Zaire ebolavirus (EBOV) causes Ebola virus disease (EVD), which carries a fatality rate between 25% and 90% in humans. Liver pathology is a hallmark of terminal EVD; however, little is known about temporal disease progression. We used multiplexed fluorescent immunohistochemistry and in situ hybridization in combination with whole slide imaging and image analysis (IA) to quantitatively characterize temporospatial signatures of viral and host factors as related to EBOV pathogenesis. Eighteen rhesus monkeys euthanized between 3 and 8 days post-infection, and 3 uninfected controls were enrolled in this study. Compared with semiquantitative histomorphologic ordinal scoring, quantitative IA detected subtle and progressive features of early and terminal EVD that was not feasible with routine approaches. Sinusoidal macrophages were the earliest cells to respond to infection, expressing proinflammatory cytokine interleukin 6 ( IL6 ) mRNA, which was subsequently also observed in fibrovascular compartments. The mRNA of interferon-stimulated gene-15 (ISG-15), also known as ISG15 ubiquitin like modifier (ISG15), was observed early, with a progressive and ubiquitous hybridization signature involving mesenchymal and epithelial compartments. ISG-15 mRNA was prominent near infected cells, but not in infected cells, supporting the hypothesis that bystander cells produce a robust interferon gene response. This study contributes to our current understanding of early EVD progression and illustrates the value that digital pathology and quantitative IA serve in infectious disease research.
The 2014 West African Ebola outbreak was unprecedented in scale and required significant international assistance. Many U.S.-based health professionals traveled to West Africa to participate in the response, whereas others considered participation, but ultimately decided against it. This study explores motivators, facilitators, and barriers to international health care worker mobilization. We conducted 24 semistructured in-depth interviews and one focus group discussion with clinical and nonclinical responders and nonresponders. Responders reported feeling duty-bound to help, confidence in their training, and prior experience in humanitarian response. Media coverage was perceived to create environments of stigma and misinformation. Supportive workplaces and clear leave of absence policies facilitated engagement, whereas unsupportive workplaces posed barriers. Although nonresponders were included in the study, the dynamics of nonresponse were less clear and warrant further exploration. Understanding how to support health professionals in responding to outbreak situations may improve mobilization in future public health crises.
In recent years, the world has witnessed the tragic outcomes of multiple global health crises. From Ebola to high prices to antibiotic resistance, these events highlight the fundamental constraints of the current biomedical research and development (R&D) system in responding to patient needs globally.To mitigate this lack of responsiveness, over 100 self-identified “alternative” R&D initiatives, have emerged in the past 15 years. To begin to make sense of this panoply of initiatives working to overcome the constraints of the current system, UAEM began an extensive, though not comprehensive, mapping of the alternative biomedical R&D landscape. We developed a two phase approach: (1) an investigation, via the RE:Route Mapping, of both existing and proposed initiatives that claim to offer an alternative approach to R&D, and (2) evaluation of those initiatives to determine which are in fact achieving increased access to and innovation in medicines. Through phase 1, the RE:Route Mapping, we examined 81 initiatives that claim to redress the inequity perpetuated by the current system via one of five commonly recognized mechanisms necessary for truly alternative R&D.Preliminary analysis of phase 1 provides the following conclusions:No initiative presents a completely alternative model of biomedical R&D.The majority of initiatives focus on developing incentives for drug discovery.The majority of initiatives focus on rare diseases or diseases of the poor and marginalized.There is an increasing emphasis on the use of push, pull, pool, collaboration and open mechanisms alongside the concept of delinkage in alternative R&D.There is a trend towards public funding and launching of initiatives by the Global South.Given the RE:Route Mapping’s inevitable limitations and the assumptions made in its methodology, it is not intended to be the final word on a constantly evolving and complex field; however, its findings are significant. The Mapping’s value lies in its timely and unique insight into the importance of ongoing efforts to develop a new global framework for biomedical R&D. As we progress to phase 2, an evaluation tool for initiatives focused on identifying which approaches have truly achieved increased innovation and access for patients, we aim to demonstrate that there are a handful of initiatives which represent some, but not all, of the building blocks for a new approach to R&D.Through this mapping and our forthcoming evaluation, UAEM aims to initiate an evidence-based conversation around a truly alternative biomedical R&D model that serves people rather than profits.
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