Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations

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

Functional Diffusion Tensor Imaging: Measuring Task-Related Fractional Anisotropy Changes in the Human Brain along White Matter Tracts

Functional neural networks in the human brain can be studied from correlations between activated gray matter regions measured with fMRI. However, while providing important information on gray matter activation, no information is gathered on the co-activity along white matter tracts in neural networks.We report on a functional diffusion tensor imaging (fDTI) method that measures task-related changes in fractional anisotropy (FA) along white matter tracts. We hypothesize that these fractional anisotropy changes relate to morphological changes of glial cells induced by axonal activity although the exact physiological underpinnings of the measured FA changes remain to be elucidated. As expected, these changes are very small as compared to the physiological noise and a reliable detection of the signal change would require a large number of measurements. However, a substantial increase in signal-to-noise ratio was achieved by pooling the signal over the complete fiber tract. Adopting such a tract-based statistics enabled us to measure the signal within a practically feasible time period. Activation in the sensory thalamocortical tract and optic radiation in eight healthy human subjects was found during tactile and visual stimulation, respectively.The results of our experiments indicate that these FA changes may serve as a functional contrast mechanism for white matter. This noninvasive fDTI method may provide a new approach to study functional neural networks in the human brain

Using computer decision support systems in NHS emergency and urgent care: ethnographic study using normalisation process theory

Background: information and communication technologies (ICTs) are often proposed as ‘technological fixes’ for problems facing healthcare. They promise to deliver services more quickly and cheaply. Yet research on the implementation of ICTs reveals a litany of delays, compromises and failures. Case studies have established that these technologies are difficult to embed in everyday healthcare.Methods: we undertook an ethnographic comparative analysis of a single computer decision support system in three different settings to understand the implementation and everyday use of this technology which is designed to deal with calls to emergency and urgent care services. We examined the deployment of this technology in an established 999 ambulance call-handling service, a new single point of access for urgent care and an established general practice out-of-hours service. We used Normalization Process Theory as a framework to enable systematic cross-case analysis.Results: our data comprise nearly 500 hours of observation, interviews with 64 call-handlers, and stakeholders and documents about the technology and settings. The technology has been implemented and is used distinctively in each setting reflecting important differences between work and contexts. Using Normalisation Process Theory we show how the work (collective action) of implementing the system and maintaining its routine use was enabled by a range of actors who established coherence for the technology, secured buy-in (cognitive participation) and engaged in on-going appraisal and adjustment (reflexive monitoring).Conclusions: huge effort was expended and continues to be required to implement and keep this technology in use. This innovation must be understood both as a computer technology and as a set of practices related to that technology, kept in place by a network of actors in particular contexts. While technologies can be ‘made to work’ in different settings, successful implementation has been achieved, and will only be maintained, through the efforts of those involved in the specific settings and if the wider context continues to support the coherence, cognitive participation, and reflective monitoring processes that surround this collective action. Implementation is more than simply putting technologies in place – it requires new resources and considerable effort, perhaps on an on-going basis