Negative Clinical Trials Research Articles

Evaluating the Evidence: Statistical Methods in Randomized Controlled Trials in the Urological Literature

Randomized controlled trials potentially provide the highest level of evidence to inform clinical decision making. Appropriate use of statistical methods is a critical aspect of all clinical research, including randomized controlled trials. We report the first formal evaluation to our knowledge of the statistical methods of randomized controlled trials published in the urological literature in 1996 and 2004. All human subjects randomized controlled trials published in 4 leading urology journals in 1996 and 2004 were identified for formal review. A standardized evaluation form was developed based on the Consolidated Standards of Reporting Trials statement. Each article was evaluated by 2 independent reviewers with formal training in research design and biostatistics who were blinded to study authors and institution. Discrepancies were settled by consensus. A total of 152 randomized controlled trials were reviewed (65 in 1996, 87 in 2004). The median sample size (IQR) per arm of parallel design randomized controlled trials published in 1996 and 2004 was 36 (11, 96) and 50 (26, 134) study subjects, respectively (p = 0.157). Sample size justifications were provided by 19% of studies in 1996 and 47% of studies in 2004 (p = 0.001). Of randomized controlled trials 16 (25%) vs 32 (37%) identified a single primary outcome variable (p = 0.110). Effect size estimates for primary or secondary outcome variables were provided by 5% vs 13% (p = 0.090) and the precision of the effect was detailed by 5% vs 10% of randomized controlled trials (p = 0.195). This formal review suggests that statistical analysis in urological randomized controlled trials has improved. However, considerable deficiencies remain. Ongoing education in applied statistics may further improve urological randomized controlled trial reporting.

Clinical trial outcome in neuropathic pain

Several recent randomized clinical trials have found that the medications being evaluated for neuropathic pain did not significantly differ from placebo for the primary efficacy endpoint, despite encouraging results from prior preclinical and clinical studies. It is unclear whether these trials were unsuccessful because the medications truly lack efficacy or whether characteristics of the trials compromised the demonstration of treatment benefits. To identify factors associated with positive (i.e., favors medication) vs negative outcomes of placebo-controlled neuropathic pain trials. We examined study characteristics associated with positive vs negative clinical trial outcomes for neuropathic pain treatments using the information provided in a comprehensive meta-analysis and additional ratings for 106 clinical trials. Univariate analyses indicated that the results of medication vs placebo comparisons were more likely to be positive when medication response rates were greater, placebo response rates were lower, and studies were published earlier. In a multivariate analysis performed to identify independent contributions of study characteristics to trial outcomes, greater medication response, reduced placebo response, and larger sample sizes were each uniquely associated with positive outcomes. In addition, greater medication response rates and parallel groups designs were each independently associated with greater placebo response rates. The results suggest that study characteristics may contribute to the outcomes of clinical trials of treatments for neuropathic pain and provide an impetus for investigating strategies for decreasing placebo response rates and thereby possibly increasing the likelihood of positive outcomes in trials of efficacious treatments.

Effects of medroxyprogesterone acetate on cerebral oedema and spatial learning performance after traumatic brain injury in rats

Background: Given after brain injury (TBI), progesterone reduces cerebral oedema and facilitates functional recovery. Progesterone analogues have been synthesized for use in many medical conditions and exhibit different chemical and biological properties. Medroxyprogesterone acetate (MPA) is widely used in clinical practice, but oestrogen/MPA combinations may increase the risk of stroke and cardiovascular disease rather than preventing them. In some conditions, MPA can exhibit pharmacological actions that are different from those of natural progesterone.Primary objective and hypothesis: Using laboratory rats, this study assessed the efficacy of MPA to determine whether this progestin and natural progesterone exert similar effects as a treatment after bilateral injury to the frontal cortex.Main outcomes and results: MPA produced a dose-related reduction of cerebral oedema at 48 hours post-TBI but neither 4 nor 16 mg/kg doses of MPA enhanced behavioural recovery.Conclusion: These findings help to clarify the divergent results from prior positive progesterone studies and the negative MPA clinical trials for hormone replacement therapy. The results can be taken to suggest that the control of cerebral oedema, while clearly desirable, is not the only contributor to progesterone-induced behavioural recovery.

Trial Registration for Public Trust: Making the Case for Medical Devices

Recently, several pharmaceutical companies have been shown to have withheld negative clinical trial results from the public. These incidents have resulted in a concerted global effort to register all trials at inception, so that all subsequent results can be tracked regardless of whether they are positive or negative. These trial registration policies have been driven in large part by concern about the pharmaceutical sector. The medical device industry is much smaller, and different from the pharmaceutical industry in some fundamental ways. This paper examines the issues surrounding registration of device trials and argues that these differences with pharmaceutical should not exempt device trials from registration.

Therapeutic Hypothermia for Global and Focal Ischemic Brain Injury—A Cool Way to Improve Neurologic Outcomes

Therapeutic hypothermia (TH) has been employed as a neuroprotective strategy for a wide array of clinical problems since the late 1940s. Animal studies have determined that the neuroprotective effect of hypothermia is pleiotropic, impacting many steps in both the ischemic cascade and reperfusion injury. Interest in the neuroprotective effects of TH for ischemic brain injury has been resurgent, fueled by both recent positive and negative clinical trials. A review of preclinical and clinical reports on TH in adult patients is provided in this article. Animal data and several large clinical studies of mild to moderate TH (32 degrees C-34 degrees C) for global cerebral ischemia describe favorable neurologic outcomes, with few adverse effects. However, clinical implementation for global ischemia remains poor. Some animal data support a role for TH in focal cerebral ischemia, if instituted soon after the onset of ischemia, and in the setting of reperfusion. Clinical studies of TH for focal cerebral ischemia have so far been equivocal. The available data suggest that, despite sharing some common components in the ischemic cascade, focal and global cerebral ischemia are pathophysiologically disparate, and may respond to different neuroprotective strategies. TH is a safe, effective neuroprotective strategy for global cerebral ischemia. Because of the neuroprotective efficacy of TH in adult comatose survivors of cardiac arrest, neurologists should advocate the implementation of this strategy. TH for focal ischemia is a promising therapeutic option, but requires more basic and clinical investigation.

Evidence Based Clinical Practice: A Primer for Urologists

Evidence based clinical practice has been defined as the conscientious, explicit and judicious use of the current best evidence in making decisions about the care of individual patients. It refers to a broad set of principles and methods intended to ensure that medical decisions, guidelines and health policy are based on well designed studies of therapeutic effectiveness and benefit. We review the principles and practice of evidence based clinical practice using examples from the urology literature. We further provide a guide to currently available web based evidence based clinical practice resources and guidelines for urologists. Evidence based clinical practice integrates a hierarchy of evidence and patient values with practitioner judgment to guide decision making for the individual patient. Important steps in the evidence based clinical practice process include the formulation of an answerable question and a systematic search of the literature. In the absence of pre-appraised evidence or disease specific guidelines, the practice of evidence based clinical practice relies heavily on the evaluation of the primary literature by the individual urologist. Depending on the question domain (therapy/prevention, etiology/cause/harm, diagnosis or prognosis) and study design, a given study is critically appraised for validity, impact and applicability. Evidence is then integrated with clinical judgment, and patient circumstances and preferences. Finally, the practice of evidence based clinical practice includes a self-assessment of provider performance. Knowledge, practice and documentation of evidence based clinical practice are of increasing importance to every urologist. Urologists should embrace evidence based clinical practice principles by acquiring the necessary skills to critically appraise the literature for the best evidence applicable to patient care.

Statistical power of negative randomized clinical trials (RCTs) presented at the American Society of Clinical Oncology (ASCO) Annual Meetings

6516 Background: Underpowered randomized clinical trials (RCTs) may expose participants to risks and burdens of research without scientific merit. We investigated the prevalence of underpowered RCTs presented at ASCO annual meetings. Methods: We surveyed all two-arm parallel phase III RCTs presented at the ASCO annual meeting from 1995–2003 where differences for the primary endpoint were non-statistically significant. Post hoc calculations were performed using a power of 80% and a=0.05 (two-sided) to determine the sample size required to detect a small, medium, and large effect size between the two groups. For studies reporting a proportion or time to event as a primary endpoint, effect size was expressed as an odds ratio (OR) or hazard ratio (HR) respectively, with a small effect size defined as OR/HR=1.3, medium effect size OR/HR=1.5, and large effect OR/HR=2.0. Logistic regression was used to identify factors associated with lack of statistical power. Results: Of 423 negative RCTs for which post hoc sample size calculations could be performed, 45 (10.6%), 138 (32.6%), and 333 (78.7%) had adequate sample size to detect small, medium, and large effect sizes respectively. Only 35 negative RCTs (7.1%) reported a reason for inadequate sample size. In a multivariable model, studies presented at plenary or oral sessions (p<0.0001) and multicenter studies supported by a co-operative group were more likely to have adequate sample size (p<0.0001). Conclusion: Two-thirds of negative RCTs presented at the ASCO annual meeting do not have an adequate sample to detect a medium-sized treatment effect. Most underpowered negative RCTs do not report a sample size calculation or reasons for inadequate patient accrual. No significant financial relationships to disclose.

Importance of the negative clinical trial: advancing the field through failure

Importance of the negative clinical trial: advancing the field through failure

New Insights into the Efficacy of Naltrexone Based on Trajectory-Based Reanalyses of Two Negative Clinical Trials

The heterogeneity of clinical findings in studies evaluating the efficacy of naltrexone in the treatment of alcohol dependence has led to growing efforts to explore novel approaches to data analysis. The objective of this study was to identify distinct trajectories of daily drinking over time in two negative clinical trials and to determine whether naltrexone affected the probability to follow a particular trajectory. The Veterans Affairs (VA) Cooperative Study #425 and the Women's Naltrexone Study failed to demonstrate efficacy on primary outcome variables. Separately for each study, we analyzed daily indicators of any drinking and heavy drinking using a semiparametric group-based approach. We estimated three distinct trajectories of daily drinking (both any and heavy drinking) which we described as "abstainer," "sporadic drinker," and "consistent drinker." Naltrexone doubled the odds of following the abstainer trajectory instead of the consistent drinker trajectory but did not significantly change the odds of following the abstainer trajectory as contrasted with the sporadic drinker trajectory. Naltrexone may have a clinically meaningful effect for alcohol-dependent patients with a high chance of consistent drinking, even in studies where it failed to show efficacy in planned analyses.

Perils and Pitfalls of Small Negative Clinical Trials

Perils and Pitfalls of Small Negative Clinical Trials

Inadequate Statistical Power of Negative Clinical Trials in Urological Literature

Negative studies provide valuable information. However, conducting studies with inadequate power is unethical and an inefficient use of resources. The purpose of this study was to determine the prevalence of negative studies with inadequate power in urological literature. The Journal of Urology, Urology and BJU International (formerly British Journal of Urology) from 1982 to 2002 were searched using the Ovid MEDLINE database. All clinical trials that contained the phrase "no difference" were identified. Data necessary for power calculation were extracted from applicable studies. Of the 417 articles identified in the MEDLINE search, 127 were negative studies that contained enough information to be analyzed. There were 70 (55%) articles from The Journal of Urology, 35 (28%) from BJU International and 22 (17%) from Urology. Of the studies that used continuous variables 65% had adequate power (greater than 80%) to detect a 50% difference between groups and 32% had adequate power to detect a 25% difference. Of the studies that used dichotomous variables only 33% had adequate power to detect a 50% difference between groups and 23% had adequate power to detect a 25% difference. Levels of adequate power in negative studies did not improve over time (p = 0.258). Many negative studies in urological literature are inconclusive because they lack adequate power to detect even large differences between groups. Inadequately powered studies often result in false conclusions that alter clinical behavior and deter further research. Therefore, it is imperative to consider power when interpreting literature. When designing future investigations power calculations should be performed to ensure sufficient patient recruitment to attain clinically meaningful results.

Delayed Massive Hemorrhage after Pancreaticoduodenectomy: A New Therapeutic Approach

riority trial require that an initial difference in outcomes between groups be designated as a clinically relevant difference. Adhering to a strict interpretation of the results of the equivalency trial, one can only make conclusions with respect to the difference in outcomes initially designated. For our study, we chose 6% as that designated difference, to avoid a potentially meaningless difference in infection rate between groups, which might be statistically different but not clinically relevant. This was balanced with the sample size requirements for a smaller equivalence threshold. In Dr Lee’s example for comparing 9% infection rate for paint-only versus 4% in paint-plus-scrub, the sample size requirements would be approximately 650 patients per group (1,300 patients total). We have contributed to the literature a controlled clinical trial that was designed to test the idea that preoperative scrubbing of skin with povidone-iodine soap adds no incremental protection against wound infection. We do not agree with Dr Lee that our results have the same interpretation as a hypothetical trial, where the actual infection frequency was 9% in the paint-only arm and 4% in the paint-plus-scrub arm. Although Dr Lee’s worst-case outcomes would be within the tolerance of our 6% equivalence threshold based on our current results and the results of previous trials, that specific outcome would be unlikely given the data that has been reported as of this writing. Admittedly, Dr Lee is correct that the interpretation of our results has not added to the possible knowledge-space: povidone-iodine scrubbing might add benefit, might have no effect at all, or might actually increase infection likelihood. Statistical reasoning does not deal in perfect knowledge states. It can lead to conclusions that speak to the likelihood of outcomes. We would argue that our data have shown that the advantage of povidone-iodine scrubbing over paint-only is minimal at best because it is the most likely interpretation. Despite the results of even the most rigorously designed single clinical trial, the thoughtful clinician will always weigh the pros and cons of altering his or her clinical practice. Results of our single clinical trial must be interpreted in the context of the four earlier clinical trials available for review, all of which are cited in our publication. Each of these was a negative trial, and each trial compared the “gold standard” scrub-plus-paint to something different and often less than scrub-pluspaint. In view of this body of literature and our clearly negative clinical trial, an objective observer who is not lost in the vagaries of statistical minutiae, can conclude that a reasonable argument can be made for abandoning scrub-and-paint.

Targeted Anticytokine Therapy and the Failing Heart

Recent studies have identified the importance of proinflammatory mediators in the development and progression of chronic heart failure (CHF). The growing appreciation of the pathophysiologic consequences of sustained expression of proinflammatory mediators in preclinical and clinical CHF models culminated in a series of multicenter clinical trials that used targeted approaches to neutralize tumor necrosis factor in patients with moderate-to-advanced CHF. However, these targeted approaches have resulted in worsening CHF, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of CHF. This review summarizes what has been learned from the negative clinical trials, as well as the potential direction of future research in this area.

Infection, Antibiotics, and Atherothrombosis — End of the Road or New Beginnings?

Two large, high-quality, and convincingly negative clinical trials for the secondary prevention of coronary heart disease,1,2 published in this issue of the Journal, raise questions as to whether we are at the end of the road or should move on to new beginnings as we explore the hypothesis that infection plays a role in atherosclerosis. Evidence that vascular inflammation is an important mechanism involved in all stages of atherogenesis continues to accumulate. Such evidence has legitimately raised the question of whether infection is one of the inflammatory stimuli that operate in the pathophysiology of atherothrombosis, either locally, within vascular . . .

Free Radical Trapping as a Therapeutic Approach to Neuroprotection in Stroke: Experimental and Clinical Studies with NXY-059 and Free Radical Scavengers

There is substantial experimental evidence that free radicals are produced in the brain during ischemia, during reperfusion and during intracranial hemorrhage. Removal of pathologically produced free radicals is therefore a viable approach to neuroprotection. Four compounds with free radical scavenging activity (tirilazad, ebselen, edaravone) or free radical trapping properties (NXY-059) have been examined in experimental models of stroke and evaluated clinically as neuroprotective agents. Both experimental and clinical results are reviewed in this article. Ebselen was a modestly effective neuroprotectant in a rat transient middle cerebral artery occlusion (MCAO) model when given before the start of ischemia, but not when the insult was severe. Data from the permanent MCAO model and an embolic stroke model suggested a bell shaped dose-response curve. The weak preclinical profile may explain the lack of success in clinical trials. Preclinical data on tirilazad in animal models of acute ischemic stroke are neither comprehensive nor consistent. There was little evidence of efficacy in permanent MCAO or when the drug was given several hours post-occlusion. This may explain the negative clinical trials as these did not target patients likely to reperfuse and treatment started several hours after stroke onset. While preclinical data on subarachnoid hemorrhage demonstrated an attenuation of vasospasm the clinical data were inconsistent. There is very limited published preclinical data on edaravone but it has been approved in Japan as a neuroprotectant for the treatment of stroke. Evidence is based on a single placebo controlled trial in a relatively small number of patients. The status of possible development of edaravone outside of Japan is not known. NXY-059 has been found to be a very effective agent in transient and permanent MCAO and thromboembolic models of acute ischemic stroke. Its preclinical development has been governed by adherence with the recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR) group and is now being investigated in Phase III clinical trials using a therapeutic time window and plasma concentrations that are effective in rat and primate models of stroke.

Confusion, Concern, Self Interest and Science: The Recent SSRI and Youth Suicide Conflagration

Free AccessConfusion, Concern, Self Interest and Science: The Recent SSRI and Youth Suicide ConflagrationMatthew Kutcher and Stan KutcherMatthew Kutcher1. Dalhousie UniversitySearch for more papers by this author and Stan KutcherSearch for more papers by this authorPublished Online:July 2005https://doi.org/10.1521/capn.10.1.1.67070PDFPDF PLUS ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutReferencesCohen , D., Gerardin, P., Mazet, P., Purper–Ouakil, D., & Flament, M. F. (2004). Pharmacological treatment of adolescent major depression. Journal of Child and Adolescent Psychopharmacolgy, 14, 19–31. Crossref, Google ScholarBrophy, B. (1995). Kindergarteners in Prozac nation. US News and World Report, Nov 13, pp. 96–97. Google ScholarClavenna , A. (2004). Increase in non–evidence based use of antidepressants in children is cause for concern. BMJ, 328, 711–712. Crossref, Google ScholarWilnes , T. E., Biederman, J., & Kwon, A. (2003). A systematic chart review of the nature of psychiatric adverse events in children and adolescents treated with serotonin–selective reuptake inhibitors. Journal of Child and Adolescent Psychopharmacology, 13, 143–152. Crossref, Google ScholarOlfson , M., Shaffer, D., Marcus, S. C., & Greenberg, T. (2003). Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry, 60, 978–982. Crossref, Google ScholarOransky , I. (2003). FDA questions antidepressant safety for children. The Lancet, 362, 1558. Crossref, Google ScholarMoynihan , R. (2004). FDA advisory panel calls for suicide warnings over new antidepressants. BMJ, 328, 303–305. Crossref, Google ScholarAmerican College of Neuropsychopharmacology (ACNP). Executive summary: preliminary report of the task force on SSRIs and suicide behavior in youth, 2004. http://www.acnp.org/exec.summary.pdf Google ScholarCouzins , J. (2004). Volatile Chemistry: Children and Antidepressants. Science, 305, 468–470. Crossref, Google ScholarThe New York Times. Risks of Antidepressants. 09/16/2004. http://www.yourlawyer.com/practice/printnews.htm?story_id=8543 (access Nov 2004) Google ScholarTreatment for Adolescents with Depression Study (TADS) Team (2004). Fluoxetine, Cognitive–Behavioral Therapy, and Their Combination for Adolescents with Depression. JAMA, 292, 807–820. Crossref, Google ScholarAvorn, J. (2004). Powerful Medicines. Knopf, New York. Google Scholar Next article FiguresReferencesRelatedDetails Cited byCited by1. A longitudinal item response model for Aberrant Behavior Checklist (ABC) data from children with autismOnline publication date: 13 April 2020. Go to citation Crossref Google Scholar Volume 10Issue 1Feb 2005 Information© The Guilford PressPDF download

Leading Medical Journals Toughen Requirements for Publication

Back to table of contents Previous article Next article Professional NewsFull AccessLeading Medical Journals Toughen Requirements for PublicationJim RosackJim RosackSearch for more papers by this authorPublished Online:15 Oct 2004https://doi.org/10.1176/pn.39.20.0390002In a bold undertaking, the editors of some of the world's most prestigious peer-reviewed medical journals announced in September that they will“ require, as a condition of consideration for publication, registration in a public trials registry” for all articles written about clinical trials. The announcement moves an APA goal one step closer to fruition.The group of 11 editors, known as the International Committee of Medical Journal Editors (ICMJE), said that for any clinical trial that starts enrollment after July 1, 2005, the trial must register “at or before the onset of patient enrollment.” For trials that begin enrollment prior to that date, registration will be required as a condition of consideration for publication as of September 13, 2005.“In return for the altruism and trust that make clinical research possible,” the ICMJE editors (Original article: see box below) wrote, “the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor's product.“Unfortunately,” the editors continued, “selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision making.”The ICMJE defined a clinical trial as “any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome.”The ICMJE did not dictate trial registration in a specific registry, instead delineating the principles it believes a registry should meet. The registry should be independently managed by a nonprofit organization and must be open to all registrants and freely accessible to the public. In addition, the editors said, there must be some mechanism for ensuring the validity of the information, and the database should be electronically searchable. The editors also created a comprehensive list of minimal data that should be contained in the registry record.Currently, the only clinical trials database that will satisfy the ICMJE requirements is the National Library of Medicine's<www.clinicaltrials.gov>. In recent months, several pharmaceutical companies said they will begin listing their clinical trials data on their own Web sites. Last month, during a congressional hearing on alleged withholding of negative clinical trials data involving antidepressants, the drug industry's trade group, the Pharmaceutical Research and Manufacturers of America, announced it would develop an online registry “to improve the transparency of the drug development process.”In addition, several members of the House of Representatives and Senate have announced that they are working to introduce legislation mandating a federally administered clinical trials registry.All of the current efforts follow the advocacy efforts of APA and the American Academy of Child and Adolescent Psychiatry (AACAP). In June 2003 APA and AACAP jointly introduced a resolution at the AMA's House of Delegates asking the AMA to support and advocate for a registry. That resolution led to a report on the issue by the AMA's Council on Scientific Affairs. Last June, an APA/AACAP joint resolution was finally approved, cementing AMA's support of a formal clinical trials registry.As this article went to press, the editorial board of the American Journal of Psychiatry was expected to review the ICMJE statement. While AJP and the other journals published by American Psychiatric Publishing Inc. are not members of ICMJE, the journals have historically conformed to ICMJE policy.The ICMJE's statement on clinical trials registry can be accessed online at<www.icmje.org> by clicking on “Clinical Trials Registry” under “ICMJE Editorials.” ▪ ISSUES NewArchived

Proceedings of the Princeton Conference on Cerebrovascular Disease. April 2-4, 2004, Baltimore, Maryland, USA.

The Princeton Conference has a one-half century history as a unique, highly focused forum for the presentation and discussion of current scientific information and future directions in stroke research. The 24th Princeton Conference on Cerebrovascular Disease was held in Baltimore, Maryland, April 2 to 4, 2004, at the Baltimore Marriott Waterfront Hotel. This conference focused on the current status and future directions of stroke pathophysiology, diagnosis and treatment, with emphasis on cellular and molecular mechanisms of ischemic cell death and cell repair, and clinical aspects of imaging, risk factors, and therapeutic strategies in stroke. There were 10 major areas of presentation and discussion. The meeting began with a discussion of vascular dementia and included discussion of amyloid and epidemiology of Alzheimer disease and vascular dementias. The next discussion concerned multimodal imaging and its future in stroke. The role of sex steroids in stroke was the next area of discussion. Estrogen and progesterone were discussed as potential neuroprotection agents, and their differences as neuroprotectants in animal models was discussed in light of the recent major negative clinical trials. The ischemic penumbra, what it is, how to image it and its molecular identification …

Can a brief video intervention improve breast cancer clinical trial knowledge and beliefs?

A total of 262 women in the USA (161 breast cancer survivors and 101 controls) were exposed to a video vignette using modeling in which a physician discussed the concept of a clinical trial (CT) with a woman who was in the process of making a treatment decision. A pretest-post-test design was used and improvements in clinical trial knowledge and beliefs were assessed. Results indicate that video modeling is a powerful tool for increasing CT knowledge (pretest mean=41.5% correct, post-test mean=77.5% correct) but not for improving CT beliefs. Increased clinical trial knowledge, as measured by change scores, was associated with white race, lower levels of education and pretest breast cancer knowledge, more negative pretest CT beliefs, and a higher estimate of the lifetime probability that a woman will have breast cancer. When pretest CT knowledge was added to the analysis using hierarchical multiple regression, all variables except white race became nonsignificant; an increase in CT knowledge was associated with having lower pretest CT knowledge. Results indicate that the effects of low education, low breast cancer knowledge, and biased probability assessment were mediated through the pretest score. An increase in post-test positive CT beliefs was associated with older age, thinking about breast cancer less often, and having lower pretest CT knowledge in the total sample. When pretest CT beliefs was added to the analysis using hierarchical multiple regression, all other variables became nonsignificant; an increase in CT beliefs was associated with having lower pretest CT beliefs, again indicating mediation of the effects of other variables.

Inflammatory mediators and the failing heart: a translational approach.

Recent studies have identified the importance of proinflammatory mediators in regulating cardiac structure in health and disease. Recent studies suggest that cytokines that are expressed within the myocardium in response to a environmental injury, namely tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and the interleukin-6 (IL-6) family of cytokines play an important role in initiating and integrating homeostatic responses within the heart. However, these "stress-activated" cytokines all have the potential to produce cardiac decompensation when expressed at sufficiently high concentrations. Indeed, there is now a growing appreciation that these molecules may play an important role in mediating disease progression in the failing heart. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in pre-clinical and clinical heart failure models culminated in a series of multicenter clinical trials that utilized "targeted" approaches to neutralize tumor necrosis factor (TNF) in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.