Cost-effectiveness of In-home Automated External Defibrillators for Individuals at Increased Risk of Sudden Cardiac Death

In-home automated external defibrillators (AEDs) are increasingly recommended as a means for improving survival of cardiac arrests that occur at home. The current study was conducted to explore the relationship between individuals' risk of cardiac arrest and cost-effectiveness of in-home AED deployment. Design : Markov decision model employing a societal perspective. Patients : Four hypothetical cohorts of American adults 60 years of age at progressively greater risk for sudden cardiac death (SCD): 1) all adults (annual probability of SCD 0.4%); 2) adults with multiple SCD risk factors (probability 2%); 3) adults with previous myocardial infarction (probability 4%); and 4) adults with ischemic cardiomyopathy unable to receive an implantable defibrillator (probability 6%). Intervention : Strategy 1: individuals suffering an in-home cardiac arrest were treated with emergency medical services equipped with AEDs (EMS-D). Strategy 2: individuals suffering an in-home cardiac arrest received initial treatment with an in-home AED, followed by EMS. Results : Assuming cardiac arrest survival rates of 15% with EMS-D and 30% with AEDs, the cost per quality-adjusted life-year gained (QALY) of providing in-home AEDs to all adults 60 years of age is $216,000. Costs of providing in-home AEDs to adults with multiple risk factors (2$132,000, $104,000, and$88,000, respectively. Conclusions : The cost-effectiveness of in-home AEDs is intimately linked to individuals' risk of SCD. However, providing in-home AEDs to all adults over age 60 appears relatively expensive.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72168/1/j.1525-1497.2005.40247.x.pd

Environmentalism in the EU-28 context: the impact of governance quality on environmental energy efficiency

Environmental policies are a significant cornerstone of a developed economy, but the question that arises is whether such policies lead to a sustainable growth path. It is clear that the energy sector plays a pivotal role in environmental policies, and although the current literature has focused on examining the link between energy consumption and economic growth through an abundance of studies, it does not explicitly consider the role of institutional or governance quality variables in the process. Both globalization and democracy are important drivers of sustainability, while environmentalism is essential for the objective of gaining a “better world.” Governance quality is expected to be the key, not only for economic purposes but also for the efficiency of environmental policies. To that end, the analysis in this paper explores the link between governance quality and energy efficiency for the EU-28 countries, spanning the period 1995 to 2014. The findings document that there is a nexus between energy efficiency and income they move together: the most efficient countries are in the group with higher GDP per capita. Furthermore, the results show that governance quality is an important driver of energy efficiency and, hence, of environmental policies.University of Granad

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs

Effects of permafrost melting on CO2 and CH4 exchange of a poorly drained black spruce lowland

Permafrost melting is occurring in areas of the boreal forest region where large amounts of carbon (C) are stored in organic soils. We measured soil respiration, net CO2 flux, and net CH4 flux during MaySeptember 2003 and March 2004 in a black spruce lowland in interior Alaska to better understand how permafrost thaw in poorly drained landscapes affects land-atmosphere CO2 and CH4 exchange. Sites included peat soils underlain by permafrost at ∼0.4 m depth (permafrost plateau, PP), four thermokarst wetlands (TW) having no permafrost in the upper 2.2 m, and peat soils bordering the thermokarst wetlands having permafrost at ∼0.5 m depth (thermokarst edges, TE). Soil respiration rates were not significantly different among the sites, and 5-cm soil temperature explained 5091% of the seasonal variability in soil respiration within the sites. Groundcover vegetation photosynthesis (calculated as net CO2 minus soil respiration) was significantly different among the sites (TW > TE > PP), which can be partly attributed to the difference in photosynthetically active radiation reaching the ground at each site type. Methane emission rates were 15 to 28 times greater from TW than from TE and PP. We modeled annual soil respiration and groundcover vegetation photosynthesis using soil temperature and radiation data, and CH4 flux by linear interpolation. We estimated all sites as net C gas sources to the atmosphere (not including tree CO2 uptake at PP and TE), although the ranges in estimates when accounting for errors were large enough that TE and TW may have been net C sinks

Resilience of Alaska's Boreal Forest to Climatic Change

This paper assesses the resilience of Alaska s boreal forest system to rapid climatic change. Recent warming is associated with reduced growth of dominant tree species, plant disease and insect outbreaks, warming and thawing of permafrost, drying of lakes, increased wildfire extent, increased postfire recruitment of deciduous trees, and reduced safety of hunters traveling on river ice. These changes have modified key structural features, feedbacks, and interactions in the boreal forest, including reduced effects of upland permafrost on regional hydrology, expansion of boreal forest into tundra, and amplification of climate warming because of reduced albedo (shorter winter season) and carbon release from wildfires. Other temperature-sensitive processes for which no trends have been detected include composition of plant and microbial communities, long-term landscape-scale change in carbon stocks, stream discharge, mammalian population dynamics, and river access and subsistence opportunities for rural indigenous communities. Projections of continued warming suggest that Alaska s boreal forest will undergo significant functional and structural changes within the next few decades that are unprecedented in the last 6000 years. The impact of these social ecological changes will depend in part on the extent of landscape reorganization between uplands and lowlands and on policies regulating subsistence opportunities for rural communities