Endothelial damage contributes to organ failure and mortality in sepsis, but the extent of the contribution remains poorly quantified. Here, we examine the association between biomarkers of ...superficial and profound endothelial damage (syndecan-1 and soluble thrombomodulin sTM, respectively), organ failure, and death in sepsis. The data from a clinical trial, including critically ill patients predominantly suffering sepsis (Clinicaltrials.gov: NCT00271752) were studied. Syndecan-1 and sTM levels at the time of study enrollment were determined. The predictive ability of biomarker levels on death and organ failures during follow-up were assessed in Cox models adjusted for potential confounders including key organ dysfunction measures assessed at enrollment. Of the 1,103 included patients, 418 died. sTM levels at the time of enrollment independently predicted risk of death in adjusted models (hazard ratio HR highest quartile > 14 ng/mL vs. lowest quartile < 7 ng/mL 2.2 95% confidence interval CI: 1.2-4.0, p = 0.02, respectively). Conversely, syndecan-1 levels failed to predict death (adjusted HR > 240 vs. < 70 ng/mL 1.0 95% CI: 0.6-1.5, p = 0.67). sTM but not syndecan-1 levels at enrollment predicted risk of multiple organ failure during follow-up (HR > 14 ng/mL vs. < 7 ng/mL 3.5 95% CI: 1.5-8.3, p = 0.005 and 2.0 95% CI: 0.8-5.0, p = 0.1321, respectively). Profound damage to the endothelium independently predicts risk of multiple organ failure and death in septic patients. Our findings also suggest that the detrimental effect of profound endothelial damage on risk of death operates via mechanisms other than causing organ failures per se. Therefore, damage to the endothelium appears centrally involved in the pathogenesis of death in sepsis and could be a target for intervention.
Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having
antiviral properties. This may improve outcomes in patients ...hospitalised for coronavirus disease 2019 (COVID-19).
Placebo-controlled double-blind randomised multicentre trial. Patients aged ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14).
After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median (interquartile range) 9.0 (3-11) DAOH14
9.0 (7-10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for one patient in the intervention group
two patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for nine patients in the intervention group
six patients receiving placebo (p=0.57).
The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.
For patients in intensive care units, sepsis is a common and potentially deadly complication and prompt initiation of appropriate antimicrobial therapy improves prognosis. The objective of this trial ...was to determine whether a strategy of antimicrobial spectrum escalation, guided by daily measurements of the biomarker procalcitonin, could reduce the time to appropriate therapy, thus improving survival.
Randomized controlled open-label trial.
Nine multidisciplinary intensive care units across Denmark.
A total of 1,200 critically ill patients were included after meeting the following eligibility requirements: expected intensive care unit stay of ≥ 24 hrs, nonpregnant, judged to not be harmed by blood sampling, bilirubin <40 mg/dL, and triglycerides <1000 mg/dL (not suspensive).
: Patients were randomized either to the "standard-of-care-only arm," receiving treatment according to the current international guidelines and blinded to procalcitonin levels, or to the "procalcitonin arm," in which current guidelines were supplemented with a drug-escalation algorithm and intensified diagnostics based on daily procalcitonin measurements.
The primary end point was death from any cause at day 28; this occurred for 31.5% (190 of 604) patients in the procalcitonin arm and for 32.0% (191 of 596) patients in the standard-of-care-only arm (absolute risk reduction, 0.6%; 95% confidence interval CI -4.7% to 5.9%). Length of stay in the intensive care unit was increased by one day (p = .004) in the procalcitonin arm, the rate of mechanical ventilation per day in the intensive care unit increased 4.9% (95% CI, 3.0-6.7%), and the relative risk of days with estimated glomerular filtration rate <60 mL/min/1.73 m was 1.21 (95% CI, 1.15-1.27).
Procalcitonin-guided antimicrobial escalation in the intensive care unit did not improve survival and did lead to organ-related harm and prolonged admission to the intensive care unit. The procalcitonin strategy like the one used in this trial cannot be recommended.
Genome-wide association study (GWAS) and genomic prediction (GP) are extensively employed to accelerate genetic gain and identify QTL in plant breeding. In this study, 1,317 spring barley and 1,325 ...winter wheat breeding lines from a commercial breeding program were genotyped with the Illumina 9 K barley or 15 K wheat SNP-chip, and phenotyped in multiple years and locations. For GWAS, in spring barley, a QTL on chr. 4H associated with powdery mildew and ramularia resistance were found. There were several SNPs on chr. 4H showing genome-wide significance with yield traits. In winter wheat, GWAS identified two SNPs on chr. 6A, and one SNP on chr. 1B, significantly associated with quality trait moisture, as well as one SNP located on chr. 5B associated with starch content in the seeds. The significant SNPs identified by multiple trait GWAS were generally the same as those found in single trait GWAS. GWAS including genotype-location information in the model identified significant SNPs in each tested location, which were not found previously when including all locations in the GWAS. For GP, in spring barley, GP using the Bayesian Power Lasso model had higher accuracy than ridge regression BLUP in powdery mildew and yield traits, whereas the prediction accuracies were similar using Bayesian Power Lasso model and rrBLUP for yield traits in winter wheat.
Functional renal magnetic resonance imaging (MRI) has seen a number of recent advances, and techniques are now available that can generate quantitative imaging biomarkers with the potential to ...improve the management of kidney disease. Such biomarkers are sensitive to changes in renal blood flow, tissue perfusion, oxygenation and microstructure (including inflammation and fibrosis), processes that are important in a range of renal diseases including chronic kidney disease. However, several challenges remain to move these techniques towards clinical adoption, from technical validation through biological and clinical validation, to demonstration of cost-effectiveness and regulatory qualification. To address these challenges, the European Cooperation in Science and Technology Action PARENCHIMA was initiated in early 2017. PARENCHIMA is a multidisciplinary pan-European network with an overarching aim of eliminating the main barriers to the broader evaluation, commercial exploitation and clinical use of renal MRI biomarkers. This position paper lays out PARENCHIMA's vision on key clinical questions that MRI must address to become more widely used in patients with kidney disease, first within research settings and ultimately in clinical practice. We then present a series of practical recommendations to accelerate the study and translation of these techniques.
Coagulation abnormalities and microthrombi contribute to septic shock, but the impact of body temperature regulation on coagulation in patients with sepsis is unknown. We tested the hypothesis that ...mild induced hypothermia reduces coagulation and platelet aggregation in patients with septic shock. Secondary analysis of randomized controlled trial. Adult patients with septic shock who required mechanical ventilation from eight intensive care units in Denmark were randomly assigned to mild induced hypothermia for 24 h or routine thermal management. Viscoelastography and platelet aggregation were assessed at trial inclusion, after 12 h of thermal management, and 24 h after inclusion. A total of 326 patients were randomized to mild induced hypothermia (n = 163) or routine thermal management (n = 163). Mild induced hypothermia slightly prolonged activated partial thromboplastin time and thrombus initiation time (R time 8.0 min interquartile range, IQR 6.6–11.1 vs. 7.2 min IQR 5.8–9.2; p = .004) and marginally inhibited thrombus propagation (angle 68° IQR 59–73 vs. 71° IQR 63–75; p = .014). The effect was also present after 24 h. Clot strength remained unaffected (MA 71 mm IQR 66–76 with mild induced hypothermia vs. 72 mm (65–77) with routine thermal management, p = .9). The proportion of patients with hyperfibrinolysis was not affected (0.7% vs. 3.3%; p = .19), but the proportion of patients with no fibrinolysis was high in the mild hypothermia group (8.8% vs. 40.4%; p < .001). The mild induced hypothermia group had lower platelet aggregation: ASPI 85U (IQR 50–113) versus 109U (IQR 74–148, p < .001), ADP 61U (IQR 40–83) versus 79 U (IQR 54–101, p < .001), TRAP 108 (IQR 83–154) versus 119 (IQR 94–146, p = .042) and COL 50U (IQR 34–66) versus 67U (IQR 46–92, p < .001). In patients with septic shock, mild induced hypothermia slightly impaired clot initiation, but did not change clot strength. Platelet aggregation was slightly impaired. The effect of mild induced hypothermia on viscoelastography and platelet aggregation was however not in a range that would have clinical implications. We did observe a substantial reduction in fibrinolysis.
Spatial resolution in existing chest x-ray (CXR)-based scoring systems for coronavirus disease 2019 (COVID-19) pneumonia is low, and should be increased for better representation of anatomy, and ...severity of lung involvement. An existing CXR-based system, the Brixia score, was modified to increase the spatial resolution, creating the MBrixia score. The MBrixia score is the sum, of a rule-based quantification of CXR severity on a scale of 0 to 3 in 12 anatomical zones in the lungs. The MBrixia score was applied to CXR images from COVID-19 patients at a single tertiary hospital in the period May 4th-June 5th, 2020. The relationship between MBrixia score, and level of respiratory support at the time of performed CXR imaging was investigated. 37 hospitalized COVID-19 patients with 290 CXRs were identified, 22 (59.5%) were admitted to the intensive care unit and 10 (27%) died during follow-up. In a Poisson regression using all 290 MBrixia scored CXRs, a higher MBrixia score was associated with a higher level of respiratory support at the time of performed CXR. The MBrixia score could potentially be valuable as a quantitative surrogate measurement of COVID-19 pneumonia severity, and future studies should investigate the score's validity and capabilities of predicting clinical outcomes.
ABSTRACT
Background
Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated ...the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis.
Methods
In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1–L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status.
Results
After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo −0.023 g/cm2 95% confidence interval (CI) −0.039 to −0.008}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015–0.085). No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants.
Conclusion
Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.
Graphical Abstract
Graphical Abstract
Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated ...with increased prevalence of invasive Candida infection.
Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010.
Nine multidisciplinary ICUs across Denmark.
A total of 1,200 critically ill patients.
Patients were randomly allocated to either a "high exposure" antibiotic therapy (intervention arm, n = 604) or a "standard exposure" guided by current guidelines (n = 596).
Seventy-four patients met the endpoint, "invasive Candida infection," 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7-1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 1.1-4.1); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6-8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4-8.0; p = 0.006).
High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin-containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk.
PDF
