNLABELLED: There is limited information on test performance for detecting cholangiocarcinoma in primary sclerosing cholangitis (PSC), particularly when used sequentially. This study aimed to characterize diagnostic performance of serum carbohydrate antigen 19-9 (CA 19-9), ultrasonography, computed tomography, magnetic resonance imaging, cholangiography, and biliary cytologic techniques for detecting cholangiocarcinoma in PSC. All consecutive patients with PSC were screened and followed for development of cholangiocarcinoma from 2000 through 2006. Of 230 patients, 23 developed cytopathologically confirmed cholangiocarcinoma with an annual incidence of 1.2%. The optimal cutoff value for serum CA 19-9 was 20 U/mL, which yielded a sensitivity of 78%, specificity of 67%, positive predictive value (PPV) of 23%, and negative predictive value (NPV) of 96%. Serum CA 19-9 combined with either ultrasonography, computed tomography, or magnetic resonance imaging provided a sensitivity of 91%, 100%, and 96%, specificity of 62%, 38%, and 37%, PPV of 23%, 22%, and 24%, and NPV of 98%, 100%, and 98%, respectively, if at least one method was positive. Subsequent cholangiographic examinations in these patients increased specificity to 69% and PPV to 42% while maintaining sensitivity of 91% and NPV of 96%. Following this group, conventional cytology, aneuploidy detection by digital imaging analysis, and aneusomy detection by fluorescence in situ hybridization in brushing samples of biliary strictures had a sensitivity of 50%, 57%, and 86%, specificity of 97%, 94%, and 83%, PPV of 86%, 89%, and 80%, and NPV of 83%, 74%, and 88%, respectively, for detecting cholangiocarcinoma. CONCLUSION: Tumor serology combined with cross-sectional liver imaging may be useful as a screening strategy and cholangiography with cytologic examination is helpful for the diagnosis of cholangiocarcinoma in patients with PSC.

Flunking asthma? When HEDIS takes the ACT.

OBJECTIVE: To test several patient-oriented asthma outcome measures and the Healthcare Effectiveness Data and Information Set (HEDIS) measure of appropriate medication for persistent asthma to determine the most useful quality indicator of asthma care. DESIGN: Prospective mail survey of adult employees and dependents with asthma. METHODS: The medical and pharmacy claims of all subjects from 12 months before and after the survey were abstracted. Outcomes measures included the Asthma Control Test (ACT), workday loss, unscheduled healthcare utilization (emergency department and inpatient care), and satisfaction with care. RESULTS: Although 81% of all responders had wellcontrolled asthma, persistent asthma was uncontrolled in 28%. Only 64.5% received appropriate controller medication. Well-controlled asthma is associated with a high degree of satisfaction, less workday loss, fewer prednisone bursts, and minimal unscheduled healthcare utilization. Except for a reduced incidence of more than 2 oral corticosteroid dispensings (6.4% vs 13.6%, P = .012), compliance with the HEDIS appropriate medication for asthma was not positively associated with any of the patient-centered outcomes studied. CONCLUSIONS: Asthma control was the most useful patient outcome quality indicator in this study. Compliance with the HEDIS asthma measure in this population was not associated with a better patient-oriented outcome. This finding may be different with different levels of asthma control. The positive association between well-controlled asthma and patient satisfaction, minimal unscheduled healthcare utilization, and low workday loss suggests that asthma control as measured by ACT may be a better performance measure in asthma.

Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures.

BACKGROUND AND AIMS: Standard techniques for evaluating bile duct strictures have poor sensitivity for detection of malignancy. Newer imaging modalities, such as intraductal ultrasound (IDUS), and advanced cytologic techniques, such as digital image analysis (DIA) and fluorescence in situ hybridization (FISH), identify chromosomal abnormalities, and may improve sensitivity while maintaining high specificity. Our aim was to prospectively evaluate the accuracy of these techniques in patients with indeterminate biliary strictures. METHODS: Cholangiography, routine cytology (RC), intraductal biopsy, DIA, FISH, and IDUS were performed in 86 patients with indeterminate biliary strictures. Patients were stratified based on the presence or absence of primary sclerosing cholangitis (PSC). RESULTS: RC provided low sensitivity (7-33%) but high specificity (95-100%) for PSC and non-PSC patients. The composite DIA/FISH results (when considering trisomy-7 [Tri-7] as a marker of benign disease) yielded a 100% specificity and increased sensitivity one- to fivefold in PSC patients versus RC, and two- to fivefold in patients without PSC, depending on how suspicious cytology results were interpreted. For the most difficult-to-manage patients with negative cytology and histology who were later proven to have malignancy (N = 21), DIA, FISH, composite DIA/FISH, and IDUS were able to predict malignant diagnoses in 14%, 62%, 67%, and 86%, respectively. CONCLUSIONS: DIA, FISH, and IDUS enhance the accuracy of standard techniques in evaluation of indeterminate bile duct strictures, allowing diagnosis of malignancy in a substantial number of patients with false-negative cytology and histology. These findings support the routine use of these newer diagnostic modalities in patients with indeterminate biliary strictures.

Endoscopic ultrasound-guided gastric botulinum toxin injections in obese subjects: a pilot study.

BACKGROUND: Gastric injections of botulinum toxin A (BTA) may induce changes in gastric emptying and body weight, but results vary. BTA dose and depth of injection may affect efficacy. This study assessed changes in gastric emptying, satiation, symptoms, and body weight after endoscopic ultrasound (EUS)-guided injection of 100 or 300 U BTA into gastric antral muscularis propria of obese subjects. METHODS: Open label study of ten healthy, obese adults (age = 29-49 years, body mass index = 31-54 kg/m(2)) who received 100 U (n = 4) or 300 U (n = 6) BTA and were followed for 16 weeks. Measures included gastric emptying of solids (by scintigraphy), satiation (by maximum tolerated volume [MTV] during nutrient drink test), gastrointestinal symptoms (by the Gastrointestinal Symptom Rating Scale), caloric intake (by food frequency questionnaire), and body weight. RESULTS: For the entire cohort, MTV decreased from 1,380 cc (range: 474-2,014) at baseline to 620 cc (range: 256-1,180) 2 weeks after BTA injection; decreases were statistically significant in the subjects receiving 300 U BTA (p = 0.03). Average body weight loss was 4.9 (+/-6.3) kg after 16 weeks. Gastric emptying T(1/2) was prolonged in the 300 U BTA group, but not significantly different from baseline (p = 0.17). BTA injections were well tolerated without significant adverse effects. CONCLUSION: EUS-guided injection of BTA into gastric muscularis propria can be performed safely with minimal adverse effects. A dose of 300 U BTA significantly enhances satiation, is associated with weight loss, and may slow gastric emptying. Further study of higher dose BTA in obese subjects is warranted.

Impact of inflammatory bowel disease and ursodeoxycholic acid therapy on small-duct primary sclerosing cholangitis.

UNLABELLED: A longitudinal, cohort study was performed to characterize the clinical features of patients with small-duct primary sclerosing cholangitis (PSC) occurring with and without inflammatory bowel disease (IBD) and to determine the influence of IBD and the effect of ursodeoxycholic acid (UDCA) therapy on the course of the liver disease. Forty-two patients with small-duct PSC (14 women and 28 men; mean age, 36.7 +/- 13.3 years) were followed for up to 24.9 years. At presentation, prevalence of signs of liver disease (none versus 35%, P = 0.002), gastroesophageal varices (5% versus 30%, P = 0.03), and stage III/IV disease (9% versus 45%, P = 0.008) were lower in those with IBD versus those without IBD. During follow-up, 6 patients underwent liver transplantation, and another died of cirrhosis. Using the Cox proportional hazard analysis, concomitant IBD was not associated with liver death or transplant, whereas the revised Mayo risk score for PSC was the only prognostic factor associated with liver-related outcomes (relative risk, 6.47; 95% confidence interval, 1.75-137.5). UDCA (13-15 mg/kg/day) therapy for an average of 40 months showed biochemical improvement (P < 0.001) in UDCA-treated patients, while no significant change occurred in untreated patients. UDCA therapy had no effect on delaying progression of disease (relative risk, 0.95; 95% confidence interval, 0.38-2.36). CONCLUSION: Small-duct PSC often is recognized at an early stage in patients with IBD; however, IBD has no impact on long-term prognosis. Although UDCA therapy improves liver biochemistries, it may not delay disease progression during the short period of treatment.

Prospective study of bacteremia and complications With EUS FNA of rectal and perirectal lesions.

BACKGROUND & AIMS: Recent studies showed that endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is a low-risk procedure for causing bacteremia and infectious complications when sampling solid lesions of the upper gastrointestinal (GI) tract. As a result, antibiotics are not recommended for prophylaxis against endocarditis. Our aim was to prospectively evaluate the risk of bacteremia and other infectious complications in patients undergoing EUS FNA of lower GI tract lesions. METHODS: Patients referred for EUS FNA of lower GI tract lesions were considered for enrollment. Patients were excluded if there was an indication for preprocedure antibiotic administration based on American Society for Gastrointestinal Endoscopy guidelines, had taken antibiotics within the prior 7 days, or if they had a cystic lesion. Blood cultures were obtained immediately before the procedure, after flexible sigmoidoscopy/radial EUS, and 15 minutes after EUS FNA. RESULTS: One hundred patients underwent a total of 471 FNAs (mean, 4.7 FNAs/patient; range, 1-10 FNAs/patient). Blood cultures were positive in 6 patients. Cultures from 4 patients (4.0%, 95% confidence interval, 1.6%-9.8%) grew coagulase-negative Staphylococcus (n = 2), Peptostreptococcus stomatis (n = 1), or Moraxella (n = 1), which were considered contaminants. Two patients (2.0%, 95% confidence interval, 0.6%-7%) developed bacteremia: Bacteroides fragilis (n = 1) and Gemella morbillorum (n = 1). No signs or symptoms of infection developed in any patient. CONCLUSIONS: EUS FNA of solid lesions in the lower GI tract should be considered a low-risk procedure for infectious complications that does not warrant prophylactic administration of antibiotics for the prevention of bacterial endocarditis.

Abnormal hepatic biochemistries in patients with inflammatory bowel disease.

OBJECTIVES: The relationship between abnormal hepatic biochemistries and inflammatory bowel disease (IBD) is unclear. We determined the prevalence of abnormal hepatic biochemistries and chronic liver disease in a cohort of IBD patients, and we compared patients with normal and abnormal liver biochemistries. METHODS: Patients with IBD evaluated at our institution between January 1, 2000 and December 31, 2000 were identified. Data on gender, age, IBD subtype, extent and activity, medications, liver disease history, liver biochemistries, and vital status were collected. The chi(2) test, Student's t-test, and Cox proportional regression were used. RESULTS: We identified 544 patients with available hepatic biochemistries. Abnormal hepatic biochemistries were found in 159 (29%). Defined chronic liver disease was present in 5.8% of patients (primary sclerosing cholangitis in 4.6%). The prevalence of abnormal hepatic biochemistries was 27% for those with active IBD and 36% for those in remission (P= 0.06). Patients with abnormal hepatic biochemistries were less frequently on 5-aminosalicylates (35%vs 51%, P < 0.001), and a smaller proportion was alive at last follow-up (90.4%vs 98.5%, P < 0.0001). The age-adjusted risk of death was 4.8 times higher in patients with abnormal hepatic biochemistries, after excluding patients with any diagnosis of liver disease. CONCLUSIONS: Abnormal hepatic biochemistries were present in nearly one-third of our patients, and surprisingly, they were not associated with IBD activity. Abnormal hepatic biochemistries and chronic liver disease appeared to have a negative impact on vital status. Persistently abnormal hepatic biochemistries should be evaluated, and not attributed to IBD activity.