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WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

ind T cells with

ind T cells with irrelevant T-cell receptors, but instead specifically bound to DDM-reactive T cells, even when present in low frequency. These studies provide the first direct evidence that mycobacterial lipopeptide antigens bind in a trimolecular interaction involving CD1 and T-cell receptors. This work was supported by the NIAID 1K08AI089858. 5) Population health benefits and cost-effectiveness of tuberculosis diagnosis with Xpert MTB/RIF Nicolas A Menzies 1,2 , Ted Cohen 3,4 , Hsien-Ho Lin 5 , Megan Murray 3 , Joshua A Salomon 6,1 1 Center for Health Decision Sciences, Harvard School of Public Health, Boston, MA; 2 Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA; 3 Department of Epidemiology, Harvard School of Public Health, Boston, MA; 4 Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA; 5 Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taiwan; 6 Department of Global Health and Population, Harvard School of Public Health, Boston, MA The Xpert MTB/RIF test enables rapid detection of tuberculosis and rifampicin resistance, and many countries are incorporating Xpert into national TB programs. As roll-out begins, it is essential to understand the potential health impact and cost-effectiveness of Xpert-based diagnostic strategies. We evaluated potential consequences of implementing Xpert in five southern African countries—Botswana, Lesotho, Namibia, South Africa, and Swaziland—where drug resistance and TB-HIV coinfection are prevalent. Using a calibrated, dynamic mathematical model, we compared the status quo diagnostic algorithm, which emphasizes sputum smear, against an algorithm incorporating Xpert for initial diagnosis. Compared to status quo, implementation of Xpert would avert 132 [55 – 284] thousand TB cases and 182 [97 – 302] thousand TB deaths over the 10 years following introduction, and reduce prevalence by 20-30% by 2022, with more modest reductions in incidence. Health system costs are projected to increase substantially with Xpert, requiring an additional $US 460 [294-699] million over 10 years. HIV treatment represents a substantial fraction of these additional costs, due to improved survival in TB/HIVinfected populations. Relative to status quo, the Xpert strategy has an estimated costeffectiveness of US$959 [$633-$1,485] per DALY averted over 10 years following introduction. Introduction of Xpert may produce substantial changes in TB morbidity and mortality through improved case-finding, though the impact on long-term epidemic dynamics is less pronounced. Xpert is projected to offer high value for money based on conventional cost-effectiveness benchmarks. However, the additional financial burden would be substantial, requiring significant increases in HIV treatment and MDR-TB care costs. 6) Characterization and molecular analysis of XDR-TB strains in Delhi Urvashi B. Singh 1* , Chhavi Porwal 1 , Amit Kaushik 1 , Nayani Makkar 1 , Jayant. N. Banavaliker 2 , Mahmud Hanif 3 , Rupak Singla 4 , Jitendra Nath Pande 5 1 Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India. 2 Rajan Babu Institute for Pulmonary Medicine and Tuberculosis, Delhi, India. 3 New Delhi TB Centre, New Delhi, India. 4 Lala Ram Swarup Institute of Tuberculosis and Respiratory Diseases, New Delhi, India. 5 Sitaram Bhartia Institute of Science and Research, New Delhi, India. *Corresponding author: Dr. Urvashi B. Singh, M.D., Ph.D., Associate Professor, Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India. 17

India has a high burden of TB and emergence of multidrug-resistant tuberculosis (MDR-TB), and extensively drug-resistant TB (XDR-TB). XDR-TB/p-XDR-TB (pre-extensively drug-resistant TB) is widely considered a serious threat to global TB control. The present study was designed to do molecular characterization of MDR-TB and XDR-TB isolates from patients with high suspicion of MDR-TB in Delhi. Drug susceptibility testing for Rifampicin (RIF) and Isoniazid (INH) was performed on 611 MDR suspected M. tuberculosis isolates. Of 611, 483 strains were found to be MDR M. tuberculosis. Further 18 of the 483 MDR-TB patients were XDR-TB isolates and 53 were p-XDR-TB isolates. DNA-sequencing was performed for the genes known to be responsible for second-line drug resistance in all XDR-TB/pre-XDR-TB and a few sensitive isolates. Spoligotyping was performed on all MDR, pre-XDR and XDR-TB isolates. DNA sequencing results showed the most predominant mutations amongst XDR-TB isolates, determining the Quinolone resistance was at position 94 in the gyrA gene QRDR region (66.6% of XDR isolates) and for aminoglycoside resistance A1401G in the rrs gene (100% of XDR isolates). Typing analysis showed the most predominant clade of XDR-TB being CAS1_DEL followed by BEIJING in Delhi region. Spoligotyping identified 184 spoligotypes (ST), 127 previously unreported. Our data demonstrate the potential of gene-sequence analyses of short regions of relatively few target genes for the rapid detection of resistance to second-line drugs among XDR-TB and pre-XDR-TB isolates and the ease of developing a rapid detection method while typing analysis raise an alarm about emerging strains of XDR TB. 7) Identifying M. tuberculosis protein antigens using NAPPA Nidia Correa 1 , Tanya Logvinenko 2 , Eliseo Mendoza 3 , Michael Gaskin 3 , Jason Steel 3 , Harriet Mayanja-Kizza 4 , W. Henry Boom 5 , Joshua LaBaer 3 , Robert Husson 1 1 Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA, 02115; 2 Tufts Medical Center, Boston, MA; 3 Arizona State University, Tempe, Arizona; 4 Makerere University, Kampala, Uganda; 5 Case Western Reserve University, Cleveland, Ohio, USA. The standard approaches of sputum smear microscopy and culture for the diagnosis of tuberculosis (TB) are poorly sensitive, particularly in children and HIV-infected persons. While a large number of antibody-based tests for TB have been developed, many perform poorly because of low sensitivity and specificity. Nucleic Acid Programmable Protein Arrays (NAPPA) provide an innovative high-throughput method that enables the simultaneous expression and capture of thousands of proteins in microarray format, proteins are produced “just-in-time” for the assay. The goal of this study was to use NAPPA to identify M. tuberculosis antigens recognized by the humoral immune response. We evaluated sera from 45 patients (18 TB positive, 14 TB negative, and 13 latent TB) obtained from the Case Western Reserve TB Research Unit serum bank and WHO-TDR. We identified a total of 101 proteins (~0.03% of the M. tuberculosis genome) that showed increased signal in TB positive vs TB negative patients. Of these proteins, 24% have been already reported as M. tuberculosis antigens. Proteins identified include mostly conserved hypothetical proteins, lipoproteins, membrane and secreted proteins and some involved in cellular metabolism. The proteins highly recognized by TB positive patients were further validated by in house ELISA with recombinant proteins. Five out of 20 (25%) were recognized again by TB positive patients. These data could provide the basis for developing new sensitive and specific antibody-based tests for the diagnosis of TB, as well as to gain new insights into TB pathogenesis. ACKNOWLEDGMENTS: Supported by NIH and NIAID R21 AI082000, NO1-AI-70022, NO1-AI- 95383 and NO1-AI-70022. 18

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