Ischémie Reperfusion, Métabolisme et Inflammation Stérile en Transplantation

Abstract CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65–79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10 −5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10 −5 were reported in 35 patients (26%, 95% confidence interval (CI) 19–34) in IsaRd versus 71 (53%, 95% CI 44–61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89–5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10 −5 and 10 −6 , and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10 −5 , the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 .

BACKGROUND: In patients with venous thromboembolism at high risk of recurrence for whom extended treatment with direct oral anticoagulants has been indicated, the optimal dose is unknown. We aimed to assess efficacy and safety of reduced-dose versus full-dose direct oral anticoagulants in patients in whom extended anticoagulation has been indicated. METHODS: RENOVE was a non-inferiority, investigator-initiated, multicentre, randomised, open-label, blinded endpoint trial done in 47 hospitals in France. Ambulatory patients aged 18 years or older with acute symptomatic venous thromboembolism (pulmonary embolism or proximal deep vein thrombosis) who had received 6-24 uninterrupted months of full-dose anticoagulation and for whom extended anticoagulation has been indicated were eligible. Eligible participants were categorised as having either a first unprovoked venous thromboembolism, recurrent venous thromboembolism, presence of persistent risk factors, or other clinical situations considered to be a high risk of recurrence. Participants were randomly assigned (1:1) to receive oral treatment with either a reduced dose of apixaban (2·5 mg twice daily) or rivaroxaban (10 mg once daily) or a full dose of apixaban (5 mg twice daily) or rivaroxaban (20 mg once daily) using a centralised randomisation procedure with an interactive web response system. The sequence generation method was a computerised random number generator and was balanced by blocks of different sizes. Randomisation was stratified by centre, type of direct oral anticoagulant, and antiplatelet drug. Physicians and participants were unmasked to treatment allocation; recurrent venous thromboembolism, clinically relevant bleeding, and all-cause death were adjudicated by an independent committee blinded to treatment allocation. The primary outcome was symptomatic recurrent venous thromboembolism, including recurrent fatal or non-fatal pulmonary embolism or isolated proximal deep vein thrombosis (non-inferiority hypothesis 90% power to exclude a hazard ratio [HR] of 1·7). The primary outcome and first two secondary outcomes were included in a hierarchical testing procedure. This trial is registered with ClinicalTrials.gov, NCT03285438. FINDINGS: From Nov 2, 2017, to July 6, 2022, 2768 patients were enrolled and randomly assigned to the reduced-dose group (n=1383) or the full-dose group (n=1385). 970 (35·0%) participants were female, 1797 (65·0%) were male, and one (<0·1%) had sex not reported. Median follow-up was 37·1 months (IQR 24·0-48·3). Recurrent venous thromboembolism occurred in 19 of 1383 patients in the reduced-dose group (5-year cumulative incidence 2·2% [95% CI 1·1-3·3]) versus 15 of 1385 patients in the full-dose group (5-year cumulative incidence 1·8% [0·8-2·7]; adjusted HR 1·32 [95% CI 0·67-2·60]; absolute difference 0·40% [95% CI -1·05 to 1·85]; p=0·23 for non-inferiority). Major or clinically relevant bleeding occurred in 96 patients in the reduced-dose group (5-year cumulative incidence 9·9% [95% CI 7·7-12·1]) and 154 patients in the full-dose group (5-year cumulative incidence 15·2% [12·8-17·6]; adjusted HR 0·61 [95% CI 0·48-0·79]). 1136 (82·1%) of 1383 patients in the reduced-dose group and 1150 (83·0%) of 1385 in the full-dose group had an adverse event; 374 (27·0%) patients in the reduced-dose group and 420 (30·3%) in the full-dose group has a serious adverse event. 35 (5-year cumulative incidence 4·3% [95% CI 2·6-6·0]) patients in the reduced-dose group and 54 (5-year cumulative incidence 6·1% [4·3-8·0]) patients in the full-dose group died during the study period. INTERPRETATION: In patients with venous thromboembolism requiring extended anticoagulation, reduction of the direct oral anticoagulant dose did not meet the non-inferiority criteria. However, the low recurrence rates in both groups and substantial reduction of clinically relevant bleeding with the reduced dose could support this regimen as an option. Further research will be needed to identify subgroups for whom the anticoagulation dose should not be reduced. FUNDING: French Ministry of Health.

BACKGROUND: Although metabolomics continues to expand in many domains of research, methodological issues such as sample type, extraction and analytical protocols have not been standardized, impeding proper comparison between studies and future research. METHODS: In the present study, five solvent-based and solid-phase extraction methods were investigated in both plasma and serum. All these extracts were analyzed using four liquid chromatography coupled with high resolution mass spectrometry (LC-MS) protocols, either in reversed or normal-phase and with both types of ionization. The performances of each method were compared according to putative metabolite coverage, method repeatability and also extraction parameters such as overlap, linearity and matrix effect; in both untargeted (global) and targeted approaches using fifty standard spiked analytes. RESULTS: Our results verified the broad specificity and outstanding accuracy of solvent precipitation, namely methanol and methanol/acetonitrile. We also reveal high orthogonality between methanol-based methods and SPE, providing the possibility of increased metabolome coverage, however we highlight that such potential benefits must be weighed against time constrains, sample consumption and the risk of low reproducibility of SPE method. Furthermore, we highlighted the careful consideration about matrix choice. Plasma showed the most suitable in this metabolomics approach combined with methanol-based methods. CONCLUSIONS: Our work proposes to facilitate rational design of protocols towards standardization of these approaches to improve the impact of metabolomics research.

Organ transplantation remains the treatment of last resort in case of failure of a vital organ (lung, liver, heart, intestine) or non-vital organ (essentially the kidney and pancreas) for which supplementary treatments exist. It remains the best alternative both in terms of quality-of-life and life expectancy for patients and of public health expenditure. Unfortunately, organ shortage remains a widespread issue, as on average only about 25% of patients waiting for an organ are transplanted each year. This situation has led to the consideration of recent donor populations (deceased by brain death with extended criteria or deceased after circulatory arrest). These organs are sensitive to the conditions of conservation during the ischemia phase, which have an impact on the graft's short- and long-term fate. This evolution necessitates a more adapted management of organ donation and the optimization of preservation conditions. In this general review, the different aspects of preservation will be considered. Initially done by hypothermia with the help of specific solutions, preservation is evolving with oxygenated perfusion, in hypothermia or normothermia, aiming at maintaining tissue metabolism. Preservation time is also becoming a unique evaluation window to predict organ quality, allowing repair and/or optimization of recipient choice.

Brain [18F]FDG-PET scans have revealed a glucose hypometabolic pattern in patients with long COVID. This hypometabolism might reflect primary astrocyte dysfunction. Astrocytes play a key role in regulating energy metabolism to support neuronal and synaptic activity, especially activity involving glutamate as the main neurotransmitter. Neuroinflammation is one of the purported mechanisms to explain brain damage caused by infection with SARS-CoV-2. Microglial activation can trigger reactive astrogliosis, contributing to neuroinflammatory changes. These changes can disturb glutamatergic homeostasis, ultimately leading to cognitive fatigue, which has been described in other clinical situations. We hypothesize that glutamatergic dysregulation related to astrocyte dysfunction could be the substrate of brain PET hypometabolism in long COVID patients with brain fog. Based on these elements, we propose that therapeutics targeting astrocytic glutamate regulation could help mitigate long COVID neurological manifestations.

PURPOSE: Whether skin disinfection of the surgical site using chlorhexidine-alcohol is superior to povidone-iodine-alcohol in reducing reoperation and surgical site infection rates after major cardiac surgery remains unclear. METHODS: CLEAN 2 was a multicenter, open-label, randomized, two-arm, assessor-blind, superiority trial conducted in eight French hospitals. We randomly assigned adult patients undergoing major heart or aortic surgery via sternotomy, with or without saphenous vein or radial artery harvesting, to have all surgical sites disinfected with either 2% chlorhexidine-alcohol or 5% povidone-iodine-alcohol. The primary outcome was any resternotomy by day 90 or any reoperation at the peripheral surgical site by day 30. RESULTS: Of 3242 patients (1621 in the chlorhexidine-alcohol group [median age, 69 years; 1276 (78.7%) men] and 1621 in the povidone-iodine-alcohol group [median age, 69 years; 1247 (76.9%) men], the percentage required reoperation within 90 days was similar (7.7% [125/1621] in the chlorhexidine-alcohol group vs 7.5% [121/1621] in the povidone-iodine-alcohol group; risk difference, 0.25 [95% confidence interval (CI), - 1.58-2.07], P = 0.79). The incidence of surgical site infections at the sternum or peripheral sites was similar (4% [65/1621] in the chlorhexidine-alcohol group vs 3.3% [53/1621] in the povidone-iodine-alcohol group; risk difference, 0.74 [95% CI - 0.55-2.03], P = 0.26). Length of hospital stay, intensive care unit or hospital readmission, mortality and surgical site adverse events were similar between the two groups. CONCLUSION: Among patients requiring sternotomy for major heart or aortic surgery, skin disinfection at the surgical site using chlorhexidine-alcohol was not superior to povidone-iodine-alcohol for reducing reoperation and surgical site infection rates.

Considering the general view that unconventional immune effectors play a major role in antitumor immunity, we recently postulated that the distinct new innate CD8 T-cell pool (co-expressing the transcription factor Eomesodermin and innate markers such as KIR/NKG2A) may counteract tumor cells, and thereby be potential target for cancer therapy. Here, to test this assumption, we used successfully targeted anti-leukemic therapy discontinuation (TFR) in chronic myeloid leukemia (CML). Numerical and functional status of innate CD8 T-cells, iNKT cells and γδ T-cells, in comparison with NK cells, was compared longitudinally between non-relapsed patients (i.e., with > 12 months TFR) and relapsed patients (i.e., who experienced molecular recurrence during the first 12 months after TKI cessation) in a prospective pilot cohort (n=32), starting from treatment discontinuation (D0). Perforin, a key cytotoxic immune player, was expressed in a significantly higher proportion of both innate CD8 T-cell and NK-cell subsets in non-relapsed patients, compared with relapsed patients at D0. In parallel, we assessed the expression of PD-1, an exhaustion marker used as target in cancer therapy. For all T-cell subsets, surface-expression level of PD-1 decreased in non-relapsed patients compared with relapsed patients at D0. This was particularly the case when considering iNKT cells for which surface-expression level of PD-1 even decreased relative to healthy control subjects. Lastly, we found a negative correlation between the proportion of innate CD8 T-cells expressing PD-1 and those expressing perforin in non-relapsed patients at D0. The fact that this was not the case in conventional CD8 T-cells is compatible with a reprogrammed effector profile preferentially targeting innate CD8 T-cells in non-relapsed patients. All in all, our results highlight NK cells and innate CD8 T-cells harboring cytotoxic content, as well as global downregulation of PD-1-expression on effector T-cells, as potential predictive functional signatures for successful TFR in CML. Considering innate CD8 T-cells, further investigations are needed to determine whether their possible contributory role in cancer surveillance in CML could be extended to other cancers, and also whether their targeting by immune cheek-point inhibitors could enhance their anti-tumoral functions.

Lyon 1. France. 5 3. PhyMedExp Inserm U1046-CNRS 9214 Université de Montpellier. France. 6 7 L-lactate metabolism was first investigated in exercise physiology since it was considered as a 8waste product of glycolysis due to oxygen deficiency. Since the 1980s', several studies showed 9 that lactate is an essential metabolic fuel and signaling molecule (Brooks). Then, the interest for 10 lactate has extended to a growing number of disciplines, from physiology to pathology and 11 exercise is now view as a metabolic trigger for tissues adaptation. 12 Lactate is transported by the monocarboxylate transporters (MCTs) family which present a 13 ubiquitous tissue distribution but lactate can additionally activate the hydroxycarboxylic acid 14 receptor 1 (HCAR1) also known as G protein-coupled receptor 81 (GPR81 Finally, the editors would like to thank all contributors and reviewers that allowed this special issue 80 to become a success in drawing attention to a long-neglected (but so interesting!) metabolite. 81 82

The actual obesity and diabetes pandemics require new approaches to stop their progression. Recent findings converged on the therapeutic potential of fibroblast growth factor 21 (FGF21) in these metabolic diseases. FGF21 is a master regulator of metabolism by acting not only directly on peripheral tissues but also through the brain. The central nervous system seems to be a target for the beneficial effects of FGF21 in the treatment of diabetes (in particular, insulin resistance) as well as obesity, highlighting the importance of investigating its central mechanisms of action. The source of this messenger and its target cells in the brain are debated topics that currently raise great interest in the field of metabolism. Under physiological conditions, the liver is the major source of circulating Fgf21. Fgf21 protein can cross the blood-brain barrier by simple diffusion1Hsuchou H. Pan W. Kastin A.J. The fasting polypeptide FGF21 can enter brain from blood.Peptides. 2007; 28: 2382-2386https://doi.org/10.1016/j.peptides.2007.10.007Crossref PubMed Scopus (194) Google Scholar but also reach part of the brain via fenestrated vessels in the hypothalamus.2Xu C. Messina A. Somm E. Miraoui H. Kinnunen T. Acierno J. Niederlander N.J. Bouilly J. Dwyer A.A. Sidis Y. et al.KLB, encoding beta-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.EMBO Mol. Med. 2017; 9: 1379-1397https://doi.org/10.15252/emmm.201607376Crossref PubMed Scopus (62) Google Scholar Recently, Zhou et al. reported in this journal a central production of neuronal Fgf21 in the thalamus and the retrosplenial cortex.3Zhou B. Claflin K.E. Flippo K.H. Sullivan A.I. Asghari A. Tadinada S.M. Jensen-Cody S.O. Abel T. Potthoff M.J. Central FGF21 production regulates memory but not peripheral metabolism.Cell Rep. 2022; 40: 111239https://doi.org/10.1016/j.celrep.2022.111239Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar This neuronal production of Fgf21 seems to be involved in the enhancement of spatial memory but does not regulate energy homeostasis or sugar intake. More surprisingly, in contrast to several recent studies, they did not detect Fgf21 production in the hypothalamus using a new transgenic mouse model. Over the past three years, several studies from independent groups with various experimental conditions reported Fgf21 mRNA expression by the hypothalamus in mouse,4Benomar Y. Amine H. Crepin D. Al Rifai S. Riffault L. Gertler A. Taouis M. Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 resistance.Diabetes. 2016; 65: 913-926https://doi.org/10.2337/db15-1029Crossref PubMed Scopus (46) Google Scholar,5Kaminskas B. Goodman T. Hagan A. Bellusci S. Ornitz D.M. Hajihosseini M.K. Characterisation of endogenous players in fibroblast growth factor-regulated functions of hypothalamic tanycytes and energy-balance nuclei.J. Neuroendocrinol. 2019; 31: e12750https://doi.org/10.1111/jne.12750Crossref PubMed Scopus (15) Google Scholar,6Geller S. Arribat Y. Netzahualcoyotzi C. Lagarrigue S. Carneiro L. Zhang L. Amati F. Lopez-Mejia I.C. Pellerin L. Tanycytes Regulate Lipid Homeostasis by Sensing Free Fatty Acids and Signaling to Key Hypothalamic Neuronal Populations via FGF21 Secretion.Cell Metab. 2019; 30: 833-844.e7https://doi.org/10.1016/j.cmet.2019.08.004Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,7Timper K. del Rio-Martin A. Cremer A.L. Bremser S. Alber J. Giavalisco P. Varela L. Heilinger C. Nolte H. Trifunovic A. et al.GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function.Cell Metab. 2020; 31: 1189-1205https://doi.org/10.1016/j.cmet.2020.05.001Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar rat,4Benomar Y. Amine H. Crepin D. Al Rifai S. Riffault L. Gertler A. Taouis M. Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 resistance.Diabetes. 2016; 65: 913-926https://doi.org/10.2337/db15-1029Crossref PubMed Scopus (46) Google Scholar,8Moro J. Chaumontet C. Even P.C. Blais A. Piedcoq J. Gaudichon C. Tome D. Azzout-Marniche D. Severe protein deficiency induces hepatic expression and systemic level of FGF21 but inhibits its hypothalamic expression in growing rats.Sci. Rep. 2021; 11: 12436https://doi.org/10.1038/s41598-021-91274-4Crossref PubMed Scopus (10) Google Scholar,9Pena-Leon V. Folgueira C. Barja-Fernandez S. Perez-Lois R. Da Silva Lima N. Martin M. Heras V. Martinez-Martinez S. Valero P. Iglesias C. et al.Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.Nat. Metab. 2022; 4: 901-917https://doi.org/10.1038/s42255-022-00602-zCrossref PubMed Scopus (8) Google Scholar and pig10Yuan X. Zhou X. Chen Z. He Y. Kong Y. Ye S. Gao N. Zhang Z. Zhang H. Li J. Genome-Wide DNA Methylation Analysis of Hypothalamus During the Onset of Puberty in Gilts.Front. Genet. 2019; 10: 228https://doi.org/10.3389/fgene.2019.00228Crossref PubMed Scopus (11) Google Scholar by using, among other techniques, PCR and in situ hybridization (such as the novel RNAscope technology). Moreover, three of these studies described an Fgf21 mRNA synthesis by glial cells including tanycytes,6Geller S. Arribat Y. Netzahualcoyotzi C. Lagarrigue S. Carneiro L. Zhang L. Amati F. Lopez-Mejia I.C. Pellerin L. Tanycytes Regulate Lipid Homeostasis by Sensing Free Fatty Acids and Signaling to Key Hypothalamic Neuronal Populations via FGF21 Secretion.Cell Metab. 2019; 30: 833-844.e7https://doi.org/10.1016/j.cmet.2019.08.004Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,7Timper K. del Rio-Martin A. Cremer A.L. Bremser S. Alber J. Giavalisco P. Varela L. Heilinger C. Nolte H. Trifunovic A. et al.GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function.Cell Metab. 2020; 31: 1189-1205https://doi.org/10.1016/j.cmet.2020.05.001Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar,9Pena-Leon V. Folgueira C. Barja-Fernandez S. Perez-Lois R. Da Silva Lima N. Martin M. Heras V. Martinez-Martinez S. Valero P. Iglesias C. et al.Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.Nat. Metab. 2022; 4: 901-917https://doi.org/10.1038/s42255-022-00602-zCrossref PubMed Scopus (8) Google Scholar peculiar ependymal cells of the hypothalamus. The recent challenge by Zhou et al.3Zhou B. Claflin K.E. Flippo K.H. Sullivan A.I. Asghari A. Tadinada S.M. Jensen-Cody S.O. Abel T. Potthoff M.J. Central FGF21 production regulates memory but not peripheral metabolism.Cell Rep. 2022; 40: 111239https://doi.org/10.1016/j.celrep.2022.111239Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar of a specific tanycytic Fgf21 production created a controversial issue on whether the protein detected in tanycytes is produced locally or comes from the bloodstream. Interestingly, a parallel study confirmed a mixed origin of Fgf21 protein detected in tanycytes.9Pena-Leon V. Folgueira C. Barja-Fernandez S. Perez-Lois R. Da Silva Lima N. Martin M. Heras V. Martinez-Martinez S. Valero P. Iglesias C. et al.Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.Nat. Metab. 2022; 4: 901-917https://doi.org/10.1038/s42255-022-00602-zCrossref PubMed Scopus (8) Google Scholar This study validated that rat tanycytes synthesize Fgf21 mRNA but also demonstrated that they transport peripheral Fgf21 protein into the hypothalamus. Indeed, hepatic Fgf21 reaches deeper hypothalamic structures through active transport by tanycytes, a mechanism shown to be necessary to observe a beneficial effect on systemic metabolism in animals that underwent delayed weaning and were exposed to a high-fat diet later in life.9Pena-Leon V. Folgueira C. Barja-Fernandez S. Perez-Lois R. Da Silva Lima N. Martin M. Heras V. Martinez-Martinez S. Valero P. Iglesias C. et al.Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.Nat. Metab. 2022; 4: 901-917https://doi.org/10.1038/s42255-022-00602-zCrossref PubMed Scopus (8) Google Scholar Intriguingly, hepatic and hypothalamic Fgf21 mRNA expression seem to be either similarly or differentially regulated according to the type of nutrients. Although a first study showed that fasting and fatty acids (such as palmitate) stimulate both hepatic and tanycytic Fgf21 mRNA expression,6Geller S. Arribat Y. Netzahualcoyotzi C. Lagarrigue S. Carneiro L. Zhang L. Amati F. Lopez-Mejia I.C. Pellerin L. Tanycytes Regulate Lipid Homeostasis by Sensing Free Fatty Acids and Signaling to Key Hypothalamic Neuronal Populations via FGF21 Secretion.Cell Metab. 2019; 30: 833-844.e7https://doi.org/10.1016/j.cmet.2019.08.004Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar delayed weaning or protein deficiency induced an opposite effect on Fgf21 mRNA expression from both tissues.8Moro J. Chaumontet C. Even P.C. Blais A. Piedcoq J. Gaudichon C. Tome D. Azzout-Marniche D. Severe protein deficiency induces hepatic expression and systemic level of FGF21 but inhibits its hypothalamic expression in growing rats.Sci. Rep. 2021; 11: 12436https://doi.org/10.1038/s41598-021-91274-4Crossref PubMed Scopus (10) Google Scholar,9Pena-Leon V. Folgueira C. Barja-Fernandez S. Perez-Lois R. Da Silva Lima N. Martin M. Heras V. Martinez-Martinez S. Valero P. Iglesias C. et al.Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.Nat. Metab. 2022; 4: 901-917https://doi.org/10.1038/s42255-022-00602-zCrossref PubMed Scopus (8) Google Scholar These observations confirm a complex regulation of Fgf21 production according to the tissue and nutritional status. The mechanisms responsible for these specific regulations need to be identified and described. Moreover, the opposite effects of nutrients on hypothalamic and hepatic Fgf21 mRNA expression raise the question about the existence of a counter-regulation or compensation system that must be coordinated somehow between both structures. Furthermore, one may wonder, in fine, what is the benefit of parallel tanycytic Fgf21 production and active transport of hepatic Fgf21 by tanycytes? It is clear that the physiological functions of such a glial Fgf21 production need to be further explored and more firmly established, although specific roles in systemic lipid and glucose homeostasis have been unraveled in lean rodents.6Geller S. Arribat Y. Netzahualcoyotzi C. Lagarrigue S. Carneiro L. Zhang L. Amati F. Lopez-Mejia I.C. Pellerin L. Tanycytes Regulate Lipid Homeostasis by Sensing Free Fatty Acids and Signaling to Key Hypothalamic Neuronal Populations via FGF21 Secretion.Cell Metab. 2019; 30: 833-844.e7https://doi.org/10.1016/j.cmet.2019.08.004Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,7Timper K. del Rio-Martin A. Cremer A.L. Bremser S. Alber J. Giavalisco P. Varela L. Heilinger C. Nolte H. Trifunovic A. et al.GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function.Cell Metab. 2020; 31: 1189-1205https://doi.org/10.1016/j.cmet.2020.05.001Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Undoubtedly, tanycytes have joined the Fgf21 team, but we need more time to read their game if we want to win against obesity and diabetes.

BACKGROUND: Preclinical studies indicate that lactate is a crucial cerebral energy substrate, with Na-L-lactate administration significantly reducing brain lesion volumes and improving motor and cognitive functions following neonatal hypoxia-ischemia in rat pups. Its neuroprotective effects are linked to neuronal metabolic utilization, making it a promising candidate for treating newborns with hypoxia-ischemia encephalopathy, a condition where hypothermia remains the only established therapy. However, before initiating a clinical trial, it is necessary to assess the effects of Na-L-lactate infusion on blood parameters. METHODS: We retrospectively analyzed blood parameters in 60 premature neonates during their first days of life. Among them, 30 received Na-L-lactate instead of Na-Cl to prevent hyperchloremic acidosis. Blood pH, lactatemia, bicarbonates, glycemia, natremia, chloremia, base excess, and hemoglobin were monitored before, during, and after Na-L-lactate infusion. RESULTS: Our findings showed that Na-L-lactate infusion lowered blood lactate levels while increasing pH from 7.25 to 7.31. After stopping the infusion, lactatemia was 1.9 mM, and pH reached 7.32. Na-L-lactate supplementation effectively restored normal blood pH, maintained natremia, and prevented hyperchloremia. Notably, even in cases of high initial lactatemia, lactate levels decreased during the infusion. CONCLUSION: Our data are promising and emphasize the need for further research to explore its potential applications in neonatal clinical care. IMPACT: Sodium L-lactate infusion does not increase blood lactate levels and restores normal pH in premature neonates. The study demonstrates that sodium L-lactate infusion avoids hyperchloremia while maintaining sodium levels, offering a potential alternative to sodium chloride. These findings highlight the need for additional research studies to further evaluate the safety, efficacy, and potential applications of sodium L-lactate infusion in neonatal care.

Background: Traumatic brain injury (TBI) is a major cause of morbimortality in the world, and it can cause potential intracranial hemorrhage (ICH), a life-threatening condition that requires rapid diagnosis with computed tomography (CT). Artificial intelligence tools for ICH detection are now commercially available. Objectives: Investigate the real-world performance of qER.ai, an artificial intelligence-based CT hemorrhage detection tool, in a post-traumatic population. Methods: Retrospective monocentric observational study of a dataset of consecutively acquired head CT scans at the emergency radiology unit to explore brain trauma. AI performance was compared to ground truth determined by expert consensus. A subset of night shift cases with the radiological report of a junior resident was compared to the AI results and ground truth. Results: A total of 682 head CT scans were analyzed. AI demonstrated a sensitivity of 88.8% and a specificity of 92.1% overall, with a positive predictive value of 65.4% and a negative predictive value of 98%. AI’s performance was comparable to that of junior residents in detecting ICH, with the latter showing a sensitivity of 85.7% and a high specificity of 99.3%. Interestingly, the AI detected two out of three ICH cases missed by the junior residents. When AI assistance was integrated, the combined sensitivity improved to 95.2%, and the overall accuracy reached 98.8%. Conclusions: This study shows better performance from AI and radiologist residents working together than each one alone. These results are encouraging for rethinking the radiological workflow and the future of triage of this large population of brain traumatized patients in the emergency unit.

Over the past thirty years, the complexity of the αβ-T cell compartment has been enriched by the identification of innate-like T cells (ITCs), which are composed mainly of invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. Based on animal studies using ischemia-reperfusion (IR) models, a key role has been attributed to iNKT cells in close connection with the alarmin/cytokine interleukin (IL)-33, as early sensors of cell-stress in the initiation of acute sterile inflammation. Here we have investigated whether the new concept of a biological axis of circulating iNKT cells and IL-33 applies to humans, and may be extended to other ITC subsets, namely MAIT and γδ-T cells, in the acute sterile inflammation sequence occurring during liver transplant (LT). From a prospective biological collection of recipients, we reported that LT was accompanied by an early and preferential activation of iNKT cells, as attested by almost 40% of cells having acquired the expression of CD69 at the end of LT (i.e. 1-3 hours after portal reperfusion), as opposed to only 3-4% of conventional T cells. Early activation of iNKT cells was positively correlated with the systemic release of the alarmin IL-33 at graft reperfusion. Moreover, in a mouse model of hepatic IR, iNKT cells were activated in the periphery (spleen), and recruited in the liver in WT mice, as early as the first hour after reperfusion, whereas this phenomenon was virtually missing in IL-33-deficient mice. Although to a lesser degree than iNKT cells, MAIT and γδ-T cells also seemed targeted during LT, as attested by 30% and 10% of them acquiring CD69 expression, respectively. Like iNKT cells, and in clear contrast to γδ-T cells, activation of MAIT cells during LT was closely associated with both release of IL-33 immediately after graft reperfusion and severity of liver dysfunction occurring during the first three post-operative days. All in all, this study identifies iNKT and MAIT cells in connection with IL-33 as new key cellular factors and mechanisms of acute sterile inflammation in humans. Further investigations are required to confirm the implication of MAIT and iNKT cell subsets, and to precisely assess their functions, in the clinical course of sterile inflammation accompanying LT.

Not available.

Induced volatolomics is an emerging field that holds promise for many biomedical applications including disease detection and prognosis. In this pilot study, we report the first use of a cocktail of volatile organic compounds (VOCs)-based probes to highlight new metabolic markers allowing disease prognosis. In this pilot study, we specifically targeted a set of circulating glycosidases whose activities could be associated with critical COVID-19 illness. Starting from blood sample collection, our approach relies on the incubation of VOC-based probes in plasma samples. Once activated, the probes released a set of VOCs in the sample headspace. The dynamic monitoring of the signals of VOC tracers enabled the identification of three dysregulated glycosidases in the initial phase after infection, for which preliminary machine learning analyses suggested an ability to anticipate critical disease development. This study demonstrates that our VOC-based probes are a new set of analytical tools that can provide access to biological signals until now unavailable to biologists and clinicians and which could be included in biomedical research to properly construct multifactorial therapy algorithms, necessary for personalized medicine.

The COVID-19 outbreak caused saturations of hospitals, highlighting the importance of early patient triage to optimize resource prioritization. Herein, our objective was to test if high definition metabolomics, combined with ML, can improve prognostication and triage performance over standard clinical parameters using COVID infection as an example. Using high resolution mass spectrometry, we obtained metabolomics profiles of patients and combined them with clinical parameters to design machine learning (ML) algorithms predicting severity (herein determined as the need for mechanical ventilation during patient care). A total of 64 PCR-positive COVID patients at the Poitiers CHU were recruited. Clinical and metabolomics investigations were conducted 8 days after the onset of symptoms. We show that standard clinical parameters could predict severity with good performance (AUC of the ROC curve: 0.85), using SpO2, first respiratory rate, Horowitz quotient and age as the most important variables. However, the performance of the prediction was substantially improved by the use of metabolomics (AUC = 0.92). Our small-scale study demonstrates that metabolomics can improve the performance of diagnosis and prognosis algorithms, and thus be a key player in the future discovery of new biological signals. This technique is easily deployable in the clinic, and combined with machine learning, it can help design the mathematical models needed to advance towards personalized medicine.

Introduction: Goodpasture disease, or antiglomerular basement membrane (anti-GBM) disease, is a rare autoimmune disorder that often leads to end-stage kidney disease (ESKD). Although kidney transplantation (KT) is the preferred treatment, concerns exist about disease recurrence and graft outcomes in patients with GBM-associated glomerulonephritis (GBM-GN). This study aimed to evaluate posttransplant outcomes in patients with GBM-GN compared with matched controls. Methods: This retrospective, multicenter study included 100 patients with anti-GBM who received KT between 2005 and 2023 in 13 French transplant centers, matched with 200 control recipients. We compared the incidence of delayed graft function (DGF), graft failure, relapse, acute rejection, and death between groups and analyzed risk factors using multivariable models. Results: = 0.055). Only 1 patient with GBM-GN (1%) experienced disease relapse. Although patients with GBM-GN were waitlisted and transplanted later than controls, specific transplant timing was not associated with improved outcomes. Conclusion: KT in patients with GBM-GN offers comparable outcomes to other nephropathies in the current era. Disease relapse is rare, even in the few patients with detectable antibodies pretransplantation. The lower incidence of acute rejection in the GBM-GN group warrants further investigation. These findings support KT as a viable option in patients with GBM-GN, though specific pre- and posttransplant monitoring is advised.

International audience

International audience

International audience

International audience