Search

Abstract Background Several systematic reviews and meta-analyses populate the literature on the effectiveness of laparoscopic surgery for colorectal cancer. The utility of this body of work is unclear. The objective of this study was to synthesize all such systematic reviews in terms of clinical effectiveness, to appraise their quality, and to determine whether areas of duplication exist across reviews. Methods Systematic reviews comparing laparoscopic and open surgery for colorectal cancer were identified using a comprehensive search protocol (1991 to 2008). The primary outcome was overall survival. The methodological quality of reviews was appraised using the Assessment of Multiple Systematic Reviews (AMSTAR) instrument. Abstraction and quality appraisal was carried out by two independent reviewers. Reviews were synthesized, and outcomes were compared qualitatively. A citation analysis was carried out using simple matrices to assess the comprehensiveness of each review. Results In total, 27 reviews were included; 13 reviews included only randomized controlled trials. Rectal cancer was addressed exclusively by four reviews. There was significant overlap between review purposes, populations and, outcomes. The mean AMSTAR score (out of 11) was 5.8 (95% CI: 4.6 to 7.0). Overall survival was evaluated by ten reviews, none of which found a significant difference. Three reviews provided a selective meta-analysis of time-to-event data. Previously published systematic reviews were poorly and highly selectively referenced (mean citation ratio 0.16, 95% CI: 0.093 to 0.22). Previously published trials were not comprehensively identified and cited (mean citation ratio 0.56, 95% CI: 0.46 to 0.65). Conclusions Numerous overlapping systematic reviews of laparoscopic and open surgery for colorectal cancer exist in the literature. Despite variable methods and quality, survival outcomes are congruent across reviews. A duplication of research efforts appears to exist in the literature. Further systematic reviews or meta-analyses are unlikely to be justified without specifying a significantly different research objective. This works lends support to the registration and updating of systematic reviews.

Background: As systematic reviews' limited coverage of the medical literature necessitates decision-making based on unsystematic review, we investigated a possible advantage of systematic review (aside from dataset size and systematic analysis): does systematic review avoid potential bias in sampling primary studies from high impact factor journals? If randomized controlled trials (RCTs) reported in higher-impact journals present different treatment benefits than RCTs reported in lower-impact journals, readers who focus on higher-impact journals for their rapid literature reviews may introduce bias which could be mitigated by complete, systematic sampling., Methods: We randomly sampled Cochrane Library (20 July 2005) treatment reviews that measured mortality as a binary outcome, published in English or French, with at least five RCTs with one or more deaths. Our domain-based assessment of risk of bias included funding source, randomness of allocation sequence, blinding, and allocation concealment. The primary analysis employed logistic regression by a generalized linear model with a generalized estimating equation to estimate the association between various factors and publication in a journal with a high journal impact factor (JIF)., Results: From the 29 included systematic reviews, 189 RCTs contributed data. However, in the primary analyses comparing RCT results within meta-analyses, there was no statistically significant association: unadjusted odds of greater than 50% mortality protection in high-JIF (> 5) journals were 1.4 (95% CI 0.42, 4.4) and adjusted, 2.5 (95% CI 0.6, 10). Elements of study quality were weakly, inconsistently, and not statistically significantly correlated with journal impact factor., Conclusions: Journal impact factor may have little to no association with study results, or methodological quality, but the evidence is very uncertain.

Background and Purpose: Cerebral venous thrombosis causes disability from venous infarct and hemorrhage and potential mortality. Anticoagulation improves survival and disability outcomes, yet direct oral anticoagulants are currently not indicated in cerebral venous thrombosis due to lack of evidence, despite being on the market for nearly a decade. This systematic review will collate evidence of reported safety and efficacy of direct oral anticoagulant therapy in cerebral venous thrombosis., Methods: A search strategy was developed with a research librarian and registered on a protocol database (PROSPERO CRD42017078398). All published studies from MEDLINE and EMBASE up to February 2019 containing patients diagnosed with cerebral venous thrombosis who were treated with a direct oral anticoagulant (dabigatran, rivaroxaban, apixaban, or edoxaban) will be included. A risk of bias analysis will be performed to evaluate quality of studies overall., Discussion: Current guidelines in the treatment of cerebral vein thrombosis dating back to 2011 from the American Heart Association/American Stroke Association endorse the utility of anticoagulation for the treatment of cerebral vein thrombosis; however, they did not support the use of direct oral anticoagulants. Updated guidelines from the European Stroke Organization, endorsed by the European Academy of Neurology in 2017, also refute utilization of direct oral anticoagulants due to a lack of evidence. There have been nearly 10 years of experience with direct oral anticoagulants in the treatment of venous thrombosis and prevention of stroke in patients with atrial fibrillation, with purported efficacy and safety in comparison with heparins and vitamin K antagonists. Our goal is to undertake a systematic review to assess the effectiveness and safety of direct oral anticoagulants in patients with cerebral vein thrombosis to help guide clinical decision-making for patients unable to take heparins or vitamin K antagonists and to direct future studies to contribute further to an area of certain evidence-based needs., Systematic Review Registration: PROSPERO CRD42017078398.

Background: Development of fistula-in-ano following incision and drainage (I&D) of anorectal abscesses occurs in over 30% of patients. It is associated with significant patient morbidity and societal cost. The use of antibiotics following drainage is controversial, with randomized controlled trials reporting opposing conclusions regarding their influence on the rate of fistula formation. Given the significant burden associated with their development, it is imperative to determine strategies to minimize their occurrence. The objective of this review is to summarize the available evidence on the role of antibiotics following I&D of anorectal abscesses on fistula formation. Secondary objectives include determining if antibiotics are associated with morbidity, repeat presentation to the emergency department, and requirement for reoperation., Methods/design: MEDLINE, EMBASE, CINAHL, Cochrane Central Registry of Controlled Trials, http://apps.who.int/trialsearch , and clinicaltrials.gov will be searched to identify published and ongoing unpublished interventional and observational studies evaluating the role of antibiotics post I&D on the incidence of fistula formation. There will be no restriction on language, date, or journal. Title and abstracts as well as full texts will be screened in duplicate based on inclusion and exclusion criteria. The Cochrane Risk of Bias tool and ROBINS-I will be used to assess risk of bias in randomized and non-randomized studies, respectively. Our primary outcome is the incidence of fistula formation; secondary outcomes include morbidity, representation to ED, and reoperation. Study heterogeneity will be calculated with Cochran's Q test, P value, and I 2 index. SASS (version 9.4) will be used for meta-analysis., Discussion: This is the first study to review the available evidence on adjuvant antibiotics and incidence of fistula formation following I&D of anorectal abscesses., Systematic Review Registration: PROSPERO CRD42018092044.

Background: Angioplasty is a fundamental treatment for atherosclerotic disease in the cardiac, cerebrovascular, and peripheral vascular beds. However, the optimal duration of balloon inflation has not been identified. Our study will investigate whether prolonged angioplasty balloon inflation of at least 1 min duration, when compared with brief inflation, affects residual stenosis after arterial angioplasty., Methods: In compliance with PRISMA, two independent reviewers will conduct a systematic review of EMBASE, MEDLINE, CENTRAL, trial registries, grey literature, and ancestry and citation search. Data abstraction, quantitative, and quantitative meta-analysis will be performed according to pre-specified criteria. The primary outcome is residual stenosis immediately after initial angioplasty; however, secondary outcomes will include multiple short and long term pre-specific clinical and radiographic outcomes. Risk of bias, subgroup analyses, and sensitivity analyses are planned., Discussion: Despite the ubiquitous use of angioplasty in atherosclerotic disease and multiple trials investigating the ideal balloon inflation duration, there are no systematic reviews evaluating prolonged angioplasty balloon inflation. Currently synthesized evidence is insufficient to confidently direct clinical decision-making, and the current variation in operator preference of balloon angioplasty duration suggests ongoing clinical equipoise. Given the known availability of current primary evidence, our study intends to synthesize the evidence and guide future clinical decision making and investigation., Systematic Review Registration: PROSPERO CRD42018092702.

Background: Achilles tendon ruptures are a common injury and are increasing in incidence. Several management strategies exist for both non-operative and operative care, with each strategy offering unique risks and benefits. Traditional pairwise meta-analyses have been performed to compare management strategies; however, all treatment options have never been integrated in a single analysis. Network meta-analysis (NMA) is a generalization of pairwise meta-analysis, which allows for the comparison of multiple interventions based on all available direct and indirect evidence. The objectives of this review are to synthesize the evidence on the management options for acute Achilles tendon rupture and identify which treatment gives the best functional outcomes., Methods: A systematic review with NMA is planned. An electronic literature search will be performed in conjunction with an experienced information specialist in MEDLINE, EMBASE, CINAHL, PEDro, and the Cochrane Central Register of Controlled Trials. We will include randomized controlled trials with a minimum 6-month follow-up. Two independent reviewers will screen citations for eligibility, extract study data, and perform risk of bias assessments. The primary outcome will be disease-specific functional outcome scores (AOFAS, Leppilahti, modified Leppilahti) at 1 year. Secondary outcomes will include complications (re-rupture, sural nerve injury, wound complications, deep infection, secondary surgeries), strength, range of motion, return to work, return to sport, and quality-of-life measures (including the SF-36 questionnaire). Traditional pairwise meta-analyses will be performed for all direct comparisons where evidence is available, and NMAs will subsequently be performed where possible to compare all management strategies., Discussion: The data generated from this review will provide health-care providers with a clear evidence synthesis of all Achilles tendon rupture management strategies. Additionally, these data will be incorporated into the development of a patient decision aid to assist patients and clinicians in making a preference-based decision when faced with an Achilles tendon rupture., Systematic Review Registration: PROSPERO CRD42018093033 .

Background: Breast cancer and its treatment can have many physical and psychological effects on affected women. Women's personal goals may provide insight into their priorities and motivations in the context of breast cancer. Incorporating personal goal-setting into support and care interventions may have an effect on psychological well-being. This protocol describes our scoping review methods, the aim of which is to examine and map the existing evidence on personal goal-setting among women with a breast cancer diagnosis., Methods: Our scoping review will search for published, full-length articles, where personal goal-setting is a major component of the study, and the study population is females with breast cancer. MEDLINE, PsycInfo, CINAHL, EMBASE, the Cochrane Library, and AMED databases will be searched. Two independent reviewers will conduct all screening and extract data. Descriptive information about the studies, participants, any interventions, measurement tools, outcomes, and results will be reported., Discussion: The results from this review will chart the literature, contributing to optimizing the incorporation of personal goal-setting approaches into effective interventions for the care and support of women with breast cancer.

Background: Current guidelines identify the choice of fluid resuscitation as important in minimizing the incidence of secondary brain injury from cerebral edema. It is widely accepted that isotonic crystalloid resuscitation fluids, specifically normal saline (NS), are optimal for resuscitation and that other relatively hypotonic fluids, such as Ringer's lactate (RL), should be avoided in this patient population. The aim of this review is to systematically compare the use of relatively hypotonic versus isotonic crystalloid resuscitation fluids in clinical and pre-clinical models of acute brain injury and their effect on outcomes. In recognition of the potential need for a network meta-analysis (NMA), we have also included all other relevant crystalloid resuscitation fluids as interventions of relevance to potentially inform indirect comparisons., Methods: Systematic searches of MEDLINE, Embase, and Web of Science BIOSIS Previews® will be used to identify eligible clinical and pre-clinical studies, which included studies examining acute brain injury (human and in vivo animal brain injury models) within the first 7 days of therapy. The intervention of interest is the intravenous use of relatively hypotonic crystalloid resuscitation fluids (e.g., Ringer's lactate, Hartmann's or Plasma Lyte® fluids). The main comparator of interest is an isotonic crystalloid resuscitation fluid, specifically normal saline (0.9%). Other crystalloid resuscitation fluids (e.g., hypertonic saline (3-23.4%)) will also be included as an additional intervention of interest. The primary outcome measures of interest are intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Secondary outcomes include the effect of resuscitation on cerebral edema, brain and serum osmolarity, and electrolyte concentrations and clinical outcomes including modified Rankin Scale (mRS), (extended) Glasgow Outcome Scale (GOS/eGOS), and mortality. Separate meta-analyses will be conducted to quantify the effects of the different fluid resuscitation on acute brain injury outcomes in clinical and pre-clinical populations. Network meta-analyses to compare interventions will also be performed to compare the effects of different interventions., Discussion: This systematic review will comprehensively summarize the difference in treatment efficacy of various crystalloid resuscitation fluids in acute brain injury. This review is essential to underscore the evidence, or lack thereof, present in the literature to date to support current preference-driven practice and to direct future study., Systematic Review Registration: PROSPERO #CRD42016042960.

Background: Contrast-induced acute kidney injury (CI-AKI) is defined as worsening of renal function after the administration of iodinated contrast material. In patients with cardiovascular disease, kidney disease, and/or diabetes, renin-angiotensin system blockers, non-steroidal anti-inflammatory drugs, diuretics, and metformin can increase the risk of CI-AKI when undergoing contrast imaging. Despite CI-AKI being the leading iatrogenic cause of acute kidney injury, there is a lack of sufficient scientific evidence supporting which drugs should be stopped, when they should be stopped, and when they should be resumed. The purpose of this systematic review is to assess (1) the effect of withholding medication before contrast procedures on the risk of CI-AKI and other clinical outcomes and (2) the incidence of adverse events occurring after withholding these drugs prior to contrast procedures. This protocol has been registered with PROSPERO, https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016033178 ., Methods: An information specialist will assist in searching MEDLINE, Embase, and the Cochrane Library databases to identify randomized controlled trials, observational studies, case reports, and case series. Relevant abstracts from professional society meetings and web-based registries of clinical trials will also be included. Studies included will compare patients aged ≥ 18 years instructed to continue taking the drugs of interest and those advised to stop taking them before undergoing contrast procedures. If these drugs are not withheld prior to contrast procedures, the studies must compare patients who are administered these drugs and those who are not before undergoing contrast procedures. Two reviewers will independently screen the titles and abstracts of the studies obtained from the search using pre-defined inclusion criteria and will then extract data from the full texts of selected studies. The quality of the studies will be assessed by two independent reviewers using the Cochrane Risk of Bias 2.0 tool for randomized trials and the Newcastle-Ottawa Scale for observational studies., Discussion: This systematic review will provide a synthesis of current evidence on the discontinuation of drugs prior to contrast procedures and its effect on CI-AKI and other clinical outcomes. These findings will provide clinicians with guidelines and serve as a strong research base for future studies in this field., Systematic Review Registration: PROSPERO CRD42016033178.

Background: Despite advances in treatment, acute myocardial infarction (MI) is still associated with significant morbidity and mortality, especially in patients with extensive damage and scar formation. Based on some promising preclinical studies, there is interest in the use of mesenchymal stromal cells (MSCs) to promote cardiac repair after acute MI. However, there is a need for a systematic review of this evidence to summarize the efficacy and safety of MSCs in preclinical models of MI. This will better inform the translation of MSC therapy for acute MI and guide the design of a future clinical trial., Methods/design: A systematic literature search of MEDLINE, Embase, and BIOSIS Previews will be conducted. We will identify comparative preclinical studies (randomized and non-randomized) of myocardial infarction that include animals given MSC therapy versus a vehicle/placebo. The primary outcome will be left ventricular ejection fraction. Secondary and tertiary outcomes will include death, infarct size, measures of cardiac function, biochemical outcomes, and MSC retention and differentiation. Risk of bias will be assessed using the Cochrane Risk of Bias Tool. Subgroup analyses will be performed to measure how various sources of preclinical study heterogeneity affect the direction and magnitude of the primary outcome. We will meta-analyze data using inverse variance random effects modeling., Discussion: This systematic review of preclinical evidence will provide a summary of the efficacy and safety of MSCs in animal models of MI. The results will help determine whether sufficient evidence exists to conduct a clinical trial in humans and inform its design.

Background: Critically ill patients frequently experience severe agitation placing them at risk of harm. Physical restraint is common in intensive care units (ICUs) for clinician concerns about safety. However, physical restraint may not prevent medical device removal and has been associated with negative physical and psychological consequences. While professional society guidelines, legislation, and accreditation standards recommend physical restraint minimization, guidelines for critically ill patients are over a decade old, with recommendations that are non-specific. Our systematic review will synthesize evidence on physical restraint in critically ill adults with the primary objective of identifying effective minimization strategies., Methods: Two authors will independently search from inception to July 2016 the following: Ovid MEDLINE, CINAHL, Embase, Web of Science, Cochrane Library, PROSPERO, Joanna Briggs Institute, grey literature, professional society websites, and the International Clinical Trials Registry Platform. We will include quantitative and qualitative study designs, clinical practice guidelines, policy documents, and professional society recommendations relevant to physical restraint of critically ill adults. Authors will independently perform data extraction in duplicate and complete risk of bias and quality assessment using recommended tools. We will assess evidence quality for quantitative studies using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and for qualitative studies using the Confidence in the Evidence from Reviews of Qualitative Research (CERQual) guidelines. Outcomes of interest include (1) efficacy/effectiveness of physical restraint minimization strategies; (2) adverse events (unintentional device removal, psychological impact, physical injury) and associated benefits including harm prevention; (3) ICU outcomes (ventilation duration, length of stay, and mortality); (4) prevalence, incidence, patterns of use including patient and treatment characteristics and chemical restraint; (5) barriers and facilitators to minimization; (6) patient, family, and healthcare professional perspectives; (7) professional society-endorsed recommendations; and (8) evidence gaps and research priorities., Discussion: We will use our systematic review findings to produce updated guidelines on physical restraint use for critically ill adults and to develop a professional society-endorsed position statement. This will foster patient and clinician safety by providing clinicians, administrators, and policy makers with a tool to promote minimal and safe use of physical restraint for critically ill adults., Systematic Review Registration: PROSPERO CRD42015027860.

Background: Pulmonary arterial hypertension (PAH) is a rare disease (15 cases per million) that is characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary vascular resistance leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies (i.e., therapies involving cells with stem or progenitor-like properties) could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. Preclinical evidence suggests that regenerative cell therapy using endothelial progenitor cells or mesenchymal stem cells may be beneficial in the treatment of PAH. These findings have led to the completion of a small number of human clinical trials, albeit with modest effect compared to animal studies. The objective of this systematic review is to compare the efficacy and safety of regenerative cell therapies in preclinical models of PAH as well as assess study quality to inform future clinical studies., Methods: We will include preclinical studies of PAH in which a regenerative cell type was administered and outcomes compared to a disease control. The primary outcome will be pulmonary hemodynamics as assessed by measurement of right ventricular systolic pressure and/or mean pulmonary arterial pressure. Secondary outcomes will include mortality, survival, right ventricular remodeling, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary acceleration time, tricuspid annular systolic excursion, and right ventricular wall thickness. Electronic searches of MEDLINE and EMBASE databases will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, and individual study reporting will be assessed according to an itemized checklist based on the Animal Research: Reporting of In vivo Experiments (ARRIVE) guidelines., Discussion: This systematic review will examine the efficacy and safety of regenerative cell therapy in preclinical models of PAH. As well, the literature will be assessed for study quality and risk of bias. The results will guide the design of future clinical trials and preclinical animal studies., Systematic Review Registration: CAMARADES ( http://www.dcn.ed.ac.uk/camarades/SyRF/Protocols.htm ).

Background: Liver resection is commonly performed for malignant and benign disease and is associated with frequent use of intraoperative and postoperative blood transfusions. Blood transfusions are potentially life-saving, but they have many adverse effects; some well understood, and others less so. Some of the poorly understood side effects include increased risk of postoperative complications and possibly worse oncologic outcomes. The objective of this systematic review is to provide estimates of transfusion prevalence and the effects of perioperative blood transfusion on postoperative mortality and morbidity and long-term cancer outcomes in patients undergoing liver resection., Methods/design: The Cochrane, Medline, and EMBASE databases will be searched for any randomized controlled trial or observational cohort study comparing liver resection patients that received intraoperative or postoperative allogeneic red blood cell transfusions to those who did not. Outcomes include postoperative mortality, postoperative morbidity (infectious, liver failure, renal failure, cardiovascular/cerebrovascular events, and thromboembolic events), and long-term disease-free and overall survival. Only studies with adult, human patients (>18 years old) undergoing liver resection, in which the primary intervention of interest is blood transfusion will be included. Data will be extracted by two reviewers in duplicate and synthesized into a narrative review. Risk of bias will be assessed. When clinically and methodologically appropriate, meta-analysis will be performed., Discussion: Our review will synthesize the literature pertaining to the potential beneficial and detrimental effects of red blood cell transfusion in patients undergoing liver resection. It will be an important step in the development of guidelines for the appropriate use of blood transfusions in patients undergoing liver resection., Systematic Review Registration: PROSPERO CRD42015026132.

Background: Traumatic brain injury (TBI) is a devastating condition with significant long-term mortality and morbidity. Despite current need for objective indicators to guide initial decision-making, few reliable acute phase prognostic factors have been identified. Early magnetic resonance imaging (MRI) has been investigated as a prognostic tool, but uncertainty remains in both its discriminative predictive value and which acute phase lesion patterns correlate with long-term outcome., Methods: We will conduct a systematic review of observational cohort studies and randomized controlled trials of adult moderate or severe TBI patients who underwent MRI in the acute phase after trauma. A high sensitivity search strategy will be employed in MEDLINE, EMBASE, BIOSIS, and Cochrane CENTRAL to identify citations. Two reviewers will independently screen all identified references for eligibility and extract data into a standardized form. Data will be collected on study design, baseline demographics, trauma characteristics, magnetic resonance (MR) technical specifications, lesion patterns, and outcomes as related to acute MRI imaging. If meta-analysis is possible, quantitative data for each outcome will be pooled per type of lesion pattern using random effects models and expressed as Mantel-Haenszel relative risks in order to determine the prognostic value of lesions detected on acute MRI and their strength as discriminatory predictors of long-term outcome. Statistical heterogeneity will be evaluated with the I (2) statistics, and risk of bias and reporting quality will be assessed with standardized scales. Subgroup analyses are planned as a function of TBI severity, MRI-timing post-TBI, MRI field strength, MRI sequence, timing of outcome assessment, and risk of bias., Discussion: We expect significant clinical heterogeneity, as eligible studies will likely encompass different periods in evolving MRI technology in addition to significant variability of image sequence protocols and timing of acquisition between centers. Based on existing studies in TBI, we expect lesions detected in the brainstem to be of significant predictive value as MRI is particularly sensitive for imaging the brain's posterior fossa. Our systematic review will allow clinicians to more accurately interpret MRI in the context of determining prognosis for moderate and severe TBI patients and inform researchers in this domain to improve the methodology of future studies., Systematic Review Registration: Prospero CRD42015017074.

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., Prospero: CRD42015024286.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease that leads to important morbidity and mortality in a young patient population. Anemia following aSAH is common and may be exacerbated by the treatments instituted by clinicians as part of standard care. The role and optimal thresholds for red blood cell (RBC) transfusion in this patient population remains unknown., Methods/design: We will conduct a systematic review of the literature using MEDLINE, EMBASE, and EBM Reviews (including Cochrane Central databases) using a comprehensive search strategy for observational and interventional studies of RBC transfusion in aSAH. Our primary objective is to evaluate the association of RBC transfusion with mortality in aSAH patients. Secondary objectives include a) determining associations between RBC transfusion and poor neurologic outcome, b) defining an optimal RBC transfusion threshold in aSAH patients, and c) describing complications associated with RBC transfusion in aSAH patients. We plan a descriptive reporting of all included citations including study characteristics, methodological quality, and reported outcomes. Clinical and statistical heterogeneity observed between studies will be described. If appropriate, meta-analyses of suitable studies and interpretation of their results will be performed. Effect measures will be converted to obtain relative risks and odds ratios (RR and ORs) with 95% confidence intervals and pooled according to study design (randomized trials and observational studies respectively) using a random effects model., Discussion: This review will summarize the existing observational and trial evidence regarding RBC transfusion in aSAH patients. The analytical plan has made considerations for different study designs, both observational and interventional in nature, and will summarize the best available evidence to inform the end user and policy and guideline producers and to highlight areas in need of further study., Systematic Review Registration: PROSPERO CRD42014014806.

Background: Contrast-induced acute kidney injury is a common cause of iatrogenic acute kidney injury (AKI). Most of the published estimates of AKI after contrast use originate from the cardiac catheterization literature despite contrast-enhanced computed tomography (CT) scans being the more common setting for contrast use. This systematic review aims to summarize the current evidence about (1)the risk of AKI following intravenous (IV) contrast-enhanced CT scans and(2) the risk of clinical outcomes (i.e. death, hospitalization and need for renal replacement therapy) due to IV contrast-enhanced CT scans., Methods/design: A systematic literature search for published studies will be performed using MEDLINE, EMBASE and The COCHRANE Library databases. Unpublished studies will be identified by searching through grey literature. No language restriction will be applied.The review will consider all studies that have examined the association between IV contrast media and AKI. To be selected, the study should include two arms: one group of exposed patients who received IV contrast material before CT scans and one group of unexposed group who did not receive contrast material before CT scans. Two authors will independently screen titles and abstracts obtained from electronic databases, extract data and will assess the quality of the studies selected using the Cochrane's 'Risk of Bias' assessment tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. A random-effects meta-analysis will be performed if there is no remarkable heterogeneity between studies., Discussion: This systematic review will provide synthesis of current evidence around the effect of IV contrast material on AKI and other clinical outcomes. Results will be helpful for making evidence-based recommendations and guidelines for clinical and radiologic settings., Systematic Review Registration: PROSPERO CRD42013003799.

Background: Acute respiratory distress syndrome (ARDS) in humans is caused by an unchecked proinflammatory response that results in diffuse and severe lung injury, and it is associated with a mortality rate of 35 to 45%. Mesenchymal stromal cells (MSCs; 'adult stem cells') could represent a promising new therapy for this syndrome, since preclinical evidence suggests that MSCs may ameliorate lung injury. Prior to a human clinical trial, our aim is to conduct a systematic review to compare the efficacy and safety of MSC therapy versus controls in preclinical models of acute lung injury that mimic some aspects of the human ARDS., Methods/design: We will include comparative preclinical studies (randomized and non-randomized) of acute lung injury in which MSCs were administered and outcomes compared to animals given a vehicle control. The primary outcome will be death. Secondary outcomes will include the four key features of preclinical acute lung injury as defined by the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar capillary barrier, lung inflammatory response, and physiological dysfunction) and pathogen clearance for acute lung injury models that are caused by infection. Electronic searches of MEDLINE, Embase, BIOSIS Previews, and Web of Science will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the Cochrane risk of bias tool, and individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines., Discussion: The results of this systematic review will comprehensively summarize the safety and efficacy of MSC therapy in preclinical models of acute lung injury. Our results will help translational scientists and clinical trialists to determine whether sufficient evidence exists to perform a human clinical trial. These results may also guide future acute lung injury preclinical and clinical research.

Background: Patients undergoing renal transplant procedures require multi-agent immunosuppressive regimens both short term (induction phase) and long term (maintenance phase) to minimize the risk of organ rejection. There are several drug classes and agents for immunosuppression. Use of these agents may increase the risk of different harms including not only infections, but also malignancies including post-transplant lymphoproliferative disorder. There is a need to identify which regimens minimize the risk of such outcomes. The objective of this systematic review and network meta-analysis of randomized and observational studies is to explore whether certain modern regimens of immunosuppression used to prevent organ rejection in renal transplant patients are associated with an increased risk of post-transplant lymphoproliferative disorder and other malignancies., Methods/design: 'Modern' regimens were defined to be those evaluated in controlled studies beginning in 1990 or later. An electronic literature search of Medline, Embase and the Cochrane Central Register of Controlled Trials has been designed by an experienced information specialist and peer reviewed by a second information specialist. Study selection and data collection will be performed by two reviewers. The outcomes of interest will include post-transplant lymphoproliferative disorder and other incident forms of malignancy occurring in adult renal transplant patients. Network meta-analyses of data from randomized and observational studies will be performed where judged appropriate based on a review of the clinical and methodological features of included studies. A sequential approach to meta-analysis will be used to combine data from different designs., Discussion: Our systematic review will include both single-agent and multi-agent modern pharmacotherapy regimens in patients undergoing renal transplantation. It will synthesize malignancy outcomes. Our work will also add to the development of methods for network meta-analysis across study designs to assess treatment safety., Trial Registration: PROSPERO Registration Number: CRD42013006951.

Background: Hypertension has been cited as the most common attributable risk factor for death worldwide, and in Canada more than one of every five adults had this diagnosis in 2007. In addition to different lifestyle modifications, such as diet and exercise, there exist many pharmaco-therapies from different drug classes which can be used to lower blood pressure, thereby reducing the risk of serious clinical outcomes. In moderate and severe cases, more than one agent may be used. The optimal mono- and combination therapies for mild hypertension and moderate/severe hypertension are unclear, and clinical guidelines provide different recommendations for first line therapy. The objective of this review is to explore the relative benefits and safety of different pharmacotherapies for management of non-diabetic patients with hypertension, whether of a mild or moderate to severe nature., Methods/design: Searches involving MEDLINE and the Cochrane Database of Systematic Reviews will be used to identify related systematic reviews and relevant randomized trials. The outcomes of interest include myocardial infarction, stroke, incident diabetes, heart failure, overall and cardiovascular related death, and important side effects (cancers, depression, syncopal episodes/falls and sexual dysfunction). Randomized controlled trials will be sought. Two reviewers will independently screen relevant reviews, titles and abstracts resulting from the literature search, and also potentially relevant full-text articles in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion. Random effect pairwise meta-analyses and network meta-analyses will be conducted where deemed appropriate. Analyses will be geared toward studying treatment of mild hypertension and moderate/severe hypertension separately., Discussion: Our systematic review results will assess the extent of currently available evidence for single agent and multi-agent pharmacotherapies in patients with mild, moderate and severe hypertension, and will provide a rigorous and updated synthesis of a range of important clinical outcomes for clinicians, decision makers and patients., Trial Registration: PROSPERO Registration Number: CRD42013004459.