Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.

BACKGROUND: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce. METHODS: In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS. FINDINGS: Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1% [95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations. INTERPRETATION: The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background). FUNDING: Bill & Melinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG.

Nitrate leaching losses from two Baltic Sea catchments under scenarios of changes in land use, land management and climate.

Pollution with excess nutrients deteriorate the water quality of the Baltic Sea. The effect of combined land use and climate scenarios on nitrate leaching and nitrogen (N) loads to surface waters from two Baltic Sea catchments (Norsminde in Denmark and Kocinka in Poland) was explored using different models; the NLES and Daisy models for nitrate leaching, and MIKE SHE or MODFLOW/MT3DMS for N transport. Three Shared Socioeconomic Pathways (SSP1, SSP2 and SSP5) defined change in land use and agricultural activities. The climate change scenarios covered 2041-2060 compared with 1991-2010 under RCP8.5, applying four different climate models. Increases in predicted N-load from climate change vary from 20 to 60% depending on climate model. SSPs moderate these N-load changes with small changes for SSP1 to large increases for SSP5, with greater increases for Norsminde than Kocinka due to land use differences. This stresses needs for new measures and governing schemes to meet sustainability targets.

Estimation of cognitive and affective disorders occurrence in patients with Lyme borreliosis.

INTRODUCTION AND OBJECTIVE: Lyme borreliosis (LB) is a disease caused by the bacteria Borrelia burgdorferi. The most common symptoms are related to the skin, musculo-scelatal system, central and peripheral nervous system, rarely to the heart muscle and the eye, and may occur in the multistage course of the disease. LB may additionally be accompanied by psychopathological symptoms. The aim of the study is estimation of the cognitive and affective disorders occurence in patients with LB. MATERIAL AND METHODS: The study was carried out in the group of 121 patients (61 females, 60 males) aged 18-65; mean age 46 years. All patients were diagnosed with late-stage of LB: 46 patients (38%) with Lyme arthritis and 75 patients (62%) with neuroborreliosis. Evaluation of the cognitive and affective functioning of patients was performed on the basis of a standardized interview and test methods: the Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT) and the Beck Depression Inventory (BDI). RESULTS: Cognitive disorders occurred statistically significantly more often in patients with neuroborreliosis (14.7%) than in patients with Lyme arthritis (4.3%). A group of females with neuroborreliosis and a group of males with the same diagnosis demonstrated cognitive deficits significantly more often (23.3% and 8.9%, respectively), compared to groups of patients with Lyme arthritis (6.5% in females and no cognitive deficits in males). A significantly higher percentage of depressive disorders was also noted in the group of males and females with neuroborreliosis (50.7%), compared to the group of patients with Lyme arthritis (39.1%). The symptoms of depression were particularly frequent in the females with neuroborreliosis (60%). The severity of depression measured by BDI was mild or moderate in most cases. In the examined groups, more patients with neuroborreliosis (44%), both in females (36.7%) and males (48.9%), demonstrated anxiety disorders. The obtained results showed a higher frequency of affective disorders compared to cognitive deficits, both in patients with Lyme arthritis and neuroborreliosis. CONCLUSIONS: An increased frequency of depressive and neurotic disorders was observed in patients with LB, particularly in patients with neuroborreliosis. Neurotic disorders, mainly adaptive, were most common in males with LB, while depressive disorders were more frequent in females. An increased frequency of cognitive deficits was observed in patients with neuroborreliosis, particularly in females.