Summary
Essentials
The relationship between atherosclerosis and venous thromboembolism (VTE) is controversial.
In total, 10 426 participants recruited from the general population were included.
...Carotid intima media thickness and total plaque area was not associated with VTE.
There was no association between plaque initiation or plaque progression and subsequent VTE.
Summary
Background
Whether a relationship between atherosclerosis and subsequent venous thromboembolism (VTE) exists is controversial.
Objective
To investigate the association between carotid atherosclerosis and VTE by using repeated measurements of intima media thickness (IMT) and total plaque area (TPA) in participants recruited from the general population.
Methods
Participants were recruited from the fourth (1994–1995), fifth (2001–2002) and sixth (2007–2008) surveys of the Tromsø Study. In total, 10 426 participants attended, for whom measurements of carotid IMT and TPA and potential confounders were updated at each available survey. Time‐varying Cox regression models were used to calculate hazard ratios (HRs) of VTE across various levels of IMT and TPA adjusted for age, sex, and body mass index.
Results
There were 368 incident VTE events during a median follow‐up of 10.8 years. Participants with increasing IMT were, on average, older and had a less favorable cardiovascular risk profile. There was no association between tertiles of increasing TPA and the risk of VTE in the time‐varying model, and increasing IMT was not associated with an increased risk of VTE (HR 0.96, 95% confidence interval CI 0.86–1.07). Neither plaque formation nor plaque progression was associated with the risk of VTE (respectively: HR 1.00, 95% CI 0.98–1.02; and HR 0.96, 95% CI 0.84–1.11).
Conclusion
Carotid IMT and TPA were not associated with an increased risk of VTE in time‐varying analyses. Furthermore, there was no association between plaque initiation or plaque progression and subsequent VTE.
Following publication of the original article 1, a typographical error in the formula for calculating d
in the "Scans for local adaptation" subsection in the Method section, was identified. The ...correct formula should be.
Ecological impact assessment modeling systems are valuable support tools for managing impacts from commercial activities on marine habitats and species. The inclusion of toxic effects modeling in ...these systems is predicated on the availability and quality of ecotoxicology data. Here we report on a data gathering exercise to obtain toxic effects data on oil compounds for a selection of cold-water marine species of fish and plankton associated with the Barents Sea ecosystem. Effects data were collated from historical and contemporary literature resources for the endpoints mortality, development, growth, bioaccumulation and reproduction. Evaluating the utility and applicability of these data for modeling, we find that data coverage is limited to a sub-set of the required endpoints. There is a need for new experimental studies for zooplankton focused on the endpoints development and bioaccumulation and for larvae and juvenile fish focused on growth and development.
•Toxicity endpoints were gathered for cold-water marine fish and plankton species exposed to oil components.•We evaluate the utility and applicability of the gathered data for an impact assessment model for the Barents Sea.•We find that the data cover a limited sub-set of species and endpoints required by the model.•New experimental studies are advised for zooplankton development and bioaccumulation and for fish growth and development.
Summary
Background and aims
It remains unclear when anticoagulant therapy should be given in patients with non‐cirrhotic portal vein thrombosis (PVT). The aim of this study was to assess the effect ...of anticoagulation on recurrent thrombotic events and gastrointestinal bleeding in non‐cirrhotic PVT patients.
Methods
Retrospective study of all patients with non‐cirrhotic PVT (n = 120), seen at our hospital from 1985 to 2009. Data were collected by systematic chart review.
Results
Sixty‐six of the 120 patients were treated with anticoagulants. Twenty‐two recurrent thrombotic events occurred in 19 patients. The overall thrombotic risk at 1, 5 and 10 years was 4%, 8% and 27%, respectively. Seventy‐four percent of all recurrent thrombotic events occurred in patients with a prothrombotic disorder. Anticoagulant therapy tended to lower the risk of recurrent thrombosis (hazard ratio HR 0.2, P = 0.1), yet the only significant predictor of recurrent thrombotic events was the presence of a prothrombotic disorder (HR 3.1, P = 0.03). In 37 patients, 83 gastrointestinal bleeding events occurred. The re‐bleeding risk at 1, 5 and 10 years was 19%, 46% and 49%, respectively. Anticoagulation therapy (HR 2.0, P ≤ 0.01) was a significant predictor of (re)bleeding. Anticoagulation therapy had no effect on the severity of gastrointestinal bleeding. Poor survival was associated with recurrent thrombotic events (HR 3.1 P = 0.02), whereas bleeding (HR 1.6 P = 0.2) and anticoagulant treatment (HR 0.5 P = 0.2) had no significant effect on survival.
Conclusions
In non‐cirrhotic PVT patients recurrent thrombotic events are mainly observed in patients with underlying prothrombotic disorders. Anticoagulation therapy tends to prevent recurrent thrombosis but also significantly increases the risk of gastrointestinal bleeding.
In the past decade, we have seen the development of a new set of tests for structural change of unknown timing in regression models, most notably the
SupF statistic of Andrews (1993, Econometrica 61, ...825–856), the
ExpF and
AveF statistics of Andrews-Ploberger (1994, Econometrica 62, 1383–1414), and the
L statistic of Nyblom (1989, Journal of American Statistical Association 84, 223–230). The distribution theory used for these tests is primarily asymptotic, and has been derived under the maintained assumption that the regressors are stationary. This excludes structural change in the marginal distribution of the regressors. As a result, these tests technically cannot discriminate between structural change in the conditional and marginal distributions. This paper attempts to remedy this deficiency by deriving the large sample distributions of the test statistics allowing for structural change in the marginal distribution of the regressors. We find that the asymptotic distributions of the
SupF,
ExpF,
AveF and
L statistics are not invariant to structural change in the regressors. To solve the size problem, we introduce a ‘fixed regressor bootstrap’ which achieves the first-order asymptotic distribution, and appears to possess reasonable size properties in small samples. Our bootstrap theory allows for arbitrary structural change in the regressors, including structural shifts, polynomial trends, and exogenous stochastic trends. It allows for lagged dependent variables and heteroskedastic error processes.
Comparisons of Neanderthal genomes to anatomically modern human (AMH) genomes show a history of Neanderthal-to-AMH introgression stemming from interbreeding after the migration of AMHs from Africa to ...Eurasia. All non-sub-Saharan African AMHs have genomic regions genetically similar to Neanderthals that descend from this introgression. Regions of the genome with Neanderthal similarities have also been identified in sub-Saharan African populations, but their origins have been unclear. To better understand how these regions are distributed across sub-Saharan Africa, the source of their origin, and what their distribution within the genome tells us about early AMH and Neanderthal evolution, we analyzed a dataset of high-coverage, whole-genome sequences from 180 individuals from 12 diverse sub-Saharan African populations. In sub-Saharan African populations with non-sub-Saharan African ancestry, as much as 1% of their genomes can be attributed to Neanderthal sequence introduced by recent migration, and subsequent admixture, of AMH populations originating from the Levant and North Africa. However, most Neanderthal homologous regions in sub-Saharan African populations originate from migration of AMH populations from Africa to Eurasia ∼250 kya, and subsequent admixture with Neanderthals, resulting in ∼6% AMH ancestry in Neanderthals. These results indicate that there have been multiple migration events of AMHs out of Africa and that Neanderthal and AMH gene flow has been bi-directional. Observing that genomic regions where AMHs show a depletion of Neanderthal introgression are also regions where Neanderthal genomes show a depletion of AMH introgression points to deleterious interactions between introgressed variants and background genomes in both groups-a hallmark of incipient speciation.
Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated ...with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL.
Leukocyte telomere length (LTL) varies significantly across human populations, with individuals of African ancestry having longer LTL than non-Africans. However, the genetic and environmental drivers ...of LTL variation in Africans remain largely unknown. We report here on the relationship between LTL, genetics, and a variety of environmental and climatic factors in ethnically diverse African adults (n = 1,818) originating from Botswana, Tanzania, Ethiopia, and Cameroon. We observe significant variation in LTL among populations, finding that the San hunter-gatherers from Botswana have the longest leukocyte telomeres and that the Fulani pastoralists from Cameroon have the shortest telomeres. Genetic factors explain ∼50% of LTL variation among individuals. Moreover, we observe a significant negative association between Plasmodium falciparum malaria endemicity and LTL while adjusting for age, sex, and genetics. Within Africa, adults from populations indigenous to areas with high malaria exposure have shorter LTL than those in populations indigenous to areas with low malaria exposure. Finally, we explore to what degree the genetic architecture underlying LTL in Africa covaries with malaria exposure.
We report on the relationship between leukocyte telomere length (LTL), genetics, and environmental factors in ethnically diverse Africans. LTL is longer in African ancestry individuals than in non-Africans and we observe a significant negative relationship between malaria endemicity and LTL, while adjusting for age, sex, and genetic ancestry.
Skin color is highly variable in Africans, yet little is known about the underlying molecular mechanism. Here we applied massively parallel reporter assays to screen 1,157 candidate variants ...influencing skin pigmentation in Africans and identified 165 single-nucleotide polymorphisms showing differential regulatory activities between alleles. We combine Hi-C, genome editing and melanin assays to identify regulatory elements for MFSD12, HMG20B, OCA2, MITF, LEF1, TRPS1, BLOC1S6 and CYB561A3 that impact melanin levels in vitro and modulate human skin color. We found that independent mutations in an OCA2 enhancer contribute to the evolution of human skin color diversity and detect signals of local adaptation at enhancers of MITF, LEF1 and TRPS1, which may contribute to the light skin color of Khoesan-speaking populations from Southern Africa. Additionally, we identified CYB561A3 as a novel pigmentation regulator that impacts genes involved in oxidative phosphorylation and melanogenesis. These results provide insights into the mechanisms underlying human skin color diversity and adaptive evolution.
Bone resorption is highly dependent on the dynamic rearrangement of the osteoclast actin cytoskeleton to allow formation of actin rings and a functional ruffled border. Hem1 is a ...hematopoietic-specific subunit of the WAVE-complex which regulates actin polymerization and is crucial for lamellipodia formation in hematopoietic cell types. However, its role in osteoclast differentiation and function is still unknown. Here, we show that although the absence of Hem1 promotes osteoclastogenesis, the ability of Hem1
osteoclasts to degrade bone was severely impaired. Global as well as osteoclast-specific deletion of Hem1 in vivo revealed increased femoral trabecular bone mass despite elevated numbers of osteoclasts in vivo. We found that the resorption defect derived from the morphological distortion of the actin-rich sealing zone and ruffled border deformation in Hem1-deficient osteoclasts leading to impaired vesicle transport and increased intracellular acidification. Collectively, our data identify Hem1 as a yet unknown key player in bone remodeling by regulating ruffled border formation and consequently the resorptive capacity of osteoclasts.
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