Calibration trial of an innovative medical device (NEVVA© ) for the evaluation of pain in non-communicating patients in the intensive care unit.

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.

Glucose fluctuation promotes mitochondrial dysfunctions in the cardiomyocyte cell line HL-1.

AIMS: Glycemic variability has been suggested as a risk factor for diabetes complications but the precise deleterious mechanisms remain poorly understood. Since mitochondria are the main source of energy in heart and cardiovascular diseases remain the first cause of death in patients with diabetes, the aim of the study was to evaluate the impact of glucose swings on mitochondrial functions in the cardiomyocyte cell line HL-1. METHODS: HL-1 cells were exposed to low (LG, 2.8 mmol/l), normal (NG, 5.5 mmol/l), high (HG, 25 mmol/l) or intermittent high glucose (IHG, swing between low and high) every 2h during 12h (short-time treatment) or every 12h during 72h (long-time treatment). Anaerobic catabolism of glucose was evaluated by measuring glucose consumption and lactate production, oxidative phosphorylation was evaluated by polarography and ATP measurement, mitochondrial superoxide anions and the mitochondrial membrane potential (MMP) were analysed using fluorescent probes, and the protein oxidation was measured by oxyblot. RESULTS: IHG and HG increased glucose consumption and lactate production compared to LG and NG but without any difference between short- and long-time treatments. After 72h and unlike to LG, NG and HG, we didn't observe any increase of the mitochondrial respiration in the presence of succinate upon IHG treatment. IHG, and to a lesser extent HG, promoted a time-dependent decrease of the mitochondrial membrane potential compared to LG and NG treatments. HG and IHG also increased superoxide anion production compared to LG and NG both at 12 and 72h but with a higher increase for IHG at 72h. At last, both HG and IHG stimulated protein oxidation at 72h compared to LG and NG treatments. CONCLUSIONS: Our results demonstrated that exposure of HL-1 cells to glucose swings promoted time-dependent mitochondrial dysfunctions suggesting a deleterious effect of such condition in patients with diabetes that could contribute to diabetic cardiomyopathy.

Identification of a novel splice site mutation in the SERAC1 gene responsible for the MEGDHEL syndrome.

BACKGROUND: MEGDHEL is an autosomal recessive syndrome defined as 3-MEthylGlutaconic aciduria (3-MGA) with Deafness, Hepatopathy, Encephalopathy, and Leigh-like syndrome on magnetic resonance imaging, due to mutations in the SERAC1 (Serine Active Site Containing 1) gene, which plays a role in the mitochondrial cardiolipin metabolism. METHODS: We report the case of a young patient who presented with a convulsive encephalopathy, 3-methylglutaconic aciduria, deafness, and bilateral T2 hypersignals of the putamen and the thalami, who passed away at 8 years of age. RESULTS: Analysis of nuclear genes using an ampliSeq™ targeted custom panel disclosed two compound heterozygous variants in the SERAC1 gene: a nonsense substitution in exon 4, c.202C>T, resulting in a premature stop codon (p.Arg68*), and a novel variant at a canonical splicing site upstream exon 4 (c.129-1G>C). mRNAs sequencing from the fibroblasts of the patient showed that the splice site variant resulted in exon 3 skipping without frameshift while Western blot experiments showed the absence of SERAC1 expression compared to controls and abnormal filipin staining. CONCLUSION: We showed that the loss of the putative transmembrane domain of SERAC1, due to a novel splice site variant, impairs the protein expression and is responsible for the MEGDHEL syndrome.

A 2 bp deletion in the mitochondrial ATP 6 gene responsible for the NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome.

Mitochondrial (mt) DNA-associated NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) syndrome is due to mutation in the MT-ATP6 gene. We report the case of a 18-year-old man who presented with deafness, a myoclonic epilepsy, muscle weakness since the age of 10 and further developed a retinitis pigmentosa and ataxia. The whole mtDNA analysis by next-generation sequencing revealed the presence of the 2 bp microdeletion m.9127-9128 del AT in the ATP6 gene at 82% heteroplasmy in muscle and to a lower load in blood (10-20%) and fibroblasts (50%). Using the patient's fibroblasts, we demonstrated a 60% reduction of the oligomycin-sensitive ATPase hydrolytic activity, a 40% decrease in the ATP synthesis and determination of the mitochondrial membrane potential using the fluorescent probe tetramethylrhodamine, ethyl ester indicated a significant reduction in oligomycin sensitivity. In conclusion, we demonstrated that this novel AT deletion in the ATP6 gene is pathogenic and responsible for the NARP syndrome.