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Background: Pain management is an essential and complex issue for non-communicative patients undergoing sedation in the intensive care unit (ICU). The Behavioral Pain Scale (BPS), although not perfect for assessing behavioral pain, is the gold standard based partly on clinical facial expression. NEVVA © , an automatic pain assessment tool based on facial expressions in critically ill patients, is a much-needed innovative medical device., Methods: In this prospective pilot study, we recorded the facial expressions of critically ill patients in the medical ICU of Caen University Hospital using the iPhone and Smart Motion Tracking System (SMTS) software with the Facial Action Coding System (FACS) to measure human facial expressions metrically during sedation weaning. Analyses were recorded continuously, and BPS scores were collected hourly over two 8 h periods per day for 3 consecutive days. For this first stage, calibration of the innovative NEVVA © medical device algorithm was obtained by comparison with the reference pain scale (BPS)., Results: Thirty participants were enrolled between March and July 2022. To assess the acute severity of illness, the Sequential Organ Failure Assessment (SOFA) and the Simplified Acute Physiology Score (SAPS II) were recorded on ICU admission and were 9 and 47, respectively. All participants had deep sedation, assessed by a Richmond Agitation and Sedation scale (RASS) score of less than or equal to -4 at the time of inclusion. One thousand and six BPS recordings were obtained, and 130 recordings were retained for final calibration: 108 BPS recordings corresponding to the absence of pain and 22 BPS recordings corresponding to the presence of pain. Due to the small size of the dataset, a leave-one-subject-out cross-validation (LOSO-CV) strategy was performed, and the training results obtained the receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.792. This model has a sensitivity of 81.8% and a specificity of 72.2%., Conclusion: This pilot study calibrated the NEVVA © medical device and showed the feasibility of continuous facial expression analysis for pain monitoring in ICU patients. The next step will be to correlate this device with the BPS scale., Competing Interests: MB and DCh participated in scientific board of SAMDOC Medical Technologies who develops NEVVA©; medical device. JL, TC, AH and TG were employed by Samdoc Medical Technologies Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bellal, Lelandais, Chabin, Heudron, Gourmelon, Bauduin, Cuchet, Daubin, De Carvalho Ribeiro, Delcampe, Goursaud, Joret, Mombrun, Valette, Cerasuolo, Morello, Mordel, Chaillot, Dutheil, Vivien and Du Cheyron.)

Introduction: This study aimed to provide an updated analysis of the different prognostic trajectories of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies., Methods: Among a cohort of 70 patients, baseline characteristics and phenotypes, treatments and outcomes were analyzed. A Cox proportional hazards model was used to identify factors associated with poor outcomes, i.e., death or progressive disease at the last follow-up., Results: Among the 70 patients, 45 were women, and 54 were Caucasian. A dermatologic involvement was observed in 58 (83%) patients, including 40 with MDA5 vasculopathy-related skin lesions. Muscular involvement was observed in 39 (56%) patients. Interstitial lung disease (ILD) was observed at baseline in 52 (74%) patients, including 23 (44%) who developed rapidly progressive (RP) ILD. Seven (10%) patients showed thromboembolic complications within the first weeks of diagnosis, and eight (11%) other patients developed a malignancy (4 before the diagnosis of anti-MDA5 disease). Poor outcomes were observed in 28 (40%) patients, including 13 (19%) deaths. Among the 23 patients with RP-ILD, 19 (79%) showed poor outcomes, including 12 (63%) who died. In multivariate analyses, RP-ILD (hazard ratio (HR), 95% CI: 8.24 [3.21-22], p<0.0001), the occurrence of thromboembolic events (HR: 5.22 [1.61-14.77], p=0.008) and the presence of any malignancy (HR: 19.73 [6.67-60], p<0.0001) were the three factors independently associated with poor outcomes., Discussion: This new independent cohort confirms the presence of different clinical phenotypes of anti-MDA5 diseases at baseline and the poor prognosis associated with RP-ILD. Thromboembolic events and malignancies were also identified as prognostic factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CB declared a shared parent affiliation with the author CC to the handling editor at the time of review., (Copyright © 2024 de Boysson, Cuchet, Cassius, Cuchet, Agard, Audemard-Verger, Marchand-Adam, Cohen-Sors, Gallay, Graveleau, Lesort, Ly, Meyer, Monseau, Néel, Bonnotte, Pérard, Schleinitz, Mariotte, Le Mauff, Bourdenet, Masmoudi, Deshayes, Dumont, Dompmartin, Kottler and Aouba.)

Purpose: Although patients with SARS-CoV-2 infection have several risk factors for ventilator-associated lower respiratory tract infections (VA-LRTI), the reported incidence of hospital-acquired infections is low. We aimed to determine the relationship between SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, and the incidence of VA-LRTI., Methods: Multicenter retrospective European cohort performed in 36 ICUs. All adult patients receiving invasive mechanical ventilation > 48 h were eligible if they had: SARS-CoV-2 pneumonia, influenza pneumonia, or no viral infection at ICU admission. VA-LRTI, including ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP), were diagnosed using clinical, radiological and quantitative microbiological criteria. All VA-LRTI were prospectively identified, and chest-X rays were analyzed by at least two physicians. Cumulative incidence of first episodes of VA-LRTI was estimated using the Kalbfleisch and Prentice method, and compared using Fine-and Gray models., Results: 1576 patients were included (568 in SARS-CoV-2, 482 in influenza, and 526 in no viral infection groups). VA-LRTI incidence was significantly higher in SARS-CoV-2 patients (287, 50.5%), as compared to influenza patients (146, 30.3%, adjusted sub hazard ratio (sHR) 1.60 (95% confidence interval (CI) 1.26 to 2.04)) or patients with no viral infection (133, 25.3%, adjusted sHR 1.7 (95% CI 1.2 to 2.39)). Gram-negative bacilli were responsible for a large proportion (82% to 89.7%) of VA-LRTI, mainly Pseudomonas aeruginosa, Enterobacter spp., and Klebsiella spp., Conclusions: The incidence of VA-LRTI is significantly higher in patients with SARS-CoV-2 infection, as compared to patients with influenza pneumonia, or no viral infection after statistical adjustment, but residual confounding may still play a role in the effect estimates.

An experimental model of hypoxia was developed on isolated rat heart to study the effects of hypoxia on cardiac performance and metabolism. Fatty acid (FA) metabolism was explored by external detection with a labelled FA, iodohexadecenoic acid (IHA). Hearts, after 30 min preperfusion in an open system, were transferred in a recirculating system for 40 min and perfused with oleate, glucose, lactate, pyruvate and IHA, either in normoxia (pO2 = 660 mmHg) or in hypoxia (pO2 = 220 mmHg). After 40 min hypoxic recirculation, oxygen uptake and dynamic parameters, except the heart rate, decreased respectively by 56% and 44%, and remained constant throughout the perfusion. Glucose utilization increased 2 fold, endogenous glycogen fell by 50% and lactate + pyruvate production increased 3 fold, showing a stimulation of glycolysis. Oleate uptake decreased by 28%, while triglycerides content remained higher. The ATP/ADP ratio decreased by 24%. Conversely to oleate, IHA uptake was not significantly modified, but its intracellular fate showed a higher radioactivity in all lipid fractions: polar lipids, diglycerides, free FAs and triglycerides. beta oxidation of IHA, evidenced by iodide production, decreased by 39%. The external detection of cardiac radioactivity allowed us to obtain time-activity curves that were analyzed with a 4-compartment mathematical model. The data evidenced an esterification ratio significantly higher in hypoxia. The metabolism of IHA as estimated by the intracellular analysis or, in a non-invasive way, by external detection, was similar to the metabolism of oleate. Thus, lipid metabolism, in hypoxia, can be explored by external detection with IHA.

In isolated rat hearts, we investigated a possible backdiffusion of fatty acids and tried to determine whether it impaired our compartmental analysis of myocardial time-radioactivity curves obtained with an iodinated fatty acid, 16-iodo-9-hexadecenoic acid (IHA). Backdiffusion was not observed directly in the coronary effluents but was estimated by analysis of the external detection curves. Furthermore, when backdiffusion was not taken into account in the mathematical analysis, we obtained similar data on IHA intramyocardial metabolism.

The association of verapamil with halothane causes ischaemic-like myocardial dysfunction. Using an isolated rat heart model perfused with a radiolabelled fatty acid (123I-labelled iodohexadecenoic acid) as a sensitive marker of ischaemia this study investigated whether or not this dysfunction is of ischaemic origin. Hearts were perfused with a control solution or with solutions containing either 1% of halothane or 150 ng ml-1 of verapamil or the association of 0.75% halothane + 120 ng ml-1 verapamil. The ischaemic group was perfused at a reduced perfusion rate (-50%). Intracellular fate of IHA was assessed, and its esterification ratio computed. Ischaemia and the drugs induced a similar depression of haemodynamics. The esterification ratio in the ischaemic group was significantly higher (0.723 +/- 0.04) than in controls (0.0526 +/- 0.03) and than in the treated groups: halothane (0.533 +/- 0.06), verapamil (0.411 +/- 0.027) or the association halothane+verapamil (0.408 +/- 0.05), suggesting a non-ischaemic origin for the dysfunction caused by halothane-verapamil.

In order to study metabolic modifications induced by short term fasting and their consequences on the uptake and intracellular fate of fatty acids iodine labelled in omega position, rats undergo a 36h fasting. Hearts are perfused in a Langendorff system with a glucose (11 mM) perfusion medium; [123I] hexadecenoic acid (IHA) is injected as a bolus. A comparison between time-activity curves p.i. demonstrates a much faster activity decrease for the hearts fasted animals. The intracellular analysis shows that short fasting did not significantly increase the myocardial uptake of fatty acids, but decreased the storage and increased the degradation of the fatty acids taken up. Mathematical analysis of the myocardial time-activity curves obtained by external detection provided results comparable to those of intracellular analysis. The coefficients of correlation between the values of the aqueous phases, organic phases and free fatty acids measured by intracellular analysis and calculated with the compartmental model are consistently higher than 0.97. Consequently, this experimental model combined with mathematical analysis of the time-course of myocardial radioactivity after 123IHA administration appears to be very promising method for studying the effects of drugs or variations of energy substrate availability on myocardial fatty-acid metabolism.

To evaluate the effect of glucose perfusion on the myocardial metabolism of [123I]-16-iodo-9-hexadecenoic acid (IHA), the latter was injected intravenously into six fasting dogs perfused with a solution lacking glucose (controls) and seven fasting dogs perfused with glucose and insulin. The distribution of myocardial 123I among iodides, free IHA, and esterified IHA was measured in myocardial biopsy specimens. The increase in esterification and decrease in oxidation of IHA due to glucose were quantified using a compartmental mathematical model of myocardial IHA metabolism. Subsequently, in six control and six glucose-perfused dogs, cardiac radioactivity was measured with a scintillation camera for 1 hr following i.v. injection of IHA. Four different methods were used to analyze the myocardial time-activity curves and to calculate the distribution of IHA between oxidation and esterification. Results comparable to those provided by analysis of biopsy specimens can be obtained by considering the curve to be the sum of an exponential and a constant, or by analyzing it with a compartmental mathematical model.

The objective of the present study was to determine the mechanism of accumulation of myocardial activity following i.v. injection of 15-(paraiodophenyl)-3 methyl pentadecanoic acid (IMPPA). IMPPA and 15 phenyl-3 methyl pentadecanoic acid (MPPA) were labeled with 14C at position 1 and used to perfuse isolated rat hearts in a closed system. After 5 min of perfusion, IMPPA reached 2/3 of its value at 45 min. 14CO2 production was low. Most of the myocardial activity was in the form of free IMPPA. Analysis of IMPPA activation by CoA SH revealed that it was very strongly inhibited. The retention of myocardial activity is thus due to intracellular accumulation of free IMPPA following inhibition of activation. Comparison of results obtained with IMPPA and MPPA showed that the presence of iodine in the molecule accentuates the inhibition of activation.

Biliary secretion was studied in normolipidemic rats after a 7 day treatment with the hypolipidemic drugs, tiadenol (bis-(hydroxyethylthio)-1,10-decane), clofibrate and clofibride (chloro-4-phenoxy-2-methyl-2-propionate of dimethylcarbamoyl-3-propyl). All three drugs decreased blood cholesterol and total lipids, increased liver weight and liver catalase content, and decreased biliary excretion of cholesterol. The biliary concentrations of bile salts, phospholipids and cholesterol decreased to a variable extent, in such a way that the ratio of bile salts + phospholipids to cholesterol was increased by the drugs. The bile salt independent fraction was increased. The effects were qualitatively similar for all three drugs tested, but quanitative differences appeared for some of the parameters.

In order to study myocardial metabolism by external detection, quantitative information on the metabolism of a gamma-emitting iodinated fatty acid (IHA) was obtained from time-activity curves of radioactivity in different compartments. A 4-compartment mathematical model was then developed; compartments 0, 1, 2, and 3 correspond respectively to vascular IHA, intracellular IHA, esterified forms, and iodide resulting from mitochondrial oxidation of IHA. We applied this model to a study of the influence of an inhibitor of fatty acid oxidation, POCA (2-[5(4 chlorophenyl) pentyl]-oxirane-2-carboxylate). Isolated rat hearts were perfused for 20 min with Krebs liquid containing increasing concentrations of POCA. IHA was then injected as a bolus at the entrance of the coronary network. The level of cardiac radioactivity was recorded for 30 min and the division into the 4 compartments was simulated at different concentrations of POCA. The drug appeared to increase the myocardial retention of IHA and slow down the speed of degradation and storage; the variations were dose-dependent. These results correspond to those obtained by intracellular analysis. The proposed method, which is reliable and sensitive, is an interesting experiment for pharmacological studies of cardiac metabolism.

External counting, intracellular and subcellular distribution of (16 123I) iodohexadecenoic acid are studied on isolated rat hearts perfused with or without glucose. The presence of an exogenous substrate reduces the fatty acid oxidation and induces an increase of total cardiac and organic fraction activities. In this fraction, activity is very low for free fatty acids, but high for triglycerides and especially for polar lipids. The presence of an exogenous substrate leads to a more active esterification of fatty acids. Coronary effluents analysis shows, in the hydrophilic phase, a lower activity rebound in the presence of glucose. In the mitochondrial fraction, activity is mostly in the organic phase, as polar lipids especially. In the non-mitochondrial fraction, activity is much higher in the aqueous phase. 90 s p.i. of (l 14C) palmitic acid, over 80% of the myocardial activity is found in the hydrophilic fraction, which indicates--as for the iodo fatty acid (IHA)--an immediate and important oxidation, especially without glucose. These data seem to prove that IHA is taken up by the myocardial cells, enters the mitochondria where it is, without an early deiodination, oxidized with iodide release. IHA metabolic changes can be seen on the external detection myocardial activity curve. Omega iodinated fatty acids do not undergo a nonspecific important deiodination and are therefore well adapted to an external study of myocardial metabolism.

The methyl-branched fatty acids, if radioiodine labelled in alpha position, are potentially adapted to a selective study of FA myocardial uptake. To determine the position and the number of methyl radicals that are necessary to obtain a maximal uptake and a minimal degradation, we measured time-activity evolution of isolated and perfused rat hearts after an injection of iodinated fatty acids which are mono- or dimethylated in alpha or beta position. Except for dimethyl fatty acid, the uptake is similar for all fatty acids studied to that of the straight chain analogue; beta mono- or dimethyl fatty acids seem best adapted to a study of the uptake because alpha monomethyl fatty acids undergo a metabolic degradation and alpha mono- and dimethyl fatty acids induce ventricular fibrillations.

This paper shows the role of the hypophysis gland on the bile elimination of essential tauroconjugated acids and cholesterol. After transauricular hypophysectomies were performed on rats which were kept under total fistula treatment, we employed an original technique of bile recuperation in rats without contention and observed, over a period of 10 or more days, the choleresis and the composition of eliminated bile.

Methylated fatty acids labeled with radioactive iodine have been proposed as a means of studying regional myocardial uptake of fatty acids in man. To investigate the methylated fatty acid that is best adapted for an assessment of uptake, we have studied the influence of the number and the position of the methyl groups of IFA intracellular metabolism; 16-iodo-2-methyl-hexadecanoic (mono-alpha), 16-iodo-2,2-methyl hexadecanoic (di-alpha), 16-iodo-3-methyl-hexadecanoic (mono-beta), and 16-iodo-3,3-methyl-hexadecanoic (di-beta) acids were injected into the coronary arteries of isolated rat hearts. Intracellular analysis shows that the degradation of mono-alpha was always lower than that of IHA and the storage was always much higher. The differences between mono-beta and IHA were similar to those observed with mono-alpha, but were much more pronounced. With the two dimethylated IFAs there was an inhibition of both oxidation and esterification which led to an accumulation of free FAs in myocardial cells. In conclusion, mono-beta, di-alpha, and di-beta are potentially suitable for studying the cellular uptake of IFA since all of them, and particularly the dimethylated IFAs, have a low oxidation rate.

In order to choose a labelled fatty acid (FA) for the external study of myocardial metabolism, FAs that are different in chain length, saturation, nature and position of the radioactive label, are injected i.v. into mice. Myocardial and blood activities are measured at various times p.i. It appears that hexadecanoic and hexadecenoic acids, iodine labelled in omega position, have the highest maximal myocardial activity among all the FAs studied. Furthermore, the myocardial and blood time-activity course is similar for both FAs. As unsaturated FAs have apparently a higher myocardial fixation in man than the saturated ones, 123I 16 iodo-9 hexadecenoic acid has been selected and seems well suited for the study of myocardial metabolism.