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.

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.

Cost-effectiveness of population-based, community, workplace and individual policies for diabetes prevention in the UK.

AIM: To analyse the cost-effectiveness of different interventions for Type 2 diabetes prevention within a common framework. METHODS: A micro-simulation model was developed to evaluate the cost-effectiveness of a range of diabetes prevention interventions including: (1) soft drinks taxation; (2) retail policy in socially deprived areas; (3) workplace intervention; (4) community-based intervention; and (5) screening and intensive lifestyle intervention in individuals with high diabetes risk. Within the model, individuals follow metabolic trajectories (for BMI, cholesterol, systolic blood pressure and glycaemia); individuals may develop diabetes, and some may exhibit complications of diabetes and related disorders, including cardiovascular disease, and eventually die. Lifetime healthcare costs, employment costs and quality-adjusted life-years are collected for each person. RESULTS: All interventions generate more life-years and lifetime quality-adjusted life-years and reduce healthcare spending compared with doing nothing. Screening and intensive lifestyle intervention generates greatest lifetime net benefit (£37) but is costly to implement. In comparison, soft drinks taxation or retail policy generate lower net benefit (£11 and £11) but are cost-saving in a shorter time period, preferentially benefit individuals from deprived backgrounds and reduce employer costs. CONCLUSION: The model enables a wide range of diabetes prevention interventions to be evaluated according to cost-effectiveness, employment and equity impacts over the short and long term, allowing decision-makers to prioritize policies that maximize the expected benefits, as well as fulfilling other policy targets, such as addressing social inequalities.

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.

Fasciola hepatica infection reduces Mycobacterium bovis burden and mycobacterial uptake and suppresses the pro-inflammatory response.

Bovine tuberculosis (BTB), caused by Mycobacterium bovis, has an annual incidence in cattle of 0.5% in the Republic of Ireland and 4.7% in the UK, despite long-standing eradication programmes being in place. Failure to achieve complete eradication is multifactorial, but the limitations of diagnostic tests are significant complicating factors. Previously, we have demonstrated that Fasciola hepatica infection, highly prevalent in these areas, induced reduced sensitivity of the standard diagnostic tests for BTB in animals co-infected with F. hepatica and M. bovis. This was accompanied by a reduced M. bovis-specific Th1 immune response. We hypothesized that these changes in co-infected animals would be accompanied by enhanced growth of M. bovis. However, we show here that mycobacterial burden in cattle is reduced in animals co-infected with F. hepatica. Furthermore, we demonstrate a lower mycobacterial recovery and uptake in blood monocyte-derived macrophages (MDM) from F. hepatica-infected cattle which is associated with suppression of pro-inflammatory cytokines and a switch to alternative activation of macrophages. However, the cell surface expression of TLR2 and CD14 in MDM from F. hepatica-infected cattle is increased. These findings reflecting the bystander effect of helminth-induced downregulation of pro-inflammatory responses provide insights to understand host-pathogen interactions in co-infection.

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.

Self-hypnosis for intrapartum pain management in pregnant nulliparous women: a randomised controlled trial of clinical effectiveness.

OBJECTIVE: (Primary) To establish the effect of antenatal group self-hypnosis for nulliparous women on intra-partum epidural use. DESIGN: Multi-method randomised control trial (RCT). SETTING: Three NHS Trusts. POPULATION: Nulliparous women not planning elective caesarean, without medication for hypertension and without psychological illness. METHODS: Randomisation at 28-32 weeks' gestation to usual care, or to usual care plus brief self-hypnosis training (two × 90-minute groups at around 32 and 35 weeks' gestation; daily audio self-hypnosis CD). Follow up at 2 and 6 weeks postnatal. MAIN OUTCOME MEASURES: Primary: epidural analgesia. Secondary: associated clinical and psychological outcomes; cost analysis. RESULTS: Six hundred and eighty women were randomised. There was no statistically significant difference in epidural use: 27.9% (intervention), 30.3% (control), odds ratio (OR) 0.89 [95% confidence interval (CI): 0.64-1.24], or in 27 of 29 pre-specified secondary clinical and psychological outcomes. Women in the intervention group had lower actual than anticipated levels of fear and anxiety between baseline and 2 weeks post natal (anxiety: mean difference -0.72, 95% CI -1.16 to -0.28, P = 0.001); fear (mean difference -0.62, 95% CI -1.08 to -0.16, P = 0.009) [Correction added on 7 July 2015, after first online publication: 'Mean difference' replaced 'Odds ratio (OR)' in the preceding sentence.]. Postnatal response rates were 67% overall at 2 weeks. The additional cost in the intervention arm per woman was £4.83 (CI -£257.93 to £267.59). CONCLUSIONS: Allocation to two-third-trimester group self-hypnosis training sessions did not significantly reduce intra-partum epidural analgesia use or a range of other clinical and psychological variables. The impact of women's anxiety and fear about childbirth needs further investigation.

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.

Meteorological conditions and incidence of Legionnaires' disease in Glasgow, Scotland: application of statistical modelling.

This study investigated the relationships between Legionnaires' disease (LD) incidence and weather in Glasgow, UK, by using advanced statistical methods. Using daily meteorological data and 78 LD cases with known exact date of onset, we fitted a series of Poisson log-linear regression models with explanatory variables for air temperature, relative humidity, wind speed and year, and sine-cosine terms for within-year seasonal variation. Our initial model showed an association between LD incidence and 2-day lagged humidity (positive, P = 0·0236) and wind speed (negative, P = 0·033). However, after adjusting for year-by-year and seasonal variation in cases there were no significant associations with weather. We also used normal linear models to assess the importance of short-term, unseasonable weather values. The most significant association was between LD incidence and air temperature residual lagged by 1 day prior to onset (P = 0·0014). The contextual role of unseasonably high air temperatures is worthy of further investigation. Our methods and results have further advanced understanding of the role which weather plays in risk of LD infection.

The good, the bad and the flexible: plant interactions with pollinators and herbivores over space and time are moderated by plant compensatory responses.

BACKGROUND AND AIMS: Plants are sessile organisms that face selection by both herbivores and pollinators. Herbivores and pollinators may select on the same traits and/or mediate each others' effects. Erysimum capitatum (Brassicaceae) is a widespread and variable plant species with generalized pollination that is attacked by a number of herbivores. The following questions were addressed. (a) Are pollinators and herbivores attracted by similar plant traits? (b) Does herbivory affect pollinator preferences? (c) Do pollinators and/or herbivores affect fitness and select on plant traits? (d) Do plant compensatory responses affect the outcome of interactions among plants, pollinators and herbivores? (e) Do interactions among E. capitatum and its pollinators and herbivores differ among sites and years? METHODS: In 2005 and 2006, observational and experimental studies were combined in four populations at different elevations to examine selection by pollinators and herbivores on floral traits of E. capitatum. KEY RESULTS: Pollinator and herbivore assemblages varied spatially and temporally, as did their effects on plant fitness and selection. Both pollinators and herbivores preferred plants with more flowers, and herbivory sometimes reduced pollinator visitation. Pollinators did not select on plant traits in any year or population and E. capitatum was not pollen limited; however, supplemental pollen resulted in altered plant resource allocation. Herbivores reduced fitness and selected for plant traits in some populations, and these effects were mediated by plant compensatory responses. CONCLUSIONS: Individuals of Erysimum capitatum are visited by diverse groups of pollinators and herbivores that shift in abundance and importance in time and space. Compensatory reproductive mechanisms mediate interactions with both pollinators and herbivores and may allow E. capitatum to succeed in this complex selective environment.

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.

Modular genetic architecture of floral morphology in Nicotiana: quantitative genetic and comparative phenotypic approaches to floral integration.

Animal-pollinated flowers are complex structures that may require a precise configuration of floral organs for proper function. As such, they represent an excellent system with which we can examine the role of phenotypic integration and modularity in morphological evolution. We use complementary quantitative genetic and comparative phenotypic approaches to examine correlations among floral characters in Nicotiana alata, N. forgetiana and their artificial fourth-generation hybrids. Flowers of both species share basic patterns of genetic and phenotypic correlations characterized by at least two integrated character suites that are relatively independent of each other and are not disrupted by four generations of recombination in hybrids. We conclude that these integrated character suites represent phenotypic modules that are the product of a modular genetic architecture. Intrafloral modularity may have been critical for rapid specialization of these species to different pollinators.

Dynamics of maternal and paternal effects on embryo and seed development in wild radish (Raphanus sativus).

BACKGROUND AND AIMS: Variability in embryo development can influence the rate of seed maturation and seed size, which may have an impact on offspring fitness. While it is expected that embryo development will be under maternal control, more controversial hypotheses suggest that the pollen donor and the embryo itself may influence development. These latter possibilities are, however, poorly studied. Characteristics of 10-d-old embryos and seeds of wild radish (Raphanus sativus) were examined to address: (a) the effects of maternal plant and pollen donor on development; (b) the effects of earlier reproductive events (pollen tube growth and fertilization) on embryos and seeds, and the influence of embryo size on mature seed mass; (c) the effect of water stress on embryos and seeds; (d) the effect of stress on correlations of embryo and seed characteristics with earlier and later reproductive events and stages; and (e) changes in maternal and paternal effects on embryo and seed characteristics during development. METHODS: Eight maternal plants (two each from four families) and four pollen donors were crossed and developing gynoecia were collected at 10 d post-pollination. Half of the maternal plants experienced water stress. Characteristics of embryos and seeds were summarized and also compared with earlier and later developmental stages. KEY RESULTS: In addition to the expected effects of the maternal plants, all embryo characters differed among pollen donors. Paternal effects varied over time, suggesting that there are windows of opportunity for pollen donors to influence embryo development. Water-stress treatment altered embryo characteristics; embryos were smaller and less developed. In addition, correlations of embryo characteristics with earlier and later stages changed dramatically with water stress. CONCLUSIONS: The expected maternal effects on embryo development were observed, but there was also evidence for an early paternal role. The relative effects of these controls may change over time. Thus, there may be times in development when selection on the maternal, paternal or embryo contributions to development are more and less likely.

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.

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.

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.

Point-source modelling using matched case-control data.

We describe an extension to matched case-control studies of the parametric modelling framework developed by Diggle (1990) and Diggle and Rowlingson (1994) to investigate raised risk around putative sources of environmental pollution. We use a conditional likelihood approach for the family of risk functions considered in Diggle and Rowlingson (1994). We show that the likelihood surface that results from these models may be highly irregular, and provide a Bayesian analysis in which we investigate the posterior distribution using Markov chain Monte Carlo. An analysis of one-one matched data that were collected to investigate the relationship between respiratory disease and distance to roads in East London is presented.