RESUMO
Genomic-based surveillance on the occurrence of drug resistance and its transmission dynamics has emerged as a powerful tool for the control of tuberculosis (TB). A whole-genome sequencing approach, phenotypic testing and clinical-epidemiological investigation were used to undertake a retrospective population-based study on drug-resistant (DR)-TB in Rio Grande do Sul, the largest state in Southern Brazil. The analysis included 305 resistant Mycobacterium tuberculosis strains sampled statewide from 2011 to 2014, and covered 75.7% of all DR-TB cases identified in this period. Lineage 4 was found to be predominant (99.3%), with high sublineage-level diversity composed mainly of 4.3.4.2 [Latin American and Mediterranean (LAM)/RD174], 4.3.3 (LAM/RD115) and 4.1.2.1 (Haarlem/RD182) sublineages. Genomic diversity was also reflected in resistance of the variants to first-line drugs. A large number of distinct resistance-conferring mutations, including variants that have not been reported previously in any other setting worldwide, and 22 isoniazid-monoresistant strains with mutations described as disputed in the rpoB gene but causing rifampicin resistance generally missed by automated phenotypic tests as BACTEC MGIT. Using a cut-off of five single nucleotide polymorphisms, the estimated recent transmission rate was 55.1%, with 168 strains grouped into 28 genomic clusters. The most worrying fact concerns multi-drug-resistant (MDR) strains, of which 73.4% were clustered. Different resistance profiles and acquisition of novel mutations intraclusters revealed important amplification of resistance in the region. This study described the diversity of M. tuberculosis strains, the basis of drug resistance, and ongoing transmission dynamics across the largest state in Southern Brazil, stressing the urgent need for MDR-TB transmission control state-wide.
Assuntos
Antibióticos Antituberculose/uso terapêutico , Proteínas de Bactérias/genética , RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/genética , Tuberculose Resistente a Múltiplos Medicamentos/transmissão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Brasil/epidemiologia , Perfilação da Expressão Gênica , Genoma Bacteriano/genética , Humanos , Isoniazida/uso terapêutico , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos Retrospectivos , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
OBJECTIVES: This study aims to determine the optimal proportion for different chemotherapy schemes in patients with metastatic colorectal cancer who have undergone surgical resection in Colombia. METHODS: A linear programming model was used to quantify the optimal proportion of the chemotherapy schemes that maximize quality-adjusted life-years (QALYs). The model was evaluated in 6 different scenarios using parametric and dynamic optimization with different budget restriction constraints. The results were compared to the current mixture of schemes used in our country. RESULTS: The results show that 63%, 37%, and 0.8% of the population should receive the FOLFOXIRI scheme (fluorouracil + leucovorin + oxaliplatin + irinotecan), FOLFIRI (irinotecan + leucovorin + fluorouracil), and FOLFIRI plus cetuximab, respectively. With these proportions, 8734 QALYs and universal coverage of the population are obtained. In an optimistic scenario (high QALYs, low costs, and budget of $40 million), the entire population should receive the FOLFIRI scheme. A pessimistic scenario (low QALYs, high costs, and budget of $15 million) would benefit only 46% of the population with the fluorouracil plus leucovorin scheme. In the other 3 scenarios with higher budget constraints, 52%, 69%, and 86% of the population should receive FOLFIRI, respectively. Dynamic optimization revealed that FOLFIRI and FOLFOX (oxaliplatin + leucovorin + fluorouracil) schemes are more likely to generate higher QALYs with lower costs and a limited budget. CONCLUSIONS: The current use of chemotherapy schemes is not optimal. An increasing proportion of FOLFIRI, FOLFOX, and FOLFOXIRI should be used more often as schemes to treat metastatic colorectal cancer in Colombia.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/uso terapêutico , Colômbia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , HumanosRESUMO
Sepsis is a multi-factorial disease that kills an estimated 1,400 people a day worldwide. The Triggering Receptor Expressed in Myeloid (TREM) cells Like Transcript (TLT)-1 is a platelet receptor expressed on activated platelets. Translational studies of TLT-1 suggest that TLT-1 affects hemostatic and immunological parameters that lead to the formation of disseminated intravascular coagulation (DIC). Evaluation of mice suffering from endotoxic shock shows a dramatic increase of soluble TLT-1 (sTLT-1) in their blood. Accordingly, when we evaluated the blood of septic patients we find increased levels of sTLT-1 that correlate with the presence of DIC in humans. Based on current data we hypothesize that TLT-1 plays an important role in maintaining vascular integrity during sepsis; perhaps by modulation of both the immune and hemostatic systems, and that TLT-1 makes an attractive target not only for better understanding of sepsis, but also as a point of therapeutic intervention as well.