Patrick E. Brown

Frequency and Spatial Distribution of Environmental Campylobacter spp.

ABSTRACT Humans are exposed to Campylobacter spp. in a range of sources via both food and environmental pathways. For this study, we explored the frequency and distribution of thermophilic Campylobacter spp. in a 10- by 10-km square rural area of Cheshire, United Kingdom. The area contains approximately 70, mainly dairy, farms and is used extensively for outdoor recreational activities. Campylobacter spp. were isolated from a range of environmental samples by use of a systematic sampling grid. Livestock (mainly cattle) and wildlife feces and environmental water and soil samples were cultured, and isolates were presumptively identified by standard techniques. These isolates were further characterized by PCR. Campylobacter jejuni was the most prevalent species in all animal samples, ranging from 11% in samples from nonavian wildlife to 36% in cattle feces, and was isolated from 15% of water samples. Campylobacter coli was commonly found in water (17%) and sheep (21%) samples, but rarely in other samples. Campylobacter lari was recovered from all sample types, with the exception of sheep feces, and was found in moderate numbers in birds (7%) and water (5%). Campylobacter hyointestinalis was only recovered from cattle (7%) and birds (1%). The spatial distribution and determinants of C. jejuni in cattle feces were examined by the use of model-based spatial statistics. The distribution was consistent with very localized within-farm or within-field transmission and showed little evidence of any larger-scale spatial dependence. We concluded that there is a potentially high risk of human exposure to Campylobacter spp., particularly C. jejuni, in the environment of our study area. The prevalence and likely risk posed by C. jejuni-positive cattle feces in the environment diminished as the fecal material aged. After we took into account the age of the fecal material, the absence or presence of rain, and the presence of bird feces, there was evidence of significant variation in the prevalence of C. jejuni-positive cattle feces between grazing fields but no evidence of spatial clustering beyond this resolution. The spatial pattern of C. jejuni is therefore consistent with that for an organism that is ubiquitous in areas contaminated with cattle feces, with a short-scale variation in infection intensity that cannot be explained solely by variations in the age of the fecal material. The observed pattern is not consistent with large-scale transmission attributable to watercourses, wildlife territories, or other geographical features that transcend field and farm boundaries.

Space–time calibration of radar rainfall data

Motivated by a specific problem concerning the relationship between radar reflectance and rainfall intensity, the paper develops a space–time model for use in environmental monitoring applications. The model is cast as a high dimensional multivariate state space time series model, in which the cross-covariance structure is derived from the spatial context of the component series, in such a way that its interpretation is essentially independent of the particular set of spatial locations at which the data are recorded. We develop algorithms for estimating the parameters of the model by maximum likelihood, and for making spatial predictions of the radar calibration parameters by using realtime computations. We apply the model to data from a weather radar station in Lancashire, England, and demonstrate through empirical validation the predictive performance of the model.

Proprotein Convertase Subtilisin Kexin Type 9 Promotes Intestinal Overproduction of Triglyceride-Rich Apolipoprotein B Lipoproteins Through Both Low-Density Lipoprotein Receptor–Dependent and –Independent Mechanisms

Background— Proprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein (LDL) receptor (LDLR), and its deficiency in humans results in low plasma LDL cholesterol and protection against coronary heart disease. Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins, another important coronary heart disease risk factor. Here, we studied the effects of physiological levels of PCSK9 on intestinal triglyceride-rich apoB lipoprotein production and elucidated for the first time the cellular and molecular mechanisms involved. Methods and Results— Treatment of human enterocytes (CaCo-2 cells) with recombinant human PCSK9 (10 &mgr;g/mL for 24 hours) increased cellular and secreted apoB48 and apoB100 by 40% to 55% each (P<0.01 versus untreated cells), whereas short-term deletion of PCSK9 expression reversed this effect. PCSK9 stimulation of apoB was due to a 1.5-fold increase in apoB mRNA (P<0.01) and to enhanced apoB protein stability through both LDLR-dependent and LDLR-independent mechanisms. PCSK9 decreased LDLR protein (P<0.01) and increased cellular apoB stability via activation of microsomal triglyceride transfer protein. PCSK9 also increased levels of the lipid-generating enzymes FAS, SCD, and DGAT2 (P<0.05). In mice, human PCSK9 at physiological levels increased intestinal microsomal triglyceride transfer protein levels and activity regardless of LDLR expression. Conclusions— PCSK9 markedly increases intestinal triglyceride-rich apoB production through mechanisms mediated in part by transcriptional effects on apoB, microsomal triglyceride transfer protein, and lipogenic genes and in part by posttranscriptional effects on the LDLR and microsomal triglyceride transfer protein. These findings indicate that targeted PCSK9-based therapies may also be effective in the management of postprandial hypertriglyceridemia.

Spatial patterns reveal negative density dependence and habitat associations in tropical trees

Understanding how plant species coexist in tropical rainforests is one of the biggest challenges in community ecology. One prominent hypothesis suggests that rare species are at an advantage because trees have lower survival in areas of high conspecific density due to increased attack by natural enemies, a process known as negative density dependence (NDD). A consensus is emerging that NDD is important for plant-species coexistence in tropical forests. Most evidence comes from short-term studies, but testing the prediction that NDD decreases the spatial aggregation of tree populations provides a long-term perspective. While spatial distributions have provided only weak evidence for NDD so far, the opposing effects of environmental heterogeneity might have confounded previous analyses. Here we use a novel statistical technique to control for environmental heterogeneity while testing whether spatial aggregation decreases with tree size in four tropical forests. We provide evidence for NDD in 22% of the 139 tree species analyzed and show that environmental heterogeneity can obscure the spatial signal of NDD. Environmental heterogeneity contributed to aggregation in 84% of species. We conclude that both biotic interactions and environmental heterogeneity play crucial roles in shaping tree dynamics in tropical forests.

The Contribution of Clinical Breast Examination to the Accuracy of Breast Screening

BACKGROUND There is controversy about whether adding clinical breast examination (CBE) to mammography improves the accuracy of breast screening. We compared the accuracy of screening among centers that offered CBE in addition to mammography with that among centers that offered only mammography. METHODS The cohort included 290 230 women aged 50-69 years who were screened at regional cancer centers or affiliated centers within the Ontario Breast Screening Program between January 1, 2002, and December 31, 2003, and were followed up for 12 months. The regional cancer centers offer screening mammography and CBE performed by a nurse. All affiliated centers provide mammography but not all provide CBE. Performance measures for 232 515 women who were screened by mammography and CBE at the nine regional cancer centers or 59 affiliated centers that provided CBE were compared with those for 57 715 women who were screened by mammography alone at 34 affiliated centers that did not provide CBE. RESULTS Sensitivity of referrals was higher for women who were screened at regional cancer centers or affiliated centers that offered CBE in addition to mammography than for women screened at affiliated centers that did not offer CBE (initial screen: 94.9% and 94.6%, respectively, vs 88.6%; subsequent screen: 94.9% and 91.7%, respectively, vs 85.3%). Mammography sensitivity was similar between centers that offered CBE and those that did not. However, women without cancer who were screened at regional cancer centers or affiliated centers that offered CBE had a higher false-positive rate than women screened at affiliated centers that offered only mammography (initial screen: 12.5% and 12.4%, respectively, vs 7.4%; subsequent screen: 6.3% and 8.3%, respectively, vs 5.4%). CONCLUSIONS Women should be informed of the benefits and risks of having a CBE in addition to mammography for breast screening.

Digital compared with screen-film mammography: performance measures in concurrent cohorts within an organized breast screening program.

PURPOSE To evaluate the performance of digital direct radiography (DR) and computed radiography (CR) compared with that of screen-film mammography (SFM) in large concurrent cohorts. MATERIALS AND METHODS This study was approved by the University of Toronto Research Ethics Board and did not require informed consent. Concurrent cohorts of women aged 50-74 years screened with DR (n = 220 520), CR (n = 64 210), or SFM (n = 403 688) between 2008 and 2009 were identified and followed for 12 months. Performance was compared between cohorts, with SFM as the referent cohort. Associations were examined by using mixed-effect logistic regression. RESULTS The cancer detection rate was similar for DR (4.9 per 1000; 95% confidence interval [CI]: 4.7, 5.2) and SFM (4.8 per 1000; 95% CI: 4.7, 5.0); however, the rate was significantly lower for CR (3.4 per 1000; 95% CI: 3.0, 3.9) (odds ratio, 0.79; 95% CI: 0.68, 0.93). Recall rates were higher for DR (7.7%; 95% CI: 7.6%, 7.8%) and lower for CR (6.6%; 95% CI: 6.5%, 6.7%) than for SFM (7.4%; 95% CI: 7.3%, 7.5%). Positive predictive value was lower for CR (5.2%; 95% CI: 4.7%, 5.8%) than for SFM (6.6%; 95% CI: 6.4%, 6.8%); however, the adjusted odds were not significant. CONCLUSION Although DR is equivalent to SFM for breast screening among women aged 50-74 years, the cancer detection rate was lower for CR. Screening programs should monitor the performance of CR separately and may consider informing women of the potentially lower cancer detection rates.

Quantifying within- and between-animal variation and uncertainty associated with counts of Escherichia coli O157 occurring in naturally infected cattle faeces

Cattle faeces are considered the most important reservoir for human infection with Escherichia coli O157. We have previously described shedding of E. coli O157 in the faeces of naturally infected cattle cohorts. However, the data require further investigation to quantify the uncertainty and variability in the estimates previously presented. This paper proposes a method for analysing both the presence and the quantity of E. coli O157 in cattle faecal samples, using two isolation procedures, one of which enumerates E. coli O157. The combination of these two measurements, which are fundamentally different in nature and yet measuring a common outcome, has necessitated the development of a novel statistical model for ascertaining the contribution of the various components of variation (both natural and observation induced) and for judging the influence of explanatory variables. Most of the variation within the sampling hierarchy was attributable to multiple samples from the same animal. The contribution of laboratory-level variation was found to be low. After adjusting for fixed and random effects, short periods of increased intensity of shedding were identified in individual animals. We conclude that within-animal variation is greater than between animals over time, and studies aiming to elucidate the dynamics of shedding should focus resources, sampling more within than between animals. These findings have implications for the identification of persistent high shedders and for assessing their role in the epidemiology of E. coli O157 in cattle populations. The development of this non-standard statistical model may have many applications to other microbial count data.

A recursive estimation approach to the spatio-temporal analysis and modelling of air quality data

This paper presents the methodology for the spatial and temporal interpolation of air quality data. As a practical example, the methodology is applied to the daily nitric oxide NO concentrations measured at 23 stations around Paris. Analysis of the temporal and spatial variability of observations of NO in the Paris area is divided into: (i) time series analysis of AirParif data; and (ii) development of combined spatial and temporal analysis techniques using NO observations from 19 stations. The first part of the paper shows how advanced methods of nonstationary time series analysis can be used to interpolate the data sets of NO concentrations over periods where measurements are missing and to decompose the time series into trend and harmonic components. The results of this analysis applied to 19 stations around Paris are then used in further spatio-temporal analysis of the data. This consists of two steps: (i) preliminary analysis of spatial relations within the data sets; and (ii) the development of a spatio-temporal model for log-transformed NO measurements. The results of the analysis indicate that the simple spatio-temporal model consisting of trend and noise efficiently represents the spatio-temporal variations in the data and it can be applied to predict air pollution variations in time and space at un-sampled locations.

Digital Compared with Screen-Film Mammography: Measures of Diagnostic Accuracy among Women Screened in the Ontario Breast Screening Program

PURPOSE To compare measures of diagnostic accuracy between large concurrent cohorts of women screened with digital computed radiography (CR), direct radiography (DR), and screen-film mammography (SFM). MATERIALS AND METHODS This study was approved by the University of Toronto Research Ethics Board; informed consent was not required. Three concurrent cohorts of women aged 50-74 years who were screened from 2008-2009 in the Ontario Breast Screening Program with SFM (487,334 screening examinations, 403,688 women), DR (254,758 screening examinations, 220,520 women), or CR (74,140 screening examinations, 64,210 women) were followed for 2 years or until breast cancer diagnosis. Breast cancers were classified as screening-detected or interval on the basis of the womans final screening and assessment results. Interval cancer rate (per 10 000 negative screening examinations), sensitivity, and specificity were compared across the cohorts by using mixed-effects logistic regression analysis. RESULTS Interval cancer rates were higher, although not significantly so, for CR (15.2 per 10,000; 95% confidence interval [CI]: 12.8, 17.8) and were similar for DR (13.7 per 10,000; 95% CI: 12.4, 15.0) compared with SFM (13.0 per 10,000; 95% CI: 12.1, 13.9). For CR versus SFM, specificity was similar while sensitivity was significantly lower (odds ratio [OR] = 0.62; 95% CI: 0.47, 0.83; P = .001), particularly for invasive cancers detected at a rescreening examination, for women with breast density of less than 75%, for women with no family history, and for postmenopausal women. For DR versus SFM, sensitivity was similar while specificity was lower (OR = 0.92; 95% CI: 0.87, 0.98; P = .01), particularly for rescreening examinations, for women aged 60-74 years, for women with breast density of less than 75%, for women with a family history, and for women who were postmenopausal. CONCLUSION Given the 38% lower sensitivity of CR imaging systems compared with SFM, programs should assess the continued use of this technology for breast screening.

Log Gaussian Cox processes and spatially aggregated disease incidence data.

This article presents a methodology for modeling aggregated disease incidence data with the spatially continuous log-Gaussian Cox process. Statistical models for spatially aggregated disease incidence data usually assign the same relative risk to all individuals in the same reporting region (census areas or postal regions). A further assumption that the relative risks in two regions are independent given their neighbors risks (the Markov assumption) makes the commonly used Besag–York–Mollié model computationally simple. The continuous model proposed here uses a data augmentation step to sample from the posterior distribution of the exact locations at each step of an Markov chain Monte Carlo algorithm, and models the exact locations with an log-Gaussian Cox process. A simulation study shows the log-Gaussian Cox process model consistently outperforming the Besag–York–Mollié model. The method is illustrated by making inference on the spatial distribution of syphilis risk in North Carolina. The effect of several known social risk factors are estimated, and areas with risk well in excess of that expected given these risk factors are identified.