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1.  Comparative safety of anti-epileptic drugs among infants and children exposed in utero or during breastfeeding: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2014;3:68.
Background
Epilepsy affects about 1% of the general population. Anti-epileptic drugs (AEDs) prevent or terminate seizures in individuals with epilepsy. Pregnant women with epilepsy may continue taking AEDs. Many of these agents cross the placenta and increase the risk of major congenital malformations, early cognitive and developmental delays, and infant mortality. We aim to evaluate the comparative safety of AEDs approved for chronic use in Canada when administered to pregnant and breastfeeding women and the effects on their infants and children through a systematic review and network meta-analysis.
Methods
Studies examining the effects of AEDs administered to pregnant and breastfeeding women regardless of indication (e.g., epilepsy, migraine, pain, psychiatric disorders) on their infants and children will be included. We will include randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort, registry, and case-control studies. The main literature search will be executed in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We will seek unpublished literature through searches of trial protocol registries and conference abstracts. The literature search results screening, data abstraction, and risk of bias appraisal will be performed by two individuals, independently. Conflicts will be resolved through discussion. The risk of bias of experimental and quasi-experimental studies will be appraised using the Cochrane Effective Practice and Organization of Care Risk-of-Bias tool, methodological quality of observational studies will be appraised using the Newcastle-Ottawa Scale, and quality of reporting of safety outcomes will be conducted using the McMaster Quality Assessment Scale of Harms (McHarm) tool. If feasible and appropriate, we will conduct random effects meta-analysis. Network meta-analysis will be considered for outcomes that fulfill network meta-analysis assumptions.
The primary outcome is major congenital malformations (overall and by specific types), while secondary outcomes include fetal loss/miscarriage, minor congenital malformations (overall and by specific types), cognitive development, psychomotor development, small for gestational age, preterm delivery, and neonatal seizures.
Discussion
Our systematic review will address safety concerns regarding the use of AEDs during pregnancy and breastfeeding. Our results will be useful to healthcare providers, policy-makers, and women of childbearing age who are taking anti-epileptic medications.
Systematic review registration
PROSPERO CRD42014008925.
doi:10.1186/2046-4053-3-68
PMCID: PMC4086277  PMID: 24964932
Anti-epileptic drug; Breastfeeding; Comparative safety; Congenital malformation; Epilepsy; Fetus; Infant; Network meta-analysis; Pregnancy; Systematic review
2.  Safety and effectiveness of antiretroviral therapies for HIV-infected women and their infants and children: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2014;3:51.
Background
Antiretroviral therapy reduces mother-to-child transmission of human immunodeficiency virus (HIV) during pregnancy, delivery, and breastfeeding. However, these agents have been associated with preterm birth, anemia and low birth weight. We aim to evaluate the comparative safety and effectiveness of the use of antiretroviral drugs among HIV-infected women and the effects on their infants and children through a systematic review and network meta-analysis.
Methods/Design
Studies examining the effects of six antiretroviral drug classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, co-receptor inhibitors) administered to HIV-infected pregnant women will be included. We will include randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort, registry, and case–control studies. No limitations will be imposed on publication status (that is, unpublished studies are eligible for inclusion), duration of follow-up, study conduct period, and language of dissemination. Comprehensive literature searches will be conducted in major electronic databases, including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Gray literature will be identified through searching dissertation databases, trial protocol registries, and conference abstracts.
Two team members will independently screen all citations, full-text articles, and abstract data; conflicts will be resolved through discussion. The risk of bias and methodological quality will be appraised using appropriate tools (for example, Cochrane Collaboration’s tool for assessing risk of bias, Newcastle-Ottawa Scale, and McMaster Quality Assessment Scale of Harms). If feasible and appropriate, we will conduct random effects meta-analysis. Network meta-analysis will be considered for outcomes with the greatest number of treatment comparisons available that fulfill network meta-analysis assumptions (for example, consistency of evidence between direct and indirect data, and low statistical heterogeneity between included studies).
The primary effectiveness outcome is mother-to-child transmission of HIV, and the primary safety outcome is major congenital malformation (overall and specific types) among newborns of HIV-infected women. Secondary safety outcomes include stillbirths, infant/child death, preterm delivery, overall and specific minor congenital malformations, and small for gestational age infants.
Discussion
Our systematic review will be of utility to healthcare providers, policy-makers, and HIV-positive women regarding the use of antiretroviral drugs.
Trial registration
PROSPERO registry number: CRD42014009071.
doi:10.1186/2046-4053-3-51
PMCID: PMC4039063  PMID: 24887455
antiretroviral therapy; breastfeeding; congenital malformation; human immunodeficiency virus; fetus; mother-to-child-transmission; pregnancy
3.  Effectiveness of brief interventions as part of the Screening, Brief Intervention and Referral to Treatment (SBIRT) model for reducing the nonmedical use of psychoactive substances: a systematic review 
Systematic Reviews  2014;3:50.
Background
The purpose of this systematic review is to assess the effectiveness of brief interventions (BIs) as part of the Screening, Brief Intervention, and Referral to Treatment (SBIRT) model for reducing the nonmedical use of psychoactive substances.
Methods
Bibliographic databases (including MEDLINE, Embase, The Cochrane Library, CINAHL, and PsycINFO to April 2012) and gray literature sources were searched. We included randomized controlled trials that opportunistically screened adolescents or adults and then provided a one-to-one, verbal BI to those at risk of substance-use harm. Of interest was the nonmedical use of psychoactive substances (for example, drugs prohibited by international law), excluding alcohol, nicotine, and caffeine. Interventions comprised four or fewer sessions and were compared with no/delayed intervention or provision of information only. Studies were assessed for bias using the Cochrane risk of bias tool. Results were synthesized narratively. Evidence was interpreted according to the GRADE framework.
Results
We identified 8,836 records. Of these, five studies met our inclusion criteria. Two studies compared BI with no BI, and three studies compared BI with information only. Studies varied in characteristics such as substances targeted, screening procedures, and BI administered. Outcomes were mostly reported by a single study, leading to limited or uncertain confidence in effect estimates.
Conclusions
Insufficient evidence exists as to whether BIs, as part of SBIRT, are effective or ineffective for reducing the use of, or harms associated with nonmedical use of, psychoactive substances when these interventions are administered to nontreatment-seeking, screen-detected populations. Updating this review with emerging evidence will be important.
Trial registration
CRD42012002414
doi:10.1186/2046-4053-3-50
PMCID: PMC4042132  PMID: 24887418
brief intervention; drug use; psychoactive substance; SBIRT; screening; substance use; systematic review
4.  Efficacy and safety of mesenchymal stromal cells in preclinical models of acute lung injury: a systematic review protocol 
Systematic Reviews  2014;3:48.
Background
Acute respiratory distress syndrome (ARDS) in humans is caused by an unchecked proinflammatory response that results in diffuse and severe lung injury, and it is associated with a mortality rate of 35 to 45%. Mesenchymal stromal cells (MSCs; ‘adult stem cells’) could represent a promising new therapy for this syndrome, since preclinical evidence suggests that MSCs may ameliorate lung injury. Prior to a human clinical trial, our aim is to conduct a systematic review to compare the efficacy and safety of MSC therapy versus controls in preclinical models of acute lung injury that mimic some aspects of the human ARDS.
Methods/Design
We will include comparative preclinical studies (randomized and non-randomized) of acute lung injury in which MSCs were administered and outcomes compared to animals given a vehicle control. The primary outcome will be death. Secondary outcomes will include the four key features of preclinical acute lung injury as defined by the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar capillary barrier, lung inflammatory response, and physiological dysfunction) and pathogen clearance for acute lung injury models that are caused by infection. Electronic searches of MEDLINE, Embase, BIOSIS Previews, and Web of Science will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the Cochrane risk of bias tool, and individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.
Discussion
The results of this systematic review will comprehensively summarize the safety and efficacy of MSC therapy in preclinical models of acute lung injury. Our results will help translational scientists and clinical trialists to determine whether sufficient evidence exists to perform a human clinical trial. These results may also guide future acute lung injury preclinical and clinical research.
doi:10.1186/2046-4053-3-48
PMCID: PMC4046388  PMID: 24887266
Mesenchymal stromal cells; Mesenchymal stem cells; Acute lung injury; Acute respiratory distress syndrome; Preclinical; Systematic review protocol
5.  Evaluation of the Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials: focus groups, online survey, proposed recommendations and their implementation 
Systematic Reviews  2014;3:37.
Background
In 2008, the Cochrane Collaboration introduced a tool for assessing the risk of bias in clinical trials included in Cochrane reviews. The risk of bias (RoB) tool is based on narrative descriptions of evidence-based methodological features known to increase the risk of bias in trials.
Methods
To assess the usability of this tool, we conducted an evaluation by means of focus groups, online surveys and a face-to-face meeting. We obtained feedback from a range of stakeholders within The Cochrane Collaboration regarding their experiences with, and perceptions of, the RoB tool and associated guidance materials. We then assessed this feedback in a face-to-face meeting of experts and stakeholders and made recommendations for improvements and further developments of the RoB tool.
Results
The survey attracted 380 responses. Respondents reported taking an average of between 10 and 60 minutes per study to complete their RoB assessments, which 83% deemed acceptable. Most respondents (87% of authors and 95% of editorial staff) thought RoB assessments were an improvement over past approaches to trial quality assessment. Most authors liked the standardized approach (81%) and the ability to provide quotes to support judgements (74%). A third of participants disliked the increased workload and found the wording describing RoB judgements confusing. The RoB domains reported to be the most difficult to assess were incomplete outcome data and selective reporting of outcomes. Authors expressed the need for more guidance on how to incorporate RoB assessments into meta-analyses and review conclusions. Based on this evaluation, recommendations were made for improvements to the RoB tool and the associated guidance. The implementation of these recommendations is currently underway.
Conclusions
Overall, respondents identified positive experiences and perceptions of the RoB tool. Revisions of the tool and associated guidance made in response to this evaluation, and improved provision of training, may improve implementation.
doi:10.1186/2046-4053-3-37
PMCID: PMC4022341  PMID: 24731537
Survey; Focus groups; Bias assessment; Quality assessment; Systematic reviews
6.  The Quality of Reporting Methods and Results in Network Meta-Analyses: An Overview of Reviews and Suggestions for Improvement 
PLoS ONE  2014;9(3):e92508.
Introduction
Some have suggested the quality of reporting of network meta-analyses (a technique used to synthesize information to compare multiple interventions) is sub-optimal. We sought to review information addressing this claim.
Objective
To conduct an overview of existing evaluations of quality of reporting in network meta-analyses and indirect treatment comparisons, and to compile a list of topics which may require detailed reporting guidance to enhance future reporting quality.
Methods
An electronic search of Medline and the Cochrane Registry of methodologic studies (January 2004–August 2013) was performed by an information specialist. Studies describing findings from quality of reporting assessments were sought. Screening of abstracts and full texts was performed by two team members. Descriptors related to all aspects of reporting a network meta-analysis were summarized.
Results
We included eight reports exploring the quality of reporting of network meta-analyses. From past reviews, authors found several aspects of network meta-analyses were inadequately reported, including primary information about literature searching, study selection, and risk of bias evaluations; statement of the underlying assumptions for network meta-analysis, as well as efforts to verify their validity; details of statistical models used for analyses (including information for both Bayesian and Frequentist approaches); completeness of reporting of findings; and approaches for summarizing probability measures as additional important considerations.
Conclusions
While few studies were identified, several deficiencies in the current reporting of network meta-analyses were observed. These findings reinforce the need to develop reporting guidance for network meta-analyses. Findings from this review will be used to guide next steps in the development of reporting guidance for network meta-analysis in the format of an extension of the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) Statement.
doi:10.1371/journal.pone.0092508
PMCID: PMC3966807  PMID: 24671099
7.  Checking whether there is an increased risk of post-transplant lymphoproliferative disorder and other cancers with specific modern immunosuppression regimens in renal transplantation: Protocol for a network meta-analysis of randomized and observational studies 
Systematic Reviews  2014;3:16.
Background
Patients undergoing renal transplant procedures require multi-agent immunosuppressive regimens both short term (induction phase) and long term (maintenance phase) to minimize the risk of organ rejection. There are several drug classes and agents for immunosuppression. Use of these agents may increase the risk of different harms including not only infections, but also malignancies including post-transplant lymphoproliferative disorder. There is a need to identify which regimens minimize the risk of such outcomes. The objective of this systematic review and network meta-analysis of randomized and observational studies is to explore whether certain modern regimens of immunosuppression used to prevent organ rejection in renal transplant patients are associated with an increased risk of post-transplant lymphoproliferative disorder and other malignancies.
Methods/design
‘Modern’ regimens were defined to be those evaluated in controlled studies beginning in 1990 or later. An electronic literature search of Medline, Embase and the Cochrane Central Register of Controlled Trials has been designed by an experienced information specialist and peer reviewed by a second information specialist. Study selection and data collection will be performed by two reviewers. The outcomes of interest will include post-transplant lymphoproliferative disorder and other incident forms of malignancy occurring in adult renal transplant patients. Network meta-analyses of data from randomized and observational studies will be performed where judged appropriate based on a review of the clinical and methodological features of included studies. A sequential approach to meta-analysis will be used to combine data from different designs.
Discussion
Our systematic review will include both single-agent and multi-agent modern pharmacotherapy regimens in patients undergoing renal transplantation. It will synthesize malignancy outcomes. Our work will also add to the development of methods for network meta-analysis across study designs to assess treatment safety.
Trial registration
PROSPERO Registration Number: CRD42013006951
doi:10.1186/2046-4053-3-16
PMCID: PMC3936935  PMID: 24559430
Renal transplant; malignancy; post-transplant lymphoproliferative disorder; systematic review; network meta-analysis
8.  Global collaborative networks on meta-analyses of randomized trials published in high impact factor medical journals: a social network analysis 
BMC Medicine  2014;12:15.
Background
Research collaboration contributes to the advancement of knowledge by exploiting the results of scientific efforts more efficiently, but the global patterns of collaboration on meta-analysis are unknown. The purpose of this research was to describe and characterize the global collaborative patterns in meta-analyses of randomized trials published in high impact factor medical journals over the past three decades.
Methods
This was a cross-sectional, social network analysis. We searched PubMed for relevant meta-analyses of randomized trials published up to December 2012. We selected meta-analyses (including at least randomized trials as primary evidence source) published in the top seven high impact factor general medical journals (according to Journal Citation Reports 2011): The New England Journal of Medicine, The Lancet, the BMJ, JAMA, Annals of Internal Medicine, Archives of Internal Medicine (now renamed JAMA Internal Medicine), and PLoS Medicine. Opinion articles, conceptual papers, narrative reviews, reviews without meta-analysis, reviews of reviews, and other study designs were excluded.
Results
Overall, we included 736 meta-analyses, in which 3,178 authors, 891 institutions, and 51 countries participated. The BMJ was the journal that published the greatest number of articles (39%), followed by The Lancet (18%), JAMA (15%) and the Archives of Internal Medicine (15%). The USA, the UK, and Canada headed the absolute global productivity ranking in number of papers. The 64 authors and the 39 institutions with the highest publication rates were identified. We also found 82 clusters of authors (one group with 55 members and one group with 54 members) and 19 clusters of institutions (one major group with 76 members). The most prolific authors were mainly affiliated with the University of Oxford (UK), McMaster University (Canada), and the University of Bern (Switzerland).
Conclusions
Our analysis identified networks of authors, institutions and countries publishing meta-analyses of randomized trials in high impact medical journals. This valuable information may be used to strengthen scientific capacity for collaboration and to help to promote a global agenda for future research of excellence.
doi:10.1186/1741-7015-12-15
PMCID: PMC3913337  PMID: 24476131
Authorship; Evidence-based medicine; Meta-analysis; Randomized controlled trial; Scientific collaboration; Social network analysis
9.  The effects of sign language on spoken language acquisition in children with hearing loss: a systematic review protocol 
Systematic Reviews  2013;2:108.
Background
Permanent childhood hearing loss affects 1 to 3 per 1000 children and frequently disrupts typical spoken language acquisition. Early identification of hearing loss through universal newborn hearing screening and the use of new hearing technologies including cochlear implants make spoken language an option for most children. However, there is no consensus on what constitutes optimal interventions for children when spoken language is the desired outcome. Intervention and educational approaches ranging from oral language only to oral language combined with various forms of sign language have evolved. Parents are therefore faced with important decisions in the first months of their child’s life.
Methods/Design
This article presents the protocol for a systematic review of the effects of using sign language in combination with oral language intervention on spoken language acquisition. Studies addressing early intervention will be selected in which therapy involving oral language intervention and any form of sign language or sign support is used. Comparison groups will include children in early oral language intervention programs without sign support. The primary outcomes of interest to be examined include all measures of auditory, vocabulary, language, speech production, and speech intelligibility skills. We will include randomized controlled trials, controlled clinical trials, and other quasi-experimental designs that include comparator groups as well as prospective and retrospective cohort studies. Case-control, cross-sectional, case series, and case studies will be excluded. Several electronic databases will be searched (for example, MEDLINE, EMBASE, CINAHL, PsycINFO) as well as grey literature and key websites. We anticipate that a narrative synthesis of the evidence will be required. We will carry out meta-analysis for outcomes if clinical similarity, quantity and quality permit quantitative pooling of data. We will conduct subgroup analyses if possible according to severity/type of hearing disorder, age of identification, and type of hearing technology.
Discussion
This review will provide evidence on the effectiveness of using sign language in combination with oral language therapies for developing spoken language in children with hearing loss who are identified at a young age. The information from this review can provide guidance to parents and intervention specialists, inform policy decisions and provide directions for future research.
PROSPERO registration number
CRD42013005426
doi:10.1186/2046-4053-2-108
PMCID: PMC4029089  PMID: 24314335
Children; Hearing loss; Spoken language; Sign language; Outcomes; Systematic review
10.  A surveillance system to assess the need for updating systematic reviews 
Systematic Reviews  2013;2:104.
Background
Systematic reviews (SRs) can become outdated as new evidence emerges over time. Organizations that produce SRs need a surveillance method to determine when reviews are likely to require updating. This report describes the development and initial results of a surveillance system to assess SRs produced by the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Program.
Methods
Twenty-four SRs were assessed using existing methods that incorporate limited literature searches, expert opinion, and quantitative methods for the presence of signals triggering the need for updating. The system was designed to begin surveillance six months after the release of the original review, and thenceforth every six months for any review not classified as being a high priority for updating. The outcome of each round of surveillance was a classification of the SR as being low, medium or high priority for updating.
Results
Twenty-four SRs underwent surveillance at least once, and ten underwent surveillance a second time during the 18 months of the program. Two SRs were classified as high, five as medium, and 17 as low priority for updating. The time lapse between the searches conducted for the original reports and the updated searches (search time lapse - STL) ranged from 11 months to 62 months: The STL for the high priority reports were 29 months and 54 months; those for medium priority reports ranged from 19 to 62 months; and those for low priority reports ranged from 11 to 33 months. Neither the STL nor the number of new relevant articles was perfectly associated with a signal for updating. Challenges of implementing the surveillance system included determining what constituted the actual conclusions of an SR that required assessing; and sometimes poor response rates of experts.
Conclusion
In this system of regular surveillance of 24 systematic reviews on a variety of clinical interventions produced by a leading organization, about 70% of reviews were determined to have a low priority for updating. Evidence suggests that the time period for surveillance is yearly rather than the six months used in this project.
doi:10.1186/2046-4053-2-104
PMCID: PMC3874670  PMID: 24225065
Systematic review; Updating; Surveillance
11.  Testing the PRISMA-Equity 2012 Reporting Guideline: the Perspectives of Systematic Review Authors 
PLoS ONE  2013;8(10):e75122.
Reporting guidelines can be used to encourage standardised and comprehensive reporting of health research. In light of the global commitment to health equity, we have previously developed and published a reporting guideline for equity-focused systematic reviews (PRISMA-E 2012). The objectives of this study were to explore the utility of the equity extension items included in PRISMA-E 2012 from a systematic review author perspective, including facilitators and barriers to its use. This will assist in designing dissemination and knowledge translation strategies. We conducted a survey of systematic review authors to expose them to the new items in PRISMA-E 2012, establish the extent to which they had historically addressed those items in their own reviews, and gather feedback on the usefulness of the new items. Data were analysed using Microsoft Excel 2008 and Stata (version 11.2 for Mac). Of 151 respondents completing the survey, 18.5% (95% CI: 12.7% to 25.7%) had not heard of the PRISMA statement before, although 83.4% (95% CI: 77.5% to 89.3%) indicated that they plan to use PRISMA-E 2012 in the future, depending on the focus of their review. Most (68.9%; 95% CI: 60.8% to 76.2%) thought that using PRISMA-E 2012 would lead them to conduct their reviews differently. Important facilitators to using PRISMA-E 2012 identified by respondents were journal endorsement and incorporation of the elements of the guideline into systematic review software. Barriers identified were lack of time, word limits and the availability of equity data in primary research. This study has been the first to ‘road-test’ the new PRISMA-E 2012 reporting guideline and the findings are encouraging. They confirm the acceptability and potential utility of the guideline to assist review authors in reporting on equity in their reviews. The uptake and impact of PRISMA-E 2012 over time on design, conduct and reporting of primary research and systematic reviews should continue to be examined.
doi:10.1371/journal.pone.0075122
PMCID: PMC3794945  PMID: 24130684
13.  The CARE guidelines: consensus-based clinical case reporting guideline development 
Background
A case report is a narrative that describes, for medical, scientific, or educational purposes, a medical problem experienced by one or more patients. Case reports written without guidance from reporting standards are insufficiently rigorous to guide clinical practice or to inform clinical study design.
Primary Objective. Develop, disseminate, and implement systematic reporting guidelines for case reports.
Methods
We used a three-phase consensus process consisting of (1) pre-meeting literature review and interviews to generate items for the reporting guidelines, (2) a face-to-face consensus meeting to draft the reporting guidelines, and (3) post-meeting feedback, review, and pilot testing, followed by finalization of the case report guidelines.
Results
This consensus process involved 27 participants and resulted in a 13-item checklist—a reporting guideline for case reports. The primary items of the checklist are title, key words, abstract, introduction, patient information, clinical findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, patient perspective, and informed consent.
Conclusions
We believe the implementation of the CARE (CAse REport) guidelines by medical journals will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports will inform clinical study design, provide early signals of effectiveness and harms, and improve healthcare delivery.
doi:10.1186/1752-1947-7-223
PMCID: PMC3844611  PMID: 24228906
Case report; Case study; EQUATOR Network; Patient reports; Meaningful use; Health research reporting guidelines
14.  Safety, effectiveness, and cost of long-acting versus intermediate-acting insulin for type 1 diabetes: Protocol for a systematic review and network meta-analysis 
Systematic Reviews  2013;2:73.
Background
Type 1 diabetes mellitus (T1DM) causes progressive destruction of pancreatic beta cells leading to absolute insulin deficiency. Treatment of T1DM requires insulin, and some evidence suggests that longer acting insulin analogues might have a higher effectiveness and greater safety profile compared to intermediate-acting insulin. Our objective is to evaluate the comparative effectiveness, safety, and cost of long-acting insulin versus intermediate-acting insulin through a systematic review and network meta-analysis.
Design/methods
Studies examining long-acting versus intermediate-acting insulin or placebo preparations for adult T1DM patients will be included. The primary outcome is glycosylated hemoglobin (A1C), and secondary outcomes include emergency department and physician visits, hospital admissions, weight gain, quality of life, microvascular complications (e.g., retinopathy), macrovascular complications (e.g., cardiovascular disease), all-cause mortality, incident cancers, and cost. We will include experimental [randomized clinical trials (RCTs), quasi-RCTs, non-RCTs], quasi-experimental (controlled before-after, interrupted time series), observational (cohort), and cost studies, of any duration of follow-up, conducted during all time periods, and disseminated in any language.
We will conduct comprehensive searches of electronic databases from inception onwards, including MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE. We will also search for difficult to locate and unpublished literature by searching dissertation databases, public health organization websites, and trial registries. After a calibration exercise using our eligibility criteria and data abstraction forms, two reviewers will screen all citations, full-text articles, and abstract data in duplicate. Conflicts will be resolved by team discussion. Using a similar process, the Cochrane Effective Practice and Organization of Care Risk of Bias tool will be used to appraise the risk of bias of experimental and quasi-experimental studies, while the Newcastle Ottawa Scale will be used to assess the methodological quality of cohort studies. If feasible and appropriate, we will conduct a random effects meta-analysis, as well as a network meta-analysis.
Discussion
Our systematic review will be of utility to healthcare providers, policy-makers, T1DM patients and family members regarding treatment options of long-acting versus intermediate-acting insulin preparations.
Trial registration
PROSPERO registry number: CRD42013003610
doi:10.1186/2046-4053-2-73
PMCID: PMC3847127  PMID: 24020869
15.  Protocol for CONSORT-SPI: an extension for social and psychological interventions 
Background
Determining the effectiveness of social and psychological interventions is important for improving individual and population health. Such interventions are complex and, where possible, are best evaluated by randomised controlled trials (RCTs). The use of research findings in policy and practice decision making is hindered by poor reporting of RCTs. Poor reporting limits the ability to replicate interventions, synthesise evidence in systematic reviews, and utilise findings for evidence-based policy and practice. The lack of guidance for reporting the specific methodological features of complex intervention RCTs contributes to poor reporting. We aim to develop an extension of the Consolidated Standards of Reporting Trials Statement for Social and Psychological Interventions (CONSORT-SPI).
Methods/design
This research project will be conducted in five phases. The first phase was the project launch, which consisted of the establishment of a Project Executive and International Advisory Group, and recruitment of journal editors and the CONSORT Group. The second phase involves a Delphi process that will generate a list of possible items to include in the CONSORT Extension. Next, there will be a formal consensus meeting to select the reporting items to add to, or modify for, the CONSORT-SPI Extension. Fourth, guideline documents will be written, including an explanation and elaboration (E&E) document that will provide detailed advice for each item and examples of good reporting. The final phase will comprise guideline dissemination, with simultaneous publication and endorsement of the guideline in multiple journals, endorsement by funding agencies, presentations at conferences and other meetings, and a dedicated website that will facilitate feedback about the guideline.
Conclusion
As demonstrated by previous CONSORT guidelines, the development of an evidence-based reporting guideline for social and psychological intervention RCTs should improve the accuracy, comprehensiveness, and transparency of study reports. This, in turn, promises to improve the critical appraisal of research and its use in policy and practice decision making. We invite readers to participate in the project by visiting our website (http://tinyurl.com/CONSORT-study).
doi:10.1186/1748-5908-8-99
PMCID: PMC3766255  PMID: 24004579
CONSORT-SPI; Randomised controlled trial; RCT; Reporting guidelines; Complex interventions
16.  Consensus-based recommendations for investigating clinical heterogeneity in systematic reviews 
Background
Critics of systematic reviews have argued that these studies often fail to inform clinical decision making because their results are far too general, that the data are sparse, such that findings cannot be applied to individual patients or for other decision making. While there is some consensus on methods for investigating statistical and methodological heterogeneity, little attention has been paid to clinical aspects of heterogeneity. Clinical heterogeneity, true effect heterogeneity, can be defined as variability among studies in the participants, the types or timing of outcome measurements, and the intervention characteristics. The objective of this project was to develop recommendations for investigating clinical heterogeneity in systematic reviews.
Methods
We used a modified Delphi technique with three phases: (1) pre-meeting item generation; (2) face-to-face consensus meeting in the form of a modified Delphi process; and (3) post-meeting feedback. We identified and invited potential participants with expertise in systematic review methodology, systematic review reporting, or statistical aspects of meta-analyses, or those who published papers on clinical heterogeneity.
Results
Between April and June of 2011, we conducted phone calls with participants. In June 2011 we held the face-to-face focus group meeting in Ann Arbor, Michigan. First, we agreed upon a definition of clinical heterogeneity: Variations in the treatment effect that are due to differences in clinically related characteristics. Next, we discussed and generated recommendations in the following 12 categories related to investigating clinical heterogeneity: the systematic review team, planning investigations, rationale for choice of variables, types of clinical variables, the role of statistical heterogeneity, the use of plotting and visual aids, dealing with outlier studies, the number of investigations or variables, the role of the best evidence synthesis, types of statistical methods, the interpretation of findings, and reporting.
Conclusions
Clinical heterogeneity is common in systematic reviews. Our recommendations can help guide systematic reviewers in conducting valid and reliable investigations of clinical heterogeneity. Findings of these investigations may allow for increased applicability of findings of systematic reviews to the management of individual patients.
doi:10.1186/1471-2288-13-106
PMCID: PMC3847163  PMID: 24004523
17.  Happy birthday: we are one year old 
Systematic Reviews  2013;2:61.
doi:10.1186/2046-4053-2-61
PMCID: PMC3751830
18.  Developing a reporting guideline for social and psychological intervention trials 
Trials  2013;14:242.
Social and psychological interventions are often complex. Understanding randomised controlled trials (RCTs) of these complex interventions requires a detailed description of the interventions tested and the methods used to evaluate them; however, RCT reports often omit, or inadequately report, this information. Incomplete and inaccurate reporting hinders the optimal use of research, wastes resources, and fails to meet ethical obligations to research participants and consumers. In this paper, we explain how reporting guidelines have improved the quality of reports in medicine, and describe the ongoing development of a new reporting guideline for RCTs: CONSORT-SPI (an Extension for social and psychological interventions). We invite readers to participate in the project by visiting our website, in order to help us reach the best-informed consensus on these guidelines (http://tinyurl.com/CONSORT-study).
doi:10.1186/1745-6215-14-242
PMCID: PMC3734002  PMID: 23915044
Randomised controlled trial; RCT; CONSORT-SPI; Reporting guideline; Reporting standards
19.  Bibliometric and content analysis of the Cochrane Complementary Medicine Field specialized register of controlled trials 
Systematic Reviews  2013;2:51.
Background
The identification of eligible controlled trials for systematic reviews of complementary and alternative medicine (CAM) interventions can be difficult. To increase access to these difficult to locate trials, the Cochrane Collaboration Complementary Medicine Field (CAM Field) has established a specialized register of citations of CAM controlled trials. The objective of this study is to describe the sources and characteristics of citations included in the CAM Field specialized register.
Methods
Between 2006 and 2011, regular searches for citations of CAM trials in MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) were supplemented with contributions of controlled trial citations from international collaborators. The specialized register was ‘frozen’ for analysis in 2011, and frequencies were calculated for publication date, language, journal, presence in MEDLINE, type of intervention, and type of medical condition.
Results
The CAM Field specialized register increased in size from under 5,000 controlled trial citations in 2006 to 44,840 citations in 2011. Most citations (60%) were from 2000 or later, and the majority (71%) were reported in English; the next most common language was Chinese (23%). The journals with the greatest number of citations were CAM journals published in Chinese and non-CAM nutrition journals published in English. More than one-third of register citations (36%) were not indexed in MEDLINE. The most common CAM intervention type in the register was non-vitamin, non-mineral dietary supplements (e.g., glucosamine, fish oil) (34%), followed by Chinese herbal medicines (e.g., Astragalus membranaceus, Schisandra chinensis) (27%).
Conclusions
The availability of the CAM Field specialized register presents both opportunities and challenges for CAM systematic reviewers. While the register provides access to thousands of difficult to locate trial citations, many of these trials are of low quality and may overestimate treatment effects. When including these trials in systematic reviews, adequate analysis of their risk of bias is of utmost importance.
doi:10.1186/2046-4053-2-51
PMCID: PMC3704678  PMID: 23826877
Complementary medicine; Randomized controlled trials; Data collection; Registries
20.  Interventions to decrease the risk of adverse cardiac events for post-surgery or chemotherapy patients taking serotonin (5-HT3) receptor antagonists: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2013;2:45.
Background
Patients undergoing surgery or chemotherapy often experience nausea and vomiting. To increase their quality of life and treatment satisfaction, antiemetic medication, such as serotonin receptor antagonists, is often prescribed for patients experiencing these symptoms. However, early warning signs suggest that serotonin receptor antagonists can cause harm, including arrhythmia. Our objective is to identify the most effective interventions that mitigate the risk of adverse cardiac events associated with serotonin receptor antagonists in patients undergoing surgery and chemotherapy through a systematic review and network meta-analysis.
Methods/design
We will search electronic databases (for example, MEDLINE, Embase) from inception onwards, as well as dissertations and governmental reports, to identify interventions (for example, telemetry, electrocardiography, electrolyte monitoring) that decrease the cardiac risk associated with serotonin receptor antagonists among surgery and chemotherapy patients. Eligible comparators include placebo or supportive care; eligible study designs are experimental studies (randomized controlled trials (RCTs), quasi-RCTs, non-RCTs), non-experimental studies (interrupted time series, controlled before-and-after studies), and cohort studies. Outcomes of interest include arrhythmia, sudden cardiac death, QT prolongation, PR prolongation, and all-cause mortality. We will include unpublished studies and studies published in languages other than English.
Draft inclusion and exclusion criteria will be established and pilot tested amongst the team. Subsequently, two team members will screen the results in duplicate and resolve conflicts through discussion. The same process will be followed to screen full-text articles, data abstraction, and appraise quality or risk of bias. To determine validity of results, experimental and quasi-experimental studies will be assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) Risk of Bias tool, while cohort studies will be appraised using the Newcastle-Ottawa Scale. We anticipate sufficient data and homogeneity to conduct random effects meta-analysis and network or mixed treatment comparisons meta-analysis, if appropriate.
Discussion
Our results will provide information regarding the utility of different strategies that can be used to mitigate cardiac risk amongst patients taking serotonin antagonist receptors. Such results are likely to be of use to clinicians prescribing these agents, as well as policy makers responsible for making decisions about antiemetic medications.
Trial registration
PROSPERO registry number: CRD42013003565
doi:10.1186/2046-4053-2-45
PMCID: PMC3701482  PMID: 23809884
21.  Comparative effectiveness of monotherapies and combination therapies for patients with hypertension: protocol for a systematic review with network meta-analyses 
Systematic Reviews  2013;2:44.
Background
Hypertension has been cited as the most common attributable risk factor for death worldwide, and in Canada more than one of every five adults had this diagnosis in 2007. In addition to different lifestyle modifications, such as diet and exercise, there exist many pharmaco-therapies from different drug classes which can be used to lower blood pressure, thereby reducing the risk of serious clinical outcomes. In moderate and severe cases, more than one agent may be used. The optimal mono- and combination therapies for mild hypertension and moderate/severe hypertension are unclear, and clinical guidelines provide different recommendations for first line therapy. The objective of this review is to explore the relative benefits and safety of different pharmacotherapies for management of non-diabetic patients with hypertension, whether of a mild or moderate to severe nature.
Methods/Design
Searches involving MEDLINE and the Cochrane Database of Systematic Reviews will be used to identify related systematic reviews and relevant randomized trials. The outcomes of interest include myocardial infarction, stroke, incident diabetes, heart failure, overall and cardiovascular related death, and important side effects (cancers, depression, syncopal episodes/falls and sexual dysfunction). Randomized controlled trials will be sought. Two reviewers will independently screen relevant reviews, titles and abstracts resulting from the literature search, and also potentially relevant full-text articles in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion. Random effect pairwise meta-analyses and network meta-analyses will be conducted where deemed appropriate. Analyses will be geared toward studying treatment of mild hypertension and moderate/severe hypertension separately.
Discussion
Our systematic review results will assess the extent of currently available evidence for single agent and multi-agent pharmacotherapies in patients with mild, moderate and severe hypertension, and will provide a rigorous and updated synthesis of a range of important clinical outcomes for clinicians, decision makers and patients.
Trial registration
PROSPERO Registration Number: CRD42013004459
doi:10.1186/2046-4053-2-44
PMCID: PMC3701495  PMID: 23809864
Hypertension; Pharmacotherapy; Systematic Review; Network Meta-analysis
22.  Safety of serotonin (5-HT3) receptor antagonists in patients undergoing surgery and chemotherapy: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2013;2:46.
Background
Serotonin (5-HT3) receptor antagonists are a class of antiemetic medications often used to prevent nausea and vomiting among patients undergoing chemotherapy, radiotherapy or surgery. However, recent studies suggest that these agents might be associated with increased cardiac harm. To examine this further, we are proposing to conduct a systematic review and network meta-analysis on the comparative safety of 5-HT3 receptor antagonists among patients undergoing chemotherapy or surgery.
Methods/Design
Studies reporting one or more safety outcomes of interest for 5-HT3 receptor antagonists compared with each other, placebo, and/or other anti-emetic agents (for example, benzamides, phenothiazines, butyrophenones, antihistamines, and anticholinergics) among children and adult patients undergoing surgery or chemotherapy will be included. Our primary outcome of interest is arrhythmia. Our secondary outcomes include cardiac death, QT prolongation, PR prolongation, all-cause mortality, nausea, and vomiting. We will include experimental studies, quasi-experimental studies (namely controlled before-after and interrupted time series), and observational studies (namely cohort studies). We will not limit inclusion by publication status, time period, duration of follow-up or language of dissemination.
Electronic databases (for example, MEDLINE, EMBASE) will be searched from inception onwards. These main searches will be supplemented by searching for difficult to locate and unpublished studies, such as dissertations, and governmental reports. The eligibility criteria will be pilot-tested and subsequently used to screen the literature search results by two reviewers in duplicate. A similar process will be followed for full-text screening, data abstraction, and risk of bias/methodological quality appraisal. The Cochrane Risk of Bias tool will be used to appraise experimental and quasi-experimental studies, and cohort studies will be assessed using the Newcastle Ottawa Scale. If the data allows, random effects meta-analysis and a network (that is, mixed treatment comparisons) meta-analysis will be conducted. All analyses will be conducted separately for different study designs, patient populations (for example, children and adults), and reason for administering 5-HT3 receptor antagonists (for example, post-surgery and chemotherapy).
Discussion
Our results will help inform patients, clinicians, and health policy-makers about the potential safety concerns, as well as the comparative safety, of using these antiemetic agents.
Trial registration
PROSPERO registry number:CRD42013003564
doi:10.1186/2046-4053-2-46
PMCID: PMC3702491  PMID: 23810058
23.  Safety, effectiveness, and cost of dipeptidyl peptidase-4 inhibitors versus intermediate acting insulin for type 2 diabetes: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2013;2:47.
Background
Type 2 diabetes mellitus (T2DM) results from insulin resistance and relative insulin deficiency. T2DM treatment is a step-wise approach beginning with lifestyle modifications (for example, diet, exercise), followed by the addition of oral hypoglycemic agents (for example, metformin). Patients who do not respond to first-line therapy are offered second-line therapy (for example, sulfonylureas). Third-line therapy may include insulin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors.
It is unclear whether DPP-4 inhibitors are safer and more effective than intermediate acting insulin for third-line management of T2DM. As such, our objective is to evaluate the comparative effectiveness, safety and cost-effectiveness of DPP-4 inhibitors versus intermediate acting insulin for T2DM patients who have failed both first- and second-line diabetes treatments.
Design/Methods
Electronic searches of MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and grey literature (for example, trial registries, public health websites) will be conducted to identify studies examining DPP-4 inhibitors compared with each other, intermediate acting insulin, no treatment, or placebo for adults with T2DM. The outcomes of interest include glycosylated hemoglobin (A1C) (primary outcome), as well as emergency department visits, physician visits, hospital admissions, weight gain, quality of life, microvascular complications, macrovascular complications, all-cause mortality, and cost (secondary outcomes). Randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort studies, and cost studies reporting data on these outcomes will be included. Eligibility will not be restricted by publication status, language of dissemination, duration of study follow-up, or time period of study conduct.
Two reviewers will screen the titles and abstracts resulting from the literature search, as well as potentially relevant full-text articles, in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion.
Our results will be described narratively. Random effects meta-analysis and network meta-analysis will be conducted, if feasible and appropriate.
Discussion
Our systematic review results can be used to determine the most effective, safe and cost-effective third-line strategies for managing T2DM. This information will be of great use to health policy-makers and clinicians, as well as patients living with T2DM and their families.
Trial registration
PROSPERO registry number: CRD42013003624
doi:10.1186/2046-4053-2-47
PMCID: PMC3702520  PMID: 23810103
Systematic review; Type 2 diabetes; Dipeptidyl peptidase-4; Intermediate-acting insulin; Glycosolated hemoglobin
24.  Systematic review of the effectiveness of training programs in writing for scholarly publication, journal editing, and manuscript peer review (protocol) 
Systematic Reviews  2013;2:41.
Background
An estimated $100 billion is lost to ‘waste’ in biomedical research globally, annually, much of which comes from the poor quality of published research. One area of waste involves bias in reporting research, which compromises the usability of published reports. In response, there has been an upsurge in interest and research in the scientific process of writing, editing, peer reviewing, and publishing (that is, journalology) of biomedical research. One reason for bias in reporting and the problem of unusable reports could be due to authors lacking knowledge or engaging in questionable practices while designing, conducting, or reporting their research. Another might be that the peer review process for journal publication has serious flaws, including possibly being ineffective, and having poorly trained and poorly motivated reviewers. Similarly, many journal editors have limited knowledge related to publication ethics. This can ultimately have a negative impact on the healthcare system. There have been repeated calls for better, more numerous training opportunities in writing for publication, peer review, and publishing. However, little research has taken stock of journalology training opportunities or evaluations of their effectiveness.
Methods
We will conduct a systematic review to synthesize studies that evaluate the effectiveness of training programs in journalology. A comprehensive three-phase search approach will be employed to identify evaluations of training opportunities, involving: 1) forward-searching using the Scopus citation database, 2) a search of the MEDLINE In-Process and Non-Indexed Citations, MEDLINE, Embase, ERIC, and PsycINFO databases, as well as the databases of the Cochrane Library, and 3) a grey literature search.
Discussion
This project aims to provide evidence to help guide the journalological training of authors, peer reviewers, and editors. While there is ample evidence that many members of these groups are not getting the necessary training needed to excel at their respective journalology-related tasks, little is known about the characteristics of existing training opportunities, including their effectiveness. The proposed systematic review will provide evidence regarding the effectiveness of training, therefore giving potential trainees, course designers, and decision-makers evidence to help inform their choices and policies regarding the merits of specific training opportunities or types of training.
doi:10.1186/2046-4053-2-41
PMCID: PMC3691595  PMID: 23773340
Training; Writing for publication; Journalology; Author; Journal editor; Manuscript peer review; Publishing
25.  Education in Health Research Methodology: Use of a Wiki for Knowledge Translation 
PLoS ONE  2013;8(5):e64922.
Introduction
A research-practice gap exists between what is known about conducting methodologically rigorous randomized controlled trials (RCTs) and what is done. Evidence consistently shows that pediatric RCTs are susceptible to high risk of bias; therefore novel methods of influencing the design and conduct of trials are required. The objective of this study was to develop and pilot test a wiki designed to educate pediatric trialists and trainees in the principles involved in minimizing risk of bias in RCTs. The focus was on preliminary usability testing of the wiki.
Methods
The wiki was developed through adaptation of existing knowledge translation strategies and through tailoring the site to the identified needs of the end-users. The wiki was evaluated for usability and user preferences regarding the content and formatting. Semi-structured interviews were conducted with 15 trialists and systematic reviewers, representing varying levels of experience with risk of bias or the conduct of trials. Data were analyzed using content analysis.
Results
Participants found the wiki to be well organized, easy to use, and straightforward to navigate. Suggestions for improvement tended to focus on clarification of the text or on esthetics, rather than on the content or format. Participants liked the additional features of the site that were supplementary to the text, such as the interactive examples, and the components that focused on practical applications, adding relevance to the theory presented. While the site could be used by both trialists and systematic reviewers, the lack of a clearly defined target audience caused some confusion among participants.
Conclusions
Participants were supportive of using a wiki as a novel educational tool. The results of this pilot test will be used to refine the risk of bias wiki, which holds promise as a knowledge translation intervention for education in medical research methodology.
doi:10.1371/journal.pone.0064922
PMCID: PMC3669055  PMID: 23741424

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