HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants.

Otitis media with effusion (OME) is the commonest cause of hearing loss in children, yet the underlying genetic pathways and mechanisms involved are incompletely understood. Ventilation of the middle ear with tympanostomy tubes is the commonest surgical procedure in children and the best treatment for chronic OME, but the mechanism by which they work remains uncertain. As hypoxia is a common feature of inflamed microenvironments, moderation of hypoxia may be a significant contributory mechanism. We have investigated the occurrence of hypoxia and hypoxia-inducible factor (HIF) mediated responses in Junbo and Jeff mouse mutant models, which develop spontaneous chronic otitis media. We found that Jeff and Junbo mice labeled in vivo with pimonidazole showed cellular hypoxia in inflammatory cells in the bulla lumen, and in Junbo the middle ear mucosa was also hypoxic. The bulla fluid inflammatory cell numbers were greater and the upregulation of inflammatory gene networks were more pronounced in Junbo than Jeff. Hif-1α gene expression was elevated in bulla fluid inflammatory cells, and there was upregulation of its target genes including Vegfa in Junbo and Jeff. We therefore investigated the effects in Junbo of small-molecule inhibitors of VEGFR signaling (PTK787, SU-11248, and BAY 43-9006) and destabilizing HIF by inhibiting its chaperone HSP90 with 17-DMAG. We found that both classes of inhibitor significantly reduced hearing loss and the occurrence of bulla fluid and that VEGFR inhibitors moderated angiogenesis and lymphangiogenesis in the inflamed middle ear mucosa. The effectiveness of HSP90 and VEGFR signaling inhibitors in suppressing OM in the Junbo model implicates HIF-mediated VEGF as playing a pivotal role in OM pathogenesis. Our analysis of the Junbo and Jeff mutants highlights the role of hypoxia and HIF-mediated pathways, and we conclude that targeting molecules in HIF-VEGF signaling pathways has therapeutic potential in the treatment of chronic OM.

A three-layer system to win the war against COVID-19 and invest in health systems of the future.

The COVID-19 pandemic taught us many lessons, most critically that its human and economic toll would have been significantly smaller if countries had in place strong layers of defence that would have either prevented the spillover of the SARS-CoV-2 into a human population in the first place, or, failing that, contained the outbreak to avert its global spread. Further, the brunt of COVID-19 impacts on some countries considered 'most prepared' for pandemics underscored the need for an integrated approach to ensure resilience to future epidemics. Consequently, as countries plan ahead to prevent future pandemics, they should give priority to investments that transform their systems, particularly in the precrises phase, to preparedness and response through a multilayered defence. We propose a three-layered approach for post-COVID-19 investments in public health functions and service delivery, particularly at the community and precrises levels. This framework highlights the interventions that enable countries to better prevent, detect and contain epidemic threats, and that strengthen the efficient use of limited resources towards high-impact precrises systems.

The Sustainable Development Goals and the Global Health Security Agenda: exploring synergies for a sustainable and resilient world.

Both the Sustainable Development Goals (SDGs) and the Global Health Security Agenda (GHSA) represent bold initiatives to address systematically gaps in previous efforts to assure that societies can be resilient when confronted with potentially overwhelming threats to health. Despite their obvious differences, and differing criticisms of both, they shift away from vertical (problem- or disease-specific) to horizontal (comprehensive) solutions. Despite the comprehensiveness of the SDGs, they lack a specific target for global health security. The GHSA focuses primarily on infectious diseases and neglects non-communicable diseases and socioeconomic drivers of health. Even though each agenda has limitations and unique challenges, they are complementary. We discuss ways to understand and implement the two agendas synergistically to hasten progress toward a more sustainable and resilient world.

Long shadow of fear in an epidemic: fearonomic effects of Ebola on the private sector in Nigeria.

BACKGROUND: The already significant impact of the Ebola epidemic on Guinea, Liberia and Sierra Leone, was worsened by a fear of contagion that aggravated the health crisis. However, in contrast to other Ebola-affected countries, Nigeria fared significantly better due to its swift containment of the disease. The objective of our study was to describe the impact of Ebola on the Nigerian private sector. This paper introduces and defines the term fearonomic effect as the direct and indirect economic effects of both misinformation as well as fear-induced aversion behaviour, exhibited by individuals, organisations or countries during an outbreak or an epidemic. METHODS: This study was designed as a cross-sectional mixed-methods study that used semistructured in-depth interviews and a supporting survey to capture the impact of Ebola on the Nigerian private sector after the outbreak. Themes were generated from the interviews on the direct and indirect impact of Ebola on the private sector; the impact of misinformation and fear-based aversion behaviour in the private sector. RESULTS: Our findings reveal that the fearonomic effects of Ebola included health service outages and reduced healthcare usage as a result of misinformation and aversion behaviour by both patients and providers. Although certain sectors (eg, health sector, aviation sector, hospitality sector) in Nigeria were affected more than others, no business was immune to Ebola's fearonomic effects. We describe how sectors expected to prosper during the outbreak (eg, pharmaceuticals), actually suffered due to the changes in consumption patterns and demand shocks. CONCLUSION: In a high-stressor epidemic-like setting, altered consumption behaviour due to distorted disease perception, misinformation and fear can trigger short-term economic cascades that can disproportionately affect businesses and lead to financial insecurity of the poorest and the most vulnerable in a society.