Summary
Aims
Whether atrial fibrillation is related to risk of venous thromboembolism (VTE) has not been extensively studied. Therefore, we investigated the association between atrial fibrillation ...and future risk of VTE in a population‐based cohort.
Methods
In total, 29 975 subjects were recruited from three surveys of the Tromsø study and followed from enrollment (1994–1995, 2001–2002 and 2007–2008) up to 2010. Incident events of atrial fibrillation and VTE during follow‐up were recorded. Information on potential confounders was obtained at baseline. Cox‐regression models with atrial fibrillation as time‐dependent variable were used to calculate hazard ratios (HRs) for VTE with 95% confidence intervals (CIs).
Results
During 16 years of median follow‐up, 1604 subjects were diagnosed with atrial fibrillation and 614 with incident VTE. The risk of VTE was substantially increased during the first 6 months after diagnosis of atrial fibrillation (HR, 8.44; 95% CI, 5.61–12.69), and remained increased throughout the study period (HR, 1.43; 95% CI, 1.43–1.99) compared with those without atrial fibrillation. Atrial fibrillation displayed higher risk estimates for pulmonary embolism (HR, 11.84; 95% CI, 6.80–20.63) than for deep vein thrombosis (HR, 6.20; 95% CI, 3.37–11.39) during the first 6 months, and was still associated with pulmonary embolism (HR, 1.96; 95% CI, 1.24–3.10) but not with deep vein thrombosis (HR, 1.08; 95% CI, 0.66–1.75) more than 6 months after diagnosis.
Conclusion
Atrial fibrillation was associated with increased risk of VTE, and pulmonary embolism in particular. Our findings support the concept that isolated pulmonary embolism may originate from right atrial thrombi due to atrial fibrillation.
Major histocompatibility complex E (MHC-E) is a highly conserved, ubiquitously expressed, nonclassical MHC class lb molecule with limited polymorphism that is primarily involved in the regulation of ...natural killer (NK) cells. We found that vaccinating rhesus macaques with rhesus cytomegalovirus vectors in which genes Rh157.5 and Rh157.4 are deleted results in MHC-E–restricted presentation of highly varied peptide epitopes to CD8αβ⁺ T cells, at ~4 distinct epitopes per 100 amino acids in all tested antigens. Computational structural analysis revealed that MHC-E provides heterogeneous chemical environments for diverse side-chain interactions within a stable, open binding groove. Because MHC-E is up-regulated to evade NK cell activity in cells infected with HIV, simian immunodeficiency virus, and other persistent viruses, MHC-E–restricted CD8⁺ T cell responses have the potential to exploit pathogen immune-evasion adaptations, a capability that might endow these unconventional responses with superior efficacy.
Essentials
We performed repeated measurements of C‐reactive protein (CRP) and obesity in a cohort study.
CRP was associated with risk of myocardial infarction and venous thromboembolism.
CRP was a ...mediator for risk of myocardial infarction in obese men and women.
CRP was a partial mediator for risk of venous thromboembolism in obese women, but not in men.
Summary
Background
Low‐grade inflammation in obesity may be a shared pathway for the risk of venous thromboembolism (VTE) and myocardial infarction (MI).
Objectives
To investigate the associations between repeated measurements of C‐reactive protein (CRP) and the risks of MI and VTE, and to explore whether CRP mediated these risks in obese subjects.
Methods
CRP and obesity measures were collected from 15 134 subjects who participated in one or more surveys of the Tromsø study in 1994–1995, 2001–2002, or 2007–2008. Incident VTEs and MIs were registered until 1 January 2011. Time‐varying Cox regression models were used to calculate hazard ratios of MI and VTE according to categories of CRP and obesity measures.
Results
There were 291 VTEs and 920 MIs during follow‐up. High levels of CRP (≥ 3 mg L−1 versus < 1 mg L−1) were associated with increased risks of MI (hazard ratio HR 1.73; 95% confidence interval CI 1.32–2.26) and VTE (HR 1.84; 95% CI 1.22–2.78) in women, but only with MI in men (HR 1.93; 95% CI 1.53–2.44). All obesity measures showed stronger associations with CRP in women than in men. In obese women (body mass index BMI of ≥ 30 kg m−2 versus < 25 kg m−2), adjustment for CRP attenuated the risk estimate for VTE by 22%, whereas the incidence rates of VTE increased with combined categories of higher BMI and CRP. No association was found in men.
Conclusions
Our findings suggest that low‐grade inflammation, assessed by measurement of CRP, is associated with the risks of MI and VTE, and may be a shared pathway for MI and VTE in obesity.
Seismic anisotropy produced by aligned olivine in oceanic lithosphere offers a window into mid‐ocean ridge (MOR) dynamics. Yet, interpreting anisotropy in the context of grain‐scale deformation ...processes and strain observed in laboratory experiments and natural olivine samples has proven challenging due to incomplete seismological constraints and length scale differences spanning orders of magnitude. To bridge this observational gap, we estimate an in situ elastic tensor for oceanic lithosphere using co‐located compressional‐ and shear‐wavespeed anisotropy observations at the NoMelt experiment located on ∼70 Ma seafloor. The elastic model for the upper 7 km of the mantle, NoMelt_SPani7, is characterized by a fast azimuth parallel to the fossil‐spreading direction, consistent with corner‐flow deformation fabric. We compare this model with a database of 123 petrofabrics from the literature to infer olivine crystallographic orientations and shear strain accumulated within the lithosphere. Direct comparison to olivine deformation experiments indicates strain accumulation of 250%–400% in the shallow mantle. We find evidence for D‐type olivine lattice‐preferred orientation (LPO) with fast 100 parallel to the shear direction and girdled 010 and 001 crystallographic axes perpendicular to shear. D‐type LPO implies similar amounts of slip on the (010)100 and (001)100 easy slip systems during MOR spreading; we hypothesize that grain‐boundary sliding during dislocation creep relaxes strain compatibility, allowing D‐type LPO to develop in the shallow lithosphere. Deformation dominated by dislocation‐accommodated grain‐boundary sliding (disGBS) has implications for in situ stress and grain size during MOR spreading and implies grain‐size dependent deformation, in contrast to pure dislocation creep.
Plain Language Summary
Earth's upper mantle is composed primarily of the mineral olivine, which responds to deformation by organizing its seismically fast axis in the flow direction. During seafloor spreading, olivine crystals align with the spreading direction and become frozen into the lithosphere preserving the near‐ridge deformation history. The resulting rock fabric can be observed in place via the directional dependence of seismic wavespeeds (seismic anisotropy) as well as in hand‐sample rocks collected from the field. However, interpreting seismic anisotropy observations in the context of laboratory and field data remains a challenge, due to large differences in length scale and incomplete seismic constraints. Here, we bridge this observational gap by incorporating multiple data types to solve for the complete anisotropic structure of oceanic lithosphere that formed ∼70 Myr ago. By comparing our model to laboratory data, we infer the magnitude of shear strain and style of olivine deformation during seafloor spreading for the first time. Our results indicate large shear strains and an olivine fabric type different to that typically assumed, consistent with deformation that is sensitive to the presence of grain boundaries even though most of the strain is produced by dislocations. This has new implications for the formation and evolution of oceanic plates.
Key Points
We develop an in situ elastic tensor for oceanic lithosphere that incorporates co‐located compressional and shear wavespeed anisotropy constraints
Seismic anisotropy is consistent with corner flow during spreading and shear strains of 250%–400%
Girdled D‐type olivine fabric implies activation of multiple olivine easy slip systems during mid‐ocean ridge spreading
Essentials
Impact of cancer stage on venous thromboembolism (VTE) risk is not well‐known in all cancers.
The Scandinavian Thrombosis and Cancer Cohort provides person‐time data and validated VTEs.
...Impact of cancer stage on VTE incidence tended to vary with cancer type.
Cancer stage may not per se be a risk factor for VTE in all cancer types.
Summary
Background
Absolute measures of the impact of cancer stage on the incidence of venous thromboembolism (VTE) in patients with distinct cancer types have not been investigated in a large population‐based cohort study.
Objectives
To investigate differences in the incidence rates of objectively confirmed VTE according to the development of cancer in a large population‐based cohort study. Cancer type and stage at the time of diagnosis were taken into account.
Patients and Methods
The Scandinavian Thrombosis and Cancer Cohort includes data regarding cancer types, stages and objectively confirmed VTE diagnoses among 144 952 participants followed from 1993 to 2012. We studied stage‐specific incidence rates of VTE, and calculated incidence rate differences (IRDs) for VTE according to stages in patients with 10 types of solid cancer.
Results
During the entire follow‐up, 335 VTEs occurred, of which 293 occurred within 5 years. The IRD of VTE in patients with distant metastasis as compared with those with localized disease indicated large variation depending on cancer type. The highest IRD was observed for pancreatic cancer (IRD of 187.0 × 10−3 person‐years p‐y; 95% confidence interval CI − 6.7 to 380.8), and the lowest IRD was observed for prostate cancer (IRD of 3.7 × 10−3 p‐y; 95% CI − 7 to 15.2). Regional spread as compared with localized disease also indicated large variation depending on cancer type; the highest IRD was observed for uterine cancer (IRD of 37.6 × 10−3 p‐y; 95% CI − 23.7 to 99), and the IRDs for breast and prostate cancer were close to zero.
Conclusion
More advanced cancer at the time of diagnosis was associated with a higher risk of VTE, but the strength of the associations differed substantially between cancer types.
Insight into the location, state, and function of a promoter in heterogeneous catalysis was obtained through atomic-resolution in situ transmission electron microscopy. In the most active ruthenium ...catalyst for ammonia synthesis known so far, the barium promoter is shown to be located in two different phases in the catalyst. The increased activity is suggested to be related to a two-dimensional barium-oxygen overlayer on the ruthenium crystals. The possibility for conducting such studies for other reactions could add substantially to our current understanding of heterogeneous catalysis. Heterogeneous catalysis plays an increasingly important role in environmental protection processes, in fuel upgrading, and in providing the majority of the chemical building blocks required by contemporary society. Most heterogeneous catalysts of industrial importance are multicomponent materials that are designed by trial-and-error experimentation. Application of even the most sophisticated physical-chemical characterization techniques is usually not sufficient to obtain a complete understanding of the structure of the active site, the reaction mechanism and kinetics, the structural dynamics, and the specific roles of all catalyst components.
Aims/hypothesis
Sirtuin 1 (SIRT1) has emerged as a key metabolic regulator of glucose homeostasis and insulin secretion. Enhanced SIRT1 activity has been shown to be protective against diabetes, ...although the mechanisms remain largely unknown. The aim of this study was to determine how SIRT1 regulates insulin secretion in the pancreatic beta cell.
Methods
Pancreatic beta cell-specific
Sirt1
deletion was induced by tamoxifen injection in 9-week-old
Pdx1CreER
:
floxSirt1
mice (
Sirt1
BKO). Controls were injected with vehicle. Mice were assessed metabolically via glucose challenge, insulin tolerance tests and physical variables. In parallel,
Sirt1
short interfering RNA-treated MIN6 cells (SIRT1KD) and isolated
Sirt1
BKO islets were used to investigate the effect of SIRT1 inactivation on insulin secretion and gene expression.
Results
OGTTs showed impaired glucose disposal in
Sirt1
BKO mice due to insufficient insulin secretion. Isolated
Sirt1
BKO islets and SIRT1KD MIN6 cells also exhibited impaired glucose-stimulated insulin secretion. Subsequent analyses revealed impaired α-ketoisocaproic acid-induced insulin secretion and attenuated glucose-induced Ca
2+
influx, but normal insulin granule exocytosis in
Sirt1
BKO beta cells. Microarray studies revealed a large cluster of mitochondria-related genes, the expression of which was dysregulated in SIRT1KD MIN6 cells. Upon further analysis, we demonstrated an explicit defect in mitochondrial function: the inability to couple nutrient metabolism to mitochondrial membrane hyperpolarisation and reduced oxygen consumption rates.
Conclusions/interpretation
Taken together, these findings indicate that in beta cells the deacetylase SIRT1 regulates the expression of specific mitochondria-related genes that control metabolic coupling, and that a decrease in beta cell
Sirt1
expression impairs glucose sensing and insulin secretion.
Measurements of hydroxyl (OH) and hydroperoxy (HO2*) radical concentrations were made at the Pasadena ground site during the CalNex‐LA 2010 campaign using the laser‐induced fluorescence‐fluorescence ...assay by gas expansion technique. The measured concentrations of OH and HO2* exhibited a distinct weekend effect, with higher radical concentrations observed on the weekends corresponding to lower levels of nitrogen oxides (NOx). The radical measurements were compared to results from a zero‐dimensional model using the Regional Atmospheric Chemical Mechanism‐2 constrained by NOx and other measured trace gases. The chemical model overpredicted measured OH concentrations during the weekends by a factor of approximately 1.4 ± 0.3 (1σ), but the agreement was better during the weekdays (ratio of 1.0 ± 0.2). Model predicted HO2* concentrations underpredicted by a factor of 1.3 ± 0.2 on the weekends, while measured weekday concentrations were underpredicted by a factor of 3.0 ± 0.5. However, increasing the modeled OH reactivity to match the measured total OH reactivity improved the overall agreement for both OH and HO2* on all days. A radical budget analysis suggests that photolysis of carbonyls and formaldehyde together accounted for approximately 40% of radical initiation with photolysis of nitrous acid accounting for 30% at the measurement height and ozone photolysis contributing less than 20%. An analysis of the ozone production sensitivity reveals that during the week, ozone production was limited by volatile organic compounds throughout the day during the campaign but NOx limited during the afternoon on the weekends.
Key Points
Measurements of OH and HO2 during CalNex‐LA displayed a weekend effect
Modeled OH and HO2 agreed with measurements after accounting for missing OH reactivity
Ozone production was VOC limited on the weekdays but NOx limited on the weekends
Essentials
It is debated whether physical activity influences the risk of venous thromboembolism.
The association was explored accounting for fluctuations in physical activity over time.
Overall and ...in the elderly, physical activity was associated with 23% and 30% lower risk.
A moderate proportion of the association (14–36%) was mediated via body mass index.
Summary
Background
Whether physical activity influences the risk of incident venous thromboembolism (VTE) remains controversial, potentially because of methodological challenges, such as regression dilution bias.
Objectives
To investigate whether physical activity was associated with VTE risk, and explore the role of body mass index (BMI) as a mediator in a population‐based cohort with repeated assessments of physical activity.
Methods
Participants (n = 30 002) attending one or more surveys of the Tromsø Study 4–6 (1994–1995, 2001–2002, and 2007–2008) were included and categorized on the basis of weekly physical activity. Incident VTE was registered until 31 December 2016. Hazard ratios (HRs) were calculated by the use of time‐varying Cox regression models. The Aalen additive hazard model was used to quantify the total, direct and indirect effects of physical activity.
Results
There were 531 incident VTEs during follow‐up. Physical activity (≥ 1 per week) was associated with a lower risk of VTE (HR 0.77, 95% confidence interval CI 0.64–0.92) than being inactive. The effect was most pronounced for those aged ≥ 65 years (HR 0.70, 95% CI 0.55–0.88) and for provoked events (HR 0.66, 95% CI 0.50–0.89). The differences in absolute risk between active and inactive individuals were − 0.42 (95% CI − 0.73 to − 0.14) and − 1.59 (95% CI − 2.74 to − 0.52) events annually per 1000 individuals in the total and elderly populations, respectively. A moderate proportion of the association (14–36%) was mediated via BMI.
Conclusion
Our findings suggest that regular physical activity is associated with a lower risk of VTE, particularly in the elderly. The association occurred at a low weekly amount of physical activity, and was only partly mediated by BMI.
PDF
