Comparative effectiveness and safety of edoxaban versus warfarin in patients with atrial fibrillation:A nationwide cohort study

Background and purposeThe effectiveness and safety of edoxaban 60 mg and 30 mg for stroke prevention compared with warfarin in patients with atrial fibrillation have not been well-described in a nationwide cohort of Caucasian patients treated in standard clinical practice.MethodsWe used Danish nationwide registries to identify patients with atrial fibrillation during June 2016 and November 2018 who were treated with edoxaban or warfarin and computed rates per 100 person-years of thromboembolic, all-cause mortality, and bleeding events using an inverse probability of treatment weighting approach to account for baseline confounding. We used weighted pooled logistic regression to compute hazard ratios with 95% confidence intervals comparing events between edoxaban 60 mg and warfarin users; edoxaban 30 mg was not included in formal comparisons.ResultsWe identified 6451 atrial fibrillation patients, mean age was 72 years and 40% were females. A total of 1772 patients were treated with edoxaban 60 mg, 537 with edoxaban 30 mg, and 4142 with warfarin. The median CHA2DS2-VASc score was similar between warfarin and edoxaban 60 mg with a score of 3 (interquartile range (IQR) 2-4). In the inverse probability of treatment-weighted pseudo-population, the thromboembolic event rate for edoxaban 60 mg was 0.95 and 1.0 for warfarin, corresponding weighted hazard ratio of 1.00 (95% confidence intervals (CI) 0.59, 1.71). Edoxaban 60 mg users were associated with lower rates of all-cause mortality (3.93) compared to warfarin (6.04), with a hazard ratio of 0.64 (95% CI 0.47 to 0.88). The event rates for bleeding were 3.36 and 3.14, respectively; hazard ratio 1.09 (95% CI 0.77, 1.57).ConclusionEdoxaban 60 mg is a safe and effective treatment compared with warfarin for stroke prevention in routine clinical care for Danish (mainly Caucasian) patients with AF, with non-significantly different risks for stroke and clinically relevant bleeding, but lower all-cause mortality

Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population: prospective cohort study

Objective To test the hypothesis that xanthelasmata and arcus corneae, individually and combined, predict risk of ischaemic vascular disease and death in the general population

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency

The established causal genes in Alzheimer’s disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease’s initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%–3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD

Road Traffic Noise and Incident Myocardial Infarction: A Prospective Cohort Study

BACKGROUND Both road traffic noise and ambient air pollution have been associated with risk for ischemic heart disease, but only few inconsistent studies include both exposures. METHODS In a population-based cohort of 57 053 people aged 50 to 64 years at enrolment in 1993-1997, we identified 1600 cases of first-ever MI between enrolment and 2006. The mean follow-up time was 9.8 years. Exposure to road traffic noise and air pollution from 1988 to 2006 was estimated for all cohort members from residential address history. Associations between exposure to road traffic noise and incident MI were analysed in a Cox regression model with adjustment for air pollution (NO(x)) and other potential confounders: age, sex, education, lifestyle confounders, railway and airport noise. RESULTS We found that residential exposure to road traffic noise (L(den)) was significantly associated with MI, with an incidence rate ratio IRR of 1.12 per 10 dB for both of the two exposure windows: yearly exposure at the time of diagnosis (95% confidence interval (CI): 1.02-1.22) and 5-years time-weighted mean (95% CI: 1.02-1.23) preceding the diagnosis. Visualizing of the results using restricted cubic splines showed a linear dose-response relationship. CONCLUSIONS Exposure to long-term residential road traffic noise was associated with a higher risk for MI, in a dose-dependent manner

Air pollution from traffic and cancer incidence: a Danish cohort study

<p>Abstract</p> <p>Background</p> <p>Vehicle engine exhaust includes ultrafine particles with a large surface area and containing absorbed polycyclic aromatic hydrocarbons, transition metals and other substances. Ultrafine particles and soluble chemicals can be transported from the airways to other organs, such as the liver, kidneys, and brain. Our aim was to investigate whether air pollution from traffic is associated with risk for other cancers than lung cancer.</p> <p>Methods</p> <p>We followed up 54,304 participants in the Danish Diet Cancer and Health cohort for 20 selected cancers in the Danish Cancer Registry, from enrolment in 1993-1997 until 2006, and traced their residential addresses from 1971 onwards in the Central Population Registry. We used modeled concentration of nitrogen oxides (NO_x) and amount of traffic at the residence as indicators of traffic-related air pollution and used Cox models to estimate incidence rate ratios (IRRs) after adjustment for potential confounders.</p> <p>Results</p> <p>NO_xat the residence was significantly associated with risks for cervical cancer (IRR, 2.45; 95% confidence interval [CI], 1.01;5.93, per 100 μg/m³NO_x) and brain cancer (IRR, 2.28; 95% CI, 1.25;4.19, per 100 μg/m³NO_x).</p> <p>Conclusions</p> <p>This hypothesis-generating study indicates that traffic-related air pollution might increase the risks for cervical and brain cancer, which should be tested in future studies.</p

Exposure to road traffic and railway noise and associations with blood pressure and self-reported hypertension: a cohort study

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies suggest that long-term exposure to transport noise increases the risk for cardiovascular disorders. The effect of transport noise on blood pressure and hypertension is uncertain.</p> <p>Methods</p> <p>In 1993-1997, 57,053 participants aged 50-64 year were enrolled in a population-based cohort study. At enrolment, systolic and diastolic blood pressure was measured. Incident hypertension during a mean follow-up of 5.3 years was assessed by questionnaire. Residential long-term road traffic noise (L_den) was estimated for 1- and 5-year periods preceding enrolment and preceding diagnosis of hypertension. Residential exposure to railway noise was estimated at enrolment. We conducted a cross-sectional analysis of associations between road traffic and railway noise and blood pressure at enrolment with linear regression, adjusting for long-term air pollution, meteorology and potential lifestyle confounders (N = 44,083). Incident self-reported hypertension was analyzed with Cox regression, adjusting for long-term air pollution and potential lifestyle confounders.</p> <p>Results</p> <p>We found a 0.26 mm Hg higher systolic blood pressure (95% confidence intervals (CI): -0.11; 0.63) per 10 dB(A) increase in 1-year mean road traffic noise levels, with stronger associations in men (0.59 mm Hg (CI: 0.13; 1.05) per 10 dB(A)) and older participants (0.65 mm Hg (0.08; 1.22) per 10 dB(A)). Road traffic noise was not associated with diastolic blood pressure or hypertension. Exposure to railway noise above 60 dB was associated with 8% higher risk for hypertension (95% CI: -2%; 19%, P = 0.11).</p> <p>Conclusions</p> <p>While exposure to road traffic noise was associated with systolic blood pressure in subgroups, we were not able to identify associations with hypertension.</p

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights