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In the News
Peer Pressure
Do you know who's peer-reviewing manuscripts? For Philip Davis and his CRAP article, it appeared to be no one.
The influence of "the literature" on daily medical practice is incalculable. Through it, researchers share and pursue new avenues of discovery, while clinicians uncover the latest information about patient care strategies. Without published studies documenting the efficacy of new drugs, physicians would be hard-pressed to adopt them into practice. Every clinician has at some point mined the literature for clues to the diagnosis or management of a challenging case. The literature can even influence insurance coverage decisions, as companies determine broad policies and decide case-by-case coverage based on available published evidence. So, it is almost taken for granted that the information doctors get from studies has been arduously critiqued with a probing magnifying glass. But this may not be the case.
A communications graduate student at Cornell University, Philip Davis became intrigued by one particular peer-reviewed journal. The open source publication The Open Information Science Journal had spammed him with invitations to submit his work. Prompted by the e-mails, a suspicious Davis formed a question in his mind and blog (scholarlykitchen.sspnet.org): Would a publisher accept a completely nonsensical manuscript if the authors were willing to pay Open Access publication charges?
In a word: yes. Davis, with the help of Kent Anderson, a member of the publishing team at the New England Journal of Medicine, employed the use of software that creates grammatically correct, "context free" papers for his submission. Posing as the work of two fictional authors, the submitted paper included head-scratchers such as "In this section, we discuss existing research into red-black trees, vacuum tubes, and courseware [10]. On a similar note, recent work by Takahashi suggests a methodology for providing robust modalities, but does not offer an implementation [9]."
To top off the are-you-kidding-me exploits, the fictional authors were said to hail from the The Center for Research in Applied Phrenology based in Ithaca, New York. Quite literally, Davis was trying to submit something from CRAP. And if the person(s) "reviewing" the piece didn't pick up on the subtlety of the acronym, the study of one's personality through the shape of their skull should have set off an alarm.
Bentham Science, which owns TOISCIJ, confirmed they received his study, and four months later, Davis received a response: his article was accepted. The letter, which can be read on Davis' blog, read: "This is to inform you that your submitted article has been accepted for publication after peer-reviewing process in TOISCIJ. I would be highly grateful to you if you please fill and sign the attached fee form and covering letter and send them back via email as soon as possible to avoid further delay in publication." Included in his letter was a claim that the article underwent a peer-review, a fee schedule and a confirmation that he would send $800 to a post office box in the SAIF Zone, a tax-free complex in the United Arab Emirates.
Davis retracted the article and in the frenzied aftermath the editor-in-chief of the journal quit and the director of publications for Bentham Science then claimed they were wise to the hoax, telling the New Scientist they "tried to find out the identity of the individual by pretending the article had been accepted for publication when in fact it was not."
The issue puts Open Access journals in an unfavorable light and quality questions will inevitably form in physician's minds when paging (or clicking, rather) through one. But Davis, who submitted a similar nonsensical piece to Bentham Science earlier this year that was indeed rejected, cautions on his blog against lumping Open Access journals together: "While one should be careful not to generalize these results to other Open Access journals using similar business models, it does raise the question of whether, at least in some cases, the producer-pays-to-publish model may unduly influence editorial decision-making. One may also question whether publishers like Bentham see a lucrative opportunity from the OA movement, considering that academic libraries are establishing author publication funds to pay Open Access charges." If nothing else, Davis' question inspires some questions about the peer preview process, a process that may be surprisingly little understood.
A Closer Look at Peer Review
Peer-review is intended to ensure the scientific rigor of a published research article. Peer reviewers generally are charged with validating the research methods employed, assessing the veracity of data and statistical analyses as presented, scrutinizing the integrity of the research from inception to data analysis, and identifying any potential biases that may invalidate or diminish the impact of findings. Peer review is hardly fool-proof, as demonstrated by the 2005 Vioxx debacle, in which the New England Journal of Medicine publicly acknowledged flaws in a 2000 published report from a Merck-sponsored study of rofecoxib, alleging that manuscript authors suppressed evidence of cardiac effects caused by the medication. Certainly peer reviewers can assess the information presented in a publication, but they cannot know what relevant information is not presented.
According to the International Committee of Medical Journal Editors (ICMJE), a peer-reviewed journal is "one that submits most of its published research articles for outside review." The group of general medical journal editors whose participants meet annually and produce the Uniform Requirements for Manuscripts (URM), acknowledges that, "The number and kind of manuscripts sent for review, the number of reviewers, the reviewing procedures, and the use made of the reviewers' opinions may vary. In the interests of transparency, each journal should publicly disclose its policies in its instructions to authors."
Another group of editors, the World Association of Medical Editors (WAME, pronounced Whammy, established in 1995), "is a voluntary association of editors from countries throughout the world who seek to foster international cooperation among editors of peer-reviewed medical journals."
WAME maintains that to be peer reviewed, "a journal should have obtained external reviews for the majority of manuscripts it publishes, including all original research and review articles. Some editors request peer review for other kinds of articles, such as opinion pieces (commentaries/editorials) and correspondence." The association adds that a manuscript should have been reviewed by at least one external reviewer to be considered peer reviewed, though it is typical to have two reviewers or more.
Ironically, within the literature there is relatively little published regarding the impact of editorial peer-review. Study of the impact of peer review is difficult, due in large part to variability in peer review processes across journals. One review of peer review practices at well-known clinically-oriented journals compared to those at interdisciplinary and specialty journals showed distinct editorial review practices for each type of journal, with less reliance on editorial peer review in the former group. Variability in peer review processes, including extent of the review process, sequence of decision points in the process, blinding practices, acceptance rates, and guidelines for reviewers, "make it difficult to define a 'peer reviewed journal' in clinical medicine," according to one publication.
Selection of reviewers is itself an area of scrutiny, with some noting that selection processes and reviewer qualifications are often ill-defined. One investigation found no particular formal training or experience that predicts reviewer performance.4
One author has suggested that "peer review" has supplanted the scientific standard of "peer usage" as a method for evaluating scientific data. Peer review, a prospective validation measure, is more rapid and less expensive than peer usage, a retrospective and largely more costly undertaking. The latter method is essential to pure science with its replication of results or refutation of hypotheses, while the former may be suitable for applied science, (e.g. medical practice). However, the role of opinion and, consequently conflict of interest, may influence the usefulness of peer review. Conflicts of interest (discussed below) may permit "damaging distortions" to become "'locked-in' to clinical practice and health policy for considerable periods."5
Finally, it is worth noting that studies suggest that editorial peer review may not provide much benefit as a means of ensuring quality of biomedical research,1 but researchers maintain that "absence of evidence on efficacy and effectiveness cannot be interpreted as evidence of absence."1
Readers of the refereed literature would benefit from publication of each journal's peer review processes so that the reader can critically assess them. This practice is encouraged by both WAME and ICMJE. A systematic review of English-language journals listed in IndexMedicus in 1994, however, revealed that half did not publish clear statements about their peer review practices.
Skin Conditions Linked to Stroke, Fibromyalgia
The field of neurology is intertwined with several fields of medicine, but with a few exceptions, it's not every day the worlds of neurology and dermatology collide—unless you bite your tongue when comparing reimbursement rates or on-call schedules. However, a study published in the May 21st online edition of the Journal of Investigative Dermatology found that "patients with psoriasis, particularly if severe, have an increased risk of stroke that is not explained by major stroke risk factors identified in routine medical care."
Researchers performed a population-based cohort study of patients seen by general practitioners participating in the General Practice Research Database in the United Kingdom between 1987 and 2002. They defined mild psoriasis as "any patient with a diagnostic code of psoriasis, but no history of systemic therapy." Severe psoriasis, meanwhile, was defined as "any patient with a diagnostic code of psoriasis and a history of systemic therapy consistent with severe psoriasis." The unexposed group consisted of patients with no history of a psoriasis diagnostic code. When amended for major risk factors for stroke, both mild (hazard ratio (HR) 1.06, 95% confidence interval (CI) 1.0-1.1) and severe (1.43, 95% CI 1.1-1.9) psoriasis were independent risk factors for stroke. "The excess risk of stroke attributable to psoriasis in patients with mild and severe disease was one in 4,115 per year and one in 530 per year, respectively," the authors write.
In light of suggestions that chronic urticaria may be mediated by peripheral cutaneous nerve fiber dysfunction, researchers investigated the relationship between the skin condition and fibromyalgia syndrome (Acta Dermato-Venereologica, 89(4): 389-392). They evaluated 126 patients with chronic urticaria and found that over 70 percent had fibromyalgia syndrome. Just 16 percent of controls had fibromyalgia—higher than estimates for the general population. Researchers concluded that chronic urticaria may, "be viewed in many patients, as a consequence of fibromyalgia syndrome; in fact, skin neuropathy (fibromyalgia syndrome) may trigger neurogenic skin inflammation (chronic urticaria)."
Short Takes
iNeurologist. It probably won't be featured in a hip Apple commercial showcasing video game and dining applications, but a neurologist has developed an iPhone and iTouch application for patients suffering from headaches. Developed by Dr. Brian D. Loftus of Bellaire Neurology, iHeadache aims to capture real-time information about headaches. By following the International Headache Society Criteria (IHS Criteria) it classifies headache type by analyzing symptoms, the duration of the headache and medications taken. It then displays the headache as a migraine, probable migraine, tension headache or unclassified headache. Migraine sufferers can use the app to maintain a digital headache diary.
Excess Weight Feeds Dementia. The notion that being overweight in midlife increases later risk of dementia received a boost after a study in the International Journal of Obesity proposed that notion in the June 9th online edition. In 1963 body mass index was assessed in 1,152 participants of The Swedish Twin Registry who were between the ages of 45 and 65 years. Subjects were later screened for dementia in a prospective study with as much as 40 years of follow-up. In all, 312 participants were diagnosed with dementia. Researchers found that that men and women categorized as overweight in their midlife had an elevated risk of dementia (OR=1.59; 95% CI: 1.21-2.07, P=0.002), Alzheimer's disease (OR=1.71; 95% CI: 1.24-2.35, P=0.003), and vascular dementia (OR=1.55; 95% CI: 0.98-2.47, P=0.059), with figures adjusted for demographic factors, smoking and alcohol habits.
Adjusting for diabetes and vascular diseases did not substantially affect the associations, except for vascular dementia (OR=1.36; 95% CI: 0.82-2.56, P=0.116), "reflecting the significance of diabetes and vascular diseases in the etiology of vascular dementia," the authors wrote. "There was no significant interaction between overweight and APOE4 status, indicating that having both risk factors does not have a multiplicative effect with regard to dementia risk."
Trials to Study Stroke Device. Two clinical trials related to medical device interventions for stroke, and conducted by Medtronic, are underway. In the global CRYSTAL AF (Study of Continuous Cardiac Monitoring to Assess Atrial Fibrillation After Cryptogenic Stroke), the trial will use the Reveal XT Insertable Cardiac Monitor to assess the incidence of atrial fibrillation in patients with cryptogenic stroke or transient ischemic attack in order to aid physicians in determining the optimal course of treatment for these patients.
A second trial, called SISTERS (Spasticity In Stroke - Randomized Study), is being initiated at centers in Europe and the United States to compare the effectiveness of Intrathecal Baclofen Therapy to best medical therapy in managing generalized, severe, post-stroke spasticity. This clinical trial is designed to add to the body of clinical evidence for ITB Therapy, which is FDA-approved for the treatment of post-stroke spasticity.
Pipeline Watch: Promising Developments Reported
Several recent reports highlight progress in the development of new therapeutic agents for Parkinson's, Alzheimer's, and stroke. While final market approval could still be years away, it's worth taking note of these early developments.
Parkinson's. Preladenant, a novel A2A receptor antagonist, reduced off-time and increased on-time when used as an add-on therapy to levodopa in people with moderate to severe Parkinson's disease, developer Schering-Plough reports. Results of Phase II clinical trials, announced at the Movement Disorder Society's 13th International Congress of Parkinson's Disease and Movement Disorders in Paris, show that this overall increase in on-time was not accompanied with a disproportionate increase in dyskinesia.
A2A receptor antagonists are believed to avoid the direct activation of the dopamine pathway affected in the disease, according to Schering. "By avoiding the direct activation of the dopaminergic pathway, preladenant offers the potential to provide benefits not afforded by other available agents." said Robert Hauser, MD, director of the Parkinson's Disease and Movement Disorders Center at the University of South Florida.
The 12-week, randomized, placebo-controlled, double-blind, multicenter, multinational dose-finding trial evaluated the efficacy and safety of four different doses (1, 2, 5 or 10mg BID) of preladenant compared to placebo. A total of 253 patients with moderate to severe Parkinson's disease with motor fluctuations and dyskinesias despite optimum and stable regimen of standard treatments were enrolled. Previous treatment was continued throughout the trial.
Patients treated with preladenant at 5mg and 10mg BID experienced statistically significantly less off-time than controls (-1.6 h [p=.049] and -1.7 h/day [p=.019] versus -0.5 h/day, respectively); Preladenant significantly increased on-time, a secondary endpoint of the study at both 5mg and 10mg doses (1.4 h [p=.024] and 1.3 h/day [p=.049], respectively) compared with the placebo group (0.2 h/day). Preladenant was found to be safe and generally well-tolerated at all four doses. Common adverse events reported in the preladenant treated groups were parkinsonism (11 percent), somnolence (10 percent) and dyskinesia (nine percent), which occurred with approximately the same frequency in the placebo group. Discontinuation rates were comparable in the preladenant and placebo treated groups.
Alzheimer's. Elan Corporation and Transition Therapeutics at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease in Vienna, Austria presented Phase I data demonstrating that treatment with ELND005 (scyllo-inositol, formerly known as AZD-103) achieves desired concentrations in human brain tissue and cerebrospinal fluid when given orally. Preclinical data also were presented showing that ELND005 administration is associated with preservation of choline acetyltransferase (ChAT). ELND005 is an orally-administered drug candidate in Phase II trials for the treatment of mild to moderate Alzheimer's disease.
Also recently, Elan Corporation and Johnson & Johnson reached an agreement paving the way for Johnson & Johnson to acquire substantially all of the assets and rights of Elan related to its Alzheimer's Immunotherapy Program, through a newly formed company. In addition, Johnson & Johnson, through its affiliate, will supply $1 billion to Elan in exchange for newly issued American Depositary Receipts (ADRs) of Elan which will represent 18.4 percent of Elan's outstanding ordinary shares. Johnson & Johnson, through its affiliate, will assume and continue Elan's activities with Wyeth under the AIP Program and will initially commit up to $500 million to continue the development and launch activities of bapineuzumab, a treatment that is being evaluated for slowing the progression of Alzheimer's disease, as well as other compounds.
Stroke. An Investigational New Drug application for DP-b99 has received the go-ahead from the FDA to begin a Phase III clinical trial. DP-b99 is a neuroprotective drug for use in acute ischemic stroke. The drug "addresses an array of brain damaging processes occurring in stroke patients," and researchers will seek 770 moderate to severely affected patients worldwide for the study, according to the maker, D-Pharm. The announcement comes on the heels of successful Phase II and III studies, both showing a favorable efficacy and safety profile. In the recently completed Phase IIb trial of 150 ischemic stroke patients, the drug increased the percentage of patients who made complete recoveries by two-fold. The trial will be known as the Membrane Activated Chelator Stroke Intervention (MACSI) study.
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