Abdus S. Wahed

Perioperative safety in the longitudinal assessment of bariatric surgery.

BACKGROUND To improve decision making in the treatment of extreme obesity, the risks of bariatric surgical procedures require further characterization. METHODS We performed a prospective, multicenter, observational study of 30-day outcomes in consecutive patients undergoing bariatric surgical procedures at 10 clinical sites in the United States from 2005 through 2007. A composite end point of 30-day major adverse outcomes (including death; venous thromboembolism; percutaneous, endoscopic, or operative reintervention; and failure to be discharged from the hospital) was evaluated among patients undergoing first-time bariatric surgery. RESULTS There were 4776 patients who had a first-time bariatric procedure (mean age, 44.5 years; 21.1% men; 10.9% nonwhite; median body-mass index [the weight in kilograms divided by the square of the height in meters], 46.5). More than half had at least two coexisting conditions. A Roux-en-Y gastric bypass was performed in 3412 patients (with 87.2% of the procedures performed laparoscopically), and laparoscopic adjustable gastric banding was performed in 1198 patients; 166 patients underwent other procedures and were not included in the analysis. The 30-day rate of death among patients who underwent a Roux-en-Y gastric bypass or laparoscopic adjustable gastric banding was 0.3%; a total of 4.3% of patients had at least one major adverse outcome. A history of deep-vein thrombosis or pulmonary embolus, a diagnosis of obstructive sleep apnea, and impaired functional status were each independently associated with an increased risk of the composite end point. Extreme values of body-mass index were significantly associated with an increased risk of the composite end point, whereas age, sex, race, ethnic group, and other coexisting conditions were not. CONCLUSIONS The overall risk of death and other adverse outcomes after bariatric surgery was low and varied considerably according to patient characteristics. In helping patients make appropriate choices, short-term safety should be considered in conjunction with both the long-term effects of bariatric surgery and the risks associated with being extremely obese. (ClinicalTrials.gov number, NCT00433810.)

Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease

Background: Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission. Methods: Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (45.0%) used only ChEIs, and 416 (40.1%) used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications). Results: Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death. Conclusions: This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.

Race, insulin resistance and hepatic steatosis in chronic hepatitis C

Hepatic steatosis is common in chronic hepatitis C and has been linked to concurrent obesity, insulin resistance, diabetes, disease severity, and poor response to therapy. Racial differences in rates of obesity and diabetes may contribute to racial differences in hepatic steatosis and treatment response. The aim of the present study was to compare hepatic steatosis and its associations between African American (AA) and Caucasian American (CA) patients with chronic hepatitis C, genotype 1, participating in a prospective study of peginterferon and ribavirin therapy. Liver biopsy results were available from 194 AA patients and 205 CA patients. The 2 groups were compared for anthropometric, clinical, and biochemical features and insulin resistance estimated by the homeostasis model assessment index (HOMA‐IR). Sixty‐one percent of the AA patients and 65% of the CA patients had hepatic steatosis (P = 0.38). In univariable analysis, steatosis was associated with HOMA‐IR, body mass index, waist circumference, serum triglycerides, aminotransferase level, and histological scores for inflammation and fibrosis. After adjusting for these features, AA patients had a lower risk of steatosis than did CA patients (OR 0.54, 95% CI 0.32‐0.91, P = 0.02). Insulin resistance but not steatosis was associated with a lower rate of sustained virological response when adjusted for known factors that predict response (relative risk 0.87, 95% CI 0.77‐0.99, P = 0.028). Conclusion: After adjusting for the higher prevalence of features associated with hepatic steatosis, AA patients had a lower prevalence of hepatic steatosis than did CA patients with chronic hepatitis C, genotype 1. Insulin resistance but not steatosis was independently associated with lower sustained virological response. (HEPATOLOGY 2006;45:80–87.)

Effect of Wearable Technology Combined With a Lifestyle Intervention on Long-term Weight Loss: The IDEA Randomized Clinical Trial

Importance Effective long-term treatments are needed to address the obesity epidemic. Numerous wearable technologies specific to physical activity and diet are available, but it is unclear if these are effective at improving weight loss. Objective To test the hypothesis that, compared with a standard behavioral weight loss intervention (standard intervention), a technology-enhanced weight loss intervention (enhanced intervention) would result in greater weight loss. Design, Setting, Participants Randomized clinical trial conducted at the University of Pittsburgh and enrolling 471 adult participants between October 2010 and October 2012, with data collection completed by December 2014. Interventions Participants were placed on a low-calorie diet, prescribed increases in physical activity, and had group counseling sessions. At 6 months, the interventions added telephone counseling sessions, text message prompts, and access to study materials on a website. At 6 months, participants randomized to the standard intervention group initiated self-monitoring of diet and physical activity using a website, and those randomized to the enhanced intervention group were provided with a wearable device and accompanying web interface to monitor diet and physical activity. Main Outcomes and Measures The primary outcome of weight was measured over 24 months at 6-month intervals, and the primary hypothesis tested the change in weight between 2 groups at 24 months. Secondary outcomes included body composition, fitness, physical activity, and dietary intake. Results Among the 471 participants randomized (body mass index [BMI], 25 to <40; age range, 18-35 years; 28.9% nonwhite, 77.2% women), 470 (233 in the standard intervention group, 237 in the enhanced intervention group) initiated the interventions as randomized, and 74.5% completed the study. For the enhanced intervention group, mean base line weight was 96.3 kg (95% CI, 94.2-98.5) and 24-month weight 92.8 kg (95% CI, 90.6- 95.0) [corrected]. For the standard intervention group, mean baseline weight was 95.2kg (95%CI,93.0-97.3)and24-month weight was 89.3 kg (95%CI, 87.1-91.5) [corrected]. Weight change at 24 months differed significantly by intervention group (estimated mean weight loss, 3.5 kg [95% CI, 2.6-4.5} in the enhanced intervention group and 5.9 kg [95% CI, 5.0-6.8] in the standard intervention group; difference, 2.4 kg [95% CI, 1.0-3.7]; P = .002). Both groups had significant improvements in body composition, fitness, physical activity, and diet, with no significant difference between groups. Conclusions and Relevance Among young adults with a BMI between 25 and less than 40, the addition of a wearable technology device to a standard behavioral intervention resulted in less weight loss over 24 months. Devices that monitor and provide feedback on physical activity may not offer an advantage over standard behavioral weight loss approaches. Trial Registration clinicaltrials.gov Identifier: NCT01131871.

Pretreatment Sequence Diversity Differences in the Full-Length Hepatitis C Virus Open Reading Frame Correlate with Early Response to Therapy

ABSTRACT Pegylated alpha interferon and ribavirin therapy for hepatitis C virus (HCV) genotype 1 infection fails for half of Caucasian American patients (CA) and more often for African Americans (AA). The reasons for these low response rates are unknown. HCV is highly genetically variable, but it is unknown how this variability affects response to therapy. To assess effects of viral diversity on response to therapy, the complete pretreatment genotype 1 HCV open reading frame was sequenced using samples from 94 participants in the Virahep-C study. Sequences from patients with >3.5 log declines in viral RNA levels by day 28 (marked responders) were more variable than those from patients with declines of <1.4 log (poor responders) in NS3 and NS5A for genotype 1a and in core and NS3 for genotype 1b. These correlations remained when all T-cell epitopes were excluded, indicating that these differences were not due to differential immune selection. When the sequences were compared by race of the patients, higher diversity in CA patients was found in E2 and NS2 but only for genotype 1b. Core, NS3, and NS5A can block the action of alpha interferon in vitro; hence, these genetic patterns are consistent with multiple amino acid variations independently impairing the function of HCV proteins that counteract interferon responses in humans, resulting in HCV strains with variable sensitivity to therapy. No evidence was found for novel HCV strains in the AA population, implying that AA patients may be infected with a higher proportion of the same resistant strains that are found in CA patients.

Cutting Edge: Programmed Death-1 Expression Is Increased on Immunocytes in Chronic Hepatitis C Virus and Predicts Failure of Response to Antiviral Therapy: Race-Dependent Differences

Up-regulation of programmed death-1 (PD-1) identifies exhausted T cells in various mouse and human viral models including chronic hepatitis C virus (HCV) infection, which is characterized by impaired CTL function. A large proportion of patients fail to eradicate HCV with current IFN-based antiviral therapy; in particular, African Americans are less likely to respond, but the mechanisms for these differences are not fully elucidated. In this study, in 72 treatment-naive patients with persistent HCV we found that PD-1 was significantly up-regulated on CD4+ and CD8+ T cells, HCV-specific CTLs, and NK cells. Increased PD-1 on HCV-specific CTLs was significantly associated with failed early and sustained virologic response to therapy in African American but not Caucasian American patients. Patients with sustained virologic response showed decreases in PD-1 on total CD4+ T cells, HCV-specific CTLs, and the CD56bright NK subset after therapy completion. Collectively, these data indicate that PD-1 is critical in persistent HCV and successful therapy results in global down-regulation of its expression.

Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self‐treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose‐exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well‐compensated, chronic noncirrhotic HCV who failed interferon‐based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady‐state exposures for silybin A and silybin B increased 11‐fold and 38‐fold, respectively, with a 5‐fold increase in dose, suggesting nonlinear pharmacokinetics. No drug‐related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy: A Randomized Controlled Trial

CONTEXT The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. OBJECTIVE To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. INTERVENTION Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. MAIN OUTCOME MEASURES The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures. RESULTS After 24 weeks of treatment, only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, -4.3 [95% CI, -17.3 to 8.7] U/L for placebo, -14.4 [95% CI, -41.6 to 12.7] U/L for 420-mg silymarin, -11.3 [95% CI, -27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, -0.05 to 0.18] log10 IU/mL for placebo, -0.03 [95% CI, -0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, -0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo. CONCLUSION Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00680342.

Increased plasma interleukin-6 in donors is associated with lower recipient hospital-free survival after cadaveric organ transplantation

Objectives:Brain death induces a massive inflammatory response. However, the influence of this inflammatory response on organ procurement, transplantation, and recipient outcome is unknown. We describe the inflammatory response characteristics in brain-dead organ donors and examine associations with organ transplantation and recipient survival. We test the hypothesis that increased inflammatory response is associated with fewer organs transplanted and decreased recipient survival. Design:Prospective, observational, cohort study. Setting:Two large intensive care units of tertiary care university hospitals in the United States. Patients:We recruited 30 consecutive brain-dead organ donors and 78 recipients between April 11, 2004, and November 23, 2004; recipients were followed through May 2005. Following declaration of brain death, we collected data on donor demographics, mechanism of brain death, number of organs procured and transplanted, and recipient characteristics. Plasma cytokines (tumor necrosis factor, interleukin-6, interleukin-10) were measured in donors at baseline following study enrollment, every hour for the first 4 hrs, and immediately before organ procurement for transplantation. Interventions:None. Measurements and Main Results:We examined the relationships among clinical characteristics, demographics, and cytokine response in donors and their influence on organ procurement and transplantation using multivariable regression and recipient’s 6-month hospital-free survival using a Cox proportional hazards regression. One hundred-eighteen organs were procured from 30 donors, and 91 (77%) were transplanted (mean of three organs transplanted per donor). All cytokines were increased following brain death. Older age in donors was significantly associated with lower number of organs transplanted (p < .001). Higher plasma interleukin-6 concentrations in donors before organ procurement was significantly associated with lower 6-month hospital-free survival in recipients (hazard ratio 1.77; 95% confidence interval, 1.17–2.69, p < .007). Conclusions:Among brain-dead organ donors, older age donors contribute fewer organs for transplantation, and increased donor interleukin-6 level before organ procurement is associated with lower recipient six-month hospital-free survival.

Associations between serum lipids and hepatitis C antiviral treatment efficacy

Approximately one half of patients who undergo antiviral therapy for chronic hepatitis C virus (HCV) genotype 1 infection do not respond to treatment. African Americans (AAs) are less responsive to treatment than Caucasian Americans (CAs), but the reasons for this disparity are largely unknown. Recent studies suggest that serum lipids may be associated with treatment response. The aims of this study were to evaluate baseline and changes in serum lipids during therapy, determine whether serum lipids are associated with virological response, and assess whether these measures explain the racial difference in efficacy. The study participants were from Virahep‐C, a prospective study of treatment‐naïve patients with genotype 1 HCV infection who received peginterferon (PEG‐IN) alfa‐2a plus ribavirin therapy for up to 48 weeks. Fasting serum lipids were analyzed at baseline and during and after therapy in 160 AAs and 170 CAs. A relative risk (RR) model was employed to evaluate characteristics associated with sustained virological response (SVR). Antiviral therapy was associated with changes in serum lipids during and after antiviral therapy, with the changes differing by race and the amount of PEG‐IFN taken. Baseline lipid measures independently associated with higher rates of SVR were lower triglyceride and higher low‐density lipoprotein cholesterol, with an interaction between high‐density lipoprotein cholesterol (HDLc) and gender. Lipid measures did not contribute significantly to an explanation of the racial difference in SVR. Conclusion: Serum lipids are associated with SVR, although these paramaters did not explain the racial difference in treatment response. The results of this study are compatible with proposed biological mechanisms of HCV entry, replication, and secretion, and may underscore new potential therapeutic targets for HCV eradication. (Hepatology 2010)