Long-term acceptability, durability and bio-efficacy of ZeroVector(®) durable lining for vector control in Papua New Guinea

This study examined the acceptability, durability and bio-efficacy of pyrethroid-impregnated durable lining (DL) over a three-year period post-installation in residential homes across Papua New Guinea (PNG).; ZeroVector(®) ITPS had previously been installed in 40 homes across four study sites representing a cross section of malaria transmission risk and housing style. Structured questionnaires, DL visual inspections and group interviews (GIs) were completed with household heads at 12- and 36-months post-installation. Three DL samples were collected from all households in which it remained 36-months post-installation to evaluate the bio-efficacy of DL on Anopheles mosquitoes. Bio-efficacy testing followed WHO guidelines for the evaluation of indoor residual spraying.; The DL was still intact in 86 and 39% of study homes at the two time periods, respectively. In homes in which the DL was still intact, 92% of household heads considered the appearance at 12-months post installation to be the same as, or better than, that at installation compared to 59% at 36-months post-installation. GIs at both time points confirmed continuing high acceptance of DL, based in large part of the perceived attractiveness and functionality of the material. However, participants frequently asserted that they, or their family members, had ceased or reduced their use of mosquito nets as a result of the DL installation. A total of 16 houses were sampled for bio-efficacy testing across the 4 study sites at 36-months post-installation. Overall, combining all sites and samples, both knock-down at 30 min and mortality at 24 h were 100%.; The ZeroVector(®) DL installation remained highly acceptable at 36-months post-installation, the material and fixtures proved durable and the efficacy against malaria vectors did not decrease. However, the DL material had been removed from over 50% of the original study homes 3 years post-installation, largely due to deteriorating housing infrastructure. Furthermore, the presence of the DL installation appeared to reduce ITN use among many participating householders. The study findings suggest DL may not be an appropriate vector control method for large-scale use in the contemporary PNG malaria control programme

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

Dissecting Alzheimer disease in Down syndrome using mouse models

Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk for Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD

Trisomy of human chromosome 21 enhances amyloid-beta deposition independently of an extra copy of APP

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.status: publishe

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Abstract Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD