The road to success: drawing parallels between 'road' and 'research data' infrastructures to foster understanding between service providers, funders and policymakers [version 1; peer review: 2 approved]

Background: The work of data research infrastructure operators is poorly understood, yet the services they provide are used by millions of scientists across the planet. Policy and implications: As the data services and the underlying infrastructure are typically funded through the public purse, it is essential that policymakers, research funders, experts reviewing funding proposals, and possibly even end-users are equipped with a good understanding of the daily tasks of service providers. Recommendations: We suggest drawing parallels between research data infrastructure and road infrastructure. To trigger the imagination and foster understanding, this policy brief contains a table of corresponding aspects of the two classes of infrastructure. Conclusions: Just as economists and specialist evaluators are typically brought in to inform policies and funding decisions for road infrastructure, we encourage this to also be done for research infrastructure

The road to success: drawing parallels between 'road' and 'research data' infrastructures to foster understanding between service providers, funders and policymakers [version 2; peer review: 2 approved]

Background: The work of data research infrastructure operators is poorly understood, yet the services they provide are used by millions of scientists across the planet. Policy and implications: As the data services and the underlying infrastructure are typically funded through the public purse, it is essential that policymakers, research funders, experts reviewing funding proposals, and possibly even end-users are equipped with a good understanding of the daily tasks of service providers. Recommendations: We suggest drawing parallels between research data infrastructure and road infrastructure. To trigger the imagination and foster understanding, this policy brief contains a table of corresponding aspects of the two classes of infrastructure, and a table of policy implications. Conclusions: Just as economists and specialist evaluators are typically brought in to inform policies and funding decisions for road infrastructure, we encourage this to also be done for research infrastructure

Characterization of protein tyrosine phosphatase H1 knockout mice in animal models of local and systemic inflammation

<p>Abstract</p> <p>Background</p> <p>PTPH1 is a protein tyrosine phosphatase expressed in T cells but its effect on immune response is still controversial. PTPH1 dephosphorylates TCRzeta <it>in vitro</it>, inhibiting the downstream inflammatory signaling pathway, however no immunological phenotype has been detected in primary T cells derived from PTPH1-KO mice. The aim of the present study is to characterize PTPH1 phenotype in two <it>in vivo </it>inflammatory models and to give insights in possible PTPH1 functions in cytokine release.</p> <p>Methods</p> <p>We challenged PTPH1-KO mice with two potent immunomodulatory molecules, carrageenan and LPS, in order to determine PTPH1 possible role in inflammatory response <it>in vivo</it>. Cytokine release, inflammatory pain and gene expression were investigated in challenged PTPH1-WT and KO mice.</p> <p>Results</p> <p>The present study shows that carrageenan induces a trend of slightly increased spontaneous pain sensitivity in PTPH1-KO mice compared to WT (wild-type) littermates, but no differences in cytokine release, induced pain perception and cellular infiltration have been detected between the two genotypes in this mouse model. On the other hand, LPS-induced TNFα, MCP-1 and IL10 release was significantly reduced in PTPH1-KO plasma compared to WTs 30 and 60 minutes post challenge. No cytokine release modulation was detectable 180 minutes post LPS challenge.</p> <p>Conclusion</p> <p>In conclusion, the present study points out a slight potential role for PTPH1 in spontaneous pain sensitivity and it indicates that this phosphatase might play a role in the positive regulation of the LPS-induced cytokines release <it>in vivo</it>, in contrast to previous reports indicating PTPH1 as potential negative regulator of immune response.</p

Search filters to identify geriatric medicine in Medline

Objectives To create user-friendly search filters with high sensitivity, specificity, and precision to identify articles on geriatric medicine in Medline. Design A diagnostic test assessment framework was used. A reference set of 2255 articles was created by hand-searching 22 biomedical journals in Medline, and each article was labeled as 'relevant', 'not relevant', or 'possibly relevant' for geriatric medicine. From the relevant articles, search terms were identified to compile different search strategies. The articles retrieved by the various search strategies were compared with articles from the reference set as the index test to create the search filters. Measures Sensitivity, specificity, precision, accuracy, and number-needed-to-read (NNR) were calculated by comparing the results retrieved by the different search strategies with the reference set. Results The most sensitive search filter had a sensitivity of 94.8%, a specificity of 88.7%, a precision of 73.0%, and an accuracy of 90.2%. It had an NNR of 1.37. The most specific search filter had a specificity of 96.6%, a sensitivity of 69.1%, a precision of 86.6%, and an accuracy of 89.9%. It had an NNR of 1.15. Conclusion These geriatric search filters simplify searching for relevant literature and therefore contribute to better evidence-based practice. The filters are useful to both the clinician who wants to find a quick answer to a clinical question and the researcher who wants to find as many relevant articles as possible without retrieving too many irrelevant article

Clinical trial registration was associated with lower risk of bias compared with non-registered trials among trials included in systematic reviews

Objective: To examine the association between clinical trial registration and risk of bias in clinical trials that have been included in systematic reviews. As a secondary objective, we evaluated the risk of bias among trials registered prospectively vs. retrospectively. Method: Clinical trials published in 2005 or after included in a sample of 100 Cochrane systematic reviews published from 2014-2019. Results: Of 1,177 clinical trials identified, we verified 368 (31%) had been registered, of which 135 (36.7%) were registered prospectively (i.e., before or up to 1 month after enrollment of the first participant). Across the bias domains (one bias assessment for each domain per trial), the percentage of trials at low risk ranged from 29% to 58%; unclear risk ranged from to 26% to 61% and high risk ranged from 2% to 38%. Trials that had been registered had less high or unclear risk of bias in five domains: random sequence generation (univariate risk ratio [RR] 0.69, 95% confidence interval [95% CI] 0.58-0.81), allocation concealment (RR 0.64, 95% CI 0.57-0.72), performance bias (RR 0.65, 95% CI 0.58-0.72), detection bias (RR 0.70, 95% CI 0.62-0.78), and reporting bias (RR 0.62, 95% CI 0.53-0.73). An association between clinical trial registration and high or unclear risk of attrition bias could not be demonstrated nor refuted (RR 1.02, 95% CI 0.89-1.17). It also was observed in terms of overall risk of bias, that registered trials had less high or unclear overall risk of bias than trials that had not been registered (univariate RR 0.29, 95% CI 0.19-0.46). Prospective clinical trial registration was associated with low risks of selection bias due to inadequate allocation concealment, performance bias, and detection bias compared with retrospective clinical trial registration. Conclusion: In a large sample of clinical trials included in recently published systematic reviews of interventions, clinical trial registration was associated with low risk of bias for five of the six domains examined

Data sources and methods used to determine pretest probabilities in a cohort of Cochrane diagnostic test accuracy reviews

BACKGROUND: A pretest probability must be selected to calculate data to help clinicians, guideline boards and policy makers interpret diagnostic accuracy parameters. When multiple analyses for the same target condition are compared, identical pretest probabilities might be selected to facilitate the comparison. Some pretest probabilities may lead to exaggerations of the patient harms or benefits, and guidance on how and why to select a specific pretest probability is minimally described. Therefore, the aim of this study was to assess the data sources and methods used in Cochrane diagnostic test accuracy (DTA) reviews for determining pretest probabilities to facilitate the interpretation of DTA parameters. A secondary aim was to assess the use of identical pretest probabilities to compare multiple meta-analyses within the same target condition. METHODS: Cochrane DTA reviews presenting at least one meta-analytic estimate of the sensitivity and/or specificity as a primary analysis published between 2008 and January 2018 were included. Study selection and data extraction were performed by one author and checked by other authors. Observed data sources (e.g. studies in the review, or external sources) and methods to select pretest probabilities (e.g. median) were categorized. RESULTS: Fifty-nine DTA reviews were included, comprising of 308 meta-analyses. A pretest probability was used in 148 analyses. Authors used included studies in the DTA review, external sources, and author consensus as data sources for the pretest probability. Measures of central tendency with or without a measure of dispersion were used to determine the pretest probabilities, with the median most commonly used. Thirty-two target conditions had at least one identical pretest probability for all of the meta-analyses within their target condition. About half of the used identical pretest probabilities were inside the prevalence ranges from all analyses within a target condition. CONCLUSIONS: Multiple sources and methods were used to determine (identical) pretest probabilities in Cochrane DTA reviews. Indirectness and severity of downstream consequences may influence the acceptability of the certainty in calculated data with pretest probabilities. Consider: whether to present normalized frequencies, the influence of pretest probabilities on normalized frequencies, and whether to use identical pretest probabilities for meta-analyses in a target condition

Poor compliance of clinical trial registration among trials included in systematic reviews: a cohort study

OBJECTIVES: The objective of the study was to examine whether clinical trials that have been included in systematic reviews have been registered in clinical trial registers and, when they have, whether results of the trials were included in the clinical trial register. STUDY DESIGN AND SETTING: This study used a sample of 100 systematic reviews published by the Cochrane Musculoskeletal, Oral, Skin and Sensory Network between 2014 and 2019. RESULTS: We identified 2,000 trials (369,778 participants) from a sample of 100 systematic reviews. The median year of trial publication was 2007. Of 1,177 trials published in 2005 or later, a clinical trial registration record was identified for 368 (31%). Of these registered trials, 135 (37%) were registered prospectively and results were posted for 114 (31%); most registered trials evaluated pharmaceutical interventions (62%). Of trials published in the last 10 years, the proportion of registered trials increased to 38% (261 of 682). CONCLUSION: Although some improvement in clinical trial registration has been observed in recent years, the proportion of registered clinical trials included in recently published systematic reviews remains less than desirable. Prospective clinical trial registration provides an essential role in assessing the risk of bias and judging the quality of evidence in systematic reviews of intervention safety and effectiveness

A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study

Background: Ferroquine (SSR97193) is a candidate anti-malarial currently undergoing clinical trials for malaria. To better understand its pharmacokinetic (PK) and pharmacodynamic (PD) parameters the compound was tested in the experimentally induced blood stage malaria infection model in volunteers. Methods: Male and non-pregnant female aged 18-50 years were screened for this phase II, controlled, single-centre clinical trial. Subjects were inoculated with ~1800 viable Plasmodium falciparum 3D7A-infected human erythrocytes, and treated with a single-dose of 800 mg ferroquine. Blood samples were taken at defined time-points to measure PK and PD parameters. The blood concentration of ferroquine and its active metabolite, SSR97213, were measured on dry blood spot samples by ultra-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Parasitaemia and emergence of gametocytes were monitored by quantitative PCR. Safety was determined by recording adverse events and monitoring clinical laboratory assessments during the course of the study. Results: Eight subjects were enrolled into the study, inoculated with infected erythrocytes and treated with 800 mg ferroquine. Ferroquine was rapidly absorbed with maximal exposure after 4-8 and 4-12 h exposure for SSR97213. Non-compartmental PK analysis resulted in estimates for half-lives of 10.9 and 23.8 days for ferroquine and SSR97213, respectively. Parasite clearance as reported by parasite reduction ratio was 162.9 (95 % CI 141-188) corresponding to a parasite clearance half-life of 6.5 h (95 % CI: 6.4-6.7 h). PK/PD modelling resulted in a predicted minimal parasiticidal concentration of 20 ng/mL, and the single dosing tested in this study was predicted to maintain an exposure above this threshold for 454 h (37.8 days). Although ferroquine was overall well tolerated, transient elevated transaminase levels were observed in three subjects. Paracetamol was the only concomitant treatment among the two out of these three subjects that may have played a role in the elevated transaminases levels. No clinically significant ECG abnormalities were observed. Conclusions: The parameters and PK/PD model derived from this study pave the way to the further rational development of ferroquine as an anti-malarial partner drug. The safety of ferroquine has to be further explored in controlled human trials. Trial registration anzctr.org.au (registration number: ACTRN12613001040752), registered 18/09/201

Anticancer properties of distinct antimalarial drug classes

We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC 50 s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC 50 s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings