The longevity risk of the Dutch Actuarial Association’s projection model

Accurate assessment of the risk that arises from further increases in life expectancy is crucial for the financial sector, in particular for pension funds and life insurance companies. The Dutch Actuarial Association presented a revised projection model in 2010, while in the same year two fundamentally different approaches were published by other institutions. This situation invites study of the consequences that the choice of projection model has on estimates of future life expectancy, which is the purpose of this paper. We firstly compare the three approaches against theoretical findings in the international literature. Secondly, we compare their outcomes in terms of period and cohort survival. In addition, we estimate the impact of each model on the present value of future pension payments. Our results indicate that, even in the short term, remarkable differences in life expectancy occur that also translate into different pension values. The literature review suggests that there is currently no blueprint for mortality projections; that calls for the application of various approaches to discount the uncertainty of the individual models. Instead of relying on extrapolation methods only, the pension sector should also take expert-driven forecasts into account as well as approaches that model causal influences on mortality. The model of the Actuarial Association could be improved by taking cohort influences into account as well as the estimate of uncertainty bounds around the outcome measure. Also, the consistency of the projection in terms of the age and gender dimensions but also other countries should be enhanced

Probing the Outer Mitochondrial Membrane in Cardiac Mitochondria with Nanoparticles

AbstractThe outer mitochondrial membrane (OMM) is the last barrier between the mitochondrion and the cytoplasm. Breaches of OMM integrity result in the release of cytochrome c oxidase, triggering apoptosis. In this study, we used calibrated gold nanoparticles to probe the OMM in rat permeabilized ventricular cells and in isolated cardiac mitochondria under quasi-physiological ionic conditions and during permeability transition. Our experiments showed that under control conditions, the OMM is not permeable to 6-nm particles. However, 3-nm particles could enter the mitochondrial intermembrane space in mitochondria of permeabilized cells and isolated cardiac mitochondria. Known inhibitors of the voltage-dependent anion channel (VDAC), König polyanion, and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid inhibited this entrance. Thus, 3-nm particles must have entered the mitochondrial intermembrane space through the VDAC. The permeation of the isolated cardiac mitochondria OMM for 3-nm particles was ∼20 times that in permeabilized cells, suggesting low availability of VDAC pores within the cell. Experiments with expressed green fluorescent protein showed the existence of intracellular barriers restricting the VDAC pore availability in vivo. Thus, our data showed that 1), the physical diameter of VDAC pores in cardiac mitochondria is ≥3nm but ≤6nm, and 2), permeability transition-related mitochondrial swelling results in breaching and disruption of the OMM

Sodium and sulfur release and recapture during black liquor burning

The objective of this study was to provide data on sulfur and sodium volatilization during black liquor burning, and on SO2 capture by solid sodium carbonate and sodium chloride. This data was interpreted and modeled into rate equations suitable for use in computational models for recovery boilers

Quantifying the contribution of changes in healthcare expenditures and smoking to the reversal of the trend in life expectancy in the Netherland

Background: Since 2001 the Netherlands has shown a sharp upturn in life expectancy (LE) after a longer period of slower improvement. This study assessed whether changes in healthcare expenditure (HCE) explain this reversal in trends in LE. As an alternative explanation, the impact of changes in smoking behavior was also evaluated. Methods: To quantify the contribution of changes in HCE to changes in LE, we estimated a health-production function using a dynamic panel regression approach with data on 19 OECD countries (1980-2009), accounting for temporal and spatial correlation. Smoking-attributable mortality was estimated using the indirect Peto-Lopez method. Results: As compared to 1990-1999, during 2000-2009 LE in the Netherlands increased by 1.8 years in females and by 1.5 years in males. Whereas changes in the impact of smoking between the two periods made almost no contribution to the acceleration of the increase in LE, changes in the trend of HCE added 0.9 years to the LE increase between 2000 and 2009. The exceptional reversal in the trend of LE and HCE was not found among the other OECD countries. Conclusion: This study suggests that changes in Dutch HCE, and not in smoking, made an important contribution to the reversal of the trend in LE; these findings support the view that investments in healthcare are increasingly important for further progress in life expectancy

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFb signaling, p53 and beta-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy