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Background Uptake of self-testing and self-management of oral coagulation has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism.
Methods We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat.
Findings Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12 800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0.51; 95% CI 0.31-0.85) but not for major haemorrhagic events (0.88, 0.74-1.06) or death (0.82, 0.62-1.09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0.33, 95% CI 0.17-0.66), as did participants with mechanical heart valve (0.52, 0.35-0.77). Analysis of major outcomes in the very elderly (age >= 85 years, n=99) showed no significant adverse effects of the intervention for all outcomes.
Interpretation Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up.
Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (R-S). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.
Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (R-S). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.
Background: Epidemiological studies suggest that an increased red meat intake is associated with a higher risk of type 2 diabetes, whereas an increased fiber intake is associated with a lower risk. Objectives: We conducted an intervention study to investigate the effects of these nutritional factors on glucose and lipid metabolism, body-fat distribution, and liver fat content in subjects at increased risk of type 2 diabetes. Methods: This prospective, randomized, and controlled dietary intervention study was performed over 6 mo. All groups decreased their daily caloric intake by 400 kcal. The "control" group (N = 40) only had this requirement. The "no red meat" group (N = 48) in addition aimed to avoid the intake of red meat, and the "fiber" group (N = 44) increased intake of fibers to 40 g/d. Anthropometric parameters and frequently sampled oral glucose tolerance tests were performed before and after intervention. Body-fat mass and distribution, liver fat, and liver iron content were assessed by MRI and single voxel proton magnetic resonance spectroscopy. Results: Participants in all groups lost weight (mean 3.3 +/- 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001). These changes did not differ between groups. Liver fat content decreased significantly (P < 0.001) with no differences between the groups. The decrease in liver fat correlated with the decrease in ferritin during intervention (r(2) = 0.08, P = 0.0021). This association was confirmed in an independent lifestyle intervention study (Tuebingen Lifestyle Intervention Program, N = 229, P = 0.0084). Conclusions: Our data indicate that caloric restriction leads to a marked improvement in glucose metabolism and body-fat composition, including liver-fat content. The marked reduction in liver fat might be mediated via changes in ferritin levels. In the context of caloric restriction, there seems to be no additional beneficial impact of reduced red meat intake and increased fiber intake on the improvement in cardiometabolic risk parameters. This trial was registered at clinicaltrials.gov as NCT03231839.
The Hartousov mofette system is a natural CO2 degassing site in the central Cheb Basin (Eger Rift, Central Europe). In early 2016 a 108 m deep core was obtained from this system to investigate the impact of ascending mantle-derived CO2 on indigenous deep microbial communities and their surrounding life habitat. During drilling, a CO2 blow out occurred at a depth of 78.5 meter below surface (mbs) suggesting a CO2 reservoir associated with a deep low-permeable CO2-saturated saline aquifer at the transition from Early Miocene terrestrial to lacustrine sediments. Past microbial communities were investigated by hopanoids and glycerol dialkyl glycerol tetraethers (GDGTs) reflecting the environmental conditions during the time of deposition rather than showing a signal of the current deep biosphere. The composition and distribution of the deep microbial community potentially stimulated by the upward migration of CO2 starting during Mid Pleistocene time was investigated by intact polar lipids (IPLs), quantitative polymerase chain reaction (qPCR), and deoxyribonucleic acid (DNA) analysis. The deep biosphere is characterized by microorganisms that are linked to the distribution and migration of the ascending CO2-saturated groundwater and the availability of organic matter instead of being linked to single lithological units of the investigated rock profile. Our findings revealed high relative abundances of common soil and water bacteria, in particular the facultative, anaerobic and potential iron-oxidizing Acidovorax and other members of the family Comamonadaceae across the whole recovered core. The results also highlighted the frequent detection of the putative sulfate-oxidizing and CO2-fixating genus Sulfuricurvum at certain depths. A set of new IPLs are suggested to be indicative for microorganisms associated to CO2 accumulation in the mofette system.
The Cheb Basin (CZ) is a shallow Neogene intracontinental basin filled with fluvial and lacustrine sediments that is located in the western part of the Eger Rift. The basin is situated in a seismically active area and is characterized by diffuse degassing of mantle-derived CO2 in mofette fields. The Hartousov mofette field shows a daily CO2 flux of 23-97 tons of CO2 released over an area of 0.35 km(2) and a soil gas concentration of up to 100% CO2. The present study aims to explore the geo-bio interactions provoked by the influence of elevated CO2 concentrations on the geochemistry and microbial community of soils and sediments. To sample the strata, two 3-m cores were recovered. One core stems from the center of the degassing structure, whereas the other core was taken 8 m from the ENE and served as an undisturbed reference site. The sites were compared regarding their geochemical features, microbial abundances, and microbial community structures. The mofette site is characterized by a low pH and high TOC/sulfate contents. Striking differences in the microbial community highlight the substantial impact of elevated CO2 concentrations and their associated side effects on microbial processes. The abundance of microbes did not show a typical decrease with depth, indicating that the uprising CO2-rich fluid provides sufficient substrate for chemolithoautotrophic anaerobic microorganisms. Illumine MiSeq sequencing of the 16S rRNA genes and multivariate statistics reveals that the pH strongly influences microbial composition and explains around 38.7% of the variance at the mofette site and 22.4% of the variance between the mofette site and the undisturbed reference site. Accordingly, acidophilic microorganisms (e.g., OTUs assigned to Acidobacteriaceae and Acidithiobacillus) displayed a much higher relative abundance at the mofette site than at the reference site. The microbial community at the mofette site is characterized by a high relative abundance of methanogens and taxa involved in sulfur cycling. The present study provides intriguing insights into microbial life and geo-bio interactions in an active seismic region dominated by emanating mantle-derived CO2-rich fluids, and thereby builds the basis for further studies, e.g., focusing on the functional repertoire of the communities. However, it remains open if the observed patterns can be generalized for different time-points or sites.
Context
For a given body mass index (BMI), both impaired metabolic health (MH) and reduced cardiorespiratory fitness (CRF) associate with increased risk of cardiovascular disease (CVD).
Objective
It remains unknown whether both risk phenotypes relate to CVD independently of each other, and whether these relationships differ in normal weight, overweight, and obese subjects.
Methods
Data from 421 participants from the Tubingen Diabetes Family Study, who had measurements of anthropometrics, metabolic parameters, CRF (maximal aerobic capacity [VO2max]) and carotid intima-media thickness (cIMT), an early marker of atherosclerosis, were analyzed. Subjects were divided by BMI and MH status into 6 phenotypes.
Results
In univariate analyses, older age, increased BMI, and a metabolic risk profile correlated positively, while insulin sensitivity and VO2max negatively with cIMT. In multivariable analyses in obese subjects, older age, male sex, lower VO2max (std. ss -0.21, P = 0.002) and impaired MH (std. ss 0.13, P = 0.02) were independent determinants of increased cIMT. After adjustment for age and sex, subjects with metabolically healthy obesity (MHO) had higher cIMT than subjects with metabolically healthy normal weight (MHNW; 0.59 +/- 0.009 vs 0.52 +/- 0.01 mm; P < 0.05). When VO2max was additionally included in this model, the difference in cIMT between MHO and MHNW groups became statistically nonsignificant (0.58 +/- 0.009 vs 0.56 +/- 0.02 mm; P > 0.05).
Conclusion
These data suggest that impaired MH and low CRF independently determine increased cIMT in obese subjects and that low CRF may explain part of the increased CVD risk observed in MHO compared with MHNW.
GrassPlot is a collaborative vegetation-plot database organised by the Eurasian Dry Grassland Group (EDGG) and listed in the Global Index of Vegetation-Plot Databases (GIVD ID EU-00-003). GrassPlot collects plot records (releves) from grasslands and other open habitats of the Palaearctic biogeographic realm. It focuses on precisely delimited plots of eight standard grain sizes (0.0001; 0.001;... 1,000 m(2)) and on nested-plot series with at least four different grain sizes. The usage of GrassPlot is regulated through Bylaws that intend to balance the interests of data contributors and data users. The current version (v. 1.00) contains data for approximately 170,000 plots of different sizes and 2,800 nested-plot series. The key components are richness data and metadata. However, most included datasets also encompass compositional data. About 14,000 plots have near-complete records of terricolous bryophytes and lichens in addition to vascular plants. At present, GrassPlot contains data from 36 countries throughout the Palaearctic, spread across elevational gradients and major grassland types. GrassPlot with its multi-scale and multi-taxon focus complements the larger international vegetationplot databases, such as the European Vegetation Archive (EVA) and the global database " sPlot". Its main aim is to facilitate studies on the scale-and taxon-dependency of biodiversity patterns and drivers along macroecological gradients. GrassPlot is a dynamic database and will expand through new data collection coordinated by the elected Governing Board. We invite researchers with suitable data to join GrassPlot. Researchers with project ideas addressable with GrassPlot data are welcome to submit proposals to the Governing Board.
The model-driven software development paradigm requires that appropriate model transformations are applicable in different stages of the development process. The transformations have to consistently propagate changes between the different involved models and thus ensure a proper model synchronization. However, most approaches today do not fully support the requirements for model synchronization and focus only on classical one-way batch-oriented transformations. In this paper, we present our approach for an incremental model transformation which supports model synchronization. Our approach employs the visual, formal, and bidirectional transformation technique of triple graph grammars. Using this declarative specification formalism, we focus on the efficient execution of the transformation rules and how to achieve an incremental model transformation for synchronization purposes. We present an evaluation of our approach and demonstrate that due to the speedup for the incremental processing in the average case even larger models can be tackled.