The impact of HIV infection on tuberculosis transmission in a country with low tuberculosis incidence: a national retrospective study using molecular epidemiology.

BACKGROUND: HIV is known to increase the likelihood of reactivation of latent tuberculosis to active TB disease; however, its impact on tuberculosis infectiousness and consequent transmission is unclear, particularly in low-incidence settings. METHODS: National surveillance data from England, Wales and Northern Ireland on tuberculosis cases in adults from 2010 to 2014, strain typed using 24-locus mycobacterial-interspersed-repetitive-units-variable-number-tandem-repeats was used retrospectively to identify clusters of tuberculosis cases, subdivided into 'first' and 'subsequent' cases. Firstly, we used zero-inflated Poisson regression models to examine the association between HIV status and the number of subsequent clustered cases (a surrogate for tuberculosis infectiousness) in a strain type cluster. Secondly, we used logistic regression to examine the association between HIV status and the likelihood of being a subsequent case in a cluster (a surrogate for recent acquisition of tuberculosis infection) compared to the first case or a non-clustered case (a surrogate for reactivation of latent infection). RESULTS: We included 18,864 strain-typed cases, 2238 were the first cases of clusters and 8471 were subsequent cases. Seven hundred and fifty-nine (4%) were HIV-positive. Outcome 1: HIV-positive pulmonary tuberculosis cases who were the first in a cluster had fewer subsequent cases associated with them (mean 0.6, multivariable incidence rate ratio [IRR] 0.75 [0.65-0.86]) than those HIV-negative (mean 1.1). Extra-pulmonary tuberculosis (EPTB) cases with HIV were less likely to be the first case in a cluster compared to HIV-negative EPTB cases. EPTB cases who were the first case had a higher mean number of subsequent cases (mean 2.5, IRR (3.62 [3.12-4.19]) than those HIV-negative (mean 0.6). Outcome 2: tuberculosis cases with HIV co-infection were less likely to be a subsequent case in a cluster (odds ratio 0.82 [0.69-0.98]), compared to being the first or a non-clustered case. CONCLUSIONS: Outcome 1: pulmonary tuberculosis-HIV patients were less infectious than those without HIV. EPTB patients with HIV who were the first case in a cluster had a higher number of subsequent cases and thus may be markers of other undetected cases, discoverable by contact investigations. Outcome 2: tuberculosis in HIV-positive individuals was more likely due to reactivation than recent infection, compared to those who were HIV-negative.

Factors associated with cytomegalovirus serostatus in young people in England: a cross-sectional study.

BACKGROUND: Human cytomegalovirus (CMV) is a common herpesvirus which is estimated to infect 83% of the global population. Whilst many infections are asymptomatic, it is an important cause of morbidity and mortality, particularly for immunocompromised people and for infants who are congenitally infected. A vaccine against CMV has been stated as a public health priority, but there are gaps in our understanding of CMV epidemiology. To guide potential future vaccination strategies, our aim was to examine risk factors for CMV seropositivity in young people in England. METHODS: The Health Survey for England (HSE) is an annual, cross-sectional representative survey of households in England during which data are collected through questionnaires, and blood samples are taken. We randomly selected individuals who participated in the HSE 2002, aiming for 25 participants of each sex in each single year age group from 11 to 24 years. Stored samples were tested for CMV antibodies. We undertook descriptive and regression analyses of CMV seroprevalence and risk factors for infection. RESULTS: Demographic data and serostatus were available for 732 individuals, of whom 175 (23.7%) were CMV-seropositive. CMV seroprevalence was associated with age, with 18.3% seropositive at 11-14 years compared to 28.3% at 22-24 years. CMV serostatus was also higher in people of non-white ethnicity (adjusted odds ratio [aOR] 6.22, 95% confidence interval [CI] 3.47-11.14), and in adults who were seropositive for EBV (aOR 2.08 [1.06-4.09]). There was no evidence that smoking status, occupation, body mass index and region of England were associated with CMV serostatus. CONCLUSIONS: CMV seroprevalence is strongly associated with ethnicity, and modestly increases with age in 11-24-year-olds. A greater understanding of the transmission dynamics of CMV, and the impact of this on CMV-associated morbidity and mortality, is necessary to inform effective vaccination strategies when a vaccine for CMV becomes available.

Peritonsillar Abscess and Antibiotic Prescribing for Respiratory Infection in Primary Care: A Population-Based Cohort Study and Decision-Analytic Model.

PURPOSE: To quantify the risk of peritonsillar abscess (PTA) following consultation for respiratory tract infection (RTI) in primary care. METHOD: A cohort study was conducted in the UK Clinical Practice Research Datalink including 718 general practices with 65,681,293 patient years of follow-up and 11,007 patients with a first episode of PTA. From a decision tree, Bayes theorem was employed to estimate both the probability of PTA following an RTI consultation if antibiotics were prescribed or not, and the number of patients needed to be treated with antibiotics to prevent 1 PTA. RESULTS: There were 11,007 patients with PTA with age-standardized incidence of new episodes of PTA of 17.2 per 100,000 patient years for men and 16.1 for women; 6,996 (64%) consulted their practitioner in the 30 days preceding PTA diagnosis, including 4,243 (39%) consulting for RTI. The probability of PTA following an RTI consultation was greatest in men aged 15 to 24 years with 1 PTA in 565 (95% uncertainty interval 527 to 605) RTI consultations without antibiotics prescribed but 1 in 1,139 consultations (1,044 to 1,242) if antibiotics were prescribed. One PTA might be avoided for every 1,121 (975 to 1,310) additional antibiotic prescriptions for men aged 15 to 24 years and 926 (814 to 1,063) for men aged 25 to 34 years. The risk of PTA following RTI consultation was smaller and the number needed to treat higher at other ages and risks were lower in women than men. CONCLUSIONS: The risk of PTA may be lower if antibiotics are prescribed for RTI but even in young men nearly 1,000 antibiotic prescriptions may be required to prevent 1 PTA case. We caution that lack of randomization and data standardization may bias estimates.

Probability of sepsis after infection consultations in primary care in the United Kingdom in 2002-2017: Population-based cohort study and decision analytic model.

BACKGROUND: Efforts to reduce unnecessary antibiotic prescribing have coincided with increasing awareness of sepsis. We aimed to estimate the probability of sepsis following infection consultations in primary care when antibiotics were or were not prescribed. METHODS AND FINDINGS: We conducted a cohort study including all registered patients at 706 general practices in the United Kingdom Clinical Practice Research Datalink, with 66.2 million person-years of follow-up from 2002 to 2017. There were 35,244 first episodes of sepsis (17,886, 51%, female; median age 71 years, interquartile range 57-82 years). Consultations for respiratory tract infection (RTI), skin or urinary tract infection (UTI), and antibiotic prescriptions were exposures. A Bayesian decision tree was used to estimate the probability (95% uncertainty intervals [UIs]) of sepsis following an infection consultation. Age, gender, and frailty were evaluated as association modifiers. The probability of sepsis was lower if an antibiotic was prescribed, but the number of antibiotic prescriptions required to prevent one episode of sepsis (number needed to treat [NNT]) decreased with age. At 0-4 years old, the NNT was 29,773 (95% UI 18,458-71,091) in boys and 27,014 (16,739-65,709) in girls; over 85 years old, NNT was 262 (236-293) in men and 385 (352-421) in women. Frailty was associated with greater risk of sepsis and lower NNT. For severely frail patients aged 55-64 years, the NNT was 247 (156-459) in men and 343 (234-556) in women. At all ages, the probability of sepsis was greatest for UTI, followed by skin infection, followed by RTI. At 65-74 years, the NNT following RTI was 1,257 (1,112-1,434) in men and 2,278 (1,966-2,686) in women; the NNT following skin infection was 503 (398-646) in men and 784 (602-1,051) in women; following UTI, the NNT was 121 (102-145) in men and 284 (241-342) in women. NNT values were generally smaller for the period from 2014 to 2017, when sepsis was diagnosed more frequently. Lack of random allocation to antibiotic therapy might have biased estimates; patients may sometimes experience sepsis or receive antibiotic prescriptions without these being recorded in primary care; recording of sepsis has increased over the study period. CONCLUSIONS: These stratified estimates of risk help to identify groups in which antibiotic prescribing may be more safely reduced. Risks of sepsis and benefits of antibiotics are more substantial among older adults, persons with more advanced frailty, or following UTIs.

Predictors of Epstein-Barr virus serostatus and implications for vaccine policy: A systematic review of the literature.

BACKGROUND: Epstein-Barr virus (EBV) is an important human pathogen; it infects >90% people globally and is linked to infectious mononucleosis and several types of cancer. Vaccines against EBV are in development. In this study we present the first systematic review of the literature on risk factors for EBV infection, and discuss how they differ between settings, in order to improve our understanding of EBV epidemiology and aid the design of effective vaccination strategies. METHODS: MEDLINE, Embase, and Web of Science were searched on 6th March 2017 for observational studies of risk factors for EBV infection. Studies were excluded if they were published before 2008 to ensure relevance to the modern day, given the importance of influencing future vaccination policies. There were no language restrictions. After title, abstract and full text screening, followed by checking the reference lists of included studies to identify further studies, data were extracted into standardised spreadsheets and quality assessed. A narrative synthesis was undertaken. RESULTS: Seventy-seven papers met our inclusion criteria, including data from 31 countries. There was consistent evidence that EBV seroprevalence was associated with age, increasing throughout childhood and adolescence and remaining constant thereafter. EBV was generally acquired at younger ages in Asia than Europe/North America. There was also compelling evidence for an association between cytomegalovirus infection and EBV. Additional factors associated with EBV seroprevalence, albeit with less consistent evidence, included ethnicity, socioeconomic status, other chronic viral infections, and genetic variants of HLA and immune response genes. CONCLUSIONS: Our study is the first systematic review to draw together the global literature on the risk factors for EBV infection and includes an evaluation of the quality of the published evidence. Across the literature, the factors examined are diverse. In Asia, early vaccination of infants would be required to prevent EBV infection. In contrast, in Western countries a vaccine could be deployed later, particularly if it has only a short duration of protection and the intention was to protect against infectious mononucleosis. There is a lack of high-quality data on the prevalence and age of EBV infection outside of Europe, North America and South-East Asia, which are essential for informing effective vaccination policies in these settings.

Risk factors for Epstein Barr virus-associated cancers: a systematic review, critical appraisal, and mapping of the epidemiological evidence.

BACKGROUND: Epstein Barr Virus (EBV) infects 90%-95% of all adults globally and causes ~ 1% of all cancers. Differing proportions of Burkitt's lymphoma (BL), gastric carcinoma (GC), Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC) are associated with EBV. We sought to systematically review the global epidemiological evidence for risk factors that (in addition to EBV) contribute to the development of the EBV-associated forms of these cancers, assess the quality of the evidence, and compare and contrast the cancers. METHODS: MEDLINE, Embase and Web of Science were searched for studies of risk factors for EBV-associated BL, GC, HL and NPC without language or temporal restrictions. Studies were excluded if there was no cancer-free comparator group or where analyses of risk factors were inadequately documented. After screening and reference list searching, data were extracted into standardised spreadsheets and quality assessed. Due to heterogeneity, a narrative synthesis was undertaken. RESULTS: 9916 hits were retrieved. 271 papers were retained: two BL, 24 HL, one GC and 244 NPC. The majority of studies were from China, North America and Western Europe. Risk factors were categorised as dietary, environmental/non-dietary, human genetic, and infection and clinical. Anti-EBV antibody load was associated with EBV-associated GC and BL. Although the evidence could be inconsistent, HLA-A alleles, smoking, infectious mononucleosis and potentially other infections were risk factors for EBV-associated HL. Rancid dairy products; anti-EBV antibody and EBV DNA load; history of chronic ear, nose and/or throat conditions; herbal medicine use; family history; and human genetics were risk factors for NPC. Fresh fruit and vegetable and tea consumption may be protective against NPC. CONCLUSIONS: Many epidemiological studies of risk factors in addition to EBV for the EBV-associated forms of BL, GC, HL and NPC have been undertaken, but there is a dearth of evidence for GC and BL. Available evidence is of variable quality. The aetiology of EBV-associated cancers likely results from a complex intersection of genetic, clinical, environmental and dietary factors, which is difficult to assess with observational studies. Large, carefully designed, studies need to be strategically undertaken to harmonise and clarify the evidence. REGISTRATION: PROSPERO CRD42017059806.

Serious bacterial infections and antibiotic prescribing in primary care: cohort study using electronic health records in the UK.

OBJECTIVE: This study evaluated whether serious bacterial infections are more frequent at family practices with lower antibiotic prescribing rates. DESIGN: Cohort study. SETTING: 706 UK family practices in the Clinical Practice Research Datalink from 2002 to 2017. PARTICIPANTS: 10.1 million registered patients with 69.3 million patient-years' follow-up. EXPOSURES: All antibiotic prescriptions, subgroups of acute and repeat antibiotic prescriptions, and proportion of antibiotic prescriptions associated with specific-coded indications. MAIN OUTCOME MEASURES: First episodes of serious bacterial infections. Poisson models were fitted adjusting for age group, gender, comorbidity, deprivation, region and calendar year, with random intercepts representing family practice-specific estimates. RESULTS: The age-standardised antibiotic prescribing rate per 1000 patient-years increased from 2002 (male 423; female 621) to 2012 (male 530; female 842) before declining to 2017 (male 449; female 753). The median family practice had an antibiotic prescribing rate of 648 per 1000 patient-years with 95% range for different practices of 430-1038 antibiotic prescriptions per 1000 patient-years. Specific coded indications were recorded for 58% of antibiotic prescriptions at the median family practice, the 95% range at different family practices was from 10% to 75%. There were 139 759 first episodes of serious bacterial infection. After adjusting for covariates and the proportion of coded consultations, there was no evidence that serious bacterial infections were lower at family practices with higher total antibiotic prescribing. The adjusted rate ratio for 20% higher total antibiotic prescribing was 1.03, (95% CI 1.00 to 1.06, p=0.074). CONCLUSIONS: We did not find population-level evidence that family practices with lower total antibiotic prescribing might have more frequent occurrence of serious bacterial infections overall. Improving the recording of infection episodes has potential to inform better antimicrobial stewardship in primary care.

Applying Artificial Intelligence Methods for the Estimation of Disease Incidence: The Utility of Language Models.

Background: AI-driven digital health tools often rely on estimates of disease incidence or prevalence, but obtaining these estimates is costly and time-consuming. We explored the use of machine learning models that leverage contextual information about diseases from unstructured text, to estimate disease incidence. Methods: We used a class of machine learning models, called language models, to extract contextual information relating to disease incidence. We evaluated three different language models: BioBERT, Global Vectors for Word Representation (GloVe), and the Universal Sentence Encoder (USE), as well as an approach which uses all jointly. The output of these models is a mathematical representation of the underlying data, known as "embeddings." We used these to train neural network models to predict disease incidence. The neural networks were trained and validated using data from the Global Burden of Disease study, and tested using independent data sourced from the epidemiological literature. Findings: A variety of language models can be used to encode contextual information of diseases. We found that, on average, BioBERT embeddings were the best for disease names across multiple tasks. In particular, BioBERT was the best performing model when predicting specific disease-country pairs, whilst a fusion model combining BioBERT, GloVe, and USE performed best on average when predicting disease incidence in unseen countries. We also found that GloVe embeddings performed better than BioBERT embeddings when applied to country names. However, we also noticed that the models were limited in view of predicting previously unseen diseases. Further limitations were also observed with substantial variations across age groups and notably lower performance for diseases that are highly dependent on location and climate. Interpretation: We demonstrate that context-aware machine learning models can be used for estimating disease incidence. This method is quicker to implement than traditional epidemiological approaches. We therefore suggest it complements existing modeling efforts, where data is required more rapidly or at larger scale. This may particularly benefit AI-driven digital health products where the data will undergo further processing and a validated approximation of the disease incidence is adequate.

Predictors of Epstein-Barr virus serostatus in young people in England.

BACKGROUND: Epstein-Barr virus (EBV) is an important human pathogen which causes lifelong infection of > 90% people globally and is linked to infectious mononucleosis (arising from infection in the later teenage years) and several types of cancer. Vaccines against EBV are in development. In order to determine the most cost-effective public health strategy for vaccine deployment, setting-specific data on the age at EBV acquisition and risk factors for early infection are required. Such data are also important to inform mathematical models of EBV transmission that can determine the required target product profile of vaccine characteristics. We thus aimed to examine risk factors for EBV infection in young people in England, in order to improve our understanding of EBV epidemiology and guide future vaccination strategies. METHODS: The Health Survey for England (HSE) is an annual, cross-sectional representative survey of households in England during which data are collected via questionnaires and blood samples. We randomly selected individuals who participated in the HSE 2002, aiming for 25 participants of each sex in each single year age group from 11 to 24 years. Stored samples were tested for EBV and cytomegalovirus (CMV) antibodies. We undertook descriptive and regression analyses of EBV seroprevalence and risk factors for infection. RESULTS: Demographic data and serostatus were available for 732 individuals. EBV seroprevalence was strongly associated with age, increasing from 60.4% in 11-14 year olds throughout adolescence (68.6% in 15-18 year olds) and stabilising by early adulthood (93.0% in those aged 22-24 years). In univariable and multivariable logistic regression models, ethnicity was associated with serostatus (adjusted odds ratio for seropositivity among individuals of other ethnicity versus white individuals 2.33 [95% confidence interval 1.13-4.78]). Smoking was less strongly associated with EBV seropositivity. CONCLUSIONS: By the age of 11 years, EBV infection is present in over half the population, although age is not the only factor associated with serostatus. Knowledge of the distribution of infection in the UK population is critical for determining future vaccination policies, e.g. comparing general versus selectively targeted vaccination strategies.

Modelling the dynamics of EBV transmission to inform a vaccine target product profile and future vaccination strategy.

Epstein-Barr virus (EBV) is one of the most common human viruses and the cause of pathologies such as infectious mononucleosis (IM) and certain cancers. No vaccine against EBV infection currently exists, but such vaccines are in development. Knowledge of how EBV is transmitted at the population level is critical to the development of target product profiles (TPPs) for such vaccines and future vaccination strategies. We present the first mathematical model of EBV transmission, parameterised using data from England, and use it to compare hypothetical prophylactic vaccines with different characteristics and the impact of vaccinating different age groups. We found that vaccine duration had more impact than vaccine efficacy on modelled EBV and IM prevalence. The age group vaccinated also had an important effect: vaccinating at a younger age led to a greater reduction in seroprevalence but an increase in IM cases associated with delayed infection. Vaccination had impact on cancer incidence only in the long run, because in England most EBV-related cancers arise in later life. Durability of protection should be a key factor to prioritise in EBV vaccine development and included in vaccine TPPs. These findings are timely and important for vaccine developers and policy-makers alike.

Trends in, and factors associated with, HIV infection amongst tuberculosis patients in the era of anti-retroviral therapy: a retrospective study in England, Wales and Northern Ireland.

BACKGROUND: HIV increases the progression of latent tuberculosis (TB) infection to active disease and contributed to increased TB in the UK until 2004. We describe temporal trends in HIV infection amongst patients with TB and identify factors associated with HIV infection. METHODS: We used national surveillance data of all TB cases reported in England, Wales and Northern Ireland from 2000 to 2014 and determined HIV status through record linkage to national HIV surveillance. We used logistic regression to identify associations between HIV and demographic, clinical and social factors. RESULTS: There were 106,829 cases of TB in adults (≥ 15 years) reported from 2000 to 2014. The number and proportion of TB patients infected with HIV decreased from 543/6782 (8.0%) in 2004 to 205/6461 (3.2%) in 2014. The proportion of patients diagnosed with HIV > 91 days prior to their TB diagnosis increased from 33.5% in 2000 to 60.2% in 2013. HIV infection was highest in people of black African ethnicity from countries with high HIV prevalence (32.3%), patients who misused drugs (8.1%) and patients with miliary or meningeal TB (17.2%). CONCLUSIONS: There has been an overall decrease in TB-HIV co-infection and a decline in the proportion of patients diagnosed simultaneously with both infections. However, high rates of HIV remain in some sub-populations of patients with TB, particularly black Africans born in countries with high HIV prevalence and people with a history of drug misuse. Whilst the current policy of testing all patients diagnosed with TB for HIV infection is important in ensuring appropriate management of TB patients, many of these TB cases would be preventable if HIV could be diagnosed before TB develops. Improving screening for both latent TB and HIV and ensuring early treatment of HIV in these populations could help prevent these TB cases. British HIV Association guidelines on latent TB testing for people with HIV from sub-Saharan Africa remain relevant, and latent TB screening for people with HIV with a history of drug misuse, homelessness or imprisonment should also be considered.

Injecting drug use predicts active tuberculosis in a national cohort of people living with HIV.

OBJECTIVES: Tuberculosis (TB) is common in people living with HIV, leading to worse clinical outcomes including increased mortality. We investigated risk factors for developing TB following HIV diagnosis. DESIGN: Adults aged at least 15 years first presenting to health services for HIV care in England, Wales or Northern Ireland from 2000 to 2014 were identified from national HIV surveillance data and linked to TB surveillance data. METHODS: We calculated incidence rates for TB occurring more than 91 days after HIV diagnosis and investigated risk factors using multivariable Poisson regression. RESULTS: A total of 95 003 adults diagnosed with HIV were followed for 635 591 person-years; overall incidence of TB was 344 per 100 000 person-years (95% confidence interval 330-359). TB incidence was high for people who acquired HIV through injecting drugs [PWID; men 876 (696-1104), women 605 (365-945)] and black Africans born in high TB incidence countries [644 (612-677)]. The adjusted incidence rate ratio for TB amongst PWID was 4.79 (3.35-6.85) for men and 6.18 (3.49-10.93) for women, compared with MSM. The adjusted incidence rate ratio for TB in black Africans from high-TB countries was 4.27 (3.42-5.33), compared with white UK-born individuals. Lower time-updated CD4 cell count was associated with increased rates of TB. CONCLUSION: PWID had the greatest risk of TB; incidence rates were comparable with those in black Africans from high TB incidence countries. Most TB cases in PWID were UK-born, and likely acquired TB through transmission within the United Kingdom. Earlier HIV diagnosis and quicker initiation of antiretroviral therapy should reduce TB incidence in these populations.

Cost-benefit analysis of management practices for ewes lame with footrot.

The aim of this study was to investigate the cost-benefit of different strategies to treat and control ovine footrot. In November 2006, 162 sheep farmers in England responded to a survey on prevalence and management of lameness. The costs of lameness per ewe per year (PEPY) were calculated for 116 flocks. Linear regression was used to model the overall cost of lameness PEPY by management method. Associations between farmer satisfaction and time and money spent managing lameness were investigated. The median prevalence of lameness was 5% (inter-quartile range, IQR, 4-10%). The overall cost of lameness PEPY in flocks with ≥10% lameness was UK £6.35 versus £3.90 for flocks with <5% lameness. Parenteral antibiotic treatment was associated with a significantly lower overall cost of lameness by £0.79 PEPY. Routine foot trimming and foot bathing were associated with significantly higher overall costs of lameness PEPY of £2.96 and £0.90, respectively. Farmers satisfied with time managing lameness spent significantly less time (1.46 h PEPY) than unsatisfied farmers (1.90 h PEPY). Farmers satisfied with money spent managing lameness had significantly lower treatment (£2.94 PEPY) and overall (£5.00 PEPY) costs than dissatisfied farmers (£5.50 and £7.60 PEPY, respectively). If the farmers in this study adopted best practice of parenteral antibiotic treatment with no routine foot trimming, and minimised foot bathing to treatment/prevention of interdigital dermatitis, the financial benefits would be approximately £4.65 PEPY. If these costs are similar on other farms the management changes would lead to significant economic benefits for the sheep industry.

Interpreting whole genome sequencing for investigating tuberculosis transmission: a systematic review.

BACKGROUND: Whole genome sequencing (WGS) is becoming an important part of epidemiological investigations of infectious diseases due to greater resolution and cost reductions compared to traditional typing approaches. Many public health and clinical teams will increasingly use WGS to investigate clusters of potential pathogen transmission, making it crucial to understand the benefits and assumptions of the analytical methods for investigating the data. We aimed to understand how different approaches affect inferences of transmission dynamics and outline limitations of the methods. METHODS: We comprehensively searched electronic databases for studies that presented methods used to interpret WGS data for investigating tuberculosis (TB) transmission. Two authors independently selected studies for inclusion and extracted data. Due to considerable methodological heterogeneity between studies, we present summary data with accompanying narrative synthesis rather than pooled analyses. RESULTS: Twenty-five studies met our inclusion criteria. Despite the range of interpretation tools, the usefulness of WGS data in understanding TB transmission often depends on the amount of genetic diversity in the setting. Where diversity is small, distinguishing re-infections from relapses may be impossible; interpretation may be aided by the use of epidemiological data, examining minor variants and deep sequencing. Conversely, when within-host diversity is large, due to genetic hitchhiking or co-infection of two dissimilar strains, it is critical to understand how it arose. Greater understanding of microevolution and mixed infection will enhance interpretation of WGS data. CONCLUSIONS: As sequencing studies have sampled more intensely and integrated multiple sources of information, the understanding of TB transmission and diversity has grown, but there is still much to be learnt about the origins of diversity that will affect inferences from these data. Public health teams and researchers should combine epidemiological, clinical and WGS data to strengthen investigations of transmission.

Changes in prevalence of, and risk factors for, lameness in random samples of English sheep flocks: 2004-2013.

The aims of this study were to update the prevalence of lameness in sheep in England and identify novel risk factors. A total of 1260 sheep farmers responded to a postal survey. The survey captured detailed information on the period prevalence of lameness from May 2012-April 2013 and the prevalence and farmer naming of lesions attributable to interdigital dermatitis (ID), severe footrot (SFR), contagious ovine digital dermatitis (CODD) and shelly hoof (SH), management and treatment of lameness, and farm and flock details. The global mean period prevalence of lameness fell between 2004 and 2013 from 10.6% to 4.9% and the geometric mean period prevalence of lameness fell from 5.4% (95% CL: 4.7%-6.0%) to 3.5% (95% CI: 3.3%-3.7%). In 2013, more farmers were using vaccination and antibiotic treatment for ID and SFR and fewer farmers were using foot trimming as a routine or therapeutic treatment than in 2004. Two over-dispersed Poisson regression models were developed with the outcome the period prevalence of lameness, one investigated associations with farmer estimates of prevalence of the four foot lesions and one investigated associations with management practices to control and treat lameness and footrot. A prevalence of ID>10%, SFR>2.5% and CODD>2.5% were associated with a higher prevalence of lameness compared with those lesions being absent, however, the prevalence of SH was not associated with a change in risk of lameness. A key novel management risk associated with higher prevalence of lameness was the rate of feet bleeding/100 ewes trimmed/year. In addition, vaccination of ewes once per year and selecting breeding replacements from never-lame ewes were associated with a decreased risk of lameness. Other factors associated with a lower risk of lameness for the first time in a random sample of farmers and a full risk model were: recognising lameness in sheep at locomotion score 1 compared with higher scores, treatment of the first lame sheep in a group compared with waiting until >5 were lame, treatment of lame sheep within 3 days, ease of catching lame sheep and quarantine for >21 days. A previously known factor associated with a lower risk of lameness was footbathing to prevent ID. We conclude that the prevalence of lameness in sheep in England has fallen and that this might be in part because of increased uptake of managements recently reported as beneficial to control lameness. Routine foot trimming should be avoided.