Systematic reviews are an important method to support evidencebased decisions in healthcare (research).Although not yet as common as clinical systematic reviews, the number of systematic reviews of animal studies has been increasing steadily in recent years. An important method to promote high-quality systematic reviews is to pre-specify the review methodology in a protocol, before the conduct of the systematic review itself. In contrast to clinical systematic reviews, a standard protocol format for systematic reviews of animal studies is not yet available. Here, we present a protocol format tailored to the preparation, registration and publication of systematic reviews of animal intervention studies (i.e. systematic reviews of animal experiments studying the efficacy and/or safety of interventions intended for use in human patients). In analogy to the Cochrane review protocol, the format helps authors predefine the methodological approach of their systematic review, from research question to data synthesis. We recommend that authors prospectively complete and agree on the protocol, and register and/or publish it to allow feedback on the proposed methodology and to avoid the introduction of bias during the review process. Opportunities for obtaining feedback, and for registration and publication of review protocols are also discussed.
BackgroundThe methodological quality of animal studies is an important factor hampering the translation of results from animal studies to a clinical setting. Systematic reviews of animal studies may provide a suitable method to assess and thereby improve their methodological quality.ObjectivesThe aims of this study were: 1) to evaluate the risk of bias assessment in animal-based systematic reviews, and 2) to study the internal validity of the primary animal studies included in these systematic reviews.Data SourcesWe systematically searched Pubmed and Embase for SRs of preclinical animal studies published between 2005 and 2012.ResultsA total of 91 systematic reviews met our inclusion criteria. The risk of bias was assessed in 48 (52.7%) of these 91 systematic reviews. Thirty-three (36.3%) SRs provided sufficient information to evaluate the internal validity of the included studies. Of the evaluated primary studies, 24.6% was randomized, 14.6% reported blinding of the investigator/caretaker, 23.9% blinded the outcome assessment, and 23.1% reported drop-outs.ConclusionsTo improve the translation of animal data to clinical practice, systematic reviews of animal studies are worthwhile, but the internal validity of primary animal studies needs to be improved. Furthermore, risk of bias should be assessed by systematic reviews of animal studies to provide insight into the reliability of the available evidence.
Despite widespread reporting on clinical results, the effect of meniscus allograft transplantation on the development of osteoarthritis is still unclear. The aim of this study was to systematically review all studies on the effect of meniscus allograft transplantation on articular cartilage in animals. Pubmed and Embase were searched for original articles concerning the effect of meniscus allograft transplantation on articular cartilage compared with both its positive (meniscectomy) and negative (either sham or non-operated) control in healthy animals. Outcome measures related to assessment of damage to articular cartilage were divided in five principal outcome categories. Standardized mean differences (SMD) were calculated and pooled to obtain an overall SMD and 95% confidence interval. 17 articles were identified, representing 14 original animal cohorts with an average timing of data collection of 24 weeks [range 4 weeks; 30 months]. Compared to a negative control, meniscus allograft transplantation caused gross macroscopic (1.45 [0.95; 1.95]), histological (3.43 [2.25; 4.61]) damage to articular cartilage, and osteoarthritic changes on radiographs (3.12 [1.42; 4.82]). Moreover, results on histomorphometrics and cartilage biomechanics are supportive of this detrimental effect on cartilage. On the other hand, meniscus allograft transplantation caused significantly less gross macroscopic (-1.19 [-1.84; -0.54]) and histological (-1.70 [-2.67; -0.74]) damage to articular cartilage when compared to meniscectomy. However, there was no difference in osteoarthritic changes on plain radiographs (0.04 [-0.48; 0.57]), and results on histomorphometrics and biomechanics did neither show a difference in effect between meniscus allograft transplantation and meniscectomy. In conclusion, although meniscus allograft transplantation does not protect articular cartilage from damage, it reduces the extent of it when compared with meniscectomy.
Implementation of the 3Rs (Replacement, Refinement and Reduction) in animal studies is a legal requirement in many countries. In The Netherlands, animal welfare officers (AWOs) are appointed to monitor the welfare of laboratory animals. As part of this task, AWOs give advice to researchers and can therefore have an influential role in implementing 3R methods in research. A national survey was conducted to gain more insight into how Dutch AWOs obtain and apply 3R information in their daily work. Nearly half of the AWO population filled out the questionnaire (15/32; a response rate of 46.9%). Two-thirds of the respondents pointed out that finding 3R information is not an easy task and more than half of the respondents believed that information on possibilities to implement the 3Rs is regularly being missed. The respondents indicated that most 3R information is obtained directly from colleagues and other AWOs. Special online 3R databases are rarely used. All the responding AWOs feel that they contribute to Refinement (15/15), nearly one-third of the respondents feel they contribute to Reduction (4/15), and one AWO feels he/she contributes to Replacement (1/15). According to the respondents, better exchange of knowledge can contribute to more successful implementation of the 3Rs. How this knowledge exchange can best be established and facilitated needs further exploration. To this end, the authors make suggestions for a 3R-integrated evidence-based approach.
BackgroundSeveral studies have reported that metformin can reduce the risk of hepatocellular carcinoma (HCC) in diabetes patients. However, the direct anti-HCC effects of metformin have hardly been studied in patients, but have been extensively investigated in animal models of HCC. We therefore performed a systematic review and meta-analysis of animal studies evaluating the effects of metformin on HCC.MethodsWe collected the relevant studies by searching EMBASE, Medline (OvidSP), Web of Science, Scopus, PubMed Publisher, and Google Scholar. Studies were included according to the following inclusion criteria: HCC, animal study, and metformin intervention. Study quality was assessed using SYRCLE’s risk of bias tool. A meta-analysis was performed for the outcome measures: tumor growth (tumor volume, weight and size), tumor number and incidence.ResultsThe search resulted in 573 references, of which 13 could be included in the review and 12 included in the meta-analysis. The study characteristics of the included studies varied considerably. Two studies used rats, while the others used mice. Only one study used female animals, nine used male, and three studies didn’t mention the gender of animals in their experiments. The quality of the included studies was low to moderate based on the assessment of their risk of bias. The meta-analysis showed that metformin significantly inhibited the growth of HCC tumour (SMD -2.20[-2.96,-1.43]; n=16), but no significant effect on the number of tumors (SMD-1.05[-2.13,0.03]; n=5) or the incidence of HCC was observed (RR 0.62[0.33,1.16]; n=6). To investigate the potential sources of significant heterogeneities found in outcome of tumor growth (I2=81%), subgroup analyses of scales of growth measures and of types of animal models used were performed.ConclusionMetformin appears to have a direct anti-HCC effect in animal models. Although the intrinsic limitations of animal studies, this systematic review could provide an important reference for future preclinical animal trials of good quality and clinical development.
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