Prostacyclin mimetics inhibit DRP1-mediated pro-proliferative mitochondrial fragmentation in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disorder, involving the remodelling of the small pulmonary arteries. Underlying this remodelling is the hyper-proliferation of pulmonary arterial smooth muscle cells within the medial layers of these arteries and their encroachment on the lumen. Previous studies have demonstrated an association between excessive mitochondrial fragmentation, a consequence of increased expression and post-translational activation of the mitochondrial fission protein dynamin-related protein 1 (DRP1), and pathological proliferation in PASMCs derived from PAH patients. However, the impact of prostacyclin mimetics, widely used in the treatment of PAH, on this pathological mitochondrial fragmentation remains unexplored. We hypothesise that these agents, which are known to attenuate the proliferative phenotype of PAH PASMCs, do so in part by inhibiting mitochondrial fragmentation. In this study, we confirmed the previously reported increase in DRP1-mediated mitochondrial hyper-fragmentation in PAH PASMCs. We then showed that the prostacyclin mimetic treprostinil signals via either the Gs-coupled IP or EP2 receptor to inhibit mitochondrial fragmentation and the associated hyper-proliferation in a manner analogous to the DRP1 inhibitor Mdivi-1. We also showed that treprostinil recruits either the IP or EP2 receptor to activate PKA and induce the phosphorylation of DRP1 at the inhibitory residue S637 and inhibit that at the stimulatory residue S616, both of which are suggestive of reduced DRP1 fission activity. Like treprostinil, MRE-269, an IP receptor agonist, and butaprost, an EP2 receptor agonist, attenuated DRP1-mediated mitochondrial fragmentation through PKA. We conclude that prostacyclin mimetics produce their anti-proliferative effects on PAH PASMCs in part by inhibiting DRP1-mediated mitochondrial fragmentation.

Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature.

Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.

A Pragmatic Randomized Controlled Trial of an Endoscopist Audit and Feedback Report for Colonoscopy.

INTRODUCTION: Variation in endoscopist performance contributes to poor-quality colonoscopy. Audit and feedback (A/F) can be used to improve physician performance, particularly among lower performing physicians. In this large pragmatic randomized controlled trial, we compared A/F to improve endoscopists' colonoscopy performance to usual practice. METHODS: Endoscopists practicing in Ontario, Canada, in 2014 were randomly assigned in October 2015 (index date) to receive (intervention group, n = 417) or not receive (control group, n = 416) an A/F report generated centrally using health administrative data. Colonoscopy performance was measured in both groups over two 12-month periods: prereport and postreport (relative to the index date). The primary outcome was polypectomy rate (PR). Secondary outcomes were cecal intubation rate, bowel preparation, and premature repeat after normal colonoscopy. A post hoc analysis used adenoma detection rate as the outcome. Outcomes were compared between groups for all endoscopists and for lower performing endoscopists using Poisson regression analyses under a difference-in-difference framework. RESULTS: Among all endoscopists, PR did not significantly improve from prereport to postreport periods for those receiving the intervention (relative rate [RR], intervention vs control: 1.07 vs 1.05, P = 0.09). Among lower performing endoscopists, PR improved significantly (RR, intervention vs control 1.34 vs 1.11, P = 0.02) in the intervention group compared with controls. In this subgroup, adenoma detection rate also improved but not significantly (RR, intervention vs control 1.12 vs 1.04, P = 0.12). There was no significant improvement in secondary outcomes between the intervention and control groups. DISCUSSION: A/F reports for colonoscopy improve performance in lower performing endoscopists (ClinicalTrials.gov: NCT02595775).

G protein coupled receptor kinase 5 modifies the nucleolar stress response activated by actinomycin D.

G protein coupled receptor kinase 5 (GRK5) is localized within the nucleus and moderates functions such as DNA transcription, in addition to its localization at the plasma membrane. In this report, we show that GRK5 modifies the nucleolar stress response activated by the DNA polymerase inhibitor, actinomycin D (ActD). We show an increased sensitivity to the apoptotic effects of ActD on cervical HeLa cells and the breast cancer cell line MDA MB 231 with reduced protein expression of GRK5. We also tested two types of breast cancer cells (MDA MB 231 and MCF7 cells) and found that the rate of response to ActD varied between them because they have innate differences in the protein expression of GRK5. We also found that GRK5 phosphorylates nucleophosmin (NPM1) at T199 before and during the early stages of ActD treatment. Phosphorylation at T199 increases the ability of NPM1 to interact with p14ARF in vitro, which may affect the protein expression levels of p14ARF. We found that the expression levels of p14ARF were lower in the cells transfected with the control shRNA, but higher in cells transfected with GRK5 shRNA. Collectively, this suggests that GRK5 modifies the nucleolar stress response associated with ActD.

G protein-coupled receptor kinase 2 modifies the cellular reaction to cisplatin through interactions with NADPH oxidase 4.

G protein-coupled receptor kinases (GRKs), in addition to their role in modulating signal transduction mechanisms associated with activated G protein-coupled receptors (GPCRs), can also interact with many non-GPCR proteins to mediate cellular responses to chemotherapeutics. The rationale for this study is based on the presumption that GRK2 modulates the responses of cancer cells to the chemotherapeutic cisplatin. In this report, we show that GRK2 modulates the responses of cancer cells to cisplatin. Cervical cancer HeLa cells stably transfected with GRK2 shRNA, to decrease GRK2 protein expression, show increased sensitivity to cisplatin. Of interest, these cells also show increased accumulation of NADPH, associating with decreased NADP buildup, at low concentrations of cisplatin tested. These changes in NADPH and NADP levels are also observed in the breast cancer MDA MB 231 cells, which has lower endogenous GRK2 protein expression levels, but not BT549, a breast cancer cell line with higher GRK2 protein expression. This effect of NADPH accumulation may be associated with a decrease in NADPH oxidase 4 (NOX4) protein expression, which is found to correlate with GRK2 protein expression in cancer cells-a relationship which mimics that observed in cardiomyocytes. Furthermore, like in cardiomyocytes, GRK2 and NOX4 interact to form complexes in cancer cells. Collectively, these results suggest that GRK2 interacts with NOX4 to modify cisplatin sensitivity in cancer cells and may also factor into the success of cisplatin-based regimens.

Directly Mailing gFOBT Kits to Previous Responders Being Recalled for Colorectal Cancer Screening Increases Participation.

BACKGROUND: Colorectal cancer (CRC) screening with guaiac fecal occult blood test (gFOBT) reduces CRC-related death. Average risk individuals should be recalled for screening with gFOBT every 2 years in order to maximize effectiveness. However, adherence with repeated testing is often suboptimal. Our aim was to evaluate whether adding a gFOBT kit to a mailed recall letter improves participation compared with a mailed recall letter alone, among previous responders to a mailed invitation. METHODS: We conducted a cluster randomized controlled trial, with the primary care provider as the unit of randomization. Eligible patients had completed a gFOBT and tested negative in an earlier pilot study and were now due for recall. The intervention group received a mailed CRC screening recall letter from their primary care provider plus a gFOBT kit (n = 431) while the control group received a mailed CRC screening mailed recall letter alone (n = 452). The primary outcome was the uptake of gFOBT or colonoscopy within 6 months. RESULTS: gFOBT uptake was higher in the intervention group (61.3%, n = 264) compared with the control group (50.4%, n = 228) with an absolute difference between the two groups of 10.8% (95% confidence interval [CI]: 1.4 to 20.2%, P = <0.01). Patients in the intervention group were more likely to complete the gFOBT compared with the control group (odds ratio [OR] = 1.4; 95% CI: 1.1 to 1.9). CONCLUSION: Our findings show that adding gFOBT kits to the mailed recall letter increased participation among persons recalled for screening. Nine gFOBT kits would have to be sent by mail in order to screen one additional person.

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients.

Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI2) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI2 analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ETA and ETB receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI2 analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ETA/ETB receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ETB receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ETA receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control; -32±06% PH) than either agent alone. Of note, while the ETB receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI2 analogue and a selective ETA receptor antagonist.

Pharmacology of the single isomer, esuberaprost (beraprost-314d) on pulmonary vascular tone, IP receptors and human smooth muscle proliferation in pulmonary hypertension.

BACKGROUND AND PURPOSE: Beraprost is a prostacyclin analogue and IP receptor agonist which is approved to treat pulmonary arterial hypertension (PAH) in Asia. The beraprost-314d isomer (esuberaprost) is one of four stereoisomers contained within the racemic mixture of beraprost. The pharmacological profile of esuberaprost is now evaluated to determine how stereoisomer separation affects its potency and mode of action in functional assays. EXPERIMENTAL APPROACH: Vascular tone was assessed using wire myography in rat and human distal pulmonary arteries (PAs) pre-contracted with U46619 (100 nM). HEK-293 cells stably expressing the human IP receptor (HEK-293-IP) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients were used to assess cyclic AMP (cAMP) generation and cell proliferation, respectively. KEY RESULTS: Esuberaprost relaxed rat PAs with a 5-fold greater potency compared with beraprost, and effects were strongly inhibited by RO3244794 (IP receptor antagonist) or L-NAME (NO synthase inhibitor). Esuberaprost caused EP3 receptor-dependent vasoconstriction at high concentrations ≥ 1000 nM, but contractions were 50% lower compared to beraprost. In HEK-293-IP cells, esuberaprost was 26-fold more potent (EC50 0.4 nM) at increasing cAMP than beraprost. In human PASMCs, esuberaprost was 40-fold more potent than beraprost at inhibiting cell proliferation (EC50 3 nM versus 120 nM), contrasting the 5-fold potency difference for cAMP elevation. Antiproliferative effects of esuberaprost appeared more dependent on NO than on the IP receptor. In PAs from patients with pulmonary hypertension, esuberaprost, caused some relaxation whereas beraprost instead produced a weak contraction. CONCLUSIONS AND IMPLICATIONS: Stereoisomer separation of beraprost has a significant effect on the pharmacology of the individual isomer, esuberaprost, identified in vitro as a highly potent prostanoid IP receptor agonist.

New COPE guidelines on publication process manipulation: why they matter.

Manipulation of the publication process is a relatively new form of misconduct affecting the publishing industry. This editorial describes what it is, why it is difficult for individual journal editors and publishers to handle and the background to the development of the new COPE guidelines on how to manage publication process manipulation. These new guidelines represent an important first step towards encouraging openness and collaboration between publishers to address this phenomenon.

Prostanoid EP2 Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells.

Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP2 receptor, the role of which is unknown in PAH. We hypothesised that EP2 receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP2 receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP2 (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP2 receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP2 receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP2 receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP2 receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH.

Do peer review models affect clinicians' trust in journals? A survey of junior doctors.

BACKGROUND: The aim of this survey was to determine the level of awareness and understanding of peer review and peer review models amongst junior hospital doctors and whether this influences clinical decision-making. METHODS: A 30-question online anonymous survey was developed aimed at determining awareness of peer review models and the purpose of peer review, perceived trustworthiness of different peer review models and the role of peer review in clinical decision-making. It was sent to 800 trainee doctors in medical specialties on the University College London Partners trainee database. RESULTS: The response rate was (178/800) 22%. Most respondents were specialist registrars. Checking that research is conducted correctly (152/178, 85%) and the data interpreted correctly (148/178, 83%) were viewed as the most important purposes of peer review. Most respondents were aware of open (133/178, 75%), double-blind (125/178, 70%) and single-blind peer review (121/178, 68%). 101/178 (57%) had heard of collaborative, 87/178 (49%) of post publication and 29/178 (16%) of decoupled peer review. Of those who were aware of double-blind, single-blind open and collaborative peer review, 85 (68%), 82 (68%), 74 (56%) and 24 (24%), respectively, understood how they worked. The NEJM, Lancet and The BMJ were deemed to have most trustworthy peer review, 137/178 (77%), 129/178 (72%) and 115/178 (65%), respectively. That peer review had taken place was important for a journal content to be used for clinical decision-making 152/178 (85%), but the ability to see peer review reports was not as important 22/178 (12%). Most felt there was a need for peer review training and that this should be at the specialist registrar stage of training. CONCLUSIONS: Junior hospital doctors view peer review to be important as a means of quality control, but do not value the ability to scrutinize peer review themselves. The unquestioning acceptance of peer review as final validation in the field of medicine emphasises not only the responsibility held by medical journals to ensure peer review is done well but also the need to raise awareness amongst the medical community of the limitations of the current peer review process.

How to Make Feedback More Effective? Qualitative Findings from Pilot Testing of an Audit and Feedback Report for Endoscopists.

Background. Audit and feedback (A/F) reports are one of the few knowledge translation activities that can effect change in physician behavior. In this study, we pilot-tested an endoscopist A/F report to elicit opinions about the proposed report's usability, acceptability and usefulness, and implications for knowledge translation. Methods. Semi-structured qualitative interviews were conducted with eleven endoscopists in Ontario, Canada. We tested an A/F report template comprising 9 validated, accepted colonoscopy quality indicators populated with simulated data. Interview transcripts were coded using techniques such as constant comparison and themes were identified inductively over several team meetings. Results. Four interrelated themes were identified: (1) overall perceptions of the A/F report; (2) accountability and consequences for poor performance; (3) motivation to change/improve skills; and (4) training for performance enhancement and available resources. The A/F report was well received; however, participants cited some possible threats to the report's effectiveness including the perceived threat of loss of privileges or licensing and the potential for the data to be dismissed. Conclusions. Participants agreed that A/F has the potential to improve colonoscopy performance. However, in order to be effective in changing physician behavior, A/F must be thoughtfully implemented with attention to the potential concerns of its recipients.

Audit and feedback interventions to improve endoscopist performance: Principles and effectiveness.

There is considerable variation in the quality of colonoscopy, attributable in part to endoscopist performance. Audit and feedback (A&F) provides health professionals with a summary of their performance over a period of time and is a common strategy used to improve provider performance. In this review, we discuss current understanding of the mechanism of A&F and describe specific features of effective A&F. To date, trials of A&F to improve colonoscopy performance report heterogeneous results, in part because colonoscopy is a complex procedural skill but also because the quality improvement interventions were sub-optimally implemented or inadequately evaluated. Nonetheless, evidence from a wide range of literature suggests that A&F has the potential to improve endoscopist performance. We discuss future directions for research in this area and provide guidance for providers or health system planners wishing to implement A&F to address quality of colonoscopy in their practice and/or jurisdiction.

When are clinical trials registered? An analysis of prospective versus retrospective registration.

BACKGROUND: Due to problems of publication bias and selective reporting, the ICMJE requires prospective registration of all clinical trials with an appropriate registry before the first participant is enrolled. Previous research has shown that not all clinical trials are registered at this time (prospectively). This study investigated the extent and timing of trial registration. The aims were to determine 1) the proportion of clinical trials that were registered prospectively or retrospectively and 2) when retrospective registration took place in relation to submission to the journal in which they were published. METHODS: All clinical trials published in the BMC series in 2013 were identified. All articles that met the study's inclusion criteria were categorised into one of three categories: 1) prospectively registered, 2) retrospectively registered before submission to the journal in which they were published or 3) retrospectively registered after submission to the journal in which they were published. RESULTS: One hundred and eight eligible studies were identified. Of these, 33 (31 %) reported studies that were registered prospectively, 72 reported studies that were registered retrospectively (67 %) and three articles (3 %) did not include a trial registration number. Of the 72 studies that were registered retrospectively, 66 (92 %) were registered before the article was submitted to the journal and six (8 %) were registered after the article was submitted to the journal. CONCLUSIONS: Ten years after the ICMJE requirements for prospective registration of clinical trials this study found that the majority of included clinical trials were registered retrospectively but before submission to a journal for publication. This highlights the need for organisations other than journals, such as research institutions and grant giving bodies, to be more involved in enforcing prospective trial registration.

Peer review: tips from field experts for junior reviewers.

This editorial introduces a series of tutorials by experts, who provide tips and advice for junior reviewers on how to conduct peer review based on specific study designs. The aim of these articles is to provide an easy-to-use, quick reference for those who are seeking more guidance on how to peer review biomedical research papers. Unlike previous tips and guides on peer review, this series is the first to provide advice from experts for those in their specific fields.

Retrospective analysis of the quality of reports by author-suggested and non-author-suggested reviewers in journals operating on open or single-blind peer review models.

OBJECTIVES: To assess whether reports from reviewers recommended by authors show a bias in quality and recommendation for editorial decision, compared with reviewers suggested by other parties, and whether reviewer reports for journals operating on open or single-blind peer review models differ with regard to report quality and reviewer recommendations. DESIGN: Retrospective analysis of the quality of reviewer reports using an established Review Quality Instrument, and analysis of reviewer recommendations and author satisfaction surveys. SETTING: BioMed Central biology and medical journals. BMC Infectious Diseases and BMC Microbiology are similar in size, rejection rates, impact factors and editorial processes, but the former uses open peer review while the latter uses single-blind peer review. The Journal of Inflammation has operated under both peer review models. SAMPLE: Two hundred reviewer reports submitted to BMC Infectious Diseases, 200 reviewer reports submitted to BMC Microbiology and 400 reviewer reports submitted to the Journal of Inflammation. RESULTS: For each journal, author-suggested reviewers provided reports of comparable quality to non-author-suggested reviewers, but were significantly more likely to recommend acceptance, irrespective of the peer review model (p<0.0001 for BMC Infectious Diseases, BMC Microbiology and the Journal of Inflammation). For BMC Infectious Diseases, the overall quality of reviewer reports measured by the Review Quality Instrument was 5% higher than for BMC Microbiology (p=0.042). For the Journal of Inflammation, the quality of reports was the same irrespective of the peer review model used. CONCLUSIONS: Reviewers suggested by authors provide reports of comparable quality to non-author-suggested reviewers, but are significantly more likely to recommend acceptance. Open peer review reports for BMC Infectious Diseases were of higher quality than single-blind reports for BMC Microbiology. There was no difference in quality of peer review in the Journal of Inflammation under open peer review compared with single blind.

Increasing participation in colorectal cancer screening: results from a cluster randomized trial of directly mailed gFOBT kits to previous nonresponders.

Regular screening using guaiac fecal occult blood test (gFOBT) reduces mortality from colorectal cancer (CRC). The objective of this study was to determine whether the addition of a gFOBT kit to a second mailed invitation compared to a second mailed invitation alone increases CRC screening among eligible persons who did not respond to an initial mailed invitation. We conducted a cluster randomized controlled trial, with the physician as the unit of randomization. Participants were persons who had been invited but who had not responded to an invitation for CRC screening in an earlier pilot project. The intervention group received a mailed gFOBT kit and second mailed CRC screening invitation (n = 2,008) while the control group received a second mailed CRC screening invitation alone (n = 1,586). The primary outcome was the uptake of gFOBT within 6 months of the second mailing. We found that the uptake of gFOBT was more than twice as high in the intervention group (20.1%) compared to the control group (9.6%). The absolute difference between the two groups was 10.5% (95% CI: 7.5-13.4%, p ≤ 0.0001). In a subsequent adjusted analysis, participants in the intervention group were twice as likely to complete the test as those in the control group (OR = 2.1; 95% CI: 1.6-2.6). These findings suggest that directly mailed gFOBT kits increase CRC screening participation among previous nonresponders to a mailed invitation and that approximately 10 gFOBT kits would have to be sent by mail in order to screen 1 additional person. (ClinicalTrials.gov: NCT01629004).

Why training and specialization is needed for peer review: a case study of peer review for randomized controlled trials.

BACKGROUND: The purpose and effectiveness of peer review is currently a subject of hot debate, as is the need for greater openness and transparency in the conduct of clinical trials. Innovations in peer review have focused on the process of peer review rather than its quality. DISCUSSION: The aims of peer review are poorly defined, with no evidence that it works and no established way to provide training. However, despite the lack of evidence for its effectiveness, evidence-based medicine, which directly informs patient care, depends on the system of peer review. The current system applies the same process to all fields of research and all study designs. While the volume of available health related information is vast, there is no consistent means for the lay person to judge its quality or trustworthiness. Some types of research, such as randomized controlled trials, may lend themselves to a more specialized form of peer review where training and ongoing appraisal and revalidation is provided to individuals who peer review randomized controlled trials. Any randomized controlled trial peer reviewed by such a trained peer reviewer could then have a searchable 'quality assurance' symbol attached to the published articles and any published peer reviewer reports, thereby providing some guidance to the lay person seeking to inform themselves about their own health or medical treatment. SUMMARY: Specialization, training and ongoing appraisal and revalidation in peer review, coupled with a quality assurance symbol for the lay person, could address some of the current limitations of peer review for randomized controlled trials.

Text recycling: acceptable or misconduct?

Text recycling, also referred to as self-plagiarism, is the reproduction of an author's own text from a previous publication in a new publication. Opinions on the acceptability of this practice vary, with some viewing it as acceptable and efficient, and others as misleading and unacceptable. In light of the lack of consensus, journal editors often have difficulty deciding how to act upon the discovery of text recycling. In response to these difficulties, we have created a set of guidelines for journal editors on how to deal with text recycling. In this editorial, we discuss some of the challenges of developing these guidelines, and how authors can avoid undisclosed text recycling.