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- Opitz, Rachel, et al.
(author)
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A Lockpick's Guide to dataARC: Designing Infrastructures and Building Communities to Enable Transdisciplinary Research
- 2021
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In: Internet Archaeology. - : Council for British Archaeology. - 1363-5387. ; 56
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Journal article (peer-reviewed)abstract
- The North Atlantic Biocultural Organization (NABO) community initiated dataARC to develop digital research infrastructures to support their work on long-term human-ecodynamics in the North Atlantic. These infrastructures were designed to address the challenges of sharing research data, the connections between those data and high-level interpretations, and the interpretations themselves. In parallel, they were also designed to support the reuse of diverse data that underpin transdisciplinary synthesis research and to contextualise materials disseminated widely to the public more firmly in their evidence base. This article outlines the research infrastructure produced by the project and reflects on its design and development. We outline the core motivations for dataARC's work and introduce the tools, platforms and (meta)data products developed. We then undertake a critical review of the project's workflow. This review focuses on our understanding of the needs of stakeholder groups, the principles that guided the design of the infrastructure, and the extent to which these principles are successfully promoted in the current implementation. Drawing on this assessment, we consider how the infrastructure, in whole or in part, might be reused by other transdisciplinary research communities. Finally, we highlight key socio-technical gaps that may emerge as structural barriers to transdisciplinary, engaged, and open research if left unaddressed.
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| 3. |
- Surendran, Praveen, et al.
(author)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Journal article (peer-reviewed)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 5. |
- Lim, Jeremy J., et al.
(author)
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A phase 2 randomized, double-blind, placebo-controlled trial of MHAA4549A, a monoclonal antibody, plus oseltamivir in patients hospitalized with severe influenza a virus infection
- 2020
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In: Antimicrobial Agents and Chemotherapy. - 0066-4804. ; 64:7
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Journal article (peer-reviewed)abstract
- For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function, defined as the time to removal of supplemental oxygen support to maintain a stable oxygen saturation (SpO2) of ≥95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed. One hundred sixty-six patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV, 4.28 days; 3,600 mg MHAA4549A+OTV, 2.78 days; 8,400 mg MHAA4549A+OTV, 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV. In hospitalized patients with influenza A virus infection, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A virus infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02293863.).
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