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We investigate the potential of surface plasmon polaritons at noble metal interfaces for surface-enhanced chiroptical sensing of dilute chiral drug solutions with nl volume. The high quality factor of surface plasmon resonances in both Otto and Kretschmann configurations enables the enhancement of circular dichroism differenatial absorption thanks to the large near-field intensity of such plasmonic excitations. Furthermore, the subwavelength confinement of surface plasmon polaritons is key to attain chiroptical sensitivity to small amounts of drug volumes placed around ≃100 nm by the metal surface. Our calculations focus on reparixin, a pharmaceutical molecule currently used in clinical studies for patients with community-acquired pneumonia, including COVID-19 and acute respiratory distress syndrome. Considering realistic dilute solutions of reparixin dissolved in water with concentration ≤ 5 mg/ml and nl volume, we find a circular-dichroism differential absorption enhancement factor of the order ≃20 and chirality-induced polarization distortion upon surface plasmon polariton excitation. Our results are relevant for the development of innovative chiroptical sensors capable of measuring the enantiomeric imbalance of chiral drug solutions with nl volume. [ABSTRACT FROM AUTHOR]

Background: There is accumulating evidence regarding the benefits of the 5-HT3 receptor antagonist ondansetron for the treatment of critical illness due to its potential anti-inflammatory effect. This study attempted to determine the potential targets and molecular mechanisms of ondansetron's action against critical illnesses. Methods: A bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets and the signaling pathways of ondansetron action against the most common critical illnesses such as acute kidney injury (AKI), sepsis, and acute respiratory distress syndrome (ARDS). Experiments of LPS- stimulated rat neutrophilswith ondansetron treatmentwere conducted to further validate the relevant hypothesis. Results: A total of 198, 111, and 26 primary causal targets were identified fromthe data for the action of ondansetron against AKI, sepsis, and ARDS respectively. We found that the pathway of neutrophil extracellular traps (NETs) formation is statistically significantly involved in the action of ondansetron against these three critical illnesses. In the pathway of NETs formation, the common drug- disease intersection targets in these three critical illnesses were toll-like receptor 8(TLR8),mitogen-activated protein kinase-14 (MAPK14), nuclear factor kappa-B1 (NFKB1), neutrophil elastase (NE), andmyeloperoxidase (MPO). Considering these bioinformatics findings, we concluded that ondansetron anti-critical illness effects are mechanistically and pharmacologically implicated with suppression of neutrophils-associated inflammatory processes. It was also showed that after treatment of LPS-stimulated rat neutrophils with ondansetron, the key proteins NE, MPO, and Peptide Arginine Deaminase 4 (PAD4) in the NETs formation were significantly reduced, and the inflammatory factors IL-6, IL-1β, TNF-α, and chemokine receptor (CXCR4) were also significantly decreased. Conclusion: The excessive formation of NETsmay have important research value in the development and progression of critical illness. Ondansetron may reduce excessive inflammatory injury in critical diseases by reducing the formation of NETs via influencing the five targets: TLR8, NFKB1, MAPK14, NE, and MPO. Ondansetron and these primary predictive biotargets may potentially be used to treat critical illness in future clinical practice. [ABSTRACT FROM AUTHOR]

Mitochondria play a significant and varied role in inflammatory lung disorders. Mitochondria, known as the powerhouse of the cell because of their role in producing energy, are now recognized as crucial regulators of inflammation and immunological responses. Asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome are characterized by complex interactions between immune cells, inflammatory substances, and tissue damage. Dysfunctional mitochondria can increase the generation of reactive oxygen species (ROS), triggering inflammatory pathways. Moreover, mitochondrial failure impacts cellular signaling, which in turn affects the expression of molecules that promote inflammation. In addition, mitochondria have a crucial role in controlling the behavior of immune cells, such as their activation and differentiation, which is essential in the development of inflammatory lung diseases. Their dynamic behavior, encompassing fusion, fission, and mitophagy, also impacts cellular responses to inflammation and oxidative stress. Gaining a comprehensive understanding of the intricate correlation between mitochondria and lung inflammation is essential in order to develop accurate treatment strategies. Targeting ROS generation, dynamics, and mitochondrial function may offer novel approaches to treating inflammatory lung diseases while minimizing tissue damage. Additional investigation into the precise contributions of mitochondria to lung inflammation will provide significant knowledge regarding disease mechanisms and potential therapeutic approaches. This review will focus on how mitochondria in the lung regulate these processes and their involvement in acute and chronic lung diseases. [ABSTRACT FROM AUTHOR]

Background: Postoperative hypoxemia and pulmonary complications remain a frequent event after on-pump cardiac surgery and mostly characterized by pulmonary atelectasis. Surfactant dysfunction or hyposecretion happens prior to atelectasis formation, and sigh represents the strongest stimulus for surfactant secretion. The role of sigh breaths added to conventional lung protective ventilation in reducing postoperative hypoxemia and pulmonary complications among cardiac surgery is unknown. Methods: The perioperative sigh ventilation in cardiac surgery (E-SIGHT) trial is a single-center, two-arm, randomized controlled trial. In total, 192 patients scheduled for elective cardiac surgery with cardiopulmonary bypass (CPB) and aortic cross-clamp will be randomized into one of the two treatment arms. In the experimental group, besides conventional lung protective ventilation, sigh volumes producing plateau pressures of 35 cmH2O (or 40 cmH2O for patients with body mass index > 35 kg/m2) delivered once every 6 min from intubation to extubation. In the control group, conventional lung protective ventilation without preplanned recruitment maneuvers is used. Lung protective ventilation (LPV) consists of low tidal volumes (6–8 mL/kg of predicted body weight) and positive end-expiratory pressure (PEEP) setting according to low PEEP/FiO2 table for acute respiratory distress syndrome (ARDS). The primary endpoint is time-weighted average SpO2/FiO2 ratio during the initial post-extubation hour. Main secondary endpoint is the severity of postoperative pulmonary complications (PPCs) computed by postoperative day 7. Discussion: The E-SIGHT trial will be the first randomized controlled trial to evaluate the impact of perioperative sigh ventilation on the postoperative outcomes after on-pump cardiac surgery. The trial will introduce and assess a novel perioperative ventilation approach to mitigate the risk of postoperative hypoxemia and PPCs in patients undergoing cardiac surgery. Also provide the basis for a future larger trial aiming at verifying the impact of sigh ventilation on postoperative pulmonary complications. Trial registration: ClinicalTrials.gov NCT06248320. Registered on January 30, 2024. Last updated February 26, 2024. [ABSTRACT FROM AUTHOR]

Fluid creep occurs when resuscitation after extensive burn injury reaches volumes higher than predicted. Since this has been described in patients with high opioid requirements, continuous analgesics and sedatives, including dexmedetomidine, have been avoided during resuscitation. This study sought to describe the impact of dexmedetomidine on fluid resuscitation requirements. This retrospective cohort study included adult patients with burns greater than 20% total body surface area (TBSA) resuscitated between January 2017 and June 2022 at a regional burn center. Patients deceased within 48 hours of burn were excluded. The primary outcome was volume of fluid required in the first 24 and 48 hours postburn. Secondary outcomes were the incidence of fluid-related adverse events within 7 days postburn. A total of 170 patients were included: 55 in the dexmedetomidine cohort and 115 in the control cohort. After propensity matching for variables associated with fluid creep, the dexmedetomidine cohort required 4.2 ± 1.7 mL/kg/%TBSA in the first 24 hours compared to 3.6 ± 1.1 mL/kg/%TBSA in the control cohort (P = 0.03). The difference was no longer significant at 48 hours (P = 0.11). There were no differences in the incidence of acute respiratory distress syndrome, delayed escharotomy/fasciotomy, intra-abdominal hypertension, or renal replacement therapy. Dexmedetomidine exposure during acute resuscitation resulted in increased fluid requirements in the first 24 hours, suggesting it is independently associated with fluid creep; however, this increase was not sustained at 48 hours. Clinical significance of this finding is unclear, as there was no increase in adverse events related to excessive fluid resuscitation between cohorts. [ABSTRACT FROM AUTHOR]

The incidence of acute respiratory infections (ARinf), including SARS-CoV-2, in unvaccinated student rugby players during phases from complete lockdown during the COVID-19 pandemic to returning to competition is unknown. The aim of the study was to determine the incidence of ARinf (including SARS-CoV-2) during non- contact and contact phases during the COVID-19 pandemic to evaluate risk mitigation strategies. In this retrospective cohort study, 319 top tier rugby players from 17 universities completed an online questionnaire. ARinf was reported during 4 phases over 14 months (April 2020-May 2021): phase 1 (individual training), phase 2 (non-contact team training), phase 3 (contact team training) and phase 4 (competition). Incidence (per 1 000 player days) and Incidence Ratio (IR) for 'All ARinf', and subgroups (SARS-CoV-2; 'Other ARinf') are reported. Selected factors associated with ARinf were also explored. The incidence of 'All ARinf' (0.31) was significantly higher for SARS-CoV-2 (0.23) vs. 'Other ARinf' (0.08) (p < 0.01). The incidence of 'All ARinf (IR = 3.6; p < 0.01) and SARS-CoV-2 (IR = 4.2; p < 0.01) infection was significantly higher during contact (phases 3 + 4) compared with non-contact (phases 1 + 2). Demographics, level of sport, co-morbidities, allergies, influenza vaccination, injuries and lifestyle habits were not associated with ARinf incidence. In student rugby, contact phases are associated with a 3-4 times higher incidence of ARinf/SARS-CoV-2 compared to non-contact phases. Infection risk mitigation strategies in the contact sport setting are important. Data from this study serve as a platform to which future research on incidence of ARinf in athletes within contact team sports, can be compared. [ABSTRACT FROM AUTHOR]

Lung microvascular endothelial cell (EC) dysfunction is the pathological hallmark of acute respiratory distress syndrome. Heat shock protein 90 (HSP90) is a key regulator in control of endothelial barrier disruption and inflammation. Our recent study has demonstrated that ubiquitin-specific peptidase 40 (USP40) preserves endothelial integrity by targeting HSP90β for its deubiquitination and inactivation. Indole-3-acetic acid (IAA), a plant hormone of the auxin class, can also be catabolized from dietary tryptophan by the intestinal microbiota. Accumulating evidence suggests that IAA reduces oxidative stress and inflammation and promotes intestinal barrier function. However, little is known about the role of IAA in endothelial cells and acute lung injury. In this study, we investigated the role of IAA in lung endothelial cell function in the context of acute lung injury. IAA exhibited EC barrier protection against LPS-induced reduction in transendothelial electrical resistance and inflammatory responses. The underlying mechanism of IAA on EC protective effects was investigated by examining the influence of IAA on degrees of HSP90 ubiquitination and USP40 activity. We identified that IAA, acting as a potential activator of USP40, reduces HSP90 ubiquitination, thereby protecting against LPS-induced inflammation in human lung microvascular endothelial cells as well as alleviating experimental lung injury. Furthermore, the EC protective effects of IAA against LPS-induced EC dysfunction and lung injury were abolished in USP40-deficient human lung microvascular endothelial cell and lungs of USP40 EC-specific knockout (USP40cdh5-ECKO) mice. Taken together, this study reveals that IAA protects against LPS-induced EC dysfunction and lung injury through the activation of USP40. [ABSTRACT FROM AUTHOR]

Introduction: Allergic bronchopulmonary mycosis (ABPM) is a chronic airway disease characterized by the presence of fungi that trigger allergic reactions and airway obstruction. Here, we present a unique case of ABPM in which a patient experienced sudden respiratory failure due to mucus plug-induced airway obstruction. The patient's life was saved by venovenous extracorporeal membrane oxygenation (VV-ECMO) and bronchoscopic removal of the plug. This case emphasizes the clinical significance of mucus plug-induced airway obstruction in the differential diagnosis of respiratory failure in patients with ABPM. Case study: A 52-year-old female clerical worker with no smoking history, presented with dyspnea. CT scan revealed mucus plugs in both lungs. Despite treatment, the dyspnea progressed rapidly to respiratory failure, leading to VV-ECMO placement. Results: CT revealed bronchial wall thickening, obstruction, and extensive atelectasis. Bronchoscopy revealed extensive mucus plugs that were successfully removed within two days. The patient's respiratory status significantly improved. Follow-up CT revealed no recurrence. Fungal cultures identified Schizophyllum commune, confirming ABPM. Histological examination of the mucus plugs revealed aggregated eosinophils, eosinophil granules, and Charcot-Leyden crystals. Galectin-10 and major basic protein (MBP) staining supported these findings. Eosinophil extracellular traps (EETs) and eosinophil cell death (ETosis), which contribute to mucus plug formation, were identified by citrullinated histone H3 staining. Conclusion: Differentiating between asthma exacerbation and mucus plug-induced airway obstruction in patients with ABPM and those with acute respiratory failure is challenging. Prompt evaluation of mucous plugs and atelectasis using CT and timely decision to introduce ECMO and bronchoscopic mucous plug removal are required. [ABSTRACT FROM AUTHOR]

Background: Patients with severe respiratory failure due to COVID‐19 who are not under mechanical ventilation may develop severe hypoxemia when complicated with spontaneous pneumomediastinum (PM). These patients may be harmed by invasive ventilation. Alternatively, veno‐venous (V‐V) extracorporeal membrane oxygenation (ECMO) may be applied. We report on the efficacy of V‐V ECMO and invasive ventilation as initial advanced respiratory support in patients with COVID‐19 and acute respiratory failure due to spontaneous PM. Methods: This was a retrospective cohort study performed between March 2020 and January 2022. Enrolled patients had COVID‐19 and acute respiratory failure due to spontaneous PM and were not invasively ventilated. Patients were treated in the intensive care unit (ICU) with invasive ventilation (invasive ventilation group) or V‐V ECMO support (V‐V ECMO group) as the main therapeutic option. The primary outcomes were mortality and ICU discharge at 90 days after ICU admission. Results: Twenty‐two patients were included in this study (invasive ventilation group: 13 [59%]; V‐V ECMO group: 9 [41%]). The V‐V ECMO strategy was significantly associated with lower mortality (hazard ratio [HR] 0.33 [95% CI 0.12–0.97], p = 0.04). Five (38%) patients in the V‐V ECMO group were intubated and eight (89%) patients in the invasive ventilation group required V‐V ECMO support within 30 days from ICU admission. Three (33%) patients in the V‐V ECMO group were discharged from ICU within 90 days compared to one (8%) patient in the invasive ventilation group (HR 4.71 [95% CI 0.48–45.3], p = 0.18). Conclusions: Preliminary data suggest that V‐V ECMO without invasive ventilation may improve survival in COVID‐19‐related acute respiratory failure due to spontaneous PM. The study's retrospective design and limited sample size underscore the necessity for additional investigation and warrant caution. [ABSTRACT FROM AUTHOR]

The article discusses the use of extracorporeal cardiopulmonary resuscitation (ECPR) as a potential intervention for patients with refractory cardiac arrest. ECPR involves draining blood from the body, oxygenating it, and then returning it to the arterial system, providing better oxygen delivery than conventional CPR. The article highlights the need for a proactive approach to implementing ECPR in the UK, as it is currently underutilized. The article also discusses the selection criteria for ECPR and the challenges in implementing ECPR services. The authors emphasize the importance of developing institutional expertise and ensuring equitable access to ECPR services across the UK. [Extracted from the article]

Rationale: Blood flow rate affects mixed venous oxygenation (SvO2) during venovenous extracorporeal membrane oxygenation (ECMO), with possible effects on the pulmonary circulation and the right heart function. Objectives: To describe the physiologic effects of different levels of SvO2 obtained by changing ECMO blood flow in patients with severe acute respiratory distress syndrome receiving ECMO and controlled mechanical ventilation. Methods: Low (SvO2 target, 70–75%), intermediate (SvO2 target, 75–80%), and high (SvO2 target, >80%) ECMO blood flows were applied for 30 minutes in random order in 20 patients. Mechanical ventilation settings were left unchanged. The hemodynamic and pulmonary effects were assessed with pulmonary artery catheter and electrical impedance tomography. Measurements and Main Results: Cardiac output decreased from low to intermediate and to high blood flow/SvO2 (9.2 [6.2–10.9] vs. 8.3 [5.9–9.8] vs. 7.9 [6.5–9.1] L/min; P = 0.014), as well as mean pulmonary artery pressure (34 ± 6 vs. 31 ± 6 vs. 30 ± 5 mm Hg; P < 0.001) and right ventricular stroke work index (14.2 ± 4.4 vs. 12.2 ± 3.6 vs. 11.4 ± 3.2 g × m/beat/m2; P = 0.002). Cardiac output was inversely correlated with mixed venous and arterial Po2 values (R2 = 0.257; P = 0.031; and R2 = 0.324; P = 0.05). Pulmonary artery pressure was correlated with decreasing mixed venous Po2 (R2 = 0.29; P < 0.001) and with increasing cardiac output (R2 = 0.378; P < 0.007). Measures of V ˙ / Q ˙ mismatch did not differ between the three steps. Conclusions: In patients with severe acute respiratory distress syndrome, increased ECMO blood flow rate resulting in higher SvO2 decreases pulmonary artery pressure, cardiac output, and right heart workload. [ABSTRACT FROM AUTHOR]

The article presents a study which tested the hypothesis that the hyperinflammatory subphenotype is associated with worse acute brain dysfunction in patients who are in mechanically ventilated intensive care units (ICUs). Topics include baseline characteristics of the overall cohort and by subphenotype, associations between hyperinflammatory subphenotype and acute brain dysfunction and death, and strengths of the study.

Cognitive impairment is a severe complication of acute respiratory distress syndrome (ARDS). Emerging studies have revealed the effects of pyrrolidine dithiocarbamate (PDTC) on improving surgery-induced cognitive impairment. The major aim of the study was to investigate whether PDTC protected against ARDS-induced cognitive dysfunction and to identify the underlying mechanisms involved. The rat model of ARDS was established by intratracheal instillation of lipopolysaccharide (LPS), followed by treatment with PDTC. The cognitive function of rats was analyzed by the Morris Water Maze, and pro-inflammatory cytokines were assessed by quantitative real-time PCR, enzyme-linked immunosorbent assay, and western blot assays. A dual-luciferase reporter gene assay was performed to identify the relationship between miR-181c and its target gene, TAK1 binding protein 2 (TAB2). The results showed that PDTC improved cognitive impairment and alleviated neuroinflammation in the hippocampus in LPS-induced ARDS model. Furthermore, we demonstrated that miR-181c expression was downregulated in the hippocampus of the ARDS rats, which was restored by PDTC treatment. In vitro studies showed that miR-181c alleviated LPS-induced pro-inflammatory response by inhibiting TAB2, a critical molecule in the nuclear factor (NF)-κB signaling pathway. PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation, providing a potential opportunity for the treatment of this disease. [ABSTRACT FROM AUTHOR]

The genome of the Nipah virus (NiV) encodes a variety of structural proteins linked to a diverse array of symptoms, including fevers, headaches, somnolence, and respiratory impairment. In instances of heightened severity, it can also invade the central nervous system (CNS), resulting in more pronounced problems. This work investigates the effects of NiV on the blood-brain barrier (BBB), the vital physiological layer responsible for safeguarding the CNS by regulating the passage of chemicals into the brain selectively. To achieve this, the researchers (MMJAO, AM and MNMD) searched a variety of databases for relevant articles on NiV and BBB disruption, looking for evidence of work on inflammation, immune response (cytokines and chemokines), tight junctions (TJs), and basement membranes related to NiV and BBB. Based on these works, it appears that the affinity of NiV for various receptors, including Ephrin-B2 and Ephrin-B3, has seen many NiV infections begin in the respiratory epithelium, resulting in the development of acute respiratory distress syndrome. The virus then gains entry into the circulatory system, offering it the potential to invade brain endothelial cells (ECs). NiV also has the ability to infect the leukocytes and the olfactory pathway, offering it a "Trojan horse" strategy. When NiV causes encephalitis, the CNS generates a strong inflammatory response, which makes the blood vessels more permeable. Chemokines and cytokines all have a substantial influence on BBB disruption, and NiV also has the ability to affect TJs, leading to disturbances in the structural integrity of the BBB. The pathogen's versatility is also shown by its capacity to impact multiple organ systems, despite particular emphasis on the CNS. It is of the utmost importance to comprehend the mechanisms by which NiV impacts the integrity of the BBB, as such comprehension has the potential to inform treatment approaches for NiV and other developing viral diseases. Nevertheless, the complicated pathophysiology and molecular pathways implicated in this phenomenon have offered several difficult challenges to researchers to date, underscoring the need for sustained scientific investigation and collaboration in the ongoing battle against this powerful virus. [ABSTRACT FROM AUTHOR]

Objective: This Study aims to investigate the risk factors of hypoglycemia in neonates through meta-analysis. Method: PubMed, Embase, Cochrane library, and Web of science databases were searched for case-control studies on risk factors for neonatal hypoglycemia. The search was done up to 1st October 2023 and Stata 15.0 was used for data analysis. Results: A total of 12 published studies were included, including 991 neonates in the hypoglycemic group and 4388 neonates in the non-hypoglycemic group. Meta-analysis results suggested caesarean section [OR = 1.90 95%CI (1.23, 2.92)], small gestational age[OR = 2.88, 95%CI (1.59, 5.20)], gestational diabetes [OR = 1.65, 95%CI (1.11, 2.46)], gestational hypertension[OR = 2,79, 95%CI (1.78, 4.35)] and respiratory distress syndrome[OR = 5.33, 95%CI (2.22, 12.84)] were risk factors for neonatal hypoglycemia. Conclusion: Based on the current study, we found that caesarean section, small gestational age, gestational diabetes, gestational hypertension, respiratory distress syndrome are risk factors for neonatal hypoglycemia. PROSPERO registration number: CRD42023472974. [ABSTRACT FROM AUTHOR]

Extracellular histones are crucial damage-associated molecular patterns involved in the development and progression of multiple critical and inflammatory diseases, such as sepsis, pancreatitis, trauma, acute liver failure, acute respiratory distress syndrome, vasculitis and arthritis. During the past decade, the physiopathologic mechanisms of histone-mediated hyperinflammation, endothelial dysfunction, coagulation activation, neuroimmune injury and organ dysfunction in diseases have been systematically elucidated. Emerging preclinical evidence further shows that anti-histone strategies with either their neutralizers (heparin, heparinoids, nature plasma proteins, small anion molecules and nanomedicines, etc.) or extracorporeal blood purification techniques can significantly alleviate histone-induced deleterious effects, and thus improve the outcomes of histone-related critical and inflammatory animal models. However, a systemic evaluation of the efficacy and safety of these histone-targeting therapeutic strategies is currently lacking. In this review, we first update our latest understanding of the underlying molecular mechanisms of histoneinduced hyperinflammation, endothelial dysfunction, coagulopathy, and organ dysfunction. Then, we summarize the latest advances in histone-targeting therapy strategies with heparin, anti-histone antibodies, histone-binding proteins or molecules, and histone-affinity hemoadsorption in pre-clinical studies. Finally, challenges and future perspectives for improving the clinical translation of histone-targeting therapeutic strategies are also discussed to promote better management of patients with histone-related diseases. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) remains a significant challenge in critical care, with high mortality rates despite advancements in treatment. Venovenous extracorporeal membrane oxygenation (VV-ECMO) is employed as salvage therapy for refractory cases. However, some patients may continue to experience persistent severe hypoxemia despite being treated with VV-ECMO. To achieve this, moderate hypothermia and short-acting selective β1-blockers have been proposed. Methods: Using a swine model of severe ARDS treated with VV-ECMO, this study investigated the efficacy of moderate hypothermia or β-blockade in improving arterial oxygen saturation (SaO2) three hours after VV-ECMO initiation. Primary endpoints included the ratio of VV-ECMO flow to cardiac output and arterial oxygen saturation before VV-ECMO start (H0) and three hours after ECMO start (H3). Secondary safety criteria encompassed hemodynamics and oxygenation parameters. Results: Twenty-two male pigs were randomized into three groups: control (n = 6), hypothermia (n = 9) and β-blockade (n = 7). At H0, all groups demonstrated similar hemodynamic and respiratory parameters. Both moderate hypothermia and β-blockade groups exhibited a significant increase in the ratio of VV-ECMO flow to cardiac output at H3, resulting in improved SaO2. At H3, despite a decrease in oxygen delivery and consumption in the intervention groups compared to the control group, oxygen extraction ratios across groups remained unchanged and lactate levels were normal. Conclusions: In a swine model of severe ARDS treated with VV-ECMO, both moderate hypothermia and β-blockade led to an increase in the ratio of VV-ECMO flow to cardiac output resulting in improved arterial oxygen saturation without any impact on tissue perfusion. [ABSTRACT FROM AUTHOR]

Background: SARS-CoV-2 pneumonia can cause significant long-term radiological changes, even resembling pulmonary fibrosis. However, the risk factors for these long-term effects are unknown. This study aims to assess radiological abnormalities and their possible risk factors six months after hospital discharge due to COVID-19 pneumonia. Material and methods: This cross-sectional study in a tertiary hospital included adults admitted for COVID-19 pneumonia from March 2020 to February 2021, who underwent high-resolution computed tomography (HRCT) scans of the chest six months after hospital discharge. The primary outcome was radiological abnormalities on HRCT, while the main explanatory variables were drawn from the patient's medical history along with the disease course, analytical indicators, and the treatment received during admission. Results: The 189 included patients had a mean age of 61.5 years; 70.9% were male, and hypertension was the main comorbidity (45%). About two-thirds (67.2%) presented acute respiratory distress syndrome (ARDS). Most (97.9%) received systemic corticosteroid therapy, and 81% presented pathological findings on HRCT, most commonly ground glass (63.5%), followed by bronchial dilatation (36%) and subpleural bands (25.4%). The multivariable analysis showed that age was the main risk factor, associated with most radiological changes. Other factors were the duration of corticosteroid therapy for ground glass (adjusted odds ratio [aOR] 1.020) as well as a longer stay in the intensive care unit (ICU) (aOR 1.290) and high levels of IL-6 for bronchial dilation (aOR 1.002). Conclusion: Radiological involvement of the lungs six months after COVID-19 pneumonia is frequent, especially ground glass. Elderly patients with prolonged ICU admission and a significant inflammatory response measured by IL-6 are more likely to present worse radiological evolution and are candidates for radiological follow-up after COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in type 2 alveolar epithelial (AT2) cells is thought to aggravate alveolar inflammation in acute lung injury. Here, the authors show that the mtLCFAO rate limiting enzyme CPT1a is decreased in AT2 cells in acute respiratory distress syndrome, highlighting the role of mtLCFAO in immunometabolism in this context. [ABSTRACT FROM AUTHOR]

Background: By controlling hypercapnia, respiratory acidosis, and associated consequences, extracorporeal CO2 removal (ECCO2R) has the potential to facilitate ultra-protective lung ventilation (UPLV) strategies and to decrease injury from mechanical ventilation. We convened a meeting of European intensivists and nephrologists and used a modified Delphi process to provide updated insights into the role of ECCO2R in acute respiratory distress syndrome (ARDS) and to identify recommendations for a future randomized controlled trial. Results: The group agreed that lung protective ventilation and UPLV should have distinct definitions, with UPLV primarily defined by a tidal volume (VT) of 4–6 mL/kg predicted body weight with a driving pressure (ΔP) ≤ 14–15 cmH2O. Fourteen (93%) participants agreed that ECCO2R would be needed in the majority of patients to implement UPLV. Furthermore, 10 participants (majority, 63%) would select patients with PaO2:FiO2 > 100 mmHg (> 13.3 kPa) and 14 (consensus, 88%) would select patients with a ventilatory ratio of > 2.5–3. A minimum CO2 removal rate of 80 mL/min delivered by continuous renal support machines was suggested (11/14 participants, 79%) for this objective, using a short, double-lumen catheter inserted into the right internal jugular vein as the preferred vascular access. Of the participants, 14/15 (93%, consensus) stated that a new randomized trial of ECCO2R is needed in patients with ARDS. A ΔP of ≥ 14–15 cmH2O was suggested by 12/14 participants (86%) as the primary inclusion criterion. Conclusions: ECCO2R may facilitate UPLV with lower volume and pressures provided by the ventilator, while controlling respiratory acidosis. Since recent European Society of Intensive Care Medicine guidelines on ARDS recommended against the use of ECCO2R for the treatment of ARDS outside of randomized controlled trials, new trials of ECCO2R are urgently needed, with a ΔP of ≥ 14–15 cmH2O suggested as the primary inclusion criterion. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 originated in China and swiftly spread worldwide, posing a significant threat to public health. Caused by SARS-CoV-2, it manifests as a flu-like illness that can escalate to Acute Respiratory Distress Syndrome, potentially resulting in fatalities. In countries where HIV/Leishmania infantum is endemic, the occurrence of concurrent SARS-CoV-2/HIV/Leishmania infantum infections is a reality, prompting inquiries into appropriate clinical management. Case presentation: We present the case of a 48-year-old woman who was hospitalized for 36 days across three different hospitals in the state of Pernambuco, Brazil. She was diagnosed with SARS-CoV-2/HIV/L. infantum coinfection. The patient exhibited severe COVID-19 symptoms, including fever, productive cough, and dyspnea. Throughout her hospitalization, she experienced oxygen saturation levels of ≤ 93%, along with fluctuations in blood pressure, respiratory rate, and heart rate. Her blood tests revealed lymphopenia, leukopenia, and neutropenia, while laboratory results indicated abnormal levels of d-dimer, AST, ALT, lactate dehydrogenase, ferritin, and C-reactive protein. A computed tomography scan revealed 75% involvement of the lung parenchyma with patchy ground-glass opacities. Conclusion: Against all odds, the patient was discharged. The leukopenia associated with HIV/L. infantum may have played a decisive role. Further studies are necessary to better understand diagnostic strategies and clinical management measures for HIV/L. infantum coinfected patients who are susceptible to SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Introduction: Acute Respiratory Distress Syndrome (ARDS) poses a significant health challenge due to its high incidence and mortality rates. The emergence of SARS-CoV-2 has added complexity, with evidence suggesting a correlation between COVID-19 induced ARDS and post-COVID symptoms. Understanding the underlying mechanisms of ARDS in COVID-19 patients is crucial for effective clinical treatment. Method: To investigate the potential role of ferroptosis in SARS-CoV-2 induced ARDS, we conducted a comprehensive analysis using bioinformatics methods. Datasets from the Gene Expression Omnibus (GEO) were utilized, focusing on COVID-19 patients with varying ARDS severity. We employed weighted gene co-expression network analysis (WGCNA), differential gene expression analysis, and single-cell sequencing to identify key genes associated with ferroptosis in ARDS. Hub genes were validated using additional GEO datasets and cell experiment. Result: The analysis discerned 916 differentially expressed genes in moderate/ severe ARDS patients compared to non-critical individuals. Weighted Gene Co-expression Network Analysis (WGCNA) unveiled two modules that exhibited a positive correlation with ARDS, subsequently leading to the identification of 15 hub genes associated with ferroptosis. Among the noteworthy hub genes were MTF1, SAT1, and TXN. Protein-protein interaction analysis, and pathway analysis further elucidated their roles. Immune infiltrating analysis highlighted associations between hub genes and immune cells. Validation in additional datasets confirmed the upregulation of MTF1, SAT1, and TXN in SARS-CoV-2-induced ARDS. This was also demonstrated by qRT-PCR results in the BEAS-2B cells vitro model, suggesting their potential as diagnostic indicators. Discussion: This study identifies MTF1, SAT1, and TXN as hub genes associated with ferroptosis in SARS-CoV-2-induced ARDS. These findings provide novel insights into the molecular mechanisms underlying ARDS in COVID-19 patients and offer potential targets for immune therapy and targeted treatment. Further experimental validation is warranted to solidify these findings and explore therapeutic interventions for ARDS in the context of COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS. Methods: We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing. Results: We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport. Discussion: These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution. [ABSTRACT FROM AUTHOR]

Background: A combination of prone positioning (PP) and venovenous extracorporeal membrane oxygenation (VV-ECMO) is safe, feasible, and associated with potentially improved survival for severe acute respiratory distress syndrome (ARDS). However, whether ARDS patients, especially non-COVID-19 patients, placed in PP before VV-ECMO should continue PP after a VV-ECMO connection is unknown. This study aimed to test the hypothesis that early use of PP during VV-ECMO could increase the proportion of patients successfully weaned from ECMO support in severe ARDS patients who received PP before ECMO. Methods: In this prospective observational study, patients with severe ARDS who were treated with VV-ECMO were divided into two groups: the prone group and the supine group, based on whether early PP was combined with VV-ECMO. The proportion of patients successfully weaned from VV-ECMO and 60-day mortality were analyzed before and after propensity score matching. Results: A total of 165 patients were enrolled, 50 in the prone and 115 in the supine group. Thirty-two (64%) and 61 (53%) patients were successfully weaned from ECMO in the prone and the supine groups, respectively. The proportion of patients successfully weaned from VV-ECMO in the prone group tended to be higher, albeit not statistically significant. During PP, there was a significant increase in partial pressure of arterial oxygen (PaO2) without a change in ventilator or ECMO settings. Tidal impedance shifted significantly to the dorsal region, and lung ultrasound scores significantly decreased in the anterior and posterior regions. Forty-five propensity score-matched patients were included in each group. In this matched sample, the prone group had a higher proportion of patients successfully weaned from VV-ECMO (64.4% vs. 42.2%; P = 0.035) and lower 60-day mortality (37.8% vs. 60.0%; P = 0.035). Conclusions: Patients with severe ARDS placed in PP before VV-ECMO should continue PP after VV-ECMO support. This approach could increase the probability of successful weaning from VV-ECMO. Trial Registration: ClinicalTrials.Gov: NCT04139733. Registered 23 October 2019. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the role of platelet count (PLT) in the prognosis of patients with acute respiratory distress syndrome (ARDS). Methods: The data were extracted from the Medical Information Mart for Intensive Care database (version 2.2). Patients diagnosed with ARDS according to criteria from Berlin Definition and had the platelet count (PLT) measured within the first day after intensive care unit admission were analyzed. Based on PLT, ARDS patients were divided into four groups: PLT ≤ 100 × 109/L, PLT 101–200 × 109/L, PLT 201–300 × 109/L, and PLT > 300 × 109/L. The primary outcome was 28-day mortality. Survival probabilities were analyzed using Kaplan–Meier. Furthermore, the association between PLT and mortality in ARDS patients was assessed using a univariate and multivariable Cox proportional hazards model. Results: Overall, the final analysis included 3,207 eligible participants with ARDS. According to the Kaplan–Meier curves for 28-day mortality of PLT, PLT ≤ 100 × 109/L was associated with a higher incidence of mortality (P = 0.001), the same trends were observed in the 60-day (P = 0.001) and 90‐day mortality (P = 0.001). In the multivariate model adjusted for the potential factors, the adjusted hazard ratio at PLT 101–200 × 109/L group, PLT 201–300 × 109/L, and PLT > 300 × 109/L was 0.681 [95% confidence interval (CI): 0.576–0.805, P < 0.001], 0.733 (95% CI: 0.604–0.889, P = 0.002), and 0.787 (95% CI: 0.624–0.994, P = 0.044) compared to the reference group (PLT ≤ 100 × 109/L), respectively. Similar relationships between the PLT ≤ 100 × 109/L group and 28-day mortality were obtained in most subgroups. Conclusion: PLT appeared to be an independent predictor of mortality in critically ill patients with ARDS. [ABSTRACT FROM AUTHOR]

Background: Ventilation management may differ between COVID–19 ARDS (COVID–ARDS) patients and patients with pre–COVID ARDS (CLASSIC–ARDS); it is uncertain whether associations of ventilation management with outcomes for CLASSIC–ARDS also exist in COVID–ARDS. Methods: Individual patient data analysis of COVID–ARDS and CLASSIC–ARDS patients in six observational studies of ventilation, four in the COVID–19 pandemic and two pre–pandemic. Descriptive statistics were used to compare epidemiology and ventilation characteristics. The primary endpoint were key ventilation parameters; other outcomes included mortality and ventilator–free days and alive (VFD–60) at day 60. Results: This analysis included 6702 COVID–ARDS patients and 1415 CLASSIC–ARDS patients. COVID–ARDS patients received lower median VT (6.6 [6.0 to 7.4] vs 7.3 [6.4 to 8.5] ml/kg PBW; p < 0.001) and higher median PEEP (12.0 [10.0 to 14.0] vs 8.0 [6.0 to 10.0] cm H2O; p < 0.001), at lower median ΔP (13.0 [10.0 to 15.0] vs 16.0 [IQR 12.0 to 20.0] cm H2O; p < 0.001) and higher median Crs (33.5 [26.6 to 42.1] vs 28.1 [21.6 to 38.4] mL/cm H2O; p < 0.001). Following multivariable adjustment, higher ΔP had an independent association with higher 60–day mortality and less VFD–60 in both groups. Higher PEEP had an association with less VFD–60, but only in COVID–ARDS patients. Conclusions: Our findings show important differences in key ventilation parameters and associations thereof with outcomes between COVID–ARDS and CLASSIC–ARDS. Trial registration: Clinicaltrials.gov (identifier NCT05650957), December 14, 2022. [ABSTRACT FROM AUTHOR]

Xanthoxylin, a bioactive phenolic compound extracted from the traditional herbal medicine Penthorum Chinense Pursh, is renowned for its anti-inflammatory effects. While previous studies have highlighted the anti-inflammatory and antioxidant properties of Xanthoxylin, its precise mechanisms, particularly concerning immune response and organ protection, remain underexplored. This study aimed to elucidate the effects of Xanthoxylin on inflammation and associated signaling pathways in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced via intratracheal administration of LPS, followed by intraperitoneal injections of Xanthoxylin at doses of 1, 2.5, 5, and 10 mg/kg, administered 30 min post-LPS exposure. Lung tissues were harvested for analysis 6 h after LPS challenge. Xanthoxylin treatment significantly mitigated lung tissue damage, pathological alterations, immune cell infiltration, and the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Additionally, Xanthoxylin modulated the expression of key proteins in the protein kinase B (Akt)/hypoxia-inducible factor 1-alpha (HIF-1α)/nuclear factor-kappa B (NF-κB) signaling pathway, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and oxidative markers such as superoxide dismutase (SOD) and malondialdehyde (MDA) in the context of LPS-induced injury. This study demonstrates that Xanthoxylin exerts protective and anti-inflammatory effects by down-regulating and inhibiting the Akt/HIF-1α/NF-κB pathways, suggesting its potential as a therapeutic target for the prevention and treatment of ALI or acute respiratory distress syndrome (ARDS). [ABSTRACT FROM AUTHOR]

Mechanical ventilation exposes the lung to injurious stresses and strains that can negatively affect clinical outcomes in acute respiratory distress syndrome or cause pulmonary complications after general anesthesia. Excess global lung strain, estimated as increased respiratory system driving pressure, is associated with mortality related to mechanical ventilation. The role of small-dimension biomechanical factors underlying this association and their spatial heterogeneity within the lung are currently unknown. Using four-dimensional computed tomography with a voxel resolution of 2.4 cubic millimeters and a multiresolution convolutional neural network for whole-lung image segmentation, we dynamically measured voxel-wise lung inflation and tidal parenchymal strains. Healthy or injured ovine lungs were evaluated as the mechanical ventilation positive end-expiratory pressure (PEEP) was titrated from 20 to 2 centimeters of water. The PEEP of minimal driving pressure (PEEPDP) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEPDP compared with PEEP values above this threshold. PEEPDP similarly characterized a breaking point in the relationships between PEEP and SD of local tidal parenchymal strain, the 95th percentile of local strains, and the magnitude of tidal overdistension. These findings advance the understanding of lung collapse, tidal overdistension, and strain heterogeneity as local triggers of ventilator-induced lung injury in large-animal lungs similar to those of humans and could inform the clinical management of mechanical ventilation to improve local lung biomechanics. Editor's summary: Mechanical ventilation is a life-sustaining tool for patients with compromised lungs but is also associated with a risk of damaging lung strain. Several ventilation parameters can be tuned by clinicians, including the amount of pressure applied at the end of expiration to maintain open alveoli [positive end-expiratory pressure (PEEP)]. The relationship between applied PEEP and small-scale lung strains is not well characterized. Here, Lagier et al. used four-dimensional computed tomography imaging with 2.4 mm3 voxel resolution in mechanically ventilated sheep to analyze localized changes in lung strain in healthy lungs and diseased lungs. They identified the PEEP of minimal respiratory driving pressure as a setting that marks a change in the relationship between PEEP settings and parameters of lung function and biomechanics. These findings will support future investigation in individualized mechanical ventilation. —Molly Ogle [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) after cardiac surgery is a severe respiratory complication with high mortality and morbidity. Traditional clinical approaches may lead to under recognition of this heterogeneous syndrome, potentially resulting in diagnosis delay. This study aims to develop and external validate seven machine learning (ML) models, trained on electronic health records data, for predicting ARDS after cardiac surgery. Methods: This multicenter, observational cohort study included patients who underwent cardiac surgery in the training and testing cohorts (data from Nanjing First Hospital), as well as those patients who had cardiac surgery in a validation cohort (data from Shanghai General Hospital). The number of important features was determined using the sliding windows sequential forward feature selection method (SWSFS). We developed a set of tree-based ML models, including Decision Tree, GBDT, AdaBoost, XGBoost, LightGBM, Random Forest, and Deep Forest. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and Brier score. The SHapley Additive exPlanation (SHAP) techinque was employed to interpret the ML model. Furthermore, a comparison was made between the ML models and traditional scoring systems. ARDS is defined according to the Berlin definition. Results: A total of 1996 patients who had cardiac surgery were included in the study. The top five important features identified by the SWSFS were chronic obstructive pulmonary disease, preoperative albumin, central venous pressure_T4, cardiopulmonary bypass time, and left ventricular ejection fraction. Among the seven ML models, Deep Forest demonstrated the best performance, with an AUC of 0.882 and a Brier score of 0.809 in the validation cohort. Notably, the SHAP values effectively illustrated the contribution of the 13 features attributed to the model output and the individual feature's effect on model prediction. In addition, the ensemble ML models demonstrated better performance than the other six traditional scoring systems. Conclusions: Our study identified 13 important features and provided multiple ML models to enhance the risk stratification for ARDS after cardiac surgery. Using these predictors and ML models might provide a basis for early diagnostic and preventive strategies in the perioperative management of ARDS patients. [ABSTRACT FROM AUTHOR]

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and H1N1 viruses are inflammatory lung pathogens that can lead to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). ALI/ARDS are still life-threatening diseases in critically ill patients with 30–40% mortality in the last decade. Currently, there are no laboratory tests for the early diagnosis or prognosis of ALI/ARDS. Club cell secretory protein (CC16) has been investigated as a potential biomarker of lung epithelial damage in various lung diseases. In this study, we evaluated whether plasma CC16 reflects the severity of COVID-19 and H1N1 infections. The plasma CC16 levels showed no significant differences between H1N1 and COVID-19 groups (p = 0.09). Among all subjects, CC16 levels were significantly higher in non-survivors than in survivors (p = 0.001). Upon the area under the receiver operating characteristic (AUROC) analysis, CC16 had an acceptable value to distinguish survivors and non-survivors (p = 0.002). In the COVID-19 group, plasma CC16 levels moderately correlated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (r = 0.374, p = 0.003) and Sequential Organ Failure Assessment (SOFA) score (r = 0.474, p < 0.001). In the H1N1 group, a positive correlation was observed between the CC16 levels and hospital length of stay (r = 0.311, p = 0.022). Among all the patients, weak correlations between plasma CC16 levels with the SOFA score (r = 0.328, p < 0.001) and hospital length of stay (r = 0.310, p < 0.001) were observed. Thus, circulating CC16 might reflect the severity of COVID-19 and H1N1 infections. [ABSTRACT FROM AUTHOR]

Background: This study aims to evaluate the association of metabolic syndrome (MetS) with the risk of all-cause mortality in elderly patients with acute respiratory distress syndrome (ARDS). Methods: Elderly ARDS patients (≥ 65 years) enrolled from our hospital between January 2018 and July 2023 were divided into the MetS group or the non-MetS group. The outcomes were 28-day and 90-day all-cause mortality rates in the total population and two subgroups stratified by age (65–75 years and ≥ 75 years). Multivariate Cox regression was employed to assess the association of MetS with all-cause mortality, after controlling for potential cofounding factors. Results: A total of 946 patients were divided into the MetS group (n = 410) or the non-MetS group (n = 536). The 28-day and 90-day all-cause mortality rates were significantly higher for MetS group compared to non-MetS group in the total population and two subgroups (all P < 0.01). Multivariate Cox regression indicated that MetS was significantly associated with a higher risk of 90-day all-cause mortality in the total population (HR = 1.62, 95% CI: 1.22–2.15; P < 0.01), and subgroups of patients aged 65–75 years (HR = 1.52, 95% CI: 1.04–2.21; P = 0.03) and ≥ 75 years (HR = 1.90, 95% CI: 1.23–2.94; P < 0.01). Moreover, with each MetS criterion added from 0 to 1 to 2, 3, and 4 of 4 criteria, both 28-day and 90-day all-cause mortality rates significantly increased (both P < 0.01). Conclusion: MetS was associated with higher risks of 28-day and 90-day all-cause mortality in elderly patients with ARDS. [ABSTRACT FROM AUTHOR]

Severe COVID-19 cases often progress to life-threatening conditions such as acute respiratory distress syndrome (ARDS), sepsis, and multiple organ dysfunction syndrome (MODS). Gelsolin (GSN), an actin-binding protein with anti-inflammatory and immunomodulatory properties, is a promising therapeutic target for severe COVID-19. Plasma GSN levels are significantly decreased in critical illnesses, including COVID-19, correlating with dysregulated immune responses and poor outcomes. GSN supplementation may mitigate acute lung injury, ARDS, and sepsis, which share pathophysiological features with severe COVID-19, by scavenging actin, modulating cytokine production, enhancing macrophage phagocytosis, and stabilizing the alveolar-capillary barrier. Preliminary data indicate that recombinant human plasma GSN improves oxygenation and lung function in severe COVID-19 patients with ARDS. Although further research is needed to optimize GSN therapy, current evidence supports its potential to mitigate severe consequences of COVID-19 and improve patient outcomes. This review provides a comprehensive analysis of the biological characteristics, mechanisms, and therapeutic value of GSN in severe COVID-19. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. Pulmonary fibrosis following COVID-19 pneumonia has been described at autopsy and following lung transplantation. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop features of pulmonary fibroproliferation. We enrolled COVID-19 patients admitted to the ICU with hypoxemic respiratory failure. (n = 195). Plasma was collected within 24h of ICU admission and at 7d. In mechanically ventilated patients, endotracheal aspirates (ETA) were collected. Protein concentrations were measured by immunoassay. We tested for associations between protein concentrations and respiratory outcomes using logistic regression adjusting for age, sex, treatment with steroids, and APACHE III score. In a subset of patients who had CT scans during hospitalization (n = 75), we tested for associations between protein concentrations and radiographic features of fibroproliferation. Among the entire cohort, plasma IL-6, TNF-α, CCL2, and Amphiregulin levels were significantly associated with in-hospital mortality. In addition, higher plasma concentrations of CCL2, IL-6, TNF-α, Amphiregulin, and CXCL12 were associated with fewer ventilator-free days. We identified 20/75 patients (26%) with features of fibroproliferation. Within 24h of ICU admission, no measured plasma proteins were associated with a fibroproliferative response. However, when measured 96h-128h after admission, Amphiregulin was elevated in those that developed fibroproliferation. ETAs were not correlated with plasma measurements and did not show any association with mortality, ventilator-free days (VFDs), or fibroproliferative response. This cohort study identifies proteins of tissue remodeling and monocyte recruitment are associated with in-hospital mortality, fewer VFDs, and radiographic fibroproliferative response. Measuring changes in these proteins over time may allow for early identification of patients with severe COVID-19 at risk for fibroproliferation. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does acetaminophen (paracetamol) improve respiratory, circulatory, or kidney dysfunction in critically ill patients with sepsis, and is acetaminophen more effective in patients with higher plasma cell-free hemoglobin? Findings: In this randomized clinical trial that included 447 adults, acetaminophen was safe but the number of days alive and free of organ support was not meaningfully different in the acetaminophen arm (20.2 days) vs the placebo arm (19.6 days). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Meaning: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill patients with sepsis. Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P =.56; difference, 0.6; 95% CI, −1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P =.01; difference, −6.3; 95% CI, −10.8 to −1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04291508 This randomized trial assesses whether acetaminophen would increase the number of days alive and free of organ support to day 28 among critically ill patients with sepsis and respiratory or circulatory organ dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Morbidly obese patients occasionally have respiratory problems owing to hypoventilation. Airway pressure release ventilation is one of the ventilation settings often used for respiratory management of acute respiratory distress syndrome. However, previous reports indicating that airway pressure release ventilation may become a therapeutic measure as ventilator management in morbid obesity with respiratory failure is limited. We report a case of markedly improved oxygenation in a morbidly obese patient after airway pressure release ventilation application. Case report: A 50s-year-old Asian man (body mass index 41 kg/m2) presented with breathing difficulties. The patient had respiratory failure with a PaO2/FIO2 ratio of approximately 100 and severe atelectasis in the left lung, and ventilator management was initiated. Although the patient was managed on a conventional ventilate mode, oxygenation did not improve. On day 11, we changed the ventilation setting to airway pressure release ventilation, which showed marked improvement in oxygenation with a PaO2/FIO2 ratio of approximately 300. We could reduce sedative medication and apply respiratory rehabilitation. The patient was weaned from the ventilator on day 29 and transferred to another hospital for further rehabilitation on day 31. Conclusion: Airway pressure release ventilation ventilator management in morbidly obese patients may contribute to improving oxygenation and become one of the direct therapeutic measures in the early stage of critical care. [ABSTRACT FROM AUTHOR]

Introduction: Sex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI is not known. To bridge this gap, the current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery from ALI. Methods: ALI was induced using a single intra-tracheal instillation of bleomycin (bleo, 2.5 mg/Kg) (day 1). Resting respiratory frequency (fR) was measured at 1-2 days pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo. The chemoreflex responses to hypoxia (10% O2, 0%CO2) and normoxic-hypercapnia (21%O2, 5%CO2) were measured before bleo administration (pre-bleo) and 1 mth post-bleo using whole-body plethysmography. The apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point. Results: Therewere no significant differences in resting fR between male and female rats at the pre-bleo time point or in the increase in resting fR at D7 post-bleo. At 1mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly lower in male rats. The AHI, post-sigh apneas, and sighs were not different between male and female rats pre-bleo and 1mth post-bleo. However, at D7 post-bleo, themale rats exhibited a higher AHI than female rats. Bothmale and female rats exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia with no significant differences between sexes. Conclusion: A sex difference in resting ventilatory parameters occurs post ALI with a prolonged increase in resting fR and larger AHI in male rats. On the other hand, we did not find any sex differences in the chemoreflex sensitization that occurs at 1 mth post-bleo. This work contributes to a better understanding of sex-based variations in lung disorders. [ABSTRACT FROM AUTHOR]

Background: COVID-19 infections can result in severe acute respiratory distress syndrome (ARDS) requiring admission to the intensive care unit (ICU). Cardiovascular manifestation or exacerbation of cardiovascular diseases could be another complication. Cardiac arrhythmias including New-Onset Atrial Fibrillation (NOAF), have been observed in hospitalized patients with COVID-19 infections. In this analysis, we aimed to systematically compare the complications associated with NOAF in critically ill COVID-19 patients admitted to the ICU. Methods: MEDLINE, EMBASE, Web of Science, the Cochrane database, http://www.ClinicalTrials.gov, Google Scholar and Mendeley were searched for relevant publications based on COVID-19 patients with NOAF admitted to the ICU. Complications including in-hospital mortality, ICU mortality, patients requiring mechanical ventilation, acute myocardial infarction, acute kidney injury, renal replacement therapy and pulmonary embolism were assessed. This is a meta-analysis and the analytical tool which was used was the RevMan software version 5.4. Risk ratios (RR) and 95% confidence intervals (CIs) were used to represent the data post analysis. Results: In critically ill COVID-19 patients with NOAF admitted to the ICU, the risks of ICU mortality (RR: 1.39, 95% CI: 1.07 – 1.80; P = 0.01), in-hospital mortality (RR: 1.56, 95% CI: 1.20 – 2.04; P = 0.001), patients requiring mechanical ventilation (RR: 1.32, 95% CI: 1.04 – 1.66; P = 0.02) were significantly higher when compared to the control group without AF. Acute myocardial infarction (RR: 1.54, 95% CI: 1.31 – 1.81; P = 0.00001), the risk for acute kidney injury (RR: 1.31, 95% CI: 1.11 – 1.55; P = 0.002) and patients requiring renal replacement therapy (RR: 1.83, 95% CI: 1.60 – 2.09; P = 0.00001) were also significantly higher in patients with NOAF. Conclusions: Critically ill COVID-19 patients with NOAF admitted to the ICU were at significantly higher risks of developing complications and death compared to similar patients without AF. [ABSTRACT FROM AUTHOR]

Adult rats exposed to hyperoxia (>95% O2) die from respiratory failure in 60–72 h. However, rats preconditioned with >95% O2 for 48 h followed by 24 h in room air acquire tolerance of hyperoxia (H-T), whereas rats preconditioned with 60% O2 for 7 days become more susceptible (H-S). Our objective was to evaluate lung tissue mitochondrial bioenergetics in H-T and H-S rats. Bioenergetics was assessed in mitochondria isolated from lung tissue of H-T, H-S, and control rats. Expressions of complexes involved in oxidative phosphorylation (OxPhos) were measured in lung tissue homogenate. Pulmonary endothelial filtration coefficient (Kf) and tissue mitochondrial membrane potential (Δψm) were evaluated in isolated perfused lungs (IPLs). Results show that ADP-induced state 3 OxPhos capacity (Vmax) decreased in H-S mitochondria but increased in H-T. Δψm repolarization time following ADP-stimulated depolarization increased in H-S mitochondria. Complex I expression decreased in H-T (38%) and H-S (43%) lung homogenate, whereas complex V expression increased (70%) in H-T lung homogenate. Δψm is unchanged in H-S and H-T lungs, but complex II has a larger contribution to Δψm in H-S than H-T lungs. Kf increased in H-S, but not in H-T lungs. For H-T, increased complex V expression and Vmax counter the effect of the decrease in complex I expression on Δψm. A larger complex II contribution to Δψm along with decreased Vmax and increased Kf could make H-S rats more hyperoxia susceptible. Results are clinically relevant since ventilation with ≥60% O2 is often required for extended periods in patients with acute respiratory distress syndrome (ARDS). NEW & NOTEWORTHY: We assessed lung tissue mitochondrial bioenergetics in rats with tolerance (H-T) or susceptibility (H-S) to hyperoxia-induced ARDS. Results from studies in isolated mitochondria, tissue homogenate, and isolated perfused lungs show that mitochondrial bioenergetics are differentially altered in H-T and H-S lungs suggesting a potential role for mitochondrial bioenergetics in hyperoxia-induced ARDS. Results are clinically relevant since hyperoxia exposure is a primary therapy for patients with ARDS, and differential sensitivity to hyperoxia surely occurs in humans. [ABSTRACT FROM AUTHOR]

The article discusses the relationship between acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS) in critically ill patients. The study analyzed data from 10 randomized controlled trials conducted in the United States between 1996 and 2018. The authors found that AKI occurred in approximately 43.7% of patients with ARDS, with a higher incidence of AKI stage 3 and acute kidney disease (AKD) in patients with more severe AKI. The study also found that AKI was associated with higher mortality rates at 28 and 90 days. However, the study has some limitations, including the lack of consideration for certain variables and the heterogeneity of ARDS and AKI subphenotypes. Further research is needed to better understand the relationship between AKI and ARDS and to identify strategies for improving outcomes. [Extracted from the article]

Purpose: Awake prone positioning has been reported to reduce endotracheal intubation in patients with coronavirus disease 2019 (COVID-19)-related acute hypoxemic respiratory failure (AHRF). However, it is still unclear whether using the awake prone positioning for longer periods can further improve outcomes. Methods: In this randomized, open-label clinical trial conducted at 12 hospitals in China, non-intubated patients with COVID-19-related AHRF were randomly assigned to prolonged awake prone positioning (target > 12 h daily for 7 days) or standard care with a shorter period of awake prone positioning. The primary outcome was endotracheal intubation within 28 days after randomization. The key secondary outcomes included mortality and adverse events. Results: In total, 409 patients were enrolled and randomly assigned to prolonged awake prone positioning (n = 205) or standard care (n = 204). In the first 7 days after randomization, the median duration of prone positioning was 12 h/d (interquartile range [IQR] 12–14 h/d) in the prolonged awake prone positioning group vs. 5 h/d (IQR 2–8 h/d) in the standard care group. In the intention-to-treat analysis, intubation occurred in 35 (17%) patients assigned to prolonged awake prone positioning and in 56 (27%) patients assigned to standard care (relative risk 0.62 [95% confidence interval (CI) 0.42–0.9]). The hazard ratio (HR) for intubation was 0.56 (0.37–0.86), and for mortality was 0.63 (0.42–0.96) for prolonged awake prone positioning versus standard care, within 28 days. The incidence of pre-specified adverse events was low and similar in both groups. Conclusion: Prolonged awake prone positioning of patients with COVID-19-related AHRF reduces the intubation rate without significant harm. These results support prolonged awake prone positioning of patients with COVID-19-related AHRF. [ABSTRACT FROM AUTHOR]

Purpose: Although noninvasive ventilation (NIV) may reduce reintubation in patients with acute hypoxemic respiratory failure following abdominal surgery, this strategy has not been specifically assessed in patients with obesity. Methods: We conducted a post hoc analysis of a multicenter randomized controlled trial comparing NIV delivered via facial mask to standard oxygen therapy among patients with obesity and acute hypoxemic respiratory failure within 7 days after abdominal surgery. The primary outcome was reintubation within 7 days. Secondary outcomes were invasive ventilation-free days at day 30, intensive care unit (ICU)-acquired pneumonia and 30-day survival. Results: Among 293 patients with hypoxemic respiratory failure following abdominal surgery, 76 (26%) patients had obesity and were included in the intention-to-treat analysis. Reintubation rate was significantly lower with NIV (13/42, 31%) than with standard oxygen therapy (19/34, 56%) within 7 days (absolute difference: − 25%, 95% confidence interval (CI) − 49 to − 1%, p = 0.03). NIV was associated with significantly more invasive ventilation-free days compared with standard oxygen therapy (27.1 ± 8.6 vs 22.7 ± 11.1 days; p = 0.02), while fewer patients developed ICU-acquired pneumonia (1/42, 2% vs 6/34, 18%; p = 0.04). The 30-day survival was 98% in the NIV group (41/42) versus 85% in the standard oxygen therapy (p = 0.08). In patients with body mass index (BMI) < 30 kg/m2, no significant difference was observed between NIV (36/105, 34%) and standard oxygen therapy (47/109, 43%, p = 0.03). An interaction test showed no statistically significant difference between the two subsets (BMI ≥ 30 kg/m2 and BMI < 30 kg/m2). Conclusions: Among patients with obesity and hypoxemic respiratory failure following abdominal surgery, use of NIV compared with standard oxygen therapy reduced the risk of reintubation within 7 days, contrary to patients without obesity. However, no interaction was found according to the presence of obesity or not, suggesting either a lack of power to conclude in the non-obese subgroup despite existing differences, or that the statistical difference found in the overall sample was driven by a large effect in the obese subsets. [ABSTRACT FROM AUTHOR]

Purpose: Human herpesviruses, particularly cytomegalovirus (CMV) and herpes simplex virus (HSV), frequently reactivate in critically ill patients, including those with acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). The clinical interpretation of pulmonary herpesvirus reactivation is challenging and there is ongoing debate about its association with mortality and benefit of antiviral medication. We aimed to quantify the incidence and pathogenicity of pulmonary CMV and HSV reactivations in critically ill COVID-19 patients. Methods: Mechanically ventilated COVID-19 patients seropositive for CMV or HSV were included in this observational cohort study. Diagnostic bronchoscopy with bronchoalveolar lavage was performed routinely and analyzed for alveolar viral loads and inflammatory biomarkers. Utilizing joint modeling, we explored the dynamic association between viral load trajectories over time and mortality. We explored alveolar inflammatory biomarker dynamics between reactivated and non-reactivated patients. Results: Pulmonary reactivation (> 104 copies/ml) of CMV occurred in 6% of CMV-seropositive patients (9/156), and pulmonary reactivation of HSV in 37% of HSV-seropositive patients (63/172). HSV viral load dynamics prior to or without antiviral treatment were associated with increased 90-day mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.04–1.47). The alveolar concentration of several inflammatory biomarkers increased with HSV reactivation, including interleukin (IL)-6, IL-1β, granulocyte colony stimulating factor (G-CSF), and tumor necrosis factor (TNF). Conclusion: In mechanically ventilated COVID-19 patients, HSV reactivations are common, while CMV reactivations were rare. HSV viral load dynamics prior to or without antiviral treatment are associated with mortality. Alveolar inflammation is elevated after HSV reactivation. [ABSTRACT FROM AUTHOR]

The article discusses the limitations of evidence-based medicine in the critical care environment and the need for personalized medicine. It highlights the challenges faced by critical care physicians in making decisions based on available evidence, such as the vast amount of literature, outdated information, and the difficulty in conducting high-quality trials. The article also emphasizes the importance of expert judgment and experience in making ad-hoc decisions when evidence is lacking. It suggests that a deeper understanding of disease mechanisms and the development of more targeted therapies may lead to more effective personalized medicine in the future. [Extracted from the article]

Purpose: Severe Pneumocystis jirovecii pneumonia (PJP) requiring intensive care has been the subject of few prospective studies. It is unclear whether delayed curative antibiotic therapy may impact survival in these severe forms of PJP. The impact of corticosteroid therapy combined with antibiotics is also unclear. Methods: This multicentre, prospective observational study involving 49 adult intensive care units (ICUs) in France was designed to evaluate the severity, the clinical spectrum, and outcomes of patients with severe PJP, and to assess the association between delayed curative antibiotic treatment and adjunctive corticosteroid therapy with mortality. Results: We included 158 patients with PJP from September 2020 to August 2022. Their main reason for admission was acute respiratory failure (n = 150, 94.9%). 12% of them received antibiotic prophylaxis for PJP before ICU admission. The ICU, hospital, and 6-month mortality were 31.6%, 35.4%, and 40.5%, respectively. Using time-to-event analysis with a propensity score-based inverse probability of treatment weighting, the initiation of curative antibiotic treatment after 96 h of ICU admission was associated with faster occurrence of death [time ratio: 6.75; 95% confidence interval (95% CI): 1.48–30.82; P = 0.014]. The use of corticosteroids for PJP was associated with faster occurrence of death (time ratio: 2.48; 95% CI 1.01–6.08; P = 0.048). Conclusion: This study showed that few patients with PJP admitted to intensive care received prophylactic antibiotic therapy, that delay in curative antibiotic treatment was common and that both delay in curative antibiotic treatment and adjunctive corticosteroids for PJP were associated with accelerated mortality. [ABSTRACT FROM AUTHOR]

Purpose: The development of acute kidney injury (AKI) after the acute respiratory distress syndrome (ARDS) reduces the chance of organ recovery and survival. The purpose of this study was to examine the AKI rate and attributable mortality in ARDS patients. Methods: We performed an individual patient-data analysis including 10 multicenter randomized controlled trials conducted over 20 years. We employed a Super Learner ensemble technique, including a time-dependent analysis, to estimate the adjusted risk of AKI. We calculated the mortality attributable to AKI using an inverse probability of treatment weighting estimator integrated with the Super Learner. Results: There were 5148 patients included in this study. The overall incidence of AKI was 43.7% (n = 2251). The adjusted risk of AKI ranged from 38.8% (95% confidence interval [CI], 35.7 to 41.9%) in ARMA, to 55.8% in ROSE (95% CI, 51.9 to 59.6%). 37.1% recovered rapidly from AKI, with a significantly lower recovery rate in recent trials (P < 0.001). The 90-day excess in mortality attributable to AKI was 15.4% (95% CI, 12.8 to 17.9%). It decreased from 25.4% in ARMA (95% CI, 18.7 to 32%), to 11.8% in FACTT (95% CI, 5.5 to 18%) and then remained rather stable over time. The 90-day overall excess in mortality attributable to acute kidney disease was 28.4% (95% CI, 25.3 to 31.5%). Conclusions: The incidence of AKI appears to be stable over time in patients with ARDS enrolled in randomized trials. The development of AKI remains a significant contributing factor to mortality. These estimates are essential for designing future clinical trials for AKI prevention or treatment. [ABSTRACT FROM AUTHOR]

This article provides information on the use of facemask noninvasive ventilation (NIV) in various clinical settings. NIV allows for positive airway pressure without the need for intubation, providing respiratory support while avoiding the negative effects of invasive mechanical ventilation. The article discusses the set-up and ventilatory settings for facemask NIV, as well as its indications and monitoring. It also highlights the limitations and contraindications of this technique. The information presented in the article is based on research and clinical experience. [Extracted from the article]

The article discusses the phenomenon of post-COVID syndrome (PCS), which refers to the persistent health problems experienced by individuals who have recovered from COVID-19. These symptoms include fatigue, muscle pain, shortness of breath, and cognitive disturbances. The article suggests that capillary rarefication, a decrease in the density of small capillaries, may be a possible cause of PCS. The authors also discuss the renal implications of PCS and the potential for chronic kidney disease to develop in these patients. However, the exact mechanisms and effective treatments for PCS are still unclear. [Extracted from the article]

Background: Severe bacterial infections can trigger acute lung injury (ALI) and acute respiratory distress syndrome, with bacterial pathogen‐associated molecular patterns (PAMPs) exacerbating the inflammatory response, particularly in COVID‐19 patients. Cyclic‐di‐GMP (CDG), one of the PAMPs, is synthesized by various Gram‐positve and Gram‐negative bacteria. Previous studies mainly focused on the inflammatory responses triggered by intracellular bacteria‐released CDG. However, how extracellular CDG, which is released by bacterial autolysis or rupture, activates the inflammatory response remains unclear. Methods: The interaction between extracellular CDG and myeloid differentiation protein 2 (MD2) was investigated using in vivo and in vitro models. MD2 blockade was achieved using specific inhibitor and genetic knockout mice. Site‐directed mutagenesis, co‐immunoprecipitation, SPR and Bis‐ANS displacement assays were used to identify the potential binding sites of MD2 on CDG. Results: Our data show that extracellular CDG directly interacts with MD2, leading to activation of the TLR4 signalling pathway and lung injury. Specific inhibitors or genetic knockout of MD2 in mice significantly alleviated CDG‐induced lung injury. Moreover, isoleucine residues at positions 80 and 94, along with phenylalanine at position 121, are essential for the binding of MD2 to CDG. Conclusion: These results reveal that extracellular CDG induces lung injury through direct interaction with MD2 and activation of the TLR4 signalling pathway, providing valuable insights into bacteria‐induced ALI mechanisms and new therapeutic approaches for the treatment of bacterial co‐infection in COVID‐19 patients. [ABSTRACT FROM AUTHOR]

The role of programmed death ligand 1 (PD-L1) has been extensively investigated in adaptive immune system. However, increasing data show that innate immune responses are also affected by the immune checkpoint molecule. It has been demonstrated that regulation of PD-L1 signaling in macrophages may be a potential therapeutic method for acute respiratory distress syndrome (ARDS). However, the PD-L1 expression pattern in local macrophages and whole lung tissues remains mysterious, hindering optimization of the potential treatment program. Therefore, we aim to determine the PD-L1 expression pattern during ARDS. Our findings show that PD-L1 levels are markedly increased in lipopolysaccharide (LPS)-stimulated lung tissues, which might be attributable to an increase in the gene expression by immune cells, including macrophages and neutrophils. In vitro experiments are performed to explore the mechanism involved in LPS-induced PD-L1 production. We find that PD-L1 generation is controlled by transcription factors early growth response 1 (Egr-1) and CCAAT/enhancer binding protein delta (C/EBPδ). Strikingly, PD-L1 production is enhanced by phosphoinositide-3 kinase (PI3K)–protein kinase B (AKT) signaling pathway via up-regulation of Egr-1 and C/EBPδ expressions. Additionally, we observe that expressions of Egr-1 and C/EBPδ mutually reinforce each other. Moreover, we observe that PD-L1 is protective for ARDS due to its regulatory role in macrophage-associated inflammatory response. In summary, during LPS-induced ARDS, PD-L1 expression, which is beneficial for the disease, is increased via the PI3K-AKT1-Egr-1/C/EBPδ signaling pathway, providing theoretical basis for application of methods controlling PD-L1 signaling in macrophages for ARDS treatment in clinic. [ABSTRACT FROM AUTHOR]

Sepsis-induced acute respiratory distress syndrome (ARDS) poses a grave danger to life, resulting from sepsis-induced multi-organ failure. Although ferroptosis, a form of iron-dependent lipid peroxidative cell death, has been associated with sepsis-induced ARDS, the specific mechanisms are not fully understood. In this study, we utilized WGCNA, PPI, friends analysis, and six machine learning techniques (Lasso, SVM, RFB, XGBoost, AdaBoost, and LightGBM) to pinpoint STAT3 as a potential diagnostic marker. A significant increase in monocyte and neutrophil levels was observed in patients with sepsis-induced ARDS, as revealed by immune infiltration analyses, when compared to controls. Moreover, there was a positive correlation between STAT3 expression and the level of infiltration. Single-cell analysis uncovered a notable disparity in B-cell expression between sepsis and sepsis-induced ARDS. Furthermore, in vitro experiments using LPS-treated human bronchial epithelial cells (BEAS-2B) and THP1 cells demonstrated a significant increase in STAT3 phosphorylation expression. Additionally, the inhibition of STAT3 phosphorylation by Stattic effectively prevented LPS-induced ferroptosis in both BEAS-2B and THP1 cells. This indicates that the activation of STAT3 phosphorylation promotes ferroptosis in human bronchial epithelial cells in response to LPS. In summary, this research has discovered and confirmed STAT3 as a potential biomarker for the diagnosis and treatment of sepsis-induced ARDS. [ABSTRACT FROM AUTHOR]