Clinical relevance assessment of animal preclinical research (RAA) tool: development and explanation.

Only a small proportion of preclinical research (research performed in animal models prior to clinical trials in humans) translates into clinical benefit in humans. Possible reasons for the lack of translation of the results observed in preclinical research into human clinical benefit include the design, conduct, and reporting of preclinical studies. There is currently no formal domain-based assessment of the clinical relevance of preclinical research. To address this issue, we have developed a tool for the assessment of the clinical relevance of preclinical studies, with the intention of assessing the likelihood that therapeutic preclinical findings can be translated into improvement in the management of human diseases. We searched the EQUATOR network for guidelines that describe the design, conduct, and reporting of preclinical research. We searched the references of these guidelines to identify further relevant publications and developed a set of domains and signalling questions. We then conducted a modified Delphi-consensus to refine and develop the tool. The Delphi panel members included specialists in evidence-based (preclinical) medicine specialists, methodologists, preclinical animal researchers, a veterinarian, and clinical researchers. A total of 20 Delphi-panel members completed the first round and 17 members from five countries completed all three rounds. This tool has eight domains (construct validity, external validity, risk of bias, experimental design and data analysis plan, reproducibility and replicability of methods and results in the same model, research integrity, and research transparency) and a total of 28 signalling questions and provides a framework for researchers, journal editors, grant funders, and regulatory authorities to assess the potential clinical relevance of preclinical animal research. We have developed a tool to assess the clinical relevance of preclinical studies. This tool is currently being piloted

Assessing the impact of predatory journals on policy and guidance documents: a cross-sectional study protocol.

peer reviewed[en] INTRODUCTION: Many predatory journals fail to follow best publication practices. Studies assessing the impact of predatory journals have focused on how these articles are cited in reputable academic journals. However, it is possible that research from predatory journals is cited beyond the academic literature in policy documents and guidelines. Given that research used to inform public policy or government guidelines has the potential for widespread impact, we will examine whether predatory journals have penetrated public policy. METHODS AND ANALYSIS: This is a descriptive study with no hypothesis testing. Policy documents that cite work from the known predatory publisher OMICS will be downloaded from the Overton database. Overton collects policy documents from over 1200 sources worldwide. Policy documents will be evaluated to determine how the predatory journal article is used. We will also extract epidemiological details of the policy documents, including: who funded their development, the discipline the work is relevant to and the name of the organisations producing the policy. The record of scholarly citations of the identified predatory articles will also be examined. Findings will be reported with descriptive statistics using counts and percentages. ETHICS AND DISSEMINATION: No ethical approval was required for this study since it does not involve human or animal research. Study findings will be discussed at workshops on journalology and predatory publishing and will be disseminated through preprint, peer-reviewed literature and conference presentations

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease

Change in Adverse Events After Enrollment in the National Surgical Quality Improvement Program: A Systematic Review and Meta-Analysis.

BACKGROUND:The American College of Surgeons' National Surgical Quality Improvement Program (NSQIP) is the first nationally validated, risk-adjusted, outcomes-based program to measure and compare the quality of surgical care across North America. Participation in this program may provide an opportunity to reduce the incidence of adverse events related to surgery. STUDY DESIGN:A systematic review of the literature was performed. MedLine, EMBASE and PubMed were searched for studies relevant to NSQIP. Patient characteristics, intervention, and primary outcome measures were abstracted. The intervention was participation in NSQIP and monitoring of Individual Site Summary Reports with or without implementation of a quality improvement program. The outcomes of interest were change in peri-operative adverse events and mortality represented by pooled risk ratios (pRR) and 95% confidence intervals (CI). RESULTS:Eleven articles reporting on 35 health care institutions were included. Nine (82%) of the eleven studies implemented a quality improvement program. Minimal improvements in superficial (pRR 0.81; 95% CI 0.72-0.91), deep (pRR 0.82; 95% CI0.64-1.05) and organ space (pRR 1.15; 95% CI 0.96-1.37) infections were observed at centers that did not institute a quality improvement program. However, centers that reported formal interventions for the prevention and treatment of infections observed substantial improvements (superficial pRR 0.55, 95% CI 0.39-0.77; deep pRR 0.61, 95% CI 0.50-0.75, and organ space pRR 0.60, 95% CI 0.50-0.71). Studies evaluating other adverse events noted decreased incidence following NSQIP participation and implementation of a formal quality improvement program. CONCLUSIONS:These data suggest that NSQIP is effective in reducing surgical morbidity. Improvement in surgical quality appears to be more marked at centers that implemented a formal quality improvement program directed at the reduction of specific morbidities

Regenerative cell therapy for pulmonary arterial hypertension in animal models: a systematic review

Abstract Background Pulmonary arterial hypertension (PAH) is a rare disease characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary arterial pressures leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. The objective of this systematic review was to compare the efficacy of regenerative cell therapies in preclinical models of PAH. Methods A systematic search strategy was developed and executed. We included preclinical animal studies using regenerative cell therapy in experimental models of PAH. Primary outcomes were right ventricular systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP). The secondary outcome was right ventricle/left ventricle + septum weight ratio (RV/LV+S). Pooled effect sizes were undertaken using random effects inverse variance models. Risk of bias and publication bias were assessed. Results The systematic search yielded 1285 studies, of which 44 met eligibility criteria. Treatment with regenerative cell therapy was associated with decreased RVSP (SMD − 2.10; 95% CI − 2.59 to − 1.60), mPAP (SMD − 2.16; 95% CI − 2.97 to − 1.35), and RV/LV+S (SMD − 1.31, 95% CI − 1.64 to − 0.97). Subgroup analysis demonstrated that cell modification resulted in greater reduction in RVSP. The effects on RVSP and mPAP remained statistically significant even after adjustment for publication bias. The majority of studies had an unclear risk of bias. Conclusions Preclinical studies of regenerative cell therapy demonstrated efficacy in animal models of PAH; however, future studies should consider incorporating design elements to reduce the risk of bias. Systematic review registration Suen CM, Zhai A, Lalu MM, Welsh C, Levac BM, Fergusson D, McIntyre L and Stewart DJ. Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol. Syst Rev. 2016;5:89. Trial registration CAMARADES-NC3Rs Preclinical Systematic Review & Meta-analysis Facility (SyRF). http://syrf.org.uk/protocols/. Syst Rev 5:89, 201

Navigating choice in the face of uncertainty: using a theory informed qualitative approach to identifying potential patient barriers and enablers to participating in an early phase chimeric antigen receptor T (CAR-T) cell therapy trial

Objectives Bench to bedside translation of groundbreaking treatments like chimeric antigen receptor T (CAR-T) cell therapy depends on patient participation in early phase trials. Unfortunately, many novel therapies fail to be adequately evaluated due to low recruitment rates, which slows patient access to emerging treatments. Using the Theoretical Domains Framework (TDF), we sought to identify potential patient barriers and enablers to participating in an early phase CAR-T cell therapy trial.Design We used qualitative semistructured interviews to identify potential barriers and enablers to patients’ hypothetical participation in an early phase CAR-T cell therapy trial. We used the TDF and directed content analysis to identify relevant domains based on frequency, relevance and the presence of conflicting beliefs.Participants Canadian adult patients diagnosed with haematological malignancies.Results In total, we interviewed 13 participants (8 women, 5 men). Participants ranged in age from 18 to 73 (median=56) and had been living with haematological cancer from a few months to several years. We found participants were unfamiliar with CAR-T cell therapy but wished to know more about treatment safety, efficacy and trial logistics (domains: knowledge, beliefs about consequences). They were motivated by altruistic considerations, though many prioritised personal health benefits despite recognising the goals (ie, establishing safety) of early phase clinical trials (domains: goals, intentions). Every participant valued receiving medical advice from their haematologists and oncologists, though some preferred impartial medical experts to inform their decision making (domain: social influences). Finally, participants indicated that improving access to financial and social supports would improve their trial participation experience (domain: environmental context and resources).Conclusion Using the TDF allowed us to identify factors that might undermine participation to a CAR-T cell therapy trial and to optimise recruitment processes by considering patient perspectives to taking part in early phase trials.Trial regestration: NCT03765177; Pre-results