Lymphatic filariasis and Brugia timori: prospects for elimination

Brugia timori is a pathogenic filarial nematode of humans, replacing the closely related species Brugia malayi on some islands in eastern Indonesia. Recent studies on Alor island show that, locally, B. timori is still of great public health importance, causing mainly acute filarial fever and chronic lymphedema. PCR-based assays to detect parasite DNA, in addition to assays for detecting specific antibodies that have been originally developed for B. malayi, can be used efficiently as diagnostic tools for B. timori. In the framework of the Global Program to Eliminate Lymphatic Filariasis, a single annual dose of diethylcarbamazine, in combination with albendazole, was found to reduce the prevalence and density of microfilaraemia persistently. Therefore, elimination of B. timori appears to be achievable.     

Lymphatic filariasis elimination in the Dominican Republic: History,progress, and remaining steps

Lymphatic filariasis (LF) is a mosquito-transmitted parasitic disease that is a leading cause of disability globally. The island of Hispaniola, which the Dominican Republic shares with Haiti, accounts for approximately 90% of LF cases in the Americas region. In 1998, the Dominican Ministry of Public Health created the Program to Eliminate Lymphatic Filariasis (PELF) with the goal of eliminating LF transmission by 2020. Baseline mapping revealed 19 (12% of total) endemic municipalities clustered into three geographic foci (Southwest, La Ciénaga and East), with a total at-risk population of 262,395 people. Beginning in 2002, PELF sequentially implemented mass drug administration (MDA) in these foci using albendazole and diethylcarbamazine (DEC). In total, 1,174,050 treatments were given over three to five annual rounds of house-to-house MDA per focus with a median coverage of 81.7% (range 67.4%–92.2%). By 2018, LF antigen prevalence was less than 2% in all foci, thus meeting criteria to stop MDA and begin post-treatment surveillance (PTS). This success has been achieved against a shifting landscape of limited domestic funding, competing domestic public health priorities, and sporadic external donor support. Remaining steps include the need to scale-up morbidity management and disability prevention services for LF and to continue PTS until LF transmission is interrupted across Hispaniola.     

Lymphatic filariasis elimination in the Pacific: PacELF replicating Japanese success

Japan successfully eliminated lymphatic filariasis and other parasitic diseases through community-driven, integrated nationwide campaigns undertaken during the 1960s and 1970s. The campaigns also created a cadre of experienced clinicians, scientists and public health workers with excellent technical and operational knowledge and a positive attitude towards filariasis elimination. These factors, and the humanitarian desire to improve health in neighbouring nations, influenced Japan to support filariasis control efforts overseas, starting in the 1970s and continuing through to the inception of the Pacific Programme to Eliminate Lymphatic Filariasis (PacELF) in 1999. The unique community-driven, self-help approach of Japan to disease control and health improvement profoundly influenced the activities of PacELF. PacELF is demonstrating that the successful national disease-elimination model in Japan can be extended to the regional level.     

Haemophilus ducreyi: clinical features,epidemiology, and prospects for disease control

Haemophilus ducreyi is the causative agent of the genital ulcer disease chancroid. Chancroid is common in developing countries and facilitates human immunodeficiency virus transmission. In this review, the clinical features, epidemiology, and prospects for disease control are discussed in the context of experimental and natural infection of humans.     

Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects

The prognosis of patients with systemic lupus erythematosus has greatly improved since treatment regimens combining corticosteroids and immunosuppressive medications have been widely adopted in therapeutic strategies given to these patients. Immune suppression is evidently efficient but also leads to higher susceptibility to infectious and malignant diseases. Toxic effects and sometimes unexpectedly dramatic complications of current therapies have been progressively reported. Identifying novel molecular targets therefore remains an important issue in the treatment of lupus. The aim of this review article is to highlight emerging pharmacological options and new therapeutic avenues for lupus with a particular focus on non-antibody molecular strategies.     

ECVAM-ICCVAM: prospects for future collaboration

The level and complexity of testing for hazard and risk assessment of marketed products and environmental agents has increased substantially over time, resulting in the use of greater numbers of both animals and humans for testing. Today, industry and regulatory bodies worldwide face increasing pressures to demonstrate responsible utilisation of laboratory animals, to limit their use, and to employ alternative non-animal tests. Institutions have also been established to identify, encourage development of, conduct research on, and validate new, improved, and surrogate test methods that will reduce and replace animal use. Two such organisations are ECVAM and the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM). As the evolutionary changes occurring in the field of toxicology result in an unprecedented increase in the introduction of alternative methodologies, these will strain the capacities of such alternative methods institutions. That realisation is causing a shift in thinking and creating an impetus to seek approaches by which to collaborate and develop more-efficient operational procedures for the validation and regulatory acceptance of alternative methods. Similarities in objectives, functions, scientific standards, and commitment to the principles of validation and animal welfare support the value of a cooperative arrangement between ECVAM and ICCVAM, to minimise duplication of effort, maximise productivity, and influence the international adoption of alternative tests. Opportunities for ECVAM-ICCVAM collaboration are discussed, which illustrate the feasibility and potential benefits of such a partnership.     

Early clinical features of dengue virus infection in nicaraguan children: a longitudinal analysis

Background

Tens of millions of dengue cases and approximately 500,000 life-threatening complications occur annually. New tools are needed to distinguish dengue from other febrile illnesses. In addition, the natural history of pediatric dengue early in illness in a community-based setting has not been well-defined.

Methods

Data from the multi-year, ongoing Pediatric Dengue Cohort Study of approximately 3,800 children aged 2–14 years in Managua, Nicaragua, were used to examine the frequency of clinical signs and symptoms by day of illness and to generate models for the association of signs and symptoms during the early phase of illness and over the entire course of illness with testing dengue-positive. Odds ratios (ORs) and 95% confidence intervals were calculated using generalized estimating equations (GEE) for repeated measures, adjusting for age and gender.

Results

One-fourth of children who tested dengue-positive did not meet the WHO case definition for suspected dengue. The frequency of signs and symptoms varied by day of illness, dengue status, and disease severity. Multivariable GEE models showed increased odds of testing dengue-positive associated with fever, headache, retro-orbital pain, myalgia, arthralgia, rash, petechiae, positive tourniquet test, vomiting, leukopenia, platelets ≤150,000 cells/mL, poor capillary refill, cold extremities and hypotension. Estimated ORs tended to be higher for signs and symptoms over the course of illness compared to the early phase of illness.

Conclusions

Day-by-day analysis of clinical signs and symptoms together with longitudinal statistical analysis showed significant associations with testing dengue-positive and important differences during the early phase of illness compared to the entire course of illness. These findings stress the importance of considering day of illness when developing prediction algorithms for real-time clinical management.     

Cocoa biotechnology: status, constraints and future prospects

Current status and future prospects of cocoa biotechnology are reviewed. Potential for improving and modifying cocoa bean yield and quality are discussed. Prospects for producing cocoa components in vitro and cocoa butter substitutes in crops other than cocoa are examined. Application of complementary research tools is expected to allow significant enhancements in cocoa bean yield. Furthermore, cocoa varieties with modified characteristics are likely to become available, in particular varieties with increased cocoa butter content and modified fatty acid patterns. In vitro production of cocoa components is less likely.     

Biology of cord blood cells and future prospects for enhanced clinical benefit

Cord blood (CB) has served as a clinically beneficial source of hematopoietic stem (HSC) and progenitor (HPC) cells for transplantation and correction of a large number of malignant and non-malignant disorders. The capacity of CB to perform these functions is intimately related to the quality and quantity of HSC and HPC present in CB. This review covers the biology of HSC and HPC, efforts to expand these cells ex vivo for enhanced clinical utility that has thus far not been very successful, and recent studies on attempts to enhance the homing and engrafting capability of HSC as an alternative means for more effective use of the limited numbers of CB cells collected. This review also highlights the presence in CB of mesenchymal stem cells, unrestricted somatic stem cells, endothelial progenitor cells and immune cells. The presence and biology of these non-HSC/HPC may open up future possibilities for additional clinical benefit of CB, a product considered mainly for discard before its clinical transplantation potential was realized in the late 1980s.     

Veterinary endectocides for malaria control and elimination: prospects and challenges

Residual transmission is the persistence of malaria transmission after scale-up of appropriate vector control tools and is one of the key challenges for malaria elimination today. Although long associated with outdoor biting, other mosquito behaviours such as partly feeding upon animals contribute greatly to sustaining transmission. Peri-domestic livestock can be used as decoy to protect humans from blood-seeking vectors but this approach often leads to an increased malaria risk in a phenomenon known as zoopotentiation. Treating the said livestock with drugs capable of killing intestinal parasites as well as mosquitoes that feed upon them has the potential to tackle malaria through a previously unexplored mechanism. The advantages and challenges associated with this approach are briefly discussed here. Numerous references are purposely provided.This article is part of the theme issue ‘Novel control strategies for mosquito-borne diseases’.     

CRISPR screens in plants: approaches,guidelines, and future prospects

Clustered regularly interspaced short palindromic repeat (CRISPR)-associated systems have revolutionized genome engineering by facilitating a wide range of targeted DNA perturbations. These systems have resulted in the development of powerful new screens to test gene functions at the genomic scale. While there is tremendous potential to map and interrogate gene regulatory networks at unprecedented speed and scale using CRISPR screens, their implementation in plants remains in its infancy. Here we discuss the general concepts, tools, and workflows for establishing CRISPR screens in plants and analyze the handful of recent reports describing the use of this strategy to generate mutant knockout collections or to diversify DNA sequences. In addition, we provide insight into how to design CRISPR knockout screens in plants given the current challenges and limitations and examine multiple design options. Finally, we discuss the unique multiplexing capabilities of CRISPR screens to investigate redundant gene functions in highly duplicated plant genomes. Combinatorial mutant screens have the potential to routinely generate higher-order mutant collections and facilitate the characterization of gene networks. By integrating this approach with the numerous genomic profiles that have been generated over the past two decades, the implementation of CRISPR screens offers new opportunities to analyze plant genomes at deeper resolution and will lead to great advances in functional and synthetic biology.

Advances in CRISPR screening techniques in plants offer new opportunities to analyze plant genomes at higher resolution and scale and will greatly enhance functional and synthetic biology studies.     

Livestock production: recent trends, future prospects

The livestock sector globally is highly dynamic. In developing countries, it is evolving in response to rapidly increasing demand for livestock products. In developed countries, demand for livestock products is stagnating, while many production systems are increasing their efficiency and environmental sustainability. Historical changes in the demand for livestock products have been largely driven by human population growth, income growth and urbanization and the production response in different livestock systems has been associated with science and technology as well as increases in animal numbers. In the future, production will increasingly be affected by competition for natural resources, particularly land and water, competition between food and feed and by the need to operate in a carbon-constrained economy. Developments in breeding, nutrition and animal health will continue to contribute to increasing potential production and further efficiency and genetic gains. Livestock production is likely to be increasingly affected by carbon constraints and environmental and animal welfare legislation. Demand for livestock products in the future could be heavily moderated by socio-economic factors such as human health concerns and changing socio-cultural values. There is considerable uncertainty as to how these factors will play out in different regions of the world in the coming decades.     

Geographic and ecologic heterogeneity in elimination thresholds for the major vector-borne helminthic disease,lymphatic filariasis

Background

Large-scale intervention programmes to control or eliminate several infectious diseases are currently underway worldwide. However, a major unresolved question remains: what are reasonable stopping points for these programmes? Recent theoretical work has highlighted how the ecological complexity and heterogeneity inherent in the transmission dynamics of macroparasites can result in elimination thresholds that vary between local communities. Here, we examine the empirical evidence for this hypothesis and its implications for the global elimination of the major macroparasitic disease, lymphatic filariasis, by applying a novel Bayesian computer simulation procedure to fit a dynamic model of the transmission of this parasitic disease to field data from nine villages with different ecological and geographical characteristics. Baseline lymphatic filariasis microfilarial age-prevalence data from three geographically distinct endemic regions, across which the major vector populations implicated in parasite transmission also differed, were used to fit and calibrate the relevant vector-specific filariasis transmission models. Ensembles of parasite elimination thresholds, generated using the Bayesian fitting procedure, were then examined in order to evaluate site-specific heterogeneity in the values of these thresholds and investigate the ecological factors that may underlie such variability

Results

We show that parameters of density-dependent functions relating to immunity, parasite establishment, as well as parasite aggregation, varied significantly between the nine different settings, contributing to locally varying filarial elimination thresholds. Parasite elimination thresholds predicted for the settings in which the mosquito vector is anopheline were, however, found to be higher than those in which the mosquito is culicine, substantiating our previous theoretical findings. The results also indicate that the probability that the parasite will be eliminated following six rounds of Mass Drug Administration with diethylcarbamazine and albendazole decreases markedly but non-linearly as the annual biting rate and parasite reproduction number increases.

Conclusions

This paper shows that specific ecological conditions in a community can lead to significant local differences in population dynamics and, consequently, elimination threshold estimates for lymphatic filariasis. These findings, and the difficulty of measuring the key local parameters (infection aggregation and acquired immunity) governing differences in transmission thresholds between communities, mean that it is necessary for us to rethink the utility of the current anticipatory approaches for achieving the elimination of filariasis both locally and globally.

     

Legume-nodulating betaproteobacteria: diversity, host range, and future prospects

Rhizobia form specialized nodules on the roots of legumes (family Fabaceae) and fix nitrogen in exchange for carbon from the host plant. Although the majority of legumes form symbioses with members of genus Rhizobium and its relatives in class Alphaproteobacteria, some legumes, such as those in the large genus Mimosa, are nodulated predominantly by betaproteobacteria in the genera Burkholderia and Cupriavidus. The principal centers of diversity of these bacteria are in central Brazil and South Africa. Molecular phylogenetic studies have shown that betaproteobacteria have existed as legume symbionts for approximately 50 million years, and that, although they have a common origin, the symbiosis genes in both subclasses have evolved separately since then. Additionally, some species of genus Burkholderia, such as B. phymatum, are highly promiscuous, effectively nodulating several important legumes, including common bean (Phaseolus vulgaris). In contrast to genus Burkholderia, only one species of genus Cupriavidus (C. taiwanensis) has so far been shown to nodulate legumes. The recent availability of the genome sequences of C. taiwanensis, B. phymatum, and B. tuberum has paved the way for a more detailed analysis of the evolutionary and mechanistic differences between nodulating strains of alpha- and betaproteobacteria. Initial analyses of genome sequences have suggested that plant-associated Burkholderia spp. have lower G+C contents than Burkholderia spp. that are opportunistic human pathogens, thus supporting previous suggestions that the plant- and human-associated groups of Burkholderia actually belong in separate genera.     

Achievements and challenges of lymphatic filariasis elimination in Sierra Leone

BackgroundLymphatic filariasis (LF) is targeted for elimination in Sierra Leone. Epidemiological coverage of mass drug administration (MDA) with ivermectin and albendazole had been reported >65% in all 12 districts annually. Eight districts qualified to implement transmission assessment survey (TAS) in 2013 but were deferred until 2017 due to the Ebola outbreak (2014–2016). In 2017, four districts qualified for conducting a repeat pre-TAS after completing three more rounds of MDA and the final two districts were also eligible to implement a pre-TAS.Methodology/Principal findingsFor TAS, eight districts were surveyed as four evaluation units (EU). A school-based survey was conducted in children aged 6–7 years from 30 clusters per EU. For pre-TAS, one sentinel and one spot check site per district (with 2 spot check sites in Bombali) were selected and 300–350 persons aged 5 years and above were selected. For both surveys, finger prick blood samples were tested using the Filariasis Test Strips (FTS).For TAS, 7,143 children aged 6–7 years were surveyed across four EUs, and positives were found in three EUs, all below the critical cut-off value for each EU. For the repeat pre-TAS/pre-TAS, 3,994 persons over five years of age were surveyed. The Western Area Urban had FTS prevalence of 0.7% in two sites and qualified for TAS, while other five districts had sites with antigenemia prevalence >2%: 9.1–25.9% in Bombali, 7.5–19.4% in Koinadugu, 6.1–2.9% in Kailahun, 1.3–2.3% in Kenema and 1.7% - 3.7% in Western Area Rural.Conclusions/SignificanceEight districts in Sierra Leone have successfully passed TAS1 and stopped MDA, with one more district qualified for conducting TAS1, a significant progress towards LF elimination. However, great challenges exist in eliminating LF from the whole country with repeated failure of pre-TAS in border districts. Effort needs to be intensified to achieve LF elimination.