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Background Drug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem. Methods We will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation. Discussion Drug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area. Systematic review registration PROSPERO no.: CRD42018099591. Electronic supplementary material The online version of this article (10.1186/s13643-019-0990-z) contains supplementary material, which is available to authorized users.

Background Despite consensus recommendations for antiemetics in breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy, control of chemotherapy-induced nausea and vomiting (CINV) remains sub-optimal. Objective To inspect available evidence from randomized controlled trials (RCT) in this population to establish treatment comparisons that have been studied, outcomes that have been reported, and the extent of study heterogeneity. Review of this data helps identify challenges for a systematic review comparing antiemetic regimens, and to identify potential future trials. Methods A search of Ovid MEDLINE®, Embase and Cochrane CENTRAL was performed. We sought RCTs comparing antiemetic regimens in breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy. We extracted information related to study design, patient characteristics and interventions compared. Patterns of outcome reporting were studied. While performing network meta-analysis was also of interest, studies were judged highly heterogeneous and it was felt findings from such work would be of uncertain validity. Results From 1062 citations, a total of 30 full texts were retained. Overall, 47 antiemetic regimens were evaluated using 15 different CINV endpoints. Treatment comparisons were diverse and many were informed by single small trials. Reporting of key endpoints was varied and all endpoints were not consistently available. Heterogeneity in patients, chemotherapies administered, and intervention doses were noted. Conclusions Despite the availability of consensus recommendations for antiemetic use, we identified challenges in synthesizing the evidence base including high diversity in treatment comparisons, varied outcome reporting, and study heterogeneity. These represent challenges to identifying an optimal antiemetic regimen. Future antiemetic trials should incorporate more informed comparator selection, report patient-oriented outcomes in a standard fashion, and provide accessible data for these measures.

BackgroundAttention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD.MethodsWe searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework.ResultsEighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration.ConclusionsOverall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs.RegistrationPROSPERO no. CRD 42015026049.

QuestionThis review compares mindfulness-based stress reduction (MBSR) to cognitive-behavioural therapy (CBT) in its ability to improve physical functioning and reduce pain intensity and distress in patients with chronic pain (CP), when evaluated against control conditions.Study selection and analysisOvid MEDLINE, EmbaseClassic+Embase, PsycINFO and the Cochrane Library were searched to identify randomised controlled trials. The primary outcome measure was physical functioning. Secondary outcomes were pain intensity and depression symptoms. We used random and fixed effects (RE and FE) network meta-analyses (NMA) to compare MBSR, CBT and control interventions on the standardised mean difference scale.FindingsTwenty-one studies were included: 13 CBT vs control (n=1095), 7 MBSR vs control (n=545) and 1 MBSR vs CBT vs control (n=341). Of the 21 articles, 12 were determined to be of fair or good quality. Findings from RE NMA for change in physical functioning, pain intensity and depression revealed clinically important advantages relative to control for MBSR and CBT, but no evidence of an important difference between MBSR and CBT was found.ConclusionsThis review suggests that MBSR offers another potentially helpful intervention for CP management. Additional research using consistent measures is required to guide decisions about providing CBT or MBSR.

Background Tobacco smoking is the leading cause of cancer, preventable death, and disability. Smoking cessation can increase life expectancy by nearly a decade if achieved in the third or fourth decades of life. Various stop smoking interventions are available including pharmacotherapies, electronic cigarettes, behavioural support, and alternative therapies. This protocol outlines an evidence review which will evaluate the benefits and harms of stop smoking interventions in adults. Methods The evidence review will consist of two stages. First, an overview of systematic reviews evaluating the benefits and harms of various stop smoking interventions delivered in or referred from the primary care setting will be conducted. The second stage will involve updating a systematic review on electronic cigarettes identified in the overview; randomized controlled trials will be considered for outcomes relating to benefits while randomized controlled trials, non-randomized controlled trials, and comparative observational studies will be considered for evaluating harms. Search strategies will be developed and peer-reviewed by medical information specialists. The search strategy for the updated review on e-cigarettes will be developed using that of the candidate systematic review. The MEDLINE®, PsycINFO, Embase, and the Cochrane Library electronic databases will be searched as of 2008 for the overview of reviews and from the last search date of the selected review for the updated review. Organizational websites and trial registries will be searched for unpublished or ongoing reviews/studies. Two reviewers will independently screen the title and abstracts of citations using the liberal accelerated method. Full-text screening will be performed independently by two reviewers. Extracted data will be verified by a second reviewer. Disagreements regarding full-text screening and data extraction will be resolved by consensus or third-party adjudication. The methodological quality of systematic reviews, risk of bias of randomized and non-randomized trials, and methodological quality of cohort studies will be evaluated using AMSTAR 2, the Cochrane risk of bias tool, and a modified version of the Scottish Intercollegiate Guidelines Network critical appraisal tool, respectively. The GRADE framework will be used to assess the quality of the evidence for outcomes. Discussion The evidence review will evaluate the benefits and harms of various stop smoking interventions for adults. Findings will be used to inform a national tobacco cessation guideline by the Canadian Task Force on Preventive Health Care. Systematic review registration PROSPERO (CRD42018099691, CRD42018099692) Electronic supplementary material The online version of this article (10.1186/s13643-018-0928-x) contains supplementary material, which is available to authorized users.

Background Venous thromboembolism (VTE) is a major global cause of morbidity and mortality. Low molecular weight heparin (LMWH) and fondaparinux (FDP) are frequently used to treat and prevent VTE and have a variety of safety and practical advantages over other anticoagulants, including use in outpatient settings. These medications are commonly listed on drug formularies, which act as a gateway for health plan prescription coverage by outlining the circumstances under which patients will be covered for specific drugs and drug products. Because patient access to medications is impacted by the nature of their listing on formularies, they must be rigorously reviewed and modernized as new evidence emerges. Methods As part of a broader drug class review team, we completed a systematic review of clinical practice guidelines to determine whether the recommendations they reported aligned with the indications listed for the coverage of LMWH and FDP in an outpatient drug formulary. Guideline quality was assessed using the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. Recommendation matrices were used to systematically compare, categorize, and summarize included recommendations. Results Twenty-seven guidelines were included from which 168 eligible recommendations were identified. Generally, AGREE II domains were adequately addressed; however, domain five (applicability) was poorly addressed. Most recommendations were based on moderate- to low-quality/limited evidence and reported on the use of LMWHs generally; few reported on specific agents. Conclusions Our findings contributed to the recommendation that the formulary listing for LMWH and FDP be streamlined to include coverage for specific outpatient indications. The paucity of available evidence on the comparative efficacy of specific LMWH agents against each other and FDP limited agent-specific listing recommendations, highlighting the need for high-quality comparative studies on this topic.

Background Pediatric epilepsy, including treatment-resistant forms, has a major effect on the quality of life, morbidity, and mortality of affected children. Interest has been growing in the use of medical cannabis as a treatment for pediatric epilepsy, yet there has been no comprehensive review of the benefits and harms of cannabis use in this population. In this systematic review, we will search for, synthesize, and assess the published and gray literature in order to provide usable and relevant information to parents, clinicians, and policy makers. Methods We will perform a living systematic review of studies involving the use of cannabis to treat pediatric epilepsy. We will search the published and gray literature for studies involving children with any type of epilepsy taking any form of cannabis. Studies will be selected for inclusion by two independent reviewers. The primary outcome is seizure freedom. Secondary outcomes are seizure frequency, quality of life (child, caregiver), quality and quantity of sleep, status epilepticus, tonic-clonic seizures, death (all-cause, sudden unexpected death in epilepsy), gastrointestinal adverse events (diarrhea, vomiting), and visits to the emergency room. The quality of each included study will be assessed. If data are sufficient in quantity and sufficiently similar, we will conduct pairwise random-effects meta-analysis. We will repeat the literature search every 6 months to identify studies published after the previous search date. Sequential meta-analysis will be performed as necessary to update the review findings. Discussion Our review aims to provide a comprehensive and up-to-date summary of the available evidence to inform decisions about the use of cannabis in children with treatment-resistant epilepsy. The results of this review will be of use to parents, clinicians, and policy makers as they navigate this rapidly evolving area. Systematic review registration PROSPERO CRD42018084755 Electronic supplementary material The online version of this article (10.1186/s13643-018-0761-2) contains supplementary material, which is available to authorized users.

Objective To assess the benefits and harms of cannabis-based products for pediatric epilepsy. Methods We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. Results Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. Significance Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.

Background Between 1 and 5% of children in industrialized countries are conceived through Assisted Reproductive Technologies (ART). As infertility and the use of ART may be associated with adverse perinatal outcomes, care plans specific to these pregnancies are needed. We conducted a systematic review to examine the existing care plans specific to women pregnant following Assisted Reproductive Technologies (ART). Methods MEDLINE, Embase and the Cochrane Library were searched by a senior information specialist. The population of interest included women becoming pregnant with ART (e.g., Intra-Uterine Insemination, In Vitro Fertilization (IVF), Intracytoplasmic Sperm Injection (ICSI), and surrogacy). All proposed care plans were sought that pertained to any aspect of care during pregnancy and delivery. Only Clinical Practice Guidelines (CPGs) addressing the recommendations and plans for the care of ART pregnant women were included. The search was restricted to the publication dates 2007 to June 12, 2017 when the search was run. The search was not restricted by language, however only English and French language guidelines were considered for inclusion. Results After screening 2078 citations, a total of ten CPGs were included. The following key clinical messages were prevalent: (1) although there was no supporting evidence, antenatal care for ART pregnancies should be provided by specialist with knowledge in obstetrics; (2) high-order multiple pregnancies are the greatest risk of ART and selective reduction options should be discussed; (3) there is some evidence of increased risk of congenital abnormalities and prenatal genetic and anatomic screening is recommended, especially in IVF-ICSI pregnancies; (4) due to a lack of or conflicting evidence, treatment of venous thromboembolism, antithrombotic therapy, treatment for hypothyroidism, and women with positive thyroid antibodies is recommended to be the same as in spontaneous pregnancies; and lastly (5) since an increased level of distress is a recognized feature in these pregnancies, psychosocial care and counselling should be considered. Conclusions There is a lack of CPGs specific to ART pregnancies. While we identified a small number of recommendations for ART pregnancies, specific interventions and models of care aiming at decreasing adverse maternal and perinatal outcomes following ART should be developed, implemented, and evaluated. Electronic supplementary material The online version of this article (10.1186/s12978-019-0667-z) contains supplementary material, which is available to authorized users.

Background In 2018, the World Health Organization reported that depression is the most common cause of disability worldwide, with over 300 million people currently living with depression. Depression affects an individual’s physical health and well-being, impacts psychosocial functioning, and has specific negative short- and long-term effects on maternal health, child health, developmental trajectories, and family health. The aim of these reviews is to identify evidence on the benefits and harms of screening for depression in the general adult population and in pregnant and postpartum women. Methods Search strategies were developed and tested through an iterative process by an experienced medical information specialist in consultation with the review team. We will search MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Library, and a randomized controlled trial filter will be used. The general adult review will be an update of a systematic review previously used by the Canadian Task Force on Preventive Health Care for their 2013 guideline recommendation. The search strategy will be updated and will start from the last search date of the previous review (May 2012). The pregnant and postpartum review will be a de novo review with no date restriction. For both reviews, we will search for unpublished documents following the CADTH Grey Matters checklist and relevant websites. Titles and abstracts will be screened using the liberal accelerated method. Two reviewers will independently screen full-text articles for relevance using pre-specified eligibility criteria and assess the risk of bias of included studies using the Cochrane Risk of Bias tool. Outcomes of interest for the general adult population review include symptoms of depression or diagnosis of major depressive disorder, health-related quality of life, day-to-day functionality, lost time at work/school, impact on lifestyle behaviour, suicidality, false-positive result, labelling/stigma, overdiagnosis or overtreatment, and harms of treatment. Outcomes of interest for the pregnant and postpartum review include mental health outcomes (e.g. diagnosis of major depressive disorder), parenting outcomes (e.g. mother-child interactions), and infant outcomes (e.g. infant health and development). Discussion These two systematic reviews will offer informative evaluations of depression screening. The findings will be used by the Task Force to help develop guideline recommendations on depression screening in the general adult population and in pregnant and postpartum women in Canada. Systematic review registration PROSPERO (CRD42018099690) Electronic supplementary material The online version of this article (10.1186/s13643-018-0930-3) contains supplementary material, which is available to authorized users.

Background The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with stenting requires consideration of patient characteristics, and decision makers require a comprehensive overview of the evidence. Methods We performed an umbrella review of systematic reviews (SRs) of randomized controlled trials of extended DAPT (> 12 months) compared with DAPT for 6 to 12 months after percutaneous coronary intervention with stenting. Outcomes of interest were death, myocardial infarction (MI), stroke, stent thrombosis, major adverse cardiac and cerebrovascular events, bleeding, and urgent revascularization. We aimed to assess the evidence of benefits and harms among clinically important subgroups (eg, elderly patients, those with diabetes, prior MI, acute coronary syndrome). We assessed the quality of the included reviews by use of A Measurement Tool to Assess Systematic Reviews (AMSTAR). Results Sixteen SRs involving 8 randomized controlled trials were included. Most scored 7 or more points on the AMSTAR checklist. There was no significant difference in outcomes with extended DAPT compared with 6 months of DAPT in most SRs, with the exception of an increased risk of major bleeding. Compared with 12 months, extended DAPT may reduce the risk of MI and stent thrombosis; however, the findings were not consistent across all reviews. There have been conflicting reports of an increased risk of death with extended DAPT. Few SRs assessed outcomes among patient subgroups. Conclusions Extended DAPT may reduce the risk of MI and stent thrombosis but increase the risk of major bleeding and death. Whether the effects of extended DAPT are consistent across patient subgroups is unclear, and future SRs should address this knowledge gap.

Background Inherited metabolic diseases (IMD) are a large group of rare single-gene disorders that are typically diagnosed early in life. There are important evidence gaps related to the comparative effectiveness of therapies for IMD, which are in part due to challenges in conducting randomized controlled trials (RCTs) for rare diseases. Registry-based RCTs present a unique opportunity to address these challenges provided the registries implement standardized collection of outcomes that are important to patients and their caregivers and to clinical providers and healthcare systems. Currently there is no core outcome set (COS) for studies evaluating interventions for paediatric IMD. This protocol outlines a study that will establish COS for each of two relatively common IMD in children, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Methods This two-part study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Part 1 includes a rapid review and development of an evidence map to identify a comprehensive listing of outcomes reported in past studies of PKU and MCAD deficiency. The review follows established methods for knowledge synthesis, including a comprehensive search strategy, two stages of screening citations against inclusion/exclusion criteria by two reviewers working independently, and extraction of important data elements from eligible studies, including details of the outcomes collected and outcome measurement instruments. The review findings will inform part 2 of our study, a set of Delphi surveys to establish consensus on the highest priority outcomes for each condition. Healthcare providers, families of children with PKU or MCAD deficiency, and health system decision-makers will be invited to participate in two to three rounds of Delphi surveys. The design of the surveys will involve parents of children with IMD who are part of a family advisory forum. Discussion This protocol is a crucial step in developing the capacity to launch RCTs with meaningful outcomes that address comparative effectiveness questions in the field of paediatric IMD. Such trials will contribute high-quality evidence to inform decision-making by patients and their family members, clinicians, and policy-makers. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2327-3) contains supplementary material, which is available to authorized users.

Objective To assess the relative effects of individual testosterone products among hypogonadal men. Design Systematic review and network meta-analysis. Methods We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (25 May 2017) for randomised-controlled trials (RCTs) and non-randomised studies (NRS) that involved hypogonadal men given testosterone replacement therapy (TRT) for ≥3 months. Comparators were placebo, another TRT, or the same product at a different dose. Outcomes were quality of life, depression, libido, erectile function, activities of daily living and testosterone levels, as well as cardiovascular death, myocardial infarction, stroke, prostate cancer, heart disease, diabetes, serious adverse events, withdrawals due to adverse events and erythrocytosis. RCT data were pooled via meta-analysis and network meta-analysis. Risk of bias was assessed using Cochrane’s risk of bias tool (RCTs) andScottish Intercollegiate Guidelines Network (SIGN)50 (NRS). Results Eighty-seven RCTs and 51 NRS were included. Most were at high or unclear risk of bias, with short treatment duration and follow-up. When compared as a class against placebo, TRT improved quality of life (standardised mean difference (SMD) −0.26, 95% CI −0.41 to –0.11), libido (SMD 0.33, 95% CI 0.16 to 0.50), depression (SMD −0.23, 95% CI −0.44 to –0.01) and erectile function (SMD 0.25, 95% CI 0.10 to 0.41). Most individual TRTs were significantly better than placebo at improving libido (6/10). Only one TRT was better than placebo at improving quality of life, and no individual TRTs improved depression or erectile function. There was no increased risk of adverse events, with the exception of withdrawals due to adverse events with the use of some TRTs. Conclusion Despite a class effect of improving quality of life, depression, erectile function and libido, major improvements were not observed with the use of any individual product. We observed no statistically significant increase in the risk of adverse events; however, longer-term high-quality trials are needed to fully assess the risk of harm. PROSPERO registration number CRD42014009963.

Background This study is to perform a systematic review of existing guidance on quality of reporting and methodology for systematic reviews of diagnostic test accuracy (DTA) in order to compile a list of potential items that might be included in a reporting guideline for such reviews: Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy (PRISMA-DTA). Methods Study protocol published on EQUATOR website. Articles in full text or abstract form that reported on any aspect of reporting systematic reviews of diagnostic test accuracy were eligible for inclusion. We used the Ovid platform to search Ovid MEDLINE®, Ovid MEDLINE® In-Process & Other Non-Indexed Citations and Embase Classic+Embase through May 5, 2016. The Cochrane Methodology Register in the Cochrane Library (Wiley version) was also searched. Title and abstract screening followed by full-text screening of all search results was performed independently by two investigators. Guideline organization websites, published guidance statements, and the Cochrane Handbook for Diagnostic Test Accuracy were also searched. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Standards for Reporting Diagnostic Accuracy (STARD) were assessed independently by two investigators for relevant items. Results The literature searched yielded 6967 results; 386 were included after title and abstract screening and 203 after full-text screening. After reviewing the existing literature and guidance documents, a preliminary list of 64 items was compiled into the following categories: title (three items); introduction (two items); methods (35 items); results (13 items); discussion (nine items), and disclosure (two items). Conclusion Items on the methods and reporting of DTA systematic reviews in the present systematic review will provide a basis for generating a PRISMA extension for DTA systematic reviews.

Background Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive disease that makes up about 20% of all invasive breast cancers. HER2+ breast cancer is associated with poor prognosis and high mortality rates, but the development of HER2-targeted therapies, such as originator trastuzumab (Herceptin®), has substantially improved patient survival. Numerous clinical trials and reviews have investigated the efficacy of HER2-targeted therapies over the past few decades; however, no study has specifically investigated the vast body of evidence on trastuzumab in comparison to chemotherapy regimens, endocrine therapies, and other targeted therapies. This systematic review and cumulative network meta-analysis (NMA) will synthesize available evidence to evaluate the survival benefit conferred by the addition of originator trastuzumab to standard chemotherapy and to compare the most widely used trastuzumab regimens in patients with HER2+ early breast cancer, based on results from randomized controlled trials (RCTs) and comparative observational studies. Methods/design A systematic search of Embase, MEDLINE®, and the Cochrane Library has been designed by an experienced medical information specialist and peer reviewed by another senior information specialist. RCTs and comparative observational studies of patients with HER2+ early breast cancer indexed from 1990 onwards will be eligible for inclusion. Two investigators will independently assess studies for inclusion and use standardized data extraction templates to collect data on study and patient characteristics. The primary outcome of interest is overall survival. Bayesian cumulative NMA methods will be used to quantify the evolution of publicly available evidence using both fixed and random effects models. Discussion This study will evaluate survival trends associated with originator trastuzumab in patients with HER2+ early breast cancer. As originator trastuzumab has been researched in both clinical and real-world settings for close to 20 years, a cumulative NMA is likely to show improved precision around the parameter estimates for trastuzumab now compared with when the drug was initially launched in the USA in 1998. A better understanding of the evolution of publicly available comparative evidence for originator trastuzumab will further inform treatment for patients with HER2+ early breast cancer, providing benefit to patients, health professionals, and researchers. Systematic review registration PROSPERO CRD42017055763 https://www.crd.york.ac.uk/PROSPERO Electronic supplementary material The online version of this article (10.1186/s13643-017-0588-2) contains supplementary material, which is available to authorized users.

Background Pre-exposure prophylaxis (PrEP) with antiretrovirals is an efficacious and effective intervention to decrease the risk of HIV (human immunodeficiency virus) acquisition. Yet drug and delivery costs prohibit access in many jurisdictions. In the absence of guidelines for the synthesis of economic evaluations, we developed a protocol for a systematic review of economic evaluation studies for PrEP by drawing on best practices in systematic reviews and the conduct and reporting of economic evaluations. We aim to estimate the incremental cost per health outcome of PrEP compared with placebo, no PrEP, or other HIV prevention strategies; assess the methodological variability in, and quality of, economic evaluations of PrEP; estimate the incremental cost per health outcome of different PrEP implementation strategies; and quantify the potential sources of heterogeneity in outcomes. Methods We will systematically search electronic databases (MEDLINE, Embase) and the gray literature. We will include economic evaluation studies that assess both costs and health outcomes of PrEP in HIV-uninfected individuals, without restricting language or year of publication. Two reviewers will independently screen studies using predefined inclusion criteria, extract data, and assess methodological quality using the Philips checklist, Second Panel on the Cost-effectiveness of Health and Medicines, and the International Society for Pharmacoeconomics and Outcomes Research recommendations. Outcomes of interest include incremental costs and outcomes in natural units or utilities, cost-effectiveness ratios, and net monetary benefit. We will perform descriptive and quantitative syntheses using sensitivity analyses of outcomes by population subgroups, HIV epidemic settings, study designs, baseline intervention contexts, key parameter inputs and assumptions, type of outcomes, economic perspectives, and willingness to pay values. Discussion Findings will guide future economic evaluation of PrEP strategies in terms of methodological and knowledge gaps, and will inform decisions on the efficient integration of PrEP into public health programs across epidemiologic and health system contexts. Systematic review registration PROSPERO CRD42016038440. Electronic supplementary material The online version of this article (10.1186/s13643-018-0710-0) contains supplementary material, which is available to authorized users.

Background Hearing loss is one of the leading causes of disability worldwide, with greater than 20% of Canadian adults having measurable hearing loss in at least one ear. Patients with hearing loss experience impaired quality of life, and emotional and financial consequences that affect themselves and their families. Sudden sensorineural hearing loss (SSNHL) is a common but difficult to treat form of hearing loss that has a sudden onset of ≤ 72 h associated with various etiologies, with the majority of cases being idiopathic. Some patients may partially or completely recover hearing ability, but for 32 to 65% of patients whose hearing does not recover, feelings of social isolation elevate the risk of anxiety and depression. Hearing loss is also associated with poorer functional status, including difficulty with sound localization and hearing in noise. There exists a wide range of therapeutic options; however, treatment of idiopathic SSNHL is controversial because some patients recover spontaneously. The planned systematic review and network meta-analysis (NMA) will assess the relative effects of competing treatments for management of idiopathic SSNHL in adults. Methods Electronic search strategies were developed by an experienced medical information specialist in consultation with the review team. We will search MEDLINE, Embase, and the Cochrane Library with no date or language restrictions. Key clinical trial registries will also be searched for in-progress and completed trials. Two reviewers will independently screen the literature using pre-specified eligibility criteria, and assess the quality of included studies using the Cochrane Risk of Bias tool. Disagreements will be resolved through consensus or third party adjudication. Bayesian NMAs will be pursued to compare interventions in terms of their effects on hearing (including audiometric thresholds and speech recognition scores), extent of hearing recovery, quality of life, and incidence of harms (including vestibular dysfunction, incidence of infections, and withdrawals due to adverse events). Discussion This systematic review and NMA will offer new and informative evaluations of current therapies for SSNHL. The results will inform clinicians as to the relative benefits of the currently available interventions for managing this difficult condition, provide optimal clinical treatment strategies, establish evidence gaps, and identify promising treatments for evaluation in future trials. Systematic review registration PROSPERO registration number: CRD 42017073756.

Background Randomized controlled trials (RCTs) on bone marrow stem cell (BMSC) therapy in ST-elevation myocardial infarction (STEMI) patients have reported conflicting results. Our main objective was to critically appraise and meta-analyze best-available evidence on efficacy and safety of intracoronary administration of autologous BMSC therapy in STEMI patients after primary percutaneous coronary intervention. Methods We conducted a search of MEDLINE, PubMed, EMBASE, CENTRAL, Global Health, CINAHL, and conference proceedings in February 2017. Our primary outcome was all-cause mortality. Secondary and safety outcomes included cardiac death, heart failure, arrhythmias, repeat myocardial infarction, or target vessel revascularizations; or improved health-related quality of life, left ventricular ejection fraction, or infarct size. Summary relative and absolute risks were obtained using random effects models. We also evaluated the strength of evidence. Results A comprehensive database search identified 42 RCTs (3365 STEMI patients). BMSC therapy did not significantly decrease mortality (risk ratio, 0.71; 95% confidence interval, 0.45-1.11; I 2 , 0%; absolute risk reduction, 0.1%; 95% confidence interval, −0.71 to 0.91; 40 trials; 3289 participants; I 2 , 0%; low strength of evidence). BMSC therapy had no effect on secondary or adverse outcomes. Trial sequential analysis for all-cause mortality showed no evidence of a clinically important difference, with a very low probability that future studies can change the current conclusion. Conclusions On the basis of evidence from 42 RCTs published in the past 15 years, we provide conclusive evidence for a lack of beneficial effect for autologous BMSC therapy in patients with STEMI.

Background Guidelines for assessing methodological and reporting quality of systematic reviews (SRs) were developed to contribute to implementing evidence-based health care and the reduction of research waste. As SRs assessing a cohort of SRs is becoming more prevalent in the literature and with the increased uptake of SR evidence for decision-making, methodological quality and standard of reporting of SRs is of interest. The objective of this study is to evaluate SR adherence to the Quality of Reporting of Meta-analyses (QUOROM) and PRISMA reporting guidelines and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) and Overview Quality Assessment Questionnaire (OQAQ) quality assessment tools as evaluated in methodological overviews. Methods The Cochrane Library, MEDLINE®, and EMBASE® databases were searched from January 1990 to October 2014. Title and abstract screening and full-text screening were conducted independently by two reviewers. Reports assessing the quality or reporting of a cohort of SRs of interventions using PRISMA, QUOROM, OQAQ, or AMSTAR were included. All results are reported as frequencies and percentages of reports and SRs respectively. Results Of the 20,765 independent records retrieved from electronic searching, 1189 reports were reviewed for eligibility at full text, of which 56 reports (5371 SRs in total) evaluating the PRISMA, QUOROM, AMSTAR, and/or OQAQ tools were included. Notable items include the following: of the SRs using PRISMA, over 85% (1532/1741) provided a rationale for the review and less than 6% (102/1741) provided protocol information. For reports using QUOROM, only 9% (40/449) of SRs provided a trial flow diagram. However, 90% (402/449) described the explicit clinical problem and review rationale in the introduction section. Of reports using AMSTAR, 30% (534/1794) used duplicate study selection and data extraction. Conversely, 80% (1439/1794) of SRs provided study characteristics of included studies. In terms of OQAQ, 37% (499/1367) of the SRs assessed risk of bias (validity) in the included studies, while 80% (1112/1387) reported the criteria for study selection. Conclusions Although reporting guidelines and quality assessment tools exist, reporting and methodological quality of SRs are inconsistent. Mechanisms to improve adherence to established reporting guidelines and methodological assessment tools are needed to improve the quality of SRs. Electronic supplementary material The online version of this article (doi:10.1186/s13643-017-0527-2) contains supplementary material, which is available to authorized users.

Background Allergic rhinitis and asthma are important public health concerns, yet there is no consensus about the benefits and harms of allergen-specific immunotherapy to treat these conditions. We performed an umbrella review of systematic reviews summarizing the current evidence for the benefits and harms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). Methods We searched MEDLINE, Embase, the Cochrane Library and the grey literature from Jan. 1, 2010 to Nov. 20, 2016 for systematic reviews of randomized controlled trials or prospectively controlled studies involving children or adults with allergic rhinitis or asthma. Outcomes were summarized narratively (benefits: total combined symptom-medication score, symptom score, medication score, disease-specific quality of life, adherence; harms: anaphylaxis, death, local and systemic reactions). Results Twenty-three systematic reviews were included. SCIT and SLIT were more effective than placebo for most outcomes. SCIT was better than SLIT at improving medication and symptom scores, with no differences in quality of life; however, data were limited for this comparison. Anaphylaxis and death were infrequently reported. Few reviews assessed benefits or harms among children. Interpretation Allergen immunotherapy appears to be effective among patients with allergic rhinitis and asthma. The safety of allergen immunotherapy is not conclusively established, although death and anaphylaxis appear to be rare. PROSPERO no.: CRD42015024590.

Background The World Health Organization (WHO) considers pregnant women to be a risk group for severe influenza disease. We conducted a systematic review to evaluate influenza disease incidence in pregnant women in order to inform estimates of influenza vaccine impact for low-resource countries. Methods We performed electronic literature searches, targeting studies on the following outcomes in pregnant women: attack rate, hospitalization rate, intensive care unit admission rate, mortality rate, and disability-adjusted life years lost. Only original studies published in peer-reviewed journals that had laboratory confirmation for influenza virus infection and included population-based incidence rates with denominator data were included. We summarized study characteristics in descriptive tables and outcome-specific Forest plots. We generated summary incidence rates using random effects models and assessed statistical heterogeneity by visual examination of Forest plots, and by χ 2 and I2 tests. Results We identified 1543 articles, of which nine articles met the study inclusion criteria. Five were case series, three were cohort studies, and one was a randomized controlled trial. Eight studies were from high-income countries, and one was from an upper middle-income country. Six studies reported results for pandemic influenza, and three reported seasonal influenza. Statistical heterogeneity was high for all outcomes, and methodologies and duration of surveillance varied considerably among studies; therefore, we did not perform meta-analyses. Conclusions Study quality was very low according to GRADE criteria. More data on influenza disease incidence in pregnant women, particularly in low- and middle-income countries and for seasonal influenza disease, are needed to inform public health decision-making. Electronic supplementary material The online version of this article (doi:10.1186/s12884-017-1333-5) contains supplementary material, which is available to authorized users.

Background We conducted a systematic review and network meta-analysis (NMA) to examine the efficacy and completion rates of treatments for latent tuberculosis infection (LTBI). While a previous review found newer, short-duration regimens to be effective, several included studies did not confirm LTBI, and analyses did not account for variable follow-up or assess completion. Methods We searched MEDLINE, Embase, CENTRAL, PubMed, and additional sources to identify RCTs in patients with confirmed LTBI that involved a regimen of interest and reported on efficacy or completion. Regimens of interest included isoniazid (INH) with rifapentine once weekly for 12 weeks (INH/RPT-3), 6 and 9 months of daily INH (INH-6; INH-9), 3–4 months daily INH plus rifampicin (INH/RFMP 3–4), and 4 months daily rifampicin alone (RFMP-4). NMAs were performed to compare regimens for both endpoints. Results Sixteen RCTs (n = 44,149) and 14 RCTs (n = 44,128) were included in analyses of efficacy and completion. Studies were published between 1968 and 2015, and there was diversity in patient age and comorbidities. All regimens of interest except INH-9 showed significant benefits in preventing active TB compared to placebo. Comparisons between active regimens did not reveal significant differences. While definitions of regimen completion varied across studies, regimens of 3–4 months were associated with a greater likelihood of adequate completion. Conclusions Most of the active regimens showed an ability to reduce the risk of active TB relative to no treatment, however important differences between active regimens were not found. Shorter rifamycin-based regimens may offer comparable benefits to longer INH regimens. Regimens of 3–4 months duration are more likely to be completed than longer regimens. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2377-x) contains supplementary material, which is available to authorized users.

Introduction Although dual antiplatelet therapy (DAPT) is routinely given to patients after percutaneous coronary intervention (PCI) with stenting, the optimal duration is unknown. Recent evidence indicates there may be benefits in extending the duration beyond 12 months but such decisions may increase the risk of bleeding. Our objective is to provide a comprehensive overview of the literature for clinicians and policymakers via an umbrella review assessing the optimal duration of DAPT. Methods and analysis We will perform a comprehensive search of the published and grey literature for systematic reviews involving randomised controlled trials (RCTs) assessing the optimal duration of DAPT following PCI with stenting. The intervention of interest is extended DAPT (beyond 12 months) compared with short-term DAPT (6–12 months). Studies will be selected for inclusion by two reviewers, and the quality will be assessed. The primary outcomes of interest are all-cause mortality and cardiovascular mortality. Secondary outcomes will be bleeding (major, minor and gastrointestinal), urgent target vessel revascularisation, major adverse cardiovascular events, myocardial infarction, stroke and stent thrombosis. Outcomes will be assessed while on DAPT and after withdrawal of DAPT. Data will be summarised with respect to the number of included RCTs, number of participants, effect estimates and heterogeneity. Data will be reported separately based on patient demographics, procedural parameters (eg, stent types, lesion complexity and concurrent disease) and clinical presentation (eg, acute coronary syndromes, infarct type). Ethics and dissemination Our umbrella review aims to provide a comprehensive overview of the benefits and harms associated with extending DAPT beyond 12 months following PCI with stenting. The results of this review will inform clinical and policy decisions regarding the optimal treatment duration and reimbursement of DAPT following PCI with stenting. Results will be disseminated through a peer-reviewed publication and conference presentations. Ethics approval is not required for this study. Trial registration number CRD42016047735.

There is a plethora of interventions and policies aimed at changing practice habits of primary healthcare professionals, but it is unclear which are the most appropriate, sustainable, and effective. We aimed to evaluate the evidence on behavior change interventions and policies directed at healthcare professionals working in primary healthcare centers.Study design: overview of reviews.MEDLINE (Ovid), Embase (Ovid), The Cochrane Library (Wiley), CINAHL (EbscoHost), and grey literature (January 2005 to July 2015).two reviewers independently, and in duplicate, identified systematic reviews, overviews of reviews, scoping reviews, rapid reviews, and relevant health technology reports published in full-text in the English language.two reviewers extracted data pertaining to the types of reviews, study designs, number of studies, demographics of the professionals enrolled, interventions, outcomes, and authors' conclusions for the included studies. We evaluated the methodological quality of the included studies using the AMSTAR scale. For the comparative evaluation, we classified interventions according to the behavior change wheel (Michie et al.).Of 2771 citations retrieved, we included 138 reviews representing 3502 individual studies. The majority of systematic reviews (91%) investigated behavior and practice changes among family physicians. Interactive and multifaceted continuous medical education programs, training with audit and feedback, and clinical decision support systems were found to be beneficial in improving knowledge, optimizing screening rate and prescriptions, enhancing patient outcomes, and reducing adverse events. Collaborative team-based policies involving primarily family physicians, nurses, and pharmacists were found to be most effective. Available evidence on environmental restructuring and modeling was found to be effective in improving collaboration and adherence to treatment guidelines. Limited evidence on nurse-led care approaches were found to be as effective as general practitioners in patient satisfaction in settings like asthma, cardiovascular, and diabetes clinics, although this needs further evaluation. Evidence does not support the use of financial incentives to family physicians, especially for long-term behavior change.Behavior change interventions including education, training, and enablement in the context of collaborative team-based approaches are effective to change practice of primary healthcare professionals. Environmental restructuring approaches including nurse-led care and modeling need further evaluation. Financial incentives to family physicians do not influence long-term practice change.

Background. The use of natural health products in prostate cancer (PrCa) is high despite a lack of evidence with respect to safety and efficacy. Fish-derived omega-3 fatty acids possess anti-inflammatory effects and preclinical data suggest a protective effect on PrCa incidence and progression; however, human studies have yielded conflicting results. Methods. A search of OVID MEDLINE, Pre-MEDLINE, Embase, and the Allied and Complementary Medicine Database (AMED) was completed for human interventional or observational data assessing the safety and efficacy of fish-derived omega-3 fatty acids in the incidence and progression of PrCa. Results. Of 1776 citations screened, 54 publications reporting on 44 studies were included for review and analysis: 4 reports of 3 randomized controlled trials, 1 nonrandomized clinical trial, 20 reports of 14 cohort studies, 26 reports of 23 case-control studies, and 3 case-cohort studies. The interventional studies using fish oil supplements in patients with PrCa showed no impact on prostate-specific antigen levels; however, 2 studies showed a decrease in inflammatory or other cancer markers. A small number of mild adverse events were reported and interactions with other interventions were not assessed. Cohort and case-control studies assessing the relationship between dietary fish intake and the risk of PrCa were equivocal. Cohort studies assessing the risk of PrCa mortality suggested an association between higher intake of fish and decreased risk of prostate cancer–related death. Conclusions. Current evidence is insufficient to suggest a relationship between fish-derived omega-3 fatty acid and risk of PrCa. An association between higher omega-3 intake and decreased PrCa mortality may be present but more research is needed. More intervention trials or observational studies with precisely measured exposure are needed to assess the impact of fish oil supplements and dietary fish-derived omega-3 fatty acid intake on safety, PrCa incidence, treatment, and progression.

Background There is a plethora of interventions and policies aimed at changing practice habits of primary healthcare professionals, but it is unclear which are the most appropriate, sustainable, and effective. We aimed to evaluate the evidence on behavior change interventions and policies directed at healthcare professionals working in primary healthcare centers. Methods Study design: overview of reviews. Data source: MEDLINE (Ovid), Embase (Ovid), The Cochrane Library (Wiley), CINAHL (EbscoHost), and grey literature (January 2005 to July 2015). Study selection: two reviewers independently, and in duplicate, identified systematic reviews, overviews of reviews, scoping reviews, rapid reviews, and relevant health technology reports published in full-text in the English language. Data extraction and synthesis: two reviewers extracted data pertaining to the types of reviews, study designs, number of studies, demographics of the professionals enrolled, interventions, outcomes, and authors’ conclusions for the included studies. We evaluated the methodological quality of the included studies using the AMSTAR scale. For the comparative evaluation, we classified interventions according to the behavior change wheel (Michie et al.). Results Of 2771 citations retrieved, we included 138 reviews representing 3502 individual studies. The majority of systematic reviews (91%) investigated behavior and practice changes among family physicians. Interactive and multifaceted continuous medical education programs, training with audit and feedback, and clinical decision support systems were found to be beneficial in improving knowledge, optimizing screening rate and prescriptions, enhancing patient outcomes, and reducing adverse events. Collaborative team-based policies involving primarily family physicians, nurses, and pharmacists were found to be most effective. Available evidence on environmental restructuring and modeling was found to be effective in improving collaboration and adherence to treatment guidelines. Limited evidence on nurse-led care approaches were found to be as effective as general practitioners in patient satisfaction in settings like asthma, cardiovascular, and diabetes clinics, although this needs further evaluation. Evidence does not support the use of financial incentives to family physicians, especially for long-term behavior change. Conclusions Behavior change interventions including education, training, and enablement in the context of collaborative team-based approaches are effective to change practice of primary healthcare professionals. Environmental restructuring approaches including nurse-led care and modeling need further evaluation. Financial incentives to family physicians do not influence long-term practice change. Electronic supplementary material The online version of this article (doi:10.1186/s13012-016-0538-8) contains supplementary material, which is available to authorized users.

Background Medication errors represent a noteworthy source of harm to patients. In recent years, several systematic reviews have assessed the frequency and causes of these events, as well as other factors such as commonly associated drugs, their incidence in different specialties, and their consequences to patients. Despite this past literature, there remains a need to study discrepancies between these reviews and establish the current state of the evidence. The planned review will bring together, compare, and contract existing evidence related to the occurrence of medication errors in acute and continuing/long-term care settings. Methods A systematic review of reviews will be performed. A literature search designed by an experienced information specialist will be carried out in Medline, Embase, and the Cochrane Library. We will seek systematic reviews and meta-analyses of primary research studies that evaluate one or more of the following aspects of the occurrence of preventable adverse drug events in hospitals and long-term care centers: the incidence of preventable adverse drug events, either overall or within subgroups of interest related to setting; drug or patient characteristics; cited consequences of these events to patients, including death, emergency room visits, or other outcomes; and established causes of the preventable adverse drug events. Two researchers will independently screen all abstracts and full texts for study selection and subsequently perform data extraction from all included studies. Quality of the reviews will be assessed using the assessing the methodological quality of systematic reviews (AMSTAR) tool. Where objectives from two or more reviews overlap, we will employ the Jadad framework to assess the causes of any noted discrepancies between reviews. An overall summary of results will be performed using tabular and graphical approaches and will be supplemented by narrative description. Discussion This overview will help synthesize the broad degree of information available on this important topic. This review is being performed by members of the Drug Safety and Effectiveness Network along with collaboration from Health Canada, and its findings will be published in a peer-reviewed journal. The results may also inform future research in this area. Systematic review registration PROSPERO CRD42016043220 Electronic supplementary material The online version of this article (doi:10.1186/s13643-016-0392-4) contains supplementary material, which is available to authorized users.

Background. Flax is a food and dietary supplement commonly used for menopausal symptoms. Flax is known for its lignan, α-linolenic acid, and fiber content, components that may possess phytogestrogenic, anti-inflammatory, and hormone modulating effects, respectively. We conducted a systematic review of flax for efficacy in improving menopausal symptoms in women living with breast cancer and for potential impact on risk of breast cancer incidence or recurrence. Methods. We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to January 2013 for human interventional or observational data pertaining to flax and breast cancer. Results. Of 1892 records, we included a total of 10 studies: 2 randomized controlled trials, 2 uncontrolled trials, 1 biomarker study, and 5 observational studies. Nonsignificant (NS) decreases in hot flash symptomatology were seen with flax ingestion (7.5 g/d). Flax (25 g/d) increased tumor apoptotic index ( P < .05) and decreased HER2 expression ( P < .05) and cell proliferation (Ki-67 index; NS) among newly diagnosed breast cancer patients when compared with placebo. Uncontrolled and biomarker studies suggest beneficial effects on hot flashes, cell proliferation, atypical cytomorphology, and mammographic density, as well as possible anti-angiogenic activity at doses of 25 g ground flax or 50 mg secoisolariciresinol diglycoside daily. Observational data suggests associations between flax and decreased risk of primary breast cancer (adjusted odds ratio [AOR] = 0.82; 95% confidence interval [CI] = 0.69-0.97), better mental health (AOR = 1.76; 95% CI = 1.05-2.94), and lower mortality (multivariate hazard ratio = 0.69; 95% CI = 0.50-0.95) among breast cancer patients. Conclusions. Current evidence suggests that flax may be associated with decreased risk of breast cancer. Flax demonstrates antiproliferative effects in breast tissue of women at risk of breast cancer and may protect against primary breast cancer. Mortality risk may also be reduced among those living with breast cancer.

Vitamin D has reported anti-cancer and anti-inflammatory properties modulated through gene transcription and non-genomic signaling cascades. The purpose of this review was to summarize the available research on interactions and pharmacokinetics between vitamin D and the pharmaceutical drugs used in patients with cancer. Hypercalcemia was the most frequently reported side effect that occurred in high dose calcitriol. The half-life of 25(OH)D3 and/or 1,25(OH)2D3 was found to be impacted by cimetidine; rosuvastatin; prednisone and possibly some chemotherapy drugs. No unusual adverse effects in cancer patients; beyond what is expected from high dose 1,25(OH)2D3 supplementation, were revealed through this review. While sufficient evidence is lacking, supplementation with 1,25(OH)2D3 during chemotherapy appears to have a low risk of interaction. Further interactions with vitamin D3 have not been studied.

This is the peer reviewed version of the following article: van Katwyk, S., Coyle, D., Cooper, C., Pussegoda, K., Cameron, C., Skidmore, B., Brener, S., Moher, D. and Thavorn, K. (2017), Transient elastography for the diagnosis of liver fibrosis: a systematic review of economic evaluations. Liver Int, 37: 851-861., which has been published in final form at https://doi.org/10.1111/liv.13260. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Background: Liver biopsy remains the gold standard for the diagnosis of liver fibrosis, but its use as a diagnostic tool is limited by its invasive nature and high cost. Objective: The aim of this study was to systematically review the cost-effectiveness of transient elastography (TE) with and without controlled attenuation parameter (CAP) for the diagnosis of liver fibrosis or steatosis in patients with hepatitis B, hepatitis C, alcoholic liver disease and non-alcoholic fatty liver disease. Methods: An economic literature search was performed. Eligibility criteria included systematic reviews, health technology assessments or economic evaluations of TE compared to liver biopsy and other non-invasive tests. After abstract screening, full-text reports of potentially relevant articles were assessed in duplicate. The methodological quality of the included studies was also appraised. Results: The database search yielded 253 records; four cost-effectiveness and four cost-utility studies were included. The methodological quality of the included studies varies. High-quality cost-effectiveness studies not only suggested that TE is less costly but also less accurate than liver biopsy. The incremental cost-effectiveness ratio (ICER) of TE improves with a greater level of diagnostic accuracy and a higher degree of liver fibrosis. High-quality cost-utility studies indicated that TE is a cost-effective alternative to biopsy with ICER between $9000 and $14 000 per QALY for patients with hepatitis C. We did not find studies that assessed the cost-effectiveness of TE with CAP for the diagnosis of liver steatosis. Conclusions: Transient elastography is an economically attractive alternative to liver biopsy and other non-invasive diagnostic tests especially for patients with a higher degree of liver fibrosis.

Background Although pregnant women are considered at high risk for severe influenza disease, comparative studies of maternal influenza and birth outcomes have not been comprehensively summarised. Objective To review comparative studies evaluating maternal influenza disease and birth outcomes. Search strategy We searched bibliographic databases from inception to December 2014. Selection criteria Studies of preterm birth, small‐for‐gestational‐age (SGA) birth or fetal death, comparing women with and without clinical influenza illness or laboratory‐confirmed influenza infection during pregnancy. Data collection and analysis Two reviewers independently abstracted data and assessed study quality. Main results Heterogeneity across 16 studies reporting preterm birth precluded meta‐analysis. In a subgroup of the highest‐quality studies, two reported significantly increased preterm birth (risk ratios (RR) from 2.4 to 4.0) following severe 2009 pandemic H1N1 (pH1N1) influenza illness, whereas those assessing mild‐to‐moderate pH1N1 or seasonal influenza found no association. Five studies of SGA birth showed no discernible patterns with respect to influenza disease severity (pooled odds ratio 1.24; 95% CI 0.96–1.59). Two fetal death studies were of sufficient quality and size to permit meaningful interpretation. Both reported an increased risk of fetal death following maternal pH1N1 disease (RR 1.9 for mild‐to‐moderate disease and 4.2 for severe disease). Conclusions Comparative studies of preterm birth, SGA birth and fetal death following maternal influenza disease are limited in number and quality. An association between severe pH1N1 disease and preterm birth and fetal death was reported by several studies; however, these limited data do not permit firm conclusions on the magnitude of any association. Tweetable abstract Comparative studies are limited in quality but suggest severe pandemic H1N1 influenza increases preterm birth., Tweetable abstract Comparative studies are limited in quality but suggest severe pandemic H1N1 influenza increases preterm birth.

Total joint replacement (TJR) procedures have been one of the most rewarding interventions for treating patients suffering from joint disease. However, developing a periprosthetic joint infection (PJI) is a serious complication that is associated with the highest burden of cost and reduction in patients' quality of life compared to other complications following TJRs. One of the main challenges facing clinicians who are treating PJIs is accurately diagnosing infection in a timely fashion. Multiple orthopedic associations have published clinical guidelines for diagnosing PJI which are based solely on consensus approaches, expert opinions, and narrative reviews. We believe that a higher quality of scientific rigor is necessary to establish a diagnostic guideline that represents current evidence more accurately and that identifies important knowledge gaps in PJI diagnosis. Therefore, we will conduct a systematic review on diagnostic performance of blood markers, synovial fluids, and tissue tests for diagnosing PJI.Electronic search strategies will be developed and tested by an experienced medical information specialist in consultation with the review team, and gray literature will be searched using the checklist from CADTH's Grey Matters Light. Two reviewers will independently screen the literature for inclusion using the prespecified eligibility criteria. Non-English language and animal-only studies will be excluded. Quality assessment and data extractions by reviewers will be verified, and disagreements will be resolved through consensus or third party adjudication. We will assess the quality of individual studies using the QUADAS-2 tool and use GRADE to summarize the strength of body of evidence. Analyses of evidence will be conducted in accordance with the Cochrane Handbook for Diagnostic Test Accuracy Reviews.We will conduct a systemic review of tests (blood markers, synovial fluids, and tissue testing) for diagnosing PJI in patients' knee, hip, and shoulder joint replacements. This will be the first scientifically rigorous and comprehensive systematic review in the field and may feed into an evidence-based clinical practice guideline. We will compare the findings of this review with the consensus-based guides and discuss the differences, similarities, and knowledge gaps.PROSPERO CRD42015023768.

Impaired glucose tolerance and impaired fasting glucose, referred to as prediabetes, are predisease states that may progress to type 2 diabetes mellitus. The value of intervening in these states, especially with respect to cardiovascular outcomes, is unclear. The purpose of this study was to develop a broad synopsis of the available literature through an evidence map of systematic reviews about interventions in adults with prediabetes. The Cochrane Library Issue 4, 2011, Ovid MEDLINE (1946–January 4, 2012) and grey literature were searched. Studies were selected according to defined eligibility criteria. Fourteen relevant systematic reviews, of mostly high quality, were retrieved. The majority of reviews evaluated pharmacotherapeutic interventions or diet/exercise/lifestyle. A few reviews assessed complementary alternative medicine, behavioural strategies, standard prevention education or gastric bypass surgery. Very few reviews reported data on clinical cardiovascular endpoints. Most reviews reported either shorter-term surrogate markers of cardiovascular outcomes or progression to type 2 diabetes mellitus. Based on an assessment of authors’ overall conclusions, the value of pharmacotherapeutic interventions and diet/exercise/lifestyle ranged from beneficial to inconclusive, behavioural strategies were beneficial, and gastric bypass surgery was probably beneficial. The value of complementary alternative medicine was inconclusive. A considerable amount of evidence pertaining to interventions in prediabetes exists. Future research should synthesize the available systematic review evidence base in an overview of reviews. In addition, more primary research should be conducted to assess clinical cardiovascular endpoints.

Background Preventable adverse drug reactions (PADRs) in inpatients are associated with harm, including increased length of stay and potential loss of life, and result in elevated costs of care. We conducted an overview of reviews (i.e., a systematic review of systematic reviews) to determine the incidence of PADRs experienced by inpatients. Secondary review objectives were related to assessment of the effects of patient age, setting, and clinical specialty on PADR incidence. Methods The protocol was registered in PROSPERO (CRD42016043220). We performed a search of Medline, Embase, and the Cochrane Library, limiting languages of publication to English and French. We included published systematic reviews that reported quantitative data on the incidence of PADRs in patients receiving acute or ambulatory care in a hospital setting. The full texts of all primary studies for which PADR data were reported in the included reviews were obtained and data relevant to review objectives were extracted. Quality of the included reviews was assessed using the AMSTAR-2 tool. Both narrative summaries of findings and meta-analyses of primary study data were undertaken. Results Thirteen systematic reviews encompassing 37 unique primary studies were included. Across primary studies, the PADR incidence was highly varied, ranging from 0.006 to 13.3 PADRs per 100 patients, with a pooled incidence estimate of 0.59 PADRs per 100 patients. Substantial heterogeneity was present across both reviews and primary studies with respect to review/study objectives, patient age, hospital setting, medical discipline, definitions and assessment tools used, event detection methods, endpoints of interest, and units of measure. Thirteen primary studies used prospective event detection methods and had a pooled PADR incidence of 3.13 (2.87–3.38) PADRs per 100 patients; however, extreme statistical heterogeneity (I2 = 97%) indicated this finding should be considered with caution. Subgroup meta-analyses demonstrated that PADR incidence varied significantly with event detection method (prospective > retrospective > voluntary reporting methods), hospital setting (ICU > wards), and medical discipline (medical > surgical). High statistical heterogeneity (I2 > 80%) was present across all analyses, indicating results should be interpreted with caution. Effects of patient age could not be assessed due to poor reporting of age groups used in primary studies. Discussion The method of event detection appeared to significantly influence PADR incidence, with prospective methods having the highest reported PADR rate. This finding is in agreement with the background literature. High methodological and statistical heterogeneity across primary studies evaluating adverse drug events reduces the validity of the overall PADR incidence derived from the meta-analyses of the pooled data. Data pooled from studies using only prospective methods of event detection should provide an overall estimate closest to the true PADR incidence; however, our estimate should be considered with caution due to the statistical heterogeneity found in this group of studies. Future studies should employ prospective methods of detection. This review demonstrates that the true overall incidence of PADRs is likely much greater than the overall pooled incidence estimate of 0.59 PADRs per 100 patients obtained when event detection method was not taken into consideration.

IntroductionThe opioid crisis has resulted in increasing rates of death caused by problematic opioid use. Current clinical guidelines recommend that individuals with persons with opioid use disorder (OUD) receive pharmacological (eg, opioid agonist therapy) and psychosocial (eg, cognitive behavioural therapy) therapy; however, the best combination of pharmacologic and psychosocial components is not known. Our objective of the planned study is to conduct a comprehensive systematic review to assess the relative benefits of psychosocial interventions as an adjunct to opioid agonist therapy among persons with OUD.Methods and analysisA comprehensive search for randomised controlled trials published in English or French will be conducted from database inception to March 2018. The search will be conducted in MEDLINE and translated for Embase, PsycINFO and the Cochrane Central Register of Controlled Trials. Two independent reviewers will screen, extract and assess risk of bias of eligible articles. Primary outcomes of interest will be treatment retention and opioid use (based on urinalysis results). Secondary outcomes will include self-reported opioid use, abstinence from illicit drugs, adherence to psychosocial therapy and opioid agonist therapy, risk for sexually transmitted disease, risk for blood borne pathogens, changes in mental health symptoms (eg, depression), measures of craving and changes in patients’ quality of life and relevant adverse events. If sufficient data and adequate homogeneity exists, network meta-analyses (NMA) will be performed.Ethics and disseminationThis will be the first systematic review to incorporate NMA to compare psychosocial treatments used as an adjunct to opioid agonist therapy for OUD. Results of this review will inform clinical management of persons with OUD.Trial registration numberCRD42018090761.

Background: There is no standardized definition of what a predatory journal is, nor have the characteristics of these journals been delineated or agreed upon. In order to study the phenomenon precisely a definition of predatory journals is needed. The objective of this scoping review is to summarize the literature on predatory journals, describe its epidemiological characteristics, and to extract empirical descriptions of potential characteristics of predatory journals. Methods: We searched five bibliographic databases: Ovid MEDLINE, Embase Classic + Embase, ERIC, and PsycINFO, and Web of Science on January 2nd, 2018. A related grey literature search was conducted March 27th, 2018. Eligible studies were those published in English after 2012 that discuss predatory journals. Titles and abstracts of records obtained were screened. We extracted epidemiological characteristics from all search records discussing predatory journals. Subsequently, we extracted statements from the empirical studies describing empirically derived characteristics of predatory journals. These characteristics were then categorized and thematically grouped. Results: 920 records were obtained from the search. 344 of these records met our inclusion criteria. The majority of these records took the form of commentaries, viewpoints, letters, or editorials (78.44%), and just 38 records were empirical studies that reported empirically derived characteristics of predatory journals. We extracted 109 unique characteristics from these 38 studies, which we subsequently thematically grouped into six categories: journal operations, article, editorial and peer review, communication, article processing charges, and dissemination, indexing and archiving, and five descriptors. Conclusions: This work identified a corpus of potential characteristics of predatory journals. Limitations of the work include our restriction to English language articles, and the fact that the methodological quality of articles included in our extraction was not assessed. These results will be provided to attendees at a stakeholder meeting seeking to develop a standardized definition for what constitutes a predatory journal.

Objectives: This study sought to identify and compare various practical and current approaches of health technology assessment (HTA) priority setting.Methods: A literature search was performed across PubMed, MEDLINE, EMBASE, BIOSIS, and Cochrane. Given an earlier review conducted by European agencies (EUR-ASSESS project), the search was limited to literature indexed from 1996 onward. We also searched Web sites of HTA agencies as well as HTAi and ISTAHC conference abstracts. Agency representatives were contacted for information about their priority-setting processes. Reports on practical approaches selected through these sources were identified independently by two reviewers.Results: A total of twelve current priority-setting frameworks from eleven agencies were identified. Ten countries were represented: Canada, Denmark, England, Hungary, Israel, Scotland, Spain, Sweden, The Netherlands, and United States. Fifty-nine unique HTA priority-setting criteria were divided into eleven categories (alternatives; budget impact; clinical impact; controversial nature of proposed technology; disease burden; economic impact; ethical, legal, or psychosocial implications; evidence; interest; timeliness of review; variation in rates of use). Differences across HTA agencies were found regarding procedures for categorizing, scoring, and weighing of policy criteria.Conclusions: Variability exists in the methods for priority setting of health technology assessment across HTA agencies. Quantitative rating methods and consideration of cost benefit for priority setting were seldom used. These study results will assist HTA agencies that are re-visiting or developing their prioritization methods.

The intrathecal drug-delivery system (IDDS) is one mode of infusing analgesic medications directly into the cerebrospinal fluid in close proximity to their site of action. This modality has been employed in patients with refractory pain either due to malignant or non-malignant causes for over 30 years. Unfortunately, and despite the number of years it has been in use, there is still a scarcity of rigorous evidence to guide its integration into clinical practice. Current best evidence is inconclusive as to the comparative effectiveness and harms of the IDDS relative to routine medical care of patients. There are far more systematic reviews than high-quality primary comparative studies of the IDDS vs. conventional pain treatment. Existing clinical practice recommendations are best viewed as expert opinion with competing interests. This article will review the existing literature for indications, contraindications, consensus statements, different technologies, and complications of the IDDS. Although approved analgesics for IDDS delivery are limited to morphine and ziconotide, many other analgesics, alone or in combination, are routinely used in this setting. This review will also focus on the pharmacology, clinical efficacy, and safety of intrathecal medications extensively used in clinical practice; including agents approved, unapproved, and under development.

Background Breast and prostate cancers are the most commonly diagnosed non-dermatologic malignancies in Canada. Agents including endocrine therapies (e.g., aromatase inhibitors, gonadotrophin-releasing hormone analogs, anti-androgens, tamoxifen) and chemotherapy have improved survival for both conditions. As endocrine manipulation is a mainstay of treatment, it is not surprising that hot flashes are a common and troublesome adverse effect. Hot flashes can cause chills, night sweats, anxiety, and insomnia, lessening patients’ quality of life. These symptoms impact treatment adherence, worsening prognosis. While short-term estrogen replacement therapy is frequently used to manage hot flashes in healthy menopausal women, its use is contraindicated in breast cancer. Similarly, testosterone replacement therapy is contraindicated in prostate cancer. It is therefore not surprising that non-hormonal pharmacological treatments (anti-depressants, anti-epilectics, anti-hypertensives), physical/behavioral treatments (e.g., acupuncture, yoga/exercise, relaxation techniques, cognitive behavioral therapy), and natural health products (e.g., black cohosh, flax, vitamin E, ginseng) have been studied for control of hot flashes. There is a need to identify which interventions minimize the frequency and severity of hot flashes and their impact on quality of life. This systematic review and network meta-analysis of randomized studies will synthesize available evidence addressing this knowledge gap. Methods/design An electronic search of Medline, Embase, AMED, PsycINFO, and the Cochrane Register of Controlled Trials has been designed by an information specialist and peer reviewed by a second information specialist. Study selection and data collection will be performed by two reviewers independently. Risk of bias assessments will be completed using the Cochrane Risk of Bias Scale. Outcomes of interest will include validated measures of hot flash severity, hot flash frequency, quality of life, and harms. Bayesian network meta-analyses will be performed where judged appropriate based on review of clinical and methodologic features of included studies. Discussion Our review will include a broad range of interventions that patients with breast and prostate cancer have attempted to use to manage hot flashes. Our work will establish the extent of evidence underlying these interventions and will employ an inclusive approach to analysis to inform comparisons between them. Our findings will be shared with Cancer Care Ontario for consideration in the development of guidance related to supportive care in these patients. Systematic review registration PROSPERO: CRD42015024286 Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0099-y) contains supplementary material, which is available to authorized users.

BACKGROUND: Although triptans are widely used in the acute management of migraine, there is uncertainty around the comparative efficacy of triptans among each other and vs non-triptan migraine treatments. We conducted systematic reviews and network meta-analyses to compare the relative efficacy of triptans (alone or in combination with other drugs) for acute treatment of migraines compared with other triptan agents, non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA), acetaminophen, ergots, opioids, or anti-emetics. METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched for randomized controlled trials that compared triptans (alone or in combination with other drugs) with placebo-controlled or active migraine treatments. Study selection, data extraction, and quality assessment were completed independently by multiple reviewers. Outcome data were combined and analyzed using a Bayesian network meta-analysis. For each outcome, odds ratios, relative risks, and absolute probability of response were calculated. RESULTS: A total of 133 randomized controlled trials met the inclusion criteria. Standard dose triptans relieved headaches within 2 hours in 42 to 76% of patients, and 2-hour sustained freedom from pain was achieved for 18 to 50% of patients. Standard dose triptans provided sustained headache relief at 24 hours in 29 to 50% of patients, and sustained freedom from pain in 18 to 33% of patients. Use of rescue medications ranged from 20 to 34%. For 2-hour headache relief, standard dose triptan achieved better outcomes (42 to 76% response) than ergots (38%); equal or better outcomes than NSAIDs, ASA, and acetaminophen (46 to 52%); and equal or slightly worse outcomes than combination therapy (62 to 80%). Among individual triptans, sumatriptan subcutaneous injection, rizatriptan ODT, zolmitriptan ODT, and eletriptan tablets were associated with the most favorable outcomes. INTERPRETATION/CONCLUSIONS: Triptans are effective for migraine relief. Standard dose triptans are associated with better outcomes than ergots, and most triptans are associated with equal or better outcomes compared with NSAIDs, ASA, and acetaminophen. Use of triptans in combination with ASA or acetaminophen, or using alternative modes of administration such as injectables, may be associated with slightly better outcomes than standard dose triptan tablets. This research was supported by the Ontario Drug Policy Research Network. CC is a recipient of a Vanier Canada Graduate Scholarship through CIHR (Funding reference number – CGV 121171) and a trainee on the CIHR Drug Safety and Effectiveness Network Meta-Analysis team grant (Funding reference number – 116573).

Objectives: Given the resource-intensive nature of stroke rehabilitation, it is important that services be delivered in an evidence-based and cost-efficient manner. The objective of this review was to assess the evidence on the relative cost or cost-effectiveness of three rehabilitation services after stroke: stroke unit care versus care on another hospital ward, early supported discharge (ESD) services versus “usual care,” and community or home-based rehabilitation versus “usual care.”Methods:A systematic literature review of cost analyses or economic evaluations was performed. Study characteristics and results (including mean total cost per patient) were summarized. The level of evidence concerning relative cost or cost-effectiveness for each service type was determined qualitatively.Results:Fifteen studies met the inclusion criteria: three on stroke unit care, eight on ESD services, and four on community-based rehabilitation. All were classified as cost-consequences analysis or cost analysis. The time horizon was generally short (1 year or less). The comparators and the scope of costs varied between studies.Conclusions:There was “some” evidence that the mean total cost per patient of rehabilitation in a stroke unit is comparable to care provided in another hospital ward. There is “moderate” evidence that ESD services provide care at modestly lower total costs than usual care for stroke patients with mild or moderate disability. There was “insufficient” evidence concerning the cost of community-based rehabilitation compared with usual care. Several methodological problems were encountered when analyzing the economic evidence.

Upon publication of the original article, it was noticed that the Acknowledgements Section was missing.

Background Chronic pain disorders impact the physical, psychological, social, and financial well-being of between 10%–30% of Canadians. The primary aims of psychological interventions targeting chronic pain disorders are to reduce patients’ pain-related disability and to improve their quality of life. Cognitive behavioral therapy (CBT) is the prevailing treatment for chronic pain, however mindfulness-based stress reduction (MBSR) has displayed promise as an alternative treatment option. The objective of this systematic review and meta-analysis is to compare MBSR to CBT in their relative ability to reduce pain-related disability and intensity, to alleviate emotional distress, and to improve global functioning in chronic pain patients. Methods/design We will conduct a systematic review with meta-analyses to compare MBSR to CBT in the treatment of chronic pain disorders in adults. We will report our review according to the recommendations provided by the PRISMA statement. Randomized studies will be included and the literature search will comprise Ovid MEDLINE®, Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Embase Classic + Embase, PsycINFO, the Cochrane Library on Wiley, including CENTRAL, Cochrane Database of Systematic Reviews, DARE, and HTA. Study selection and data extraction will be conducted by independent investigators and in duplicate. Outcomes of interest will include pain interference, pain intensity, emotional functioning, and patient global impression of change. The Cochrane risk of bias tool will be used to assess risk of bias of included studies. As we anticipate that scales used to measure participant responses will be related but varied from study to study, standardized mean differences will be used to compare effect sizes between treatment modalities. Given the possibility of little or no head-to-head evidence comparing MBSR with CBT, we will use indirect treatment comparison methodology to assess the relative effectiveness of these interventions. Discussion The findings from this study will assist patients and treatment providers to make informed decisions regarding evidence-based treatment selection for chronic pain disorders. Systematic review registration PROSPERO CRD42014009356

Background. Intravenous vitamin C (IVC) is a contentious adjunctive cancer therapy, widely used in naturopathic and integrative oncology settings. We conducted a systematic review of human interventional and observational studies assessing IVC for use in cancer patients. Methods. We searched MEDLINE, EMBASE, The Cochrane Library, CINAHL, and AMED from inception to April 2013 for human studies examining the safety, effectiveness, or pharmacokinetics of IVC use in cancer patients. Results. Of 897 records, a total of 39 reports of 37 studies were included: 2 randomized controlled trials (RCTs), 15 uncontrolled trials, 6 observational studies, and 14 case reports. IVC dosing ranged from 1 g to more than 200 g ascorbic acid per infusion, typically administered 2 to 3 times weekly. IVC does not appear to increase toxicity or interfere with antitumor effects of gemcitabine/erlotinib therapy or paclitaxel and carboplatin. Based on 1 RCT and data from uncontrolled human trials, IVC may improve time to relapse and possibly enhance reductions in tumor mass and improve survival in combination with chemotherapy. IVC may improve quality of life, physical function, and toxicities associated with chemotherapy, including fatigue, nausea, insomnia, constipation, and depression. Case reports document several instances of tumor regression and long-term disease-free survival associated with use of IVC. Conclusion. There is limited high-quality clinical evidence on the safety and effectiveness of IVC. The existing evidence is preliminary and cannot be considered conclusive but is suggestive of a good safety profile and potentially important antitumor activity; however, more rigorous evidence is needed to conclusively demonstrate these effects. IVC may improve the quality of life and symptom severity of patients with cancer, and several cases of cancer remission have been reported. Well-designed, controlled studies of IVC therapy are needed.

International audience; BACKGROUND: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications.METHODS/DESIGN: We conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy.DISCUSSION: The goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin.SYSTEMATIC REVIEW REGISTRATION: PROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249.

Objective:Technological change accounts for approximately 25 percent of health expenditure growth. To date, limited research has been published on case studies of disinvestment and resource allocation decision making in clinical practice. Our research objective is to systematically review and catalogue the application of frameworks and tools for disinvestment and resource allocation decision making in health care.Methods:An electronic literature search was executed for studies on disinvestment, obsolete and ineffective technologies, and priority healthcare setting, published from January 1990 until January 2012. Databases searched were MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, Embase, The Cochrane Library, PubMed, and HEED.Results:Fourteen case studies on the application of frameworks and tools for disinvestment and resource allocation decisions were included. Most studies described the application of program budgeting and marginal analysis (PBMA), and two reports used health technology assessment (HTA) methods for coverage decisions in a national fee-for-service structure. Numerous healthcare technologies and services were covered across the studies. We describe the multiple criteria considered for decision making, and the strengths and limitations of these frameworks and tools are highlighted.Conclusions:Disinvestment and resource allocation decisions require evidence to ensure their transparency and objectivity. PBMA was used to assess resource allocation of health services and technologies in a fixed budget jurisdiction, while HTA reviews focused on specific technologies, principally in fee-for-service structures. Future research can review the data requirements and explore opportunities to increase the quantity of available evidence for disinvestment and resource allocation decisions.

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.

Background. Many women use black cohosh as a natural treatment for menopausal symptoms. However, controversy exists around safety in breast cancer, because of its purported estrogenic activity. We conducted a systematic review of black cohosh use in women with or at risk of breast cancer. Methods. We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to July 2012 and October 2012 for human interventional or observational data pertaining to the safety and efficacy of black cohosh in patients with or at risk of breast cancer, including an assessment of the effect of black cohosh on estrogen responsive tissues. Results. Of 450 records, we included 26 articles: 14 randomized controlled trials, 7 uncontrolled trials, and 5 observational studies.The evidence on efficacy for ho t flashes is divided, with some benefits seen when compared with baseline, but not when compared with placebo. Two observational studies found no association between black cohosh and risk of breast cancer, whereas 2 studies reported significant reductions in risk of primary breast cancer among postmenopausal women (adjusted odds ratio = 0.47, 95% confidence interval = 0.27-0.82), and risk of recurrence (adjusted hazard ratio = 0.75, 95% confidence interval = 0.63-0.89). Seventeen trials showed no significant impact on circulating hormone levels or proliferation in estrogen responsive tissues. Conclusions. Current evidence does not support an association between black cohosh and increased risk of breast cancer. There is a lack of evidence supporting the efficacy of black cohosh for reduction of hot flashes in breast cancer patients. Given conflicting but promising results, and apparent safety, further research is warranted.

Background Soy and red clover isoflavones are controversial due to purported estrogenic activity and possible effects on breast cancer. We conducted a systematic review of soy and red clover for efficacy in improving menopausal symptoms in women with breast cancer, and for potential impact on risk of breast cancer incidence or recurrence. Methods We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to March 2013 for human interventional or observational data pertaining to the safety and efficacy of soy and red clover isoflavones in patients with or at risk of breast cancer. Results Of 4179 records, we included a total of 131 articles: 40 RCTs, 11 uncontrolled trials, and 80 observational studies. Five RCTs reported on the efficacy of soy for hot flashes, showing no significant reductions in hot flashes compared to placebo. There is lack of evidence showing harm from use of soy with respect to risk of breast cancer or recurrence, based on long term observational data. Soy intake consistent with that of a traditional Japanese diet (2-3 servings daily, containing 25-50mg isoflavones) may be protective against breast cancer and recurrence. Human trials show that soy does not increase circulating estradiol or affect estrogen-responsive target tissues. Prospective data of soy use in women taking tamoxifen does not indicate increased risk of recurrence. Evidence on red clover is limited, however existing studies suggest that it may not possess breast cancer-promoting effects. Conclusion Soy consumption may be associated with reduced risk of breast cancer incidence, recurrence, and mortality. Soy does not have estrogenic effects in humans. Soy intake consistent with a traditional Japanese diet appears safe for breast cancer survivors. While there is no clear evidence of harm, better evidence confirming safety is required before use of high dose (≥100mg) isoflavones can be recommended for breast cancer patients.

To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications.MEDLINE®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, Genetics Abstracts, and EconLit™ to May 2009, for English language records.A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations.1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability. There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events. Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent. The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent. Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous.There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature.