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Oxazolidinones are a class of synthetic antimicrobial agents with potent activity against a wide range of multidrug-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Oxazolidinones exhibit their antibacterial effects by inhibiting protein synthesis acting on the ribosomal 50S subunit of the bacteria and thus preventing formation of a functional 70S initiation complex. Currently, two oxazolidinones have been approved by the US Food and Drug Administration: linezolid and more recently tedizolid. Other oxazolidinones are currently under investigation in clinical trials. These antimicrobial agents exhibit a favourable pharmacokinetic profile with an excellent bioavailability and a good tissue and organ penetration. In-vitro susceptibility studies have shown that oxazolidinones are bacteriostatic against enterococci and staphylococci, and bactericidal for the majority of strains of streptococci. In the context of emergence of resistance to glycopeptides, oxazolidinones have become an effective alternative to vancomycin treatment frequently associated with nephrotoxicity. However, oxazolidinones, and linezolid in particular, are associated with significant adverse events, myelosuppression representing the main unfavourable side effect. More recently, tedizolid has been shown to effectively treat acute bacterial skin and skin structure infections. This newer oxazolidinone offers the advantages of once-daily dosing and a better safety profile in healthy volunteer studies (fewer gastrointestinal and haematological side effects). The potential use of tedizolid for other infections that could require longer therapy warrants further studies for positioning this new oxazolidinone in the available antimicrobial armamentarium. Moreover, other oxazolidinones are currently under active investigation.

Exosomes are membrane-bound vesicles found in all biological fluids. AML patients' plasma collected at diagnosis contains elevated exosome levels relative to normal donor (ND) plasma. The molecular profile of AML exosomes changes in the course of therapy and may serve as a measure of disease progression or response to therapy. However, plasma contains a mix of exosomes derived from various cell types. To be able to utilize blast-derived exosomes as biomarkers for AML, we have developed an immunoaffinity-based capture method utilizing magnetic microbeads coated with anti-CD34 antibody (Ab). This Ab is specific for CD34, a unique marker of AML blasts. The capture procedure was developed using CD34+ exosomes derived from Kasumi-1 AML cell culture supernatants. The capture capacity of CD34microbeads was shown to linearly correlate with the input exosomes. A 10 uL aliquot of CD34 microbeads was able to capture all of CD34+ exosomes present in 100-1,000 uL of AML plasma. The levels of immunocaptured CD34+ exosomes correlated with the percentages of CD34+ blasts in the AML patients' peripheral blood. The immunocaptured exosomes had a typical cup-shaped morphology by transmission electron microscopy, and their molecular cargo was similar to that of parental blasts. These exosomes were biologically-active. Upon co-incubation with natural killer (NK) cells, captured blast-derived exosomes down-regulated surface NKG2D expression, while non-captured exosomes reduced expression levels of NKp46. Our data provide a proof-of-principle that blast-derived exosomes can be quantitatively recovered from AML patients' plasma, their molecular profile recapitulates that of autologous blasts and they retain the ability to mediate immune suppression. These data suggest that immunocaptured blast-derived exosomes might be useful in diagnosis and/or prognosis of AML in the future.

Tumour-derived exosomes (TEX) are a subset of extracellular vesicles (EVs) present in body fluids of patients with cancer. The role of this exosome subset in melanoma progression has been of interest ever since ex vivo studies of exosomes produced by melanoma cell lines were shown to suppress anti-melanoma immune responses. To study the impact of melanoma-derived exosomes (MTEX) present in patients' plasma on melanoma progression, isolation of MTEX from total plasma exosomes is necessary. We have developed an immunoaffinity-based method for MTEX capture from plasma of melanoma patients. Using mAb 763.74 specific for the CSPG4 epitope uniquely expressed on melanoma cells, we separated MTEX from non-tumour cell-derived exosomes and evaluated the protein cargo of both fractions by quantitative flow cytometry. Melanoma-associated antigens were carried by MTEX but were not detectable in exosomes produced by normal cells. Separation of plasma-derived MTEX from non-MTEX provides an opportunity for future evaluation of MTEX as potential biomarkers of melanoma progression and as surrogates of melanoma in tumour liquid biopsy studies.

Objective To describe current use and diagnostic and therapeutic impacts of point-of-care ultrasound (POCUS) in the intensive care unit (ICU). Background POCUS is of growing importance in the ICU. Several guidelines recommend its use for procedural guidance and diagnostic assessment. Nevertheless, its current use and clinical impact remain unknown. Methods Prospective multicentric study in 142 ICUs in France, Belgium, and Switzerland. All the POCUS procedures performed during a 24-h period were prospectively analyzed. Data regarding patient condition and the POCUS procedures were collected. Factors associated with diagnostic and therapeutic impacts were identified. Results Among 1954 patients hospitalized during the study period, 1073 (55 %) POCUS/day were performed in 709 (36 %) patients. POCUS served for diagnostic assessment in 932 (87 %) cases and procedural guidance in 141 (13 %) cases. Transthoracic echocardiography, lung ultrasound, and transcranial Doppler accounted for 51, 17, and 16 % of procedures, respectively. Diagnostic and therapeutic impacts of diagnostic POCUS examinations were 84 and 69 %, respectively. Ultrasound guidance was used in 54 and 15 % of cases for central venous line and arterial catheter placement, respectively. Hemodynamic instability, emergency conditions, transthoracic echocardiography, and ultrasounds performed by certified intensivists themselves were independent factors affecting diagnostic or therapeutic impacts. Conclusions With regard to guidelines, POCUS utilization for procedural guidance remains insufficient. In contrast, POCUS for diagnostic assessment is of extensive use. Its impact on both diagnosis and treatment of ICU patients seems critical. This study identified factors associated with an improved clinical value of POCUS.

Isolation from human plasma of exosomes that retain functional and morphological integrity for probing their protein, lipid and nucleic acid content is a priority for the future use of exosomes as biomarkers. A method that meets these criteria and can be scaled up for patient monitoring is thus desirable. Plasma specimens (1 mL) of patients with acute myeloid leukaemia (AML) or a head and neck squamous cell carcinoma (HNSCC) were differentially centrifuged, ultrafiltered and fractionated by size exclusion chromatography in small disposable columns (mini-SEC). Exosomes were eluted in phosphate-buffered saline and were evaluated by qNano for particle size and counts, morphology by transmission electron microscopy, protein content, molecular profiles by western blots, and for ability to modify functions of immune cells. Exosomes eluting in fractions #3-5 had a diameter ranging from 50 to 200 nm by qNano, with the fraction #4 containing the bulk of clean, unaggregated exosomes. The exosome elution profiles remained constant for repeated runs of the same plasma. Larger plasma volumes could be fractionated running multiple mini-SEC columns in parallel. Particle concentrations per millilitre of plasma in #4 fractions of AML and HNSCC were comparable and were higher (p<0.003) than those in normal controls. Isolated AML exosomes co-incubated with normal human NK cells inhibited NKG2D expression levels (p<0.004), and HNSCC exosomes suppressed activation (p<0.01) and proliferation of activated T lymphocytes (p<0.03). Mini-SEC allows for simple and reproducible isolation from human plasma of exosomes retaining structural integrity and functional activity. It enables molecular/functional analysis of the exosome content in serial specimens of human plasma for clinical applications.

Objective To determined whether the implementation of an intubation management protocol leads to the reduction of intubation-related complications in the intensive care unit (ICU). Design Two-phase, prospective, multicenter controlled study. Setting Three medical-surgical ICUs in two university hospitals. Patients Two hundred three consecutive ICU patients required 244 intubations. Interventions All intubations performed during two consecutive phases (a 6-month quality control phase followed by a 6-month intervention phase based on the implementation of an ICU intubation bundle management protocol) were evaluated. The ten bundle components were: preoxygenation with noninvasive positive pressure ventilation, presence of two operators, rapid sequence induction, cricoid pressure, capnography, protective ventilation, fluid loading, preparation and early administration of sedation and vasopressor use if needed. Measurements and main results The primary end points were the incidence of life-threatening complications occurring within 60 min after intubation (cardiac arrest or death, severe cardiovascular collapse and hypoxemia). Other complications (mild to moderate) were also evaluated. Baseline characteristics, including demographic data and reason for intubation (mainly acute respiratory failure), were similar in the two phases. The intubation procedure in the intervention phase ( n  = 121) was associated with significant decreases in both life-threatening complications (21 vs. 34%, p  = 0.03) and other complications (9 vs. 21%, p  = 0.01) compared to the control phase ( n  = 123). Conclusions The implementation of an intubation management protocol can reduce immediate severe life-threatening complications associated with intubation of ICU patients.

Background Front-of-Package nutrition labels (FoPLs) are intended to help reduce the incidence of nutrition-related non-communicable diseases through an improvement in diet quality. FoPLs have been shown to improve the nutritional quality of purchases and have been associated with improved diet quality, which is in turn associated with reduced risk of non-communicable diseases. However, the potential impact of FoPLs on reducing mortality from chronic diseases has never been estimated. Methods Data from a laboratory experimental economics test were used to investigate the effects of five different FoPLs (Nutri-Score, Health Star Rating system, Multiple Traffic lights, Reference intakes and SENS ( Système d’Etiquetage Nutritionnel Simplifié )) on the nutritional quality of household purchases. The relative differences in nutrient content and composition of food purchases were then applied to dietary intakes using data from an observational study, thus yielding estimates for ‘reference’ and ‘labelled’ diets. A macro-simulation study using the PRIME model was then conducted to estimate the impact of the modification in dietary intake as a result of FoPL use on mortality from diet-related non-communicable diseases. Results The use of FoPLs led to a substantial reduction in mortality from chronic diseases. Approximately 3.4% of all deaths from diet-related non-communicable diseases was estimated to be avoidable when the Nutri-Score FoPL was used. The remaining FoPLs likewise resulted in mortality reduction, although to a lesser extent: Health Star Rating system (2.8%), Reference Intakes (1.9%), Multiple Traffic Lights (1.6%), and SENS (1.1%). Conclusions FoPLs have the potential to help decrease mortality from diet-related non-communicable diseases, and the Nutri-Score appears to be the most efficient among the five formats tested.

In vitro 3D culture systems provide promising tools for screening novel therapies and understanding drug resistance mechanisms in cancer because they are adapted for high throughput analysis. One of the main current challenges is to reproducibly culture patient samples containing cancer and stromal cells to faithfully recapitulate tumor microenvironment and move toward efficient personalized medicine. Tumors are composed of heterogeneous cell populations and characterized by chaotic vascularization in a remodeled microenvironment. Indeed, tumor angiogenesis occurs in a complex stroma containing immune cells and cancer-associated fibroblasts that secrete important amounts of cytokines, growth factors, extracellular vesicles, and extracellular matrix (ECM). This process leads to the formation of inflated, tortuous, and permeable capillaries that display deficient basement membrane (BM) and perivascular coverage. These abnormal capillaries affect responses to anti-cancer therapies such as anti-angiogenic, radio-, and immunotherapies. Current pre-clinical models are limited for investigating interactions between tumor cells and vascularization during tumor progression as well as mechanisms that lead to drug resistance. In vitro approaches developed for vascularization are either the result of engineered cell lining or based on physiological processes including vasculogenesis and sprouting angiogenesis. They allow investigation of paracrine and direct interactions between endothelial and tumor and/or stromal cells, as well as impact of biochemical and biophysical cues of the microenvironment, using either natural matrix components or functionalized synthetic hydrogels. In addition, microfluidic devices provide access to modeling the impact of shear stress and interstitial flow and growth factor gradients. In this review, we will describe the state of the art co-culture models of vascularized micro-tumors in order to study tumor progression and metastatic dissemination including intravasation and/or extravasation processes.

Background The benefit–risk ratio of prophylactic non-invasive ventilation (NIV) and high-flow nasal oxygen therapy (HFNC-O 2 ) 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 PaO 2 /FiO 2 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-O 2 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 PaO 2 /FiO 2 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-O 2 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.

The members of the lysyl oxidase (LOX) family are amine oxidases, which initiate the covalent cross-linking of the extracellular matrix (ECM), regulate ECM stiffness, and contribute to cancer progression. The aim of this study was to build the first draft of the interactome of the five members of the LOX family in order to determine its molecular functions, the biological and signaling pathways mediating these functions, the biological processes it is involved in, and if and how it is rewired in cancer. In vitro binding assays, based on surface plasmon resonance and bio-layer interferometry, combined with queries of interaction databases and interaction datasets, were used to retrieve interaction data. The interactome was then analyzed using computational tools. We identified 31 new interactions and 14 new partners of LOXL2, including the α5β1 integrin, and built an interactome comprising 320 proteins, 5 glycosaminoglycans, and 399 interactions. This network participates in ECM organization, degradation and cross-linking, cell-ECM interactions mediated by non-integrin and integrin receptors, protein folding and chaperone activity, organ and blood vessel development, cellular response to stress, and signal transduction. We showed that this network is rewired in colorectal carcinoma, leading to a switch from ECM organization to protein folding and chaperone activity.