New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Comparison of three methods for in vitro susceptibility testing of Candida species with flucytosine

Optimal methods for susceptibility testing of Candida spp. with flucytosine have not been deter-mined. Breakpoints were recommended in 1984, but never validated. In this study, we compared the 1984 recommended macrodilution broth method (using an 80 % endpoint) with a modification of the more recent NCCLS-recommended microdilution broth method with three endpoints— spectrophotometric 50 % and 80 % and a no growth endpoint determined by eye. NCCLS and British Society for Medical Mycology (BSMM) breakpoints were also compared. One hundred and fifty isolates comprised of Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Candida parapsilosis and Candida lusitaniae were tested. Reproducibility was excellent. For C. albicans (n = 65), the correlation between tests was excellent (>75%), with few major discrepancies (<5%). For C. tropicalis (n = 27), correlation was good (59%), but there were a small number of major discrepancies (up to 11%, depending on breakpoint used). Results by the broth macrodilution method were generally higher than both microdilution methods for C. glabrata (n = 16; correlation of 18.8%), but only one major discrepancy was seen. Ten of the 11 C. parapsilosis isolates tested were susceptible by all methods, regardless of breakpoint chosen, with a correlation of 18.2%, but no major discrepancies were seen. A correlatio