A panel of kallikrein markers can predict outcome of prostate biopsy following clinical work-up: an independent validation study from the European Randomized Study of Prostate Cancer screening, France

<p>Abstract</p> <p>Background</p> <p>We have previously shown that a panel of kallikrein markers - total prostate-specific antigen (PSA), free PSA, intact PSA and human kallikrein-related peptidase 2 (hK2) - can predict the outcome of prostate biopsy in men with elevated PSA. Here we investigate the properties of our panel in men subject to clinical work-up before biopsy.</p> <p>Methods</p> <p>We applied a previously published predictive model based on the kallikrein panel to 262 men undergoing prostate biopsy following an elevated PSA (≥ 3 ng/ml) and further clinical work-up during the European Randomized Study of Prostate Cancer screening, France. The predictive accuracy of the model was compared to a "base" model of PSA, age and digital rectal exam (DRE).</p> <p>Results</p> <p>83 (32%) men had prostate cancer on biopsy of whom 45 (54%) had high grade disease (Gleason score 7 or higher). Our model had significantly higher accuracy than the base model in predicting cancer (area-under-the-curve [AUC] improved from 0.63 to 0.78) or high-grade cancer (AUC increased from 0.77 to 0.87). Using a decision rule to biopsy those with a 20% or higher risk of cancer from the model would reduce the number of biopsies by nearly half. For every 1000 men with elevated PSA and clinical indication for biopsy, the model would recommend against biopsy in 61 men with cancer, the majority (≈80%) of whom would have low stage <it>and </it>low grade disease at diagnosis.</p> <p>Conclusions</p> <p>In this independent validation study, the model was highly predictive of prostate cancer in men for whom the decision to biopsy is based on both elevated PSA and clinical work-up. Use of this model would reduce a large number of biopsies while missing few cancers.</p

Managing action research: the PEArL framework

The difficulty of managing and validating Action Research field studies has been widely discussed. Several different approaches to Action Research have emerged, and one of the most widely used models is Checkland’s FMA model, where a framework is provided to facilitate interested individuals in ‘recovering’ the route of the inquiry. In this paper, I argue that the FMA model is a valuable tool for planning the application of theoretical ideas in a practical situation, but that, as a guide to Action Research, it still fails to provide a sense of the manner in which an inquiry is undertaken. The PEArL mnemonic has been previously offered as a guide to facilitate researchers, participants, and those interested in gaining an appreciation of the manner in which an inquiry is conducted. In this paper, it is argued that applying the PEArL elements does not provide insight into the dynamic nature of collaborative inquiry. In order to gain a sense of the manner in which an inquiry was undertaken it is necessary to apply the PEArL mnemonic alongside a framework that facilitates the flow of the action research cycle. To illustrate the framework, an Action Research field study is described that was undertaken with residents and key workers in a shelter for the homeless, where the aim was to create a shared understanding of complex needs and support requirements

Acupuncture for dyspnea in advanced cancer: a randomized, placebo-controlled pilot trial [ISRCTN89462491]

BACKGROUND: Dyspnea, or shortness of breath, is a common symptom in patients with advanced cancer. Pharmacologic management is of proven benefit, but it does not help all patients. Preliminary data suggest that acupuncture can relieve dyspnea in a variety of populations, including cancer patients. We conducted a pilot study (ISRCTN89462491) preparatory to a fully powered randomized, placebo-controlled trial to determine whether acupuncture reduces dyspnea in patients with lung or breast cancer. METHODS: The study sample was comprised of forty-seven patients with lung or breast cancer presenting with dyspnea. Patients receiving symptomatic treatments were not excluded as long as no changes in management were planned during the trial. Patients were randomized to receive a single session of true or placebo acupuncture in addition to their existing dyspnea treatments. Semi-permanent acupuncture "studs" were then inserted: patients applied pressure to these studs twice a day to provide ongoing stimulation to acupuncture points. The subjective sensation of dyspnea was assessed with a 0 – 10 numerical rating scale immediately before and after acupuncture treatment and daily for a week thereafter. RESULTS: All but two of 47 randomized patients provided follow-up data. Dyspnea scores were slightly higher for patients receiving true versus placebo acupuncture, for both the period immediately following acupuncture treatment and for the daily one week follow-up (differences between means of 0.34, 95% C.I. -0.33, 1.02 and 0.56, 95% C.I. -0.39, 1.51). The 95% confidence interval excludes the prespecified minimum clinically significant difference of a 20% greater improvement in dyspnea for patients receiving acupuncture. CONCLUSION: The acupuncture technique used in this trial is unlikely to have effects on dyspnea importantly larger than placebo for patients with advanced cancer

Evidence-based effect size estimation:An illustration using the case of acupuncture for cancer-related fatigue

<p>Abstract</p> <p>Background</p> <p>Estimating a realistic effect size is an important issue in the planning of clinical studies of complementary and alternative medicine therapies. When a minimally important difference is not available, researchers may estimate effect size using the published literature. This evidence-based effect size estimation may be used to produce a range of empirically-informed effect size and consequent sample size estimates. We provide an illustration of deriving plausible effect size ranges for a study of acupuncture in the relief of post-chemotherapy fatigue in breast cancer patients.</p> <p>Methods</p> <p>A PubMed search identified three uncontrolled studies reporting the effect of acupuncture in relieving fatigue. A separate search identified five randomized controlled trials (RCTs) with a wait-list control of breast cancer patients receiving standard care that reported data on fatigue. We use these published data to produce best, average, and worst-case effect size estimates and related sample size estimates for a trial of acupuncture in the relief of cancer-related fatigue relative to a wait-list control receiving standard care.</p> <p>Results</p> <p>Use of evidence-based effect size estimation to calculate sample size requirements for a study of acupuncture in relieving fatigue in breast cancer survivors relative to a wait-list control receiving standard care suggests that an adequately-powered phase III randomized controlled trial comprised of two arms would require at least 101 subjects (52 per arm) if a strong effect is assumed for acupuncture and 235 (118 per arm) if a moderate effect is assumed.</p> <p>Conclusion</p> <p>Evidence-based effect size estimation helps justify assumptions in light of empirical evidence and can lead to more realistic sample size calculations, an outcome that would be of great benefit for the field of complementary and alternative medicine.</p

Simpson's Paradox, Lord's Paradox, and Suppression Effects are the same phenomenon – the reversal paradox

This article discusses three statistical paradoxes that pervade epidemiological research: Simpson's paradox, Lord's paradox, and suppression. These paradoxes have important implications for the interpretation of evidence from observational studies. This article uses hypothetical scenarios to illustrate how the three paradoxes are different manifestations of one phenomenon – the reversal paradox – depending on whether the outcome and explanatory variables are categorical, continuous or a combination of both; this renders the issues and remedies for any one to be similar for all three. Although the three statistical paradoxes occur in different types of variables, they share the same characteristic: the association between two variables can be reversed, diminished, or enhanced when another variable is statistically controlled for. Understanding the concepts and theory behind these paradoxes provides insights into some controversial or contradictory research findings. These paradoxes show that prior knowledge and underlying causal theory play an important role in the statistical modelling of epidemiological data, where incorrect use of statistical models might produce consistent, replicable, yet erroneous results

Lines of Descent: Kuhn and Beyond

yesThomas S. Kuhn is famous both for his work on the Copernican Revolution and his ‘paradigm’ view of scientific revolutions. But Kuhn later abandoned the notion of paradigm (and related notions) in favour of a more ‘evolutionary’ view of the history of science. Kuhn’s position therefore moved closer to ‘continuity’ models of scientific progress, for instance ‘chain-of-reasoning’ models, originally championed by D. Shapere. The purpose of this paper is to contribute to the debate around Kuhn’s new ‘developmental’ view and to evaluate these competing models with reference to some major innovations in the history of cosmology, from Copernicanism to modern cosmology. This evaluation is made possible through some unexpected overlap between Kuhn’s earlier discontinuity model and various versions of the later continuity models. It is the thesis of this paper that the ‘chain-of-reasoning’ model accounts better for the cosmological evidence than both Kuhn’s early paradigm model and his later developmental view of the history of science

The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial

BACKGROUND: At the time of feasibility work and final design of the trial there was no randomised control trial evidence for the long-term risks and benefits of hormone replacement therapy. Observational studies had suggested that long term use of estrogen was likely to be associated, amongst other things, with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer. Concomitant use of progestogens had been shown to protect against endometrial cancer, but there were few data showing how progestogen might affect estrogen actions on other conditions. Disease specific risks from observational studies suggested that, overall, long-term HRT was likely to be beneficial. Several studies showed that mortality from all causes was lower in HRT users than in non-users. Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women. The WISDOM trial was designed to compare combined estrogen and progestogen versus placebo, and estrogen alone versus combined estrogen and progestogen. During the development of WISDOM the Women's Health Initiative trial was designed, funded and started in the US. DESIGN: Randomised, placebo, controlled, trial. METHODS: The trial was set in general practices in the UK (384), Australia (94), and New Zealand (24). In these practices 284175 women aged 50–69 years were registered with 226282 potentially eligible. We sought to randomise 22300 postmenopausal women aged 50 – 69 and treat for ten years. The interventions were: conjugated equine estrogens, 0.625 mg orally daily; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily; matched placebo. Primary outcome measures were: major cardiovascular disease, osteoporotic fractures, breast cancer and dementia. Secondary outcomes were: other cancers, all cause death, venous thromboembolism and cerebro-vascular disease. RESULTS: The trial was prematurely closed during recruitment following publication of early results from the Women's Health Initiative. At the time of closure, 56583 had been screened, 8980 entered run-in, and 5694 (26% of target of 22,300) randomised. Those women randomised had received a mean of one year of therapy, mean age was 62.8 years and total follow-up time was 6491 person years. DISCUSSION: The WISDOM experience leads to some simple messages. The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery. When a trial is very costly and beyond the resources of one country, funders and investigators should make every effort to develop international collaboration with joint funding

Getting inside acupuncture trials - Exploring intervention theory and rationale

<p>Abstract</p> <p>Background</p> <p>Acupuncture can be described as a complex intervention. In reports of clinical trials the mechanism of acupuncture (that is, the process by which change is effected) is often left unstated or not known. This is problematic in assisting understanding of how acupuncture might work and in drawing together evidence on the potential benefits of acupuncture. Our aim was to aid the identification of the assumed mechanisms underlying the acupuncture interventions in clinical trials by developing an analytical framework to differentiate two contrasting approaches to acupuncture (traditional acupuncture and Western medical acupuncture).</p> <p>Methods</p> <p>Based on the principles of realist review, an analytical framework to differentiate these two contrasting approaches was developed. In order to see how useful the framework was in uncovering the theoretical rationale, it was applied to a set of trials of acupuncture for fatigue and vasomotor symptoms, identified from a wider literature review of acupuncture and early stage breast cancer.</p> <p>Results</p> <p>When examined for the degree to which a study demonstrated adherence to a theoretical model, two of the fourteen selected studies could be considered TA, five MA, with the remaining seven not fitting into any recognisable model. When examined by symptom, five of the nine vasomotor studies, all from one group of researchers, are arguably in the MA category, and two a TA model; in contrast, none of the five fatigue studies could be classed as either MA or TA and all studies had a weak rationale for the chosen treatment for fatigue.</p> <p>Conclusion</p> <p>Our application of the framework to the selected studies suggests that it is a useful tool to help uncover the therapeutic rationale of acupuncture interventions in clinical trials, for distinguishing between TA and MA approaches and for exploring issues of model validity. English language acupuncture trials frequently fail to report enough detail relating to the intervention. We advocate using this framework to aid reporting, along with further testing and refinement of the framework.</p

Decrease of miR-146b-5p in Monocytes during Obesity Is Associated with Loss of the Anti-Inflammatory but Not Insulin Signaling Action of Adiponectin

Background: Low adiponectin, a well-recognized antidiabetic adipokine, has been associated with obesity-related inflammation, oxidative stress and insulin resistance. Globular adiponectin is an important regulator of the interleukin-1 receptor-associated kinase (IRAK)/NFkB pathway in monocytes of obese subjects. It protects against inflammation and oxidative stress by inducing IRAK3. microRNA (miR)-146b-5p inhibits NFkB-mediated inflammation by targeted repression of IRAK1 and TNF receptor-associated factor-6 (TRAF6). Therefore, we measured the expression of miR-146b-5p in monocytes of obese subjects. Because it was low we determined the involvement of this miR in the anti-inflammatory, antioxidative and insulin signaling action of globular adiponectin. Methods: miR-146b-5p expression in monocytes of obese subjects was determined by qRT-PCR. The effect of miR-146b-5p silencing on molecular markers of inflammation, oxidative stress and insulin signaling and the association with globular adiponectin was assessed in human THP-1 monocytes. Results: miR-146b-5p was downregulated in monocytes of obese persons. Low globular adiponectin decreased miR-146b-5p and IRAK3 in THP-1 monocytes, associated with increased mitochondrial reactive oxygen species (ROS). Intracellular ROS and insulin receptor substrate-1 (IRS1) protein were unchanged. Silencing of miR-146b-5p with an antisense inhibitor resulted in increased expression of IRAK1 and TRAF6 leading to more NFkB p65 DNA binding activity and TNFa. As