Low Percentage of Perforin-Expressing NK Cells during Severe SARS-CoV-2 Infection: Consumption Rather than Primary Deficiency.

Genetic defects in the ability to deliver effective perforin have been reported in patients with hemophagocytic lymphohistiocytosis. We tested the hypothesis that a primary perforin deficiency might also be causal in severe SARS-CoV-2 infection. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to intensive care units or non-intensive care units and age- and sex-matched healthy controls. Compared with healthy controls, the percentage of perforin-expressing CD3-CD56+ NK cells quantified by flow cytometry was low in COVID-19 patients (69.9 ± 17.7 versus 78.6 ± 14.6%, p = 0.026). There was no correlation between the proportions of perforin-positive NK cells and T8 lymphocytes. Moreover, the frequency of NK cells producing perforin was neither linked to disease severity nor predictive of death. Although IL-6 is known to downregulate perforin production in NK cells, we did not find any link between perforin expression and IL-6 plasma level. However, we unveiled a negative correlation between the degranulation marker CD107a and perforin expression in NK cells (r = -0.488, p = 10-4). PRF1 gene expression and the frequency of NK cells harboring perforin were normal in patients 1 y after acute SARS-CoV-2 infection. A primary perforin defect does not seem to be a driver of COVID-19 because NK perforin expression is 1) linked neither to T8 perforin expression nor to disease severity, 2) inversely correlated with NK degranulation, and 3) normalized at distance from acute infection. Thus, the cause of low frequency of perforin-positive NK cells appears, rather, to be consumption.

Towards a qualitative theory of the interruption of eating behavior change.

The poor maintenance of eating behavior change is one of the main obstacles to minimizing weight regain after weight loss during diets for non-surgical care of obese or overweight patients. We start with a known informal explanation of interruption in eating behavior change during severe restriction and formalize it as a causal network involving psychological variables, which we extend with energetic variables governed by principles of thermodynamics. The three core phenomena of dietary behavior change, i.e., non-initiation, initiation followed by discontinuation and initiation followed by non-discontinuation, are expressed in terms of the value of the key variable representing mood or psychological energy, the fluctuation of which is the result of three causal relationships. Based on our experimental knowledge of the time evolution profile of the three causal input variables, we then proceed to a qualitative analysis of the resulting theory, i.e., we consider an over-approximation of it which, after discretization, can be expressed in the form of a finite integer-based model. Using Answer Set Programming, we show that our formal model faithfully reproduces the three phenomena and, under a certain assumption, is minimal. We generalize this result by providing all the minimal models reproducing these phenomena when the possible causal relationships exerted on mood are extended to all the other variables (not just those assumed in the informal explanation), with arbitrary causality signs. Finally, by a direct analytical resolution of an under-approximation of our theory, obtained by assuming linear causalities, as a system of linear ODEs, we find exactly the same minimal models, proving that they are also equal to the actual minimal models of our theory since these are framed below and above by the models of the under-approximation and the over-approximation. We determine which parameters need to be person-specific and which can be considered invariant, i.e., we explain inter-individual variability. Our approach could pave the way for universally accepted theories in the field of behavior change and, more broadly, in other areas of psychology.

Tensions between end-of-life care and organ donation in controlled donation after circulatory death: ICU healthcare professionals experiences.

BACKGROUND: The development of controlled donation after circulatory death (cDCD) is both important and challenging. The tension between end-of-life care and organ donation raises significant ethical issues for healthcare professionals in the intensive care unit (ICU). The aim of this prospective, multicenter, observational study is to better understand ICU physicians' and nurses' experiences with cDCD. METHODS: In 32 ICUs in France, ICU physicians and nurses were invited to complete a questionnaire after the death of end-of-life ICU patients identified as potential cDCD donors who had either experienced the withdrawal of life-sustaining therapies alone or with planned organ donation (OD(-) and OD( +) groups). The primary objective was to assess their anxiety (State Anxiety Inventory STAI Y-A) following the death of a potential cDCD donor. Secondary objectives were to explore potential tensions experienced between end-of-life care and organ donation. RESULTS: Two hundred six ICU healthcare professionals (79 physicians and 127 nurses) were included in the course of 79 potential cDCD donor situations. STAI Y-A did not differ between the OD(-) and OD( +) groups for either physicians or nurses (STAI Y-A were 34 (27-38) in OD(-) vs. 32 (27-40) in OD( +), p = 0.911, for physicians and 32 (25-37) in OD(-) vs. 39 (26-37) in OD( +), p = 0.875, for nurses). The possibility of organ donation was a factor influencing the WLST decision for nurses only, and a factor influencing the WLST implementation for both nurses and physicians. cDCD experience is perceived positively by ICU healthcare professionals overall. CONCLUSIONS: cDCD does not increase anxiety in ICU healthcare professionals compared to other situations of WLST. WLST and cDCD procedures could further be improved by supporting professionals in making their intentions clear between end-of-life support and the success of organ donation, and when needed, by enhancing communication between ICU physician and nurses. TRIAL REGISTRATION: This research was registered in ClinicalTrials.gov (Identifier: NCT05041023, September 10, 2021).

Agreement between manual and automatic ultrasound measurement of the velocity-time integral in the left ventricular outflow tract in intensive care patients: evaluation of the AUTO-VTI® tool.

Transthoracic echocardiography is widely used in intensive care unit (ICU) to manage patients with acute circulatory failure. Recently, automated ultrasound (US) measurement applications have been developed but their clinical performance has not been evaluated yet. The aim of this study was to assess the agreement between automated and manual measurements of the velocity-time integral in the left ventricular outflow tract (VTI-LVOT) using the auto-VTI® tool. This prospective, single-center, interventional study included ICU patients with acute circulatory failure. The examination involved two successive manual measurements of VTI-LVOT (mean of 3 consecutive heartbeats in regular sinus rhythm, and 5 heartbeats in irregular rhythm), followed by a measurement using auto-VTI® software. In patients receiving a fluid challenge, trending ability in detecting fluid responsiveness was also evaluated. Seventy patients were included between January 19, 2020, and September 24, 2020, at the Nîmes University Hospital. The feasibility of the auto-VTI® was 94%. The mean difference between the two methods was 11% with limits of agreement from - 19% to 42%. The proportion of agreement at the 15% difference threshold was 68% [58%; 80%]. The precision and least significant change measured for the manual measurement of VTI were 7.4 and 10.5%, respectively, and by inference for the automated method 28% and 40%. The new auto-VTI® tool, despite interesting feasibility, demonstrated an insufficient agreement with a systematic bias and an insufficient precision limiting its implementation in critically ill patients.Clinical trial registration: ClinicalTrials.gov identifier: NCT04360304.

Principles and Validations of an Artificial Intelligence-Based Recommender System Suggesting Acceptable Food Changes.

BACKGROUND: Along with the popularity of smartphones, artificial intelligence-based personalized suggestions can be seen as promising ways to change eating habits toward more desirable diets. OBJECTIVES: Two issues raised by such technologies were addressed in this study. The first hypothesis tested is a recommender system based on automatically learning simple association rules between dishes of the same meal that would make it possible to identify plausible substitutions for the consumer. The second hypothesis tested is that for an identical set of dietary-swaps suggestions, the more the user is-or thinks to be-involved in the process of identifying the suggestion, the higher is their probability of accepting the suggestion. METHODS: Three studies are presented in this article, first, we present the principles of an algorithm to mine plausible substitutions from a large food consumption database. Second, we evaluate the plausibility of these automatically mined suggestions through the results of online tests conducted for a group of 255 adult participants. Afterward, we investigated the persuasiveness of 3 suggestion methods of such recommendations in a population of 27 healthy adult volunteers through a custom designed smartphone application. RESULTS: The results firstly indicated that a method based on automatic learning of substitution rules between foods performed relatively well identifying plausible swaps suggestions. Regarding the form that should be used to suggest, we found that when users are involved in selecting the most appropriate recommendation for them, the resulting suggestions were more accepted (OR = 3.168; P < 0.0004). CONCLUSIONS: This work indicates that food recommendation algorithms can gain efficiency by taking into account the consumption context and user engagement in the recommendation process. Further research is warranted to identify nutritionally relevant suggestions.

Early non-invasive ventilation and high-flow nasal oxygen therapy for preventing endotracheal intubation in hypoxemic blunt chest trauma patients: the OptiTHO randomized trial.

BACKGROUND: The benefit-risk ratio of prophylactic non-invasive ventilation (NIV) and high-flow nasal oxygen therapy (HFNC-O2) during the early stage of blunt chest trauma remains controversial because of limited data. The main objective of this study was to compare the rate of endotracheal intubation between two NIV strategies in high-risk blunt chest trauma patients. METHODS: The OptiTHO trial was a randomized, open-label, multicenter trial over a two-year period. Every adult patients admitted in intensive care unit within 48 h after a high-risk blunt chest trauma (Thoracic Trauma Severity Score ≥ 8), an estimated PaO2/FiO2 ratio < 300 and no evidence of acute respiratory failure were eligible for study enrollment (Clinical Trial Registration: NCT03943914). The primary objective was to compare the rate of endotracheal intubation for delayed respiratory failure between two NIV strategies: i) a prompt association of HFNC-O2 and "early" NIV in every patient for at least 48 h with vs. ii) the standard of care associating COT and "late" NIV, indicated in patients with respiratory deterioration and/or PaO2/FiO2 ratio ≤ 200 mmHg. Secondary outcomes were the occurrence of chest trauma-related complications (pulmonary infection, delayed hemothorax or moderate-to-severe ARDS). RESULTS: Study enrollment was stopped for futility after a 2-year study period and randomization of 141 patients. Overall, 11 patients (7.8%) required endotracheal intubation for delayed respiratory failure. The rate of endotracheal intubation was not significantly lower in patients treated with the experimental strategy (7% [5/71]) when compared to the control group (8.6% [6/70]), with an adjusted OR = 0.72 (95%IC: 0.20-2.43), p = 0.60. The occurrence of pulmonary infection, delayed hemothorax or delayed ARDS was not significantly lower in patients treated by the experimental strategy (adjusted OR = 1.99 [95%IC: 0.73-5.89], p = 0.18, 0.85 [95%IC: 0.33-2.20], p = 0.74 and 2.14 [95%IC: 0.36-20.77], p = 0.41, respectively). CONCLUSION: A prompt association of HFNC-O2 with preventive NIV did not reduce the rate of endotracheal intubation or secondary respiratory complications when compared to COT and late NIV in high-risk blunt chest trauma patients with non-severe hypoxemia and no sign of acute respiratory failure. CLINICAL TRIAL REGISTRATION: NCT03943914, Registered 7 May 2019.

High success rates of ultrasound-guided distal internal jugular vein and axillary vein approaches for central venous catheterization: A randomized controlled open-label pilot trial.

BACKGROUND: Ultrasound (US)-guided axillary vein (AV) catheterization has been considered as the preferred site of insertion to minimize catheter-related infections. Given its difficulty of realization, internal jugular vein (IJV) access remains, thus, the first choice of catheter insertion site. This descriptive study was aimed to assess the success and complication rates of in-plane short axis approach of IJV in the lower neck and the AV approach under US-guidance. METHODS: In a prospective randomized controlled open-label pilot trial, all patients requiring central venous catheterization (CVC) in intensive care unit or operating room were randomly assigned to low IJV or AV groups. The primary objective was to estimate the overall success rate of both approaches. The secondary objectives were immediate complication rates, procedure durations, success rate after the first puncture, late complication rates (i.e., thrombosis, catheter colonization, and catheter-related infections), and nurse satisfaction regarding insertion site dressings. RESULTS: One hundred and seventy-three out of two hundred and ten included patients were fully analyzed (90 and 83 in the IJV and AV approach groups, respectively). Overall success rates for IJV and AV sites were 96% (95% confidence interval (CI) [90-99]) and 89% (95% CI [81-94]) respectively. First puncture success rates were 90% and 80% respectively. The median overall procedure duration from US pre-procedural screening to guidewire insertion was 8 and 10 min in IJV and AV groups. Overall immediate complications rates for IJV and AV sites were 11.6% and 14.6%, respectively. Incidence of catheter colonization were 7.9% and 6.8% and catheter-related infection rate were 2.6% and 0%, respectively. CONCLUSION: In this pilot study, US-guided low IJV and AV approaches are safe and efficient techniques for CVC insertion associated with high success and low complications rates. Duration for guidewire insertion seemed to be shorter in the short axis in-plane IJV approach. It provides the basis for a future randomized trial comparing these two approaches.

Angiotensin II induces reactive oxygen species, DNA damage, and T-cell apoptosis in severe COVID-19.

BACKGROUND: Lymphopenia is predictive of survival in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: The aim of this study was to understand the cause of the lymphocyte count drop in severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Monocytic production of reactive oxygen species (ROSs) and T-cell apoptosis were measured by flow cytometry, DNA damage in PBMCs was measured by immunofluorescence, and angiotensin II (AngII) was measured by ELISA in patients infected with SARS-CoV-2 at admission to an intensive care unit (ICU) (n = 29) or not admitted to an ICU (n = 29) and in age- and sex-matched healthy controls. RESULTS: We showed that the monocytes of certain patients with COVID-19 spontaneously released ROSs able to induce DNA damage and apoptosis in neighboring cells. Of note, high ROS production was predictive of death in ICU patients. Accordingly, in most patients, we observed the presence of DNA damage in up to 50% of their PBMCs and T-cell apoptosis. Moreover, the intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, angiotensin-converting enzyme 2, which is a protease capable of catabolizing AngII. Accordingly, in certain patients with COVID-19 we observed high plasma levels of AngII. When looking for the stimulus responsible for their monocytic ROS production, we revealed that AngII triggers ROS production by monocytes via angiotensin receptor I. ROSs released by AngII-activated monocytes induced DNA damage and apoptosis in neighboring lymphocytes. CONCLUSION: We conclude that T-cell apoptosis provoked via DNA damage due to the release of monocytic ROSs could play a major role in COVID-19 pathogenesis.

Echocardiographic hemodynamic assessment in decompensated cirrhosis: comparison between Intensivists and Gastroenterologists.

BACKGROUND & AIMS: Ascites is a frequent complication of cirrhosis. In intensive care units, initial hemodynamic assessment is frequently performed by echocardiography. This study evaluated the feasibility and usefulness of early hemodynamic assessment in the gastroenterology ward. METHODS: This observational cohort study prospectively included all patients admitted to a teaching hospital's gastroenterology unit for decompensated cirrhosis. A gastroenterologist with minimal training and an intensivist both performed an echocardiography exam. The primary outcome was inter-rater agreement and reliability for three echocardiography parameters: visual LVEF (Left Ventricular Ejection Fraction), subaortic VTI (velocity time integral) and E wave velocity. Secondary outcomes were agreement for presence of pleural effusion, description of 3 hemodynamics profiles (hypovolemic, hyperkinetic and intermediate), and 28-day mortality. RESULTS: From March 2018 to March 2020, 53 patients were included. The median age was 62 years and 81% were men. Patients presented mostly advanced liver disease, with 43% Child-Pugh C and median MELD score of 15.2. The limits of agreement between intensivists and gastroenterologists for subaortic VTI were - 6.6 to 7.2 cm, and ranged from - 0.6 to 0.37 m.s-1 for E wave velocity. Clinically significant differences between intensivists and gastroenterologists were found in 22% for subaortic VTI and 24.5% for E wave velocity. Reliability was good for subaortic VTI (ICC: 0.79, 95% CI [0.58; 0.9;]) and moderate for E wave velocity (0.53, 95% CI [0.19; 0.74]). The three hemodynamics profiles had different prognosis, with a 28-day mortality for Hypovolemic, Intermediate and Hyperkinetic group of 31, 18, and 4%, respectively. CONCLUSION: Reliability of hemodynamic assessment by gastroenterologists was good, while agreement was unsatisfactory, advocating for further training. Transthoracic echocardiography can differentiate hypovolemia from hyperkinetic states. The role of transthoracic echocardiography in managing decompensated cirrhosis requires further study. CLINICAL TRIAL NUMBER: NCT03650660.

Effects of Fluid Therapy on Mesenteric Microcirculation Using New Probe-Based Confocal Laser Endomicroscopy (Cellvizio®) in a Porcine Model of Endotoxic Shock.

BACKGROUND: Microcirculatory alterations have been observed at the early phase of sepsis, although macrocirculation seems preserved. The aim of this study was to analyze the effect of crystalloid fluid therapy on mesenteric microcirculation, assessed by using the confocal laser endomicroscope Cellvizio®, in an endotoxic porcine model. METHODS: It is a prospective endotoxic shock (lipopolysaccharide infusion) experimental trial. Piglets were divided into 3 groups: 6 in the sham group (no LPS injection, no fluid), 9 in the control group (LPS infusion, no fluid), and 6 in the crystalloids group (LPS infusion and fluid resuscitation with crystalloids). Fluid resuscitation consisted in a fluid bolus of 20 mL/kg 0.9% saline over 30 min followed by a 10 mL/kg/h fluid rate over 4 h. Mesenteric microcirculation was assessed using a confocal laser endomicroscope (Cellvizio®). Blood flow within capillaries was visually assessed according to the point of care microcirculation (POEM) score. RESULTS: At baseline, the 3 groups were similar regarding hemodynamic, biological, and microcirculatory parameters. At T360, the POEM score significantly decreased in the control and crystalloids groups, whereas it remained unchanged in the sham group (respectively, 1.62 ± 1.06, 1.2 ± 0.45, and 5.0 ± 0, p = 0.011). There was no significant difference in cardiac output at T360 between the sham and crystalloids groups (3.1 ± 0.8 vs. 2.3 ± 0.6, p = 0.132) or between the control and crystalloids groups (2.0 ± 0.6 vs. 2.3 ± 0.6, p = 0.90). CONCLUSION: There was no significant improvement of microcirculatory alterations after crystalloids resuscitation despite improvement in macrocirculatory parameters in early experimental sepsis.

Differential Immunomodulatory Effects of Head and Neck Cancer-Derived Exosomes on B Cells in the Presence of ATP.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy. Tumor-derived exosomes (TEX) have immunoregulatory properties. Adenosine triphosphate (ATP) and its immunosuppressive precursor adenosine (ADO) have been found in cancerous tissue. We investigated the effect of TEX on B cells in the presence of ATP. TEX were isolated from human HNSCC cell line (PCI-13) cultures and co-cultured with peripheral blood B cells of healthy donors, with or without TEX in different concentrations and with or without a low (20 µM) or high (2000 µM) ATP dose. We were able to demonstrate that TEX inhibit B-cell proliferation. The addition of TEX to either ATP concentration showed a decreasing trend in CD39 expression on B cells in a dose-dependent manner. High ATP levels (2000 µM) increased apoptosis and necrosis, and analysis of apoptosis-associated proteins revealed dose-dependent effects of ATP, which were modified by TEX. Altogether, TEX exhibited dual immunomodulatory effects on B cells. TEX were immunosuppressive by inhibiting B-cell proliferation; they were immunostimulatory by downregulating CD39 expression. Furthermore, TEX were able to modulate the expression of pro- and anti-apoptotic proteins. In conclusion, our data indicate that TEX play an important, but complex, role in the tumor microenvironment.

Dynamics of Endothelial Engagement and Filopodia Formation in Complex 3D Microscaffolds.

The understanding of endothelium-extracellular matrix interactions during the initiation of new blood vessels is of great medical importance; however, the mechanobiological principles governing endothelial protrusive behaviours in 3D microtopographies remain imperfectly understood. In blood capillaries submitted to angiogenic factors (such as vascular endothelial growth factor, VEGF), endothelial cells can transiently transdifferentiate in filopodia-rich cells, named tip cells, from which angiogenesis processes are locally initiated. This protrusive state based on filopodia dynamics contrasts with the lamellipodia-based endothelial cell migration on 2D substrates. Using two-photon polymerization, we generated 3D microstructures triggering endothelial phenotypes evocative of tip cell behaviour. Hexagonal lattices on pillars ("open"), but not "closed" hexagonal lattices, induced engagement from the endothelial monolayer with the generation of numerous filopodia. The development of image analysis tools for filopodia tracking allowed to probe the influence of the microtopography (pore size, regular vs. elongated structures, role of the pillars) on orientations, engagement and filopodia dynamics, and to identify MLCK (myosin light-chain kinase) as a key player for filopodia-based protrusive mode. Importantly, these events occurred independently of VEGF treatment, suggesting that the observed phenotype was induced through microtopography. These microstructures are proposed as a model research tool for understanding endothelial cell behaviour in 3D fibrillary networks.

Extracellular matrix scaffolding in angiogenesis and capillary homeostasis.

The extracellular matrix (ECM) of blood vessels, which is composed of both the vascular basement membrane (BM) and the interstitial ECM is identified as a crucial component of the vasculature. We here focus on the unique molecular composition and scaffolding of the capillary ECM, which provides structural support to blood vessels and regulates properties of endothelial cells and pericytes. The major components of the BM are collagen IV, laminins, heparan sulfate proteoglycans and nidogen and also associated proteins such as collagen XVIII and fibronectin. Their organization and scaffolding in the BM is required for proper capillary morphogenesis and maintenance of vascular homeostasis. The BM also regulates vascular mechanosensing. A better understanding of the mechanical and structural properties of the vascular BM and interstitial ECM therefore opens new perspectives to control physiological and pathological angiogenesis and vascular homeostasis. The overall aim of this review is to explain how ECM scaffolding influences angiogenesis and capillary integrity.

Prospective Cohort Study of Micafungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-abdominal Infections.

The objective of this study was to describe the pharmacokinetics (PK) of micafungin in plasma and peritoneal fluid in septic patients with intra-abdominal infections. Twelve patients with secondary peritonitis in septic shock receiving 100 mg micafungin once daily were included. Total micafungin plasma and peritoneal fluid were subjected to a population pharmacokinetic analysis using Pmetrics. Monte Carlo simulations were performed considering the total area under the curve from 0 to 24 h (AUC0-24)/MIC ratios in plasma. Micafungin concentrations in both plasma and the peritoneal exudate were best described by a three-compartmental PK model with the fat-free mass (FFM) as a covariate of clearance (CL) and the volume of the central compartment (Vc). The mean parameter estimates (standard deviations [SD]) were 1.18 (0.40) liters/h for CL and 12.85 (4.78) liters for Vc. The mean peritoneal exudate/plasma ratios (SD) of micafungin were 25% (5%) on day 1 and 40% (8%) between days 3 and 5. Dosing simulations supported the use of standard 100-mg daily dosing for Candida albicans (FFM, <60 kg), C. glabrata (FFM, <50 kg), and C. tropicalis (FFM, <30 kg) on the second day of therapy. There is a moderate penetration of micafungin into the peritoneal cavity (25 to 40%). For empirical treatment, a dose escalation of at least a loading dose of 150 mg depending on the FFM of patients and the Candida species is suggested to be effective from the first day of therapy.

Micafungin Population PK Analysis in Healthy and Septic Pigs: Can the Septic Porcine Model Predict the Micafungin PK in Septic Patients?

OBJECTIVES: To describe micafungin pharmacokinetic (PK) alterations of sepsis induced in piglets and to determine whether the porcine septic model is able to predict the PK of micafungin in septic patients at the plasma and peritoneal sites. METHODS: From healthy (n = 8) and septic piglet group (n = 16), total micafungin concentrations were subject to a population PK analysis using Monolix®. Data from 16 septic humans patients from others studies was used to compare micafungin PK between septic piglets and septic patients. RESULTS: Sepsis induced in piglets slightly alters the total clearance and the volume of distribution, while inter-compartment clearance is increased (from 3.88 to 5.74 L/h) as well as the penetration into peritoneal cavity (from 61 to 90%). In septic human patients, PK parameters are similar except for the Vd, which is corrected by an allometric factor based on the body weight of each species. Micafungin penetration into peritoneal cavity of humans is lower than in septic piglets (40 versus 90%). CONCLUSIONS: The sepsis induced in the porcine model alters the PK of micafungin comparable to that in humans. In addition, micafungin PK is similar between these two species at the plasma level taking into account the allometric relationship of the body weight of these species on the central volume of distribution. The porcine septic plasma model would be able to predict the micafungin PK in the septic patients. However, further studies on peritoneal penetration are necessary to characterize this inter-species difference.

A Loading Micafungin Dose in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration or Continuous Venovenous Hemodiafiltration: A Population Pharmacokinetic Analysis.

BACKGROUND: In this study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous venovenous hemofiltration (CVVH, 30 mL·kg-1·h-1) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL·kg-1·h-1 + 15 mL·kg-1·h-1) and determine the optimal dosing regimen using the developed model. METHODS: Patients with septic shock undergoing continuous renal replacement therapy and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from 8 CVVH sessions and 8 CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 hours to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma. RESULTS: The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a 2-compartmental PK model. No covariates, including continuous renal replacement therapy modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (SD) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis. CONCLUSIONS: No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.

Pneumothorax diagnosis with lung sliding quantification by speckle tracking: A prospective multicentric observational study.

INTRODUCTION: Lung ultrasound is commonly used for the diagnosis of pneumothorax. However, recognition of pleural sliding is subjective and can be difficult for novice. The primary objective was to compare a novices physician's performance in diagnosing pneumothorax from ultrasound (US) scans either with visual evaluation or with maximum longitudinal pleural strain (MLPS). The secondary objective was to compare the diagnostic relevance of US with visual evaluation or MLPS to diagnose pneumothorax with an intermediately experienced and an expert physician. METHODS: We conducted a prospective, observational study in two emergency department and two intensive care unit, between February 2019 and June 2020. We included 99 adult patients with suspected pneumothorax, who received a chest computed tomography (CT). Three physicians with different experience of interpreting US scans (a novice physician, an intermediately experienced physician, and an expert) analyzed the US scans of 99 patients with suspected pneumothorax (50 (51%) with confirmed pneumothorax), which were confirmed by CT scan. RESULTS: With a threshold of 5%, the MLPS sensitivity was 94% (95% CI [83%; 98%]), and the specificity was 100% (95% CI [93%; 100%]). The novice physician had an area under the curve (AUC) with visual analysis of 0.75 (95% CI [0.67; 0.83]) vs 0.86 (95% CI [0.79; 0.94]) with MLPS (p = 0.04). The intermediate physician's AUC for diagnosing pneumothorax with visual analysis was 0.93 (95% CI [0.88; 0.99]) vs 1.00 (95% CI [1.00; 1.00]) with MLPS (p < 0.01) and for the expert physician it was 0.98 (95% CI [0.95;1.00]) vs 0.97 (95% CI [0.93; 1.00]), respectively (p = 0.69). CONCLUSION: In our study, speckle tracking analysis improved the accuracy of US for the novice and the intermediate but not the expert sonographer in the diagnosis of pneumothorax.

Magnetic needle-tracking device for ultrasound guidance of radial artery puncture: A randomized study on a simulation model.

INTRODUCTION: Ultrasound-guidance of radial artery catheter insertion improves the first attempt success and reduces the occurrence of hematomas. Needle-tracking devices optimize needle-ultrasound beam alignment by displaying in real-time the needle tip position. We compared the median time need by experienced physicians to achieve radial artery puncture using either a conventional ultrasonography device (CUD) or a magnetic needle-tracking ultrasound device (MUD) in a simulation training arm model. METHODS: Fifty experienced residents and physicians performed two punctures in randomized order with the CUD and the MUD. The primary outcome was puncture duration; the secondary outcomes were puncture success, rate of accidental vein puncture, and practitioner's comfort (subjective scale 0-10). RESULTS: The median [lower-upper quartile] puncture time was 10 [6-14] seconds when using CUD and 4 [3-7] seconds when using MUD (P < .01). In the multivariate analysis, MUD use was associated with decreased puncture duration whatever the puncture order (OR 1.13 [1.07-1.20], P < .01). The participants performed 99 (99%) successful punctures: 50 with the MUD (100%) and 49 with the CUD (98%). There was no accidental venous puncture. The practitioner's comfort level was 6.5 [6, 7] with the CUD and 8 [7-9] with the MUD (P < .01). CONCLUSION: MUD reduced radial artery puncture time and improved physician comfort in a simulation training arm model.

Prognostic value and time course evolution left ventricular global longitudinal strain in septic shock: an exploratory prospective study.

Our main objective was to describe the course of GLS during the first days of septic shock and to assess the agreement between GLS values and longitudinal strain measured in apical four chambers. A prospective observational single centre study was conducted at the Nimes University Hospital's ICU. All patients admitted for a diagnosis of septic shock without pre-existing heart disease were eligible. Echocardiography (LVEF and GLS) was performed on the first day, and repeated once between day 3 and day 5 then once between day 6 and day 8. We enrolled 40 consecutive patients. Four patients were excluded. In overall population, GLS at T1 was impaired (- 11.0%, IQR(interquartile range) [- 15; - 10]). On T2 exams, a significant improvement of the GLS (- 11% vs - 16% p = 0.02) was observed whereas LVEF remained stable over time. A good agreement between GLS and longitudinal strain measured on a four chambers view was found. Based on the Bland and Altman method, the mean of differences for T1 exams was 0.1 (95% CI [- 0.6; 0.8]) with limits of agreement ranging from - 4 to 4. Myocardial strain is depressed at the early phase of septic shock and improves over time. A single measurement of LS4C view appears sufficient at bedside.

Exosomes: Small EVs with Large Immunomodulatory Effect in Glioblastoma.

Glioblastomas are among the most aggressive tumors, and with low survival rates. They are characterized by the ability to create a highly immunosuppressive tumor microenvironment. Exosomes, small extracellular vesicles (EVs), mediate intercellular communication in the tumor microenvironment by transporting various biomolecules (RNA, DNA, proteins, and lipids), therefore playing a prominent role in tumor proliferation, differentiation, metastasis, and resistance to chemotherapy or radiation. Exosomes are found in all body fluids and can cross the blood-brain barrier due to their nanoscale size. Recent studies have highlighted the multiple influences of tumor-derived exosomes on immune cells. Owing to their structural and functional properties, exosomes can be an important instrument for gaining a better molecular understanding of tumors. Furthermore, they qualify not only as diagnostic and prognostic markers, but also as tools in therapies specifically targeting aggressive tumor cells, like glioblastomas.