In rheumatoid arthritis (RA), activated synovial tissue-derived mesenchymal stem cells (MSC) acquire a pathogenic phenotype and produce pro-inflammatory cytokines, chemokines, metalloproteinases, pro-osteoclastic and pro-angiogenic factors. The acquisition of this aggressive phenotype might be due to modified expression of micro-RNAs. We aimed to clarify the role of specific micro-RNAs (miR-146a-5p, miR-221-3p, miR-34a-3p, miR-150, miR-203a-3p and miR-155-3p) in an in vitro model of RA. Methods: Micro-RNA expression was determined in RA patient plasma and in commercial human synovial tissue-derived MSC-like cells stimulated with a panel of pro-inflammatory mediators (poly I:C, TNF-α, IL-1β, IFN-γ) to mimic the rheumatoid arthritis pathogenic setting. Next, unstimulated cells or TNF-α stimulated cells were transfected with miR-146a-5p mimic or miR-221-3p mimic. Protein and/or mRNA expressions of chemokines, cytokines, VEGF, MMPs and RANKL were determined by ELISA or qRT-PCR. MiR-34a-3p, miR-146a-5p, miR-150, miR-221-3p and miR-203a-5p were upregulated in RA patient plasma versus healthy controls. Moreover, synovial tissue-derived MSC-like cells expressed miR-146a-5p and miR-221-3p in response to pro-inflammatory mediators. Overexpression of miR-146a-5p increased CCL2 and CXCL8 expression and miR-221-3p increased IL-1β and IL-6 expression in synovial tissue-derived MSC-like cells stimulated with TNF-α. Conclusion: Overexpression of miR-146a-5p and miR-221-3p might favour inflammation and participate in rheumatoid arthritis pathogenesis.

Introduction: Polymorphonuclear neutrophils (PMN) are actively recruited during COVID-19 and yet dysfunctions are associated with its prognosis. The PMN receptor CXCR4 and its ligand SDF-1/CXCL12 are known to play a role in the recruitment of PMN. The primary objective was to evaluate the modulation of this pathway in COVID-19 patients and after treatment with dexamethasone (DXM). Secondary objectives were to evaluate miRNA expression profiles. Material and Methods We conducted a prospective study comparing patients admitted to the emergency department from December 2022 to April 2023 for SARS-CoV-2 infection with a control population. We studied the PMN surface expression of the CXCR4 receptor, circulating levels of SDF-1 and miR levels. Patients treated with dexamethasone (DXM) were sampled again at H48. Results Forty-four infected patients and 20 controls were analyzed. SDF-1 levels were significantly increased in COVID-19 patients and significantly decreased after treatment by DXM and CXCR4 + PMN percentages increased significantly. SDF-1 levels on admission were associated with the risk of mechanical ventilation. Levels of miR 15b-5p, miR 146a-5p, miR 155-5p and miR 30d-5p were significantly increased in COVID-19 patients. Levels of miR-hsa-122 on admission were found significantly associated with mortality and its variation with the need for mechanical ventilation. Conclusions Our study suggests a possible involvement of the SDF-1/CXCR4 axis in the physiopathogenesis of COVID-19.

Objectives Ultrasound (US) measurements of diaphragmatic excursion (DE) are widely used to provide a non-invasive assessment of the diaphragmatic function at the bedside, especially in intensive care. However, this measurement has never been validated against a less operator-dependent technique such as MRI. Dynamic MRI is the only imaging modality that creates a four-dimensional reconstruction of the diaphragm. The primary objective of this study was to assess the agreement between DE obtained using dynamic MRI with those obtained using ultrasound. The secondary objectives were to define DE thresholds for the diagnosis of DD using MRI and to compare the performance of US and MRI to diagnose DD. Methods Prospective single-center study in which consecutive outpatients referred for a dynamic thoracic MRI were included. This study was conducted at a university hospital in Paris, where there was daily access to ultrasound (US) and extensive expertise in diaphragmatic MRI The DE of each hemi-diaphragm was measured sequentially using ultrasound and MRI in random order, during spontaneous breathing (SB) and forced inspiration (FI) by independent observers blinded to each other. We analyzed the agreement between DE obtained using US and MRI for each hemi-diaphragm. Results We enrolled forty-five patients, aged 58 ± 36 years, of which twenty-eight (68%) had a confirmed DD. During SB, the mean bias for DE measurement was −3.8 mm, 95% CI [−7.1; −0.6] for the left hemi-diaphragm, and 1.0 mm, 95% CI [−3.5; 5.5] for the right hemi-diaphragm. Limits of agreement (millimeters) were [−25; 17] on the left side, and [−28; 30] on the right side. MRI threshold values for DE defining dysfunction were 11 mm for quiet SB, and 38 mm for FI. These thresholds had a sensitivity of 77.7% and a specificity of 77.4% during SB, with an AUC of 0.86. Conclusion US and MRI provide different values for DE, probably because the measurements were not obtained exactly at the same localization. Nevertheless, diagnostic performances of MRI and US to recognize DD appeared comparable.

La intubación traqueal es una parte inseparable de la práctica diaria en la anestesia-reanimación, en la medicina de urgencias y en ciertas especialidades médicas y quirúrgicas como la otorrinolaringología. El recurso frecuente a esta técnica desde su aparición puede llevar a veces a considerar su realización si no fácil, al menos accesible al profano. Sin embargo, la intubación orotraqueal sigue siendo un procedimiento que provoca una importante morbilidad y mortalidad y que requiere un cierto dominio, especialmente en las situaciones de «intubación difícil». Por lo tanto, la especial gravedad de las complicaciones que pueden producirse en condiciones de intubación difícil requiere una preparación y una detección temprana de la probabilidad de encontrarse con una situación de este tipo. Por lo tanto, la elección del equipo debe tener en cuenta los algoritmos disponibles en la literatura y debe permitir hacer frente a todas las situaciones. El desarrollo de los distintos algoritmos forma parte de un enfoque de gestión de riesgos. La elaboración de una estrategia de tratamiento permite anticiparse a una situación crítica y se centra en el mantenimiento de la oxigenación del paciente. Desde hace varios años, nuevas técnicas y conocimientos han enriquecido la paleta técnica disponible para el profesional de la intubación con la aparición, en particular, de los dispositivos de videolaringoscopia. Estas nuevas técnicas han cambiado los algoritmos y la ergonomía del abordaje de la vía aérea superior en el paciente, tanto en la práctica de rutina como en contexto de urgencia.

IntroductionRight diaphragmatic excursion is a reliable and reproducible technique used in intensive care to assess diaphragmatic function. The aim of this study was to investigate the relationship between the appearance of diaphragmatic motion and the etiological diagnosis of patients admitted to the emergency department with acute respiratory failure (ARF).MaterialsA prospective, observational, and multicenter pilot study was conducted. All adult patients admitted in the emergency department with ARF were included. The different visual patterns of diaphragmatic motion were analyzed according to the three main etiologies of ARF encountered in emergency departments.ResultsA total of 39 adult patients were included. We observed a different visual pattern in patients with pneumonia. A sum of plateau times of less than 0.2 s predicted that the main diagnosis was pneumonia, with sensitivity = 89% 95%CI [52%; 100%], specificity = 87% 95%CI [69%; 96%].ConclusionOur study seems to show that the shape of diaphragmatic motion in patients with ARF secondary to pneumonia is different from that in patients with exacerbation of chronic obstructive pulmonary disease or acute heart failure. Trial Registration: : NCT04591509ConclusionOur study seems to show that the shape of diaphragmatic motion in patients with ARF secondary to pneumonia is different from that in patients with exacerbation of chronic obstructive pulmonary disease or acute heart failure. Trial Registration: : NCT04591509

Introduction: ICU patients with SARS-CoV-2-related pneumonia are at risk to develop a central dysautonomia which can contribute to mortality and respiratory failure. The pupillary size and its reactivity to light are controlled by the autonomic nervous system. Pupillometry parameters (PP) allow to predict outcomes in various acute brain injuries. We aim at assessing the most predictive PP of in-hospital mortality and the need for invasive mechanical ventilation (IV). Material and methods: We led a prospective, two centers, observational study. We recruited adult patients admitted to ICU for a severe SARS-CoV-2 related pneumonia between April and August 2020. The pupillometry was performed at admission including the measurement of baseline pupillary diameter (PD), PD variations (PDV), pupillary constriction velocity (PCV) and latency (PDL). Results: Fifty patients, 90 % males, aged 66 (60-70) years were included. Seven (14 %) patients died in hospital. The baseline PD (4.1 mm [3.5; 4.8] vs 2.6 mm [2.4; 4.0], P = 0.009), PDV (33 % [27; 39] vs 25 % [15; 36], P = 0.03) and PCV (3.5 mm.s(-1) [2.8; 4.4] vs 2.0 mm.s(-1) [1.9; 3.8], P = 0.02) were significantly lower in patients who will die. A PD value <2.75 mm was the most predictive parameter of in-hospital mortality, with an AUC = 0.81, CI 95 % [0.63; 0.99]. Twenty-four (48 %) patients required IV. PD and PDV were significantly lower in patients who were intubated (3.5 mm [2.8; 4.4] vs 4.2 mm [3.9; 5.2], P = 0.03; 28 % [25; 36 %] vs 35 % [32; 40], P = 0.049, respectively). Conclusions: A reduced baseline PD is associated with bad outcomes in COVID-19 patients admitted in ICU. It is likely to reflect a brainstem autonomic dysfunction.

In the version of this article initially published, there was an error in the fifth sentence of the "Function is nsPs" subsection, where in the text now reading "sgRNA is translated to produce the structural proteins," "structural proteins" initially read "nsPs" (non-structural proteins).In Figure 2, step 1, the percentage values "7-13%" on the left and "87-93%" on the right were initially reversed.The third sentence of the Figure 2 legend referred to "micropinocytosis" instead of "macropinocytosis".The errors have been corrected in the HTML and PDF versions of the article.

Chikungunya virus is widespread throughout the tropics, where it causes recurrent outbreaks of chikungunya fever. In recent years, outbreaks have afflicted populations in East and Central Africa, South America and Southeast Asia. The virus is transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Chikungunya fever is characterized by severe arthralgia and myalgia that can persist for years and have considerable detrimental effects on health, quality of life and economic productivity. The effects of climate change as well as increased globalization of commerce and travel have led to growth of the habitat of Aedes mosquitoes. As a result, increasing numbers of people will be at risk of chikungunya fever in the coming years. In the absence of specific antiviral treatments and with vaccines still in development, surveillance and vector control are essential to suppress re-emergence and epidemics.

Glioblastoma, IDH wild-type is the most common and aggressive form of glial tumors. The exact mechanisms of glioblastoma oncogenesis, including the identification of the glioma-initiating cell, are yet to be discovered. Recent studies have led to the hypothesis that glioblastoma arises from neural stem cells and glial precursor cells and that cell lineage constitutes a key determinant of the glioblastoma molecular subtype. These findings brought significant advancement to the comprehension of gliomagenesis. However, the cellular origin of glioblastoma with mesenchymal molecular features remains elusive. Mesenchymal stromal cells emerge as potential glioblastoma-initiating cells, especially with regard to the mesenchymal molecular subtype. These fibroblast-like cells, which derive from the neural crest and reside in the perivascular niche, may underlie gliomagenesis and exert pro-tumoral effects within the tumor microenvironment. This review synthesizes the potential roles of mesenchymal stromal cells in the context of glioblastoma and provides novel research avenues to better understand this lethal disease.

Old world alphaviruses (e.g., chikungunya) are known to cause severe acute and chronic debilitating arthralgia/arthritis. However, atypical neurological manifestations and, in particular, unexpected cases of acute inflammatory Guillain–Barre syndrome (GBS) have been associated with the arthritogenic alphaviruses. The pathogenesis of alphavirus-associated GBS remains unclear. We herein addressed for the first time the role of Schwann cells (SC) in peripheral neuropathy post-alphaviral infection using the prototypical ONNV alphavirus model. We demonstrated that human SC expressed the recently identified alphavirus receptor MxRA8 and granting viral entry and robust replication. A canonical innate immune response was engaged by ONNV-infected SC with elevated gene expression for RIG-I, MDA5, IFN-β, and ISG15 and inflammatory chemokine CCL5. Transcription levels of prostaglandin E2-metabolizing enzymes including cPLA2α, COX-2, and mPGES-1 were also upregulated in ONNV-infected SC. Counterintuitively, we found that ONNV failed to affect SC regenerative properties as indicated by elevated expression of the pro-myelinating genes MPZ and MBP1 as well as the major pro-myelin transcription factor Egr2. While ONNV infection led to decreased expression of CD55 and CD59, essential to control complement bystander cytotoxicity, it increased TRAIL expression, a major pro-apoptotic T cell signal. Anti-apoptotic Bcl2 transcription levels were also increased in infected SC. Hence, our study provides new insights regarding the remarkable immunomodulatory role of SC of potential importance in the pathogenesis of GBS following alphavirus infection.

The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.

Mesenchymal stem cells (MSCs) play a critical role in response to stress such as infection. They initiate the removal of cell debris, exert major immunoregulatory activities, control pathogens, and lead to a remodeling/scarring phase. Thus, host-derived ‘danger’ factors released from damaged/infected cells (called alarmins, e.g., HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (LPS, single strand RNA) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of growth factors and chemoattractant molecules that influence immune cell recruitment and stem cell mobilization. MSC, in an ultimate contribution to tissue repair, may also directly trans- or de-differentiate into specific cellular phenotypes such as osteoblasts, chondrocytes, lipofibroblasts, myofibroblasts, Schwann cells, and they may somehow recapitulate their neural crest embryonic origin. Failure to terminate such repair processes induces pathological scarring, termed fibrosis, or vascular calcification. Interestingly, many viruses and particularly those associated to chronic infection and inflammation may hijack and polarize MSC’s immune regulatory activities. Several reports argue that MSC may constitute immune privileged sanctuaries for viruses and contributing to long-lasting effects posing infectious challenges, such as viruses rebounding in immunocompromised patients or following regenerative medicine therapies using MSC. We will herein review the capacity of several viruses not only to infect but also to polarize directly or indirectly the functions of MSC (immunoregulation, differentiation potential, and tissue repair) in clinical settings.

PURPOSE Ultrasound (US) allows non-invasive repeated assessments of diaphragmatic excursion (DE) and thickening fraction (DTF) at the bedside, reflecting diaphragmatic dysfunction (DD). We aimed at determining the prevalence and time-course of DD following elective thoracic surgery and the association with postoperative complications. MATERIAL AND METHODS Prospective, single-centre, observational study with consecutive patients undergoing thoracic surgery. DE/DTF were measured by two observers blinded to each other at 3 different time-points: prior to surgery, immediately after extubation and on postoperative day 3. The changes in DE/DTF of both hemi-diaphragms over time were compared according to the side (operated/non-operated) using a two-way-ANOVA. The association with postoperative complications was assessed using logistic regression. RESULTS Fifty patients, 60% males, aged 60 ± 15 years were included. Surgical procedures included lobectomy (n = 30), wedge-resection (n = 17) or pneumonectomy (n = 3). On the operated side, we observed a decrease in DE/DTF at D0 (-0.71 ± 0.12 mm, P < 0.05; -44 ± 30%, P < 0.05) and D3 (-0.82 ± 0.19 mm, P < 0.05; -39 ± 19%, P < 0.05) with respect to preoperative and non-operated side values over the study period. Persistent DD on the operated side was associated with an increased risk of lung infection (OR: 9.0, 95%CI [1.92-65.93], P = 0.001), ICU-admission (OR: 3.9, 95%CI [1.10-15.53], P = 0.04) according to univariate analysis and a prolonged length in hospital (OR: 1.3, 95%CI [1.1-1.7], P = 0.016) according to multivariate analysis. CONCLUSIONS Thoracic surgery generates DD mainly observed on the operated side, which persists at least up to postoperative D3 and is associated with an increase in hospital stay.

The weaker diffusion of echinocandins in the peritoneal fluid (PF) could promote Candida-resistant isolates. The aim of this study was to analyze the pharmacokinetics (PK)/pharmacodynamics (PD) of caspofungin in plasma and PF samples from liver transplant recipients. Liver transplant patients received caspofungin as postoperative prophylaxis. Caspofungin concentrations were quantified in plasma and PF samples on days 1, 3, and 8. Data were analyzed using nonlinear mixed-effect modeling and Monte Carlo simulations. Area under the curve (AUC) values for plasma and PF were simulated under three dosing regimens. Probabilities of target attainment (PTAs) were calculated using area under the unbound plasma concentration-time curve from 0 to 24 h at steady state (fAUC(0-24))/MIC ratios, with MICs ranging from 0.008 to 8 mg/L. All of the patients included were monitored weekly for Candida colonization and for Candida infections. Twenty patients were included. The median daily dose of caspofungin was 0.81 mg/kg. Plasma (n = 395) and PF (n = 50) concentrations at steady state were available. A two-compartment model with first-order absorption and elimination was described. Our two-compartment model with first-order absorption and elimination produced an effective PK/PD relationship in plasma, achieving a PTA of >= 90% with MICs ranging from 0.008 to 0.12 mg/L for Candida albicans and Candida glabrata. In PF, PTAs at D8 were optimal only for a MIC of 0.008 mg/L in patients weighing 60 kg under the three dosing regimens. Among the 16 patients colonized, all MIC values were below the maximal concentration (C-max) in plasma but not in PF. PF concentrations of caspofungin were low. Simulations showed that the PTAs for Candida spp. in PF were not optimal, which might suggest a potential risk of resistance.

L’intubazione tracheale costituisce un atto imprescindibile della pratica quotidiana in anestesia-rianimazione, in medicina d’urgenza e in alcune specialità medicochirurgiche, come l’oto-rino-laringoiatria. L’uso frequente di questa tecnica sin dal suo avvento può, talvolta, portare a considerare la sua realizzazione, se non agevole, almeno accessibile al profano. Tuttavia, l’intubazione orotracheale rimane un gesto responsabile di una significativa morbimortalità e richiede una certa esperienza, a maggior ragione nelle cosiddette situazioni di “intubazione difficile”. La particolare gravità delle complicanze che possono manifestarsi in condizioni di intubazione difficile richiede, quindi, di essere preparati e di rilevare a monte la probabilità di incontrare tale situazione. Pertanto, la scelta delle attrezzature deve tenere conto degli algoritmi disponibili in letteratura e deve consentire di affrontare tutte le situazioni. Lo sviluppo dei vari algoritmi fa parte di un processo di padronanza del rischio. Lo sviluppo di una strategia di gestione consente di anticipare una situazione critica e rimane focalizzato sul mantenimento dell’ossigenazione del paziente. Da diversi anni, nuove tecniche e conoscenze hanno arricchito la gamma di tecniche a disposizione del professionista per l’intubazione, con la comparsa, in particolare, dei dispositivi di videolaringoscopia. Queste nuove tecniche hanno rivoluzionato gli algoritmi e l’ergonomia d’accesso delle vie aeree superiori nel paziente sia nella pratica quotidiana che nei contesti di urgenza.