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Diagnostic exome sequencing in 266 Dutch patients with visual impairment

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective

The role of volatile organic compounds as predictors of treatment response in drug susceptible TB patients: An initial proof of concept study

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Multi-azole-resistant Aspergillus fumigatus in the environment in Tanzania

Item does not contain fulltextOBJECTIVES: Azole resistance in Aspergillus fumigatus isolates has been increasingly reported with variable prevalence worldwide and is challenging the effective management of aspergillosis. Here we report the coexistence of both TR(3)(4)/L98H and TR(4)(6)/Y121F/T289A resistance mechanisms in azole-resistant A. fumigatus (ARAF) isolates originating from Tanzania, Africa. METHODS: A total of 30 soil and woody debris samples from the surroundings of Kilimanjaro Christian Medical Centre, Moshi, Tanzania, were processed for detection of ARAF isolates and were investigated for susceptibility to itraconazole, voriconazole, posaconazole and isavuconazole. All ARAF isolates were subjected to a real-time PCR assay for detection of mutations and were genotyped by microsatellite typing. RESULTS: Of the 30 samples, 29 yielded 108 A. fumigatus isolates. Overall, 15 ARAF isolates were obtained, which included 4 ARAF harbouring the TR(4)(6)/Y121F/T289A mutation and 11 isolates carrying TR(3)(4)/L98H. All four TR(4)(6)/Y121F/T289A A. fumigatus isolates showed high MICs of voriconazole (>16 mg/L) and isavuconazole (8 mg/L). In contrast, the 11 TR(3)(4)/L98H A. fumigatus isolates were pan-azole resistant. The isolates were cross-resistant to azole fungicides. Notably, 20% of environmental samples harboured ARAF and the TR(4)(6)/Y121F/T289A resistance mechanism was found in 5.5% of the soil samples, where it coexisted with TR(3)(4)/L98H. The Tanzanian TR(4)(6)/Y121F/T289A strains had a genotype identical to Dutch clinical TR(4)(6)/Y121F/T289A isolates. CONCLUSIONS: The present study reports the isolation of resistant A. fumigatus strains harbouring the TR(4)(6)/Y121F/T289A mutation from Africa. Recovery of TR(4)(6)/Y121F/T289A from the environment is worrisome and we must strive for effective surveillance of clinical and environmental sources to detect azole resistance in A. fumigatus