Field-Isolated Genotypes of Mycobacterium bovis Vary in Virulence and Influence Case Pathology but Do Not Affect Outbreak Size

Strains of many infectious agents differ in fundamental epidemiological parameters including transmissibility, virulence and pathology. We investigated whether genotypes of Mycobacterium bovis (the causative agent of bovine tuberculosis, bTB) differ significantly in transmissibility and virulence, combining data from a nine-year survey of the genetic structure of the M. bovis population in Northern Ireland with detailed records of the cattle population during the same period. We used the size of herd breakdowns as a proxy measure of transmissibility and the proportion of skin test positive animals (reactors) that were visibly lesioned as a measure of virulence. Average breakdown size increased with herd size and varied depending on the manner of detection (routine herd testing or tracing of infectious contacts) but we found no significant variation among M. bovis genotypes in breakdown size once these factors had been accounted for. However breakdowns due to some genotypes had a greater proportion of lesioned reactors than others, indicating that there may be variation in virulence among genotypes. These findings indicate that the current bTB control programme may be detecting infected herds sufficiently quickly so that differences in virulence are not manifested in terms of outbreak sizes. We also investigated whether pathology of infected cattle varied according to M. bovis genotype, analysing the distribution of lesions recorded at post mortem inspection. We concentrated on the proportion of cases lesioned in the lower respiratory tract, which can indicate the relative importance of the respiratory and alimentary routes of infection. The distribution of lesions varied among genotypes and with cattle age and there were also subtle differences among breeds. Age and breed differences may be related to differences in susceptibility and husbandry, but reasons for variation in lesion distribution among genotypes require further investigation. © 2013 Wright et al.

Beta-blocker usage and prostate cancer survival:A nested case-control study in the UK Clinical Practice Research Datalink cohort

Background: Recent laboratory and epidemiological evidence suggests that beta-blockers could inhibit prostate cancer progression. Methods: We investigated the effect of beta-blockers on prostate cancer-specific mortality in a cohort of prostate cancer patients. Prostate cancer patients diagnosed between 1998 and 2006 were identified from the UK Clinical Practice Research Database and confirmed by cancer registries. Patients were followed up to 2011 with deaths identified by the Office of National Statistics. A nested case-control analysis compared patients dying from prostate cancer (cases) with up to three controls alive at the time of their death, matched by age and year of diagnosis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Results: Post-diagnostic beta-blocker use was identified in 25% of 1184 prostate cancer-specific deaths and 26% of 3531 matched controls. There was little evidence (P=0.40) of a reduction in the risk of cancer-specific death in beta-blocker users compared with non-users (OR=0.94 95% CI 0.81, 1.09). Similar results were observed after adjustments for confounders, in analyses by beta-blocker frequency, duration, type and for all-cause mortality. Conclusions: Beta-blocker usage after diagnosis was not associated with cancer-specific or all-cause mortality in prostate cancer patients in this large UK study.

The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Comparing the decline in coronary heart disease and stroke mortality in neighbouring countries with different healthcare systems

Objective
To examine age and gender specific trends in coronary heart disease (CHD) and stroke mortality in two neighbouring countries, the Republic of Ireland (ROI) and Northern Ireland (NI). Design Epidemiological study of time trends in CHD and stroke mortality.

Setting/patients
The populations of the ROI and NI, 1985–2010.

Interventions
None.

Main outcome measures
Directly age standardised CHD and stroke mortality rates were calculated and analysed using joinpoint regression to identify years where the slope of the linear trend changed significantly. This was performed separately for specific age groups (25–54, 55–64, 65–74 and 75–84 years) and by gender. Annual percentage change (APC) and 95% CIs are presented.

Results
There was a striking similarity between the two countries, with percentage change between 1985 and 1989 and between 2006 and 2010 of 67% and 69% in
CHD mortality, and 64% and 62% in stroke mortality for the ROI and NI, respectively. However, joinpoint analysis identified differences in the pace of change between the two countries. There was an accelerated pace of decline (negative APC) in mortality for both CHD and stroke in both countries from the mid-1990s (APC ROI −8% (95% CI −9.5 to 6.5) and NI −6.6% (−6.9 to −6.3)), but the accelerated decrease started later for CHD mortality in the ROI. In recent years, a levelling off in CHD mortality was observed in the 25–54 year age group in NI and in stroke mortality for men and women in the ROI.

Conclusions
While differences in the pace of change in mortality were observed at different time points, similar, substantial decreases in CHD and stroke mortality were achieved between 1985 and 1989 and between 2006 and 2010 in the ROI and NI despite important differences in health service structures. There is evidence of a levelling in mortality rates in some groups in recent years.

Multiple Biomarkers for the prediction of ischemic stroke: the PRIME study

Objective: To simultaneously evaluate 14 biomarkers from distinct biological pathways for risk prediction of ischemic stroke, including biomarkers of hemostasis, inflammation, and endothelial activation as well as chemokines and adipocytokines.
Methods and Results: The Prospective Epidemiological Study on Myocardial Infarction (PRIME) is a cohort of 9771 healthy men 50 to 59 years of age who were followed up over 10 years. In a nested case–control study, 95 ischemic stroke cases were matched with 190 controls. After multivariable adjustment for traditional risk factors, fibrinogen (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.03–2.28), E-selectin (OR, 1.76; 95% CI, 1.06–2.93), interferon-γ-inducible-protein-10 (OR, 1.72; 95% CI, 1.06–2.78), resistin (OR, 2.86; 95% CI, 1.30–6.27), and total adiponectin (OR, 1.82; 95% CI, 1.04–3.19) were significantly associated with ischemic stroke. Adding E-selectin and resistin to a traditional risk factor model significantly increased the area under the receiver-operating characteristic curve from 0.679 (95% CI, 0.612–0.745) to 0.785 and 0.788, respectively, and yielded a categorical net reclassification improvement of 29.9% (P=0.001) and 28.4% (P=0.002), respectively. Their simultaneous inclusion in the traditional risk factor model increased the area under the receiver-operating characteristic curve to 0.824 (95% CI, 0.770–0.877) and resulted in an net reclassification improvement of 41.4% (P<0.001). Results were confirmed when using continuous net reclassification improvement.
Conclusion: Among multiple biomarkers from distinct biological pathways, E-selectin and resistin provided incremental and additive value to traditional risk factors in predicting ischemic stroke.

Periodontal systemic associations: review of the evidence

Aim: To critically appraise recent research into associations between periodontal disease and systemic diseases and conditions specifically respiratory disease, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer.

Methods: A MEDLINE literature search of papers published between 2002 and April 2012 was conducted. Studies that included periodontitis as an exposure were identified. Cross-sectional epidemiological investigations on large samples, prospective studies and systematic reviews formed the basis of the narrative review. A threshold set for the identification of periodontitis was used to identify those studies that contributed to the conclusions of the review.

Results: Many of the investigations were cross-sectional secondary analyses of existing data sets in particular the NHANES studies. There were a small number of systematic reviews and prospective studies. There was substantial variability in the definitions of exposure to periodontitis. A small number of studies met the threshold set for periodontitis and supported associations; however, in some of the chronic diseases there were no such studies. There was strong evidence from randomized controlled trials that interventions, which improve oral hygiene have positive effects on the prevention of nosocomial pneumonias.

Conclusions: There was substantial heterogeneity in the definitions used to identify periodontitis and very few studies met a stringent threshold for periodontitis. Published evidence supports modest associations between periodontitis and some, although not all, of the diseases and conditions reviewed. There is a need to reach a consensus on what constitutes periodontitis for future studies of putative associations with systemic diseases.

Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina

Clinical epidemiological studies have revealed relatively weak, yet statistically significant, associations between dyslipidemia/dyslipoproteinemia and diabetic retinopathy (DR). Recent large interventional studies, however, demonstrated an unexpectedly robust efficacy of fenofibrate on the development of DR, possibly independent of plasma lipids. To unify the apparent discrepancies, we hypothesize that plasma lipoproteins play an indirect but important role in DR, contingent on the integrity of the blood-retina-barrier (BRB). In retinas with an intact BRB, plasma lipoproteins may be largely irrelevant; however, important effects become operative after the BRB is impaired in diabetes, leading to lipoprotein extravasation and subsequent modification, hence toxicity to the neighbouring retinal cells. In this hypothesis, BRB leakage is the key, plasma lipoprotein concentrations mainly modulate its consequences, and fenofibrate has intra-retinal actions. This review summarizes our current knowledge of the direct effects and mechanisms of modified lipoproteins on retinal cells and their potential contribution to the pathogenesis of DR.

Validation study to compare effects of processing protocols on measured N (ε)-(carboxymethyl)lysine and N (ε)-(carboxyethyl)lysine in blood

Epidemiological studies show that elevated plasma levels of advanced glycation end products (AGEs) are associated with diabetes, kidney disease, and heart disease. Thus AGEs have been used as disease progression markers. However, the effects of variations in biological sample processing procedures on the level of AGEs in plasma/serum samples have not been investigated. The objective of this investigation was to assess the effect of variations in blood sample collection on measured N (ε)-(carboxymethyl)lysine (CML), the best characterised AGE, and its homolog, N (ε)-(carboxyethyl)lysine (CEL). The investigation examined the effect on CML and CEL of different blood collection tubes, inclusion of a stabilising cocktail, effect of freeze thaw cycles, different storage times and temperatures, and effects of delaying centrifugation on a pooled sample from healthy volunteers. CML and CEL were measured in extracted samples by ultra-performance liquid chromatography-tandem mass spectrometry. Median CML and CEL ranged from 0.132 to 0.140 mM/M lys and from 0.053 to 0.060 mM/M lys, respectively. No significant difference was shown CML or CEL in plasma/serum samples. Therefore samples collected as part of epidemiological studies that do not undergo specific sample treatment at collection are suitable for measuring CML and CEL.

Interspecific competition in honeybee intracellular gut parasites is asymmetric and favours the spread of an emerging infectious disease

There is increasing appreciation that hosts in natural populations are subject to infection by multiple parasite species. Yet the epidemiological and ecological processes determining the outcome of mixed infections are poorly understood. Here, we use two intracellular gut parasites (Microsporidia), one exotic and one co-evolved in the western honeybee (Apis mellifera), in an experiment in which either one or both parasites were administered either simultaneously or sequentially. We provide clear evidence of within-host competition; order of infection was an important determinant of the competitive outcome between parasites, with the first parasite significantly inhibiting the growth of the second, regardless of species. However, the strength of this ‘priority effect’ was highly asymmetric, with the exotic Nosema ceranae exhibiting stronger inhibition of Nosema apis than vice versa. Our results reveal an unusual asymmetry in parasite competition that is dependent on order of infection. When incorporated into a mathematical model of disease prevalence, we find asymmetric competition to be an important predictor of the patterns of parasite prevalence found in nature. Our findings demonstrate the wider significance of complex multi-host–multi-parasite interactions as drivers of host–pathogen community structure

Multiplex Touchdown PCR for Rapid Typing of the Opportunistic Pathogen Propionibacterium acnes.

The opportunistic human pathogen Propionibacterium acnes is comprised of a number of distinct phylogroups, designated types IA1, IA2, IB, IC, II and III, that vary in their production of putative virulence factors, inflammatory potential, as well as biochemical, aggregative and morphological characteristics. Although Multilocus Sequence Typing (MLST) currently represents the gold standard for unambiguous phylogroup classification, and individual strain identification, it is a labour and time-consuming technique. As a consequence, we have developed a multiplex touchdown PCR assay that will, in a single reaction, confirm species identity and phylogeny of an isolate based on its pattern of reaction with six primer sets that target the 16S rRNA (all isolates), ATPase (type IA1, IA2, IC), sodA (type IA2, IB), atpD (type II) and recA (type III) housekeeping genes, as well as a Fic family toxin gene (type IC). When applied to 312 P. acnes isolates previously characterised by MLST, and representing type IA1 (n=145), IA2 (n=20), IB (n=65), IC (n=7), II (n=45) and III (n=30), the multiplex displayed 100% sensitivity and 100% specificity for the detection of isolates within each targeted phylogroup. No cross-reactivity with isolates from other bacterial species was observed. The multiplex assay will provide researchers with a rapid, high-throughput and technically undemanding typing method for epidemiological and phylogenetic investigations. It will facilitate studies investigating the association of lineages with various infections and clinical conditions, as well as a pre-screening tool to maximise the number of genetically diverse isolates selected for downstream, higher resolution sequence-based analyses.

Is the shortened dental arch an underused treatment strategy in the Republic of Ireland?

OBJECTIVES: To determine the proportion of Republic of Ireland 35-44 and 65+ year-olds currently satisfying the criteria for a classic shortened dental arch (SDA) of 20 anterior teeth.

RESEARCH DESIGN: Secondary analysis of data collected in the 2000/02 epidemiological survey of the oral health of Irish adults.

CLINICAL SETTING: Participants underwent a clinical oral examination in health board dental clinics and completed a detailed interview pertaining to dental and general health.

PARTICIPANTS: The analysis is based on a random sample of adults, aged 35 to 44 years (n = 978), and 65 years and older (n = 714).

MAIN OUTCOME MEASURES: The SDA was measured as 20 teeth in the mouth in the positions normally described as from the left second premolar to the right second premolar in each arch.

RESULTS: Only one of the 35-44 year-olds and none of the 65+ year-olds had teeth in their mouths in positions normally described as a classic SDA. However, of the 35-44 year old age group only five patients who had at least a premolar dentition of 20 contiguous teeth had been provided with a removable denture compared to one patient from the 65+ years group.

CONCLUSIONS: Very few older patients in the Republic of Ireland have a SDA based on the measure used. However, very few have been provided with removable dentures where they already possess at least a premolar dentition of 20 contiguous teeth. Suggested reasons for this may include limitations of the data recorded, patient preferences and economic factors.

Digital pathology and image analysis in tissue biomarker research

Digital pathology and the adoption of image analysis have grown rapidly in the last few years. This is largely due to the implementation of whole slide scanning, advances in software and computer processing capacity and the increasing importance of tissue-based research for biomarker discovery and stratified medicine. This review sets out the key application areas for digital pathology and image analysis, with a particular focus on research and biomarker discovery. A variety of image analysis applications are reviewed including nuclear morphometry and tissue architecture analysis, but with emphasis on immunohistochemistry and fluorescence analysis of tissue biomarkers. Digital pathology and image analysis have important roles across the drug/companion diagnostic development pipeline including biobanking, molecular pathology, tissue microarray analysis, molecular profiling of tissue and these important developments are reviewed. Underpinning all of these important developments is the need for high quality tissue samples and the impact of pre-analytical variables on tissue research is discussed. This requirement is combined with practical advice on setting up and running a digital pathology laboratory. Finally, we discuss the need to integrate digital image analysis data with epidemiological, clinical and genomic data in order to fully understand the relationship between genotype and phenotype and to drive discovery and the delivery of personalized medicine.

Inequality and Heights

This chapter discusses opportunities and limitations of height inequality, especially the role of social status and income distribution in determining height inequality. The more unequal the income distribution in a society, the more unequal the corresponding height distribution. At one time, the height gap between rich and poor teenagers in industrializing England was as high as 22 cm (8.7 inches); today, height inequality tends to be much lower (on the order of a few centimeters) because the gap between rich and poor in developed countries tends to be smaller. Results presented here suggest that height inequality is driven by differences in purchasing power, education, physical workload, and epidemiological environment. In a modern setting, social safety and redistribution of income is also relevant. An introduction into the literature helps illustrate opportunities this methodology has to offer to understand better the dynamics of the way populations experience economic development.

Genetics of Diabetic Nephropathy: a Long Road of Discovery

The global prevalence of diabetic nephropathy is rising in parallel with the increasing incidence of diabetes in most countries. Unfortunately, up to 40 % of persons diagnosed with diabetes may develop kidney complications. Diabetic nephropathy is associated with substantially increased risks of cardiovascular disease and premature mortality. An inherited susceptibility to diabetic nephropathy exists, and progress is being made unravelling the genetic basis for nephropathy thanks to international research collaborations, shared biological resources and new analytical approaches. Multiple epidemiological studies have highlighted the clinical heterogeneity of nephropathy and the need for better phenotyping to help define important subgroups for analysis and increase the power of genetic studies. Collaborative genome-wide association studies for nephropathy have reported unique genes, highlighted novel biological pathways and suggested new disease mechanisms, but progress towards clinically relevant risk prediction models for diabetic nephropathy has been slow. This review summarises the current status, recent developments and ongoing challenges elucidating the genetics of diabetic nephropathy.

Deriving meteorological variables across Africa for the study and control of vector-borne disease:a comparison of remote sensing and spatial interpolation of climate

This paper presents the results of an investigation into the utility of remote sensing (RS) using meteorological satellites sensors and spatial interpolation (SI) of data from meteorological stations, for the prediction of spatial variation in monthly climate across continental Africa in 1990. Information from the Advanced Very High Resolution Radiometer (AVHRR) of the National Oceanic and Atmospheric Administration's (NOAA) polar-orbiting meteorological satellites was used to estimate land surface temperature (LST) and atmospheric moisture. Cold cloud duration (CCD) data derived from the High Resolution Radiometer (HRR) onboard the European Meteorological Satellite programme's (EUMETSAT) Meteosat satellite series were also used as a RS proxy measurement of rainfall. Temperature, atmospheric moisture and rainfall surfaces were independently derived from SI of measurements from the World Meteorological Organization (WMO) member stations of Africa. These meteorological station data were then used to test the accuracy of each methodology, so that the appropriateness of the two techniques for epidemiological research could be compared. SI was a more accurate predictor of temperature, whereas RS provided a better surrogate for rainfall; both were equally accurate at predicting atmospheric moisture. The implications of these results for mapping short and long-term climate change and hence their potential for the study anti control of disease vectors are considered. Taking into account logistic and analytical problems, there were no clear conclusions regarding the optimality of either technique, but there was considerable potential for synergy.