Trigger and Aperture of the Surface Detector Array of the Pierre Auger Observatory

The surface detector array of the Pierre Auger Observatory consists of 1600 water-Cherenkov detectors, for the study of extensive air showers (EAS) generated by ultra-high-energy cosmic rays. We describe the trigger hierarchy, from the identification of candidate showers at the level of a single detector, amongst a large background (mainly random single cosmic ray muons), up to the selection of real events and the rejection of random coincidences. Such trigger makes the surface detector array fully efficient for the detection of EAS with energy above $3\times 10^{18}$ eV, for all zenith angles between 0$^\circ$ and 60$^\circ$, independently of the position of the impact point and of the mass of the primary particle. In these range of energies and angles, the exposure of the surface array can be determined purely on the basis of the geometrical acceptance.Comment: 29 pages, 12 figure

Essai Sur La Nature Des Vrilles En Particulier Et Sur La Disposition Des Organes Appendiculaires De La Vigne En G\ue9n\ue9ral

Volume: 26Start Page: 92End Page: 9

Genetic variants and their association with phenotypic resistance to bedaquiline in Mycobacterium tuberculosis : a systematic review and individual isolate data analysis

BACKGROUND: Bedaquiline is a crucial drug for control of rifampicin-resistant tuberculosis. Molecular drug resistance assays could facilitate effective use of bedaquiline and surveillance of drug resistance emergence. To facilitate molecular assay development, we aimed to identify genomic markers of bedaquiline resistance. METHODS: In this systematic review and individual isolate analysis, we searched Europe PubMed Central and Scopus for studies published from the inception of each database until Oct 19, 2020, that assessed genotypic and phenotypic bedaquiline resistance in clinical or non-clinical Mycobacterium tuberculosis isolates. All studies reporting on the assessment of variants in the four genes of interest (Rv0678, atpE, pepQ, and Rv1979c) and phenotypic bedaquiline data in both clinical and non-clinical samples were included. We collated individual isolate data from eligible studies to assess the association between genomic variants with phenotypic bedaquiline resistance, using a standardised method endorsed by WHO. Risk of bias of the extracted data was independently assessed by two authors using the Quality Assessment of Diagnostic Accuracy Studies tool for clinical studies and Systematic Review Center for Laboratory Animal Experimentation tool for animal studies. The primary outcome was to identify mutations associated with resistance in four genes of interest (Rv0678, atpE, pepQ, and Rv1979c); for each genomic variant, the odds ratio (OR), 95% CI, and p value were calculated to identify resistance markers associated with bedaquiline resistance. This study is registered with PROSPERO, CRD42020221498. FINDINGS: Of 1367 studies identified, 41 published between 2007 and 2020 were eligible for inclusion. We extracted data on 1708 isolates: 1569 (91·9%) clinical isolates and 139 (8·1%) non-clinical isolates. We identified 237 unique variants in Rv0678, 14 in atpE, 28 in pepQ, and 11 in Rv1979c. Most clinical isolates with a single variant reported in Rv0678 (229 [79%] of 287 variants), atpE (14 [88%] of 16 variants), pepQ (32 [100%] of 32 variants), or Rv1979c (115 [98%] of 119 variants) were phenotypically susceptible to bedaquiline. Except for the atpE 187G→C (OR ∞, [95% CI 13·28–∞]; p<0·0001) and Rv0678 138_139insG (OR 6·91 [95% CI 1·16–47·38]; p=0·016) variants, phenotypic–genotypic associations were not significant (p≥0·05) for any single variant in Rv0678, atpE, pepQ, and Rv1979c. INTERPRETATION: Absence of clear genotypic–phenotypic associations for bedaquiline complicates the development of molecular drug susceptibility tests. A concerted global effort is urgently needed to assess the genotypic and phenotypic drug susceptibility of M tuberculosis isolates, especially in patients who have received unsuccessful bedaquiline-containing regimens. Treatment regimens should be designed to prevent emergence of bedaquiline resistance and phenotypic drug susceptibility tests should be used to guide and monitor treatment. FUNDING: Research Foundation Flanders, South African Medical Research Council, Department of Science and Innovation - National Research Foundation, National Institute of Health Institute of Allergy and Infectious Diseases, and Doris Duke Charitable Foundation

Variants in bedaquiline-candidate-resistance genes : prevalence in bedaquiline-naive patients, effect on MIC, and association with Mycobacterium tuberculosis lineage

Studies have shown that variants in bedaquiline-resistance genes can occur in isolates from bedaquiline-naive patients. We assessed the prevalence of variants in all bedaquiline-candidate-resistance genes in bedaquiline-naive patients, investigated the association between these variants and lineage, and the effect on phenotype. We used whole-genome sequencing to identify variants in bedaquiline-resistance genes in isolates from 509 bedaquiline treatment naive South African tuberculosis patients. A phylogenetic tree was constructed to investigate the association with the isolate lineage background. Bedaquiline MIC was determined using the UKMYC6 microtiter assay. Variants were identified in 502 of 509 isolates (98.6%), with the highest (85%) prevalence of variants in the Rv0676c (mmpL5) gene. We identified 36 unique variants, including 19 variants not reported previously. Only four isolates had a bedaquiline MIC equal to or above the epidemiological cut-off value of 0.25 μg/mL. Phylogenetic analysis showed that 14 of the 15 variants observed more than once occurred monophyletically in one Mycobacterium tuberculosis (sub)lineage. The bedaquiline MIC differed between isolates belonging to lineage 2 and 4 (Fisher’s exact test, P = 0.0004). The prevalence of variants in bedaquiline-resistance genes in isolates from bedaquiline-naive patients is high, but very few (<2%) isolates were phenotypically resistant. We found an association between variants in bedaquiline resistance genes and Mycobacterium tuberculosis (sub)lineage, resulting in a lineage-dependent difference in bedaquiline phenotype. Future studies should investigate the impact of the presence of variants on bedaquiline-resistance acquisition and treatment outcome