Whole Genome Sequencing Reveals Local Transmission Patterns of Mycobacterium bovis in Sympatric Cattle and Badger Populations

Whole genome sequencing (WGS) technology holds great promise as a tool for the forensic epidemiology of bacterial pathogens. It is likely to be particularly useful for studying the transmission dynamics of an observed epidemic involving a largely unsampled 'reservoir' host, as for bovine tuberculosis (bTB) in British and Irish cattle and badgers. BTB is caused by Mycobacterium bovis, a member of the M. tuberculosis complex that also includes the aetiological agent for human TB. In this study, we identified a spatio-temporally linked group of 26 cattle and 4 badgers infected with the same Variable Number Tandem Repeat (VNTR) type of M. bovis. Single-nucleotide polymorphisms (SNPs) between sequences identified differences that were consistent with bacterial lineages being persistent on or near farms for several years, despite multiple clear whole herd tests in the interim. Comparing WGS data to mathematical models showed good correlations between genetic divergence and spatial distance, but poor correspondence to the network of cattle movements or within-herd contacts. Badger isolates showed between zero and four SNP differences from the nearest cattle isolate, providing evidence for recent transmissions between the two hosts. This is the first direct genetic evidence of M. bovis persistence on farms over multiple outbreaks with a continued, ongoing interaction with local badgers. However, despite unprecedented resolution, directionality of transmission cannot be inferred at this stage. Despite the often notoriously long timescales between time of infection and time of sampling for TB, our results suggest that WGS data alone can provide insights into TB epidemiology even where detailed contact data are not available, and that more extensive sampling and analysis will allow for quantification of the extent and direction of transmission between cattle and badgers. © 2012 Biek et al.

Adjusting HIV Prevalence Estimates for Non-participation: an Application to Demographic Surveillance

Introduction: HIV testing is a cornerstone of efforts to combat the HIV epidemic, and testing conducted as part of surveillance provides invaluable data on the spread of infection and the effectiveness of campaigns to reduce the transmission of HIV. However, participation in HIV testing can be low, and if respondents systematically select not to be tested because they know or suspect they are HIV positive (and fear disclosure), standard approaches to deal with missing data will fail to remove selection bias. We implemented Heckman-type selection models, which can be used to adjust for missing data that are not missing at random, and established the extent of selection bias in a population-based HIV survey in an HIV hyperendemic community in rural South Africa.

Methods: We used data from a population-based HIV survey carried out in 2009 in rural KwaZulu-Natal, South Africa. In this survey, 5565 women (35%) and 2567 men (27%) provided blood for an HIV test. We accounted for missing data using interviewer identity as a selection variable which predicted consent to HIV testing but was unlikely to be independently associated with HIV status. Our approach involved using this selection variable to examine the HIV status of residents who would ordinarily refuse to test, except that they were allocated a persuasive interviewer. Our copula model allows for flexibility when modelling the dependence structure between HIV survey participation and HIV status.

Results: For women, our selection model generated an HIV prevalence estimate of 33% (95% CI 27–40) for all people eligible to consent to HIV testing in the survey. This estimate is higher than the estimate of 24% generated when only information from respondents who participated in testing is used in the analysis, and the estimate of 27% when imputation analysis is used to predict missing data on HIV status. For men, we found an HIV prevalence of 25% (95% CI 15–35) using the selection model, compared to 16% among those who participated in testing, and 18% estimated with imputation. We provide new confidence intervals that correct for the fact that the relationship between testing and HIV status is unknown and requires estimation.

Conclusions: We confirm the feasibility and value of adopting selection models to account for missing data in population-based HIV surveys and surveillance systems. Elements of survey design, such as interviewer identity, present the opportunity to adopt this approach in routine applications. Where non-participation is high, true confidence intervals are much wider than those generated by standard approaches to dealing with missing data suggest.

Vaccinations and childhood type 1 diabetes mellitus: a meta-analysis of observational studies

Aims/hypothesis The aim of this study was to investigate the association between routine vaccinations and the risk of childhood type 1 diabetes mellitus by systematically reviewing the published literature and performing meta-analyses where possible.

Methods A comprehensive literature search was performed of MEDLINE and EMBASE to identify all studies that compared vaccination rates in children who subsequently developed type 1 diabetes mellitus and in control children. ORs and 95% CIs were obtained from published reports or derived from individual patient data and then combined using a random effects meta-analysis.

Results In total, 23 studies investigating 16 vaccinations met the inclusion criteria. Eleven of these contributed to meta-analyses which included data from between 359 and 11,828 childhood diabetes cases. Overall, there was no evidence to suggest an association between any of the childhood vaccinations investigated and type 1 diabetes mellitus. The pooled ORs ranged from 0.58 (95% CI 0.24, 1.40) for the measles, mumps and rubella (MMR) vaccination in five studies up to 1.04 (95% CI 0.94, 1.14) for the haemophilus influenza B (HiB) vaccination in 11 studies. Significant heterogeneity was present in most of the pooled analyses, but was markedly reduced when analyses were restricted to study reports with high methodology quality scores. Neither this restriction by quality nor the original authors’ adjustments for potential confounding made a substantial difference to the pooled ORs.

Conclusions/interpretation This study provides no evidence of an association between routine vaccinations and childhood type 1 diabetes.

Application of the pMHC Array to Characterise Tumour Antigen Specific T Cell Populations in Leukaemia Patients at Disease Diagnosis

Immunotherapy treatments for cancer are becoming increasingly successful, however to further improve our understanding of the T-cell recognition involved in effective responses and to encourage moves towards the development of personalised treatments for leukaemia immunotherapy, precise antigenic targets in individual patients have been identified. Cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen specific T-cell populations naturally circulating in patients and normal donors. We have developed the pMHC array to detect CD8+ T-cell populations in leukaemia patients that recognise epitopes within viral antigens (cytomegalovirus (CMV) and influenza (Flu)) and leukaemia antigens (including Per Arnt Sim domain 1 (PASD1), MelanA, Wilms' Tumour (WT1) and tyrosinase). We show that the pMHC array is at least as sensitive as flow cytometry and has the potential to rapidly identify more than 40 specific T-cell populations in a small sample of T-cells (0.8-1.4 x 106). Fourteen of the twenty-six acute myeloid leukaemia (AML) patients analysed had T cells that recognised tumour antigen epitopes, and eight of these recognised PASD1 epitopes. Other tumour epitopes recognised were MelanA (n = 3), tyrosinase (n = 3) and WT1126-134 (n = 1). One of the seven acute lymphocytic leukaemia (ALL) patients analysed had T cells that recognised the MUC1950-958 epitope. In the future the pMHC array may be used provide point of care T-cell analyses, predict patient response to conventional therapy and direct personalised immunotherapy for patients.

Glucagon-like peptide-1 based therapies as a novel approach for chronic heart failure

Glucagon-like peptide-1 (GLP-1) is an endogenous peptide hormone whose metabolic effects have been exploited for glycaemic control in diabetes, but which also exerts important cardiovascular actions. We have recently reported that the GLP-1 mimetic, exendin-4, exerts clear benefits post-myocardial infarction via specific effects on extracellular matrix remodelling which is dysregulated in the diabetic heart (Robinson E et al, Basic Res Cardiol 2015; 110: 20), and have now shown similar cardioprotective actions in experimental diabetes, which are mediated via direct effects on infiltrating macrophages (Tate M et al, Basic Res Cardiol 2015; in press). Taken together with the apparent complexity of GLP-1 signalling and disappointing results of recent cardiovascular trials, our work strongly suggests that selective targeting of GLP-1 may be required in order to realise therapeutic benefit for both diabetic and non-diabetic heart failure patients. This is particularly important given the epidemic increase in the incidence of diabetes which is associated with a markedly enhanced susceptibility to cardiovascular stress.

Anomaly Detection for Data with Spatial Attributes

The problem of detecting spatially-coherent groups of data that exhibit anomalous behavior has started to attract attention due to applications across areas such as epidemic analysis and weather forecasting. Earlier efforts from the data mining community have largely focused on finding outliers, individual data objects that display deviant behavior. Such point-based methods are not easy to extend to find groups of data that exhibit anomalous behavior. Scan Statistics are methods from the statistics community that have considered the problem of identifying regions where data objects exhibit a behavior that is atypical of the general dataset. The spatial scan statistic and methods that build upon it mostly adopt the framework of defining a character for regions (e.g., circular or elliptical) of objects and repeatedly sampling regions of such character followed by applying a statistical test for anomaly detection. In the past decade, there have been efforts from the statistics community to enhance efficiency of scan statstics as well as to enable discovery of arbitrarily shaped anomalous regions. On the other hand, the data mining community has started to look at determining anomalous regions that have behavior divergent from their neighborhood.In this chapter,we survey the space of techniques for detecting anomalous regions on spatial data from across the data mining and statistics communities while outlining connections to well-studied problems in clustering and image segmentation. We analyze the techniques systematically by categorizing them appropriately to provide a structured birds eye view of the work on anomalous region detection;we hope that this would encourage better cross-pollination of ideas across communities to help advance the frontier in anomaly detection.

Glucagon-like peptide-1 based therapies as a novel approach for chronic heart failure

Glucagon-like peptide-1 (GLP-1) is an endogenous peptide hormone whose metabolic effects have been exploited for glycaemic control in diabetes, but which also exerts important cardiovascular actions. We have recently reported that the GLP-1 mimetic, exendin-4, exerts clear benefits post-myocardial infarction via specific effects on extracellular matrix remodelling which is dysregulated in the diabetic heart (Robinson E et al, Basic Res Cardiol 2015; 110: 20), and have now shown similar cardioprotective actions in experimental diabetes, which are mediated via direct effects on infiltrating macrophages (Tate M et al, Basic Res Cardiol 2016; 111: 1). Taken together with the apparent complexity of GLP-1 signalling and disappointing results of recent cardiovascular trials, our work strongly suggests that selective targeting of GLP-1 may be required in order to realise therapeutic benefit for both diabetic and non-diabetic heart failure patients. This is particularly important given the epidemic increase in the incidence of diabetes which is associated with a markedly enhanced susceptibility to cardiovascular stress.

Old Town Glasgow: Squalor, Agitation and City Improvements

In 1862, Glasgow Corporation initiated the first of a series of three legislative acts which would become known collectively as the City Improvements Acts. Despite having some influence on the nature of the built fabric on the expanding city as a whole, the most extensive consequences of these acts was reserved for one specific area of the city, the remnants of the medieval Old Town. As the city had expanded towards all points of the compass in a regular, grid-iron structure throughout the nineteenth century, the Old Town remained singularly as a densely wrought fabric of medieval wynds, vennels, oblique passageways and accelerated tenementalisation. Here, as the rest of the city began to assume the form of an ordered entity, visible and classifiable, one could still find and addresses such as ‘Bridgegate, No. 29, backland, stair first left, three up, right lobby, door facing’ (quoted in Pacione, 1995).

Unsurprisingly, this place, where proximity to the midden (dung-heap) was considered an enviable position, was seen by the authorities as a major health hazard and a source not only of cholera, but also of the more alarming typhoid epidemic of 1842. Accordingly, the demolitions which occurred in the backlands of the Old Town under the first of the acts, the Glasgow Police Act of 1862, were justified on health and medical grounds. But disease was not the only social problem thought to issue from this district. Reports from social reformers including Fredrick Engels suggested that the decay of the area’s physical fabric could be extended to the moral profile of its inhabitants. This was in such a state of degeneracy that there were calls for a nearby military barracks to be relocated to more salubrious climes because troops were routinely coming into contact ‘with the most dissolute and profligate portion of the population’ (Peter Clonston, Lord Provost, June 1861). Perhaps more worrying for the city fathers, however, was that the barracks’ arsenal was seen as a potential source of arms for the militant and often illegal cotton workers’ unions and organisations who inhabited the Old Town as well as the districts to the east. In fact, the Old Town and East End had been the site of numerous working class actions and riots since 1787, including a strike of 60,000 workers in 1820, 100,000 in 1838, and the so-called Bread Riots of 1848 where shouts of ‘Vive La Revolution’ were reported in the Gallowgate.

The events in Paris in 1848 precipitated Baron Hausmann’s interventions into that city. The boulevards were in turn visited by members of Glasgow Corporation and ultimately, it can be argued, provided an example for Old Town Glasgow. This paper suggests that the city improvement acts carried a similarly complex and pervasive agenda, one which embodied not only health, class conflict and sexual morality but also the more local condition of sectarianism. And, like in Paris, these were played out spatially in a extensive reconfiguration of the urban fabric of the Old Town which, through the creation of new streets and a railway yard, not only made it more amenable to large scale military manoeuvres but also, opened up the area to capitalist accumulation. By the end of the works, the medieval heritage of the Old Town had been almost completely razed, the working class and Catholic East End had, through the insertion of the railway yard, been isolated from the city centre and approximately 70,000 people had been made homeless.

Nutrition and the eye

The topic "nutrition and the eye" cannot adequately be covered in a single review article; indeed, dozens of books and hundreds of articles have been written on the subject. This review concentrates on three areas in which specific nutrients are known or theorized to have a major impact on vision and the visual system: vitamin A deficiency; antioxidants and their proposed role in the prevention of age-related cataract and macular degeneration; and nutritional optic neuropathies, including those of the recent Cuban epidemic. In addition, this article touches on nutritional treatments that have been suggested for several less common eye diseases and, finally, considers several less prevalent conditions in which deficiency of or excess exposure to a particular nutrient has been associated with ocular pathology.

Do Gifts Increase Consent to Home-based HIV Testing? A Difference-in-differences Study in Rural KwaZulu-Natal, South Africa

Background Despite the importance of HIV testing for controlling the HIV epidemic, testing rates remain low. Efforts to scale-up testing coverage and frequency in hard-to-reach and at-risk populations commonly focus on home-based HIV testing. This study evaluates the effect of a gift (a food voucher for families, worth US$ 5) on consent rates for home-based HIV testing.
Methods We use data on 18,478 men and women who participated in the 2009 and 2010 population-based HIV surveillance carried out by the Wellcome Trust Africa Centre for Health and Population Studies in rural KwaZulu-Natal, South Africa. Our quasi-experimental difference-in-differences approach controls for unobserved confounding in estimating the causal effect of the intervention on HIV testing consent rates.
Results Allocation of the gift to a family in 2010 increased the probability of family members consenting to test in 2010 by 25 percentage points (95% CI 21-30; p<0.001). The intervention effect persisted, slightly attenuated, in the year following the intervention (2011), further increasing intervention value for money.
Conclusions In HIV hyperendemic settings a gift can be highly effective at increasing consent rates for home-based HIV testing. Given the importance of HIV testing for treatment uptake and individual health, as well as for HIV treatment-and-prevention strategies and for monitoring the population impact of the HIV response, gifts should be considered as a supportive intervention for HIV testing initiatives where consent rates have been low.

Relapsing Fever Borreliae: A Global Review

Relapsing fever borreliae were notorious and feared infectious agents that earned their place in history through their devastating impact as causes of both epidemic and endemic infection. More recently they are considered more as an oddity and their burden of infection is largely overshadowed by other infections such as malaria, which presents in a similar clinical way. Despite this, they remain the most common bacterial infection in some developing countries. Transmitted by soft ticks or lice, these fascinating spirochaetes have evolved a myriad of mechanisms to survive within their diverse environments.

A identidade social : trajectória de um discurso ideológico em José Saramago e Miguel Otero Silva

Tese de doutoramento, Estudos de Literatura e de Cultura (Estudos Comparatistas), Universidade de Lisboa, Faculdade de Letras, 2014

Target identification of situations of improvement through Medication Review in patients type 2 diabetes

Introduction: Prevention, early detection and management of diabetes are fundamental for stopping this present epidemic. Medication review may contribute to the early detection of negative clinical outcomes risk factors associated to the use of medicines. Aims: To use the medication review to identify the situations that may lead to clinical negative outcomes, described as findings, in the process of medicines use in type 2 diabetic patients. To verify if the inclusion criteria list of the Pharmaceutical Society of Australia for medication review allows identifying patients of higher risks of obtaining clinical negative outcomes.

Topical bacteriophage therapy of the infected diabetic foot

Tese de doutoramento, Medicina (Medicina Interna), Universidade de Lisboa, Faculdade de Medicina, 2014

Acute Asthma Epidemics, Weather and Pollen in England, 1987-1994

Recent epidemics of acute asthma have caused speculation that, if their causes were known, early warnings might be feasible. In particular, some epidemics seemed to be associated with thunderstorms. We wondered what risk factors predicting epidemics could be identified. Daily asthma admissions counts during 1987-1994, for two age groups (0-14 yrs and > or = 15 yrs), were measured using the Hospital Episodes System (HES). Epidemics were defined as combinations of date, age group and English Regional Health Authority (RHA) with exceptionally high asthma admission counts compared to the predictions of a log-linear autoregression model. They were compared with control days 1 week before and afterwards, regarding seven meteorological variables and 5 day average pollen counts for four species. Fifty six asthma epidemics were identified. The mean density of sferics (lightning flashes), temperature and rainfall on epidemic days were greater than those on control days. High sferics densities were overrepresented in epidemics. Simultaneously high sferics and grass pollen further increased the probability of an epidemic, but only to 15% (95% confidence interval 2-45%). Two thirds of epidemics were not preceded by thunderstorms. Thunderstorms and high grass pollen levels precede asthma epidemics more often than expected by chance. However, most epidemics are not associated with thunderstorms or unusual weather conditions, and most thunderstorms, even following high grass pollen levels, do not precede epidemics. An early warning system based on the indicators examined here would, therefore, detect few epidemics and generate an unacceptably high rate of false alarms.