Changes in aortic blood flow induced by passive leg raising predict fluid responsiveness in critically ill patients

INTRODUCTION: Esophageal Doppler provides a continuous and non-invasive estimate of descending aortic blood flow (ABF) and corrected left ventricular ejection time (LVETc). Considering passive leg raising (PLR) as a reversible volume expansion (VE), we compared the relative abilities of PLR-induced ABF variations, LVETc and respiratory pulsed pressure variations (ΔPP) to predict fluid responsiveness. METHODS: We studied 22 critically ill patients in acute circulatory failure in the supine position, during PLR, back to the supine position and after two consecutive VEs of 250 ml of saline. Responders were defined by an increase in ABF induced by 500 ml VE of more than 15%. RESULTS: Ten patients were responders and 12 were non-responders. In responders, the increase in ABF induced by PLR was similar to that induced by a 250 ml VE (16% versus 20%; p = 0.15). A PLR-induced increase in ABF of more than 8% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 83%. Corresponding positive and negative predictive values (PPV and NPV, respectively) were 82% and 91%, respectively. A ΔPP threshold value of 12% predicted fluid responsiveness with a sensitivity of 70% and a specificity of 92%. Corresponding PPV and NPV were 87% and 78%, respectively. A LVETc of 245 ms or less predicted fluid responsiveness with a sensitivity of 70%, and a specificity of 67%. Corresponding PPV and NPV were 60% and 66%, respectively. CONCLUSION: The PLR-induced increase in ABF and a ΔPP of more than 12% offer similar predictive values in predicting fluid responsiveness. An isolated basal LVETc value is not a reliable criterion for predicting response to fluid loading

Is there a rationale for the continuous infusion of cefepime? A multidisciplinary approach

This review is the fruit of multidisciplinary discussions concerning the continuous administration of β-lactams, with a special focus on cefepime. Pooling of the analyses and viewpoints of all members of the group, based on a review of the literature on this subject, has made it possible to test the hypothesis concerning the applicability of this method of administering cefepime. Cefepime is a cephalosporin for injection which exhibits a broader spectrum of activity than that of older, third-generation cephalosporins for injection (cefotaxime, ceftriaxone, ceftazidime). The specific activity of cefepime is based on its more rapid penetration (probably due to its zwitterionic structure, this molecule being both positively and negatively charged) through the outer membrane of Gram-negative bacteria, its greater affinity for penicillin-binding proteins, its weak affinity for β-lactamases, and its stability versus certain β-lactamases, particularly derepressed cephalosporinases. The stability of cefepime in various solutions intended for parenteral administration has been studied, and the results obtained demonstrated the good compatibility of cefepime with these different solutions. These results thus permit the administration of cefepime in a continuous infusion over a 24-h period, using two consecutive syringes

No sex scandals please, we're French: French attitudes towards politicians' public and private conduct

The notion of distinct ‘public’ and ‘private’ spheres underpins much normative and practical engagement with political misconduct. What is less clear is whether citizens draw distinctions between misdemeanours in the ‘public’ and ‘private’ spheres, and whether they judge these in systematically different ways. This paper explores attitudes to political misconduct in France. French citizens are often said to be particularly relaxed about politicians’ private affairs, but there has been little empirical evidence for this proposition. Drawing on original survey data, this paper demonstrates clearly that French citizens draw a sharp distinction between politicians’ public and private transgressions, and are more tolerant of the latter

CyBase: a database of cyclic protein sequences and structures, with applications in protein discovery and engineering

CyBase was originally developed as a database for backbone-cyclized proteins, providing search and display capabilities for sequence, structure and function data. Cyclic proteins are interesting because, compared to conventional proteins, they have increased stability and enhanced binding affinity and therefore can potentially be developed as protein drugs. The new CyBase release features a redesigned interface and internal architecture to improve user-interactivity, collates double the amount of data compared to the initial release, and hosts a novel suite of tools that are useful for the visualization, characterization and engineering of cyclic proteins. These tools comprise sequence/structure 2D representations, a summary of grafting and mutation studies of synthetic analogues, a study of N- to C-terminal distances in known protein structures and a structural modelling tool to predict the best linker length to cyclize a protein. These updates are useful because they have the potential to help accelerate the discovery of naturally occurring cyclic proteins and the engineering of cyclic protein drugs. The new release of CyBase is available at http://research1t.imb.uq.edu.au/cybas

COVID-19 rapidly increases MDSCs and prolongs innate immune dysfunctions.

We used unsupervised immunophenotyping of blood leukocytes and measured cytokine production by innate immune cell exposed to LPS and R848. We show that COVID-19 induces a rapid, transient upregulation of myeloid-derived suppressor cells (MDSCs) accompanied by a rapid, sustained (up to 3 months) hyporesponsiveness of dendritic cells and monocytes. Blood MDSCs may represent biomarkers and targets for intervention strategies in COVID-19 patients

Optimizing structural modeling for a specific protein scaffold: knottins or inhibitor cystine knots

<p>Abstract</p> <p>Background</p> <p>Knottins are small, diverse and stable proteins with important drug design potential. They can be classified in 30 families which cover a wide range of sequences (1621 sequenced), three-dimensional structures (155 solved) and functions (> 10). Inter knottin similarity lies mainly between 15% and 40% sequence identity and 1.5 to 4.5 Å backbone deviations although they all share a tightly knotted disulfide core. This important variability is likely to arise from the highly diverse loops which connect the successive knotted cysteines. The prediction of structural models for all knottin sequences would open new directions for the analysis of interaction sites and to provide a better understanding of the structural and functional organization of proteins sharing this scaffold.</p> <p>Results</p> <p>We have designed an automated modeling procedure for predicting the three-dimensionnal structure of knottins. The different steps of the homology modeling pipeline were carefully optimized relatively to a test set of knottins with known structures: template selection and alignment, extraction of structural constraints and model building, model evaluation and refinement. After optimization, the accuracy of predicted models was shown to lie between 1.50 and 1.96 Å from native structures at 50% and 10% maximum sequence identity levels, respectively. These average model deviations represent an improvement varying between 0.74 and 1.17 Å over a basic homology modeling derived from a unique template. A database of 1621 structural models for all known knottin sequences was generated and is freely accessible from our web server at <url>http://knottin.cbs.cnrs.fr</url>. Models can also be interactively constructed from any knottin sequence using the structure prediction module Knoter1D3D available from our protein analysis toolkit PAT at <url>http://pat.cbs.cnrs.fr</url>.</p> <p>Conclusions</p> <p>This work explores different directions for a systematic homology modeling of a diverse family of protein sequences. In particular, we have shown that the accuracy of the models constructed at a low level of sequence identity can be improved by 1) a careful optimization of the modeling procedure, 2) the combination of multiple structural templates and 3) the use of conserved structural features as modeling restraints.</p

Endoscopic internal drainage for the management of leak, fistula, and collection after sleeve gastrectomy: our experience in 617 consecutive patients

Background: Endoscopy plays a pivotal role in the management of adverse events (AE) following bariatric surgery. Leaks, fistulae, and post-operative collection after sleeve gastrectomy (SG) may occur in up to 10% of cases. Objectives: To evaluate the efficacy and safety of endoscopic internal drainage (EID) for the management of leak, fistula, and collection following SG. Setting: Retrospective, observational, single center study on patients referred from several bariatric surgery departments to an endoscopic referral center. Methods: EID was used as first-line treatment for the management of leaks, fistulae, and collections. Leaks and fistulae were treated with double pigtail stent (DPS) deployment in order to guarantee internal drainage and second intention cavity obliteration. Collections were treated with endoscropic ultrasound (EUS)–guided deployment of DPS or lumen apposing metal stents. Results: A total of 617 patients (83.3% female; mean age, 43.1 yr) were enrolled in the study for leak (n = 300, 48.6%), fistula (n = 285, 46.2%), and collection (n = 32, 5.2%). Median follow-up was 19.5 months. Overall clinical success was 84.7% whereas 15.3% of cases required revisional surgery after EID failure. Clinical success according to type of AE was 89.5%, 78.5%, and 90% for leak, fistula, and collection, respectively. A total of 10 of 547 (1.8%) presented a recurrence during follow-up. A total of 28 (4.5%) AE related to the endoscopic treatment occurred. At univariate logistic regression predictors of failure were: fistula (OR 2.012), combined endoscopic approach (OR 2.319), need for emergency surgery (OR 1.755), and previous endoscopic treatment (OR 4.818). Conclusion: Early EID for the management of leak, fistula, and post-operative collection after SG seems a safe and effective first-line approach with good long-term results

A Novel Repertoire of Blood Transcriptome Modules Based on Co-expression Patterns across sixteen Disease and Physiological States

Blood transcriptomics measures the abundance of circulating leukocyte RNA on a genome-wide scale. Dimension reduction is an important analytic step which condenses the number of variables and permits to enhance the robustness of data analyses and functional interpretation. An approach consisting in the construction of modular repertoires based on differential co-expression observed across multiple biological states of a given system has been described before. In this report, a new blood transcriptome modular repertoire is presented based on an expended range of disease and physiological states (16 in total, encompassing 985 unique transcriptome profiles). The input datasets have been deposited in NCBI public repository, GEO. The composition of the set of 382 modules constituting the repertoire is shared, along with extensive functional annotations and a custom fingerprint visualization scheme. Finally, the similarities and differences between the blood transcriptome profiles of this wide range of biological states are presented and discussed

Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust