Publications by authors named "Blanca I Restrepo"

46 Publications

New Developments and Insights in the Improvement of Vaccines and Diagnostics Within the End TB Strategy.

Curr Epidemiol Rep 2021 Apr 7:1-13. Epub 2021 Apr 7.

Population Health Program, Tuberculosis Group, Texas Biomedical Research Institute, 8715 W. Military Dr, San Antonio, TX 78227 USA.

Purpose Of Review: The alignment of sustainable development goals (SDGs) with the End Tuberculosis (TB) strategy provides an integrated roadmap to implement key approaches towards TB elimination. This review summarizes current social challenges for TB control, and yet, recent developments in TB diagnosis and vaccines in the context of the End TB strategy and SDGs to transform global health.

Recent Findings: Advances in non-sputum based TB biomarkers and whole genome sequencing technologies could revolutionize TB diagnostics. Moreover, synergistic novel technologies such as mRNA vaccination, nanovaccines and promising TB vaccine models are key promising developments for TB prevention and control.

Summary: The End TB strategy depends on novel developments in point-of-care TB diagnostics and effective vaccines. However, despite outstanding technological developments in these fields, TB elimination will be unlikely achieved if TB social determinants are not fully addressed. Indeed, the End TB strategy and SDGs emphasize the importance of implementing sustainable universal health coverage and social protection.
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http://dx.doi.org/10.1007/s40471-021-00269-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024105PMC
April 2021

Human monocyte-derived macrophage responses to M. tuberculosis differ by the host's tuberculosis, diabetes or obesity status, and are enhanced by rapamycin.

Tuberculosis (Edinb) 2021 01 30;126:102047. Epub 2020 Dec 30.

Houston Methodist Research Institute, Houston, Weill-Cornell Medicine, TX, USA. Electronic address:

Human macrophages play a major role in controlling tuberculosis (TB), but their anti-mycobacterial mechanisms remain unclear among individuals with metabolic alterations like obesity (TB protective) or diabetes (TB risk). To help discern this, we aimed to: i) Evaluate the impact of the host's TB status or their comorbidities on the anti-mycobacterial responses of their monocyte-derived macrophages (MDMs), and ii) determine if the autophagy inducer rapamycin, can enhance these responses. We used MDMs from newly diagnosed TB patients, their close contacts and unexposed controls. The MDMs from TB patients had a reduced capacity to activate T cells (surrogate for antigen presentation) or kill M. tuberculosis (Mtb) when compared to non-TB controls. The MDMs from obese participants had a higher antigen presenting capacity, whereas those from chronic diabetes patients displayed lower Mtb killing. The activation of MDMs with rapamycin led to an enhanced anti-mycobacterial activity irrespective of TB status but was not as effective in patients with diabetes. Further studies are warranted using MDMs from TB patients with or without metabolic comorbidities to: i) elucidate the mechanisms through which host factors affect Mtb responses, and ii) evaluate host directed therapy using autophagy-inducing drugs like rapamycin to enhance macrophage function.
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http://dx.doi.org/10.1016/j.tube.2020.102047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887072PMC
January 2021

Hyperglycemia and dyslipidemia: Reduced HLA-DR expression in monocyte subpopulations from diabetes patients.

Hum Immunol 2021 Feb 8;82(2):124-129. Epub 2020 Dec 8.

Dept. of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.

Immune dysfunction contributes to the higher risk of communicable and non-communicable diseases among diabetics. HLA-DR expression is a robust marker of immune competence in mononuclear cells, including antigen presentation to CD4 lymphocytes. Given the high prevalence of obesity among diabetics, we evaluated the independent association between hyperglycemia and dyslipidemias with respect to HLA-DR expression in blood monocytes from type 2 diabetes patients. The monocytes from individuals with (n = 16) or without diabetes (n = 25) were phenotyped by flow cytometry to assess the differential expression of HLA-DR on their three subpopulations (classical, intermediate and non-classical monocytes). Diabetes was independently associated with lower HLA-DR expression across all monocyte subpopulations (p < 0.05). Blood triglycerides were associated with further HLA-DR depression (interaction p < 0.002). Cholesterols counterbalanced the reductive effect, with CD36, a receptor for oxidized cholesterol, correlating with HLA-DR (rho = 0.373; p = 0.016). Future studies are warranted to elucidate the complex interactions between hyperglycemia and dyslipidemias on antigen presentation in diabetic monocytes.
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http://dx.doi.org/10.1016/j.humimm.2020.11.005DOI Listing
February 2021

Antibody Fc Glycosylation Discriminates Between Latent and Active Tuberculosis.

J Infect Dis 2020 11;222(12):2093-2102

Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.

Background: Mycobacterium tuberculosis remains a global health problem and clinical management is complicated by difficulty in discriminating between latent infection and active disease. While M. tuberculosis-reactive antibody levels are heterogeneous, studies suggest that levels of IgG glycosylation differ between disease states. Here we extend this observation across antibody domains and M. tuberculosis specificities to define changes with the greatest resolving power.

Methods: Capillary electrophoretic glycan analysis was performed on bulk non-antigen-specific IgG, bulk Fc domain, bulk Fab domain, and purified protein derivative (PPD)- and Ag85A-specific IgG from subjects with latent (n = 10) and active (n = 20) tuberculosis. PPD-specific isotype/subclass, PPD-specific antibody-dependent phagocytosis, cellular cytotoxicity, and natural killer cell activation were assessed. Discriminatory potentials of antibody features were evaluated individually and by multivariate analysis.

Results: Parallel profiling of whole, Fc, and Fab domain-specific IgG glycosylation pointed to enhanced differential glycosylation on the Fc domain. Differential glycosylation was observed across antigen-specific antibody populations. Multivariate modeling highlighted Fc domain glycan species as the top discriminatory features, with combined PPD IgG titers and Fc domain glycans providing the highest classification accuracy.

Conclusions: Differential glycosylation occurs preferentially on the Fc domain, providing significant discriminatory power between different states of M. tuberculosis infection and disease.
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http://dx.doi.org/10.1093/infdis/jiz643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661770PMC
November 2020

The re-emerging association between tuberculosis and diabetes: Lessons from past centuries.

Tuberculosis (Edinb) 2019 05 3;116S:S89-S97. Epub 2019 May 3.

University of Texas Health Houston, School of Public Health, Brownsville Campus, Brownsville, TX 78520, USA; University of Texas Rio Grande Valley, South Texas Diabetes and Obesity Institute, School of Medicine, Edinburg, TX 78541, USA. Electronic address:

The association between tuberculosis (TB) and diabetes mellitus (DM) had a common place in the literature up to the first half of the 20th century, but virtually disappeared with the discovery of insulin to treat DM and antibiotics to cure TB. In the late 1990s the literature began to re-emerge with the worldwide increase in type 2 DM, particularly in TB-endemic countries. Today, type 2 DM is the most prevalent comorbidity among TB patients and the World Health Organization considers it a threat to TB control. We summarize the literature on TB and DM up to the 1960s. Then we evaluate unique aspects of this comorbidity in older times, such as the frequent diabetic comas that suggest challenges for proper DM management as insulin was being implemented, or the absence of antibiotics to cure TB. Despite the unique aspects of each study period, the literature across times is consistent in key aspects of the association. Namely, a higher TB prevalence among DM (versus non-DM patients), the importance of glucose control and chronic DM on TB susceptibility and the higher risk of death among patients with the co-morbidity. From the older literature, we can infer the likely contribution of type 1 DM to TB (in addition to type 2), regardless of their differing autoimmune or metabolic pathophysiology, respectively. Furthermore, in the older literature there was a notable reporting of DM development among TB patients, even though DM usually preceded TB. This observation deserves further epidemiological and basic studies to elucidate this intriguing aspect of the relationship between TB and DM.
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http://dx.doi.org/10.1016/j.tube.2019.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626679PMC
May 2019

Diabetes screen during tuberculosis contact investigations highlights opportunity for new diabetes diagnosis and reveals metabolic differences between ethnic groups.

Tuberculosis (Edinb) 2018 12 18;113:10-18. Epub 2018 Aug 18.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia. Electronic address:

Type 2 diabetes (T2D) is a prevalent risk factor for tuberculosis (TB), but most studies on TB-T2D have focused on TB patients, been limited to one community, and shown a variable impact of T2D on TB risk or treatment outcomes. We conducted a cross-sectional assessment of sociodemographic and metabolic factors in adult TB contacts with T2D (versus no T2D), from the Texas-Mexico border to study Hispanics, and in Cape Town to study South African Coloured ethnicities. The prevalence of T2D was 30.2% in Texas-Mexico and 17.4% in South Africa, with new diagnosis in 34.4% and 43.9%, respectively. Contacts with T2D differed between ethnicities, with higher smoking, hormonal contraceptive use and cholesterol levels in South Africa, and higher obesity in Texas-Mexico (p < 0.05). PCA analysis revealed striking differences between ethnicities in the relationships between factors defining T2D and dyslipidemias. Our findings suggest that screening for new T2D in adult TB contacts is effective to identify new T2D patients at risk for TB. Furthermore, studies aimed at predicting individual TB risk in T2D patients, should take into account the heterogeneity in dyslipidemias that are likely to modify the estimates of TB risk or adverse treatment outcomes that are generally attributed to T2D alone.
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http://dx.doi.org/10.1016/j.tube.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284235PMC
December 2018

Characterization of the Antigenic Heterogeneity of Lipoarabinomannan, the Major Surface Glycolipid of , and Complexity of Antibody Specificities toward This Antigen.

J Immunol 2018 05 2;200(9):3053-3066. Epub 2018 Apr 2.

Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103;

Lipoarabinomannan (LAM), the major antigenic glycolipid of , is an important immunodiagnostic target for detecting tuberculosis (TB) infection in HIV-1-coinfected patients, and is believed to mediate a number of functions that promote infection and disease development. To probe the human humoral response against LAM during TB infection, several novel LAM-specific human mAbs were molecularly cloned from memory B cells isolated from infected patients and grown in vitro. The fine epitope specificities of these Abs, along with those of a panel of previously described murine and phage-derived LAM-specific mAbs, were mapped using binding assays against LAM Ags from several mycobacterial species and a panel of synthetic glycans and glycoconjugates that represented diverse carbohydrate structures present in LAM. Multiple reactivity patterns were seen that differed in their specificity for LAM from different species, as well as in their dependence on arabinofuranoside branching and nature of capping at the nonreducing termini. Competition studies with mAbs and soluble glycans further defined these epitope specificities and guided the design of highly sensitive immunodetection assays capable of detecting LAM in urine of TB patients, even in the absence of HIV-1 coinfection. These results highlighted the complexity of the antigenic structure of LAM and the diversity of the natural Ab response against this target. The information and novel reagents described in this study will allow further optimization of diagnostic assays for LAM and may facilitate the development of potential immunotherapeutic approaches to inhibit the functional activities of specific structural motifs in LAM.
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http://dx.doi.org/10.4049/jimmunol.1701673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911930PMC
May 2018

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes: Part 2: Underlying Biologic Mechanisms.

Chest 2017 07 20;152(1):174-180. Epub 2017 Apr 20.

School of Public Health, University of Texas Health Science Center Houston, Brownsville, TX.

There is growing interest in the re-emerging interaction between type 2 diabetes (DM) and TB, but the underlying biologic mechanisms are poorly understood despite their possible implications in clinical management. Experts in epidemiologic, public health, basic science, and clinical studies recently convened and identified research priorities for elucidating the underlying mechanisms for the co-occurrence of TB and DM. We identified gaps in current knowledge of altered immunity in patients with DM during TB, where most studies suggest an underperforming innate immunity, but exaggerated adaptive immunity to Mycobacterium tuberculosis. Various molecular mechanisms and pathways may underlie these observations in the DM host. These include signaling induced by excess advanced glycation end products and their receptor, higher levels of reactive oxidative species and oxidative stress, epigenetic changes due to chronic hyperglycemia, altered nuclear receptors, and/or differences in cell metabolism (immunometabolism). Studies in humans at different stages of DM (no DM, pre-DM, and DM) or TB (latent or active TB) should be complemented with findings in animal models, which provide the unique opportunity to study early events in the host-pathogen interaction. Such studies could also help identify biomarkers that will complement clinical studies in order to tailor the prevention of TB-DM, or to avoid the adverse TB treatment outcomes that are more likely in these patients. Such studies will also inform new approaches to host-directed therapies.
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http://dx.doi.org/10.1016/j.chest.2017.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577357PMC
July 2017

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes: Part 1: Epidemiology and Clinical Management.

Chest 2017 07 20;152(1):165-173. Epub 2017 Apr 20.

Department of Internal Medicine, Radbourd University Medical Center, Nijmegen, the Netherlands.

There is growing interest in the interaction between type 2 diabetes mellitus (DM) and TB, but many research questions remain unanswered. Epidemiologists, basic scientists, and clinical experts recently convened and identified priorities. This is the first of two reviews on this topic, summarizing priority areas of research regarding epidemiology, clinical management, and public health. First, from an epidemiologic point of view, more study is needed to determine the importance of transient hyperglycemia in patients with TB and on the importance of DM for the global epidemic of multidrug resistant (MDR)-TB. Second, regarding the screening and clinical management of combined TB and DM (TB-DM), clinical trials and large cohort studies should examine the benefits of improved DM care as well as prolonged or intensified TB treatment on the outcome of TB-DM and investigate the cost-effectiveness of screening methods for DM among patients newly diagnosed with TB. Third, from a public health and health systems point of view, the population health impact and cost-effectiveness of different interventions to prevent or treat DM and TB in high-burden populations should be examined, and health-system interventions should be developed for routine TB-DM screening, management of DM after completion of TB treatment, and better access to DM services worldwide. Studies are needed across different ethnicities and settings given the heterogeneity of metabolic perturbations, inflammatory responses, medications, and access to health care. Finally, studies should address interactions between TB, DM, and HIV because of the convergence of epidemics in sub-Saharan Africa and some other parts of the world.
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http://dx.doi.org/10.1016/j.chest.2017.04.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989639PMC
July 2017

The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes.

Tuberculosis (Edinb) 2017 03 24;103:83-91. Epub 2017 Jan 24.

Public Health Institute, University of Veracruz, Veracruz, Mexico; Red multidisciplinaria de Investigación en tuberculosis, Mexico. Electronic address:

Objective: To evaluate the effect size of type 2 diabetes mellitus (T2DM) on tuberculosis (TB) treatment outcomes and multi drug resistance (MDR).

Methods: A cohort with 507 individuals with diagnosed TB included 183 with coexistence of T2DM and TB (TB-T2DM). Participants were identified at the time of TB diagnosis and followed during the course of TB treatment. Then we computed relative risks and adjustments by Cox proportional hazards for outcome variables (drug resistance, death, relapse, treatment failure), and the size of their effect as Cohen's-d.

Results: Patients with TB-T2DM were more likely to remain positive for acid-fast bacilli after two months of anti-TB treatment RR = [2.01 (95% CI: 1.3, 3.1)], to have drug resistant (DR) [OR 3.5 (95% CI: 1.8, 6.7)] and multi-drug resistant (MDR) TB [OR 3.5 (95% CI: 1.8, 7.1)]. The Cohen's-d for DR or MDR in T2DM was 0.69 when compared with non-DM subjects. The T2DM patients had higher odds of resistance to isoniazid (OR 3.9, 95% CI: 2.01, 7.9), rifampicin (OR 3.4, 95% CI: 1.6, 7.2) and pyrazinamide (OR 9.4, 95% CI: 2.8, 25.6), and their effect sizes were ≥0.67. Patients with TB-T2DM (versus no DM) were more likely to present with MDR TB (HR 3.1; 95% CI: 1.7, 5.8; p < 0.001), treatment failure (HR 2.04; 95% CI: 1.07, 3.8; p = 0.02) and relapse (HR 1.86; 95% CI: 1.09, 3.1; p = 0.02), with effect size ≥0.34.

Conclusion: T2DM showed a substantial contribution to the presence of DR or MDR-TB and to adverse clinical outcomes during and after TB treatment. Our findings support the importance for routine screening of T2DM among newly-diagnosed TB patients in order to stratify them for immediate DR assessment, and highlight the need for clinical trials to evaluate variations to the standard TB treatment in TB-T2DM to prevent adverse treatment outcomes.
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http://dx.doi.org/10.1016/j.tube.2017.01.006DOI Listing
March 2017

Diabetes and Tuberculosis.

Microbiol Spectr 2016 12;4(6)

UTHealth Houston, School of Public Health at Brownsville, Brownsville, TX 78520.

The increase in type 2 diabetes mellitus (DM) patients in countries where tuberculosis (TB) is also endemic has led to the reemerging importance of DM as a risk factor for TB. DM causes a 3-fold increase in TB risk and a 2-fold increase in adverse TB treatment outcomes. Given the sheer numbers of DM patients worldwide, there are now more TB patients with TB-DM comorbidity than TB-HIV coinfection. There is an urgent need to implement strategies for TB prevention and control among the millions of DM patients exposed to Mycobacterium tuberculosis. This chapter summarizes the current epidemiological, clinical, and immunological knowledge on TB and DM and their clinical and public health implications. These include the underlying mechanisms for TB risk in DM patients and their clinical and sociodemographic characteristics that distinguish them from TB patients without DM. TB-DM comorbidity is posing a new challenge for integrating the short-term care for TB with the long-term care for DM, particularly in low- and middle-income countries.
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http://dx.doi.org/10.1128/microbiolspec.TNMI7-0023-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240796PMC
December 2016

Tuberculosis-diabetes epidemiology in the border and non-border regions of Tamaulipas, Mexico.

Tuberculosis (Edinb) 2016 12 28;101S:S124-S134. Epub 2016 Sep 28.

Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health in Brownsville, University of Texas Health Science Center at Houston, Brownsville, TX, USA.

Type 2 diabetes mellitus (DM) is a re-emerging risk factor for TB development and adverse TB outcomes. As a follow-up of our previous study in 1998-2004, we reassessed prevalence of DM and its associated factors among 8431 TB patients using surveillance data from 2006 to 2013 for the Mexican state of Tamaulipas, across the border with Texas. Prevalence of DM was 25.2%, with an increase of at least 2.8% over the study period. Newly discovered factors associated with TB-DM (versus no DM) were lower education and higher unemployment (p < 0.001), which are reportedly associated with poorer DM management. At least 15% of the DM patients were newly-diagnosed and younger than those previously diagnosed, showing the importance of early DM diagnosis at TB clinics. TB-DM patients were more likely to have smear-positive, pulmonary (versus extra-pulmonary) and drug-resistant TB (1.9-, 3.8- and 1.4-fold, respectively). During treatment, TB-DM patients were more likely to be smear-positive, and less likely to die or abandon TB treatment. Thus, the increasing prevalence of DM among TB, and its association with low education, features of a more contagious TB, and drug resistance, highlight the need for design of TB management programs in DM patients, blood testing of all new TB patients for DM, and if positive for DM, testing for drug resistance.
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http://dx.doi.org/10.1016/j.tube.2016.09.024DOI Listing
December 2016

Differential positive TSPOT assay responses to ESAT-6 and CFP-10 in health care workers.

Tuberculosis (Edinb) 2016 12 28;101S:S83-S91. Epub 2016 Sep 28.

Houston Methodist Hospital Institute, 6670 Bertner Ave, Houston, TX, 77030, USA. Electronic address:

Background: The TSPOT.TB (TSPOT) diagnostic test for latent tuberculosis infection is based on a cell-mediated response to the Mycobacteria tuberculosis antigens, ESAT-6 and/or CFP-10, producing an "interferon-gamma footprint". We investigated the within-sample and within-subject variability of positive TSPOT assays due to the individual assay antigens' reactivity.

Methods: Positive TSPOT assay frequencies due to ESAT-6 or CFP-10 among health care workers (HCWs) at 6-month intervals for 18 months were compared. Differences in result interpretation (positive or negative) for ESAT-6 and CFP10 and potential prognostic factors were investigated.

Results: There were 576 positive results in 8805 TSPOT assays representing 2418 participants. A significant difference was detected in positive TSPOT results due to a positive response to either ESAT-6, CFP-10 or both antigens at baseline through 12 M (p < 0.001), but not for the 18 M follow-up. Gender, ethnicity, occupation, previous positive tuberculin skin test (TST) and study site were significantly associated with specific antigen positivity.

Conclusions: Among our HCW samples with positive TSPOT assays, CFP-10 induced a larger proportion of positive TSPOT results than ESAT-6. Potential causes for this finding include: BCG vaccinated subpopulations, certain jobs, history of positive TST, U.S. birth, and study site. A high proportion of single-positive specimens may reflect false-positives results.
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http://dx.doi.org/10.1016/j.tube.2016.09.012DOI Listing
December 2016

Comparing TSPOT assay results between an Elispot reader and manual counts.

Tuberculosis (Edinb) 2016 12 28;101S:S92-S98. Epub 2016 Sep 28.

Houston Methodist Hospital Institute, 6670 Bertner Ave, Houston, TX, 77030, USA. Electronic address:

Background: The interferon gamma release assay, TSPOT.TB (TSPOT) can be read by several methodologies, including an Elispot reader or manually by technician. We compared the results from these two counting methods.

Methods: Automated and manual TSPOT results among 2481 United States health care workers were compared. Cohen's kappa coefficient was used to determine the inter-rater agreement. Univariate and multiple logistic regression were used to investigate selected variable contributions.

Results: No prognostic factors were associated with agreement of TSPOT results between counting methods. Agreement between TSPOT results were 92.3%, 89.5%, 93.0%, and 93.1% at baseline, and at follow-up at 6, 12, and 18 months, respectively. The inter-rater agreement for all test results was good (kappa = 0.71). There was a significant difference between individual technicians kappa coefficients (p < 0.001), but no significant increase in agreement over time for technicians (p = 0.394).

Conclusion: Commercial Elispot readers and manual counts have good agreement of TSPOT results in a low TB burden setting. Levels of agreement differed between individual technicians and automated reader from moderate to very good, indicating borderline results may be misinterpreted due to inter-rater variability. With no latent tuberculosis infection (LTBI) gold standard, it cannot be determined if one TSPOT reading method is better than another.
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http://dx.doi.org/10.1016/j.tube.2016.09.013DOI Listing
December 2016

Metformin: Candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients.

Tuberculosis (Edinb) 2016 12 28;101S:S69-S72. Epub 2016 Sep 28.

UTHealth Houston, Department of Epidemiology, School of Public Health at Brownsville, 80 Fort Brown, SPH Bldg, Brownsville, TX 78520, USA. Electronic address:

Despite major advances in tuberculosis (TB) control, TB continues to be a leading cause of death worldwide. The discovery of new anti-TB treatment drugs and regimens that target drug-sensitive and drug-resistant TB are being complemented with a search for adjunct host-directed therapies that synergize for Mycobacterium tuberculosis (Mtb) elimination. The goal of host-directed therapies is to boost immune mechanisms that diminish excess inflammation to reduce lung tissue damage and limit Mtb growth. Metformin is the most commonly-used medication for type 2 diabetes, and a candidate for host-directed therapy for TB. Preliminary data suggests metformin may be beneficial for TB control by reducing the deleterious inflammation associated with immune pathology and enhancing the anti-mycobacterial activity of immune cells. In this review I summarize current findings, knowledge gaps and the potential benefits as well as points of caution for using metformin as adjunct therapy for TB in patients with and without type 2 diabetes.
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http://dx.doi.org/10.1016/j.tube.2016.09.008DOI Listing
December 2016

A Functional Role for Antibodies in Tuberculosis.

Cell 2016 Oct 22;167(2):433-443.e14. Epub 2016 Sep 22.

Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address:

While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.
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http://dx.doi.org/10.1016/j.cell.2016.08.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526202PMC
October 2016

Impact of diabetes on the natural history of tuberculosis.

Diabetes Res Clin Pract 2014 Nov 14;106(2):191-9. Epub 2014 Jul 14.

Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, 460W 12th Avenue, Columbus, OH 43210, United States.

Tuberculosis (TB) is the number one bacterial killer worldwide and the current increase in type 2 diabetes mellitus patients (DM), particularly in countries where TB is also endemic, has led to the re-emerging importance of DM2 as a risk factor for TB. There is an urgent need to implement strategies for TB prevention among the millions of DM patients exposed to Mycobacterium tuberculosis (Mtb) worldwide, but knowledge is limited on how and when DM2 alters the natural history of this infection. In this review we summarize the current epidemiological, clinical and immunologic studies on TB and DM and discuss the clinical and public health implications of these findings. Specifically, we evaluate the mechanisms by which DM patients have a higher risk of Mtb infection and TB development, present with signs and symptoms indicative of a more infectious TB infection, and are more likely to have adverse TB treatment outcomes, including death. Emphasis is placed on type 2 DM given its higher prevalence in contemporary times, but the underlying role of hyperglycemia and of type 1 DM is also discussed.
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http://dx.doi.org/10.1016/j.diabres.2014.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260985PMC
November 2014

A missed tuberculosis diagnosis resulting in hospital transmission.

Infect Control Hosp Epidemiol 2014 May 14;35(5):534-7. Epub 2014 Mar 14.

Hidalgo County Health and Human Services, Edinburg, Texas.

Objective: To find the source of tuberculin skin test conversions among 38 hospital employees on 1 floor during routine testing January-February 2010.

Methods: Record review of patients at a private hospital during September-December 2009 and interviews with hospital employees. Names of patients from the state tuberculosis (TB) registry were cross-referenced with hospital records for admissions. Mycobacterium tuberculosis genotype results in the county and adjacent counties were examined, and contacts were evaluated for TB infection and disease.

Results: One of the 38 employees, a nurse, was diagnosed with pulmonary TB with a matching M. tuberculosis genotype and drug resistance pattern (isoniazid monoresistant) to those of a county jail inmate also recently diagnosed with pulmonary TB. The nurse had no known contact with that inmate; however, another inmate in his 20's from the same jail had been hospitalized under that nurse's care in October 2009. That young man died, and a postmortem examination result subsequently confirmed TB, which had not been suspected. Exposure to this man with undiagnosed TB could explain the transmission: 87 (27%) of the 318 hospital-based contacts without previous positive tuberculin skin test results were infected, and 9 contacts had active TB.

Conclusions: This investigation demonstrated M. tuberculosis transmission in a hospital due to a missed diagnosis and nonadherence to national TB infection control guidelines. Routine TB screening of employees allowed early detection of this missed TB diagnosis, facilitating prompt evaluation of contacts. Healthcare providers should suspect TB in symptomatic persons and adhere to TB control policies.
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http://dx.doi.org/10.1086/675833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019171PMC
May 2014

Phagocytosis via complement or Fc-gamma receptors is compromised in monocytes from type 2 diabetes patients with chronic hyperglycemia.

PLoS One 2014 26;9(3):e92977. Epub 2014 Mar 26.

Center for Microbial Interface Biology and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, United States of America.

Type 2 diabetes patients (DM2) have a higher risk of tuberculosis (TB) that may be attributed to functional defects in their mononuclear phagocytes given the critical role of these cells in Mycobacterium tuberculosis containment. Our previous findings suggest that monocytes from DM2 have reduced association with serum-opsonized M. tuberculosis. To determine if this alteration is due to defects in phagocytosis via complement or Fc-gamma receptors (FcγRs), in this study we evaluated the uptake of sheep red blood cells coated with IgG or complement, respectively, by monocytes from individuals with and without DM2. We found that chronic hyperglycemia was significantly associated with reduced phagocytosis via either receptor by univariable and multivariable analyses. This defect was independent of host serum opsonins and flow cytometry data indicated this was not attributed to reduced expression of these phagocytic receptors on DM2 monocytes. The positive correlation between both pathways (R = 0.64; p = 0.003) indicate that monocytes from individuals with chronic hyperglycemia have a defect in the two predominant phagocytic pathways of these cells. Given that phagocytosis is linked to activation of effector mechanisms for bacterial killing, it is likely that this defect is one factor contributing to the higher susceptibility of DM2 patients to pathogens like M. tuberculosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966862PMC
December 2015

Epidemiology of tuberculosis in young children in the United States.

Pediatrics 2014 Mar 10;133(3):e494-504. Epub 2014 Feb 10.

Department of Epidemiology, University of Washington, Seattle, Washington;

Objectives: To estimate tuberculosis (TB) rates among young children in the United States by children's and parents' birth origins and describe the epidemiology of TB among young children who are foreign-born or have at least 1 foreign-born parent.

Methods: Study subjects were children <5 years old diagnosed with TB in 20 US jurisdictions during 2005-2006. TB rates were calculated from jurisdictions' TB case counts and American Community Survey population estimates. An observational study collected demographics, immigration and travel histories, and clinical and source case details from parental interviews and health department and TB surveillance records.

Results: Compared with TB rates among US-born children with US-born parents, rates were 32 times higher in foreign-born children and 6 times higher in US-born children with foreign-born parents. Most TB cases (53%) were among the 29% of children who were US born with foreign-born parents. In the observational study, US-born children with foreign-born parents were more likely than foreign-born children to be infants (30% vs. 7%), Hispanic (73% vs. 37%), diagnosed through contact tracing (40% vs. 7%), and have an identified source case (61% vs. 19%); two-thirds of children were exposed in the United States.

Conclusions: Young children who are US born of foreign-born parents have relatively high rates of TB and account for most cases in this age group. Prompt diagnosis and treatment of adult source cases, effective contact investigations prioritizing young contacts, and targeted testing and treatment of latent TB infection are necessary to reduce TB morbidity in this population.
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http://dx.doi.org/10.1542/peds.2013-2570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135007PMC
March 2014

Differential expression of monocyte surface markers among TB patients with diabetes co-morbidity.

Tuberculosis (Edinb) 2013 Dec;93 Suppl:S78-82

Center for Microbial Interface Biology and Department of Microbial Infection and Immunity, 460W 12th Ave, The Ohio State University, Columbus, Ohio 43210, USA. Electronic address:

The expression of monocyte surface markers was compared between tuberculosis patients with and without type 2 diabetes (DM2). DM2 was associated with increased CCR2 expression, which may restrain monocyte traffic to the lung. Other host factors associated with baseline monocyte changes were older age (associated with lower CD11b) and obesity (associated with higher RAGE). Given that DM2 patients are more likely to be older and obese, their monocytes are predicted to be altered in function in ways that affect their interaction with Mycobacterium tuberculosis.
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http://dx.doi.org/10.1016/S1472-9792(13)70015-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028445PMC
December 2013

Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus.

Tuberculosis (Edinb) 2013 Dec;93 Suppl:S10-4

Center for Microbial Interface Biology and Department of Microbial Infection and Immunity, 460W 12th Ave, The Ohio State University, Columbus, Ohio 43210, USA.

Tuberculosis (TB) is known to be fueled by HIV as well as social and economic factors. With progression of the diabetes mellitus (DM) pandemic in countries where TB is also endemic, focus is increasing on the potential links between DM and TB. Despite the magnitude of the DM-TB association worldwide, it is striking how little we know about the underlying biology that promotes this association which is a major concern to public health. In this review we summarize current findings regarding the alterations in the innate and adaptive immune responses of DM patients to Mycobacterium tuberculosis (Mtb). Current findings suggest underperforming innate immunity followed by a hyper-reactive cellular response to Mtb, but the contribution of these altered responses to TB susceptibility or to the more adverse clinical outcomes of TB patients with DM remains unclear. Elucidating the basic mechanisms underlying the higher susceptibility of DM patients to TB should lead to a strategy for stratification of the millions of DM patients worldwide into those with the highest TB risk for targeted TB prevention.
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http://dx.doi.org/10.1016/S1472-9792(13)70004-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019931PMC
December 2013

Dipstick urinalysis for diabetes screening in TB patients.

Int Health 2013 Jun;5(2):157-9

Division of Epidemiology, School of Public Health in Brownsville, University of Texas Health Science Center at Houston, 80 Fort Brown, SPH Building, Brownsville, TX 78520, USA.

Introduction: Diabetes knowledge among TB patients can contribute to improved TB treatment outcomes, but lack of diabetes diagnosis awareness is a limitation in developing countries. Given its low cost, the sensitivity of urine glucose dipsticks for diabetes screening in TB patients was assessed.

Methods: Glycosuria was assessed in 90 newly diagnosed TB patients (38 with diabetes) in south Texas, USA (n = 20) and northeast Mexico (n = 70) during January 2009-December 2010.

Results: Glycosuria was detected in 65% of the diabetic patients with chronic hyperglycemia (positive predictive value 91%, negative predictive value 84%).

Conclusion: We propose that TB clinics with limited budgets where portable glucometers may not be available conduct universal screening for diabetes with urine dipsticks. This could be followed by blood glucose or HbA1c testing in the subset of patients requiring confirmation or higher sensitivity assessment, to improve the comanagement of TB and diabetes.
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http://dx.doi.org/10.1093/inthealth/iht007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679672PMC
June 2013

Validation of Mycobacterium tuberculosis Rv1681 protein as a diagnostic marker of active pulmonary tuberculosis.

J Clin Microbiol 2013 May 6;51(5):1367-73. Epub 2013 Feb 6.

Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

The development of an accurate antigen detection assay for the diagnosis of active tuberculosis (TB) would represent a major clinical advance. Here, we demonstrate that the Mycobacterium tuberculosis Rv1681 protein is a biomarker for active TB with potential diagnostic utility. We initially identified, by mass spectroscopy, peptides from the Rv1681 protein in urine specimens from 4 patients with untreated active TB. Rabbit IgG anti-recombinant Rv1681 detected Rv1681 protein in lysates and culture filtrates of M. tuberculosis and immunoprecipitated it from pooled urine specimens from two TB patients. An enzyme-linked immunosorbent assay formatted with these antibodies detected Rv1681 protein in unconcentrated urine specimens from 11/25 (44%) TB patients and 1/21 (4.8%) subjects in whom TB was initially clinically suspected but then ruled out by conventional methods. Rv1681 protein was not detected in urine specimens from 10 subjects with Escherichia coli-positive urine cultures, 26 subjects with confirmed non-TB tropical diseases (11 with schistosomiasis, 5 with Chagas' disease, and 10 with cutaneous leishmaniasis), and 14 healthy subjects. These results provide strong validation of Rv1681 protein as a promising biomarker for TB diagnosis.
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http://dx.doi.org/10.1128/JCM.03192-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647908PMC
May 2013

Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control.

Tuberculosis (Edinb) 2013 Mar 3;93(2):192-7. Epub 2012 Nov 3.

Division of Epidemiology, University of Texas Health Science Center at Houston, School of Public Health at Brownsville, 80 Fort Brown, SPH Bldg, Brownsville, TX 78520, USA.

The re-emerging importance of type 2 diabetes mellitus (DM) to tuberculosis (TB) control is of growing concern, but the basis for this relationship is poorly understood. Given the importance of mononuclear phagocytes for TB control and the reported alterations in monocytes of DM patients, we evaluated whether the initial interaction between both was affected in diabetics. Mycobacterium tuberculosis-naïve individuals with and without DM were group matched by age and gender and the efficiency of M. tuberculosis association (attachment and ingestion) with their monocytes was assessed in the presence of autologous serum. The association of M. tuberculosis with monocytes was significantly lower in diabetics (19.2 ± 6.1) than non-diabetics (27.5 ± 7.9; p = 0.02). Multivariate analysis controlling for host socio demographics, DM characteristics and serum lipids indicated that male gender (p = 0.04) and poorly-controlled DM (high HbA1c and hyperglycemia; p = 0.01) were significantly associated with the lower interaction of M. tuberculosis with monocytes. Serum heat-inactivation reduced the association of M. tuberculosis to similar levels in both study groups (p = 0.69) suggesting alterations in the complement pathway of DM patients. These findings suggest an altered route of entry of the pathogen in DM patients that may influence the downstream activation of signaling pathways in the monocyte and the survival of mycobacteria.
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http://dx.doi.org/10.1016/j.tube.2012.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580120PMC
March 2013

Validation of increased blood storage times with the T-SPOT.TB assay with T-Cell Xtend reagent in individuals with different tuberculosis risk factors.

J Clin Microbiol 2012 Jul 18;50(7):2469-71. Epub 2012 Apr 18.

Department of Internal Medicine, Division of Infectious Diseases, The Ohio State University, Columbus, Ohio, USA.

We compared the performance of the T-SPOT.TB assay with blood used within 0 to 3.5 h after collection (control) to its performance with blood stored for 0 to 3.5, 5 to 8, 18 to 21, or 31 to 33 h with the addition of T-Cell Xtend (experimental), using samples from 154 participants. The 95.4% concordance between paired specimens indicated that blood can be stored for up to 33 h prior to T-SPOT.TB testing.
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http://dx.doi.org/10.1128/JCM.00674-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405595PMC
July 2012

Rapid DNA extraction for specific detection and quantitation of Mycobacterium tuberculosis DNA in sputum specimens using Taqman assays.

Tuberculosis (Edinb) 2011 Dec 15;91 Suppl 1:S43-8. Epub 2011 Nov 15.

Division of Epidemiology, School of Public Health in Brownsville, University of Texas Health Science Center at Houston, 80 Fort Brown, SPH Bldg, Brownsville, Texas 78520, USA.

Rapid tuberculosis (TB) detection is critical for disease control, and further quantitation of Mycobacterium tuberculosis (Mtb) in sputum is valuable for epidemiological and clinical studies. We evaluated a simple, robust and cost-efficient in-house DNA extraction and downstream Taqman approach for detection and quantitation of Mtb genomes from sputum of newly-diagnosed TB patients and non-TB controls. DNA was extracted using guanidine isothiocyanate and silica-based spin columns in less than 2 h, stored frozen, and Taqman assays were used to detect Mtb with IS6110 and quantify it targeting RD1 and IS1081. The Taqmans had a sensitivity >95% in 108 culture-confirmed TB patients and specificity of 100% in 43 non-TB controls. Genome counts were correlated with the Mycobacterial Growth Indicator Tubes' (MGIT) time-to-detection values (1/TTD × 1000; rho = 0.66; p < 0.001) in 91 TB patients (33 excluded with MGIT contamination). This linear relationship was nearly identical between mycobacteria isolated from sputum and H37Rv Mtb grown in-vitro to its log phase. TB treatment between 3 and 7 days was associated with lower 1/TTD × 1000 values but not with genome counts. Together, our protocol provides rapid, specific, inexpensive and quantitative detection of Mtb DNA in fresh or stored sputa making it a robust tool for prompt TB diagnosis, and with potential use for clinical and epidemiologic studies.
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http://dx.doi.org/10.1016/j.tube.2011.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248966PMC
December 2011

Cross-sectional assessment reveals high diabetes prevalence among newly-diagnosed tuberculosis cases.

Bull World Health Organ 2011 May 30;89(5):352-9. Epub 2011 Mar 30.

School of Public Health in Brownsville, University of Texas Health Science Center at Houston, Brownsville, 78520, USA.

Objective: To estimate the contribution of clinically-confirmed diabetes mellitus to tuberculosis (TB) rates in communities where both diseases are prevalent as a way to identify opportunities for TB prevention among diabetic patients.

Methods: This is a prospective study in which TB patients ≥ 20 years old at TB clinics in the Texas-Mexico border were tested for diabetes. The risk of tuberculosis attributable to diabetes was estimated from statistics for the corresponding adult population.

Findings: The prevalence of diabetes among TB patients was 39% in Texas and 36% in Mexico. Diabetes contributed 25% of the TB cases studied, whereas human immunodeficiency virus (HIV) infection contributed 5% or fewer. Among TB patients, fewer Mexicans than Texans were aware that they had diabetes before this study (4% and 19%, respectively). Men were also less frequently aware than women that they had diabetes (P = 0.03). Patients who knew that they had diabetes before the study had an 8-year history of the disease, on average, before being diagnosed with TB.

Conclusion: Patients with diabetes are at higher risk of contracting TB than non-diabetic patients. Integrating TB and diabetes control programmes worldwide would facilitate TB prevention among diabetes patients and increase the number of diabetics who learn of their condition, particularly among males. Such a strategy would lead to earlier case detection and improve the management of both TB and diabetes.
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http://dx.doi.org/10.2471/BLT.10.085738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089389PMC
May 2011

Socioeconomic status and prevalence of obesity and diabetes in a Mexican American community, Cameron County, Texas, 2004-2007.

Prev Chronic Dis 2010 May 15;7(3):A53. Epub 2010 Apr 15.

Division of Epidemiology, University of Texas School of Public Health, Brownsville Campus, 80 Fort Brown, Brownsville, TX 78520, USA.

Introduction: Mexican Americans are at increased risk for obesity and diabetes. We established a cohort on the United States-Mexico border to determine the prevalence of obesity and diabetes in this Mexican American population and to see whether minor economic advantages had any effect on health.

Methods: We randomly selected and extensively documented 810 people aged 35 to 64 years. Weighted data were analyzed to establish prevalence of obesity and diabetes and other markers of poor health such as elevated glycated hemoglobin levels.

Results: Rates of obesity (body mass index > or = 30 kg/m(2)) were 57% in the first (lower) of 4 socioeconomic strata by income and were 55.5% in the third (higher). People in the higher socioeconomic stratum were significantly less likely to have undiagnosed diabetes (2% vs 9%). Among people aged 55 to 64 years, rates of diabetes were significantly higher among those in the lower socioeconomic stratum than among those in the higher stratum. Rates of undiagnosed diabetes had similar differences. Approximately three-fourths of the respondents reported having no health insurance, and we found no difference between people in different socioeconomic strata.

Conclusion: Rates of obesity and diabetes in this border community are among the highest in the United States. Belonging to the lower socioeconomic stratum significantly increased the likelihood of having undiagnosed diabetes and, in patients too young to be eligible for Medicare, the overall risk of developing diabetes. Modest improvement in income has a beneficial effect on health in this racial/ethnic minority community.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879985PMC
May 2010

Systematic interpretation of molecular beacon polymerase chain reaction for identifying rpoB mutations in Mycobacterium tuberculosis isolates with mixed resistant and susceptible bacteria.

Diagn Microbiol Infect Dis 2010 May 12;67(1):37-46. Epub 2010 Mar 12.

The University of Texas Health Science Center Houston, School of Public Health at Brownsville, Brownsville, TX 78520, USA.

Detection of multidrug-resistant tuberculosis (MDR-TB), a frequent cause of treatment failure, takes 2 or more weeks to identify by culture. Rifampicin (RIF) resistance is a hallmark of MDR-TB, and detection of mutations in the rpoB gene of Mycobacterium tuberculosis using molecular beacon probes with real-time quantitative polymerase chain reaction (qPCR) is a novel approach that takes
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http://dx.doi.org/10.1016/j.diagmicrobio.2009.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854294PMC
May 2010