The Molecular Epidemiology of Tuberculosis and the Impact of HIV Infection and Antiretroviral Therapy

This thesis investigates the epidemiology of tuberculosis (TB) disease in populations. It applies molecular epidemiological methods to elucidate the relative effects of HIV on TB disease following recent first infection, reactivation and recent reinfection with Mycobacterium tuberculosis (Mtb). Finally it aims to explore the impact of Antiretroviral Therapy (ART) on the incidence of TB in a population in rural Sub Saharan Africa. The data in chapters 2 and 3 is taken from a systematic literature review I performed of population based studies that reported TB molecular epidemiological data. In the subsequent chapters I analyse existing and newly collected data from the Karonga Prevention Study, set in Northern Malawi, to address the research questions. The results strongly suggest that HIV-infection increases an individual’s risk of TB disease due to recent Mtb (re)infection more than through reactivation in populations with generalised HIV epidemics. The last chapter suggests that patients on ART experience a high risk of TB compared to HIV positive/ART naive patients, especially in the first months after initiating ART. Also, it appears that after the introduction of ART in 2005 TB incidence in Karonga District plateaued after declining in the previous 10 years. These findings strongly suggest that TB programmes in areas with generalised HIV epidemics should focus more of their efforts on reducing Mtb transmission. Improved collaboration between TB and ART programmes may help to reduce TB rates in the highly vulnerable ART receiving population and subsequently in the general population

Food assistance to tuberculosis patients: lessons from Afghanistan.

Poverty, food insecurity and poor nutrition in the population are important contributors to the burden of tuberculosis (TB). For poor and food-insecure individuals, accessing and successfully completing anti-tuberculosis treatment over an extended period of time is challenging. Food and nutritional support as an incentive and enabler is employed by national TB control programmes (NTPs) worldwide as a means to encourage treatment initiation and adherence and to improve the nutritional status of patients with TB. It also offers a safety net for food-insecure households affected by TB to mitigate the financial consequences of the disease. This paper reports on the primary lessons from the review of the World Food Programme's (WFP's) Food Assistance Programme for TB patients in Afghanistan. It aims to inform the design, implementation and scale-up of TB programmes in settings where food insecurity and malnutrition are prevalent. It also documents qualitative findings that suggest that patients, their families and providers viewed food support as an important asset and an essential element of the national TB control strategy. While the impact on treatment success or case detection could not be quantified, it is likely that the WFP intervention had a positive impact on the patients and their households, therefore contributing to the success of the DOTS-based NTP

How can mathematical models advance tuberculosis control in high HIV prevalence settings?

Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly

Molecular Epidemiology of HIV-Associated Tuberculosis in Dar es Salaam, Tanzania: Strain Predominance, Clustering, and Polyclonal Disease.

Molecular typing of Mycobacterium tuberculosis can be used to elucidate the epidemiology of tuberculosis, including the rates of clustering, the frequency of polyclonal disease, and the distribution of genotypic families. We performed IS6110 typing and spoligotyping on M. tuberculosis strains isolated from HIV-infected subjects at baseline or during follow-up in the DarDar Trial in Tanzania and on selected community isolates. Clustering occurred in 203 (74%) of 275 subjects: 124 (80%) of 155 HIV-infected subjects with baseline isolates, 56 (69%) of 81 HIV-infected subjects with endpoint isolates, and 23 (59%) of 39 community controls. Overall, 113 (41%) subjects had an isolate representing the East Indian "GD" family. The rate of clustering was similar among vaccine and placebo recipients and among subjects with or without cellular immune responses to mycobacterial antigens. Polyclonal disease was detected in 6 (43%) of 14 patients with multiple specimens typed. Most cases of HIV-associated tuberculosis among subjects from this study in Dar es Salaam resulted from recently acquired infection. Polyclonal infection was detected and isolates representing the East Indian GD strain family were the most common

Changes in Mycobacterium tuberculosis Genotype Families Over 20 Years in a Population-Based Study in Northern Malawi

BACKGROUND: Despite increasing interest in possible differences in virulence and transmissibility between different genotypes of M. tuberculosis, very little is known about how genotypes within a population change over decades, or about relationships to HIV infection. METHODS AND PRINCIPAL FINDINGS: In a population-based study in rural Malawi we have examined smears and cultures from tuberculosis patients over a 20-year period using spoligotyping. Isolates were grouped into spoligotype families and lineages following previously published criteria. Time trends, HIV status, drug resistance and outcome were examined by spoligotype family and lineage. In addition, transmissibility was examined among pairs of cases with known epidemiological contact by assessing the proportion of transmissions confirmed for each lineage, on the basis of IS6110 RFLP similarity of the M tuberculosis strains. 760 spoligotypes were obtained from smears from 518 patients from 1986-2002, and 377 spoligotypes from cultures from 347 patients from 2005-2008. There was good consistency in patients with multiple specimens. Among 781 patients with first episode tuberculosis, the majority (76%) had Lineage 4 ("European/American") strains; 9% had Lineage 3 ("East-African/Indian"); 8% Lineage 1 ("Indo-Oceanic"); and 2% Lineage 2 ("East-Asian"); others unclassifiable. Over time the proportion of Lineage 4 decreased from >90% to 60%, with an increase in the other 3 lineages (p<0.001). Lineage 1 strains were more common in those with HIV infection, even after adjusting for age, sex and year. There were no associations with drug resistance or outcome, and no differences by lineage in the proportion of pairs in which transmission was confirmed. CONCLUSIONS: This is the first study to describe long term trends in the four M. tuberculosis lineages in a population. Lineage 4 has probably been longstanding in this population, with relatively recent introductions and spread of Lineages1-3, perhaps influenced by the HIV epidemic

The Relationship between Telomere Length and Mortality in Chronic Obstructive Pulmonary Disease (COPD)

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV1 and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy “mid-life” volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy “mid-life” volunteers (p<.001). Compared to individuals in the 4th quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD

Psychometric Properties and factor structure of the spanish version of the HC-PAIRS questionnaire

Objective To develop a Spanish version of the Health Care Providers" Pain and Impairment Relationship Scale (HC-PAIRS) and to test its psychometric properties. Methods A forward and backward translation methodology was used to translate the questionnaire, which was then applied to 206 participants (174physiotherapy students and 32 family physicians). The intraclass correlation coefficient was calculated to assess testretest reliability. Internal consistency was evaluated using Cronbach"s alpha and item analysis. Construct validity was measured using Pearson correlation coefficients between HC-PAIRS and FABQ, FABQ-Phys, FABQ-Work and the responses given by participants to three clinical case scenarios. An exploratory factor analysis was carried out following the Kaiser normalization criteria and principal axis factoring with an oblique rotation (quartimax). Sensitivity to change was assessed after a teaching module. Results Testretest reliability was ICC 0.50 (p\0.01)and Cronbach"s alpha was 0.825. The HC-PAIRS scores correlated significantly with the scores of the FABQ and also with the recommendations for work and activity given by the participants in the three clinical case scenarios. Sensitivity to change test showed an effect size of 1.5, which is considered a large change. Factor analysis suggests that the Spanish version of HC-PAIRS measures a unidimensional construct. Conclusion The Spanish version of the HC-PAIRS has proven to be a reliable, valid and sensitive instrument to assess health care providers" attitudes and beliefs about LBP. It can be used in evaluating clinical practice and in undergraduate acquisition of skills and knowledge

Fungal infestation boosts fruit aroma and fruit removal by mammals and birds

For four decades, an influential hypothesis has posited that competition for food resources between microbes and vertebrates selects for microbes to alter these resources in ways that make them unpalatable to vertebrates. We chose an understudied cross kingdom interaction to experimentally evaluate the effect of fruit infection by fungi on both vertebrate (mammals and birds) fruit preferences and on ecologically relevant fruit traits (volatile compounds, toughness, etc). Our well-replicated field experiments revealed that, in contrast to previous studies, frugivorous mammals and birds consistently preferred infested over intact fruits. This was concordant with the higher level of attractive volatiles (esters, ethanol) in infested fruits. This investigation suggests that vertebrate frugivores, fleshyfruited plants, and microbes form a tripartite interaction in which each part could interact positively with the other two (e.g. both orange seeds and fungal spores are likely dispersed by mammals). Such a mutualistic view of these complex interactions is opposed to the generalized idea of competition between frugivorous vertebrates and microorganisms. Thus, this research provides a new perspective on the widely accepted plant evolutionary dilemma to make fruits attractive to mutualistic frugivores while unattractive to presumed antagonistic microbes that constrain seed dispersalinfo:eu-repo/semantics/publishedVersio

The diagnostic role of gut feelings in general practice A focus group study of the concept and its determinants

Contains fulltext : 81297.pdf (publisher's version ) (Open Access)BACKGROUND: General practitioners sometimes base clinical decisions on gut feelings alone, even though there is little evidence of their diagnostic and prognostic value in daily practice. Research into these aspects and the use of the concept in medical education require a practical and valid description of gut feelings. The goal of our study was therefore to describe the concept of gut feelings in general practice and to identify their main determinants METHODS: Qualitative research including 4 focus group discussions. A heterogeneous sample of 28 GPs. Text analysis of the focus group discussions, using a grounded theory approach. RESULTS: Gut feelings are familiar to most GPs in the Netherlands and play a substantial role in their everyday routine. The participants distinguished two types of gut feelings, a sense of reassurance and a sense of alarm. In the former case, a GP is sure about prognosis and therapy, although they may not always have a clear diagnosis in mind. A sense of alarm means that a GP has the feeling that something is wrong even though objective arguments are lacking. GPs in the focus groups experienced gut feelings as a compass in situations of uncertainty and the majority of GPs trusted this guide. We identified the main determinants of gut feelings: fitting, alerting and interfering factors, sensation, contextual knowledge, medical education, experience and personality. CONCLUSION: The role of gut feelings in general practice has become much clearer, but we need more research into the contributions of individual determinants and into the test properties of gut feelings to make the concept suitable for medical education