The use of continuous electronic prescribing data to infer trends in antimicrobial consumption and estimate the impact of stewardship interventions in hospitalized children.

BACKGROUND: Understanding antimicrobial consumption is essential to mitigate the development of antimicrobial resistance, yet robust data in children are sparse and methodologically limited. Electronic prescribing systems provide an important opportunity to analyse and report antimicrobial consumption in detail. OBJECTIVES: We investigated the value of electronic prescribing data from a tertiary children's hospital to report temporal trends in antimicrobial consumption in hospitalized children and compare commonly used metrics of antimicrobial consumption. METHODS: Daily measures of antimicrobial consumption [days of therapy (DOT) and DDDs] were derived from the electronic prescribing system between 2010 and 2018. Autoregressive moving-average models were used to infer trends and the estimates were compared with simulated point prevalence surveys (PPSs). RESULTS: More than 1.3 million antimicrobial administrations were analysed. There was significant daily and seasonal variation in overall consumption, which reduced annually by 1.77% (95% CI 0.50% to 3.02%). Relative consumption of meropenem decreased by 6.6% annually (95% CI -3.5% to 15.8%) following the expansion of the hospital antimicrobial stewardship programme. DOT and DDDs exhibited similar trends for most antimicrobials, though inconsistencies were observed where changes to dosage guidelines altered consumption calculation by DDDs, but not DOT. PPS simulations resulted in estimates of change over time, which converged on the model estimates, but with much less precision. CONCLUSIONS: Electronic prescribing systems offer significant opportunities to better understand and report antimicrobial consumption in children. This approach to modelling administration data overcomes the limitations of using interval data and dispensary data. It provides substantially more detailed inferences on prescribing patterns and the potential impact of stewardship interventions.

A spatial analysis of giardiasis and cryptosporidiosis in relation to public water supply distribution in North West England.

Giardia and Cryptosporidium are both waterborne parasites and leading causes of gastroenteritis. Although specimens from diarrhoeic patients are routinely examined for Cryptosporidium, they are often not examined for Giardia so many cases go undiagnosed. Since 2002, all faecal specimens in Central Lancashire have been tested for infection with Giardia and Cryptosporidium. The aim of this paper is to gain insight into the factors contributing to giardiasis and cryptosporidiosis, including evidence of transmission via drinking water. Our analysis found a higher risk of both conditions for young children and a second peak in risk of giardiasis in adults. There was a significantly higher risk of giardiasis for males and a higher risk of cryptosporidiosis for females. The geographical location was significant, with an increased risk in the north. Residence in an area with increased supply from one water treatment works was a significant predictor for cryptosporidiosis.

Evidence of multiple intraspecific transmission routes for Leptospira acquisition in Norway rats (Rattus norvegicus).

Infectious diseases frequently have multiple potential routes of intraspecific transmission of pathogens within wildlife and other populations. For pathogens causing zoonotic diseases, knowing whether these transmission routes occur in the wild and their relative importance, is critical for understanding maintenance, improving control measures and ultimately preventing human disease. The Norway rat (Rattus norvegicus) is the primary reservoir of leptospirosis in the urban slums of Salvador, Brazil. There is biological evidence for potentially three different transmission routes of leptospire infection occurring in the rodent population. Using newly obtained prevalence data from rodents trapped at an urban slum field site, we present changes in cumulative risk of infection in relation to age-dependent transmission routes to infer which intra-specific transmission routes occur in the wild. We found that a significant proportion of animals leave the nest with infection and that the risk of infection increases throughout the lifetime of Norway rats. We did not observe a significant effect of sexual maturity on the risk of infection. In conclusion, our results suggest that vertical and environmental transmission of leptospirosis both occur in wild populations of Norway rats.

The impact of Type 2 diabetes prevention programmes based on risk-identification and lifestyle intervention intensity strategies: a cost-effectiveness analysis.

AIMS: To develop a cost-effectiveness model to compare Type 2 diabetes prevention programmes targeting different at-risk population subgroups with a lifestyle intervention of varying intensity. METHODS: An individual patient simulation model was constructed to simulate the development of diabetes in a representative sample of adults without diabetes from the UK population. The model incorporates trajectories for HbA1c , 2-h glucose, fasting plasma glucose, BMI, systolic blood pressure, total cholesterol and HDL cholesterol. Patients can be diagnosed with diabetes, cardiovascular disease, microvascular complications of diabetes, cancer, osteoarthritis and depression, or can die. The model collects costs and utilities over a lifetime horizon. The perspective is the UK National Health Service and personal social services. We used the model to evaluate the population-wide impact of targeting a lifestyle intervention of varying intensity to six population subgroups defined as high risk for diabetes. RESULTS: The intervention produces 0.0003 to 0.0009 incremental quality-adjusted life years and saves up to £1.04 per person in the general population, depending upon the subgroup targeted. Cost-effectiveness increases with intervention intensity. The most cost-effective options are to target individuals with HbA1c > 42 mmol/mol (6%) or with a high Finnish Diabetes Risk (FINDRISC) probability score (> 0.1). CONCLUSION: The model indicates that diabetes prevention interventions are likely to be cost-effective and may be cost-saving over a lifetime. In the model, the criteria for selecting at-risk individuals differentially impact upon diabetes and cardiovascular disease outcomes, and on the timing of benefits. These findings have implications for deciding who should be targeted for diabetes prevention interventions.

Feasibility and acceptability of web-based enhanced relapse prevention for bipolar disorder (ERPonline): trial protocol.

BACKGROUND: Relapse prevention interventions for Bipolar Disorder are effective but implementation in routine clinical services is poor. Web-based approaches offer a way to offer easily accessible access to evidence based interventions at low cost, and have been shown to be effective for other mood disorders. METHODS/DESIGN: This protocol describes the development and feasibility testing of the ERPonline web-based intervention using a single blind randomised controlled trial. Data will include the extent to which the site was used, detailed feedback from users about their experiences of the site, reported benefits and costs to mental health and wellbeing of users, and costs and savings to health services. We will gain an estimate of the likely effect size of ERPonline on a range of important outcomes including mood, functioning, quality of life and recovery. We will explore potential mechanisms of change, giving us a greater understanding of the underlying processes of change, and consequently how the site could be made more effective. We will be able to determine rates of recruitment and retention, and identify what factors could improve these rates. DISCUSSION: The findings will be used to improve the site in accordance with user needs, and inform the design of a large scale evaluation of the clinical and cost effectiveness of ERPonline. They will further contribute to the growing evidence base for web-based interventions designed to support people with mental health problems.

Giardiasis in North West England: faecal specimen requesting rates by GP practice.

Many cases of giardiasis in the UK are undiagnosed and among other things, diagnosis is dependent upon the readiness of GPs to request a specimen. The aim of this study is to assess the rate of specimens requested per GP practice in Central Lancashire, to examine the differences between GP practices and to estimate the pattern of unexplained spatial variation in the practice rate of specimens after adjustment for deprivation. To achieve this, we fitted a set of binomial and Poisson regression models, with random effects for GP practice. Our analysis suggests that there were differences in the rate of specimens by GP practices (P < 0·001) for a single year, but no difference in the proportion of positive tests per specimen submitted or in the rate of positive specimens per practice population. There was a difference in the cumulative rate of positive specimens per practice population over a 9-year period (P < 0·001). Neither the specimen rate per practice for a single year nor the cumulative rate of positive specimens over multiple years demonstrated significant spatial correlation. Hence, spatial variation in the incidence of giardiasis is unlikely to be confounded by variation in GP rate of specimens.

Temporal and farm-management-associated variation in faecal pat prevalence of Arcobacter spp. in ruminants.

In a 2-year longitudinal study of adult animals on 15 dairy farms and four sheep farms in Lancashire, UK, Arcobacter spp. were isolated from all farms although not at every sampling occasion. Faecal samples were collected and cultured using standard techniques for isolation of campylobacters. Assignment to species was via PCR assays. Apparent prevalence of Arcobacter spp. was higher in dairy cattle compared to sheep (40.1% vs. 8%, P < 0.001) and in housed cattle compared to cattle at pasture (50.1% vs. 20.9%, P < 0.001). This was reflected in the higher prevalence observed in herds that were housed (n = 4) all year compared to herds that grazed cattle on pasture in the summer and housed cattle in the winter (n = 11) (55.5% vs. 36%, P < 0.001). In the case of sheep, peak prevalence was observed in autumn with increased prevalence also being associated with improving pasture quality. There was an apparent inverse association between the faecal pat prevalence of Arcobacter spp. and Campylobacter jejuni although this may in part be an artefact of laboratory test method sensitivity, whereby a relative increase in the frequency of one bacterial species would reduce the sensitivity of detecting the other.

A multi-state spatio-temporal Markov model for categorized incidence of meningitis in sub-Saharan Africa.

Meningococcal meningitis is a major public health problem in the African Belt. Despite the obvious seasonality of epidemics, the factors driving them are still poorly understood. Here, we provide a first attempt to predict epidemics at the spatio-temporal scale required for in-year response, using a purely empirical approach. District-level weekly incidence rates for Niger (1986-2007) were discretized into latent, alert and epidemic states according to pre-specified epidemiological thresholds. We modelled the probabilities of transition between states, accounting for seasonality and spatio-temporal dependence. One-week-ahead predictions for entering the epidemic state were generated with specificity and negative predictive value >99%, sensitivity and positive predictive value >72%. On the annual scale, we predict the first entry of a district into the epidemic state with sensitivity 65∙0%, positive predictive value 49∙0%, and an average time gained of 4∙6 weeks. These results could inform decisions on preparatory actions.

Cross-sectional study of antimicrobial-resistant bacteria in horses. Part 1: Prevalence of antimicrobial-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus.

REASONS FOR PERFORMING STUDY: The increasing prevalence of antimicrobial-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and antimicrobial-resistant Escherichia coli represents a significant problem. However, the carriage of such bacteria by horses in the UK has not been well characterised. OBJECTIVES: To estimate the prevalence of nasal carriage of MRSA and faecal carriage of antimicrobial-resistant E. coli amongst horses in the general equine community of the mainland UK. METHODS: A cross-sectional study of horses recruited by 65 randomly selected equine veterinary practices was conducted, with nasal swabs and faecal samples collected. Faecal samples were cultured for antimicrobial-resistant E. coli. Nasal swabs were cultured for staphylococcal species; methicillin-resistant isolates identified as S. aureus were characterised by SCCmec and spa gene typing. Multilevel logistic regression models were used to calculate prevalence estimates with adjustment for clustering at practice and premises levels. Spatial variation in risk of antimicrobial resistance was also examined. RESULTS: In total, 650 faecal samples and 678 nasal swabs were collected from 692 horses located on 525 premises. The prevalence of faecal carriage of E. coli with resistance to any antimicrobial was 69.5% (95% CI 65.9-73.1%) and the prevalence of extended-spectrum ß-lactamase (ESBL)-producing E. coli was 6.3% (95% CI 4.1-9.6%). The prevalence of nasal carriage of MRSA was 0.6% (95% CI 0.2-1.5%). Spatial analysis indicated variation across the UK for risk of carriage of resistant and multidrug-resistant (resistant to more than 3 antimicrobial classes) E. coli. CONCLUSIONS AND POTENTIAL RELEVANCE: Carriage of MRSA by horses in the community appears rare, but the prevalence of antimicrobial-resistant E. coli (including ESBL-producing E. coli) is higher. A high prevalence of antimicrobial-resistant bacteria could have significant health implications for the horse population of the UK.

Is closure of entire wards necessary to control norovirus outbreaks in hospital? Comparing the effectiveness of two infection control strategies.

The standard approach for norovirus control in hospitals in the UK, as outlined by the Health Protection Agency guidance and implemented previously by Lancashire Teaching Hospitals, involves the early closure of affected wards. However, this has a major impact on bed-days lost and cancelled admissions. In 2008, a new strategy was introduced in the study hospital, key elements of which included closure of affected ward bays (rather than wards), installation of bay doors, enhanced cleaning, a rapid in-house molecular test and an enlarged infection control team. The impact of these changes was assessed by comparing two norovirus seasons (2007-08 and 2009-10) before and after implementation of the new strategy, expressing the contrast between seasons as a ratio (r) of expected counts in the two seasons. There was a significant decrease in the ratio of confirmed hospital outbreaks to community outbreaks (r = 0.317, P = 0.025), the number of days of restricted admissions on hospital wards per outbreak (r = 0.742, P = 0.041), and the number of hospital bed-days lost per outbreak (r = 0.344, P <0.001). However, there was no significant change in the number of patients affected per hospital outbreak (r = 1.080, P = 0.517), or the number of hospital staff affected per outbreak (r = 0.651, P = 0.105). Closure of entire wards during norovirus outbreaks is not always necessary. The changes implemented at the study hospital resulted in a significant reduction in the number of bed-days lost per outbreak, and this, together with a reduction in outbreak frequency, resulted in considerable cost savings.

A hierarchical model for real-time monitoring of variation in risk of non-specific gastrointestinal infections.

The AEGISS (Ascertainment and Enhancement of Disease Surveillance and Statistics) project uses spatio-temporal statistical methods to identify anomalies in the incidence of gastrointestinal infections in the UK. The focus of this paper is the modelling of temporal variation in incidence using data from the Southampton area in southern England. We identified and fitted a hierarchical stochastic model for the time series of daily incident cases to enable probabilistic prediction of temporal variation in risk, and demonstrated the resulting gains in predictive accuracy by comparison with a conventional analysis based on an over-dispersed Poisson log-linear regression model. We used Bayesian methods of inference in order to incorporate parameter uncertainty in our predictive inference of risk. Incorporation of our model in the overall spatio-temporal model, will contribute to the accurate and timely prediction of unusually high food-poisoning incidence, and thus to the identification and prevention of future outbreaks.

Molecular epidemiology and genetic diversity of Campylobacter jejuni in ruminants.

Multi-locus sequence typing was performed on 1003 Campylobacter jejuni isolates collected in a 2-year longitudinal study of 15 dairy farms and four sheep farms in Lancashire, UK. There was considerable farm-level variation in occurrence and prevalence of clonal complexes (CC). Clonal complexes ST61, ST21, ST403 and ST45 were most prevalent in cattle while in sheep CC ST42, ST21, ST48 and ST52 were most prevalent. CC ST45, a complex previously shown to be more common in summer months in human cases, was more prevalent in summer in our ruminant samples. Gene flow analysis demonstrated a high level of genetic heterogeneity at the within-farm level. Sequence-type diversity was greater in cattle compared to sheep, in cattle at pasture vs. housed, and in isolates from farms on the Pennines compared to the Southern Fylde. Sequence-type diversity was greatest in isolates belonging to CC ST21, ST45 and ST206.

Spatio-temporal epidemiology of Campylobacter jejuni enteritis, in an area of Northwest England, 2000-2002.

A total of 969 isolates of Campylobacter jejuni originating in the Preston, Lancashire postcode district over a 3-year period were characterized using multi-locus sequence typing. Recently developed statistical methods and a genetic model were used to investigate temporal, spatial, spatio-temporal and genetic variation in human C. jejuni infections. The analysis of the data showed statistically significant seasonal variation, spatial clustering, small-scale spatio-temporal clustering and spatio-temporal interaction in the overall pattern of incidence, and spatial segregation in cases classified according to their most likely species-of-origin.

Variation in composition of the intervillous space lining in term placentas of mothers with pre-eclampsia.

OBJECTIVE(S): To define composition of chorionic plate and test effects of pre-eclampsia on basal plate composition. STUDY DESIGN: Retrospective cohort study where distinct area fractions were measured in: healthy term chorionic plate (CP: n = 11), healthy placental basal plate (n = 11), mild pre-eclamptic basal plate (n = 10) and severe pre-eclamptic basal plate (n = 11). RESULTS: CP lining is partly endothelial. Mean anchoring villus (AV)/acellular (NS) basal plate area ratio decreased in pre-eclampsia (p = 0.048). There was a decreasing trend with increasing disease severity. Basal plate endothelial cell proportion was not significantly lower in severe pre-eclampsia than in healthy or mild pre-eclamptics. CONCLUSION(S): An inverse relationship between the proportions of fibrin and anchoring villi indicates that increased basal plate fibrin deposition and reduced basal plate materno-fetal anchoring area are part of pre-eclamptic disease progression. Endothelium lining intervillous surfaces may originate from circulating maternal endothelial progenitor cells.

Temporal and farm-management-associated variation in the faecal-pat prevalence of Campylobacter jejuni in ruminants.

In a 2-year longitudinal study of adult animals on 15 dairy farms and four sheep farms in Lancashire, UK. C. jejuni was isolated from all farms, although not on every occasion. Faecal samples were collected and cultured using standard techniques for isolation of Campylobacter. Assignment to species was via PCR assays. Peak prevalence of C. jejuni in both cattle and sheep was observed during the summer and in cattle this apparent seasonality was associated with grazing pasture [odds ratio (OR) 2.14], while in sheep it was independent of grazing. Increased prevalence was associated with increased milk yield (OR 1.05) and herd size (OR 1.01) in dairy cattle, and with increased stocking density (OR 1.29) and pasture quality (OR 2.16) in sheep. There was considerable variation in prevalence between farms but no evidence of large-scale spatial variation. The association between C. jejuni prevalence and diet in dairy cattle deserves further investigation.

Spatial and spatio-temporal analysis of Salmonella infection in dairy herds in England and Wales.

Using data from a cohort study conducted by the Veterinary Laboratories Agency (VLA), evidence of spatial clustering at distances up to 30 km was found for S. Agama and S. Dublin (P values of 0.001) and borderline evidence was found for spatial clustering of S. Typhimurium (P=0.077). The evolution of infection status of study farms over time was modelled using a Markov Chain model with transition probabilities describing changes in status at each of four visits, allowing for the effect of sampling visit. The degree of geographical clustering of infection, having allowed for temporal effects, was assessed by comparing the residual deviance from a model including a measure of recent neighbourhood infection levels with one excluding this variable. The number of cases arising within a defined distance and time period of an index case was higher than expected. This provides evidence for spatial and spatio-temporal clustering, which suggests either a contagious process (e.g. through direct or indirect farm-to-farm transmission) or geographically localized environmental and/or farm factors which increase the risk of infection. The results emphasize the different epidemiology of the three Salmonella serovars investigated.

Spatial modelling and the prediction of Loa loa risk: decision making under uncertainty.

Health decision-makers working in Africa often need to act for millions of people over large geographical areas on little and uncertain information. Spatial statistical modelling and Bayesian inference have now been used to quantify the uncertainty in the predictions of a regional, environmental risk map for Loa loa (a map that is currently being used as an essential decision tool by the African Programme for Onchocerciasis Control). The methodology allows the expression of the probability that, given the data, a particular location does or does not exceed a predefined high-risk threshold for which a change in strategy for the delivery of the antihelmintic ivermectin is required.

Second-order analysis of inhomogeneous spatial point processes using case-control data.

Methods for the statistical analysis of stationary spatial point process data are now well established, methods for nonstationary processes less so. One of many sources of nonstationary point process data is a case-control study in environmental epidemiology. In that context, the data consist of a realization of each of two spatial point processes representing the locations, within a specified geographical region, of individual cases of a disease and of controls drawn at random from the population at risk. In this article, we extend work by Baddeley, Møller, and Waagepetersen (2000, Statistica Neerlandica54, 329-350) concerning estimation of the second-order properties of a nonstationary spatial point process. First, we show how case-control data can be used to overcome the problems encountered when using the same data to estimate both a spatially varying intensity and second-order properties. Second, we propose a semiparametric method for adjusting the estimate of intensity so as to take account of explanatory variables attached to the cases and controls. Our primary focus is estimation, but we also propose a new test for spatial clustering that we show to be competitive with existing tests. We describe an application to an ecological study in which juvenile and surviving adult trees assume the roles of controls and cases.

Campylobacter lari: genotype and antibiotic resistance of isolates from cattle, wildlife and water in an area of mixed dairy farmland in the United Kingdom.

Campylobacter lari is a rare human pathogen most commonly associated with birds and shellfish. Little information has been published regarding its prevalence in other environments, or on its potential role as a reservoir of antibiotic resistance. In this study, we characterized 109 C. lari isolated from a range of hosts using pulsed-field gel electrophoresis of macro-restricted chromosomal DNA, and by determining their susceptibility to a panel of four antibiotics. Pulsed-field gel electrophoresis analysis showed C. lari to be genetically diverse, particularly in isolates from wild birds and environmental water. The most common composite macro-restriction profile (cMRP) was found in multiple hosts (cattle, badgers, wild birds and rabbits), and seven other cMRPs were recovered from more than one host. All isolates were resistant to nalidixic acid and ciprofloxacin. Resistance to erythromycin and ampicillin was uncommon, but was observed in isolates from wild birds, cattle, wild mammals and water samples. The presence of the same cMRP in multiple hosts provides further evidence of transmission between livestock, wildlife and the environment, or for a common source of infection.