ABSTRACT
The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET-CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET-CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.
Subject(s)
Lung/diagnostic imaging , Mycobacterium tuberculosis/genetics , RNA, Messenger/metabolism , Tuberculosis, Pulmonary/diagnostic imaging , Adolescent , Adult , Aged , Antitubercular Agents/therapeutic use , Bronchoalveolar Lavage Fluid , Female , Humans , Lung/metabolism , Lung/microbiology , Male , Middle Aged , Positron Emission Tomography Computed Tomography , South Africa , Sputum/metabolism , Tuberculosis, Pulmonary/drug therapy , Young AdultABSTRACT
BACKGROUND: Toll-like receptors (TLRs) are involved in the recognition of conserved microbial structures, leading to activation of an inflammatory response and formation of an adaptive immune response. METHODS: Twenty-three polymorphisms in five TLR genes were genotyped in 729 tuberculosis cases and 487 healthy controls in a population-based case-control association study in a South African population. RESULTS: We detected sex-specific associations for TLR8 polymorphisms, with rs3761624 (OR=1.54, p<0.001), rs3764879 (OR=1.41, p=0.011) and rs3764880 (OR=1.42, p=0.011) associated in females and rs3764879 (OR=0.72, p=0.013) and rs3764880 (OR=0.75, p=0.036) associated in males. Epistatic interactions between the TLR genes were investigated and the TLR1_rs4833095 polymorphism was shown to interact with TLR2_rs3804100 and (GT)n microsatellite (p=0.002) and alter susceptibility to TB. We also studied the role of TLRs in disease caused by different Mycobacterium tuberculosis genotypes in 257 tuberculosis cases, and identified associations between specific TLR polymorphisms and disease caused by specific strains. CONCLUSION: This study provides further evidence that the TLRs play an important role in the outcome of tuberculosis disease, and suggests a partial explanation for the male bias in tuberculosis ratios.
Subject(s)
Toll-Like Receptor 8/genetics , Tuberculosis, Pulmonary/genetics , Adult , Case-Control Studies , Epistasis, Genetic , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , Sex Characteristics , Young AdultABSTRACT
BACKGROUND: Competing interests occur frequently in health care. This results in the potential for conflict of interest (COI). COI can lead to biased generation or assessment of evidence and misinform healthcare decision makers. Declaration of COI is insufficient to neutralize potentially harmful effects. Medical professional societies are obliged to develop robust mechanisms to "manage" COI, particularly in the development of official guidance documents that affect health care. PURPOSE: This document describes the background, methods, and content of the new "American Thoracic Society (ATS) Policy on Management of COI in Official ATS Documents, Projects, and Conferences." METHODS: We used existing reviews on COI policies that were prepared for the World Health Organization and for an ATS guideline methodology workshop as the evidence base for this work. We reviewed existing policies of selected organizations and other relevant literature. Members of the ATS Documents Development and Implementation Committee and the ATS Ethics and COI Committee collaborated to draft a COI policy. We used face-to-face meetings, electronic correspondence, and teleconferences to finalize the draft. The policy then underwent review and ultimate approval by the ATS Board of Directors. RESULTS: The ATS developed a new policy and procedures for declaration and management of COI. These procedures include: (1) self declaration of COI, (2) review of potential participants' COI, (3) disclosure of COI to project participants, (4) refusal or excusal from certain decisions or recommendations when appropriate, (5) disclosure of COI to users of documents or attendees of conferences, (6) handling disputes in COI resolution. This policy includes a tool that may be useful for supporting decision makers in management of COIs as they assess the value and relevance of conflicts. CONCLUSIONS: The ATS Policy on Management of COI in Official ATS Documents, Projects, and Conferences, in effect since March 2008, promises greater organizational transparency. Application and ongoing evaluation of the policy will give the ATS the opportunity to determine its usefulness in specific settings.
