TB Modeling and Translational Epi Group

Group Publications

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- October 2013 -

Clostridium difficile carriage and serum antitoxin responses in children with inflammatory bowel disease. (2013). Hourigan SK., Chirumamilla SR., Ross T., Golub JE., Rabizadeh S., Saeed SA., Elson CO., Kelly CP., Carroll KC., Oliva-Hemker M., Sears C, Inflammatory bowel diseases, 19, 2744-52

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BACKGROUND: Adults with inflammatory bowel disease (IBD) have a high prevalence of Clostridium difficile carriage, but little data exist regarding pediatric patients with IBD. Serum antibody responses to C. difficile toxins in correlation with organism carriage are not described in IBD. This study determines the prevalence of C. difficile carriage and compares serum antibody responses to C. difficile toxins in pediatric outpatients with IBD and controls. METHODS: Fecal and serum samples were prospectively collected from pediatric outpatients with IBD (n = 85) and age-matched controls (n = 78). Initial and follow-up stool samples were tested using cytotoxigenic C. difficile culture and PCR to detect the toxin B gene. Pulsed-field gel electrophoresis determined the strain type. Enzyme-linked immunosorbent assay determined serum immunoglobulin responses to C. difficile toxins. RESULTS: Asymptomatic C. difficile carriage was significantly greater in IBD (17%) versus controls (3%) (P = 0.012). IBD type, disease severity, IBD therapy, recent antibiotics, and hospitalizations were not associated with carriage. Proton pump inhibitor use was significantly higher in patients with C. difficile carriage (54% versus 25%, P < 0.05). North American pulsed-field (NAP) strain carriage varied over time in patients colonized with C. difficile. A significantly greater proportion of patients with IBD had a positive serum antibody response to toxin A (69%) compared with controls (53%) (P < 0.05). CONCLUSIONS: Asymptomatic toxigenic C. difficile carriage was increased in pediatric outpatients with IBD compared with controls. Proton pump inhibitor use was associated with increased carriage. Antibody responses to C. difficile toxins were increased in IBD, potentially promoting asymptomatic colonization. Future studies should identify the risk factors for symptomatic C. difficile in pediatric IBD.

AIDS-related Kaposi's sarcoma in Brazil: trends and geopolitical distribution. (2013). Saraceni V., Talhari CC., Pereira GF., Golub JE., Talhari S., Miranda AE, International journal of dermatology, 52, 1525-9

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BACKGROUND: AIDS-related Kaposi's sarcoma (KS) is a unique model of the relationship between viral infection, immunity, environmental, and genetic factors in viral cancers. The goal was to determine the distribution of KS cases among Brazilian geopolitical regions, looking at the ecological relationship with median CD4 cell count. METHODS: Ecological study using Brazilian National Diseases Reporting Databases: 1982-2009. Subjects >/= 13 years of age who have KS cited in their AIDS reporting form were selected, and demographic and HIV exposure data were collected. RESULTS: We found 11,731 KS cases in the period, with a prevalence of 2.4% among AIDS cases; 88% were male, and 68% lived in the Southeast region, which accounted for 59% of AIDS cases. The regional and national prevalence trends were similar, although the highest proportion among women was found in the North region, which has the lowest number of both AIDS and KS cases. Heterosexual transmission accounted for 87% of HIV among women compared to 18% among men. Fifty-seven percent of all KS cases were diagnosed before antiretroviral therapy (ART). Injection drug use accounted for 11% of KS cases. Median survival was 472 days before the ART era and 1482 after it (P < 0.001). Median CD4 counts increased in all regions in the period as ART coverage expanded, and a resulting correlating decline in KS cases was observed. CONCLUSIONS: Prevalence of KS declined after the introduction of ART in all regions of Brazil, suggesting individual protection conveyed by ART.

Modeling the impact of alternative strategies for rapid molecular diagnosis of tuberculosis in Southeast Asia. (2013). Sun AY., Pai M., Salje H., Satyanarayana S., Deo S., Dowdy DW, American journal of epidemiology, 178, 1740-9

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Novel diagnostic tests hold promise for improving tuberculosis (TB) control, but their epidemiologic impact remains uncertain. Using data from the World Health Organization (2011-2012), we developed a transmission model to evaluate the deployment of 3 hypothetical TB diagnostic tests in Southeast Asia under idealized scenarios of implementation. We defined diagnostics by their sensitivity for smear-negative TB and proportion of patients testing positive who initiate therapy ("point-of-care amenability"), with tests of increasing point-of-care amenability having lower sensitivity. Implemented in the public sector (35% of care-seeking attempts), each novel test reduced TB incidence by 7%-9% (95% uncertainty range: 4%-13%) and mortality by 20%-22% (95% uncertainty range: 14%-27%) after 10 years. If also deployed in the private sector (65% of attempts), these tests reduced incidence by 13%-16%, whereas a perfect test (100% sensitivity and treatment initiation) reduced incidence by 20%. Annually detecting 20% of prevalent TB cases through targeted screening (70% smear-negative sensitivity, 85% treatment initiation) also reduced incidence by 19%. Sensitivity and point-of-care amenability are equally important considerations when developing novel diagnostic tests for TB. Novel diagnostics can substantially reduce TB incidence and mortality in Southeast Asia but are unlikely to transform TB control unless they are deployed actively and in the private sector.

- September 2013 -

Fever is associated with delayed ventilator liberation in acute lung injury. (2013). Netzer G., Dowdy DW., Harrington T., Chandolu S., Dinglas VD., Shah NG., Colantuoni E., Mendez-Tellez PA., Shanholtz C., Hasday JD., Needham DM, Annals of the American Thoracic Society, 10, 608-15

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BACKGROUND: Acute lung injury (ALI) is characterized by inflammation, leukocyte activation, neutrophil recruitment, endothelial dysfunction, and epithelial injury, which are all affected by fever. Fever is common in the intensive care unit, but the relationship between fever and outcomes in ALI has not yet been studied. We evaluated the association of temperature dysregulation with time to ventilator liberation, ventilator-free days, and in-hospital mortality. METHODS: Analysis of a prospective cohort study, which recruited consecutive patients with ALI from 13 intensive care units at four hospitals in Baltimore, Maryland. The relationship of fever and hypothermia with ventilator liberation was assessed with a Cox proportional hazards model. We evaluated the association of temperature during the first 3 days after ALI with ventilator-free days, using multivariable linear regression models, and the association with mortality was evaluated by robust Poisson regression. MEASUREMENTS AND MAIN RESULTS: Of 450 patients, only 12% were normothermic during the first 3 days after ALI onset. During the first week post-ALI, each additional day of fever resulted in a 33% reduction in the likelihood of successful ventilator liberation (95% confidence interval [CI] for adjusted hazard ratio, 0.57 to 0.78; P < 0.001). Hypothermia was independently associated with decreased ventilator-free days (hypothermia during each of the first 3 d: reduction of 5.58 d, 95% CI: -9.04 to -2.13; P = 0.002) and increased mortality (hypothermia during each of the first 3 d: relative risk, 1.68; 95% CI, 1.06 to 2.66; P = 0.03). CONCLUSIONS: Fever and hypothermia are associated with worse clinical outcomes in ALI, with fever being independently associated with delayed ventilator liberation.

From Fort Lee to Phnom Penh: a journey of self-discovery. (2013). Golub JE., Diament-Golub J, Journal of the New Jersey Dental Association, 84, 24-5

- August 2013 -

Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial. (2013). Durovni B., Saraceni V., Moulton LH., Pacheco AG., Cavalcante SC., King BS., Cohn S., Efron A., Chaisson RE., Golub JE, The Lancet. Infectious diseases, 13, 852-8

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BACKGROUND: Preventive therapy for tuberculosis in patients with HIV is effective, but it has not been widely implemented in moderate or high-burden settings. We assessed the effect of widespread use of isoniazid preventive therapy on rates of tuberculosis and death in people with HIV in Brazil. METHODS: We did a stepped wedge, cluster-randomised trial with patients actively enrolled in 29 HIV clinics in Rio de Janeiro. Clinic staff were trained in tuberculosis screening, use of tuberculin skin tests, and use of isoniazid preventive therapy. Clinics were randomly allocated a date to begin the intervention period, with two clinics beginning the intervention every 2 months starting from Sept 1, 2005. The primary outcome was tuberculosis incidence alone or combined with death in the control versus intervention periods until Aug 31, 2009. This trial is registered at ClinicalTrials.gov, number NCT00107887. RESULTS: Of 17,413 patients in the cohort, 12,816 were eligible for the intervention. Overall, there were 475 tuberculosis cases and 838 deaths. The intervention increased the rate of patients receiving skin tests from 19 per 100 person-years to 59 per 100 person-years, and from 36 per 100 person-years to 144 per 100 person-years for those eligible for isoniazid preventive therapy. In the control period, 221 cases of tuberculosis were diagnosed (1.31 per 100 person-years) compared with 254 (1.10 per 100 person-years) in the intervention period (unadjusted hazard ratio [HR] 0.87; 95% CI 0.69-1.10). Rates of tuberculosis incidence or death were 3.64 and 3.04 per 100 person-years, respectively (0.76; 95% CI 0.66-0.87). When adjusted for age, sex, entry CD4 count, and use of antiretroviral therapy, the HR for tuberculosis was 0.73 (95% CI 0.54-0.99) and for tuberculosis or death was 0.69 (0.57-0.83). INTERPRETATION: Operational training aimed at increasing tuberculosis screening, provision of tuberculin skin tests, and use of isoniazid preventive therapy in Brazilian HIV clinics significantly reduced incident tuberculosis and death. Thus, scale-up of preventive therapy for HIV-infected patients in settings of moderate tuberculosis incidence is achievable and should be widely implemented in Brazil and elsewhere. FUNDING: Bill & Melinda Gates Foundation and the National Institutes of Health.

Population-level impact of same-day microscopy and Xpert MTB/RIF for tuberculosis diagnosis in Africa. (2013). Dowdy DW., Davis JL., den Boon S., Walter ND., Katamba A., Cattamanchi A, PloS one, 8, e70485

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OBJECTIVE: To compare the population-level impact of two World Health Organization-endorsed strategies for improving the diagnosis of tuberculosis (TB): same-day microscopy and Xpert MTB/RIF (Cepheid, USA). METHODS: We created a compartmental transmission model of TB in a representative African community, fit to the regional incidence and mortality of TB and HIV. We compared the population-level reduction in TB burden over ten years achievable with implementation over two years of same-day microscopy, Xpert MTB/RIF testing, and the combination of both approaches. FINDINGS: Same-day microscopy averted an estimated 11.0% of TB incidence over ten years (95% uncertainty range, UR: 3.3%-22.5%), and prevented 11.8% of all TB deaths (95% UR: 7.7%-27.1%). Scaling up Xpert MTB/RIF to all centralized laboratories to achieve 75% population coverage had similar impact on incidence (9.3% reduction, 95% UR: 1.9%-21.5%) and greater effect on mortality (23.8% reduction, 95% UR: 8.6%-33.4%). Combining the two strategies (i.e., same-day microscopy plus Xpert MTB/RIF) generated synergistic effects: an 18.7% reduction in incidence (95% UR: 5.6%-39.2%) and 33.1% reduction in TB mortality (95% UR: 18.1%-50.2%). By the end of year ten, combining same-day microscopy and Xpert MTB/RIF could reduce annual TB mortality by 44% relative to the current standard of care. CONCLUSION: Scaling up novel diagnostic tests for TB and optimizing existing ones are complementary strategies that, when combined, may have substantial impact on TB epidemics in Africa.

The eye of the beholder: tuberculosis screening for elderly long-term care residents. (2013). Schwartzman K., Dowdy D, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 1121

Analysis of latent tuberculosis infection treatment adherence among refugees and other patient groups referred to the Baltimore City Health Department TB clinic, February 2009-March 2011. (2013). Nuzzo JB., Golub JE., Chaulk P., Shah M, Journal of immigrant and minority health, 17, 56-65

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We sought to determine the proportion of refugee patients at the Baltimore City Health Department Tuberculosis program (BCHD-TB) successfully completing latent tuberculosis infection (LTBI) treatment, as compared to other referral groups, and to identify factors associated with treatment completion. We completed a retrospective cohort analysis of individuals referred to BCHD-TB program for LTBI care between February 1, 2009 and March 31, 2011. Among 841 patients evaluated by BCHD-TB and diagnosed with LTBI, 81% of refugees, 50% of non-refugee foreign-born, and 35% of US-born patients completed LTBI treatment. In multivariate analysis, refugees had greater odds of LTBI treatment completion (Adjusted Odds Ratio 7.2; 95% CI 4.2-12.4, p < 0.001) compared to US-born individuals adjusting for age, gender, and treatment regimen. Overall, LTBI treatment completion remains suboptimal. At BCHD-TB, LTBI treatment completion was significantly higher among refugees than other referral groups. Additional efforts are needed to optimize LTBI care, and future efforts may need to be tailored for different risk groups.

- July 2013 -

Prevalence of tobacco smoking in adults with tuberculosis in South Africa. (2013). Lam C., Martinson N., Hepp L., Ambrose B., Msandiwa R., Wong ML., Apelberg B., Tamplin S., Golub JE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 1354-7

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We conducted a tobacco prevalence survey among 707 in-patients diagnosed with tuberculosis (TB) at the Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Current smoking status was expanded to include both patients who self-reported at the time of TB diagnosis and patients who stopped smoking in the 2-month period before diagnosis. Six per cent reported current smoking at the time of TB diagnosis, 26% within 2 months before TB diagnosis. Human immunodeficiency virus status (73% positive) was not associated with current smoking. Classifying current smoking status among newly diagnosed TB patients should be extended to include smoking at time of the onset of TB symptoms.

- June 2013 -

Understanding the disparity: predictors of virologic failure in women using highly active antiretroviral therapy vary by race and/or ethnicity. (2013). McFall AM., Dowdy DW., Zelaya CE., Murphy K., Wilson TE., Young MA., Gandhi M., Cohen MH., Golub ET., Althoff KN, Journal of acquired immune deficiency syndromes (1999), 64, 289-98

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BACKGROUND: Stark racial/ethnic disparities in health outcomes exist among those living with HIV in the United States. One of 3 primary goals of the National HIV/AIDS Strategy is to reduce HIV-related disparities and health inequities. METHODS: Using data from HIV-infected women participating in the Women's Interagency HIV Study from April 2006 to March 2011, we measured virologic failure (HIV RNA >200 copies/mL) after suppression (HIV RNA < 80 copies/mL) on highly active antiretroviral therapy. We identified predictors of virologic failure using discrete time survival analysis and calculated racial/ethnic-specific population-attributable fractions (PAFs). RESULTS: Of 887 eligible women, 408 (46%) experienced virologic failure during the study period. Hispanic and white women had significantly lower hazards of virologic failure than African American women [Hispanic hazard ratio, (HR) = 0.8, 95% confidence interval: (0.6 to 0.9); white HR = 0.7 (0.5 to 0.9)]. The PAF of virologic failure associated with low income was higher in Hispanic [adjusted hazard ratios (aHR) = 2.2 (0.7 to 6.5), PAF = 49%] and African American women [aHR = 1.8 (1.1 to 3.2), PAF = 38%] than among white women [aHR = 1.4 (0.6 to 3.4), PAF = 16%]. Lack of health insurance compared with public health insurance was associated with virologic failure only among Hispanic [aHR = 2.0 (0.9 to 4.6), PAF = 22%] and white women [aHR = 1.9 (0.7 to 5.1), PAF = 13%]. By contrast, depressive symptoms were associated with virologic failure only among African-American women [aHR = 1.6 (1.2 to 2.2), PAF = 17%]. CONCLUSIONS: In this population of treated HIV-infected women, virologic failure was common, and correlates of virologic failure varied by race/ethnicity. Strategies to reduce disparities in HIV treatment outcomes by race/ethnicity should address racial/ethnic-specific barriers including depression and low income to sustain virologic suppression.

Challenges in evaluating the cost-effectiveness of new diagnostic tests for HIV-associated tuberculosis. (2013). Andrews JR., Lawn SD., Dowdy DW., Walensky RP, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 57, 1021-6

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With an emerging array of rapid diagnostic tests for tuberculosis, cost-effectiveness analyses are needed to inform scale-up in various populations and settings. Human immunodeficiency virus (HIV)-associated tuberculosis poses unique challenges in estimating and interpreting the cost-effectiveness of novel diagnostic tools. First, gains in sensitivity and specificity do not directly correlate with impact on clinical outcomes. Second, the cost-effectiveness of implementing tuberculosis diagnostics in HIV-infected populations is heavily influenced by downstream costs of HIV care. As a result, tuberculosis diagnostics may appear less cost-effective in this population than among HIV-uninfected individuals, raising important ethical and policy questions about the design and interpretation of cost-effectiveness analyses in this setting. Third, conventional cost-effectiveness benchmarks may be inadequate for making decisions about whether to adopt new diagnostics. If we are to appropriately deploy novel diagnostics for tuberculosis to people living with HIV in resource-constrained settings, these challenges in measuring cost-effectiveness must be more widely recognized and addressed.

Economic evaluations of point of care testing strategies for active tuberculosis. (2013). Zwerling A., Dowdy D, Expert review of pharmacoeconomics & outcomes research, 13, 313-25

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Point of care (POC) diagnostics are often hailed as having the potential to transform tuberculosis (TB) control efforts. However, POC testing is better conceptualized as a system of diagnosis and treatment, not simply a test that can provide rapid, deployable results. Economic evaluations may help decision makers allocate scarce resources for TB control, but evaluations of POC testing face unique challenges that include evaluating the full diagnostic system, incorporating implementation costs, translating diagnostic results into health and accounting for downstream treatment costs. For economic evaluations to reach their full potential as decision-making tools for POC testing in TB, these challenges must be understood and addressed.

Data needs for evidence-based decisions: a tuberculosis modeler's 'wish list'. (2013). Dowdy DW., Dye C., Cohen T, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 866-77

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Infectious disease models are important tools for understanding epidemiology and supporting policy decisions for disease control. In the case of tuberculosis (TB), such models have informed our understanding and control strategies for over 40 years, but the primary assumptions of these models--and their most urgent data needs--remain obscure to many TB researchers and control officers. The structure and parameter values of TB models are informed by observational studies and experiments, but the evidence base in support of these models remains incomplete. Speaking from the perspective of infectious disease modelers addressing the broader TB research and control communities, we describe the basic structure common to most TB models and present a 'wish list' that would improve the evidence foundation upon which these models are built. As a comprehensive TB research agenda is formulated, we argue that the data needs of infectious disease models--our primary long-term decision-making tools--should figure prominently.

Screening for active tuberculosis: methodological challenges in implementation and evaluation. (2013). Golub JE., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 856-65

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As active screening strategies for tuberculosis (TB) continue to rise globally, it has become increasingly important to consider the methodological challenges in designing and implementing these strategies. The key challenges associated with TB screening can be summarized in terms of four continua or spectra, namely those of 1) TB disease and diagnostic yield, 2) TB risk and resource availability, 3) TB screening strategies, and 4) outcomes and impact measurements of screening programs. In this review, we provide a discussion of these challenges to help guide development of TB screening strategies that will be effective in a given epidemiological setting.

- May 2013 -

Pulmonary tuberculosis. (2013). Trajman A., Lapa E Silva JR., Dalcolmo M., Golub JE, Pulmonary medicine, 2013, 645747

- April 2013 -

Cost-consequence analysis of multimodal interventions with environmental components for pediatric asthma in the state of Maryland. (2013). Jassal MS., Diette GB., Dowdy DW, The Journal of asthma : official journal of the Association for the Care of Asthma, 50, 672-80

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BACKGROUND: Applied environmental strategies for asthma control are often expensive, but may save longer-term healthcare costs. Whether these savings outweigh additional costs of implementing these strategies is uncertain. METHODS: We conducted a systematic review to estimate the expenditures and savings of environmental interventions for asthma in the state of Maryland. Direct costs included hospitalizations, emergency room, and clinic visits. Indirect expenditures included costs of lost work productivity and travel incurred during the usage of healthcare services. We used decision analysis, assuming a hypothetical cohort of the approximated 49,290 pediatric individuals in Maryland with persistent asthma, to compare costs and benefits of environmental asthma interventions against the standard of care (no intervention) from the societal perspective. RESULTS: Three interventions among nine articles met the inclusion criteria for the systematic review: 1) environmental education using medical professionals; 2) education using non-medical personnel; and 3) multi-component strategy involving education with non-medical personnel, allergen-impermeable covers, and pest management. All interventions were found to be cost-saving relative to the standard of care. Home environmental education using non-medical professionals yielded the highest net savings of $14.1 million (95% simulation interval (SI): $-.283 million, $19.4 million), while the multi-component intervention resulted in the lowest net savings of $8.1 million (95% SI: $-4.9 million, $15.9 million). All strategies were most sensitive to the baseline number of hospitalizations in those not receiving targeted interventions for asthma. CONCLUSIONS: Limited environmental reduction strategies for asthma are likely to be cost-saving to the healthcare system in Maryland and should be considered for broader scale-up in other economically similar settings.

Cost-effectiveness of novel first-line treatment regimens for tuberculosis. (2013). Owens JP., Fofana MO., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 590-6

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OBJECTIVE: To evaluate the cost-effectiveness of novel first-line treatment regimens for tuberculosis (TB). DESIGN: Using decision analysis, we projected the costs and effectiveness, from the health care perspective, of treating a patient cohort in the public sector for active TB without known or suspected resistance to first-line drugs. We compared standard (6-month) treatment to hypothetical regimens of equal efficacy, higher cost and shorter duration. RESULTS: For every 100 TB patients treated, replacing standard treatment with shorter-course regimens would avert an estimated 2-4 failures/relapses, 0.2-0.4 deaths and 8-14 disability-adjusted life years (DALYs), or 6-11% of all DALYs suffered. We identified three primary determinants of cost-effectiveness: drug price, continuation phase treatment delivery costs and deaths averted through fewer relapses. In a high treatment cost scenario (similar to Brazil), averted delivery costs outweighed higher drug costs, making novel regimens cost-saving. In a low treatment cost scenario (similar to the Philippines), a 4-month regimen with a drug price of $1/day cost $66 per patient, or $840 per DALY averted, and became cost-saving if the drug price dropped below $0.37/day. CONCLUSION: Although they avert a small proportion of total DALYs, novel, shorter-course first-line regimens for TB are likely to be cost-effective or cost-saving in most settings.

- March 2013 -

Alignment of new tuberculosis drug regimens and drug susceptibility testing: a framework for action. (2013). Wells WA., Boehme CC., Cobelens FG., Daniels C., Dowdy D., Gardiner E., Gheuens J., Kim P., Kimerling ME., Kreiswirth B., Lienhardt C., Mdluli K., Pai M., Perkins MD., Peter T., Zignol M., Zumla A., Schito M, The Lancet. Infectious diseases, 13, 449-58

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New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease.

A comparative analysis of clinical and molecular factors with the stage of cervical cancer in a Brazilian cohort. (2013). Amaro-Filho SM., Golub JE., Nuovo GJ., Cunha CB., Levi JE., Villa LL., Andrade CV., Russomano FB., Tristao A., Pires A., Nicol AF, PloS one, 8, e57810

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UNLABELLED: Cell cycle protein expression plays an important role in the pathophysiology of cervical cancer. However, few studies have attempted to correlate the use of these biomarkers with the clinical progression of the tumor. OBJECTIVES: 1) To analyze the expression of Ki-67, p53 and p16(INK4a) in cervical cancer, 2) to correlate the relative expression of these proteins as well as clinical parameters with the stage of disease, and 3) to determine the HPV DNA prevalence and subtype distribution. METHODS: Tissue Micro-Arrays (TMA) from patients with invasive cervical cancer (ICC) and controls were analyzed. HPV DNA detection was done by PCR and in situ hybridization. Ki-67, p53 and p16(INK4a) were analyzed by immunohistochemistry; clinical data was derived from the chart review. RESULTS: Advanced tumor stage (III and IV) was strongly associated (p<0.005) with advanced age (>55 years old), with more than four pregnancies and with the lack of formal education. HPV DNA was found in 94.3% of cases with the most prevalent types being HPV16 (67.5%), followed by HPV33 (12.0%) and HPV35 (3.6%). High expression of Ki-67 and p16 was more common in the advanced FIGO stages (p = 0.023). Women with HPV16 tended to be younger (50.9 years; SE 1.9) compared to women with other types (59.9 years; SE 2.8). CONCLUSION: We found that Ki-67 and p16 expression were independently associated with the tumor stage. We also noted that about 1/3 of the cervical cancers in this Brazilian cohort were not associated with HPV types directly targeted by the current HPV vaccines.

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