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Mutations in the Survival of Motor Neuron 1 gene lead to a loss of survival motor neuron protein in patients with spinal muscular atrophy. Revolutionary advances in gene therapy have led to survival motor neuron-replacement therapies that significantly prolong life expectancy and improve neuromuscular function. However, accumulating evidence suggests that the timing of survival motor neuron-replacement therapies is a critical determinant of success. We performed a systematic review and meta-analysis of all pre-clinical studies testing survival motor neuron replacement therapies in mouse models of spinal muscular atrophy to assess the impact of timing of delivery on therapeutic effectiveness. We incorporated four databases in this pre-registered study (PROSPERO 2020 CRD42020200180): EMBASE, PubMed, Scopus and Web of Science. Inclusion criteria were; primary research article, a measure of survival analysis, use of survival motor neuron mouse model and evaluation of survival motor neuron-targeting therapy. Exclusion criteria included; use of therapies not known to directly target survival motor neuron, genetic manipulations and/or lack of appropriate controls. We screened papers using the SyRF platform. The main outcome we assessed was survival in treated groups compared to untreated groups. We performed meta-analysis of survival using median survival ratio and the random effects model and measured heterogeneity using the I 2 statistic. Subgroup analyses were performed to assess treatment efficacy based on timing of intervention (embryonic delivery, day of birth, postnatal day 2 and postnatal day 3 or later) and treatment type. If detailed in the studies, body weight compared to untreated spinal muscular atrophy models and motor neuron number were included as secondary outcomes for meta-analysis. 3469 studies were initially identified, with 78 ultimately included. Survival motor neuron-replacement therapies significantly affected survival in favour of treatment by a factor of 1.20 (95% CI 1.10-1.30, P < 0.001) with high heterogeneity (I 2 = 95%). Timing of treatment was a significant source of heterogeneity (P < 0.01), with earlier treatment having a greater impact on survival. When stratified by type of treatment, earlier treatment continued to have the strongest effect with viral vector replacement therapy and antisense oligonucleotide therapy. Secondary outcome measures of body weight and spinal motor neuron counts were also positively associated with early treatment. Earlier delivery of survival motor neuron replacement therapies is therefore a key determinant of treatment efficacy in spinal muscular atrophy.
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BACKGROUND: Despite extensive investment, the development of effective treatments for Alzheimer's disease (AD) has been largely unsuccessful. To improve translation, it is crucial to ensure the quality and reproducibility of foundational evidence generated from laboratory models. Systematic reviews play a key role in providing an unbiased overview of the evidence, assessing rigour and reporting, and identifying factors that influence reproducibility. However, the sheer pace of evidence generation is prohibitive to evidence synthesis and assessment. NEW METHOD: To address these challenges, we have developed AD-SOLES, an integrated workflow of automated tools that collect, curate, and visualise the totality of evidence from in vivo experiments. RESULTS: AD-SOLES is a publicly accessible interactive dashboard aiming to surface and expose data from in vivo experiments. It summarises the latest evidence, tracks reporting quality and transparency, and allows research users to easily locate evidence relevant to their specific research question. COMPARISON WITH EXISTING METHODS: Using automated screening methodologies within AD-SOLES, systematic reviews can begin at an accelerated starting point compared to traditional approaches. Furthermore, through text-mining approaches within the full-text of publications, users can identify research of interest using specific models, outcomes, or interventions without relying on details in the title and/or abstract. CONCLUSIONS: By automating the collection, curation, and visualisation of evidence from in vivo experiments, AD-SOLES addresses the challenges posed by the rapid pace of evidence generation. AD-SOLES aims to offer guidance for research improvement, reduce research waste, highlight knowledge gaps, and support informed decision making for researchers, funders, patients, and the public.
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Enfermedad de Alzheimer , Humanos , Animales , Investigación Biomédica/métodos , Investigación Biomédica/normas , Minería de Datos/métodos , Internet , Modelos Animales de EnfermedadRESUMEN
Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results: Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D 2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions: TAAR1 agonists may be less efficacious than dopamine D 2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration: PROSPERO-ID: CRD42023451628.
There is a need for more effective treatments for psychosis, including schizophrenia. Psychosis is a collection of mental health symptoms, such as hearing voices, that can cause distress and impair functioning. These symptoms are thought to be caused by changes in a chemical messenger system in the brain called dopamine. Currently used antipsychotic medications target brain receptors that respond to dopamine. They are not effective in some people and can cause uncomfortable adverse events, such as weight gain and movement disorders, especially with long-term use. A new type of drug is the trace amine-associated receptor 1 (TAAR1) agonists. These drugs act on different brain receptors that can affect the activity of the dopamine system, but do not directly bind to dopamine receptors. We aimed to understand if TAAR1 agonists can reduce symptoms of psychosis, what adverse events they might have, and how they work. We did this by reviewing and collating all available evidence until November 2023. This is a "living" systematic review, so it will be regularly updated in the future. We looked at both human and animal studies investigating TAAR1 agonists. Human studies suggested that two TAAR1 agonists (namely, ulotaront or ralmitaront) might have little to no effect on reducing symptoms of psychosis compared to placebo in people with schizophrenia. They seemed to cause fewer adverse events than current antipsychotics. Data from animal studies suggested that TAAR1 agonists had some positive effects but potentially smaller than other antipsychotics. There were little to no data from both human and animal studies about how TAAR1 agonists actually work. From the current evidence we are uncertain about these results. With the ongoing development of new TAAR1 agonists, more evidence is needed to understand their potential role in the treatment of psychosis.
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BACKGROUND: Researchers performing high-quality systematic reviews search across multiple databases to identify relevant evidence. However, the same publication is often retrieved from several databases. Identifying and removing such duplicates ("deduplication") can be extremely time-consuming, but failure to remove these citations can lead to the wrongful inclusion of duplicate data. Many existing tools are not sensitive enough, lack interoperability with other tools, are not freely accessible, or are difficult to use without programming knowledge. Here, we report the performance of our Automated Systematic Search Deduplicator (ASySD), a novel tool to perform automated deduplication of systematic searches for biomedical reviews. METHODS: We evaluated ASySD's performance on 5 unseen biomedical systematic search datasets of various sizes (1845-79,880 citations). We compared the performance of ASySD with EndNote's automated deduplication option and with the Systematic Review Assistant Deduplication Module (SRA-DM). RESULTS: ASySD identified more duplicates than either SRA-DM or EndNote, with a sensitivity in different datasets of 0.95 to 0.99. The false-positive rate was comparable to human performance, with a specificity of > 0.99. The tool took less than 1 h to identify and remove duplicates within each dataset. CONCLUSIONS: For duplicate removal in biomedical systematic reviews, ASySD is a highly sensitive, reliable, and time-saving tool. It is open source and freely available online as both an R package and a user-friendly web application.
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Programas Informáticos , Revisiones Sistemáticas como Asunto , Humanos , Proyectos de InvestigaciónRESUMEN
Thigmotaxis is an innate predator avoidance behaviour of rodents. To gain insight into how injury and disease models, and analgesic drug treatments affect thigmotaxis, we performed a systematic review and meta-analysis of studies that assessed thigmotaxis in the open field test. Systematic searches were conducted of 3 databases in October 2020, March and August 2022. Study design characteristics and experimental data were extracted and analysed using a random-effects meta-analysis. We also assessed the correlation between thigmotaxis and stimulus-evoked limb withdrawal. This review included the meta-analysis of 165 studies We report thigmotaxis was increased in injury and disease models associated with persistent pain and this increase was attenuated by analgesic drug treatments in both rat and mouse experiments. Its usefulness, however, may be limited in certain injury and disease models because our analysis suggested that thigmotaxis may be associated with the locomotor function. We also conducted subgroup analyses and meta-regression, but our findings on sources of heterogeneity are inconclusive because analyses were limited by insufficient available data. It was difficult to assess internal validity because reporting of methodological quality measures was poor, therefore, the studies have an unclear risk of bias. The correlation between time in the centre (type of a thigmotactic metric) and types of stimulus-evoked limb withdrawal was inconsistent. Therefore, stimulus-evoked and ethologically relevant behavioural paradigms should be viewed as two separate entities as they are conceptually and methodologically different from each other.
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Prueba de Campo Abierto , Roedores , Ratas , Animales , Ratones , Dolor , Trastorno de Personalidad Antisocial , Bases de Datos FactualesRESUMEN
INTRODUCTION: The prevalence of outcome reporting bias (ORB, i.e. selective reporting according to the results observed) across primary outcomes in randomised controlled trials (RCTs) including participants with stroke or transient ischaemic attack (TIA) is unknown. MATERIALS AND METHODS: We searched the Cochrane Database of Systematic Reviews on 3 February 2021 for reviews published 2008-2020 with at least one RCT of a therapeutic intervention, for participants with stroke or TIA, and a safety or efficacy outcome. We took a random sample of these RCTs and included those with a trial registry record or protocol published before reporting results. Two reviewers assessed discrepancies in outcome reporting across the trial registry record, protocol, statistical analysis plan, and publication for each RCT, using the classification system designed by the Outcome Reporting Bias in Trials group. RESULTS: Of 600 RCTs, we identified a trial registry record in 120 (20%), a protocol in 28 (5%), and a statistical analysis plan in 5 (1%) with 123 (21%) distinct RCTs being eligible for assessment: 110 (89%, 95% CI 83-94) were at no risk, 7 (6%, 95% CI 3-11) RCTs were at low risk, and 6 (5%, 95% CI 2-10) were at high risk of ORB. DISCUSSION: The prevalence of ORB in primary outcomes was low in stroke/TIA RCTs that were included in Cochrane reviews and had an identifiable trial registry record or protocol. Concerningly, we were unable to identify a trial registry record or protocol in most of our sample. CONCLUSION: Work is needed to further reduce ORB in stroke/TIA RCTs and explore the generalisability of these findings to RCTs outside of Cochrane reviews or without a registry record or protocol, as well as to secondary outcomes.
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Ataque Isquémico Transitorio , Accidente Cerebrovascular , Humanos , Sesgo , Ataque Isquémico Transitorio/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/epidemiologíaRESUMEN
In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community-including patients, carers, clinicians, researchers and funders-to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world.
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Depresión , Trastornos Psicóticos , Humanos , Depresión/diagnóstico , Trastornos Psicóticos/diagnóstico , Ansiedad/terapia , Trastornos de Ansiedad/diagnóstico , Salud MentalRESUMEN
In biomedicine and many other fields, there are growing concerns around the reproducibility of research findings, with many researchers being unable to replicate their own or others' results. This raises important questions as to the validity and usefulness of much published research. In this review, we aim to engage researchers in the issue of research reproducibility and equip them with the necessary tools to increase the reproducibility of their research. We first highlight the causes and potential impact of non-reproducible research and emphasise the benefits of working reproducibly for the researcher and broader research community. We address specific targets for improvement and steps that individual researchers can take to increase the reproducibility of their work. We next provide recommendations for improving the design and conduct of experiments, focusing on in vivo animal experiments. We describe common sources of poor internal validity of experiments and offer practical guidance for limiting these potential sources of bias at different experimental stages, as well as discussing other important considerations during experimental design. We provide a list of key resources available to researchers to improve experimental design, conduct, and reporting. We then discuss the importance of open research practices such as study preregistration and the use of preprints and describe recommendations around data management and sharing. Our review emphasises the importance of reproducible work and aims to empower every individual researcher to contribute to the reproducibility of research in their field.
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Experimentación Animal , Animales , Reproducibilidad de los Resultados , Proyectos de InvestigaciónRESUMEN
The state of open science needs to be monitored to track changes over time and identify areas to create interventions to drive improvements. In order to monitor open science practices, they first need to be well defined and operationalized. To reach consensus on what open science practices to monitor at biomedical research institutions, we conducted a modified 3-round Delphi study. Participants were research administrators, researchers, specialists in dedicated open science roles, and librarians. In rounds 1 and 2, participants completed an online survey evaluating a set of potential open science practices, and for round 3, we hosted two half-day virtual meetings to discuss and vote on items that had not reached consensus. Ultimately, participants reached consensus on 19 open science practices. This core set of open science practices will form the foundation for institutional dashboards and may also be of value for the development of policy, education, and interventions.
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Investigación Biomédica , Humanos , Consenso , Técnica Delphi , Encuestas y Cuestionarios , Proyectos de InvestigaciónRESUMEN
OBJECTIVE: Existing strategies to identify relevant studies for systematic review may not perform equally well across research domains. We compare four approaches based on either human or automated screening of either title and abstract or full text, and report the training of a machine learning algorithm to identify in vitro studies from bibliographic records. METHODS: We used a systematic review of oxygen-glucose deprivation (OGD) in PC-12 cells to compare approaches. For human screening, two reviewers independently screened studies based on title and abstract or full text, with disagreements reconciled by a third. For automated screening, we applied text mining to either title and abstract or full text. We trained a machine learning algorithm with decisions from 2000 randomly selected PubMed Central records enriched with a dataset of known in vitro studies. RESULTS: Full-text approaches performed best, with human (sensitivity: 0.990, specificity: 1.000 and precision: 0.994) outperforming text mining (sensitivity: 0.972, specificity: 0.980 and precision: 0.764). For title and abstract, text mining (sensitivity: 0.890, specificity: 0.995 and precision: 0.922) outperformed human screening (sensitivity: 0.862, specificity: 0.998 and precision: 0.975). At our target sensitivity of 95% the algorithm performed with specificity of 0.850 and precision of 0.700. CONCLUSION: In this in vitro systematic review, human screening based on title and abstract erroneously excluded 14% of relevant studies, perhaps because title and abstract provide an incomplete description of methods used. Our algorithm might be used as a first selection phase in in vitro systematic reviews to limit the extent of full text screening required.
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Algoritmos , Minería de Datos , Humanos , Minería de Datos/métodos , Proyectos de Investigación , Aprendizaje Automático , GlucosaRESUMEN
BACKGROUND: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. METHODS: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis. PROTOCOL REGISTRATION: PROSPERO-ID: CRD42023451628.
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Objetivo:Caracterizar o perfil sociodemográfico e profissional de enfermeiros egressos de um programa de monitoria acadêmica, bem como as contribuições do programa para suas atuações profissionais.Métodos:Trata-se de uma pesquisa descritiva, retrospectiva, deabordagem quantitativa e realizada em ambiente virtual, utilizando uma plataforma eletrônica onlinepara a coleta de dados, com enfermeiros egressosdo programa de monitoria da Universidade do Estado do Pará(UEPA).Resultados:Evidenciou-se que os egressos são, predominantemente, mulheres, de idade entre 27 e30 anos e foram bolsistas. Um número significativo destes inseriu-seem programas de pós-graduação lato sensu, a nível de especialização e/ou residência, trabalham na assistência ou gestão e gerenciamento, possuem experiência como docente e atuaram principalmente no ensino básico.Conclusão:O programa de monitoria acadêmica contribuiu para as atuações profissionais dos enfermeiros egressosanalisados, demonstrando ser um mecanismo para atingir-se o nívelde excelênciaalmejado pelas diretrizes curriculares nacionais em Enfermagem.
Objective: To characterize the sociodemographic and professional profile of graduate nurses from an academic monitoring program, as well as theprogram's contributions to their professional performance. Methods: This is a descriptive and retrospective research study, with a quantitative approach and carried out in a virtual environment, using an online electronic platform for data collection and conducted with graduate nurses from the monitoring program of the University of the State of Pará (Universidade do Estado do Pará, UEPA).Results:It was evidenced that the graduates are predominantly women, aged between 27 and 30 years old, and scholarship holders. A significant number of them were attending lato sensu graduate programs, at the specialization and/or residency level, worked in assistance or in administration and management, had teaching experience and worked mainly in basic education.Conclusion: The academic monitoring program contributed to the professional performance of the graduate nurses analyzed, proving to be a mechanism to achieve the level of excellence desired by the national curricular guidelines in Nursing
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Enseñanza , Educación en Enfermería , Tutoría , AprendizajeRESUMEN
STUDY DESIGN: Systematic review and meta-analysis of preclinical literature. OBJECTIVES: To assess the effects of biomaterial-based combination (BMC) strategies for the treatment of Spinal Cord Injury (SCI), the effects of individual biomaterials in the context of BMC strategies, and the factors influencing their efficacy. To assess the effects of different preclinical testing paradigms in BMC strategies. METHODS: We performed a systematic literature search of Embase, Web of Science and PubMed. All controlled preclinical studies describing an in vivo or in vitro model of SCI that tested a biomaterial in combination with at least one other regenerative strategy (cells, drugs, or both) were included. Two review authors conducted the study selection independently, extracted study characteristics independently and assessed study quality using a modified CAMARADES checklist. Effect size measures were combined using random-effects models and heterogeneity was explored using meta-regression with tau2, I2 and R2 statistics. We tested for small-study effects using funnel plot-based methods. RESULTS: 134 publications were included, testing over 100 different BMC strategies. Overall, treatment with BMC therapies improved locomotor recovery by 25.3% (95% CI, 20.3-30.3; n = 102) and in vivo axonal regeneration by 1.6 SD (95% CI 1.2-2 SD; n = 117) in comparison with injury only controls. CONCLUSION: BMC strategies improve locomotor outcomes after experimental SCI. Our comprehensive study highlights gaps in current knowledge and provides a foundation for the design of future experiments.
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Traumatismos de la Médula Espinal , Regeneración de la Medula Espinal , Animales , Humanos , Traumatismos de la Médula Espinal/terapia , Materiales Biocompatibles/uso terapéutico , Modelos Animales de Enfermedad , Procedimientos NeuroquirúrgicosRESUMEN
ABSTRACT: Burrowing behaviour is used to assess pain-associated behaviour in laboratory rodents. To gain insight into how models of disease-associated persistent pain and analgesics affect burrowing behaviour, we performed a systematic review and meta-analysis of studies that assessed burrowing behaviour. A systematic search in March 2020 and update in September 2020 was conducted in 4 databases. Study design characteristics and experimental data were extracted, followed by a random-effects meta-analysis. We explored the association between burrowing and monofilament-induced limb withdrawal. Dose response relationship was investigated for some analgesics. Forty-five studies were included in the meta-analysis, in which 16 model types and 14 drug classes were used. Most experiments used rat (79%) and male (72%) animals. Somatic inflammation and trauma-induced neuropathy models were associated with reduced burrowing behaviour. Analgesics (nonsteroidal anti-inflammatory drug and gabapentinoids) attenuated burrowing deficits in these models. Reporting of measures to reduce risk of bias was unclear except for randomisation which was high. There was not a correlation ( R2 = 0.1421) between burrowing and monofilament-induced limb withdrawal. Opioids, gabapentin, and naproxen showed reduced burrowing behaviour at high doses, whereas ibuprofen and celecoxib showed opposite trend. The findings indicate that burrowing could be used to assess pain-associated behaviour. We support the use of a portfolio of composite measures including spontaneous and stimulus-evoked tests. The information collected here could help in designing experiments involving burrowing assessment in models of disease-associated pain.
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Ibuprofeno , Naproxeno , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Conducta Animal/fisiología , Celecoxib/uso terapéutico , Modelos Animales de Enfermedad , Gabapentina/farmacología , Gabapentina/uso terapéutico , Ibuprofeno/farmacología , Ibuprofeno/uso terapéutico , Masculino , Naproxeno/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiología , Ratas , RoedoresRESUMEN
The workshop titled "Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks" was co-organized by the Evidence-based Toxicology Collaboration and the European Food Safety Authority (EFSA) and hosted by EFSA at its headquarters in Parma, Italy on October 2 and 3, 2019. The goal was to explore integration of systematic review with mechanistic evidence evaluation. Participants were invited to work on concrete products to advance the exploration of how evidence-based approaches can support the development and application of adverse outcome pathways (AOP) in chemical risk assessment. The workshop discussions were centered around three related themes: 1) assessing certainty in AOPs, 2) literature-based AOP development, and 3) integrating certainty in AOPs and non-animal evidence into decision frameworks. Several challenges, mostly related to methodology, were identified and largely determined the workshop recommendations. The workshop recommendations included the comparison and potential alignment of processes used to develop AOP and systematic review methodology, including the translation of vocabulary of evidence-based methods to AOP and vice versa, the development and improvement of evidence mapping and text mining methods and tools, as well as a call for a fundamental change in chemical risk and uncertainty assessment methodology if to be conducted based on AOPs and new approach methodologies (NAM). The usefulness of evidence-based approaches for mechanism-based chemical risk assessments was stressed, particularly the potential contribution of the rigor and transparency inherent to such approaches in building stakeholders' trust for implementation of NAM evidence and AOPs into chemical risk assessment.
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Rutas de Resultados Adversos , Inocuidad de los Alimentos , Humanos , Italia , Medición de Riesgo/métodosRESUMEN
BACKGROUND: Time-to-event data is frequently reported in both clinical and preclinical research spheres. Systematic review and meta-analysis is a tool that can help to identify pitfalls in preclinical research conduct and reporting that can help to improve translational efficacy. However, pooling of studies using hazard ratios (HRs) is cumbersome especially in preclinical meta-analyses including large numbers of small studies. Median survival is a much simpler metric although because of some limitations, which may not apply to preclinical data, it is generally not used in survival meta-analysis. We aimed to appraise its performance when compared with hazard ratio-based meta-analysis when pooling large numbers of small, imprecise studies. METHODS: We simulated a survival dataset with features representative of a typical preclinical survival meta-analysis, including with influence of a treatment and a number of covariates. We calculated individual patient data-based hazard ratios and median survival ratios (MSRs), comparing the summary statistics directly and their performance at random-effects meta-analysis. Finally, we compared their sensitivity to detect associations between treatment and influential covariates at meta-regression. RESULTS: There was an imperfect correlation between MSR and HR, although the opposing direction of treatment effects between summary statistics appeared not to be a major issue. Precision was more conservative for HR than MSR, meaning that estimates of heterogeneity were lower. There was a slight sensitivity advantage for MSR at meta-analysis and meta-regression, although power was low in all circumstances. CONCLUSIONS: We believe we have validated MSR as a summary statistic for use in a meta-analysis of small, imprecise experimental survival studies-helping to increase confidence and efficiency in future reviews in this area. While assessment of study precision and therefore weighting is less reliable, MSR appears to perform favourably during meta-analysis. Sensitivity of meta-regression was low for this set of parameters, so pooling of treatments to increase sample size may be required to ensure confidence in preclinical survival meta-regressions.
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Análisis de Supervivencia , HumanosRESUMEN
In an effort to better utilize published evidence obtained from animal experiments, systematic reviews of preclinical studies are increasingly more common-along with the methods and tools to appraise them (e.g., SYstematic Review Center for Laboratory animal Experimentation [SYRCLE's] risk of bias tool). We performed a cross-sectional study of a sample of recent preclinical systematic reviews (2015-2018) and examined a range of epidemiological characteristics and used a 46-item checklist to assess reporting details. We identified 442 reviews published across 43 countries in 23 different disease domains that used 26 animal species. Reporting of key details to ensure transparency and reproducibility was inconsistent across reviews and within article sections. Items were most completely reported in the title, introduction, and results sections of the reviews, while least reported in the methods and discussion sections. Less than half of reviews reported that a risk of bias assessment for internal and external validity was undertaken, and none reported methods for evaluating construct validity. Our results demonstrate that a considerable number of preclinical systematic reviews investigating diverse topics have been conducted; however, their quality of reporting is inconsistent. Our study provides the justification and evidence to inform the development of guidelines for conducting and reporting preclinical systematic reviews.
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Revisión de la Investigación por Pares/métodos , Revisión de la Investigación por Pares/normas , Proyectos de Investigación/normas , Experimentación Animal/normas , Animales , Sesgo , Lista de Verificación/normas , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Investigación Empírica , Métodos Epidemiológicos , Epidemiología/tendencias , Humanos , Revisión de la Investigación por Pares/tendencias , Publicaciones , Reproducibilidad de los Resultados , Proyectos de Investigación/tendenciasRESUMEN
Preclinical research is a vital step in the drug discovery pipeline and more generally in helping to better understand human disease aetiology and its management. Systematic reviews (SRs) can be powerful in summarising and appraising this evidence concerning a specific research question, to highlight areas of improvements, areas for further research and areas where evidence may be sufficient to take forward to other research domains, for instance clinical trial. Guidance and tools for preclinical research synthesis remain limited despite their clear utility. We aimed to create an online end-to-end platform primarily for conducting SRs of preclinical studies, that was flexible enough to support a wide variety of experimental designs, was adaptable to different research questions, would allow users to adopt emerging automated tools and support them during their review process using best practice. In this article, we introduce the Systematic Review Facility (https://syrf.org.uk), which was launched in 2016 and designed to support primarily preclinical SRs from small independent projects to large, crowdsourced projects. We discuss the architecture of the app and its features, including the opportunity to collaborate easily, to efficiently manage projects, to screen and annotate studies for important features (metadata), to extract outcome data into a secure database, and tailor these steps to each project. We introduce how we are working to leverage the use of automation tools and allow the integration of these services to accelerate and automate steps in the systematic review workflow.
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OBJECTIVE: Thigmotaxis is an innate predator avoidance behaviour of rodents and is enhanced when animals are under stress. It is characterised by the preference of a rodent to seek shelter, rather than expose itself to the aversive open area. The behaviour has been proposed to be a measurable construct that can address the impact of pain on rodent behaviour. This systematic review will assess whether thigmotaxis can be influenced by experimental persistent pain and attenuated by pharmacological interventions in rodents. SEARCH STRATEGY: We will conduct search on three electronic databases to identify studies in which thigmotaxis was used as an outcome measure contextualised to a rodent model associated with persistent pain. All studies published until the date of the search will be considered. SCREENING AND ANNOTATION: Two independent reviewers will screen studies based on the order of (1) titles and abstracts, and (2) full texts. DATA MANAGEMENT AND REPORTING: For meta-analysis, we will extract thigmotactic behavioural data and calculate effect sizes. Effect sizes will be combined using a random-effects model. We will assess heterogeneity and identify sources of heterogeneity. A risk-of-bias assessment will be conducted to evaluate study quality. Publication bias will be assessed using funnel plots, Egger's regression and trim-and-fill analysis. We will also extract stimulus-evoked limb withdrawal data to assess its correlation with thigmotaxis in the same animals. The evidence obtained will provide a comprehensive understanding of the strengths and limitations of using thigmotactic outcome measure in animal pain research so that future experimental designs can be optimised. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines and disseminate the review findings through publication and conference presentation.
RESUMEN
Great expectations have been set around the clinical potential of regenerative and reparative medicine in the treatment of cardiovascular diseases [i.e. in particular, heart failure (HF)]. Initial excitement, spurred by encouraging preclinical data, resulted in a rapid translation into clinical research. The sobering outcome of the resulting clinical trials suggests that preclinical testing may have been insufficient to predict clinical outcome. A number of barriers for clinical translation include the inherent variability of the biological products and difficulties to develop potency and quality assays, insufficient rigour of the preclinical research and reproducibility of the results, manufacturing challenges, and scientific irregularities reported in the last years. The failure to achieve clinical success led to an increased scrutiny and scepticism as to the clinical readiness of stem cells and gene therapy products among clinicians, industry stakeholders, and funding bodies. The present impasse has attracted the attention of some of the most active research groups in the field, which were then summoned to analyse the position of the field and tasked to develop a strategy, to re-visit the undoubtedly promising future of cardiovascular regenerative and reparative medicine, based on lessons learned over the past two decades. During the scientific retreat of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine (CARE) in November 2018, the most relevant and timely research aspects in regenerative and/or reparative medicine were presented and critically discussed, with the aim to lay out a strategy for the future development of the field. We report herein the main ideas and conclusions of that meeting.