Investigating Mycobacterium tuberculosis transmission in rural Malawi

Current control strategies are failing to contain the tuberculosis (TB) epidemic and are limited by our lack of understanding of Mycobacterium tuberculosis (M.tb) transmission dynamics, especially in high HIV prevalence settings. M.tb infection in children aged under 5 years of age indicates recent transmission, acting as a sentinel for infectious (typically adult) TB and highlights recent failures in community control measures. The overall aim of this research, which was based in a high HIV prevalence rural community in northern Malawi, was to delineate M.tb transmission events occurring within the context of a wellimplemented TB control programme, and thereby elucidate factors driving transmission that are not being addressed by current control strategies. This thesis presents findings from a series of linked studies, including a longitudinal tuberculin skin-test (TST) study of pre-school children in an area under demographic surveillance, and a household contact study of smear-positive TB cases. Estimates of the average annual risk of M.tb infection (ARTI) in this population of young BCG-vaccinated children varied widely depending on the method used to estimate infection prevalence. A previously overlooked method of estimating M.tb infection prevalence, initially published by Rust and Thomas in 1975, appeared to be only method to appropriately adjust for the marked effect of BCGattributable induration in the youngest children (aged <2 years). Marked differences in the estimates of the risk of M.tb infection when using crosssectional data compared to using longitudinal data are also highlighted. Age, known contact with a smear-positive TB case and community M.tb exposure (defined as the average notification rate of smear-positive TB per 100,000 population) were risk factors for prevalent and incident M.tb infection in children. Being HIV-exposed in utero was the strongest risk factor for prevalent infection, whilst having an HIV-positive father was strongly associated with incident infection. Additional risk factors for incident infection included church attendance and travel on mini-buses. No evidence was found in the household contact study that smear-positive tuberculosis patients on antiretroviral treatment (ART) were more likely to transmit M.tb infection to household child contacts (as inferred from TST positivity) compared to smear-positive tuberculosis patients not on ART. However, child contacts of HIV-negative individuals had nearly three times the odds of having a positive TST compared to child contacts of HIV-positive TB patients not on ART; this was partly explained by differences in the degree of smear positivity. HIV-related risk factors for prevalent and incident M.tb infection in pre-school children highlight that interventions, such as screening for HIV and TB with implementation of isoniazid preventive therapy where indicated within the household of HIV-positive individuals may further reduce the burden of TB at a community level in the longer term. Findings from this research also highlight the need for better infection control practices (improved ventilation) in congregate settings such as churches and mini-buses. There is an urgent need for improved ongoing surveillance to guide the implementation of context-specific TB control strategies

Does antiretroviral treatment increase the infectiousness of smear-positive pulmonary tuberculosis?

BACKGROUND: Understanding of the effects of human immunodeficiency virus (HIV) infection and antiretroviral treatment (ART) on Mycobacterium tuberculosis transmission dynamics remains limited. We undertook a cross-sectional study among household contacts of smear-positive pulmonary tuberculosis (TB) cases to assess the effect of established ART on the infectiousness of TB. METHOD: Prevalence of tuberculin skin test (TST) positivity was compared between contacts of index cases aged 2-10 years who were HIV-negative, HIV-positive but not on ART, on ART for <1 year and on ART for 1 year. Random-effects logistic regression was used to take into account clustering within households. RESULTS: Prevalence of M. tuberculosis infection in contacts of HIV-negative patients, HIV-positive patients on ART 1 year and HIV-positive patients not on ART/on ART <1 year index cases was respectively 44%, 21% and 22%. Compared to contacts of HIV-positive index cases not on ART or recently started on ART, the odds of TST positivity was similar in contacts of HIV-positive index cases on ART 1 year (adjusted OR [aOR] 1.0, 95%CI 0.3-3.7). The odds were 2.9 times higher in child contacts of HIV-negative index cases (aOR 2.9, 95%CI 1.0-8.2). CONCLUSIONS: We found no evidence that established ART increased the infectiousness of smear-positive, HIV-positive index cases

Risk factors for Mycobacterium tuberculosis infection in 2-4 year olds in a rural HIV-prevalent setting.

BACKGROUND: Mycobacterium tuberculosis infection in children acts as a sentinel for infectious tuberculosis. OBJECTIVE: To assess risk factors associated with tuberculous infection in pre-school children. METHOD: We conducted a population-wide tuberculin skin test (TST) survey from January to December 2012 in Malawi. All children aged 2-4 years residing in a demographic surveillance area were eligible. Detailed demographic data, including adult human immunodeficiency virus (HIV) status, and clinical and sociodemographic data on all diagnosed tuberculosis (TB) patients were available. RESULTS: The prevalence of M. tuberculosis infection was 1.1% using a TST induration cut-off of 15 mm (estimated annual risk of infection of 0.3%). The main identifiable risk factors were maternal HIV infection at birth (adjusted OR [aOR] 3.6, 95%CI 1.1-12.2), having three or more adult members in the household over a lifetime (aOR 2.4, 95%CI 1.2-4.8) and living in close proximity to a known case of infectious TB (aOR 1.6, 95%CI 1.1-2.4), modelled as a linear variable across categories (>200 m, 100-200 m, <100 m, within household). Less than 20% of the infected children lived within 200 m of a known diagnosed case. CONCLUSION: Household and community risk factors identified do not explain the majority of M. tuberculosis infections in children in our setting

Development and internal validation of a diagnostic prediction model for COVID-19 at time of admission to hospital.

BACKGROUND: Early coronavirus disease 2019 (COVID-19) diagnosis prior to laboratory testing results is crucial for infection control in hospitals. Models exist predicting COVID-19 diagnosis, but significant concerns exist regarding methodology and generalizability. AIM: To generate the first COVID-19 diagnosis risk score for use at the time of hospital admission using the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) checklist. DESIGN: A multivariable diagnostic prediction model for COVID-19 using the TRIPOD checklist applied to a large single-centre retrospective observational study of patients with suspected COVID-19. METHODS: 581 individuals were admitted with suspected COVID-19; the majority had laboratory-confirmed COVID-19 (420/581, 72.2%). Retrospective collection was performed of electronic clinical records and pathology data. RESULTS: The final multivariable model demonstrated AUC 0.8535 (95% confidence interval 0.8121-0.8950). The final model used six clinical variables that are routinely available in most low and high-resource settings. Using a cut-off of 2, the derived risk score has a sensitivity of 78.1% and specificity of 86.8%. At COVID-19 prevalence of 10% the model has a negative predictive value (NPV) of 96.5%. CONCLUSIONS: Our risk score is intended for diagnosis of COVID-19 in individuals admitted to hospital with suspected COVID-19. The score is the first developed for COVID-19 diagnosis using the TRIPOD checklist. It may be effective as a tool to rule out COVID-19 and function at different pandemic phases of variable COVID-19 prevalence. The simple score could be used by any healthcare worker to support hospital infection control prior to laboratory testing results

Challenges in the Estimation of the Annual Risk of Mycobacterium tuberculosis Infection in Children Aged Less Than 5 Years.

Accurate estimates of Mycobacterium tuberculosis infection in young children provide a critical indicator of ongoing community transmission of M. tuberculosis. Cross-reactions due to infection with environmental mycobacteria and/or bacille Calmette-Guérin (BCG) vaccination compromise the estimates derived from population-level tuberculin skin-test surveys using traditional cutoff methods. Newer statistical approaches are prone to failure of model convergence, especially in settings where the prevalence of M. tuberculosis infection is low and environmental sensitization is high. We conducted a tuberculin skin-test survey in 5,119 preschool children in the general population and among household contacts of tuberculosis cases in 2012-2014 in a district in northern Malawi where sensitization to environmental mycobacteria is common and almost all children are BCG-vaccinated. We compared different proposed methods of estimating M. tuberculosis prevalence, including a method described by Rust and Thomas more than 40 years ago. With the different methods, estimated prevalence in the general population was 0.7%-11.5% at ages <2 years and 0.8%-3.3% at ages 2-4 years. The Rust and Thomas method was the only method to give a lower estimate in the younger age group (0.7% vs 0.8%), suggesting that it was the only method that adjusted appropriately for the marked effect of BCG-attributable induration in the very young

The NeuARt II system: a viewing tool for neuroanatomical data based on published neuroanatomical atlases

BACKGROUND: Anatomical studies of neural circuitry describing the basic wiring diagram of the brain produce intrinsically spatial, highly complex data of great value to the neuroscience community. Published neuroanatomical atlases provide a spatial framework for these studies. We have built an informatics framework based on these atlases for the representation of neuroanatomical knowledge. This framework not only captures current methods of anatomical data acquisition and analysis, it allows these studies to be collated, compared and synthesized within a single system. RESULTS: We have developed an atlas-viewing application ('NeuARt II') in the Java language with unique functional properties. These include the ability to use copyrighted atlases as templates within which users may view, save and retrieve data-maps and annotate them with volumetric delineations. NeuARt II also permits users to view multiple levels on multiple atlases at once. Each data-map in this system is simply a stack of vector images with one image per atlas level, so any set of accurate drawings made onto a supported atlas (in vector graphics format) could be uploaded into NeuARt II. Presently the database is populated with a corpus of high-quality neuroanatomical data from the laboratory of Dr Larry Swanson (consisting 64 highly-detailed maps of PHAL tract-tracing experiments, made up of 1039 separate drawings that were published in 27 primary research publications over 17 years). Herein we take selective examples from these data to demonstrate the features of NeuArt II. Our informatics tool permits users to browse, query and compare these maps. The NeuARt II tool operates within a bioinformatics knowledge management platform (called 'NeuroScholar') either as a standalone or a plug-in application. CONCLUSION: Anatomical localization is fundamental to neuroscientific work and atlases provide an easily-understood framework that is widely used by neuroanatomists and non-neuroanatomists alike. NeuARt II, the neuroinformatics tool presented here, provides an accurate and powerful way of representing neuroanatomical data in the context of commonly-used brain atlases for visualization, comparison and analysis. Furthermore, it provides a framework that supports the delivery and manipulation of mapped data either as a standalone system or as a component in a larger knowledge management system

Activation of the Fas/Fas ligand pathway in hypertensive renal disease in Dahl/Rapp rats

BACKGROUND: Hypertensive nephrosclerosis is the second most common cause of end-stage renal failure in the United States. The mechanism by which hypertension produces renal failure is incompletely understood. Recent evidence demonstrated that an unscheduled and inappropriate increase in apoptosis occurred in the Dahl/Rapp rat, an inbred strain of rat that uniformly develops hypertension and hypertensive nephrosclerosis; early correction of the hypertension prevents the renal injury. The present study examined the role of the Fas/FasL pathway in this process. METHODS: Young male Dahl/Rapp salt-sensitive (S) and Sprague-Dawley rats were fed diets that contained 0.3% or 8.0% NaCl diets. Kidneys were examined at days 7 and 21 of the study. RESULTS: An increase in Fas and FasL expression was observed in glomerular and tubular compartments of kidneys of hypertensive S rats, whereas dietary salt did not change expression of either of these molecules in normotensive Sprague-Dawley rats. Associated with this increase was cleavage of Bid and activation of caspase-8, the initiator caspase in this apoptotic pathway, by day 21 of the study. CONCLUSIONS: Augmented expression of apoptotic signaling by the Fas/FasL pathway occurred during development of end-stage renal failure in this model of hypertensive nephrosclerosis