Selecting an appropriate target population is essential to maximize survival benefits of anticoagulant therapy against sepsis. Our meta-analysis of three populations with sepsis and nationwide ...observational study in Japan showed that anticoagulants improved mortality only in sepsis-induced disseminated intravascular coagulation (DIC) but not in non-DIC. This divergent effect was physiologically explained by host-protective immune responses of local thrombosis, which are mandatory in the early stage of sepsis. Meanwhile, the lack of definitive evidence for survival benefit provided by several trials of sepsis-induced DIC indicated that this condition was probably not the best target of anticoagulants. Our multicenter cohort study including only patients with sepsis-induced DIC showed a survival benefit from recombinant thrombomodulin only in patients with high disease severity. Thus, we believe that the population with sepsis and DIC and high disease severity is the optimal target for anticoagulant therapy. Anticoagulant therapy without appropriate target selection should be avoided because of the increased risk of bleeding with no survival benefit.
ESSENTIALS: Most anticoagulant therapy has failed to demonstrate a survival benefit in the overall sepsis population. We conducted separate meta-analyses of anticoagulant therapy in three different ...populations. Survival benefit was observed only in the septic disseminated intravascular coagulation (DIC) population. Further randomized controlled trials should focus on specific populations with septic DIC.
Although many preclinical trials have indicated the effectiveness and safety of anticoagulant therapy as an adjuvant therapy against sepsis, there is little evidence to support its effectiveness to reduce mortality in the overall population with sepsis in clinical situations. However, several studies suggested that specific anticoagulant therapy may potentially reduce mortality in patients with sepsis-induced disseminated intravascular coagulation (DIC).
We investigated whether the survival benefit of anticoagulant therapy might pertain to the coagulopathic population with sepsis.
We conducted separate meta-analyses of randomized controlled trials for anticoagulant therapy in three different populations: (i) overall population with sepsis, (ii) population with sepsis-induced coagulopathy, and (iii) population with sepsis-induced DIC. We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials comparing anticoagulant therapy with placebo or no intervention in sepsis patients. We measured all-cause mortality as the primary outcome and bleeding complications as the secondary outcome.
We analyzed 24 trials enrolling 14 767 patients. There were no significant reductions in mortality in the overall sepsis population and the population with sepsis-induced coagulopathy. Otherwise, we observed significant reductions in mortality (risk ratio 0.72, 95% confidence interval 0.62-0.85) in the population with sepsis-induced DIC. As adverse events, bleeding complications tended to increase similarly with anticoagulant therapy in all three populations.
Although associated with an increased risk of bleeding, anticoagulant therapy resulted in no survival benefits in the overall sepsis population and even the population with sepsis-induced coagulopathy; beneficial effects on mortality were observed only in the population with sepsis-induced DIC.
Although recombinant human soluble thrombomodulin (rhTM) is a widely used novel anticoagulant agent for disseminated intravascular coagulation (DIC) in Japan, its clinical efficacy in sepsis-induced ...DIC has not been demonstrated convincingly.
To assess the benefits and harms of rhTM in sepsis-induced DIC patients.
We conducted a systematic review and meta-analysis of rhTM therapy for sepsis-induced DIC for both randomized controlled trials (RCTs) and observational studies (retrospective case-control studies and/or prospective cohort studies) separately. All-cause mortality (28-30 days) as efficacy and serious bleeding complications as adverse effect were measured as primary outcomes. We assessed body of evidence quality at the outcome level by using the Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach.
We analyzed 12 studies (838 patients/3 RCTs; 571 patients/9 observational studies). Pooled relative risk was 0.81 (95% CI, 0.62-1.06) in the RCTs, indicating non-significant reduction in mortality, and 0.59 (95% CI, 0.45-0.77) in the observational studies. Meta-regression analysis revealed a significant negative slope between effect size of rhTM therapy and baseline mortality rate in individual studies (P = 0.012), suggesting that probability of a beneficial effect with rhTM therapy increases with increasing baseline risk. Risk of serious bleeding complications was not significantly different between rhTM and control groups. We judged the quality of evidence as moderate for mortality and serious bleeding.
The rhTM was associated with a trend in reduction of mortality at 28-30 days in sepsis-induced DIC patients. Further large rigorous trials are needed to confirm or refute these findings before implications for practice are clear.
Summary
Increased levels of serum undercarboxylated osteocalcin, which were associated with bone metabolism markers, correlated inversely with indices of glucose metabolism (plasma glucose, ...hemoglobin A1C, and glycated albumin) in hemodialysis patients with abnormalities of bone metabolism.
Introduction
Undercarboxylated osteocalcin (ucOC), a possible marker of bone metabolism and one of the osteoblast-specific secreted proteins, has recently been reported to be associated with glucose metabolism. We tested the hypothesis that ucOC levels are associated with indices of glucose metabolism in chronic hemodialysis patients with abnormalities of bone metabolism.
Methods
Serum ucOC, bone alkaline phosphatase (BAP, a bone formation marker), and tartrate-resistant acid phosphatase-5b (TRACP-5b, a bone resorption marker) were measured in 189 maintenance hemodialysis patients (96 diabetics and 93 non-diabetics), and their relationships with glucose metabolism were examined.
Results
ucOC correlated positively with BAP (
ρ
= 0.489,
p
< 0.0001), TRACP-5b (
ρ
= 0.585,
p
< 0.0001) and intact parathyroid hormone (iPTH;
ρ
= 0.621,
p
< 0.0001). Serum ucOC levels in the diabetic patients were lower than those of non-diabetic patients (
p
< 0.001), although there were no significant differences in serum BAP or TRACP-5b between diabetic and non-diabetic patients. Serum ucOC correlated negatively with plasma glucose (
ρ
= −0.303,
p
< 0.0001), hemoglobin A1C (
ρ
= −0.214,
p
< 0.01), and glycated albumin (
ρ
= −0.271,
p
< 0.001), although serum BAP or TRACP-5b did not. In multiple linear regression analysis, log plasma glucose, log hemoglobin A1C, and log glycated albumin were associated significantly with log ucOC after adjustment for age, gender, hemodialysis duration, and body mass index but were not associated with log BAP, log TRACP-5b, or log intact PTH.
Conclusion
Increased levels of serum ucOC, which were associated with bone metabolism markers, were inversely associated with indices of glucose metabolism in hemodialysis patients.
A simplified exchange coupled composite (ECC) dot structure with a reduced switching field and small applied field angle dependence in the switching field is proposed. It was found from a spin model ...analysis that a reduced switching field as well as a small applied field angle dependence of the field is obtainable even for two-layer ECC dot when the anisotropy axis is weakly inclined with an increased anisotropy for the soft layer. The switching properties of the two-layer ECC dots were confirmed using a micromagnetic simulation. A minimum normalized switching field of 0.51 was obtained for a two-layer ECC dot model of stacked cubes with a size of 5 nm and an anisotropy inclination angle of 10°. Recording simulation on a bit-pattered medium of the two-layer ECC dot array suggested the possibility of a high areal density recording beyond 4 Tdot/in 2 by shingled recording. It was also confirmed by simulation that the proposed inclined anisotropy ECC dot could be applicable to granular media for narrow track recoding.
In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain ...dysplasia called microdysgenesis.
Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick.
A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia.
Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).
The desire to have a more sustainable future, with lower emissions of carbon and sulfur to the atmosphere, a more appropriate reuse and valorization of wastes, and less dependency on oil has ...motivated the society to develop processes where renewable biomass is used as a feedstock for the production of fuels, chemicals, energy and materials. In addition, a bio-based economy has also potential to generate new jobs and new opportunities for entrepreneurship, with further benefits to the society. In view of this, great efforts have been done in order to develop efficient, sustainable and cost competitive bio-based processes able to be implemented in industrial scale. Although important advances were achieved and some processes are already available in a large scale, improvements are still needed to have a final product at a more competitive market price. In this sense, the strategy of integrating biorefineries to produce a variety of products from biomass has been considered as an important alternative to improve the financial performance. This paper highlights the most recent advances and opportunities in biomass conversion technologies and biorefineries for the development of a bio-based economy. Technological aspects including the hemicellulose integration and use of sugars for different products, lignin valorization, development of efficient and low-cost pretreatment technologies and development of highly efficient fermentation processes are also presented and discussed.
•Motivation to move towards a bio-based economy and opportunities.•Hemicellulose and lignin valorization in a biorefinery.•Sugars conversion to different valuable products.•Development of efficient and low-cost technologies for biomass pretreatment.•Strategies for the development of highly efficient fermentation processes.
This study assessed the feasibility of using bleached cellulose pulp from Eucalyptus wood as a feedstock for the production of itaconic acid by fermentation. Additionally, different process ...strategies were tested with the aim of selecting suitable conditions for an efficient production of itaconic acid by the fungus Aspergillus terreus. The feasibility of using cellulose pulp was demonstrated through assays that revealed the preference of the strain in using glucose as carbon source instead of xylose, mannose, sucrose or glycerol. Additionally, the cellulose pulp was easily digested by enzymes without requiring a previous step of pretreatment, producing a glucose-rich hydrolysate with a very low level of inhibitor compounds, suitable for use as a fermentation medium. Fermentation assays revealed that the technique used for sterilization of the hydrolysate (membrane filtration or autoclaving) had an important effect in its composition, especially on the nitrogen content, consequently affecting the fermentation performance. The carbon-to-nitrogen ratio (C:N ratio), initial glucose concentration and oxygen availability, were also important variables affecting the performance of the strain to produce itaconic acid from cellulose pulp hydrolysate. By selecting appropriate process conditions (sterilization by membrane filtration, medium supplementation with 3 g/L (NH4)2SO4, 60 g/L of initial glucose concentration, and oxygen availability of 7.33 (volume of air/volume of medium)), the production of itaconic acid was maximized resulting in a yield of 0.62 g/g glucose consumed, and productivity of 0.52 g/L·h.
PDF
