Henrike Grund

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.

<ns3:p>Background: The coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There is however a need for greater coordination, with limited resources and the shifting global nature of the pandemic resulting in a proliferation of research projects underpowered and unable to achieve their aims.</ns3:p> <ns3:p>Methods: The UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15th April 2021 the database contains 10,608 projects, funded by 201 funders, taking place across 142 countries representing an investment of at least $4.7 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus. It is being used by the WHO, governments and multi-lateral policy makers, research funders and researchers.</ns3:p> <ns3:p>This living mapping review aims to supplement the database by providing an open accessible and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analysis will be presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio.</ns3:p> <ns3:p>Results: In this version four analysis we provide an updated detailed descriptive analysis of the database (three months after version three) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations and research locations (with a focus on resource-limited countries).</ns3:p> <ns3:p>Conclusions: As the global funding response to COVID-19 plateaus, this living mapping review helps both funders and researchers to prioritise resources to areas where there is continued unmet research need.</ns3:p>

<ns3:p> <ns3:bold>Background:</ns3:bold> The coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There is however a need for greater coordination, with limited resources and the shifting global nature of the pandemic resulting in a proliferation of research projects underpowered and unable to achieve their aims. </ns3:p> <ns3:p> <ns3:bold>Methods:</ns3:bold> The UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15 <ns3:sup>th</ns3:sup> July 2021 the database contains 12,419 projects, funded by 255 funders, taking place across 149 countries representing an investment of at least $4.9 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus. It is being used by the WHO, governments and multi-lateral policy makers, research funders and researchers. </ns3:p> <ns3:p>This living mapping review aims to supplement the database by providing an open accessible and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analysis will be presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio.</ns3:p> <ns3:p> <ns3:bold>Results:</ns3:bold> In this version five analysis we provide an updated detailed descriptive analysis of the database (three months after version four) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations and research locations (with a focus on resource-limited countries). </ns3:p> <ns3:p> <ns3:bold>Conclusions:</ns3:bold> As the global funding response to COVID-19 plateaus, this living mapping review helps both funders and researchers to prioritise resources to areas where there is continued unmet research need. </ns3:p>

BACKGROUND: The coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There has however been an ongoing need for greater coordination, with limited resources for research and the shifting global pandemic. METHODS: The UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15th October 2022 the database contains 20,006 projects, funded by 351 funders, taking place across 157 countries representing an investment of at least $7.4 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus and the UN Research Roadmap for the COVID-19 Recovery. It is being used by the WHO, governments and further policy makers, research funders and researchers. This living mapping review aims to supplement the database by providing an open, accessible, and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analyses are presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio. RESULTS: In this final version ten analysis, we provide an updated detailed descriptive analysis of the database (on data from three months after version nine) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations, and research locations (with a focus on resource-limited countries). CONCLUSIONS: As the global research response to COVID-19 plateaus, this living mapping review has helped both funders and researchers to prioritise resources and review investments.

<ns3:p>Background: The coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There has however been an ongoing need for greater coordination, with limited resources for research and the shifting global pandemic.</ns3:p><ns3:p> Methods: The UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15th July 2022 the database contains 17,955 projects, funded by 345 funders, taking place across 157 countries representing an investment of at least $6.5 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus and the UN Research Roadmap for the COVID-19 Recovery. It is being used by the WHO, governments and further policy makers, research funders and researchers.</ns3:p><ns3:p> This living mapping review aims to supplement the database by providing an open accessible and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analysis are presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio.</ns3:p><ns3:p> Results: In this version nine analysis we provide an updated detailed descriptive analysis of the database (on data from three months after version eight) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations and research locations (with a focus on resource-limited countries).</ns3:p><ns3:p> Conclusions: As the global funding response to COVID-19 plateaus, this living mapping review helps both funders and researchers to prioritise resources and review investments.</ns3:p>