C Smith

Recovery of sperm activity after osmotic shock in the three-spined stickleback: Implications for pre-oviposition ejaculation

Pre-oviposition ejaculation is known to occur in the three-spined stickleback and may help to determine fertilisation success when sperm competition occurs as a consequence of males adopting alternative mating tactics. However, fish sperm typically show a rapid reduction in motility after exposure to fresh water, which would appear to limit the utility of such a strategy. Here, we use computer-assisted sperm analysis (CASA) to examine changes in stickleback sperm motion over time in fresh water, showing for the first time that this reduction in motility can be reversed by an increase in osmolality. We consider the possibility that ovarian fluid may have the same effect, and suggest that pre-oviposition ejaculation may be associated with higher fertilisation success than might otherwise be the case.

Spatial methods for infectious disease outbreak investigations: systematic literature review.

Investigations of infectious disease outbreaks are conventionally framed in terms of person, time and place. Although geographic information systems have increased the range of tools available, spatial analyses are used relatively infrequently. We conducted a systematic review of published reports of outbreak investigations worldwide to estimate the prevalence of spatial methods, describe the techniques applied and explore their utility. We identified 80 reports using spatial methods published between 1979 and 2013, ca 0.4% of the total number of published outbreaks. Environmental or waterborne infections were the most commonly investigated, and most reports were from the United Kingdom. A range of techniques were used, including simple dot maps, cluster analyses and modelling approaches. Spatial tools were usefully applied throughout investigations, from initial confirmation of the outbreak to describing and analysing cases and communicating findings. They provided valuable insights that led to public health actions, but there is scope for much wider implementation and development of new methods.

Twenty years and counting: epidemiology of an outbreak of isoniazid-resistant tuberculosis in England and Wales, 1995 to 2014

An outbreak of isoniazid-resistant tuberculosis first identified in London has now been ongoing for 20 years, making it the largest drug-resistant outbreak of tuberculosis documented to date worldwide. We identified culture-confirmed cases with indistinguishable molecular strain types and extracted demographic, clinical, microbiological and social risk factor data from surveillance systems. We summarised changes over time and used kernel-density estimation and k-function analysis to assess geographic clustering. From 1995 to 2014, 508 cases were reported, with a declining trend in recent years. Overall, 70% were male (n = 360), 60% born in the United Kingdom (n = 306), 39% white (n = 199), and 26% black Caribbean (n = 134). Median age increased from 25 years in the first 5 years to 42 in the last 5. Approximately two thirds of cases reported social risk factors: 45% drug use (n = 227), 37% prison link (n = 189), 25% homelessness (n = 125) and 13% alcohol dependence (n = 64). Treatment was completed at 12 months by 52% of cases (n = 206), and was significantly lower for those with social risk factors (p < 0.05), but increased over time for all patients (p < 0.05). The outbreak remained focused in north London throughout. Control of this outbreak requires continued efforts to prevent and treat further active cases through targeted screening and enhanced case management.

Spatial Targeting for Bovine Tuberculosis Control: Can the Locations of Infected Cattle Be Used to Find Infected Badgers?

Bovine tuberculosis is a disease of historical importance to human health in the UK that remains a major animal health and economic issue. Control of the disease in cattle is complicated by the presence of a reservoir species, the Eurasian badger. In spite of uncertainty in the degree to which cattle disease results from transmission from badgers, and opposition from environmental groups, culling of badgers has been licenced in two large areas in England. Methods to limit culls to smaller areas that target badgers infected with TB whilst minimising the number of uninfected badgers culled is therefore of considerable interest. Here, we use historical data from a large-scale field trial of badger culling to assess two alternative hypothetical methods of targeting TB-infected badgers based on the distribution of cattle TB incidents: (i) a simple circular ‘ring cull’; and (ii) geographic profiling, a novel technique for spatial targeting of infectious disease control that predicts the locations of sources of infection based on the distribution of linked cases. Our results showed that both methods required coverage of very large areas to ensure a substantial proportion of infected badgers were removed, and would result in many uninfected badgers being culled. Geographic profiling, which accounts for clustering of infections in badger and cattle populations, produced a small but non-significant increase in the proportion of setts with TB-infected compared to uninfected badgers included in a cull. It also provided no overall improvement at targeting setts with infected badgers compared to the ring cull. Cattle TB incidents in this study were therefore insufficiently clustered around TB-infected badger setts to design an efficient spatially targeted cull; and this analysis provided no evidence to support a move towards spatially targeted badger culling policies for bovine TB control.

Multiple large clusters of tuberculosis in London: a cross-sectional analysis of molecular and spatial data

Large outbreaks of tuberculosis (TB) represent a particular threat to disease control because they reflect multiple instances of active transmission. The extent to which long chains of transmission contribute to high TB incidence in London is unknown. We aimed to estimate the contribution of large clusters to the burden of TB in London and identify risk factors. We identified TB patients resident in London notified between 2010 and 2014, and used 24-locus mycobacterial interspersed repetitive units–variable number tandem repeat strain typing data to classify cases according to molecular cluster size. We used spatial scan statistics to test for spatial clustering and analysed risk factors through multinomial logistic regression. TB isolates from 7458 patients were included in the analysis. There were 20 large molecular clusters (with n>20 cases), comprising 795 (11%) of all cases; 18 (90%) large clusters exhibited significant spatial clustering. Cases in large clusters were more likely to be UK born (adjusted odds ratio 2.93, 95% CI 2.28–3.77), of black-Caribbean ethnicity (adjusted odds ratio 3.64, 95% CI 2.23–5.94) and have multiple social risk factors (adjusted odds ratio 3.75, 95% CI 1.96–7.16). Large clusters of cases contribute substantially to the burden of TB in London. Targeting interventions such as screening in deprived areas and social risk groups, including those of black ethnicities and born in the UK, should be a priority for reducing transmission. Large clusters contribute substantially to the burden of tuberculosis in London, indicating ongoing transmission http://ow.ly/3xk23068P6w

Incidence and risk factors for drug intolerance and association with incomplete treatment for tuberculosis: analysis of national case registers for England, Wales and Northern Ireland, 2001–2010

Anti-tuberculosis drug regimens are efficacious, but drug intolerance can be severe and may impact on treatment completion rates. The Enhanced Tuberculosis Surveillance (ETS) system is a case register of all new notifications of tuberculosis in England, Wales and Northern Ireland. We conducted a cohort study to estimate the incidence of, and risk factors for, drug intolerance reported through ETS between 2001 and 2010 and to assess its relationship with treatment non-completion. Reports of drug intolerance were found for 868/67 547 (1.28%) patients in the cohort, and important risk factors were female sex, older age, later case report year and white ethnicity. Drug intolerance was associated with an approximate fivefold increased odds of treatment non-completion (p<0.001). These results highlight the need for better-tolerated drug regimens and close case management of patients at risk of drug intolerance to improve treatment completion rates and contribute to more effective disease control.

DotMapper: an open source tool for creating interactive disease point maps

BackgroundMolecular strain typing of tuberculosis isolates has led to increased understanding of the epidemiological characteristics of the disease and improvements in its control, diagnosis and treatment. However, molecular cluster investigations, which aim to detect previously unidentified cases, remain challenging. Interactive dot mapping is a simple approach which could aid investigations by highlighting cases likely to share epidemiological links. Current tools generally require technical expertise or lack interactivity.ResultsWe designed a flexible application for producing disease dot maps using Shiny, a web application framework for the statistical software, R. The application displays locations of cases on an interactive map colour coded according to levels of categorical variables such as demographics and risk factors. Cases can be filtered by selecting combinations of these characteristics and by notification date. It can be used to rapidly identify geographic patterns amongst cases in molecular clusters of tuberculosis in space and time; generate hypotheses about disease transmission; identify outliers, and guide targeted control measures.ConclusionsDotMapper is a user-friendly application which enables rapid production of maps displaying locations of cases and their epidemiological characteristics without the need for specialist training in geographic information systems. Enhanced understanding of tuberculosis transmission using this application could facilitate improved detection of cases with epidemiological links and therefore lessen the public health impacts of the disease. It is a flexible system and also has broad international potential application to other investigations using geo-coded health information.

S29 A randomised controlled trial comparing smartphone enabled remote video observation with direct observation of treatment for tuberculosis

Background Directly observed treatment (DOT) has been the standard of care for tuberculosis since the early 1990s. In England DOT is targeted at those considered to be at high risk of poor adherence and clinically complex patients. We report the first randomised controlled trial of smartphone-enabled video observation of treatment (VOT) for active tuberculosis compared to DOT. Methods Tuberculosis patients eligible for selective DOT in England were randomised to an offer of asynchronous VOT (daily remote observation using a smartphone app) or DOT (3 or 5 times weekly observation in community or clinic settings). Results 58% of 226 randomised patients had a history of homelessness, drug use, imprisonment, alcohol or mental health problems. Of the 112 patients randomised to an offer of VOT, 70% had over 80% of scheduled observations completed over two months (the primary outcome measure) compared to 31% of 114 patients randomised to an offer of DOT (p<0.001). The effect was, in part, due to 51% of those randomised to DOT having less than one week of observation (compared to 10% of those randomised to VOT), and so not starting treatment with their allocated regimen. VOT patients sustained high observation levels throughout treatment, whereas this declined rapidly in DOT patients. We estimate that observation of a six month course of treatment with daily VOT cost £1645 per patient compared to £5700 for five times per week DOT. Conclusions VOT is a more effective and cheaper approach to observation of tuberculosis treatment than clinic or community based DOT.

Development of a novel application for visualising infectious diseases in hospital settings

Abstract Background Whole-genome sequencing, and other molecular methods, can be used to identify potential chains of transmission of infections in hospitals. However, integrating this information with epidemiological data to guide control measures is challenging. We aimed to produce an interactive application for visualisation of hospital infections for use by infection control teams and researchers. Methods We developed this application using Shiny, the web application framework for R. The minimum data set required to run the application comprises admission and sample dates and the ward on which the sample was taken. Optional additional data are dates of patient ward transfers, descriptive patient characteristics including genetically defined clusters, and genetic distances between infections. We demonstrate this application with a case-study of 242 influenza samples from a UK hospital (September, 2012, to March, 2014), which were sequenced as part of the ICONIC project. Findings The application presents three data visualisations: one displays epidemic curves of the numbers of cases of the infection over time, both overall and separately for each ward. Interactive options allow the user to change graph scales and display subsets of the data. The second visualisation is a schematic representation of hospital wards that shows patient locations on a given date. It then highlights epidemiological and genetic links between patients. The third visualisation is an interactive timeline displaying the wards that patients were staying on and on which dates they were likely to be exposed to, or transmitting, an infection. Interpretation This novel application produces visual displays to aid interpretation of complex epidemiological and genomic data in hospital settings. It can be used to highlight areas in a hospital in which infections may have been transmitted, and to trace possible chains of transmission by highlighting patients who share epidemiological or genetic links. Advantages include its user-friendly interface and flexibility for use in any setting with similar data on any pathogen. A challenge is integration with existing hospital systems to facilitate data import, since some expertise is needed to extract appropriately formatted data from hospital systems. Funding Supported by the Health Innovation Challenge Fund (T5-355) (ICONIC), a parallel funding partnership between the Department of Health and the Wellcome Trust.

S88 Neither uk tuberculosis infection testing guideline appears cost-effective in a contemporary hiv infected population

UK guidelines advise testing for latent tuberculosis infection (LTBI) in people with known HIV. Both National Institute for Health and Care Excellence (NICE) 2011 and 2016, and British HIV Association (BHIVA) guidelines use targeted testing, in comparison to those from other countries, notably the United States. None of these have been compared for cost-effectiveness in a contemporary HIV population. We sought to determine the cost-effectiveness of each UK guideline from an NHS perspective, plus alternatives, using prospective data. All patients with a new HIV diagnosis attending an ambulatory HIV clinic, plus a sample of those with known HIV were approached; and offered a symptom questionnaire, chest radiograph (CXR), tuberculin skin test (TST), blood interferon gamma release assay (IGRA) and induced sputum for mycobacterial culture (IS). The uptake and results were used to calculate the cost-effectiveness of thirty different testing strategies using univariate, multivariate and probabilistic sensitivity analyses (PSA). 219 subjects, representative of the total clinic population, took part. 73% were male, 28% black African and 95% on antiretroviral therapy (ART). During testing, 2 cases (0.9%) of subclinical TB and 14 (6%) of LTBI were detected. Half the patients with LTBI completed preventive treatment. Over a median of 28 months follow up, no new cases of active TB were identified. When compared to no testing, only three of the thirty strategies were below the maximum NICE threshold for cost-effectiveness <£30,000/QALY gained. Testing black Africans with just TST or IGRA cost £23,429/QALY and £28,971/QALY respectively, whilst testing black Africans plus those from countries with a TB incidence of >20/100,000 (‘middle incidence’, MI) cost £25,218/QALY and £32,410/QALY using TST alone or IGRA alone respectively. NICE, BHIVA, or more extensive strategies, were not cost-effective. (Table) Using PSA, no testing was most likely cost-effective up to £30,000/QALY. In a contemporary HIV population with very high uptake of ART, neither current UK guideline is cost-effective. Testing black Africans, or black Africans and people from middle TB incidence countries appear at best marginally cost-effective. Future UK guidance needs to reflect changing health demographics, improved outcomes for people in HIV care, and clinical pragmatism. Abstract S88 Table 1 Costs for selected strategies, discounted cost/case prevented and cost/QALY gained compared to no testing and last (non-dominated) strategy Strategy Total cost of strategy per 10,000 people living with HIV Cases TB prevented (discounted) QALYs gained compared to no testing (discounted) Cost/case averted Cost/QALY compared to no testing Incremental cost/QALY compared to last strategy BHIVA 2011 £749,274 2.28 1.28 £21,371 £37,952 EXTENDED DOMINANCE TST in BA £749,660 3.9 2.09 £12,566 £23,429 £23,429 TST in BA and MI £761,797 4.49 2.43 £13,614 £25,218 EXTENDED DOMINANCE NICE 2011 £788,037 1.11 0.63 £78,429 £139,281 DOMINATED IGRA in BA £812,048 6.83 3.85 £16,314 £28,971 EXTENDED DOMINANCE IGRA in BA and MI £865,959 9.06 5.1 £18,250 £32,410 EXTENDED DOMINANCE IGRA in all £1,056,702 10.17 5.72 £35,030 £62,209 EXTENDED DOMINANCE NICE 2016 £1,058,522 10.17 5.72 £35,234 £62,571 DOMINATED TST&IGRA in all £1,219,154 10.99 5.88 £47,166 £88,139 EXTENDED DOMINANCE TST&IGRA&CXR&IS in all £1,999,789 20.58 10.44 £63,142 £124,393 EXTENDED DOMINANCE BA - Black African, BHIVA – British HIV Association, CXR – chest X ray, IGRA – Interferon-gamma release assay, IS – induced sputum, MI – middle [TB] incidence countries, NICE – National Institute of Health and Care Excellence, QALY – Quality adjusted life year, TB – tuberculosis (includes active disease and subclinical tuberculosis cases), TST – tuberculin skin test.