68 research outputs found

    Genetic Selection of Low Fertile Onchocerca volvulus by Ivermectin Treatment

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    Onchocerca volvulus is the causative agent of onchocerciasis, or “river blindness”. Ivermectin has been used for mass treatment of onchocerciasis for up to 18 years, and recently there have been reports of poor parasitological responses to the drug and evidence of drug resistance. Drug resistance has a genetic basis. In this study, genetic changes in ÎČ-tubulin, a gene associated with ivermectin resistance in nematodes, were seen in parasites obtained from the patients exposed to repeated ivermectin treatment compared with parasites obtained from the same patients before any exposure to ivermectin. Furthermore, the extent of the genetic changes was dependent on the level of ivermectin treatment exposure. This genetic selection was associated with a lower reproductive rate in the female parasites. The data indicates that this genetic selection is for a population of O. volvulus that is more tolerant to ivermectin. This selection could have implications for the development of ivermectin resistance in O. volvulus and for the ongoing onchocerciasis control programmes. Monitoring for the possible development and spread of ivermectin resistance, as part of the control programmes, should be implemented so that any foci of resistant parasites can be treated by alternative control measures

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

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    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

    A Multicenter Evaluation of Diagnostic Tools to Define Endpoints for Programs to Eliminate Bancroftian Filariasis

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    Successful mass drug administration (MDA) campaigns have brought several countries near the point of Lymphatic Filariasis (LF) elimination. A diagnostic tool is needed to determine when the prevalence levels have decreased to a point that MDA campaigns can be discontinued without the threat of recrudescence. A six-country study was conducted assessing the performance of seven diagnostic tests, including tests for microfilariae (blood smear, PCR), parasite antigen (ICT, Og4C3) and antifilarial antibody (Bm14, PanLF, Urine SXP). One community survey and one school survey were performed in each country. A total of 8,513 people from the six countries participated in the study, 6,443 through community surveys and 2,070 through school surveys. Specimens from these participants were used to conduct 49,585 diagnostic tests. Each test was seen to have both positive and negative attributes, but overall, the ICT test was found to be 76% sensitive at detecting microfilaremia and 93% specific at identifying individuals negative for both microfilariae and antifilarial antibody; the Og4C3 test was 87% sensitive and 95% specific. We conclude, however, that the ICT should be the primary tool recommended for decision-making about stopping MDAs. As a point-of-care diagnostic, the ICT is relatively inexpensive, requires no laboratory equipment, has satisfactory sensitivity and specificity and can be processed in 10 minutes—qualities consistent with programmatic use. Og4C3 provides a satisfactory laboratory-based diagnostic alternative

    Cyborg practices: call-handlers and computerised decision support systems in urgent and emergency care

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    This article draws on data collected during a 2-year project examining the deployment of a computerised decision support system. This computerised decision support system was designed to be used by non-clinical staff for dealing with calls to emergency (999) and urgent care (out-of-hours) services. One of the promises of computerised decisions support technologies is that they can 'hold' vast amounts of sophisticated clinical knowledge and combine it with decision algorithms to enable standardised decision-making by non-clinical (clerical) staff. This article draws on our ethnographic study of this computerised decision support system in use, and we use our analysis to question the 'automated' vision of decision-making in healthcare call-handling. We show that embodied and experiential (human) expertise remains central and highly salient in this work, and we propose that the deployment of the computerised decision support system creates something new, that this conjunction of computer and human creates a cyborg practice. <br/

    The remarkable invisibility of NHS 111 online

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    In 2017, the NHS 111 telephone service was augmented by an online service. This is an exemplar of ‘digital-first’, the push to enrol digital technologies to deliver services, and is viewed by policymakers as an important vehicle for managing demand for overburdened health services. This article reports the qualitative component of a larger multi-method study of NHS 111 online. Qualitative telephone interviews with 80 staff and stakeholders implicated in primary, urgent and emergency care service delivery explored the impact of NHS 111 online on health-care work. The analysis presented here draws on Susie Scott’s work on the ‘sociology of nothing’ and theories of the marked and unmarked, which we reached for when confronted by the remarkable invisibility of this seemingly core NHS service in the wider landscape of health care. Despite the apparently high use by patients and the public (30 million visits over 6 months in the 2020 pandemic), we were surprised to find very low awareness among our interviewees. Confusion about nomenclature, an exceedingly crowded digital field (littered with alternative technologies and ways of accessing care) and constant change in service provision provide some cogent reasons for this invisibility, and sociology helps explain our data about this digital technology.</p

    Risk work in NHS 111:: the everyday work of managing risk in telephone assessment using a computer decision support system

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    The substitution of clinical with non-clinical staff to triage and manage calls in the NHS urgent care services is one of the number of measures designed to meet growing health services demand. The deployment of a Computer Decision Support System ‘NHS Pathways’to support this work has created a new type of health worker and a new form of risk work. In this article, we examine how call handlers manage, experience and respond to risk in their everyday practice of telephone assessment. We draw on data from an ethnographic study of 5 NHS 111 sites involving 356 h of observation plus 6 focus groups with 47 health services staff in 2011–2012. We found that there was a‘risk problem’involving balancing the competing demands of asses- sing patients safely against rationing limited health resources. The new service used technology to support risk management but this technology also created risk work for call handlers, clinicians and patients. We found that call handlers engaged in risk work that involved interpretation, judgement and flexibility in using NHS Pathways. Call handlers also deferred some risk work to both clinicians and patients/callers. Risk work now involves‘making the technology work’and much of this work has been delegated to non-clinical call handlers. These new healthcare workers are interpreters of risk. Risk work creates a sense of responsibility (and sometimes anxiety) for these non- clinical call handlers

    Genetic polymorphism in Dirofilaria immitis

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    a b s t r a c t Dirofilaria immitis is the causative agent of heartworm disease. Reports of macrocyclic lactone inefficacy prompted an investigation of genetic polymorphism in D. immitis. Currently, there is a lack of genetic information for this parasite. Information on baseline levels of genetic heterogeneity in the dog heartworm would have important implications for the possible development of macrocyclic lactone resistance in D. immitis. Genetic variability was investigated to assess the extent of genetic polymorphism in D. immitis populations from the USA (field and laboratory samples) and Japan (field samples). Single nucleotide polymorphisms (SNPs) were investigated in a full-length ␀-tubulin gene and segments of genes encoding heat shock protein 60 (Hsp60), a P-glycoprotein (Pgp), sarco-endoplasmic reticulum Ca 2+ ATPase (Serca) and phosphofructokinase (PFK). Significant differences in SNP frequencies were found in all genes except PFK. A combined genotype built from two SNPs from ␀-tubulin, Hsp60, Pgp and Serca was analyzed in the US lab, US field and Japan field samples. Some combined genotypes were unique to each sample group while others were shared between groups. F coefficients calculated for 15 SNPs from ␀-tubulin, Hsp60, Pgp and Serca were not in equilibrium. Differences in F coefficients were observed between the groups. D. immitis was found to be genetically heterogeneous. This genetic heterogeneity has implication for the development of genetically selected strains of the parasite
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