Proposition de protocole de recherche clinique AXES (étude multicentrique randomisée évaluant l'effet sur la mortalité de l'administration d'albumine à la phase précoce du sepsis sévère chez le cirrhotique)

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Intramyocardial delivery of mesenchymal stem cell-seeded hydrogel preserves cardiac function and attenuates ventricular remodeling after myocardial infarction.

BACKGROUND: To improve the efficacy of bone marrow-derived mesenchymal stem cell (MSC) therapy targeted to infarcted myocardium, we investigated whether a self-setting silanized hydroxypropyl methylcellulose (Si-HPMC) hydrogel seeded with MSC (MSC+hydrogel) could preserve cardiac function and attenuate left ventricular (LV) remodeling during an 8-week follow-up study in a rat model of myocardial infarction (MI). METHODOLOGY/PRINCIPAL FINDING: Si-HPMC hydrogel alone, MSC alone or MSC+hydrogel were injected into the myocardium immediately after coronary artery ligation in female Lewis rats. Animals in the MSC+hydrogel group showed an increase in cardiac function up to 28 days after MI and a mid-term prevention of cardiac function alteration at day 56. Histological analyses indicated that the injection of MSC+hydrogel induced a decrease in MI size and an increase in scar thickness and ultimately limited the transmural extent of MI. These findings show that intramyocardial injection of MSC+hydrogel induced short-term recovery of ventricular function and mid-term attenuation of remodeling after MI. CONCLUSION/SIGNIFICANCE: These beneficial effects may be related to the specific scaffolding properties of the Si-HPMC hydrogel that may provide the ability to support MSC injection and engraftment within myocardium

Monitoring Transcutaneously Measured Partial Pressure of CO(2) During Intubation in Critically Ill Subjects

International audienceBACKGROUND: The risk for severe hypoxemia during endotracheal intubation is a major concern in the ICU, but little attention has been paid to CO(2) variability. The objective of this study was to assess transcutaneously measured partial pressure of CO(2) (P(tcCO(2)) ) throughout intubation in subjects in the ICU who received standard oxygen therapy, high-flow nasal cannula oxygen therapy, or noninvasive ventilation for preoxygenation. We hypothesized that the 3 methods differ in terms of ventilation and CO(2) removal. METHODS: In this single-center, prospective, observational study, we recorded P(tcCO(2)) from preoxygenation to 3 h after the initiation of mechanical ventilation among subjects requiring endotracheal intubation. Subjects were sorted into 3 groups according to the preoxygenation method. We then assessed the link between P(tcCO(2)) variability and the development of postintubation hypotension. RESULTS: A total of 202 subjects were included in the study. The P(tcCO(2)) values recorded at endotracheal intubation, at the initiation of mechanical ventilation, and after 30 min and 1 h of mechanical ventilation were significantly higher than those recorded during preoxygenation (P < .05). P(tcCO(2)) variability differed significantly according to the preoxygenation method (P < .001, linear mixed model). A decrease in P(tcCO(2)) by > 5 mm Hg within 30 min after the start of mechanical ventilation was independently associated with postintubation hypotension (odds ratio = 2.14 [95% CI 1.03-4.44], P = .039) after adjustments for age, Simplified Acute Physiology Score II, COPD, cardiac comorbidity, the use of propofol for anesthetic induction, and minute ventilation at the start of mechanical ventilation. CONCLUSIONS: P(tcCO(2)) variability during intubation is significant and differs with the method of preoxygenation. A decrease in P(tcCO(2)) after the beginning of mechanical ventilation was associated with postintubation hypotension. (ClinicalTrials.gov registration NCT0388430.)

Predicting the microbial cause of community-acquired pneumonia: Can physicians or a data-driven method differentiate viral from bacterial pneumonia at patient presentation?

International audienceBackground: Community-acquired pneumonia (CAP) requires urgent and specific antimicrobial therapy. However, the causal pathogen is typically unknown at the point when anti-infective therapeutics must be initiated. Physicians synthesize information from diverse data streams to make appropriate decisions. Artificial intelligence (AI) excels at finding complex relationships in large volumes of data. We aimed to evaluate the abilities of experienced physicians and AI to answer this question at patient admission: is it a viral or a bacterial pneumonia? Methods: We included patients hospitalized for CAP and recorded all data available in the first 3-h period of care (clinical, biological and radiological information). For this proof-of-concept investigation, we decided to study only CAP caused by a singular and identified pathogen. We built a machine learning model prediction using all collected data. Finally, an independent validation set of samples was used to test the pathogen prediction performance of: (i) a panel of three experts and (ii) the AI algorithm. Both were blinded regarding the final microbial diagnosis. Positive likelihood ratio (LR) values > 10 and negative LR values < 0.1 were considered clinically relevant. Results: We included 153 patients with CAP (70.6% men; 62 [51-73] years old; mean SAPSII, 37 [27-47]), 37% had viral pneumonia, 24% had bacterial pneumonia, 20% had a co-infection and 19% had no identified respiratory pathogen. We performed the analysis on 93 patients as co-pathogen and no-pathogen cases were excluded. The discriminant abilities of the AI approach were low to moderate (LR+ = 2.12 for viral and 6.29 for bacterial pneumonia), and the discriminant abilities of the experts were very low to low (LR+ = 3.81 for viral and 1.89 for bacterial pneumonia). Conclusion: Neither experts nor an AI algorithm can predict the microbial etiology of CAP within the first hours of hospitalization when there is an urgent need to define the anti-infective therapeutic strategy

Evaluation of cardiac function by echocardiography in rats after myocardial infarction (MI).

<p>Measurements were performed at baseline before MI and 1, 7, 28 and 56 days after MI as indicated. (A) Left ventricular end-diastolic diameter (LVEDD). (B) Left ventricular end-systolic diameter (LVESD). (C) Left ventricular fractional shortening (LVFS). (D) Left ventricular ejection fraction (LVEF). ^¥<i>p</i><0.05 compared to day 1 post-MI in the same group, one-way repeated measures ANOVA.<i>*p</i><0.001 <i>vs.</i> the PBS group at the same time-point, <i>^$p</i><0.05 <i>vs.</i> the hydrogel group at the same time-point and <i>⁺p</i><0.05 <i>vs.</i> the MSC group at the same time-point, one-way ANOVA. All values represent mean ± SEM.</p

Evaluation of scar thickness and infarct expansion.

<p>(A) Representative photomicrographs of Masson trichrome staining of the scar area (collagen-rich areas in blue and healthy myocardium in red). The double arrow depicts the LV wall (<i>epi</i>, epicardium; <i>endo</i>, endocardium). The arrows show chondroid metaplasia of the endocardium. Scale bar = 0.5 mm. (B) Relative scar thickness (scar thickness/wall thickness). (C) Infarct expansion index ([LV cavity area/whole LV area]/relative scar thickness). For (B) and (C): *<i>p</i><0.05 and **<i>p</i><0.001, one-way ANOVA. All values represent mean ± SEM.</p

Echocardiography measurements at baseline (Bsl) and at 1 day (d1), 7 days (d7), 28 days (d28) and 56 days (d56) after MI.

<p>LVESD, left ventricular end-systolic diameter; LVEDD, left ventricular end-diastolic diameter; LVEF, ejection fraction; LVFS, fraction shortening.</p>¥<p><i>p</i><0.05 compared to Day 1 post-infarction in the same group, one-way repeated measures ANOVA.</p>*<p><i>p</i><0.001 <i>vs.</i> the PBS group,</p>$<p><i>p</i><0.05 vs. the hydrogel group and,</p>+<p><i>p</i><0.05 <i>vs.</i> the MSC, one-way ANOVA.</p><p>All values represent mean ± SEM.</p

MSC characterization and viability in 3D culture within the Si-HPMC hydrogel.

<p>(A and B) Flow cytometric analysis of MSC for CD29, CD54, CD90, CD34, CD45 and CD86 expression. 10,000 events were scored. Results are expressed as % of positive cells in the whole population on representative histogram plots. (C and D) MSC were cultured in 3D Si-HPMC hydrogel for the indicated times. (C) Labeling cells with calcein-AM (green color) and with EthD-1 (red color) revealed living and dead cells, respectively. Representative samples of MSC cultures visualized by confocal microscopy. (D) As described in the Materials section, the percentages of living and dead MSC cultured in 3D within hydrogel over 7 days (<i>p</i> = NS as compared between time points, one-way ANOVA). All values represent mean ± SEM. Scale bar = 100 µm.</p

Evaluation of myocardial infarction size and left ventricular fibrosis.

<p>(A) Representative transversal histology sections of heart and Masson trichrome staining for infarct size measurement at day 56 after MI. Collagen-rich areas (scar tissue) are colored in blue and healthy myocardium in red. Scale bar = 1.5 mm. (B) Percentage of circumferential infarct size (MI size) divided by total LV tissue, and (C) percentage of fibrosis in total LV tissue. For (B) and (C): *<i>p</i><0.05 and **<i>p</i><0.001 <i>vs.</i> the PBS group, ^$<i>p</i><0.05 and ^$$<i>p</i><0.001 <i>vs.</i> the hydrogel group, one-way ANOVA. <i>LV, left ventricle; RV, right ventricle.</i> All values represent mean ± SEM.</p

Evaluation of MSC engraftment 24 hours and 14 days after <i>in vivo</i> injection with Si-HPMC hydrogel into cardiac tissue.

<p>MSC engraftment 24 hours and 14 days after <i>in vivo</i> MSC+Si-HPMC hydrogel injection into cardiac tissue is shown on representative transversal histology heart sections. (A, B) Cell nuclei were labeled with To-Pro-3 (red fluorescence). MSC were labeled prior to injection with a fluorescent dye, CFSE (green fluorescence) and visualized 24 h after the implantation. (C) CD90 staining allowed identification of implanted MSC in left ventricle 24 h after injection. (D) PKH26 labeled MSC (red fluorescence) in heart wall with DAPI for cell nuclei (blue fluorescence), 14 days after implantation. (A) Scale bar = 1.5 mm. (B, C and D) scale bar Scale bar = 0.5 mm.</p