Bias Due to Changes in Specified Outcomes during the Systematic Review Process

Background Adding, omitting or changing outcomes after a systematic review protocol is published can result in bias because it increases the potential for unacknowledged or post hoc revisions of the planned analyses. The main objective of this study was to look for discrepancies between primary outcomes listed in protocols and in the subsequent completed reviews published on the Cochrane Library. A secondary objective was to quantify the risk of bias in a set of meta-analyses where discrepancies between outcome specifications in protocols and reviews were found. Methods and Findings New reviews from three consecutive issues of the Cochrane Library were assessed. For each review, the primary outcome(s) listed in the review protocol and the review itself were identified and review authors were contacted to provide reasons for any discrepancies. Over a fifth (64/288, 22%) of protocol/review pairings were found to contain a discrepancy in at least one outcome measure, of which 48 (75%) were attributable to changes in the primary outcome measure. Where lead authors could recall a reason for the discrepancy in the primary outcome, there was found to be potential bias in nearly a third (8/28, 29%) of these reviews, with changes being made after knowledge of the results from individual trials. Only 4(6%) of the 64 reviews with an outcome discrepancy described the reason for the change in the review, with no acknowledgment of the change in any of the eight reviews containing potentially biased discrepancies. Outcomes that were promoted in the review were more likely to be significant than if there was no discrepancy (relative risk 1.66 95% CI (1.10, 2.49), p = 0.02). Conclusion In a review, making changes after seeing the results for included studies can lead to biased and misleading interpretation if the importance of the outcome (primary or secondary) is changed on the basis of those results. Our assessment showed that reasons for discrepancies with the protocol are not reported in the review, demonstrating an under-recognition of the problem. Complete transparency in the reporting of changes in outcome specification is vital; systematic reviewers should ensure that any legitimate changes to outcome specification are reported with reason in the review

Integrated disease management of leaf spots and crown rust of oat

Non-Peer ReviewedCrown rust and leaf spots can reduce the yield and quality of oats. The objective of this research was to determine the effect of conventional fungicides, Actigard® and oat cultivars that vary in resistance to crown rust on leaf spot and crown rust severity, and oat yield and quality. Two experiments were established at two locations in Saskatchewan: Saskatoon and Melfort. Experiment 1 consisted of three oat varieties: AC Morgan (crown rust susceptible), CDC Dancer (intermediate) and CDC Morrison (resistant) and three fungicide treatments: check (unsprayed), propiconazole and pyraclostrobin. Experiment 2 consisted of the application of Actigard® at two rates: 8.75 g ai/ha and 26.25 g ai/ha; three crop growth stages: seedling, boot and heading; on two varieties: CDC Dancer and CDC Morrison, with an unsprayed check for each variety. At Saskatoon, crown rust was observed while leaf spot severity was low. At Melfort, no crown rust was observed and leaf spot severity was low. Fungicide reduced the severity of crown rust and increased yield and quality of oat at Saskatoon for the susceptible variety (AC Morgan) and somewhat for the moderately susceptible variety (CDC Dancer). The crown rust resistant variety (CDC Morrison) did not benefit from fungicide. Leaf spots were reduced by fungicide application at Melfort, but little increase in yield or quality was detected. There was little difference between AC Morgan and CDC Morrison for leaf spot symptoms, but CDC Dancer appeared to suffer slightly more than the other varieties. There was no impact of fungicide on beta-glucan content at either location, although there were differences among varieties, but only at Saskatoon. Actigard® was not observed to have any positive or negative effects on disease severity (crown rust or leaf spots) or any of the factors measured, including nutritional characteristics, at either location, although there were differences among varieties for many of the factors measured

Integrated disease management of leaf spots and crown rust of oat

Non-Peer ReviewedCrown rust and leaf spots can reduce the yield and quality of oats. The objective of this research was to determine the effect of conventional fungicides, Actigard® and oat cultivars that vary in resistance to crown rust on leaf spot and crown rust severity, and oat yield and quality. Two experiments were established at each location in Saskatchewan: Saskatoon and Melfort. Experiment one consisted of three oat varieties: AC Morgan (crown rust susceptible), CDC Dancer (intermediate) and CDC Morrison (resistant) and three fungicide treatments: check (unsprayed), propiconazole and pyraclostrobin. Experiment two consisted of the application of Actigard® at two rates: 8.75 g ai/ha and 26.25 g ai/ha; three crop growth stages: seedling, boot and heading; on two varieties: CDC Dancer and CDC Morrison, with an unsprayed check for each variety. At Saskatoon, crown rust was observed while leaf spot severity was low. At Melfort, no crown rust was observed but leaf spot severity was low to moderate. Fungicide reduced the severity of crown rust and increased yield and quality of oat at Saskatoon for the susceptible variety (AC Morgan) and somewhat for the moderately susceptible variety (CDC Dancer). The crown rust resistant variety (CDC Morrison) did not benefit from fungicide. Leaf spots were reduced by fungicide application at Melfort, but little increase in yield or quality was detected. There was little difference between AC Morgan and CDC Morrison for leaf spot symptoms, but CDC Dancer appeared to suffer slightly more than the other varieties. There was no impact of fungicide on beta-glucan content at either location, although there were differences among varieties, but only at Saskatoon. Actigard® was not observed to have any positive or negative effects on disease severity (crown rust or leaf spots) or any of the factors measured, including nutritional characteristics, at either location, although there were differences among varieties for many of the factors measured

Self-avoiding walks on a bilayer Bethe lattice

We propose and study a model of polymer chains in a bilayer. Each chain is confined in one of the layers and polymer bonds on first neighbor edges in different layers interact. We also define and comment results for a model with interactions between monomers on first neighbor sites of different layers. The thermodynamic properties of the model are studied in the grand-canonical formalism and both layers are considered to be Cayley trees. In the core region of the trees, which we may call a bilayer Bethe lattice, we find a very rich phase diagram in the parameter space defined by the two activities of monomers and the Boltzmann factor associated to the interlayer interaction between bonds or monomers. Beside critical and coexistence surfaces, there are tricritical, bicritical and critical endpoint lines, as well as higher order multicritical points.Comment: 21 pages, 10 figures. Journal of Statistical Mechanics: Theory and Experiment (in press

Biomimetic peptide enriched nonwoven scaffolds promote calcium phosphate mineralisation

Cell-free translational strategies are needed to accelerate the repair of mineralised tissues, particularly large bone defects, using minimally invasive approaches. Regenerative bone scaffolds should ideally mimic aspects of the tissue's ECM over multiple length scales and enable surgical handling and fixation during implantation in vivo. Leveraging the knowledge gained with bioactive self-assembling peptides (SAPs) and SAP-enriched electrospun fibres, we presented a cell free approach for promoting mineralisation via apatite deposition and crystal growth, in vitro, of SAP-enriched nonwoven scaffolds. The nonwoven scaffold was made by electrospinning poly(ε-caprolactone) (PCL) in the presence of either peptide P11-4 (Ac-QQRFEWEFEQQ-Am) or P11-8 (Ac QQRFOWOFEQQ-Am), in light of the polymer's fibre forming capability and its hydrolytic degradability as well as the well-known apatite nucleating capability of SAPs. The 11-residue family of peptides (P11-X) has the ability to self-assemble into β-sheet ordered structures at the nano-scale and to generate hydrogels at the macroscopic scale, some of which are capable of promoting biomineralisation due to their apatite-nucleating capability. Both variants of SAP-enriched nonwoven used in this study were proven to be biocompatible with murine fibroblasts and supported nucleation and growth of apatite minerals in simulated body fluid (SBF) in vitro. The fibrous nonwoven provided a structurally robust scaffold, with the capability to control SAP release behaviour. Up to 75% of P11-4 and 45% of P11-8 were retained in the fibres after 7 day incubation in aqueous solution at pH 7.4. The encapsulation of SAP in a nonwoven system with apatite-forming as well as localised and long-term SAP delivery capabilities is appealing as a potential means of achieving cost-effective bone repair therapy for critical size defects

Interventions to improve adherence to reporting guidelines in health research: a scoping review protocol

Introduction There is evidence that the use of some reporting guidelines, such as the Consolidated Standards for Reporting Trials, is associated with improved completeness of reporting in health research. However, the current levels of adherence to reporting guidelines are suboptimal. Over the last few years, several actions aiming to improve compliance with reporting guidelines have been taken and proposed. We will conduct a scoping review of interventions to improve adherence to reporting guidelines in health research that have been evaluated or suggested, in order to inform future interventions. Methods and analysis Our review will follow the Joanna Briggs Institute scoping review methods manual. We will search for relevant studies in MEDLINE, EMBASE and Cochrane Library databases. Moreover, we will carry out lateral searches from the reference lists of the included studies, as well as from the lists of articles citing the included ones. One reviewer will screen the full list, which will be randomly split into two halves and independently screened by the other two reviewers. Two reviewers will perform data extraction independently. Discrepancies will be solved through discussion. In addition, this search strategy will be supplemented by a grey literature search. The interventions found will be classified as assessed or suggested, as well as according to different criteria, in relation to their target (journal policies, journal editors, authors, reviewers, funders, ethical boards or others) or the research stage at which they are performed (design, conducting, reporting or peer review). Descriptive statistical analysis will be performed. Ethics and dissemination A paper summarising the findings from this review will be published in a peer reviewed journal. This scoping review will contribute to a better understanding and a broader perspective on how the problem of adhering better to reporting guidelines has been tackled so far. This could be a major first step towards developing future strategies to improve compliance with reporting guidelines in health research

Core Outcome Set-STAndards for Development: The COS-STAD recommendations

Background The use of core outcome sets (COS) ensures that researchers measure and report those outcomes that are most likely to be relevant to users of their research. Several hundred COS projects have been systematically identified to date, but there has been no formal quality assessment of these studies. The Core Outcome Set-STAndards for Development (COS-STAD) project aimed to identify minimum standards for the design of a COS study agreed upon by an international group, while other specific guidance exists for the final reporting of COS development studies (Core Outcome Set-STAndards for Reporting [COS-STAR]). Methods and findings An international group of experienced COS developers, methodologists, journal editors, potential users of COS (clinical trialists, systematic reviewers, and clinical guideline developers), and patient representatives produced the COS-STAD recommendations to help improve the quality of COS development and support the assessment of whether a COS had been developed using a reasonable approach. An open survey of experts generated an initial list of items, which was refined by a 2-round Delphi survey involving nearly 250 participants representing key stakeholder groups. Participants assigned importance ratings for each item using a 1–9 scale. Consensus that an item should be included in the set of minimum standards was defined as at least 70% of the voting participants from each stakeholder group providing a score between 7 and 9. The Delphi survey was followed by a consensus discussion with the study management group representing multiple stakeholder groups. COS-STAD contains 11 minimum standards that are the minimum design recommendations for all COS development projects. The recommendations focus on 3 key domains: the scope, the stakeholders, and the consensus process. Conclusions The COS-STAD project has established 11 minimum standards to be followed by COS developers when planning their projects and by users when deciding whether a COS has been developed using reasonable methods

Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta

Amelogenesis imperfecta (AI) describes a heterogeneous group of inherited dental enamel defects reflecting failure of normal amelogenesis. Ameloblastin (AMBN) is the second most abundant enamel matrix protein expressed during amelogenesis. The pivotal role of AMBN in amelogenesis has been confirmed experimentally using mouse models. However, no AMBN mutations have been associated with human AI. Using autozygosity mapping and exome sequencing, we identified genomic deletion of AMBN exon 6 in a second cousin consanguineous family with three of the six children having hypoplastic AI. The genomic deletion corresponds to an in-frame deletion of 79 amino acids, shortening the protein from 447 to 368 residues. Exfoliated primary teeth (unmatched to genotype) were available from family members. The most severely affected had thin, aprismatic enamel (similar to that reported in mice homozygous for Ambn lacking exons 5 and 6). Other teeth exhibited thicker but largely aprismatic enamel. One tooth had apparently normal enamel. It has been suggested that AMBN may function in bone development. No clinically obvious bone or other co-segregating health problems were identified in the family investigated. This study confirms for the first time that AMBN mutations cause non-syndromic human AI and that mouse models with disrupted Ambn function are valid

Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis. Methods: In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01752634. Findings: Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42–13·56; p<0·0001), 150 mg (51 [51%] patients; 6·52, 3·25–13·08; p<0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14–4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. Interpretation: Subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder