scholarly journals Identifying stroke therapeutics from preclinical models: A protocol for a novel application of network meta-analysis

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 11 ◽  
Author(s):  
Manoj M. Lalu ◽  
Dean A. Fergusson ◽  
Wei Cheng ◽  
Marc T. Avey ◽  
Dale Corbett ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Burden Of Illness ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Synthesis Methods ◽  
Preclinical Models ◽  
Ovid Medline ◽  
Scientific Meetings ◽  
Ischemia Testing

Introduction: Globally, stroke is the second leading cause of death. Despite the burden of illness and death, few acute interventions are available to patients with ischemic stroke. Over 1,000 potential neuroprotective therapeutics have been evaluated in preclinical models. It is important to use robust evidence synthesis methods to appropriately assess which therapies should be translated to the clinical setting for evaluation in human studies. This protocol details planned methods to conduct a systematic review to identify and appraise eligible studies and to use a network meta-analysis to synthesize available evidence to answer the following questions: in preclinical in vivo models of focal ischemic stroke, what are the relative benefits of competing therapies tested in combination with the gold standard treatment alteplase in (i) reducing cerebral infarction size, and (ii) improving neurobehavioural outcomes? Methods: We will search Ovid Medline and Embase for articles on the effects of combination therapies with alteplase. Controlled comparison studies of preclinical in vivo models of experimentally induced focal ischemia testing the efficacy of therapies with alteplase versus alteplase alone will be identified. Outcomes to be extracted include infarct size (primary outcome) and neurobehavioural measures. Risk of bias and construct validity will be assessed using tools appropriate for preclinical studies. Here we describe steps undertaken to perform preclinical network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. This will be a novel use of this evidence synthesis approach in stroke medicine to assess pre-clinical therapeutics. Combining all evidence to simultaneously compare mutliple therapuetics tested preclinically may provide a rationale for the clinical translation of therapeutics for patients with ischemic stroke.  Dissemination: Review findings will be submitted to a peer-reviewed journal and presented at relevant scientific meetings to promote knowledge transfer. Registration: PROSPERO number to be submitted following peer review.

scholarly journals Diagnosis of DWI-negative acute ischemic stroke

Neurology ◽  
2017 ◽  
Vol 89 (3) ◽  
pp. 256-262 ◽  
Author(s):  
Brian L. Edlow ◽  
Shelley Hurwitz ◽  
Jonathan A. Edlow
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Clinical Diagnosis ◽  
Clinical Characteristics ◽  
Meta Analysis ◽  
Reperfusion Therapy ◽  
Posterior Circulation ◽  
Anterior Circulation ◽  
Ovid Medline ◽  
Level Data

Objective:To determine the prevalence of diffusion-weighted imaging (DWI)–negative acute ischemic stroke (AIS) and to identify clinical characteristics of patients with DWI-negative AIS.Methods:We systematically searched PubMed and Ovid/MEDLINE for relevant studies between 1992, the year that the DWI sequence entered clinical practice, and 2016. Studies were included based upon enrollment of consecutive patients presenting with a clinical diagnosis of AIS prior to imaging. Meta-analysis was performed to synthesize study-level data, estimate DWI-negative stroke prevalence, and estimate the odds ratios (ORs) for clinical characteristics associated with DWI-negative stroke.Results:Twelve articles including 3,236 AIS patients were included. The meta-analytic synthesis yielded a pooled prevalence of DWI-negative AIS of 6.8%, 95% confidence interval (CI) 4.9–9.3. In the 5 studies that reported proportion data for DWI-negative and DWI-positive AIS based on the ischemic vascular territory (n = 1,023 AIS patients), DWI-negative stroke was strongly associated with posterior circulation ischemia, as determined by clinical diagnosis at hospital discharge or repeat imaging (OR 5.1, 95% CI 2.3–11.6, p < 0.001).Conclusions:A small but significant percentage of patients with AIS have a negative DWI scan. Patients with neurologic deficits consistent with posterior circulation ischemia have 5 times the odds of having a negative DWI scan compared to patients with anterior circulation ischemia. AIS remains a clinical diagnosis and urgent reperfusion therapy should be considered even when an initial DWI scan is negative.

VP82 Impact of Evidence Synthesis Methods on Outcome of Economic Evaluation

2019 ◽  
Vol 35 (S1) ◽  
pp. 93-94
Author(s):  
Claire Gorry ◽  
Joy Leahy ◽  
Felicity Lamrock ◽  
Cathal Walsh ◽  
Arthur White ◽  
...  
Keyword(s):  
Economic Evaluation ◽  
Proportional Hazards ◽  
Failure Time ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Trial Data ◽  
Alternative Methods ◽  
Synthesis Methods ◽  
Proportional Hazards Assumption ◽  
The Impact

IntroductionEvidence synthesis (ES) is often required for economic evaluation (EE) of pharmaceuticals. Commonly used methods are based on the assumption of proportional hazards in trial data, using the hazard ratio (HR). Alternative methods for ES are increasingly used in EE, in situations where the pattern of hazards in the trial data indicates that the proportional hazards assumption may be violated. The impact of these methodological choices on model outcomes is explored.MethodsA network of trials of BRAF-targeted treatments for advanced melanoma, derived using a systematic review of the literature, is chosen for the study. Guyot's method is used to create individual-patient Kaplan-Meier (K-M) data from published survival curves. Log-cumulative hazard plots and Schoenfeld residuals are derived to examine patterns in hazards within the trial data. All analyses are conducted in R version 3.5.0©. Three alternative methods for ES are tested: 1) Network meta-analysis (NMA) based on published HRs and the assumption of proportional hazards. 2) NMA using fractional polynomials (FP) based on digitised K-M data, allowing the relaxation of the proportional hazards assumption. 3) NMA using an accelerated failure time (AFT) model based on digitised K-M data, allowing the relaxation of the proportional hazards assumption. The derived estimates of relative efficacy from each method are applied in a partitioned survival cost-effectiveness model programmed in Microsoft Excel™.ResultsThe model outcomes predicted by each method (HR, FP and AFT) are presented and compared. Both deterministic and probabilistic results are presented, alongside a discussion around how the uncertainty in these structural assumptions may be captured in EE.ConclusionsStructural assumptions in ES may lead to differences in model outcomes. The impact of these differences may be important in situations where decision uncertainty is high. Methods should be chosen and justified based on patterns of hazard present in the trial data.

scholarly journals Scoping review protocol to understand the conceptualisation, implementation and practices of health promotion within the context of primary healthcare in Africa

BMJ Open ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. e049084
Author(s):  
Miriam Nkangu ◽  
Pamela Obegu ◽  
Constantine Asahngwa ◽  
Veronica Shiroya ◽  
Ronald Gobina ◽  
...  
Keyword(s):  
Health Promotion ◽  
Scoping Review ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Grey Literature ◽  
Cochrane Library ◽  
Dissemination Strategy ◽  
Ottawa Charter ◽  
Ovid Medline ◽  
Scoping Reviews

IntroductionThe ongoing COVID-19 pandemic has highlighted the importance of health promotion in empowering and sustaining communities, as well as the need to build resilient health systems and work collectively with other sectors to protect and promote health. The WHO has mainstreamed health promotion in the Global health agenda. However, the definition and practices of health promotion in Africa are not well understood and documented, with often, an interchangeable use of the concept of health promotion and health prevention. This scoping review is to explore how health promotion is defined and practised in Africa and identify gaps in its implementation within the framework of the Ottawa Charter.Methods and analysisThe scoping review will employ the approach described by Arksey and O’Malley in 2005. The approach consists of five stages: (1) formulating the research questions, (2) identifying relevant studies, (3) selecting eligible studies, (4) charting the data and (5) collating, summarising and reporting the results. This protocol employed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). The review will apply the PRISMA extension for scoping reviews to present the results. The scoping review will adapt the five principles set forth in the Ottawa Charter to categorise the outcomes and uses its strategies to define the interventions. Data bases searched are Ovid Medline, Embase, Cochrane Library, CINAHL, SCOPUS, CABI, JBI Evidence Synthesis and grey literature. The database last searched was January 2021.Ethics and disseminationThis review does not require ethics approval. Our dissemination strategy includes peer review publication, policy brief, presentation at conferences and relevant stakeholders.

scholarly journals Old men with prostate cancer have higher risk of Gleason score upgrading and pathological upstaging after initial diagnosis: a systematic review and meta-analysis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaochuan Wang ◽  
Yu Zhang ◽  
Zhengguo Ji ◽  
Peiqian Yang ◽  
Ye Tian
Keyword(s):  
Prostate Cancer ◽  
Gleason Score ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Predictive Performance ◽  
Cochrane Library ◽  
Case Control Studies ◽  
Ovid Medline ◽  
Increased Risk ◽  
Diagnostic Biopsy

Abstract Background To evaluate the predictive performance of age for the risk of Gleason score change and pathologic upstaging. Evidence acquisition Ovid MEDLINE, Ovid Embase, and the Cochrane Library were searched from inception until May 2020. Quality of included studies was appraised utilizing the Newcastle-Ottawa Quality Assessment Scale for case-control studies. The publication bias was evaluated by funnel plots and Egger’s tests. Evidence synthesis Our search yielded 27 studies with moderate-to-high quality including 84296 patients with mean age of 62.1 years. From biopsy to prostatectomy, upgrading and upstaging occurred in 32.3% and 9.8% of patients, respectively. Upgrading from diagnostic biopsy to confirmatory biopsy was found in 16.8%. Older age was associated with a significant increased risk of upgrading (OR 1.04, 95% CI 1.03–1.05), and similar direction of effect was found in studies focused on upgrading from diagnostic biopsy to confirmatory biopsy (OR 1.06, 95% CI 1.04–1.08). For pathologic upstaging within older men compared with younger, the pooled odds was 1.03 (95% CI 1.01–1.04). Conclusion Thorough consideration of age in the context of effect sizes for other factors not only prompts more accurate risk stratification but also helps providers to select optimal therapies for patients with prostate cancer.

scholarly journals Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke

2016 ◽  
Vol 36 (10) ◽  
pp. 1686-1694 ◽  
Author(s):  
Charles K Davis ◽  
Peter J Laud ◽  
Zsanett Bahor ◽  
GK Rajanikant ◽  
Arshad Majid
Keyword(s):  
Systematic Review ◽  
Ischemic Stroke ◽  
Methodological Quality ◽  
Infarct Volume ◽  
Weighted Mean Difference ◽  
Meta Analysis ◽  
Young Male ◽  
In Vivo Models

Carnosine is a naturally occurring pleotropic dipeptide which influences multiple deleterious mechanisms that are activated during stroke. Numerous published studies have reported that carnosine has robust efficacy in ischemic stroke models. To further evaluate these data, we have conducted a systematic review and meta-analysis of published studies. We included publications describing in vivo models of ischemic stroke where the neuroprotective efficacy of carnosine was being evaluated through the reporting of infarct volume and/or neurological score as outcomes. Overall efficacy was evaluated using weighted mean difference random effects meta-analysis. We also evaluated for study quality and publication bias. We identified eight publications that met our inclusion criteria describing a total of 29 comparisons and 454 animals. Overall methodological quality of studies was moderate (median = 4/9). Carnosine reduced infarct volume by 29.4% (95% confidence interval (CI), 24.0% to 34.9%; 29 comparisons). A clear dose-response effect was observed, and efficacy was reduced when carnosine was administered more than 6 h after ischemia. Our findings suggest that carnosine administered before or after the onset of ischemia exhibits robust efficacy in experimental ischemic stroke. However, the methodological quality of some of the studies was low and testing occurred only in healthy young male animals.

scholarly journals Incident Cerebral Microbleeds After Intracerebral Hemorrhage

Stroke ◽  
2019 ◽  
Vol 50 (8) ◽  
pp. 2227-2230
Author(s):  
Luke A Perry ◽  
Mark Rodrigues ◽  
Rustam Al-Shahi Salman ◽  
Neshika Samarasekera
Keyword(s):  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Meta Analysis ◽  
Brain Magnetic Resonance Imaging ◽  
Cerebral Microbleeds ◽  
Resonance Imaging ◽  
Ovid Medline ◽  
Subgroup Analyses ◽  
Prognostic Implications

Background and Purpose— The frequency and prognostic implications of incident cerebral microbleeds (CMB), defined as development of one or more new CMB, after intracerebral hemorrhage (ICH) is unclear. Therefore, we performed a systematic review and meta-analysis to investigate the frequency and prognostic implications of incident CMB after ICH. Methods— We searched Ovid Medline and Embase in May 2018 for longitudinal studies of adults who underwent brain magnetic resonance imaging at 2 or more times after ICH. We calculated the pooled proportion of adults with incident CMB and sought associations between incident CMB and clinical outcomes (death, recurrent ICH, or new ischemic stroke). We planned subgroup analyses to investigate clinical variables associated with incident CMB. Results— We identified 2354 publications, of which we included 4 cohort studies involving 349 patients. The pooled proportion of adults with at least one new CMB during a mean 27 months follow-up (SD 20 months) was ≈40% (95% CI, 30%–50%). In one study, as the number of incident CMB increased (0 versus 1–3 new CMB versus ≥4 new CMB) the risk of recurrent symptomatic lobar ICH increased (hazard ratio 3.0; 95% CI, 1.2–7.3). No study reported on outcomes of incident ischemic stroke or death. Conclusions— Incident CMB occurs in ≈40% of adults after ICH. The association of incident CMB with recurrent lobar ICH needs confirmation and their association with death and ischemic stroke investigation.

scholarly journals A review of the quantitative effectiveness evidence synthesis methods used in public health intervention guidelines

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ellesha A. Smith ◽  
Nicola J. Cooper ◽  
Alex J. Sutton ◽  
Keith R. Abrams ◽  
Stephanie J. Hubbard
Keyword(s):  
Public Health ◽  
Decision Making ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Public Health Intervention ◽  
Health Intervention ◽  
Health Interventions ◽  
Synthesis Methods ◽  
Public Health Interventions ◽  
Guidance Documents

Abstract Background The complexity of public health interventions create challenges in evaluating their effectiveness. There have been huge advancements in quantitative evidence synthesis methods development (including meta-analysis) for dealing with heterogeneity of intervention effects, inappropriate ‘lumping’ of interventions, adjusting for different populations and outcomes and the inclusion of various study types. Growing awareness of the importance of using all available evidence has led to the publication of guidance documents for implementing methods to improve decision making by answering policy relevant questions. Methods The first part of this paper reviews the methods used to synthesise quantitative effectiveness evidence in public health guidelines by the National Institute for Health and Care Excellence (NICE) that had been published or updated since the previous review in 2012 until the 19th August 2019.The second part of this paper provides an update of the statistical methods and explains how they address issues related to evaluating effectiveness evidence of public health interventions. Results The proportion of NICE public health guidelines that used a meta-analysis as part of the synthesis of effectiveness evidence has increased since the previous review in 2012 from 23% (9 out of 39) to 31% (14 out of 45). The proportion of NICE guidelines that synthesised the evidence using only a narrative review decreased from 74% (29 out of 39) to 60% (27 out of 45).An application in the prevention of accidents in children at home illustrated how the choice of synthesis methods can enable more informed decision making by defining and estimating the effectiveness of more distinct interventions, including combinations of intervention components, and identifying subgroups in which interventions are most effective. Conclusions Despite methodology development and the publication of guidance documents to address issues in public health intervention evaluation since the original review, NICE public health guidelines are not making full use of meta-analysis and other tools that would provide decision makers with fuller information with which to develop policy. There is an evident need to facilitate the translation of the synthesis methods into a public health context and encourage the use of methods to improve decision making.

A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania

2014 ◽  
Vol 45 (2) ◽  
pp. 299-317 ◽  
Author(s):  
A. Yildiz ◽  
M. Nikodem ◽  
E. Vieta ◽  
C. U. Correll ◽  
R. J. Baldessarini
Keyword(s):  
Evidence Synthesis ◽  
Meta Analysis ◽  
Similar Efficacy ◽  
Mean Difference ◽  
Mood Stabilizers ◽  
Synthesis Methods ◽  
Comparative Efficacy ◽  
Rank Ordering ◽  
Point Estimates ◽  
Standardized Mean Difference

BackgroundEvidence synthesis methods enabling direct and indirect comparisons over the entire set of relevant clinical data produce quantitative point estimates for the treatments contrasts between competing interventions, and provide a hierarchical rank ordering between them. We aimed to provide evidence-based guidance on the efficacy and all-cause discontinuation of antimanic treatments.MethodWe conducted a network meta-analysis within a Bayesian framework. We searched all standard literature databases without language restrictions up to 15 January 2014 to identify reports of short-term, randomized, blinded trials of putative antimanic drugs as monotherapy for adults with bipolar-I mania.ResultsAltogether, 14256 manic patients randomized to one of 18 active treatments or placebo provided 95 direct comparisons on 128 data points. For the primary outcome, standardized mean difference as Hedges’ g (standardized mean difference; SMD), the hierarchies indicated by surface under the cumulative ranking (SUCRA) probabilities were in agreement with the point estimates for all antimanic drugs identified as effective. For the 12 effective antimanic drugs on clinical use, SMDs against placebo ranged from 0.32 to 0.66 without superiority of one over another, except for risperidone v. aripiprazole and valproate. Aripiprazole, olanzapine, quetiapine, risperidone, and valproate had less all-cause discontinuation rates than placebo. Sensitivity analysis by drug class indicated similar efficacy profiles for haloperidol, second-generation antipsychotics, and mood stabilizers.ConclusionsHierarchical rank ordering by comparative efficacy and risk of all-cause discontinuations should help to guide antimanic treatment choices by clinicians, healthcare policy makers, and guideline developers.

scholarly journals Lentivirus- or AAV-mediated gene therapy interventions in ischemic stroke: A systematic review of preclinical in vivo studies

2021 ◽  
pp. 0271678X2110399
Author(s):  
Laura Skukan ◽  
Matea Brezak ◽  
Rok Ister ◽  
Lars Klimaschewski ◽  
Aleksandar Vojta ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Ischemic Stroke ◽  
Viral Vector ◽  
Infarct Volume ◽  
Meta Analysis ◽  
Artery Occlusion ◽  
In Vivo Studies ◽  
Specific Cell ◽  
Systematic Analysis

Due to the limited therapeutic options after ischemic stroke, gene therapy has emerged as a promising choice, especially with recent advances in viral vector delivery systems. Therefore, we aimed to provide the current state of the art of lentivirus (LV) and adeno-associated virus (AAV) mediated gene interventions in preclinical ischemic stroke models. A systematic analysis including qualitative and quantitative syntheses of studies published until December 2020 was performed. Most of the 87 selected publications used adult male rodents and the preferred stroke model was transient middle cerebral artery occlusion. LV and AAV vectors were equally used for transgene delivery, however loads of AAVs were higher than LVs. Serotypes having broad cell tropism, the use of constitutive promoters, and virus delivery before the stroke induction via stereotaxic injection in the cortex and striatum were preferred in the analyzed studies. The meta-analysis based on infarct volume as the primary outcome confirmed the efficacy of the preclinical interventions. The quality assessment exposed publication bias and setbacks in regard to risks of bias and study relevance. The translational potential could increase by using specific cell targeting, post-stroke interventions, non-invasive systematic delivery, and use of large animals.

OP380 A Review Of The Methodology Used To Synthesize Continuous And Time-To-Event Outcomes For Clinical And Cost-Effectiveness

2020 ◽  
Vol 36 (S1) ◽  
pp. 7-7
Author(s):  
Suzanne Freeman ◽  
Alex Sutton ◽  
Nicola Cooper
Keyword(s):  
Cost Effectiveness ◽  
Decision Model ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Clinical Effectiveness ◽  
Evidence Base ◽  
Synthesis Methods ◽  
Time To Event ◽  
Health Technologies ◽  
Treatment Comparison

IntroductionSynthesis of continuous and time-to-event outcomes is often complicated by the use of multiple outcome scales and heterogeneous reporting of outcomes across trials. Simple methods of evidence synthesis for clinical effectiveness can fail to account for these issues and result in a reduction of the evidence base, which can be further reduced at the cost-effectiveness stage as common outcome measures, such as standardized mean differences, cannot easily be incorporated into the economic decision model. Recent methodological advances for synthesizing continuous and time-to-event outcomes aim to include a greater proportion of the available evidence base within a single coherent analysis.MethodsTo assess the statistical methods commonly used in health technology assessment (HTA) and establish whether recent advances in synthesis methods have been adopted in practice, we conducted a review of HTA reports and guidelines published in the United Kingdom (UK) between 1 April 2018 and 31 March 2019 reporting a quantitative meta-analysis (MA), network meta-analysis (NMA) or indirect treatment comparison (ITC) of at least one continuous or time-to-event outcome.ResultsForty-seven articles were considered eligible for this review. Fifty-one percent of eligible articles reported at least one continuous outcome and 55 percent at least one time-to-event outcome. Twenty-nine articles reported NMA or ITC and twenty-seven reported MA of a continuous or time-to-event outcome. Forty articles included a decision model, of which twenty-seven incorporated evidence from a synthesis of a continuous or time-to-event outcome with eleven informed by a single trial (despite synthesis being conducted).ConclusionsUptake of methods to include a greater proportion of the available evidence base within a single coherent analysis in UK HTA reports has been slow. Evaluating health technologies using an evidence-based approach often results in better outcomes for patients. Therefore, HTA analysts and decision modelers must be aware of the expanding literature for synthesis of continuous and time-to-event outcomes and appreciate the limitations of simpler approaches.

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