Martin Kidd

A Recently Evolved Sublineage of the Mycobacterium tuberculosis Beijing Strain Family Is Associated with an Increased Ability to Spread and Cause Disease

ABSTRACT This study aimed to reconstruct the evolutionary history of Beijing strains of Mycobacterium tuberculosis and to test the hypothesis that evolution has influenced the ability of the Beijing strains within the different Beijing sublineages to spread and cause disease. A PCR-based method was used to analyze the genome structure of 40 different loci in 325 Beijing isolates collected from new and retreatment tuberculosis patients from an urban setting and 270 Beijing isolates collected from high-risk tuberculosis patients from a rural setting in the Western Cape, South Africa. The resulting data were subjected to phylogenetic analysis using the neighbor joining algorithm. Phylogenetic reconstructions were highly congruent with the “gold standard” phylogenetic tree based on synonymous single-nucleotide polymorphisms, thereby allowing a prediction of the order in which the evolutionary events had occurred. A total of seven independently evolving Beijing sublineages were identified. Analysis of epidemiological data in relation to the Beijing sublineage suggested an association between recent evolutionary change and frequency of occurrence in an urban population (P < 0.001) as well as in the rural population (P < 0.001). This concept was further supported by an association between more recently evolved Beijing strains and an increased ability to transmit and to cause disease (odds ratio, 5.82; 95% confidence interval, 3.13 to 10.82 [P < 0.001]). An association between Beijing sublineage and demographic and clinical parameters and drug resistance could not be demonstrated. From these data, we suggest that the pathogenic characteristics of Beijing strains are not conserved but rather that strains within individual lineages have evolved unique pathogenic characteristics.

Psychometric properties of the Multidimensional Scale of Perceived Social Support in youth

INTRODUCTION There is increasing awareness of the contribution of perceived social support (PSS) to emotional and physical well-being. Numerous scales measuring PSS have been developed, including the Multidimensional Scale of Perceived Social Support (MSPSS). The psychometric properties of the MSPSS have been demonstrated in diverse samples, although its reproducibility in the South African youth has not yet been investigated. METHODS This study aimed to investigate the psychometric properties of the MSPSS in the South African youth using confirmatory factor analysis. The relationship of PSS to depressive and anxiety symptoms, as well as the effects of sex and ethnicity, was investigated. Participants completed a battery of self-report measures, including the MSPSS, Beck Depression Inventory, and the Child Posttraumatic Stress Disorder Checklist on a single occasion. Confirmatory factor analysis was performed to validate the a priori factor structure of the MSPSS. In addition, Cronbach alpha coefficients and intercorrelations (for clinical variables) were calculated. A missing value analysis was performed to assess the influence of missing data on our findings. RESULTS Data are reported for 502 youth (11.3-23.5 years). The 3-factor structure of the MSPSS (significant other, family, and friends) fitted the data well. The MSPSS showed good internal consistency. Perceived social support was also positively correlated with resilience and negatively correlated with depression, exposure to community violence, and other potentially life-threatening traumas. Females and youth of white or mixed race reported significantly higher levels of PSS than males and black youth, respectively. CONCLUSIONS The MSPSS is a psychometrically sound instrument that can be applied to South African youth.

Host markers in QuantiFERON supernatants differentiate active TB from latent TB infection: Preliminary report

BackgroundInterferon gamma release assays, including the QuantiFERON® TB Gold In Tube (QFT) have been shown to be accurate in diagnosing Mycobacterium tuberculosis infection. These assays however, do not discriminate between latent TB infection (LTBI) and active TB disease.MethodsWe recruited twenty-three pulmonary TB patients and 34 household contacts from Cape Town, South Africa and performed the QFT test. To investigate the ability of new host markers to differentiate between LTBI and active TB, levels of 29 biomarkers in QFT supernatants were evaluated using a Luminex multiplex cytokine assay.ResultsEight out of 29 biomarkers distinguished active TB from LTBI in a pilot study. Baseline levels of epidermal growth factor (EGF) soluble CD40 ligand (sCD40L), antigen stimulated levels of EGF, and the background corrected antigen stimulated levels of EGF and macrophage inflammatory protein (MIP)-1β were the most informative single markers for differentiation between TB disease and LTBI, with AUCs of 0.88, 0.84, 0.87, 0.90 and 0.79 respectively. The combination of EGF and MIP-1β predicted 96% of active TB cases and 92% of LTBIs. Combinations between EGF, sCD40L, VEGF, TGF-α and IL-1α also showed potential to differentiate between TB infection states. EGF, VEGF, TGF-α and sCD40L levels were higher in TB patients.ConclusionThese preliminary data suggest that active TB may be accurately differentiated from LTBI utilizing adaptations of the commercial QFT test that includes measurement of EGF, sCD40L, MIP-1β, VEGF, TGF-α or IL-1α in supernatants from QFT assays. This approach holds promise for development as a rapid diagnostic test for active TB.

APRI: A simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH

BACKGROUND Non-alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. The NASH fibrosis score (NFS) has proven to be a reliable, non-invasive marker for prediction of advanced fibrosis. Aspartate aminotransferase-to-platelet ratio index (APRI) is a simpler calculation than NFS, but has never been studied in patients with non-alcoholic fatty liver disease (NAFLD). AIM To validate APRI as a non-invasive marker of liver fibrosis in subjects with NAFLD to be used in clinical practice. DESIGN/METHODS The cohort consisted of 111 patients with histological diagnoses of NAFLD. The biopsy samples were staged and graded according to the NASH clinical research network (CRN) criteria. These were grouped into fatty liver disease (FLD), NASH, no/mild fibrosis, and advanced fibrosis. The sensitivity and specificity of APRI were compared with NFS and aspartate aminotransferase-to-alanine aminotransferase (AST/ALT) ratio. RESULTS The APRI was significantly higher in the advanced fibrosis group. The area under receiver operating characteristic (ROC) curve for APRI was 0.85 with an optimal cut-off of 0.98, giving a sensitivity of 75% and a specificity of 86%. The NFS was significantly lower in the advanced fibrosis group. The ROC for NFS gave an area under curve (AUC) of 0.77 and a cut-off value of -1.3 with a sensitivity of 76% and specificity of 69%. The positive predictive value for APRI was 54% as opposed to 34% for NFS. The negative predictive value was 93% for APRI and 94% for NFS. CONCLUSION APRI compared favourably to NFS and was superior to AST/ALT for the prediction of advanced fibrosis. We therefore propose the use of APRI in a new algorithm for the detection of advanced fibrosis.

Changes in leucocyte and lymphocyte subsets during tuberculosis treatment; prominence of CD3dimCD56+ natural killer T cells in fast treatment responders

The immune responses against pulmonary tuberculosis are still poorly defined. This study describes changes in leucocyte and lymphocyte subsets during treatment to find reliable immunological markers for the disease and treatment response. Flow cytometric peripheral blood immune phenotyping, routine haematology and sputum microbiology were performed on 21 HIV‐negative adult tuberculosis (TB) patients with positive sputum cultures during therapy in comparison with 14 healthy purified protein derivative (PPD)‐positive volunteers. Patients at diagnosis showed high absolute neutrophil and monocyte counts which fell during treatment but low lymphocyte subset counts which increased [except natural killer (NK) and NK T cells]. High counts of a population of CD3dim/CD56+ NK T cells at diagnosis correlated significantly with negative sputum culture after 8 weeks of treatment. A multivariate classification technique showed improved correlation when NK cells were taken into account. In conclusion, peripheral blood white cell counts change significantly during treatment and counts at diagnosis, especially CD3dim/CD56+ NK T cells, hold promise in predictive models of TB treatment response.

Short-Term Reproducibility of a Commercial Interferon Gamma Release Assay

ABSTRACT Interferon gamma release assays (IGRAs) have been shown to be sensitive and highly specific for the detection of immune memory against Mycobacterium tuberculosis. Little is known about the reproducibility and within-person variability of these assays. Various aspects of short-term reproducibility of a commercial IGRA, the QuantiFERON-TB Gold In-Tube (QFT-IT) assay, were assessed. The QFT-IT assay was performed twice within 3 days in 27 health care workers in Cape Town, South Africa. Two sets of tests were performed by different operators on day 1, and one set was performed on day 3. Aspects such as interoperator, intraoperator, day-to-day variability, and test-retest variability as well as different the storage methods of plasma were investigated. Seventeen of 27 (63%) of participants had at least one positive QFT-IT text; six had discordant results. The agreement of all aspects studied was high, with kappa values between 0.82 and 1.00 for dichotomous measures, and interclass correlations (ICC) of 0.809 to 0.965 were observed for continuous gamma interferon (IFN-γ) measures. The variability of the magnitude of response was highest comparing measures obtained from individuals on different days (ICC of 0.809). The magnitude of the IFN-γ responses between assays performed for individual participants was variable, with ranges from 0.03 to 11 IU/ml, resulting is discordant results for five participants. The results indicate that the QFT-IT assay is a robust and highly reproducible assay. Considerable intraindividual variability occurs in the magnitude of IFN-γ responses, which may influence the interpretation of serial measures.

Validity of the K-10 in detecting DSM-IV-defined depression and anxiety disorders among HIV-infected individuals

Abstract It has been suggested that an HIV diagnosis may increase the likelihood of mental disorders among infected individuals and that the progression of HIV may be hastened by mental disorders like anxiety and depression. Therefore, a brief screening measure, with good sensitivity/specificity for psychiatric diagnoses that could be given to HIV-infected individuals would be useful. We assessed the validity of the K-10, using the MINI International Neuropsychiatric Interview as the gold standard, in a sample of 429 HIV-infected adults enrolled in HIV care and treatment services near Cape Town, South Africa. There was significant agreement between the K-10 and the MINI-defined depressive and anxiety disorders. A receiver operating characteristic (ROC) curve analysis indicated that the K-10 showed agreeable sensitivity and specificity in detecting depression (area under the ROC curve, 0.77), generalized anxiety disorder (0.78), and posttraumatic stress disorder (PTSD) (0.77). The K-10 may be a useful screening measure for detecting mood and anxiety disorders, including PTSD, in patients with HIV/AIDS.

Immune parameters as markers of tuberculosis extent of disease and early prediction of anti-tuberculosis chemotherapy response.

This study investigates how the extent of pre-treatment radiological disease and early anti-tuberculous treatment response affect levels of selected circulating host immune markers. Twenty HIV-uninfected tuberculosis patients with BACTEC culture positivity for Mycobacterium tuberculosis at diagnosis and treated with directly observed short course anti-tuberculosis chemotherapy and 13 healthy community controls were enrolled. Serum samples were collected throughout treatment. After the intensive phase of treatment, 12 patients remained sputum culture-positive (slow responders) and eight patients were culture negative (fast responders). C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), soluble urokinase plasminogen activator receptor (suPAR), soluble lymphocyte activation gene-3 (sLAG-3), granzyme B, soluble tumour necrosis factor receptor one and two (sTNFR I and sTNFR II) and soluble death receptor 5 (sDR5) concentrations were measured. High levels of CRP at diagnosis were found to be associated (p</=0.05) with the presence of multiple cavities on chest x-rays and high levels of suPAR and sICAM-1 at diagnosis were associated (p</=0.05) with the extent of alveolar disease. Also significant were the associations between the level of granzyme B (p</=0.01) and LAG-3 (p</=0.05) at diagnosis, and the size of the cavities. The combination of diagnosis and week one measurements of selected serological markers in mathematical models was able to identify the fast responders with up to 87.5% accuracy and the slow responders with up to 83.3% accuracy These preliminary results suggest that predictive models for differential early treatment responses using combinations of host markers hold promise.

Immune markers measured before treatment predict outcome of intensive phase tuberculosis therapy

The development of a statistical model based on simple immunological markers which could predict the response to tuberculosis treatment would facilitate clinical trials of new anti‐tuberculosis drugs. We have examined the ability of immunological biomarkers, measured at diagnosis and after 4 weeks of treatment, to predict sputum smear status at week 8. Eighteen tuberculosis patients with positive Ziehl–Nielsen (ZN)‐stained sputum smears 8 weeks after initiation of treatment (slow response) were matched for age, gender, sputum smear grade and extent of disease on chest radiograph to 18 patients with negative sputum smears at week 8 (fast response). In addition to total white blood cell (WBC) counts and absolute lymphocyte, monocyte and neutrophil numbers, concentrations of six serum markers were measured by enzyme‐linked immunosorbent assay (ELISA) in all patients (soluble interleukin‐2 receptor alpha (sIL‐2Rα), granzyme B, soluble tumour necrosis factor alpha receptors 1 and 2 (sTNF‐R1 and ‐2), nitrotyrosine and interferon‐gamma (IFN‐γ). At diagnosis, 4 biomarkers (sTNF‐R1, total WBC, absolute monocyte and absolute neutrophil numbers) were significantly higher in slow response patients. At week 4, total WBC count and absolute monocyte and neutrophil numbers remained significantly higher in slow responders. Discriminant analysis of the diagnosis and week 4 data provided models for classification of slow response patients with 67% and 83% predictive accuracy. We suggest that treatment response phenotypes can be determined before the start of treatment. Reliable predictive models would allow targeted interventions for patients at risk for slow treatment response to standard tuberculosis therapy.

Meta-analysis of attitudes toward damage-causing mammalian wildlife.

Many populations of threatened mammals persist outside formally protected areas, and their survival depends on the willingness of communities to coexist with them. An understanding of the attitudes, and specifically the tolerance, of individuals and communities and the factors that determine these is therefore fundamental to designing strategies to alleviate human-wildlife conflict. We conducted a meta-analysis to identify factors that affected attitudes toward 4 groups of terrestrial mammals. Elephants (65%) elicited the most positive attitudes, followed by primates (55%), ungulates (53%), and carnivores (44%). Urban residents presented the most positive attitudes (80%), followed by commercial farmers (51%) and communal farmers (26%). A tolerance to damage index showed that human tolerance of ungulates and primates was proportional to the probability of experiencing damage while elephants elicited tolerance levels higher than anticipated and carnivores elicited tolerance levels lower than anticipated. Contrary to conventional wisdom, experiencing damage was not always the dominant factor determining attitudes. Communal farmers had a lower probability of being positive toward carnivores irrespective of probability of experiencing damage, while commercial farmers and urban residents were more likely to be positive toward carnivores irrespective of damage. Urban residents were more likely to be positive toward ungulates, elephants, and primates when probability of damage was low, but not when it was high. Commercial and communal farmers had a higher probability of being positive toward ungulates, primates, and elephants irrespective of probability of experiencing damage. Taxonomic bias may therefore be important. Identifying the distinct factors explaining these attitudes and the specific contexts in which they operate, inclusive of the species causing damage, will be essential for prioritizing conservation investments. Meta-Análisis de las Posturas hacia la Mamíferos Silvestres Causantes de Daños Resumen Muchas poblaciones de mamíferos amenazados persisten fuera de áreas protegidas formales y su supervivencia depende de la buena voluntad de las comunidades que coexisten con ellos. Un entendimiento de las posturas, y específicamente de la tolerancia, de los individuos y las comunidades y los factores que los determinan es fundamental para diseñar estrategias que alivien el conflicto humano – vida silvestre. Llevamos a cabo un meta-análisis para identificar los factores que afectaron las posturas hacia cuatro grupos de mamíferos terrestres. Los elefantes (65%) provocaron las posturas más positivas. Los siguieron los primates (55%), los ungulados (53%) y los carnívoros (44%). Los residentes urbanos presentaron las posturas más positivas (80%), seguidos por los granjeros comerciales (51%) y los granjeros comunales (26%). Un índice de tolerancia a los daños mostró que la tolerancia humana a los ungulados y primates fue proporcional a la probabilidad de experimentar daños mientras que los elefantes provocaron niveles de tolerancia más altos de lo esperado y los carnívoros provocaron niveles de tolerancia más bajos de lo esperado. Contrario a la sabiduría convencional, experimentar daños no fue siempre el factor dominante para determinar las posturas. Los granjeros comunales tuvieron una baja probabilidad de ser positivos hacia los carnívoros independientemente de la probabilidad de experimentar daños, mientras que los granjeros comerciales y los residentes urbanos tuvieron mayor probabilidad de ser positivos hacia los carnívoros independientemente de los daños. Los residentes urbanos tuvieron mayor probabilidad de ser positivos hacia los ungulados, los elefantes y los primates cuando la probabilidad de daños fue baja, pero no cuando fue alta. Los granjeros comerciales y comunales tuvieron una mayor probabilidad de ser positivos hacia los ungulados, los primates y los elefantes independientemente de la probabilidad de experimentar daños. El prejuicio taxonómico por eso puede ser importante. El identificar los distintos factores que explican estas posturas y los contextos específicos en los cuales operan, inclusivo de especies que causan daños, será esencial para priorizar las inversiones en la conservación.