Tuberculous meningitis remains highly lethal. In this trial, an intensified regimen of levofloxacin and higher-dose rifampin added to standard therapy was compared with standard antituberculosis ...therapy alone. The intensified regimen did not result in a higher survival rate.
Early treatment with antituberculosis chemotherapy and adjunctive treatment with glucocorticoids reduce the rate of death and disability from tuberculous meningitis, but the disease still kills or disables almost half the patients with the condition.
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The current guidelines recommend treatment with four antituberculosis drugs for at least the first 2 months of therapy, followed by treatment with two drugs (rifampin and isoniazid) for an additional 7 to 10 months.
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However, these recommendations are based on data from pulmonary tuberculosis and do not take into account the differential ability of antituberculosis drugs to penetrate the brain.
Rifampin is considered to . . .
Central nervous system (CNS) infections are common causes of morbidity and mortality worldwide. We aimed to discover protein biomarkers that could rapidly and accurately identify the likely cause of ...the infections, essential for clinical management and improving outcome.
We applied liquid chromatography tandem mass spectrometry on 45 cerebrospinal fluid (CSF) samples from a cohort of adults with and without CNS infections to discover potential diagnostic biomarkers. We then validated the diagnostic performance of a selected biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS infections admitted to a referral hospital in Vietnam.
In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of bacterial meningitis (BM) other than tuberculous meningitis. The analysis of the validation cohort showed that LCN2 could discriminate BM from other CNS infections (including tuberculous meningitis, cryptococcal meningitis and virus/antibody-mediated encephalitis), with sensitivity of 0.88 (95% confident interval (CI), 0.77–0.94), specificity of 0.91 (95% CI, 0.88–0.94) and diagnostic odds ratio of 73.8 (95% CI, 31.8–171.4). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) commonly used in routine care worldwide. The combination of LCN2, CSF leukocytes, glucose, protein and lactate resulted in the highest diagnostic performance for BM (area under the receiver operating characteristics curve, 0.96; 95% CI, 0.93–0.99). Data are available via ProteomeXchange with identifier PXD020510.
LCN2 is a sensitive and specific biomarker for discriminating BM from a broad spectrum of other CNS infections. A prospective study is needed to assess the diagnostic utility of LCN2 in the diagnosis and management of CNS infections.
Background. The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)—associated tuberculous meningitis is unknown. Methods. We conducted a randomized, ...double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, perprotocol, and prespecified subgroup analyses. Results. A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio HR, 1.12; 95% confidence interval CI,.81-1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI,.87-1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04). Conclusions. Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis.
OBJECTIVES: To determine 1) the relationship between specific streptomycin (SM) resistance mutations and the minimum inhibitory concentration (MIC), and 2) whether these mutations are preferentially ...associated with the Beijing genotype in Viet Nam.METHODS: A total of 131 consecutive
Mycobacterium tuberculosis isolates resistant to either isoniazid (INH) or rifampicin (RMP), collected previously, were tested for SM resistance, spoligotyped and sequenced in the rpsL, rrs and gidB genes. The MIC for 50 mutants was also determined.RESULTS:
Overall, 116/131 isolates were SM-resistant. The three most frequently occurring mutation sites in rpsL and rrs were at codon 43 of rpsL (72/116, 62.1%), rpsL88 (22/116, 18.9%) and rrs514 (8/116, 6.9%). Mutations in the rrs910 region were found in
two isolates (1.7%), and three isolates had mutations in both rpsL and rrs (2.6%). gidB mutations were found in both resistant and susceptible strains. Among SM-resistant isolates resistant to INH/RMP, the Beijing genotype was strongly associated with rpsL43 mutation
(aOR 23.6, 95%CI 2.9-193.4, P = 0.002). The median MIC for each mutation was as follows: rpsL43 = 256 μg/ml, rpsL88 = 16 μg/ml, 515 loop = 4 μg/ml, 910 region = 8 μg/ml, and double mutation = 256 μg/ml. We found a strong association between rpsL43 and high drug resistance levels, with all rpsL43 mutants having an MIC >256 μg/ml (P < 0.001).
An ultra-high plasmonic refractive index sensing structure composed of a metal–insulator–metal (MIM) waveguide coupled to a T-shape cavity and several metal nanorod defects is proposed and ...investigated by using finite element method. The designed plasmonic MIM waveguide can constitute a cavity resonance zone and the metal nanorod defects can effectively trap the light in the T-shape cavity. The results reveal that both the size of defects in wider rectangular cavity and the length of narrower rectangular cavity are primary factors increasing the sensitivity performance. The sensitivity can achieve as high as 8280 nm/RIU (RIU denotes the refractive index unit), which is the highest sensitivity reported in plasmonic MIM waveguide-based sensors to our knowledge. In addition, the proposed structure can also serve as a temperature sensor with temperature sensitivity as high as 3.30 nm/°C. The designed structure with simplicity and ease of fabrication can be applied in sensitivity nanometer scale refractive index sensor and may potentially be used in optical on-chip nanosensor.
The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M.tb). However, it ...is not known whether MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and identified an intronic single-nucleotide polymorphism (rs1052632) that was significantly associated with susceptibility to tuberculosis in a discovery and validation cohort of Vietnamese adults with tuberculosis. Stratification by site of disease revealed that rs1052632 genotype GG was strongly associated with the development of meningeal tuberculosis (odds ratio=2.99; 95% confidence interval (CI) 1.64-5.43; P=0.00006). Among patients with meningeal disease, absence of the G allele was associated with an increased risk of death (hazard ratio=3.86; 95% CI 1.49-9.98; P=0.005). Variant annotation tools using public databases indicate that rs1052632 is strongly associated with MR1 gene expression in lymphoblastoid cells (P=0.004) and is located within a transcriptional enhancer in epithelial keratinocytes. These data support a role for MR1 in the pathogenesis of human tuberculosis by revealing that rs1052632 is associated with MR1 gene expression and susceptibility to tuberculosis in Vietnam.
Tuberculous meningitis (TBM) results from the haematogenous dissemination of Mycobacterium tuberculosis from the lung to the brain. Dissemination is believed to occur early during infection, before ...the development of adaptive immunity. Toll-like receptor 2 (TLR2) mediates recognition of M. tuberculosis and initiates the innate immune response to infection. We hypothesized that polymorphisms in the TLR2 gene influence bacterial dissemination and the development of TBM. A case-control study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n=183) and TBM (n=175), and cord blood controls (n=389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR)=2.22, 95% confidence interval (CI): 1.23-3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR=3.26, 95% CI: 1.72-6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR=5.28, 95% CI: 2.20-12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR=1.93, 95% CI: 0.54-6.92; grade II, OR=3.32, 95% CI: 0.84-13.2; and grade III, OR=5.70, 95% CI: 1.81-18.0). These results demonstrate a strong association of TLR2 SNP T597C with the development of TBM and miliary TB and indicate that TLR2 influences the dissemination of M. tuberculosis.
Klebsiella pneumoniae is a leading cause of bloodstream infection (BSI). Strains producing extended-spectrum beta-lactamases (ESBLs) or carbapenemases are considered global priority pathogens for ...which new treatment and prevention strategies are urgently required, due to severely limited therapeutic options. South and Southeast Asia are major hubs for antimicrobial-resistant (AMR) K. pneumoniae and also for the characteristically antimicrobial-sensitive, community-acquired "hypervirulent" strains. The emergence of hypervirulent AMR strains and lack of data on exopolysaccharide diversity pose a challenge for K. pneumoniae BSI control strategies worldwide.
We conducted a retrospective genomic epidemiology study of 365 BSI K. pneumoniae from seven major healthcare facilities across South and Southeast Asia, extracting clinically relevant information (AMR, virulence, K and O antigen loci) using Kleborate, a K. pneumoniae-specific genomic typing tool.
K. pneumoniae BSI isolates were highly diverse, comprising 120 multi-locus sequence types (STs) and 63 K-loci. ESBL and carbapenemase gene frequencies were 47% and 17%, respectively. The aerobactin synthesis locus (iuc), associated with hypervirulence, was detected in 28% of isolates. Importantly, 7% of isolates harboured iuc plus ESBL and/or carbapenemase genes. The latter represent genotypic AMR-virulence convergence, which is generally considered a rare phenomenon but was particularly common among South Asian BSI (17%). Of greatest concern, we identified seven novel plasmids carrying both iuc and AMR genes, raising the prospect of co-transfer of these phenotypes among K. pneumoniae.
K. pneumoniae BSI in South and Southeast Asia are caused by different STs from those predominating in other regions, and with higher frequency of acquired virulence determinants. K. pneumoniae carrying both iuc and AMR genes were also detected at higher rates than have been reported elsewhere. The study demonstrates how genomics-based surveillance-reporting full molecular profiles including STs, AMR, virulence and serotype locus information-can help standardise comparisons between sites and identify regional differences in pathogen populations.
We numerically and theoretically investigate a highly sensitive and tunable plasmonic refractive index sensor that is composed of a metal-insulator-metal waveguide with a side-coupled nanoring, ...containing silver nanorods using the finite element method. Results reveal that the presence of silver nanorods in the nanoring has a significant impact on sensitivity and tunability performance. It gives a flexible way to tune the system response in the proposed structure. Our designed sensor has a sensitivity of 2080 nm/RIU (RIU is the refractive index unit) along with a figure of merit and a quality factor of 29.92 and 29.67, respectively. The adequate refractive index sensitivity can increase by adding the silver nanorods in a nanoring, which can induce new surface plasmon polaritons (SPPs) modes that cannot be found by a regular nanoring. For a practical application, a valid introduction of silver nanorods in the nanoring can dramatically reduce the dimension of the proposed structure without sacrificing performance.
In this paper, a periodic metallic-dielectric nanorod array which consists of Si nanorods coated with 30 nm Ag thin film set in a hexagonal configuration is fabricated and characterized. The ...fabrication procedure is performed by using nanosphere lithography with reactive ion etching, followed by Ag thin-film deposition. The mechanism of the surface and gap plasmon modes supported by the fabricated structure is numerically demonstrated by the three-dimensional finite element method. The measured and simulated absorptance spectra are observed to have a same trend and a qualitative fit. Our fabricated plasmonic sensor shows an average sensitivity of 340.0 nm/RIU when applied to a refractive index sensor ranging from 1.0 to 1.6. The proposed substrates provide a practical plasmonic nanorod-based sensing platform, and the fabrication methods used are technically effective and low-cost.
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