Training In Tropical Diseases Research Articles

Delivering two new treatments for malaria: a story of inventive partnerships

The World Health Organisation (WHO) currently recommends the use of five artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated Plasmodium falciparum malaria. ACT combines two effective antimalarial drugs and is the cornerstone of successful malaria control and ultimately, elimination. Fixed-dose combinations (FDC) of ACTs are preferred, as they promote adherence to treatment and reduce the risk of selecting for drug-resistant parasites. In order to strengthen the ACT portfolio of FDCs, which at the time was minimal, the Drugs for Neglected Diseases initiative (DNDi), together with the WHO Special Programme for Research and Training in Tropical Diseases (TDR), launched the FACT (Fixed Dose Artesunate Combination Therapy) project in 2002, with original funding from INCO/DEV. The FACT core group also included the Brazilian government-owned pharmaceutical company, Farmanguinhos/Fiocruz, the University of Bordeaux, Universiti Sains Malaysia, Mahidol University and the Shoklo Malaria Research Unit in Thailand, the Centre National de Recherche et de Formation sur le Paludisme in Burkina Faso and the University of Oxford, combining epidemiological and drug development expertise. Additional competencies in clinical studies, clinical supplies and regulatory matters strengthened the core team. Through innovative collaborations with this variety of partners, the FACT project delivered FDCs of Artesunate (AS) plus Amodiaquine (ASAQ), and AS plus Mefloquine (MQ). Key contributions in scale-up, industrial production and regulatory filing were still needed to make the products available to patients, and different strategies were set up for each product. Both strategies were based on an initial development within the public and not-for-profit sector, with an extension to the private sector when a viable product was available, for registration, production and distribution. Sanofi took over the last steps of industrial development and regulatory filing for ASAQ and the product was pre-qualified by WHO in 2008. Since then, ASAQ has been registered in over 30 countries, mostly in sub-Saharan Africa and over 120 million treatments have been delivered - making this the second most widely used ACT. Deployment was accompanied by a risk-management plan, together with an extensive training and educational programme developed by Sanofi. ASMQ FDC production was scaled up by Farmaguinhos/Fiocruz and registered in Brazil in 2008. A large intervention study involving over 23,000 patients was performed by the National Malaria Control Programme in Brazil showing the efficacy of the product in real-life conditions. Through a South-South technology transfer, ASMQ FDC production was transferred to the Indian pharmaceutical company Cipla to ensure availability in India and South East Asia. ASMQ FDC was registered in India in 2011 and in Malaysia in early 2012 and is under review for WHO prequalification. The FACT project demonstrates that alternative drug development strategies can make safe, affordable and sustainable treatments available to patients. Diverse partnerships gathering a wide range of expertise, from national programmes ensuring the most appropriate therapy is used in endemic areas to industrial partners for product implementation and wide distribution, were key to success. Both ASAQ and ASMQ FDCs are critical drugs for malaria control across Africa, Latin America and South East Asia.

Reviewing the development, evidence base, and application of the revised dengue case classification

With the example of dengue, an evidence-based approach to prospectively develop a case classification is described, gathering evidence for identifying strength and weaknesses of the existing model, collecting new data describing the disease as it occurs globally, further developing a new model that can be applied in practice and field testing the newly developed model in comparison to the previous model. For each step in this process, the highest available level of evidence has been applied. This process has been initiated by the World Health Organization’s (WHO) Special Programme for Research and Training in Tropical Diseases (TDR) and WHO’s Department for Control of Neglected Tropical Diseases (NTD), developing the following for dengue. Since the early 1970s, dengue has been classified into dengue fever, dengue haemorrhagic fever grades I and II and dengue shock syndrome grades III and IV (DF/DHF/DSS). However, in recent years, a growing number of dengue clinicians have questioned the shortcomings of this scheme. The issues have revolved around the complexity of confirming DHF in clinical practice, misclassifying severe cases as DF, and the emphasis on haemorrhage rather than plasma leakage as the underlying problem in most severe dengue cases. Step 1: A systematic literature review highlighted the shortcomings of the DF/DHF/DSS scheme: (1) difficulties in applying the criteria for DHF/DSS; (2) the tourniquet test has a low sensitivity for distinguishing between DHF and DF; and (3) most DHF criteria had a large variability in frequency of occurrence. Step 2: An analysis of regional and national dengue guidelines and their application in the clinical practice showed a need to re-evaluate and standardize guidelines as the actual ones showed a large variation of definitions, an inconsistent application by medical staff, and a lack of diagnostic facilities necessary for the DHF diagnosis in frontline services. Step 3: A prospective cohort study in seven countries, confirmed the difficulties in applying the DF/DHF/DSS criteria even in tertiary care hospitals, that DF/DHF/DSS do not represent levels of disease severity and that a clear distinction between severe dengue (defined by plasma leakage and/or severe haemorrhage, and/or organ failure) and (non-severe) dengue can be made using highly sensitive and specific criteria. In contrast, the sub-grouping of (non-severe) dengue into two further severity levels was only possible with criteria that gave approximately 70% sensitivity and specificity. Step 4: Three regional expert consensus groups in the Americas and Asia concluded that ‘dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome’ and that, revising the results of Step 3, DF/DHF/DSS is not related to disease severity. Step 5: In a global expert consensus meeting at WHO in Geneva/Switzerland the evidence collected in Steps 1–4 was reviewed and a revised scheme was developed and accepted, distinguishing: dengue with or without warning signs and severe dengue; the further field testing and acquisition of further prospective evidence of the revised scheme was recommended. Step 6: In 18 countries, the usefulness and applicability of the revised classification compared to the DF/DHF/DSS scheme were tested showing clear results in favour of the revised classification. Step 7: Studies are under way on the predictive value of warning signs for severe dengue and on criteria for the clinical diagnosis of dengue which will complete the evidence foundation of the revised classification. The analysis has shown that the revised dengue case classification is better able to standardize clinical management, raise awareness about unnecessary interventions, match patient categories with specific treatment instructions, and make the key messages of patient management understandable for all health care staff dealing with dengue patients. Furthermore, the evidence-based approach to develop prospectively the dengue case classification could be a model approach for other disease classifications.

A Research Agenda for Helminth Diseases of Humans: Diagnostics for Control and Elimination Programmes

Diagnostic tools appropriate for undertaking interventions to control helminth infections are key to their success. Many diagnostic tests for helminth infection have unsatisfactory performance characteristics and are not well suited for use in the parasite control programmes that are being increasingly implemented. Although the application of modern laboratory research techniques to improve diagnostics for helminth infection has resulted in some technical advances, uptake has not been uniform. Frequently, pilot or proof of concept studies of promising diagnostic technologies have not been followed by much needed product development, and in many settings diagnosis continues to rely on insensitive and unsatisfactory parasitological or serodiagnostic techniques. In contrast, PCR-based xenomonitoring of arthropod vectors, and use of parasite recombinant proteins as reagents for serodiagnostic tests, have resulted in critical advances in the control of specific helminth parasites. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR) was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, the diagnostic technologies relevant to control of helminth infections, either available or in development, are reviewed. Critical gaps are identified and opportunities to improve needed technologies are discussed.

A Research Agenda for Helminth Diseases of Humans: Modelling for Control and Elimination

Mathematical modelling of helminth infections has the potential to inform policy and guide research for the control and elimination of human helminthiases. However, this potential, unlike in other parasitic and infectious diseases, has yet to be realised. To place contemporary efforts in a historical context, a summary of the development of mathematical models for helminthiases is presented. These efforts are discussed according to the role that models can play in furthering our understanding of parasite population biology and transmission dynamics, and the effect on such dynamics of control interventions, as well as in enabling estimation of directly unobservable parameters, exploration of transmission breakpoints, and investigation of evolutionary outcomes of control. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A research and development agenda for helminthiasis modelling is proposed based on identified gaps that need to be addressed for models to become useful decision tools that can support research and control operations effectively. This agenda includes the use of models to estimate the impact of large-scale interventions on infection incidence; the design of sampling protocols for the monitoring and evaluation of integrated control programmes; the modelling of co-infections; the investigation of the dynamical relationship between infection and morbidity indicators; the improvement of analytical methods for the quantification of anthelmintic efficacy and resistance; the determination of programme endpoints; the linking of dynamical helminth models with helminth geostatistical mapping; and the investigation of the impact of climate change on human helminthiases. It is concluded that modelling should be embedded in helminth research, and in the planning, evaluation, and surveillance of interventions from the outset. Modellers should be essential members of interdisciplinary teams, propitiating a continuous dialogue with end users and stakeholders to reflect public health needs in the terrain, discuss the scope and limitations of models, and update biological assumptions and model outputs regularly. It is highlighted that to reach these goals, a collaborative framework must be developed for the collation, annotation, and sharing of databases from large-scale anthelmintic control programmes, and that helminth modellers should join efforts to tackle key questions in helminth epidemiology and control through the sharing of such databases, and by using diverse, yet complementary, modelling approaches.

A Research Agenda for Helminth Diseases of Humans: The Problem of Helminthiases

A disproportionate burden of helminthiases in human populations occurs in marginalised, low-income, and resource-constrained regions of the world, with over 1 billion people in developing areas of sub-Saharan Africa, Asia, and the Americas infected with one or more helminth species. The morbidity caused by such infections imposes a substantial burden of disease, contributing to a vicious circle of infection, poverty, decreased productivity, and inadequate socioeconomic development. Furthermore, helminth infection accentuates the morbidity of malaria and HIV/AIDS, and impairs vaccine efficacy. Polyparasitism is the norm in these populations, and infections tend to be persistent. Hence, there is a great need to reduce morbidity caused by helminth infections. However, major deficiencies exist in diagnostics and interventions, including vector control, drugs, and vaccines. Overcoming these deficiencies is hampered by major gaps in knowledge of helminth biology and transmission dynamics, platforms from which to help develop such tools. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, we provide an overview of the forces driving the persistence of helminthiases as a public health problem despite the many control initiatives that have been put in place; identify the main obstacles that impede progress towards their control and elimination; and discuss recent advances, opportunities, and challenges for the understanding of the biology, epidemiology, and control of these infections. The helminth infections that will be discussed include: onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, food-borne trematodiases, and taeniasis/cysticercosis.

A research agenda for helminth diseases of humans: towards control and elimination.

Human helminthiases are of considerable public health importance in sub-Saharan Africa, Asia, and Latin America. The acknowledgement of the disease burden due to helminth infections, the availability of donated or affordable drugs that are mostly safe and moderately efficacious, and the implementation of viable mass drug administration (MDA) interventions have prompted the establishment of various large-scale control and elimination programmes. These programmes have benefited from improved epidemiological mapping of the infections, better understanding of the scope and limitations of currently available diagnostics and of the relationship between infection and morbidity, feasibility of community-directed or school-based interventions, and advances in the design of monitoring and evaluation (M&E) protocols. Considerable success has been achieved in reducing morbidity or suppressing transmission in a number of settings, whilst challenges remain in many others. Some of the obstacles include the lack of diagnostic tools appropriate to the changing requirements of ongoing interventions and elimination settings; the reliance on a handful of drugs about which not enough is known regarding modes of action, modes of resistance, and optimal dosage singly or in combination; the difficulties in sustaining adequate coverage and compliance in prolonged and/or integrated programmes; an incomplete understanding of the social, behavioural, and environmental determinants of infection; and last, but not least, very little investment in research and development (R&D). The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to undertake a comprehensive review of recent advances in helminthiases research, identify research gaps, and rank priorities for an R&D agenda for the control and elimination of these infections. This review presents the processes undertaken to identify and rank ten top research priorities; discusses the implications of realising these priorities in terms of their potential for improving global health and achieving the Millennium Development Goals (MDGs); outlines salient research funding needs; and introduces the series of reviews that follow in this PLoS Neglected Tropical Diseases collection, “A Research Agenda for Helminth Diseases of Humans.”

A Research Agenda for Helminth Diseases of Humans: Intervention for Control and Elimination

Recognising the burden helminth infections impose on human populations, and particularly the poor, major intervention programmes have been launched to control onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, and cysticercosis. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A summary of current helminth control initiatives is presented and available tools are described. Most of these programmes are highly dependent on mass drug administration (MDA) of anthelmintic drugs (donated or available at low cost) and require annual or biannual treatment of large numbers of at-risk populations, over prolonged periods of time. The continuation of prolonged MDA with a limited number of anthelmintics greatly increases the probability that drug resistance will develop, which would raise serious problems for continuation of control and the achievement of elimination. Most initiatives have focussed on a single type of helminth infection, but recognition of co-endemicity and polyparasitism is leading to more integration of control. An understanding of the implications of control integration for implementation, treatment coverage, combination of pharmaceuticals, and monitoring is needed. To achieve the goals of morbidity reduction or elimination of infection, novel tools need to be developed, including more efficacious drugs, vaccines, and/or antivectorial agents, new diagnostics for infection and assessment of drug efficacy, and markers for possible anthelmintic resistance. In addition, there is a need for the development of new formulations of some existing anthelmintics (e.g., paediatric formulations). To achieve ultimate elimination of helminth parasites, treatments for the above mentioned helminthiases, and for taeniasis and food-borne trematodiases, will need to be integrated with monitoring, education, sanitation, access to health services, and where appropriate, vector control or reduction of the parasite reservoir in alternative hosts. Based on an analysis of current knowledge gaps and identification of priorities, a research and development agenda for intervention tools considered necessary for control and elimination of human helminthiases is presented, and the challenges to be confronted are discussed.

A Research and Development Agenda for the Control and Elimination of Human Helminthiases

In this issue of PLoS Neglected Tropical Diseases, the Disease Reference Group on Helminth Infections (DRG4) has put forward a collection of eight reviews that, taken together, outline a compelling research and development agenda for the control and elimination of helminth diseases of humans (http://www.ploscollections.org/helminths [1]–[8]). Emphasis is placed on six major helminth infections: (i) soil-transmitted helminthiasis; (ii) schistosomiasis; (iii) lymphatic filariasis; (iv) onchocerciasis; (v) food-borne trematodiasis; and (vi) cysticercosis/taeniasis. Selection of these helminthiases is justified on multiple grounds. Firstly, as shown in Table 1, more than half of the world's population is at risk of one or several of these helminthiases, and hundreds of millions of people are currently infected. Secondly, consequences of the mainly long-term chronic infection include suffering, stigmatisation, subtle and gross morbidity (e.g., anaemia, limb deformations and blindness), and premature death, hence causing an intolerable global burden [9]–[17]. These features, in turn, exacerbate poverty [18]–[20]. Thirdly, there is growing commitment at all levels—from local communities to politicians, philanthropic organisations, and civil society—to control and eventually eliminate/eradicate the major human helminthiases. Table 1 Helminth Infections Emphasised by DRG4 for Development of a Research Agenda for Control and Elimination. Figure 1 shows that the six helminthiases are at distinctively different stages of control and elimination with geographical idiosyncrasies for some of them [21]. Several helminthiases have been targeted for elimination (e.g., lymphatic filariasis and onchocerciasis in the Americas), and progress made thus far gives hope that this goal can indeed be achieved by 2015 or 2020 if certain conditions are met [14], [21]. For schistosomiasis and soil-transmitted helminthiasis, discussions are escalating to shift the focus from control to elimination [22], [23], and in Africa, the African Programme for Onchocerciasis Control (APOC) is also moving towards this goal [24]. The pivotal role of research, coupled with teaching and training of strong cadres of researchers from endemic settings as essential backbones and platforms to design, implement, and adapt the control and elimination agenda for major helminthiases as well as other tropical diseases, cannot be emphasised enough [25]–[27]. Figure 1 Stages of control/elimination of the six helminthiases emphasised by DRG4. In 2007/2008, the Special Programme for Research and Training in Tropical Diseases (TDR), based at and executed by the World Health Organization (WHO), and co-sponsored by the United Nations Children's Fund (UNICEF), the United Nations Development Programme (UNDP), the World Bank and WHO, initiated a network of disease-specific and thematic reference groups (DRGs/TRGs). DRG4 was particularly prolific, as witnessed in the collection of authoritative reviews presented here. This accompanying editorial summarises the goal, objectives and expected outcomes of the DRGs/TRGs global research “think tank”. Next, light is shed on the composition of DRG4, its mode of operation and its first outputs. It is then argued that PLoS Neglected Tropical Diseases is an appropriate outlet for the studies reviewed and synthesised by DRG4. Indeed, open access to the identified and ranked research priorities by all stakeholders is a major asset and is likely to reinforce the control and elimination agenda of the major helminthiases.

A Research Agenda for Helminth Diseases of Humans: Basic Research and Enabling Technologies to Support Control and Elimination of Helminthiases

Successful and sustainable intervention against human helminthiases depends on optimal utilisation of available control measures and development of new tools and strategies, as well as an understanding of the evolutionary implications of prolonged intervention on parasite populations and those of their hosts and vectors. This will depend largely on updated knowledge of relevant and fundamental parasite biology. There is a need, therefore, to exploit and apply new knowledge and techniques in order to make significant and novel gains in combating helminthiases and supporting the sustainability of current and successful mass drug administration (MDA) programmes. Among the fields of basic research that are likely to yield improved control tools, the Disease Reference Group on Helminth Infections (DRG4) has identified four broad areas that stand out as central to the development of the next generation of helminth control measures: 1) parasite genetics, genomics, and functional genomics; 2) parasite immunology; 3) (vertebrate) host–parasite interactions and immunopathology; and 4) (invertebrate) host–parasite interactions and transmission biology. The DRG4 was established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR). The Group was given the mandate to undertake a comprehensive review of recent advances in helminthiases research in order to identify notable gaps and highlight priority areas. This paper summarises recent advances and discusses challenges in the investigation of the fundamental biology of those helminth parasites under the DRG4 Group's remit according to the identified priorities, and presents a research and development agenda for basic parasite research and enabling technologies that will help support control and elimination efforts against human helminthiases.

A research agenda for helminth diseases of humans: health research and capacity building in disease-endemic countries for helminthiases control.

Capacity building in health research generally, and helminthiasis research particularly, is pivotal to the implementation of the research and development agenda for the control and elimination of human helminthiases that has been proposed thematically in the preceding reviews of this collection. Since helminth infections affect human populations particularly in marginalised and low-income regions of the world, they belong to the group of poverty-related infectious diseases, and their alleviation through research, policy, and practice is a sine qua non condition for the achievement of the United Nations Millennium Development Goals. Current efforts supporting research capacity building specifically for the control of helminthiases have been devised and funded, almost in their entirety, by international donor agencies, major funding bodies, and academic institutions from the developed world, contributing to the creation of (not always equitable) North–South “partnerships”. There is an urgent need to shift this paradigm in disease-endemic countries (DECs) by refocusing political will, and harnessing unshakeable commitment by the countries' governments, towards health research and capacity building policies to ensure long-term investment in combating and sustaining the control and eventual elimination of infectious diseases of poverty. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. This paper discusses the challenges confronting capacity building for parasitic disease research in DECs, describes current capacity building strategies with particular reference to neglected tropical diseases and human helminthiases, and outlines recommendations to redress the balance of alliances and partnerships for health research between the developed countries of the “North” and the developing countries of the “South”. We argue that investing in South–South collaborative research policies and capacity is as important as their North–South counterparts and is essential for scaled-up and improved control of helminthic diseases and ultimately for regional elimination.

A Research Agenda for Helminth Diseases of Humans: Social Ecology, Environmental Determinants, and Health Systems

In this paper, the Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), with the mandate to review helminthiases research and identify research priorities and gaps, focuses on the environmental, social, behavioural, and political determinants of human helminth infections and outlines a research and development agenda for the socioeconomic and health systems research required for the development of sustainable control programmes. Using Stockols' social-ecological approach, we describe the role of various social (poverty, policy, stigma, culture, and migration) and environmental determinants (the home environment, water resources development, and climate change) in the perpetuation of helminthic diseases, as well as their impact as contextual factors on health promotion interventions through both the regular and community-based health systems. We examine these interactions in regard to community participation, intersectoral collaboration, gender, and possibilities for upscaling helminthic disease control and elimination programmes within the context of integrated and interdisciplinary approaches. The research agenda summarises major gaps that need to be addressed.

Investing in African research training institutions creates sustainable capacity for Africa: the case of the University of the Witwatersrand School of Public Health masters programme in epidemiology and biostatistics

BackgroundImproving health in Africa is a high priority internationally. Inadequate research capacity to produce local, relevant research has been identified as a limitation to improved population health. Increasing attention is being paid to the higher education sector in Africa as a method of addressing this; evidence that such investment is having the desired impact is required. A 1998 3-year investment by the Special Programme for Research and Training in Tropical Diseases (TDR) in research training at the School of Public Health, University of the Witwatersrand, South Africa was reviewed to assess its' impact.MethodsA descriptive cross-sectional survey of the 70 students registered for the masters programme in epidemiology & biostatistics from 2000-2005 was conducted. Data were collected from self-administered questionnaires.ResultsSixty percent (42/70) of students responded. At the time of the survey 19% of respondents changed their country of residence after completion of the masters course, 14% migrated within Africa and 5% migrated out of Africa. Approximately half (47%) were employed as researchers and 38% worked in research institutions. Sixty percent reported research output, and four graduates were pursuing PhD studies. Government subsidy to higher education institutions, investments of the University of the Witwatersrand in successful programmes and ongoing bursaries for students to cover tuition fees were important for sustainability.ConclusionsInvesting in African institutions to improve research training capacity resulted in the retention of graduates in Africa in research positions and produced research output. Training programmes can be sustained when national governments invest in higher education and where that funding is judiciously applied. Challenges remain if funding for students bursaries is not available.

The Interplay of PPARs with Parasites and Related Intracellular Pathogens

The objective of this special issue is to present current findings on how PPARs can tilt the delicate balance between host defense and parasite survival to affect the outcome of parasitic infections. The volume contains five comprehensive reviews and one original research article that describe the mechanisms of action of PPARs on several parasitic diseases which infect differently. The pathogens include the malaria parasite Plasmodium falciparum which invades hepatocytes and erythrocytes, the Leishmania species which infect macrophages, the intracellular protozoan Trypanosoma cruzi which invades all tissues, and the helminth Schistosoma species, which live in extracellular environment of specific organs. Whereas it is well known that many parasitic diseases are exacerbated by the activation of T helper 2, recent research on the anti-inflammatory alternatively activated macrophage (AAM), which is activated by PPARγ, shows that there is another facet to the host immune response [1]. PPARγ primes the differentiation of macrophages towards AAM rather than the proinflammatory classically activated macrophage (CAM) phenotype, by promoting arginase while suppressing inducible nitric oxide synthase expression. This activity favors the survival of pathogens, which may be susceptible to the free radical nitric oxide. On the other hand, PPARγ activation becomes beneficial to the host in malaria. This special issue presents studies that, timely, characterize the interaction between parasites and these macrophages which express the PPAR nuclear factors. Malaria is the most devastating among diseases of parasitic protozoa. L. Serghides explains how PPAR agonists relieve immunopathology in cerebral malaria. PPARγ-mediated transcription of CD36, a scavenger receptor which enhances phagocytosis and facilitates the removal of parasitized erythrocytes, leads to reduced parasitemia. In addition, the anti-inflammatory action of PPARγ protects the central nervous system from inflammation-mediated destruction. Y. Ren concurs that the strategy to augment the upregulation of CD36 is potentially therapeutic. Using PPARγ agonist rosiglitazone as adjunctive therapy during treatment of cerebral malaria has successfully gone through phase I/IIa trial in Thailand and now awaits a final randomized double-blind placebo-controlled clinical trial. On the contrary, PPAR activation may benefit the parasite in other infections. For protozoan parasites, trypanosomatids set as examples. M. Chan et al. describe how the activation of PPARα and PPARγ by cutaneous and visceral Leishmania species may promote their survival within macrophages. E. Hovsepian et al. also discuss how Trypanosoma cruzi-mediated PPAR activation influences intracellular parasite survival. For metazoan parasites, B. Anthony et al. review how the Schistosoma species activate PPARα, PPARγ, and AAM to potentiate survival. The PPARγ agonist rosiglitazone has been shown to possess anti-inflammatory, neuroprotective and neuroregenerative properties. However, although rosiglitazone (drug name Avandia, from GlaxoSmithKline) is still being used to treat type 2 diabetes in the United States, the drug is withdrawn in Europe because of adverse effects, especially to the heart. Pioglitazone may be a better alternative. Extending from rosiglitazone and PPARγ, K. Chen et al. report the protective activity of Wy14643, an agonist of PPARα, the isoform prevalent in the liver, towards hypoxia reoxygenation injury in rodent hepatocytes. Many parasitic diseases are widespread in developing countries. Historically, they have been regarded as “neglected tropical diseases” [2]. With parasitic infections being increasingly diagnosed in developed countries due to global travel and immigration, their control is being pursued by many investigators [3, 4]. Public and private agencies, such as TDR, Special Programme for Research and Training in Tropical Diseases of World Health Organization, and Bill & Melinda Gates Foundation, using arrangements such as public-private partnerships, are determined to target such diseases of poverty. Scientists from many countries are actively researching various aspects of parasitic diseases. With this background, we sincerely thank the international cast of scientists who have contributed to this special issue on PPARs and parasites. They come from different countries: Argentina, Australia, Canada, China, United Kingdom, and United States, covering the continents Australia, Europe, North, and South America. In summary, this special issue provides a glimpse of our contemporary understanding on PPAR involvement in parasitic diseases. Different angles have been explored, for example, while PPAR agonists may decrease immunopathology of cerebral malaria, they may enhance parasite survival in leishmaniasis. We hope the readers will find this special issue of PPAR Research informative and will be inspired to make their own contributions to the challenge our world faces from the diverse parasitic infections.

The TDR Tuberculosis Strain Bank: a resource for basic science, tool development and diagnostic services

The Special Programme for Research and Training in Tropical Diseases recently launched a Mycobacterium tuberculosis strain bank (TDR-TB Strain Bank). To describe the TDR-TB Strain Bank, the characterisation of strains, bank management and the procedure for releasing materials. The TDR-TB Strain Bank consists of 229 clinical M. tuberculosis isolates (single-colony derived cultures) plus five mycobacterial reference strains for purposes of identification. These are available as freeze-dried, viable strains or as heat-inactivated bacterial suspensions, quality controlled for purity, viability and authenticity. Isolates originated from diverse geographical settings and were selected for their resistance profiles against first- and second-line drugs. Low and high levels of resistance were determined by the minimum inhibitory concentrations of isoniazid, rifampicin, ethambutol, streptomycin, ofloxacin, kanamycin, capreomycin, ethionamide and para-aminosalicylic acid. Sequencing for drug resistance mutations was performed on the relevant sections of the rpoB, katG, inhA, embB, rpsL, rrs, gyrA and gyrB genes. Typing using lineage-defining loci of mycobacterial interspersed repetitive unit-variable number tandem repeats indicated that the most important genetic lineages were represented. The TDR-TB Strain Bank is a high quality bioresource for basic science, supporting the development of new diagnostics and drug-resistant detection tools and providing reference materials for laboratory quality management programmes.

Impact of Health Research Capacity Strengthening in Low- and Middle-Income Countries: The Case of WHO/TDR Programmes

BackgroundMeasuring the impact of capacity strengthening support is a priority for the international development community. Several frameworks exist for monitoring and evaluating funding results and modalities. Based on its long history of support, we report on the impact of individual and institutional capacity strengthening programmes conducted by the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) and on the factors that influenced the outcome of its Research Capacity Strengthening (RCS) activities.Methodology and Principal FindingsA mix of qualitative and quantitative methods (questionnaires and in-depth interviews) was applied to a selected group of 128 individual and 20 institutional capacity development grant recipients that completed their training/projects between 2000 and 2008. A semi-structured interview was also conducted on site with scientists from four institutions. Most of the grantees, both individual and institutional, reported beneficial results from the grant. However, glaring inequities stemming from gender imbalances and a language bias towards English were identified. The study showed that skills improvement through training contributed to better formulation of research proposals, but not necessarily to improved project implementation or communication of results. Appreciation of the institutional grants' impact varied among recipient countries. The least developed countries saw the programmes as essential for supporting basic infrastructure and activities. Advanced developing countries perceived the research grants as complementary to available resources, and particularly suitable for junior researchers who were not yet able to compete for major international grants.ConclusionThe study highlights the need for a more equitable process to improve the effectiveness of health research capacity strengthening activities. Support should be tailored to the existing research capacity in disease endemic countries and should focus on strengthening national health research systems, particularly in the least developing countries. The engagement of stakeholders at country level would facilitate the design of more specific and comprehensive strategies based on local needs.

Innovative Partnerships for Drug Discovery against Neglected Diseases

Innovative Partnerships for Drug Discovery against Neglected Diseases

Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis.

We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than that of the tuberculin skin test (TST). Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals. 15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2-6), even in IGRA-positive individuals, was 4-48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42-3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 [95% CI 1·29-3·46] for IGRA vs 1·60 [0·94-2·72] for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals. Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients' preferences rather than on predictive ability alone. Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.

The Struggle of Neglected Scientific Groups: Ten Years of NeTropica Efforts to Promote Research in Tropical Diseases in Central America

The general strategy used by high-income countries to address global health challenges in low- and middle-income countries (LMICs) relies heavily on short-term strategies designed to diminish the burden of diseases afflicting the populations of those countries. Thanks to the support and funding of international agencies, in many cases these initiatives have resulted in health improvements. However, in order to have a sustainable impact on the public health of LMICs, “vibrant local scientific communities” need to be implemented in parallel efforts [1]. In this article we describe 10 years of activities of the Network for Research and Training in Tropical Diseases in Central America (NeTropica), aimed to develop a competitive Central American scientific community in the field of tropical diseases, with the assistance of the Swedish International Development Cooperation Agency (SIDA) and the participation of the public universities of Central America (CA).

Perspective: Postearthquake Haiti Renews the Call for Global Health Training in Medical Education

On January 12, 2010, Haiti experienced one of the worst disasters in human history, a magnitude 7.0 earthquake, resulting in the deaths of approximately 222,000 Haitians and grievous injury to hundreds of thousands more. International agencies, academic institutions, nongovernmental organizations, and associations responded by sending thousands of medical professionals, including nurses, doctors, medics, and physical therapists, to support the underresourced Haitian health system. The volunteers who came to provide medical care to disaster victims worked tirelessly under extremely challenging conditions, but in many cases they had no previous work experience in resource-limited settings, minimal training in tropical disease, and no knowledge of the historical background that contributed to the catastrophe. Often, this lack of preparedness hindered their ability to care adequately for their patients. The authors of this perspective argue that the academic medicine community must prepare medical trainees not only to treat the illnesses of patients in resource-limited settings but also to fight the injustice that fosters disease and allows such catastrophes to unfold. The authors advocate purposeful attention to building global health curricula; providing adequate time, funding, and opportunity to work in resource-limited international settings; and ensuring sufficient supervision for trainees to work safely. They also call for an interdisciplinary approach to global health that both affirms health care as a fundamental human right and explores the historical, economic, and political causes of inequitable health care.

Zoonoses and marginalised infectious diseases of poverty: where do we stand?

Despite growing awareness of the importance of controlling neglected tropical diseases as a contribution to poverty alleviation and achieving the Millennium Development Goals, there is a need to up-scale programmes to achieve wider public health benefits. This implementation deficit is attributable to several factors but one often overlooked is the specific difficulty in tackling diseases that involve both people and animals - the zoonoses. A Disease Reference Group on Zoonoses and Marginalised Infectious Diseases (DRG6) was convened by the Special Programme for Research and Training in Tropical Diseases (TDR), a programme executed by the World Health Organization and co-sponsored by UNICEF, UNDP, the World Bank and WHO. The key considerations included: (a) the general lack of reliable quantitative data on their public health burden; (b) the need to evaluate livestock production losses and their additional impacts on health and poverty; (c) the relevance of cross-sectoral issues essential to designing and implementing public health interventions for zoonotic diseases; and (d) identifying priority areas for research and interventions to harness resources most effectively. Beyond disease specific research issues, a set of common macro-priorities and interventions were identified which, if implemented through a more integrated approach by countries, would have a significant impact on human health of the most marginalised populations characteristically dependent on livestock.