Three-Armed Trials Including Placebo and No-Treatment Groups May Be Subject to Publication Bias: Systematic Review

Background: It has been argued that placebos may not have important clinical impacts in general. However, there is increasing evidence of a publication bias among trials published in journals. Therefore, we explored the potential for publication bias in randomized trials with active treatment, placebo, and no-treatment groups. Methods: Three-armed randomized trials of acupuncture, acupoint stimulation, and transcutaneous electrical stimulation were obtained from electronic databases. Effect sizes between treatment and placebo groups were calculated for treatment effect, and effect sizes between placebo and no-treatment groups were calculated for placebo effect. All data were then analyzed for publication bias. Results: For the treatment effect, small trials with fewer than 100 patients per arm showed more benefits than large trials with at least 100 patients per arm in acupuncture and acupoint stimulation. For the placebo effect, no differences were found between large and small trials. Further analyses showed that the treatment effect in acupuncture and acupoint stimulation may be subject to publication bias because study design and any known factors of heterogeneity were not associated with the small study effects. In the simulation, the magnitude of the placebo effect was smaller than that calculated after considering publication bias. Conclusions: Randomized three-armed trials, which are necessary for estimating the placebo effect, may be subject t

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference