Therapeutic potential of Takeda‐G‐protein‐receptor‐5 (TGR5) agonists. Hope or hype?

The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda‐G‐protein‐receptor‐5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy.     

Transfusion‐associated graft vs. host disease in a patient with high‐grade B‐cell lymphoma. Should cellular products for patients with non‐Hodgkin's lymphoma be irradiated?

We present the case of a 64-year-old man who died from transfusion-associated graft vs. host disease (TA-GVHD) having been treated 2 years earlier for a high-grade, non-Hodgkin's lymphoma (NHL). We suggest that he was at increased risk of developing TA-GVHD as a result of the NHL and its subsequent treatment, and propose that patients with NHL should be added to those 'at risk' groups who receive irradiated cellular blood components.     

Over‐expansion of balloon‐expandable transcatheter heart valves. Is there a limit?

• Transcatheter aortic valve implantation can be successful in selected patients with annuli beyond the current recommended limits for available transcatheter valves.
• Over‐expansion of balloon‐expandable valves beyond current guidelines may play a role.
• The limits of over‐expansion of balloon‐expandable valves are not well understood.

     

Clinical and angiographic follow‐up after coronary drug‐eluting and bare metal stent implantation. Do drug‐eluting stents hold the promise?

OBJECTIVES: To investigate the influence of drug-eluting stent (DES) implantation on clinical and angiographic restenosis. DESIGN: Registry study of data from the Swedish Coronary Angiography and Angioplasty Registry with a coronary angiographic substudy. SETTING: Multi-centre study. SUBJECTS: During October 2002 to May 2004 a total of 23 590 percutaneous coronary intervention (PCI) procedures were performed at 25 hospitals. After selection, to achieve comparable groups, a total of 5068 patients of whom 4111 had a bare metal stent (BMS) implanted and 957 had a DES implanted, remained. End-point in the registry follow-up was >50% diameter restenosis at clinically driven reangiography within 12 months after index PCI. The primary end-point in the angiographic substudy was late loss in patients' DES at 6-month angiographic follow-up. RESULTS: The rate of clinically driven restenosis, within 12 months, in patients receiving DES was less (3.9%) compared with those who received BMS (7.0%). In multivariate analysis the risk of clinical restenosis was one-third for DES compared with BMS (HR 0.36, 95% CI 0.25-0.52). In the angiographic substudy late loss was 0.07+/-0.53 mm (range -0.88 to 1.62). The amount of late loss was related to the presence of diabetes mellitus or not (0.19+/-0.45 mm vs. -0.12+/-0.58 mm), and lack of postdilatation of the stent or not (0.23+/-0.51 mm vs. -0.09+/-0.50 mm). CONCLUSIONS: The use of DES in the Swedish 'real world' is effective in reducing the clinically driven restenosis rate, when compared with patients with BMS treatment. In the angiographic follow-up the average late loss was as low as observed in recent randomized multi-centre trials.     

Does Effect Size in Naltrexone Trials for Alcohol Dependence Differ for Single‐Site vs. Multi‐Center Studies?

BACKGROUND: The opioid antagonist naltrexone was first shown in single-site trials to be efficacious in the treatment of alcohol dependence. Recent clinical trials of the medication have used multi-center designs, which permit greater generalization and increased statistical power. We compared effect sizes for these two kinds of trial design on the hypothesis that multi-center trials introduce sources of variation that reduce the observed effect size. METHODS: A meta-analysis of data from 19 placebo-controlled trials of the efficacy of naltrexone (7 multi-center and 12 single-site studies) was performed. Effect size estimates for these two study designs were compared using two outcomes: percentage of days drinking and percentage of subjects relapsing to heavy drinking. RESULTS: Compared with single-site studies, multi-center studies were estimated to yield a nonsignificantly smaller effect on the percentage of days drinking (Cohen's d = 0.20 vs. 0.33, respectively) and a significantly smaller effect on the percentage of subjects relapsing to heavy drinking (Cohen's d = 0.17 vs. 0.41, respectively; p = 0.014). Earlier studies showed a larger effect size than later studies. CONCLUSION: The smaller effect size seen with multi-center studies may reflect random error due to heterogeneity among the sites. However, because multi-center studies were, in general, conducted more recently than single-site studies, it was not possible conclusively to disentangle the moderating impact of study type and year of publication on effect size. Further research on factors that moderate effect size can contribute to the development of medications to treat alcohol dependence.     

Is Non‐suicidal Self‐injury Related to Impulsivity in Anorexia Nervosa? Results from Self‐report and Performance‐based Tasks

The present study investigates the association between non‐suicidal self‐injury (NSSI) and impulsivity in anorexia nervosa (AN) patients by means of self‐report and behavioural tasks. In total, 60 female AN patients were included in the study, filled out the Barratt Impulsiveness Scale‐11 (BIS‐11) and performed three performance‐based tasks to assess different facets of impulsivity. Overall, 30% of the AN patients engaged in at least one form of NSSI during their lifetime. AN patients with and without NSSI did not significantly differ on the BIS‐11 impulsiveness scale. On the performance‐based measures, few differences emerged between AN patients with and without NSSI. Patients with NSSI showed more perseverations and perseveration errors (p < .05). The associations between self‐report and performance‐based measures were rather low, except for the association between the BIS‐11 and Wisconsin Card Sorting Task perseveration responses and errors (correlations |r| range between .32 and .42). The implications for theory and treatment of AN patients with and without NSSI will be discussed. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.