Patients with severe sepsis often present with concurrent coagulopathy, microcirculatory failure and evidence of vascular endothelial activation and damage. Given the critical role of the endothelium ...in balancing hemostasis, we investigated single-point associations between whole blood coagulopathy by thrombelastography (TEG) and plasma/serum markers of endothelial activation and damage in patients with severe sepsis.
A post-hoc multicenter prospective observational study in a subgroup of 184 patients from the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) Trial. Study patients were admitted to two Danish intensive care units. Inclusion criteria were severe sepsis, pre-intervention whole blood TEG measurement and a plasma/serum research sample available from baseline (pre-intervention) for analysis of endothelial-derived biomarkers. Endothelial-derived biomarkers were measured in plasma/serum by enzyme-linked immunosorbent assay (syndecan-1, thrombomodulin, protein C (PC), tissue-type plasminogen activator and plasminogen activator inhibitor-1). Pre-intervention TEG, functional fibrinogen (FF) and laboratory and clinical data, including mortality, were retrieved from the trial database.
Most patients presented with septic shock (86%) and pulmonary (60%) or abdominal (30%) focus of infection. The median (IQR) age was 67 years (59 to 75), and 55% were males. The median SOFA and SAPS II scores were 8 (6 to 10) and 56 (41 to 68), respectively, with 7-, 28- and 90-day mortality rates being 21%, 39% and 53%, respectively. Pre-intervention (before treatment with different fluids), TEG reaction (R)-time, angle and maximum amplitude (MA) and FF MA all correlated with syndecan-1, thrombomodulin and PC levels. By multivariate linear regression analyses, higher syndecan-1 and lower PC were independently associated with TEG and FF hypocoagulability at the same time-point: 100 ng/ml higher syndecan-1 predicted 0.64 minutes higher R-time (SE 0.25), 1.78 mm lower TEG MA (SE 0.87) and 0.84 mm lower FF MA (SE 0.42; all P < 0.05), and 10% lower protein C predicted 1.24 mm lower TEG MA (SE 0.31).
In our cohort of patients with severe sepsis, higher circulating levels of biomarkers of mainly endothelial damage were independently associated with hypocoagulability assessed by TEG and FF. Endothelial damage is intimately linked to coagulopathy in severe sepsis.
Clinicaltrials.gov number: NCT00962156. Registered 13 July 2009.
In Swedish practice, there is a long tradition of evaluating undrained shear strength from fall-cone tests and field vane tests. During the last 20years cone penetration tests have also become widely ...used. However, the results from all these test methods have to be evaluated using empirical factors. The factors generally used for Swedish clays are related to liquid limit and overconsolidation, but they are not applicable to all types of fine-grained soils and can often be improved by local calibration for the particular type of soil in the area of current interest. For this calibration, the results of direct simple shear tests and/or triaxial tests in the laboratory are normally used. This paper presents an evaluation for Swedish fine-grained sulphide soils, for which a general correction factor of 0.65 for field vane tests and fall-cone tests, a cone factor Nkt of 20.2 for cone penetration tests and a relation cu,DSS/(σ′cOCR−0.2) of 0.28 have been found. No correlations were found between these empirical factors and the clay content, liquid limit or organic content, but a relationship was found between the overconsolidation ratio and both the cone penetration test and the field vane test. The sulphide soils in question are found in northern Sweden along the coast of the Gulf of Bothnia. They are mostly classified as organic silt or organic clay, which is normally silty.
•Empirical factors given to evaluate undrained shear strength of sulphide soils•No correlation to liquid limit for the empirical factors for CPTs, FVTs and FCs•Correlation to overconsolidation ratio for the empirical factors for CPTs and FVTs•Hypothesis OCR-corr and effects of modes of deformation and effective stress paths•Sulphide soils behave intermediate between a mineral (inorganic) and an organic soil.
Important features of the multivariate approach are discussed, and an extension to this approach is proposed whereby the total uncertainty in site investigation methods due to spatial averaging is ...assessed prior to its adoption. Results from a site investigation of spatially averaged values of undrained shear strength (
S
¯
u
) and the corresponding coefficient of variation (
COV
S
¯
u
) in Veda sulphide clay were used as a practical illustration of the extended multivariate approach and provide a basis for discussion. The inherent variability and scales of fluctuation for different methods are presented. The study shows the usefulness of the extended multivariate approach for the evaluation of representative values of
S
¯
u
and
COV
S
¯
u
based on results from different methods. It is also a way of implicitly reducing the transformation errors that arise when a property is derived from measurement results. Nevertheless, considerable care must be taken as a much lower COV for one method will have a significant impact on the results.
For staging the construction of embankments on soft clay, an important aspect in deterministic or probabilistic stability analyses is the assessment of the representative average values and ...associated uncertainties for the undrained shear strength as the height of the embankment is sequentially increased. Assessments made prior to construction can be verified by performing observations during the construction phase. All relevant available information should be incorporated into an analysis to increase the level of confidence and the objectivity of the assessment. To this end, we apply an extended multivariate approach to assess the undrained shear strength using different indirect measurement methods during the staged construction of the Veda embankment (Sweden). This multivariate approach implies that uncertainties associated with the assessments are reduced, and objectively weighted averages are obtained. The resulting implications on the calculated deterministic safety factors and the probabilistically retrieved reliability indices of the embankment are thoroughly discussed in this work.
Chimeric antigen receptor-T cells have spearheaded the field of adoptive cell therapy and have shown remarkable results in treating hematological neoplasia. Because of the different biology of solid ...tumors compared to hematological tumors, response rates of CAR-T cells could not be transferred to solid entities yet. CAR engineering has added co-stimulatory domains, transgenic cytokines and switch receptors to improve performance and persistence in a hostile tumor microenvironment, but because of the inherent cell type limitations of CAR-T cells, including HLA incompatibility, toxicities (cytokine release syndrome, neurotoxicity) and high costs due to the logistically challenging preparation process for autologous cells, the use of alternative immune cells is gaining traction. NK cells and γδ T cells that do not need HLA compatibility or macrophages and dendritic cells with additional properties such as phagocytosis or antigen presentation are increasingly seen as cellular vehicles with potential for application. As these cells possess distinct properties, clinicians and researchers need a thorough understanding of their peculiarities and commonalities. This review will compare these different cell types and their specific modes of action seen upon CAR activation.
Since its introduction, Eurocode 7 has acknowledged the observational method as a valid design approach for geotechnical structures. The observational method is defined in five paragraphs. Although ...several case studies have concluded that the observational method is useful, the method is still sparsely used. This study compares the actual implementation of the observational method in the Veda embankment project according to the definitions given in Eurocode 7. The outcome of the observational method as a design approach, and the major deviations compared to the definitions in Eurocode 7 are discussed. It is concluded that the design of a multi-staged embankment, where the building process is governed by consolidation in the subsoil, can only partly be adapted to the observational method as defined in Eurocode 7. Furthermore, when this is the case, the possibility of combining “design by calculations” and the observational method is discussed.
•A case study discussing the observational method (OM) and its definitions in EC7•The design methodology used in the case partly follows the OM definitions in EC7.•The OM definitions in EC7 are not suitable for embankment design in all aspects.•For embankments, a combination of “design by calculation” and the OM is recommended.•Clarification of the OM definitions in EC7 is desired.
Purpose
It has been speculated that certain subgroups of sepsis patients may benefit from treatment with hydroxyethyl starch (HES) 130/0.42, specifically in the earlier resuscitation of patients with ...more severely impaired circulation.
Methods
This was a post-hoc, subgroup analysis of all 798 patients with severe sepsis randomised in the 6S trial according to time from ICU admission to randomisation, surgery and fluids given prior to randomisation and markers of shock at randomisation. Intervention effects estimated as risk ratios were analysed between the HES versus Ringer’s acetate groups to detect subgroup heterogeneity of the effects on 90-day mortality. Multiple logistic regression was used to adjust for risk factors.
Results
Most baseline characteristics were comparable between the HES and Ringer’s acetate groups in the different subgroups. There was no heterogeneity in the intervention effect on 90-day mortality in the following subgroups: randomisation earlier than 4 h after ICU admission versus later (test of interaction
P
= 0.85), surgery versus no surgery (
P
= 0.42), colloids given versus not given (
P
= 0.57), <2 l of crystalloids given prior to randomisation vs. >2 l (
P
= 0.88) or plasma lactate >4 mmol/l versus <4 mmol/l (
P
= 0.54), hypotension versus no hypotension (
P
= 0.32) or use of vasopressor or inotropic agents at randomisation versus no use (
P
= 0.10).
Conclusions
The increased 90-day mortality observed in patients with severe sepsis resuscitated with HES 130/0.42 did not appear to depend on time course, surgery or fluids given prior to randomisation or on markers of shock at randomisation. As the analyses were planned post hoc and their power is reduced, the results should be interpreted with caution.
Abstract Purpose The Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial showed increased mortality in patients resuscitated with hydroxyethyl starch 130/0.42 (HES) vs Ringer acetate. ...Different effects of the fluids on the endothelium may have contributed to the observed outcome. We aimed to investigate associations between HES vs Ringer and changes in plasma biomarkers reflecting endothelial damage and coagulation impairment. Materials and methods Six biomarkers, including soluble thrombomodulin (sTM) and plasminogen activator inhibitor 1 (PAI-1), were assessed in a subgroup of 208 patients from the 6S trial. We analyzed differences in plasma concentration in the 2 intervention groups using linear or logistic regression models. Results The increase in plasma sTM was lower in the HES group (− 1.8 ng/mL; 95% confidence interval, − 2.9 to − 0.7; P = .002). The change was not statistically significant associated with mortality whereas increase in plasminogen activator inhibitor 1 was (odds ratio for 1-unit increase, 1.04; 95% confidence interval, 1.01-1.08; P = .01). Conclusions Resuscitation with HES vs Ringer decreased early endothelial damage. Although this finding should be interpreted with caution, it indicates that the increased mortality observed with HES in the 6S trial may not be explained by endothelial damage and it emphasizes the challenge of using surrogate markers as outcome.
Nitric oxide (NO) likely plays a pivotal role in the pathogenesis of sepsis. Arginine is a substrate for NO, whereas the methylated arginines-asymmetric dimethylarginine (ADMA) and symmetric ...dimethylarginine (SDMA)-are endogenous by-products of proteolysis that inhibit NO production.We investigated if high-plasma levels of ADMA, SDMA, and arginine/ADMA ratio were associated with 90-day mortality in patients with severe sepsis or septic shock.
We included 267 adult patients admitted to intensive care unit with severe sepsis or septic shock. The patients had previously been included in the randomized controlled trial "Scandinavian Starch for Severe Sepsis and Septic Shock (6S)." ADMA, SDMA, and arginine/ADMA ratio were measured in plasma. The risk of death within 90 days was estimated in multivariate Cox regression analyses adjusted for gender, age ≥65 years, major cardiovascular disease, diabetes, hypertension, respiratory failure, vasopressor treatment, highest quartile of creatinine and bilirubin, and lowest quartile of platelet count. In the regression analyses missing values were estimated using multiple imputation.
Twenty-five patients had missing data in one or more of the baseline variables and 44 patients had missing methylarginine values. Both ADMA and SDMA were independently associated with 90-day mortality (ADMA: hazard ratio 1.54; 95% CI, 1.00-2.38; P = 0.046, and SDMA: hazard ratio 1.78; 95% CI, 1.14-2.72; P = 0.011). Arginine/ADMA ratio was not associated with 90-day mortality neither in univariate nor in multivariate analyses. The difference in mortality between patients with high and low ADMA was most pronounced in the first week after inclusion.
High levels of ADMA and SDMA in plasma were associated with increased 90-day mortality in patients with severe sepsis or septic shock. Interfering with the methylarginine-NO systems may be a novel target in these patients.
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