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Aims To assess the efficacy and safety of a standardised hyperbaric oxygen therapy protocol (HBOT) monitored by fluorescein angiography (FA) in patients with retinal artery occlusion (RAO). Methods It is a prospective, non-comparative, monocentric study conducted between July 2016 and March 2022. All consecutive patients diagnosed with RAO within 7 days underwent visual acuity measurement, FA, macular optical coherence tomography (OCT) and OCT-angiography. They received two daily HBOT sessions (2.5 atmosphere absolute, 90 min) until revascularisation assessed by FA. Complete ophthalmic follow-up was scheduled at day 14, day 21 and at 1 month. The main outcome measure was a best-corrected visual acuity (BCVA) improvement defined as a decrease =0.3 logMAR at 1 month. Results Thirty-one patients were included and received a mean number of 33.9 (13-56) HBOT sessions. Retinal revascularisation was observed in 48.4% and 87.1% of patients at days 14 and 21, respectively. The mean BCVA on referral and at 1 month was 1.51 logMAR and 1.10 logMAR, respectively. Fifteen (48.4%) patients achieved the main outcome measure. Six (19.4%) patients experienced minor barotrauma that did not require HBOT discontinuation. The univariate analysis showed that antiplatelet-treated patients (p=0.044) and patients with a poor initial BCVA (p=0.008) were more likely to achieve a BCVA improvement. OCT-angiography was not sensitive enough to diagnose RAO or assess revascularisation. Conclusion In RAO patients monitored by FA until spontaneous revascularisation of the central retinal artery, HBOT was effective and safe. [ABSTRACT FROM AUTHOR]

The French Committee for Monitoring and Anticipating Health Risks (COVARS) has been strengthening the One Health approach through its interdisciplinary and multi-sectoral composition, the emerging risks it addresses (Covid-19, Mpox, vector-borne diseases, avian influenza...), its holistic approach to risks and its position at the science-decision interface. Following the COVID-19 pandemic, the French government established a committee for monitoring and anticipating health risks. In this Comment, the authors describe the One Health approach taken by the committee, and outline its aims, composition, and initial actions. [ABSTRACT FROM AUTHOR]

As new SARS-CoV-2 variants emerge, there is an urgent need to increase the efficiency and availability of viral genome sequencing, notably to detect the lineage in samples with a low viral load. SARS-CoV-2 genome next-generation sequencing (NGS) was performed retrospectively in a single center on 175 positive samples from individuals. An automated workflow used the Ion AmpliSeq SARS-CoV-2 Insight Research Assay on the Genexus Sequencer. All samples were collected in the metropolitan area of the city of Nice (France) over a period of 32 weeks (from 19 July 2021 to 11 February 2022). In total, 76% of cases were identified with a low viral load (Ct ≥ 32, and ≤200 copies/µL). The NGS analysis was successful in 91% of cases, among which 57% of cases harbored the Delta variant, and 34% the Omicron BA.1.1 variant. Only 9% of cases had unreadable sequences. There was no significant difference in the viral load in patients infected with the Omicron variant compared to the Delta variant (Ct values, p = 0.0507; copy number, p = 0.252). We show that the NGS analysis of the SARS-CoV-2 genome provides reliable detection of the Delta and Omicron SARS-CoV-2 variants in low viral load samples. [ABSTRACT FROM AUTHOR]

Purpose Point‐of‐care ultrasound using a pocket‐ultrasound‐device (PUD) is increasing in clinical medicine but the optimal way to teach focused cardiac ultrasound is not clear. We evaluated whether teaching using a PUD or a conventional‐ultrasound‐device (CUD) is different when the final exam was conducted on a PUD. The primary aim was to compare the weighted total quality scale (WTQS, out of 100) obtained by participants in the two groups (CUD and PUD) on a live volunteer 2–4 weeks after their initial training. The secondary aims were to compare examination time and students' confidence levels (out of 50). Methods: This bicentric, prospective single‐blind randomized trial included undergraduate medical students. After watching a 15 min video about echocardiography views, students had a 45 min hands‐on training session with a live volunteer using a PUD or a CUD. The final examination was conducted with a PUD on a live volunteer. Results: Eighty‐six comparable students were included, with 4 ± 1 years of medical training. In the PUD group, the mean WTQS was 65 ± 16 versus 60 ± 15 in the CUD group [p = 0.22; in multivariate analysis, OR 0.8 95% CI (0.1;1.6), p = 0.34]. The examination time was 10.0 [6.2–12.4] min in the PUD group versus 11.4 [7.3–13.2] in the CUD group (p = 0.39), while the confidence level was 27.9 ± 7.7 in the PUD group versus 27.4 ± 7.2 in the CUD group (p = 0.76). Conclusion: There was no difference between teaching echocardiographic views using a PUD as compared to a CUD on the PUD image quality, exam time, or confidence level of students. [ABSTRACT FROM AUTHOR]

The variant 20I/501Y.V1, associated to a higher risk of transmissibility, emerged in Nice city (Southeast of France, French Riviera) during January 2021. The pandemic has resumed late December 2020 in this area. A high incidence rate together with a fast turn-over of the main circulating variants, provided us the opportunity to analyze modifications in clinical profile and outcome traits. We performed an observational study in the University hospital of Nice from December 2020 to February 2021. We analyzed data of sequencing of SARS-CoV-2 from the sewage collector and PCR screening from all positive samples at the hospital. Then, we described the characteristics of all COVID-19 patients admitted in the emergency department (ED) (n = 1247) and those hospitalized in the infectious diseases ward or ICU (n = 232). The UK-variant was absent in this area in December, then increasingly spread in January representing 59% of the PCR screening performed mid-February. The rate of patients over 65 years admitted to the ED decreased from 63 to 50% (p = 0.001). The mean age of hospitalized patients in the infectious diseases ward decreased from 70.7 to 59.2 (p < 0.001) while the proportion of patients without comorbidity increased from 16 to 42% (p = 0.007). Spread of the UK-variant in the Southeast of France affects younger and healthier patients. [ABSTRACT FROM AUTHOR]

Key points: Patients with end‐stage renal failure need arteriovenous fistulas (AVF) to undergo dialysis. However, AVFs present a high rate of failure as a result of excessive venous thickness.Excessive venous thickness may be a consequence of surgical dissection and change in oxygen concentration within the venous wall.We show that venous cells adapt their metabolism and growth depending on oxygen concentration, and drugs targeting the hypoxic response pathway modulate this response in vitro.We used the same drugs on a mouse model of AVF and show that direct or indirect inhibition of the hypoxia‐inducible factors (HIFs) help decrease excessive venous thickness.Hypoxia and HIFs can be targets of therapeutic drugs to prevent excessive venous thickness in patients undergoing AVF surgical creation. Because the oxygen concentration changes in the venous wall, surrounding tissue and the blood during surgical creation of arteriovenous fistula (AVF), we hypothesized that hypoxia could contribute to AVF failure as a result of neointimal hyperplasia. We postulated that modulation of the hypoxia‐inducible factors (HIF) with pharmacological compounds could promote AVF maturation. Fibroblasts [normal human fibroblasts (NHF)], smooth muscle cells [human umbilical vein smooth muscle cells (HUVSMC)] and endothelial cells [human umbilical vein endothelial cells (HUVEC)], representing the three layers of the venous wall, were tested in vitro for proliferation, cell death, metabolism, reactive oxygen species production and migration after silencing of HIF1/2‐α or after treatment with deferioxamine (DFO), everolimus (Eve), metformin (Met), N‐acetyl‐l‐cysteine (NAC) and topoisomerase I (TOPO), which modulate HIF‐α stability or activity. Compounds that were considered to most probably modify intimal hyperplasia were applied locally to the vessels in a mouse model of aortocaval fistula. We showed, in vitro, that NHF and HUVSMC can adapt their metabolism and thus their growth depending on oxygen concentration, whereas HUVEC appears to be less flexible. siHIF1/2α, DFO, Eve, Met, NAC and TOPO can modulate metabolism and proliferation depending on the cell type and the oxygen concentration. In vivo, siHIF1/2α, Eve and TOPO decreased neointimal hyperplasia by 32%–50%, 7 days after treatment. Within the vascular wall, hypoxia and HIF‐1/2 mediate early failure of AVF. Local delivery of drugs targeting HIF‐1/2 could inhibit neointimal hyperplasia in a mouse model of AVF. Such compounds may be delivered during the surgical procedure for AVF creation to prevent early AVF failure. Key points: Patients with end‐stage renal failure need arteriovenous fistulas (AVF) to undergo dialysis. However, AVFs present a high rate of failure as a result of excessive venous thickness.Excessive venous thickness may be a consequence of surgical dissection and change in oxygen concentration within the venous wall.We show that venous cells adapt their metabolism and growth depending on oxygen concentration, and drugs targeting the hypoxic response pathway modulate this response in vitro.We used the same drugs on a mouse model of AVF and show that direct or indirect inhibition of the hypoxia‐inducible factors (HIFs) help decrease excessive venous thickness.Hypoxia and HIFs can be targets of therapeutic drugs to prevent excessive venous thickness in patients undergoing AVF surgical creation. [ABSTRACT FROM AUTHOR]

Arteriovenous fistulas (AVFs) are the preferred vascular access for haemodialysis of patients suffering from end‐stage renal disease, a worldwide public health problem. However, they are prone to a high rate of failure due to neointimal hyperplasia and stenosis. This study aimed to determine if osteopontin (OPN) was induced in hypoxia and if OPN could be responsible for driving AVF failure. Identification of new factors that participate in remodelling of AVFs is a challenge. Three cell lines representing the cells of the three layers of the walls of arteries and veins, fibroblasts, smooth muscle cells and endothelial cells, were tested in mono‐ and co‐culture in vitro for OPN expression and secretion in normoxia compared to hypoxia after silencing the hypoxia‐inducible factors (HIF‐1α, HIF‐2α and HIF‐1/2α) with siRNA or after treatment with an inhibitor of NF‐kB. None of the cells in mono‐culture showed OPN induction in hypoxia, whereas cells in co‐culture secreted OPN in hypoxia. The changes in oxygenation that occur during AVF maturation up‐regulate secretion of OPN through cell‐cell interactions between the different cell layers that form AVF, and in turn, these promote endothelial cell proliferation and could participate in neointimal hyperplasia. [ABSTRACT FROM AUTHOR]

We evaluate in this retrospective cohort, the clinical situations leading emergency physicians to take a blood lactate sample, the prevalence of hyperlactatemia and its impact on short-term adverse outcome. ED patients requiring a blood lactate measurement (BLM) during a two-year period were included. Early patients' outcomes were extracted and discharge diagnoses were classified into 12 diagnostic categories. A total of 118,737 patients were analyzed. A BLM was carried out in 13,089 of them. Surprisingly, the proportion of patients having a BLM was higher in those admitted for seizure (31.4%) than in those admitted for infection (27.9%). Ten percent of patients who had a blood lactate test had a lactate level >4 mmol/l (1,315). Among them, 23.2% were admitted for infections, 20% for seizures, and 11% for cardiovascular diseases. After excluding the patients older than 75 years from the analysis in order to prevent a selection bias, the patient's severity was independently associated to an age over 65 years (OR: 1.26), an arterial blood sampling (OR: 2.77) and the blood lactate level (OR: 1.31). The blood lactate level was very informative to detect the sicker patients in the infection group whereas its interest was poor in the group of patients admitted for seizures. In conclusion, blood lactate testing has become routine in emergency departments and a large proportion of patients have abnormal blood lactate levels. The most frequent causes of high blood lactate in the ED are infection and seizures but the prognostic value of blood lactate seems to be different from one diagnostic category to the other. [ABSTRACT FROM AUTHOR]

Objectives: Measurement of blood lactate concentration in the early management of sepsis is an important step in severity assessment. High blood lactate levels in the early phase of sepsis have classically been thought to be related to tissue hypoxia, but other factors could intervene. We hypothesized that the activation of glycolysis through β-adrenergic stimulation by endogenous catecholamines plays an important role in lactate production and that long-term β-blocker therapy could affect the lactate concentration in patients with severe sepsis and septic shock.Design: Retrospective cohort study.Setting: Emergency department.Patients: Two hundred sixty patients with severe sepsis or septic shock were included. Twenty-five percent were previously treated with β-blockers.Interventions: None.Measurements and Main Results: We recorded initial vital signs, the source of infection, mortality at 28 days, blood lactate concentration, and Predisposition Insult Response of Organ failure and Sequential Organ Failure Assessment scores using an electronic database. Blood lactate concentration was significantly lower in patients previously treated with β-blockers (3.9 ± 2.3 mmol/L vs 5.6 ± 3.6 mmol/L; p < 0.001). This difference was still significant after controlling for mortality (p < 0.005), for the level of the Predisposition Insult Response of Organ failure (p < 0.05) and Sequential Organ Failure Assessment (p < 0.05) scores, and for the source of infection (p < 0.05). Nearly four times more patients treated with β-blockers had normal blood lactate levels (p< 0.001). Only two factors were significantly and independently associated with normal blood lactate concentration during severe sepsis and septic shock: survival (p = 0.03) and β-blocker therapy (p = 0.01).Conclusions: Long-term β-blocker therapy decreases blood lactate concentration of severely ill septic patients at presentation. We conclude that the use of blood lactate measurement as a triage tool in the initial assessment of septic patients with β-blocker therapy may underestimate the severity of the sepsis. [ABSTRACT FROM AUTHOR]

Simple Summary: Here, we demonstrate that the hypoxia-induced cleaved form of VDAC1 (VDAC1-ΔC) reprograms the cell to utilize more metabolites and is implicated in up-regulation of glycolysis and mitochondrial respiration, conferring a direct survival advantage in hypoxic microenvironment. We further highlight a direct relationship between VDAC1-ΔC, the primary cilium and cell metabolism. Metabolic flexibility is the ability of a cell to adapt its metabolism to changes in its surrounding environment. Such adaptability, combined with apoptosis resistance provides cancer cells with a survival advantage. Mitochondrial voltage-dependent anion channel 1 (VDAC1) has been defined as a metabolic checkpoint at the crossroad of these two processes. Here, we show that the hypoxia-induced cleaved form of VDAC1 (VDAC1-ΔC) is implicated in both the up-regulation of glycolysis and the mitochondrial respiration. We demonstrate that VDAC1-ΔC, due to the loss of the putative phosphorylation site at serine 215, concomitantly with the loss of interaction with tubulin and microtubules, reprograms the cell to utilize more metabolites, favoring cell growth in hypoxic microenvironment. We further found that VDAC1-ΔC represses ciliogenesis and thus participates in ciliopathy, a group of genetic disorders involving dysfunctional primary cilium. Cancer, although not representing a ciliopathy, is tightly linked to cilia. Moreover, we highlight, for the first time, a direct relationship between the cilium and cancer cell metabolism. Our study provides the first new comprehensive molecular-level model centered on VDAC1-ΔC integrating metabolic flexibility, ciliogenesis, and enhanced survival in a hypoxic microenvironment. [ABSTRACT FROM AUTHOR]

For patients with end-stage renal disease requiring hemodialysis, their vascular access is both their lifeline and their Achilles heel. Despite being recommended as primary vascular access, the arteriovenous fistula (AVF) shows sub-optimal results, with about 50% of patients needing a revision during the year following creation. After the AVF is created, the venous wall must adapt to new environment. While hemodynamic changes are responsible for the adaptation of the extracellular matrix and activation of the endothelium, surgical dissection and mobilization of the vein disrupt the vasa vasorum, causing wall ischemia and oxidative stress. As a consequence, migration and proliferation of vascular cells participate in venous wall thickening by a mechanism of neointimal hyperplasia (NH). When aggressive, NH causes stenosis and AVF dysfunction. In this review we show how hypoxia, metabolism, and flow parameters are intricate mechanisms responsible for the development of NH and stenosis during AVF maturation. [ABSTRACT FROM AUTHOR]

A response from the author of the article "Long-term β-blocker therapy decreases blood lactate concentration in severely septic patients" that was published in the previous issue, is presented.

A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here, we show that specific RAC2 activating mutations induce the NLRP3 inflammasome activation leading to the secretion of IL-1β and IL-18 from macrophages. This activation depends on the activation state of the RAC2 variant and is mediated by the downstream kinase PAK1. Inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients., (© 2024 Doye et al.)

Rationale : Renal cell carcinoma (RCC) accounts for about 2% of all adult cancers, and clear cell RCC (ccRCC) is the most common RCC histologic subtype. A hallmark of ccRCC is the loss of the primary cilium, a cellular antenna that senses a wide variety of signals. Loss of this key organelle in ccRCC is associated with the loss of the von Hippel-Lindau protein (VHL). However, not all mechanisms of ciliopathy have been clearly elucidated. Methods : By using RCC4 renal cancer cells and patient samples, we examined the regulation of ciliogenesis via the presence or absence of the hypoxic form of the voltage-dependent anion channel (VDAC1-ΔC) and its impact on tumor aggressiveness. Three independent cohorts were analyzed. Cohort A was from PREDIR and included 12 patients with hereditary pVHL mutations and 22 sporadic patients presenting tumors with wild-type pVHL or mutated pVHL; Cohort B included tissue samples from 43 patients with non-metastatic ccRCC who had undergone surgery; and Cohort C was composed of 375 non-metastatic ccRCC tumor samples from The Cancer Genome Atlas (TCGA) and was used for validation. The presence of VDAC1-ΔC and legumain was determined by immunoblot. Transcriptional regulation of IFT20/GLI1 expression was evaluated by qPCR. Ciliogenesis was detected using both mouse anti-acetylated α-tubulin and rabbit polyclonal ARL13B antibodies for immunofluorescence. Results : Our study defines, for the first time, a group of ccRCC patients in which the hypoxia-cleaved form of VDAC1 (VDAC1-ΔC) induces resorption of the primary cilium in a Hypoxia-Inducible Factor-1 (HIF-1)-dependent manner. An additional novel group, in which the primary cilium is re-expressed or maintained, lacked VDAC1-ΔC yet maintained glycolysis, a signature of epithelial-mesenchymal transition (EMT) and more aggressive tumor progression, but was independent to VHL. Moreover, these patients were less sensitive to sunitinib, the first-line treatment for ccRCC, but were potentially suitable for immunotherapy, as indicated by the immunophenoscore and the presence of PDL1 expression. Conclusion : This study provides a new way to classify ccRCC patients and proposes potential therapeutic targets linked to metabolism and immunotherapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: An accurate diagnosis of sepsis in the emergency department must be made before appropriate treatment can be started. Many biomarkers that are potentially useful have been studied. The main aim of this study was to compare the diagnostic accuracy of blood levels of presepsin, lactate, C-reactive protein (CRP), and procalcitonin (PCT) for predicting sepsis as defined by the Sepsis-3 criteria. The secondary aim was to evaluate the diagnostic accuracy of these biomarkers for predicting bacteremia whether or not sepsis or septic shock was present., Material and Methods: Single-center, prospective, observational cohort study in the emergency department of a university hospital. Consecutive patients suspected of having infection were enrolled prospectively if they had at least 2 criteria for systemic inflammatory response syndrome. We measured presepsin, PCT, CRP, and lactate in blood extracted on admission., Results: Blood samples from 359 patients were analyzed; 228 (63.5%) met the criteria for sepsis and 20 (5.6%) met the criteria for septic shock. PCT and presepsin levels were the best predictors of sepsis and septic shock with areas under the receiver operating characteristic curve (AUC) of 0.711 (95% CI, 0.660-0.758) and 0.709 (95% CI, 0.658- 0.756), respectively (P <.001, both comparisons). The AUCs for CRP and lactate concentrations were, respectively, 0.63 (95% CI, 0.58-0.69) and 0.61 (95% CI, 0.56-0.66) (P <.05, both comparisons). On applying the diagnostic cut points of 0.25 ng/mL for PCT and 500 pg/mL for presepsin, the odds ratios were 2.51 (95% CI, 1.53-4.12) for PCT and 3.19 (95% CI, 1.91-5.31) for presepsin. The diagnostic accuracy of the combination of presepsin and PCT results (AUC, 0.71; 95% CI 0.66-0.76; P <.001) was no better than the accuracy of PCT alone. The most accurate predictor of bacteremia was PCT (AUC, 0.835; 95% CI, 0.79-0.87; P <.001)., Conclusion: Presepsin and PCT seem to be the best predictors of a diagnosis of sepsis or septic shock in emergency department patients.