ABSTRACT
Background: Drug-resistant tuberculosis (DR-TB) is considered to be a public health threat and is difficult to cure, requiring a lengthy treatment with potent, potentially toxic drugs. The novel antimicrobial agent bedaquiline has shown promising results for patients with DR-TB, improving the rate of culture conversion and reducing TB-related mortality. However, increasing numbers of cases with acquired bedaquiline resistance (ABR) have been reported in recent years. Methods: This systematic review aimed to assess the frequency of ABR and characteristics of patients acquiring it. Studies showing data on sequential bedaquiline drug-susceptibility testing in patients treated with a bedaquiline-containing regimen were included. The databases CENTRAL, PubMed and Embase were manually searched, and 866 unique records identified, eventually leading to the inclusion of 13 studies. Phenotypic ABR was assessed based on predefined MIC thresholds and genotypic ABR based on the emergence of resistance-associated variants. Results: The median (IQR) frequency of phenotypic ABR was 2.2% (1.1%-4.6%) and 4.4% (1.8%-5.8%) for genotypic ABR. Among the studies reporting individual data of patients with ABR, the median number of likely effective drugs in a treatment regimen was five, in accordance with WHO recommendations. In regard to the utilization of important companion drugs with high and early bactericidal activity, linezolid was included in the regimen of most ABR patients, whereas the usage of other group A (fluoroquinolones) and former group B drugs (second-line injectable drugs) was rare. Conclusions: Our findings suggest a relevant frequency of ABR, urging for a better protection against it. Therefore, treatment regimens should include drugs with high resistance-preventing capacity through high and early bactericidal activity.
ABSTRACT
BACKGROUND: In a seminal paper, Galea et al. (Modulation of cerebellar excitability by polarity-specific noninvasive direct current stimulation. 2009. J Neurosci 29, 9115-9122) showed that cerebellar transcranial direct current stimulation (ctDCS) alters cerebellar-M1 connectivity. This effect has been explained by ctDCS-related changes of excitability of the cerebellar cortex with consecutive modulation of its main output, the dentate-thalamo-cortical pathway. OBJECTIVES: The aim of this functional magnetic resonance imaging (fMRI) study was to provide evidence that cathodal ctDCS decreases the activity of the cerebellar cortex, resulting in increased activity of the cerebellar nuclei, whereas anodal ctDCS has the opposite effect. METHODS: A total of 48 participants (female/male: 23/25, age: 23.8⯱â¯4.1yrs., mean⯱â¯standard deviation) performed a finger tapping task with the right hand in a 3T MRI scanner. Functional MR images were acquired prior, during and after tDCS of the right cerebellum. Participants were assigned randomly to anodal, cathodal or sham ctDCS. RESULTS: No significant difference of cerebellar cortical activation was found after comparing the three modes of stimulation. On the level of the dentate nuclei, however, a significant increase of activation was detected during and after cathodal stimulation. Furthermore, dentate nuclei activation was suppressed on a trend level following anodal stimulation. CONCLUSIONS: The present findings support the hypothesis that cathodal ctDCS leads to a disinhibition of the dentate nucleus, whereas anodal ctDCS may have the opposite effect.
