Entomological outcomes of cluster-randomised, community-driven dengue vector-suppression interventions in Kampong Cham province, Cambodia.

Cambodia has one of the highest dengue infection rates in Southeast Asia. Here we report quantitative entomological results of a large-scale cluster-randomised trial assessing the impact on vector populations of a package of vector control interventions including larvivorous guppy fish in household water containers, mosquito trapping with gravid-ovitraps, solid waste management, breeding-container coverage through community education and engagement for behavioural change, particularly through the participation of school children. These activities resulted in major reductions in Container Index, House Index, Breteau Index, Pupal Index and Adult Index (all p-values 0.002 or lower) in the Intervention Arm compared with the Control Arm in a series of household surveys conducted over a follow-up period of more than one year, although the project was not able to measure the longer-term sustainability of the interventions. Despite comparative reductions in Adult Index between the study arms, the Adult Index was higher in the Intervention Arm in the final household survey than in the first household survey. This package of biophysical and community engagement interventions was highly effective in reducing entomological indices for dengue compared with the control group, but caution is required in extrapolating the reduction in household Adult Index to a reduction in the overall population of adult Aedes mosquitoes, and in interpreting the relationship between a reduction in entomological indices and a reduction in the number of dengue cases. The package of interventions should be trialled in other locations.

Fostering social innovation and building adaptive capacity for dengue control in Cambodia: a case study.

BACKGROUND: The social-ecological systems theory, with its unique conception of resilience (social-ecological systems & resilience, SESR), provides an operational framework that currently best meets the need for integration and adaptive governance as encouraged by the Sustainable Development Goals. SESR accounts for the complex dynamics of social-ecological systems and operationalizes transdisciplinarity by focusing on community engagement, value co-creation, decentralized leadership and social innovation. Targeting Social Innovation (SI) in the context of implementation research for vector-borne diseases (VBD) control offers a low-cost strategy to contribute to lasting and contextualized community engagement in disease control and health development in low and middle income countries of the global south. In this article we describe the processes of community engagement and transdisciplinary collaboration underpinning community-based dengue management in rural primary schools and households in two districts in Cambodia. METHODS: Multiple student-led and community-based interventions have been implemented focusing on empowering education, communication for behavioral change and participatory epidemiology mapping in order to engage Cambodian communities in dengue control. We describe in particular the significance of the participatory processes that have contributed to the design of SI products that emerged following iterative consultations with community stakeholders to address the dengue problem. RESULTS: The SI products that emerged following our interaction with community members are 1) adult mosquito traps made locally from solid waste collections, 2) revised dengue curriculum with hands-on activities for transformative learning, 3) guppy distribution systems led by community members, 4) co-design of dengue prevention communication material by students and community members, 5) community mapping. CONCLUSIONS: The initiative described in this article put in motion processes of community engagement towards creating ownership of dengue control interventions tools by community stakeholders, including school children. While the project is ongoing, the project's interventions so far implemented have contributed to the emergence of culturally relevant SI products and provided initial clues regarding 1) the conditions allowing SI to emerge, 2) specific mechanisms by which it happens and 3) how external parties can facilitate SI emergence. Overall there seems to be a strong argument to be made in supporting SI as a desirable outcome of project implementation towards building adaptive capacity and resilience and to use the protocol supporting this project implementation as an operational guiding document for other VBD adaptive management in the region.

Research on vector-borne diseases: implementation of research communication strategies.

BACKGROUND: Effective communication of research findings on vector-borne diseases in Africa is challenging for a number of reasons. Following the experiences of a number of researchers over the life of a project, this article looks for lessons that can be shared with the wider research community. MAIN BODY: Between 2014 and 2017, a set of five inter-disciplinary teams from seven African countries collaborated on a project focusing on vector-borne diseases in the context of climate change. A central objective of this work was to influence policy and programming with relevant research findings. This article examines how principles of research communication, derived from the literature and current guidelines, can be applied in practice. Several challenges and lessons are highlighted, showing that research communication takes place within difficult constraints and in complex, fluid institutional and political environments. The processes of communication between policymakers and researchers including stakeholder mapping, defining research communication plans and tailoring communication products are discussed. CONCLUSIONS: The article concludes that while guidelines and frameworks for research communication are helpful, they should not detract from the ability of local teams to adapt to circumstances. Of key importance are the relationships and networks of local research teams.

Vector-borne disease and climate change adaptation in African dryland social-ecological systems.

BACKGROUND: Drylands, which are among the biosphere's most naturally limiting and environmentally variable ecosystems, constitute three-quarters of the African continent. As a result, environmental sustainability and human development along with vector-borne disease (VBD) control historically have been especially challenging in Africa, particularly in the sub-Saharan and Sahelian drylands. Here, the VBD burden, food insecurity, environmental degradation, and social vulnerability are particularly severe. Changing climate can exacerbate the legion of environmental health threats in Africa, the social dimensions of which are now part of the international development agenda. Accordingly, the need to better understand the dynamics and complex coupling of populations and environments as exemplified by drylands is increasingly recognized as critical to the design of more sustainable interventions. MAIN BODY: This scoping review examines the challenge of vector-borne disease control in drylands with a focus on Africa, and the dramatic, ongoing environmental and social changes taking place. Dryland societies persisted and even flourished in the past despite changing climates, extreme and unpredictable weather, and marginal conditions for agriculture. Yet intrusive forces largely out of the control of traditional dryland societies, along with the negative impacts of globalization, have contributed to the erosion of dryland's cultural and natural resources. This has led to the loss of resilience underlying the adaptive capacity formerly widely exhibited among dryland societies. A growing body of evidence from studies of environmental and natural resource management demonstrates how, in light of dryland system's inherent complexity, these factors and top-down interventions can impede sustainable development and vector-borne disease control. Strengthening adaptive capacity through community-based, participatory methods that build on local knowledge and are tailored to local ecological conditions, hold the best promise of reversing current trends. CONCLUSIONS: A significant opportunity exists to simultaneously address the increasing threat of vector-borne diseases and climate change through methods aimed at strengthening adaptive capacity. The integrative framework and methods based on social-ecological systems and resilience theory offers a novel set of tools that allow multiple threats and sources of vulnerability to be addressed in combination. Integration of recent advances in vector borne disease ecology and wider deployment of these tools could help reverse the negative social and environmental trends currently seen in African drylands.

Data and tools to integrate climate and environmental information into public health.

BACKGROUND: During the last 30 years, the development of geographical information systems and satellites for Earth observation has made important progress in the monitoring of the weather, climate, environmental and anthropogenic factors that influence the reduction or the reemergence of vector-borne diseases. Analyses resulting from the combination of geographical information systems (GIS) and remote sensing have improved knowledge of climatic, environmental, and biodiversity factors influencing vector-borne diseases (VBDs) such as malaria, visceral leishmaniasis, dengue, Rift Valley fever, schistosomiasis, Chagas disease and leptospirosis. These knowledge and products developed using remotely sensed data helped and continue to help decision makers to better allocate limited resources in the fight against VBDs. MAIN BODY: Because VBDs are linked to climate and environment, we present here our experience during the last four years working with the projects under the, World Health Organization (WHO)/ The Special Programme for Research and Training in Tropical Diseases (TDR)-International Development Research Centre (IDRC) Research Initiative on VBDs and Climate Change to integrate climate and environmental information into research and decision-making processes. The following sections present the methodology we have developed, which uses remote sensing to monitor climate variability, environmental conditions, and their impacts on the dynamics of infectious diseases. We then show how remotely sensed data can be accessed and evaluated and how they can be integrated into research and decision-making processes for mapping risks, and creating Early Warning Systems, using two examples from the WHO TDR projects based on schistosomiasis analysis in South Africa and Trypanosomiasis in Tanzania. CONCLUSIONS: The tools presented in this article have been successfully used by the projects under the WHO/TDR-IDRC Research Initiative on VBDs and Climate Change. Combined with capacity building, they are an important piece of work which can significantly contribute to the goals of WHO Global Vector Control Response and to the Sustainable Development Goals especially those on health and climate action.

Support for research towards understanding the population health vulnerabilities to vector-borne diseases: increasing resilience under climate change conditions in Africa.

BACKGROUND: Diseases transmitted to humans by vectors account for 17% of all infectious diseases and remain significant public health problems. Through the years, great strides have been taken towards combatting vector-borne diseases (VBDs), most notably through large scale and coordinated control programmes, which have contributed to the decline of the global mortality attributed to VBDs. However, with environmental changes, including climate change, the impact on VBDs is anticipated to be significant, in terms of VBD-related hazards, vulnerabilities and exposure. While there is growing awareness on the vulnerability of the African continent to VBDs in the context of climate change, there is still a paucity of research being undertaken in this area, and impeding the formulation of evidence-based health policy change. MAIN BODY: One way in which the gap in knowledge and evidence can be filled is for donor institutions to support research in this area. The collaboration between the WHO Special Programme for Research and Training in Tropical Diseases (TDR) and the International Centre for Research and Development (IDRC) builds on more than 10 years of partnership in research capacity-building in the field of tropical diseases. From this partnership was born yet another research initiative on VBDs and the impact of climate change in the Sahel and sub-Saharan Africa. This paper lists the projects supported under this research initiative and provides a brief on some of the policy and good practice recommendations emerging from the ongoing implementation of the research projects. CONCLUSION: Data generated from the research initiative are expected to be uptaken by stakeholders (including communities, policy makers, public health practitioners and other relevant partners) to contribute to a better understanding of the impacts of social, environmental and climate change on VBDs(i.e. the nature of the hazard, vulnerabilities, exposure), and improve the ability of African countries to adapt to and reduce the effects of these changes in ways that benefit their most vulnerable populations.

A look at the ASEAN-NDI: building a regional health R&D innovation network.

Globally, there are growing efforts to address diseases through the advancement in health research and development (R&D), strengthening of regional cooperation in science and technology (particularly on product discovery and development), and implementation of the World Health Assembly Resolution 61.21 (WHA61.21) on the Global Strategy and Plan of Action on Public Health, Innovation, and Intellectual Property (GSPA-PHI). As such, the Association of Southeast Asian Nations (ASEAN) is responding to this through the establishment of the ASEAN-Network for Drugs, Diagnostics, Vaccines, and Traditional Medicines Innovation (ASEAN-NDI). This is important in the ASEAN considering that infectious tropical diseases remain prevalent, emerging, and reemerging in the region. This paper looks into the evolution of the ASEAN-NDI from its inception in 2009, to how it is at present, and its plans to mitigate public health problems regionally and even globally.

Analysis of pan-African Centres of excellence in health innovation highlights opportunities and challenges for local innovation and financing in the continent.

A pool of 38 pan-African Centres of Excellence (CoEs) in health innovation has been selected and recognized by the African Network for Drugs and Diagnostics Innovation (ANDI), through a competitive criteria based process. The process identified a number of opportunities and challenges for health R&D and innovation in the continent: i) it provides a direct evidence for the existence of innovation capability that can be leveraged to fill specific gaps in the continent; ii) it revealed a research and financing pattern that is largely fragmented and uncoordinated, and iii) it highlights the most frequent funders of health research in the continent. The CoEs are envisioned as an innovative network of public and private institutions with a critical mass of expertise and resources to support projects and a variety of activities for capacity building and scientific exchange, including hosting fellows, trainees, scientists on sabbaticals and exchange with other African and non-African institutions.

Integrated dataset of screening hits against multiple neglected disease pathogens.

New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.

In Vitro Activity of Geldanamycin Derivatives against Schistosoma japonicum and Brugia malayi.

Geldanamycin (GA) is a benzoquinone-containing ansamycin that inhibits heat shock protein 90. GA derivatives are being evaluated as anti-neoplastic agents, but their utility against parasites whose heat shock proteins (Hsps) have homology with human Hsp90 is unknown. The activities of four synthetic GA derivatives were tested in vitro using adult Brugia malayi and Schistosoma japonicum. Two of the derivatives, 17-N-allyl-17-demethoxygeldanamycin (17-AAG) and 17-N-(2-dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG), are currently in human clinical trials as anticancer drugs. Using concentrations considered safe peak plasma concentrations for these two derivatives, all four derivatives were active against both parasites. The less toxic derivative 17-AAG was as effective as GA in killing S. japonicum, and both DMAG and 5'-bromogeldanoxazinone were more active than 17-AAG against B. malayi. This work supports continued evaluation of ansamycin derivatives as broad spectrum antiparasitic agents.

Advancing drug innovation for neglected diseases-criteria for lead progression.

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North-South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts.

Schistosomes: challenges in compound screening.

Major progress in studying the biology of schistosomes had been achieved since the late 1960s with the successful laboratory cultivation of the parasite's life cycle stages in the vertebrate (in vivo animal models) and snail hosts. This was followed by establishment of in vitro culture techniques for cultivation of the different life cycle stages to understand the mechanisms regulating the parasite's growth, development, transformation, pathogenicity and survival, with prospects to develop and identify relevant candidate diagnostic, immunological and chemotherapeutic targets. Chemotherapeutic measures have been the mainstay in the control of schistosomiasis. The use of praziquantel, a relatively safe and orally administered drug, in targeted or mass treatment programmes had significantly reduced the prevalence of schistosomiasis in disease-endemic countries. However, with only one drug of choice for treatment, parasite resistance remains a major concern. Thus, new drug discovery against schistosomes cannot be overemphasised. Undoubtedly, this will require an integrated system that includes not only rational chemical synthesis and lead optimisation, but also appropriate drug screening strategies. This paper reviews the present state of in vitro and in vivo drug screening strategies against schistosomes. It also highlights the best practices for compound screening in the TDR-designated compound screening centres and details some of the challenges involved in in vitro and in vivo compound screening.

Challenges in drug discovery for novel antifilarials.

Control programmes are at present focused on the elimination of onchocerciasis and lymphatic filariasis as public health problems in countries where they are endemic. The availability of effective drugs used in combination (diethylcarbamazine, albendazole and ivermectin) has paved the way for the implementation of Mass Drug Administration (MDA) campaigns. Considerable progress in the implementation of MDA programmes had led to significant reductions in transmission and morbidity. However, new drugs are needed to overcome the threat of resistance to existing microfilaricides as well as to identify new macrofilaricides. This paper discusses the existing screening tools available for antifilarial drug discovery and efforts towards optimising their use through the Helminth Drug Initiative.

Capacity building in anthelmintic drug discovery.

International collaboration in anthelmintic drug discovery holds special challenges compared with local or national discovery projects, and at the same time presents the opportunity to build capacity, forge long lasting inter-institutional relationships and strengthen infrastructure in multinational priority areas. This chapter discusses important issues that should be considered in the context of anthelmintic screening centre development and will give examples (Philippines and Egypt) of the productivity of developing country based screening centres. The positive outcomes of infrastructure building is realised in greater capacities for anthelmintic screening at institutions in the countries where the parasitic diseases are endemic and allows for optimum use of specialised resources for public health priority diseases that may be different from those in Western countries. Support for developing country based screening centres also can help countries optimise product development procedures and policies and can facilitate diffusion of desirable technology in corresponding global regions around the world.

Brugia malayi asparaginyl-transfer RNA synthetase induces chemotaxis of human leukocytes and activates G-protein-coupled receptors CXCR1 and CXCR2.

Background. Lymphatic filariasis is a chronic human parasitic disease in which the parasites repeatedly provoke acute and chronic inflammatory reactions in the host bloodstream and lymphatics. Excretory-secretory products derived from filariae are believed to play an important role in the development of associated immunologic conditions; however, the specific mechanisms involved in these changes are not well understood. Recently, human cytoplasmic aminoacyl-transfer (t) RNA synthetases, which are autoantigens in idiopathic inflammatory myopathies, were shown to activate chemokine receptors on T lymphocytes, monocytes, and immature dendritic cells by recruiting immune cells that could induce innate and adaptive immune responses. Filarial (Brugia malayi) asparaginyl-tRNA synthetase (AsnRS) is known to be an immunodominant antigen that induces strong human immunoglobulin G3 responses.Methods. Recombinant B. malayi AsnRS was used to perform cellular function assays--for example, chemotaxis and kinase activation assays.Results. Unlike human AsnRS, parasite AsnRS is chemotactic for neutrophils and eosinophils. Recombinant B. malayi AsnRS but not recombinant human AsnRS induced chemotaxis of CXCR1 and CXCR2 single-receptor-transfected HEK-293 cell lines, blocked CXCL1-induced calcium flux, and induced mitogen-activated protein kinase.Conclusions. Our findings suggest that a filarial parasite chemoattractant protein may contribute to the development of chronic inflammatory disease and that chemokine receptors may be therapeutic targets to ameliorate parasite-induced pathology.

Do tissue levels of autoantigenic aminoacyl-tRNA synthetase predict clinical disease?

The etiologies of most autoimmune diseases are not completely understood. Aminoacyl-tRNA synthetases (AARS) are a family of heterogenous enzymes responsible for protein synthesis and whose secondary functions include a role in autoimmune myositis. A subset of patients with idiopathic inflammatory myopathies demonstrate autoantibody against specific cytoplasmic AARS and the human asparaginyl-tRNA synthetase (AsnRS) has been shown to be a potent chemokine that interacts with CCR3 chemokine receptors. One way in which a chemotactic cytoplasmic enzyme might contribute to tissue inflammation is if it were abundant in a specific injured tissue and thereby released to the microenvironment at times of cellular damage. To test this hypothesis, the relative levels of AsnRS mRNA were studied in six human tissues. A 1.6 kbF RNA probe identified highly variable levels of the corresponding mRNA in Northern blot analysis of human lung, brain, heart, skeletal muscle, pancreas and liver. The highest levels of signal were noted in muscle and pancreas. Polyclonal antibody raised against recombinant human AsnRS identified abundant antigenic material in the pancreas, in particular in islet cells. Thus, the local abundance of an endogenous pro-inflammatory autoantigen may provide one explanation for perpetuation or exacerbation of tissue specific immune-mediated pathologies.

Contrasting Wuchereria bancrofti microfilaria rates in two Mangyan-populated Philippine villages.

Lymphatic filariasis caused by infection with Wuchereria bancrofti and Brugia malayi is endemic in 45 of 77 provinces in The Philippines. To prepare the island of Mindoro for mass treatment using diethylcarbamazine and albendazole, complete census data were collected in rural villages. A sample of individuals selected from each of two adjacent villages was examined for microfilaremia. Microfilariae were detected from thin smears in 34 (13%) of 272 patients examined from the village of Bayanan and 10 (3.4%) of 292 in the village of Mangangan (P < 0.01, by chi-square test). In these villages, the majority of those infected were members of the ethnic group known as Mangyans: 33 (97%) of 24 in Bayanan and 7 (70%) of 10 in Mangangan (risk ratio = 89, 95% confidence interval = 33-240, P < 0.001.) In children examined who were less than 10 years of age (n = 165), girls were more commonly infected than boys, even though the proportion of males in the general population was greater. Understanding sociocultural characteristics and related behaviors in future observations among the Mangyan may help to explain local differences in the distribution of filariasis. This information should also be helpful in designing more culturally appropriate strategies for the control of lymphatic filariasis among ethnic minorities in The Philippines.