Effect of Noninvasive Airway Management of Comatose Patients With Acute Poisoning: A Randomized Clinical Trial.

Importance: Tracheal intubation is recommended for coma patients and those with severe brain injury, but its use in patients with decreased levels of consciousness from acute poisoning is uncertain. Objective: To determine the effect of intubation withholding vs routine practice on clinical outcomes of comatose patients with acute poisoning and a Glasgow Coma Scale score less than 9. Design, Setting, and Participants: This was a multicenter, randomized trial conducted in 20 emergency departments and 1 intensive care unit (ICU) that included comatose patients with suspected acute poisoning and a Glasgow Coma Scale score less than 9 in France between May 16, 2021, and April 12, 2023, and followed up until May 12, 2023. Intervention: Patients were randomized to undergo conservative airway strategy of intubation withholding vs routine practice. Main Outcomes and Measures: The primary outcome was a hierarchical composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Key secondary outcomes included adverse events resulting from intubation as well as pneumonia within 48 hours. Results: Among the 225 included patients (mean age, 33 years; 38% female), 116 were in the intervention group and 109 in the control group, with respective proportions of intubations of 16% and 58%. No patients died during the in-hospital stay. There was a significant clinical benefit for the primary end point in the intervention group, with a win ratio of 1.85 (95% CI, 1.33 to 2.58). In the intervention group, there was a lower proportion with any adverse event (6% vs 14.7%; absolute risk difference, 8.6% [95% CI, -16.6% to -0.7%]) compared with the control group, and pneumonia occurred in 8 (6.9%) and 16 (14.7%) patients, respectively (absolute risk difference, -7.8% [95% CI, -15.9% to 0.3%]). Conclusions and Relevance: Among comatose patients with suspected acute poisoning, a conservative strategy of withholding intubation was associated with a greater clinical benefit for the composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Trial Registration: ClinicalTrials.gov Identifier: NCT04653597.

Pharmacokinetics/Pharmacodynamics of Caspofungin in Plasma and Peritoneal Fluid of Liver Transplant Recipients.

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 (fAUC0-24)/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 (Cmax) 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.

Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs).

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.

Perivascular Mesenchymal Stem/Stromal Cells, an Immune Privileged Niche for Viruses?

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.

Intramolecular Metal-Free N-N Bond Formation with Heteroaromatic Amines: Mild Access to Fused-Triazapentalene Derivatives.

Formation of N-N bonds may offer an original approach to various nitrogen-containing heterocycles with numerous applications. For this purpose, we found that readily available heteroaromatic amines are appropriate substrates for providing an efficient and innovative approach for the formation of N-N bonds in the presence of iodine (III) reagent in very mild conditions. This method makes it possible to synthesize nitrogen rich triazapentalene derivatives exhibiting fluorescent properties, inaccessible with existing approaches.

Prognosis value of pupillometry in COVID-19 patients admitted in intensive care unit.

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.

Chikungunya fever.

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.

Deciphering the Role of Schwann Cells in Inflammatory Peripheral Neuropathies Post Alphavirus Infection.

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-ß, 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.

Prevalence and time-course of diaphragmatic dysfunction following lung resection: A repeated ultrasonic assessment.

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.