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Abstract 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.

ObjectivePneumonia is a common clinical condition primarily treated with antibiotics and organ support. Exploring the pathogenesis to identify therapeutic targets may aid in the adjunct treatment of pneumonia and improve survival rates.MethodsTranscriptomic data from peripheral blood of 183 pneumonia patients were analyzed using Gene Set Variation Analysis (GSVA) and univariate Cox regression analysis to identify signaling pathways associated with pneumonia mortality. A pneumonia mouse model was established via airway injection of Klebsiella pneumoniae, and pathway-specific blockers were administered via tail vein infusion to assess whether the identified signaling pathways impact the mortality in pneumonia.ResultsThe combination of GSVA and Cox analysis revealed 17 signaling pathways significantly associated with 28-day mortality in pneumonia patients (P < 0.05). Notably, the RIG-I-like receptor signaling pathway exhibited the highest hazard ratio of 2.501 with a 95% confidence interval of [1.223–5.114]. Infusion of RIG012 via the tail vein effectively inhibited the RIG-I-like receptor signaling pathway, significantly ameliorated lung injury in pneumonia mice, reduced pulmonary inflammatory responses, and showed a trend toward improved survival rates.ConclusionRIG012 may represent a novel adjunctive therapeutic agent for pneumonia.

Abstract Background Uncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear. Methods In this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14+ cells obtained from the peripheral blood of 140 ARDS patients. Results Our investigation revealed that lipopolysaccharide, a critical component derived from Gram‐negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1‐binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double‐stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double‐stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1‐induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram‐negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury. Conclusions This study revealed a novel mechanism involving IBR1, an endogenous double‐stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS. Highlights In monocytes and macrophages, the endogenous double‐stranded RNA, IFIH1‐binding RNA 1 (IBR1), binds to the helicase domain of IFIH1 because of its unique double‐stranded structure. IBR1 plays a significant role in macrophage polarisation and the development of acute respiratory distress syndrome (ARDS) induced by Gram‐negative bacteria or lipopolysaccharide (LPS). Administration of IFIH1 variants has potential for eliminating pulmonary IBR1 and reducing inflammatory lung injury in ARDS patients.

Background: The dead space fraction (VD/VT) has proven to be a powerful predictor of higher mortality in acute respiratory distress syndrome (ARDS). However, its measurement relies on expired carbon dioxide, limiting its widespread application in clinical practice. Several estimates employing routine variables have been found to be reliable substitutes for direct measurement of VD/VT. In this study, we evaluated the prognostic value of these dead space estimates obtained in the first 7 days following the initiation of ventilation. Methods: This retrospective observational study was conducted using data from the Chinese database in intensive care (CDIC). Eligible participants were adult ARDS patients receiving invasive mechanical ventilation while in the intensive care unit between 1st January 2014 and 31st March 2021. We collected data during the first 7 days of ventilation to calculate various dead space estimates, including ventilatory ratio (VR), corrected minute ventilation (V˙Ecorr), VD/VT (Harris–Benedict), VD/VT (Siddiki estimate), and VD/VT (Penn State estimate) longitudinally. A time-dependent Cox model was used to handle these time-varying estimates. Results: A total of 392 patients (median age 66 [interquartile range: 55–77] years, median SOFA score 9 [interquartile range: 7–12]) were finally included in our analysis, among whom 132 (33.7%) patients died within 28 days of admission. VR (hazard ratio [HR]=1.04 per 0.1 increase, 95% confidence interval [CI]: 1.01 to 1.06; P=0.013), V˙Ecorr (HR=1.08 per 1 increase, 95% CI: 1.04 to 1.12; P < 0.001), VD/VT (Harris–Benedict) (HR=1.25 per 0.1 increase, 95% CI: 1.06 to 1.47; P=0.006), and VD/VT (Penn State estimate) (HR=1.22 per 0.1 increase, 95% CI: 1.04 to 1.44; P=0.017) remained significant after adjustment, while VD/VT (Siddiki estimate) (HR=1.10 per 0.1 increase, 95% CI: 1.00 to 1.20; P=0.058) did not. Given a large number of negative values, VD/VT (Siddiki estimate) and VD/VT (Penn State estimate) were not recommended as reliable substitutes. Long-term exposure to VR >1.3, V˙Ecorr >7.53, and VD/VT (Harris–Benedict) >0.59 was independently associated with an increased risk of mortality in ARDS patients. These findings were validated in the fluid and catheter treatment trial (FACTT) database. Conclusions: In cases where VD/VT cannot be measured directly, early time-varying estimates of VD/VT such as VR, V˙Ecorr, and VD/VT (Harris–Benedict) can be considered for predicting mortality in ARDS patients, offering a rapid bedside application.

Abstract Background Organising pneumonia (OP) is one of the most common and lethal diseases in the category of interstitial pneumonia, along with lung cancer. Reprogramming of lipid metabolism is a newly recognized hallmark of many diseases including cancer, cardiovascular disorders, as well as liver fibrosis and sclerosis. Increased levels of ceramides composed of sphingosine and fatty acid, are implicated in the development of both acute and chronic lung diseases. However, their pathophysiological significance in OP is unclear. The aim of this study was to investigate the role of lipid metabolism reprogramming in OP, focusing on inflammation and fibrosis. Methods Comprehensive multi‐omics profiling approaches, including single‐cell RNA sequencing, Visium CytAssist spatial transcriptomics, proteomics, metabolomics and mass spectrometry, were employed to analyze the tissues. OP mice model was utilized and molecular mechanisms were investigated in macrophages. Results The results revealed a significant association between OP and lipid metabolism reprogramming, characterized by an abnormal expression of several genes related to lipid metabolism, including CD36, SCD1, and CES1 mainly in macrophages. CD36 deficiency in alveolar macrophages, led to an increased expression of C16/24 ceramides that accumulated in mitochondria, resulting in mitophagy or mitochondrial dysfunction. The number of alveolar macrophages in OP was significantly reduced, which was probably due to the ferroptosis signaling pathway involving GSH/SLC3A2/GPX4 through CD36 downregulation in OP. Furthermore, macrophage secretion of DPP7 and FABP4 influenced epithelial cell fibrosis. Conclusions CD36 inhibited the ferroptosis pathway involving SLC3A2/GPX4 in alveolar macrophages of OP tissue by regulating lipid metabolism, thus representing a new anti‐ferroptosis and anti‐fibrosis effect of CD36 mediated, at least in part, by ceramides. Highlights Our findings reveal a significant association between organising pneumonia and lipid metabolism reprogramming and will make a substantial contribution to the understanding of the mechanism of organising pneumonia in patients.

Abstract Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host responses to infection. Not only does sepsis pose a serious hazard to human health, but it also imposes a substantial economic burden on the healthcare system. The cornerstones of current treatment for sepsis remain source control, fluid resuscitation, and rapid administration of antibiotics, etc. To date, no drugs have been approved for treating sepsis, and most clinical trials of potential therapies have failed to reduce mortality. The immune response caused by the pathogen is complex, resulting in a dysregulated innate and adaptive immune response that, if not promptly controlled, can lead to excessive inflammation, immunosuppression, and failure to re-establish immune homeostasis. The impaired immune response in patients with sepsis and the potential immunotherapy to modulate the immune response causing excessive inflammation or enhancing immunity suggest the importance of demonstrating individualized therapy. Here, we review the immune dysfunction caused by sepsis, where immune cell production, effector cell function, and survival are directly affected during sepsis. In addition, we discuss potential immunotherapy in septic patients and highlight the need for precise treatment according to clinical and immune stratification.

Abstract Epidemiological and clinical data of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (BA.2) admitted to three designated hospitals in Quanzhou City, Fujian Province, China, were collected and analyzed. Overall, 2,541 patients infected with BA.2, comprising 1,060 asymptomatic, 1,287 mild, and 194 moderate infections, were enrolled. The percentage of moderate infections was higher in patients aged ≥ 60 years than in those aged

Abstract Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life‐threatening syndrome with no effective pharmacotherapy. Sepsis‐related ARDS is the main type of ARDS and is more fatal than other types. Extracellular vesicles (EVs) are considered novel mediators in the development of inflammatory diseases. Our previous research suggested that endothelial cell‐derived EVs (EC‐EVs) play a crucial role in ALI/ARDS development, but the mechanism remains largely unknown. Here, we demonstrated that the number of circulating EC‐EVs was increased in sepsis, exacerbating lung injury by targeting monocytes and reprogramming them towards proinflammatory macrophages. Bioinformatics analysis and further mechanistic studies revealed that vascular cell adhesion molecule 1 (VCAM1), overexpressed on EC‐EVs during sepsis, activated the NF‐κB pathway by interacting with integrin subunit alpha 4 (ITGA4) on the monocyte surface, rather than the tissue resident macrophage surface, thereby regulating monocyte differentiation. This effect could be attenuated by decreasing VCAM1 levels in EC‐EVs or blocking ITGA4 on monocytes. Furthermore, the number of VCAM1+ EC‐EVs was significantly increased in patients with sepsis‐related ARDS. These findings not only shed light on a previously unidentified mechanism underling sepsis‐related ALI/ARDS, but also provide potential novel targets and strategies for its precise treatment.

Abstract To generate arbitrary shape magnetic field waveforms for advanced scientific research, a reconfigurable pulsed high magnetic field facility (PHMFF) was developed at Wuhan National Pulsed High Magnetic Field Centre (WHMFC). First, the basic elements of PHMFF are introduced, and a ternary physical model composed of energy storage unit, magnet, transmission circuits and other auxiliary units is summarised to describe various magnetic field systems. Second, in order to realise the reconfiguration of magnetic field systems based on detailed elements, the control system with the ability of dynamic construction and control sequence reconfiguration is designed. On this basis, the PHMFF has been realised and various magnetic field systems are constructed to produce arbitrary shape magnetic field waveforms, such as half‐sine, ultra‐high, flat‐top and repetitive field pulses, which not only enhances the capability and efficiency of PHMFF, but also makes more scientific research possible in pulsed magnetic fields. So far, a peak magnetic field of 94.8 T, a flat‐top magnetic field of 64 T/10 ms and a repetitive magnetic field waveform of 20 T/60 Hz have been achieved, and some experiments and studies on the physical properties of materials have been carried out at WHMFC.

Abstract Background Limited data are available on renal complications in patients with acute fulminant myocarditis (AFM) receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) support in China. To evaluate the impact of renal complications on outcomes in adult patients with AFM supported with VA-ECMO. Methods Data were extracted from Chinese Society of ExtraCorporeal Life Support (CSECLS) Registry database. Adult patients who were diagnosed with AFM receiving VA-ECMO support in the database were included. The primary outcome was 30-day mortality in patients with AFM supported with VA-ECMO. Logistic regression model was used to examine the impact of renal complications on 30-day mortality by adjusting confounders. Results A total of 202 patients were included. The median age was 38 years (IQR 29–48) and males (n = 103) represented 51.0% of the total accounted patients. The median ECMO duration was 142.9 h (IQR 112.1–188.8 h). 178 (88.1%) patients weaned from ECMO and 156 (71.9%) patients survived. 94(46.5%) patients developed renal complications while on ECMO course. Patients with renal complications had higher 30-day mortality (40.7% (37 of 94) vs 8.3% (9 of 108), P

Abstract Background Although the mean arterial pressure (MAP) target of 65 mmHg was achieved, diastolic blood pressure (DBP) was still low in some septic shock patients. The effects of DBP on the prognosis and optimal target for patients with septic shock are unclear. We sought to investigate the relationship between DBP and 28-day mortality in septic shock patients. Methods In this retrospective observational study, we obtained data from the Chinese Database in Intensive Care (CDIC). We included patients with an admission diagnosis of septic shock and shock was controlled. DBP was measured every 1 h, and the mean DBP during the first 24 h (mDBP24h) was recorded. The primary outcome was 28-day mortality. Multivariable logistic regression determined the relationship between mDBP24h and 28-day mortality. Results In total, 1251 patients were finally included. The 28-day mortality of included septic shock patients was 28.3%. The mDBP24h, not mSBP24h, was higher among 28-day survivors compared with non-survivors. 28-day mortality was inversely associated with mDBP24h (unadjusted OR 0.814 per 10 mmHg higher mDBP24h, P = 0.003), with a stepwise increase in 28-day mortality at lower mDBP24h. The 28-day mortality of patients with mDBP24h

A vector–host model of dengue with multiple stages and independent fluctuations is investigated in this paper. Firstly, the existence and uniqueness of the positive solution are shown by contradiction. When the death rates of aquatic mosquitoes, adult mosquitoes, and human beings respectively control the intensities of white noises, and if R0s>1, then the persistence in the mean for both infective mosquitoes and infective human beings is derived. When R0s>1 is valid, the existence of stationary distribution is derived through constructing several appropriate Lyapunov functions. If the intensities of white noises are controlled and φ<0 is valid, then the extinction for both infective mosquitoes and infective human beings is obtained by applying the comparison theorem and ergodic theorem. Further, the main findings are verified through numerical simulations by using the positive preserving truncated Euler–Maruyama method (PPTEM). Moreover, several numerical simulations on the infection scale of dengue in Fuzhou City were conducted using surveillance data. The main results indicate that the decrease in the transfer proportion from aquatic mosquitoes to adult mosquitoes reduces the infection scale of infective human beings with dengue virus, and the death rates of aquatic mosquitoes and adult mosquitoes affect the value of the critical threshold R0s. Further, the controls of the death rates of mosquitoes are the effective routes by the decision-makers of the Chinese mainland against the spread of dengue.

Abstract Background Albumin infusion is the primary therapeutic strategy for septic patients with liver cirrhosis. Although recent studies have investigated the efficacy of albumin in the resuscitation stage of septic patients with liver cirrhosis, it remains unclear whether daily albumin administration can improve outcomes. Furthermore, the indications for initiating albumin therapy are not well defined. Methods Septic patients with liver cirrhosis were obtained from the Medical Information Mart for Intensive Care (MIMIC-IV 2.0) database. Marginal structural Cox models were employed to investigate the association between daily albumin infusion and 28-day mortality. We also aimed to explore under what circumstances enrolled patients could benefit most from albumin administration, based on the clinical parameters collected on the day of albumin infusion, including serum albumin concentration, serum lactate concentration, mean arterial pressure (MAP), and vasopressor dosage. Results A total of 2265 patients were included in the final analysis, of whom 1093 (48.3%) had received albumin treatment at least once. The overall 28-day mortality was 29.6%. After marginal structural modeling, daily albumin infusion was associated with a reduced risk of 28-day death (hazard ratio, 0.76; 95% CI 0.61–0.94). We found that patients benefit most from albumin infusion when initiated on the day of serum albumin concentration between 2.5 and 3.0 g/dL, serum lactate concentration greater than or equal to 2 mmol/L, MAP less than 60 mmHg, or vasopressor dosage between 0.2 and 0.3 mcg/kg/min (norepinephrine equivalent, NEE). Conclusions Albumin infusion is associated with a reduction in mortality in septic patients with liver cirrhosis under specific circumstances. Serum albumin concentration, serum lactate, MAP, and vasopressor dosage were found to be modifiers of treatment effectiveness and should be considered when deciding to initial albumin infusion.

ObjectiveTo explore epidemiological characteristics and re-positivity incidence of imported and local infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant during a period of coronavirus disease 2019 (COVID-19) epidemic in Fujian province. MethodsFrom National Information System of Disease Prevention and Control and Information System of Public Health Emergency Management, we extracted the information on 69 genome sequencing-confirmed imported infections and 264/212 genome sequencing-/epidemiologically confirmed local infections with SARS-CoV-2 Delta variant registered in Fujian province from March 2021 through February 2022. Descriptive statistics was used to analyze disease characteristics and incubation period of the SARS-CoV-2 Delta variant infections. The 'R0' and 'EpiEstim' packages of R software were used to estimate the serial interval (SI) and the time-dependent reproduction number (Rt). Influencing factors of the re-positivity were analyzed with logistic regression.ResultsThe period of COVID-19 epidemic induced by SARS-CoV-2 Delta variant was approximately from March 2021 to February 2022 in Fujian province, with a continuous incidence of sporadic imported cases and local outbreak of the infections. The majority of the imported cases were seafarers (28.99%), students (15.94%) and commercial service personnel (14.49%) from Southeast Asia, Japan, the United States, the United Kingdom and other regions and entered Fujian province via Xiamen Customs. The local epidemics due to rapid transmission of Delta variant occurred mainly in schools and factories in Putian and Xiamen city. The SI of the local infections was fitted to Gamma distribution, with the mean and standard deviation of 2.28 and 2.06, respectively. For the 149 infector-infectee pairs of local infections during the local outbreak，the maximum value of Rt was 7.35 and the median incubation period was 6.50 days. The incidence of re-positivity was 37.98% for all the Delta variant infections. The results of multivariate regression analysis revealed that the local infections with Delta variant were at a significantly higher risk of re-positivity ( odds ratio = 2.47, 95% confidence interval: 1.25 – 4.87) compared to the imported infections. No associates of gender, age, occupation and clinical type with the re-positivity were observed. ConclusionThe period of COVID-19 epidemic due to SARS-CoV-2 Delta variant infections in Fujian province was approximately from March 2021 to February 2022, with continuously sporadic imported and local infections and the local epidemic was under effective control rapidly. The incidence rate of re-positivity was 37.98% among all infections with Delta variant.

Abstract Objective Early intervention with neutralizing antibodies is considered to be effective in preventing disease progression in patients with mild to moderate COVID-19 infection. Elderly patients are the most susceptible and at a higher risk of COVID-19 infection. The present study aimed to assess the necessity and possible clinical benefits of the early administration of Amubarvimab/Romlusevimab (BRII-196/198) in the elderly population. Methods The present study was designed as a retrospective, multi-center cohort study conducted with 90 COVID-19 patients aged over 60, who were divided into two groups based on the timing of the administration of BRII-196/198 (administration at ≤ 3 days or > 3 days from the onset of infection symptoms). Results The ≤ 3 days group exhibited a greater positive effect (HR 5.94, 95% CI, 1.42–24.83; P 3 days group who exhibited disease progression. The multivariate Cox regression analysis revealed low flow oxygen support prior to BRII-196/198 administration (HR 3.53, 95% CI 1.42–8.77, P

Abstract Background Acute respiratory syndrome distress (ARDS) is a clinical common syndrome with high mortality. Electrical impedance tomography (EIT)-guided positive end-expiratory pressure (PEEP) titration can achieve the compromise between lung overdistension and collapse which may minimize ventilator-induced lung injury in these patients. However, the effect of EIT-guided PEEP titration on the clinical outcomes remains unknown. The objective of this trial is to investigate the effects of EIT-guided PEEP titration on the clinical outcomes for moderate or severe ARDS, compared to the low fraction of inspired oxygen (FiO2)-PEEP table. Methods This is a prospective, multicenter, single-blind, parallel-group, adaptive designed, randomized controlled trial (RCT) with intention-to-treat analysis. Adult patients with moderate to severe ARDS less than 72 h after diagnosis will be included in this study. Participants in the intervention group will receive PEEP titrated by EIT with a stepwise decrease PEEP trial, whereas participants in the control group will select PEEP based on the low FiO2-PEEP table. Other ventilator parameters will be set according to the ARDSNet strategy. Participants will be followed up until 28 days after enrollment. Three hundred seventy-six participants will be recruited based on a 15% decrease of 28-day mortality in the intervention group, with an interim analysis for sample size re-estimation and futility assessment being undertaken once 188 participants have been recruited. The primary outcome is 28-day mortality. The secondary outcomes include ventilator-free days and shock-free days at day 28, length of ICU and hospital stay, the rate of successful weaning, proportion requiring rescue therapies, compilations, respiratory variables, and Sequential Organ Failure Assessment (SOFA). Discussion As a heterogeneous syndrome, ARDS has different responses to treatment and further results in different clinical outcomes. PEEP selection will depend on the properties of patients and can be individually achieved by EIT. This study will be the largest randomized trial to investigate thoroughly the effect of individual PEEP titrated by EIT in moderate to severe ARDS patients to date. Trial registration ClinicalTrial.gov NCT05207202. First published on January 26, 2022.

BackgroundDistinguishing ARDS phenotypes is of great importance for its precise treatment. In the study, we attempted to ascertain its phenotypes based on metabolic and autophagy-related genes and infiltrated immune cells.MethodsTranscription datasets of ARDS patients were obtained from Gene expression omnibus (GEO), autophagy and metabolic-related genes were from the Human Autophagy Database and the GeneCards Database, respectively. Autophagy and metabolism-related differentially expressed genes (AMRDEGs) were further identified by machine learning and processed for constructing the nomogram and the risk prediction model. Functional enrichment analyses of differentially expressed genes were performed between high- and low-risk groups. According to the protein-protein interaction network, these hub genes closely linked to increased risk of ARDS were identified with CytoHubba. ssGSEA and CIBERSORT was applied to analyze the infiltration pattern of immune cells in ARDS. Afterwards, immunologically characterized and molecular phenotypes were constructed according to infiltrated immune cells and hub genes.ResultsA total of 26 AMRDEGs were obtained, and CTSB and EEF2 were identified as crucial AMRDEGs. The predictive capability of the risk score, calculated based on the expression levels of CTSB and EEF2, was robust for ARDS in both the discovery cohort (AUC = 1) and the validation cohort (AUC = 0.826). The mean risk score was determined to be 2.231332, and based on this score, patients were classified into high-risk and low-risk groups. 371 differential genes in high- and low-risk groups were analyzed. ITGAM, TYROBP, ITGB2, SPI1, PLEK, FGR, MPO, S100A12, HCK, and MYC were identified as hub genes. A total of 12 infiltrated immune cells were differentially expressed and have correlations with hub genes. According to hub genes and implanted immune cells, ARDS patients were divided into two different molecular phenotypes (Group 1: n = 38; Group 2: n = 19) and two immune phenotypes (Cluster1: n = 22; Cluster2: n = 35), respectively.ConclusionThis study picked up hub genes of ARDS related to autophagy and metabolism and clustered ARDS patients into different molecular phenotypes and immunophenotypes, providing insights into the precision medicine of treating patients with ARDS.

Introduction Sepsis is one of the most common risk factors for acute respiratory distress syndrome (ARDS). Neutrophil elastase (NE) is believed to be an important mediator of ARDS. When sepsis occurs, a large number of inflammatory factors are activated and released, which makes neutrophils migrate into the lung, eventually leading to the occurrence of ARDS. Sivelestat sodium is an NE inhibitor that can inhibit the inflammatory reaction during systemic inflammatory response syndrome and alleviate lung injury. Therefore, we hypothesise that intravenous sivelestat sodium may prevent the occurrence of ARDS in patients with sepsis.Methods and analysis This is a prospective, investigator-initiated, double-blind, adaptive, multicentre, randomised, controlled clinical trial with an adaptive ‘sample size re-estimation’ design. Patients meeting the inclusion criteria who were transferred into the intensive care unit will be randomly assigned to receive sivelestat sodium or placebo for up to 7 days. The primary outcome is the development of ARDS within 7 days after randomisation. A total of 238 patients will be recruited based on a 15% decrease in the incidence of ARDS in the intervention group in this study. A predefined interim analysis will be performed to ensure that the calculation is reasonable after reaching 50% (120) of the planned sample size.Ethics and dissemination The study protocol was approved by the Ethics Committee of ZhongDa Hospital affiliated to Southeast University (identifier: Clinical Ethical Approval No. 2021ZDSYLL153-P03). Results will be submitted for publication in peer-reviewed journals and presented at relevant conferences and meetings.Trial registration number NCT04973670.

Abstract Background Acute respiratory distress syndrome (ARDS) patients with different lung morphology have distinct pulmonary mechanical dysfunction and outcomes. Whether lung morphology impacts the association between ventilatory variables and mortality remains unclear. Moreover, the impact of a novel combined ventilator variable [(4×DP) + RR] on morality in ARDS patients needs external validation. Methods We obtained data from the Chinese Database in Intensive Care (CDIC), which included adult ARDS patients who received invasive mechanical ventilation for at least 24 h. Patients were further classified into two groups based on lung morphology (focal and non-focal). Ventilatory variables were collected longitudinally within the first four days of ventilation. The primary outcome was 28-day mortality. Extended Cox regression models were employed to explore the interaction between lung morphology and longitudinal ventilatory variables on mortality. Findings We included 396 ARDS patients with different lung morphology (64.1% non-focal). The overall 28-day mortality was 34.4%. Patients with non-focal lung morphology have more severe and persistent pulmonary mechanical dysfunction and higher mortality than those with focal lung morphology. Time-varying driving pressure (DP) was more significantly associated with 28-day mortality in patients with non-focal lung morphology compared to focal lung morphology patients (P for interaction = 0.0039). The impact of DP on mortality was more significant than that of respiratory rate (RR) only in patients with non-focal lung morphology. The hazard ratio (HR) of mortality for [(4×DP) + RR] was significant in patients with non-focal lung morphology (HR 1.036, 95% CI 1.027–1.045), not in patients with focal lung morphology (HR 1.019, 95% CI 0.999–1.039). Interpretation The association between ventilator variables and mortality varied among patients with different lung morphology. [(4×DP) + RR] was only associated with mortality in patients with non-focal lung morphology. Further validation is needed.

Purpose Terlipressin improves renal function in patients with septic shock. However, the mechanism remains unclear. Here, we aimed to evaluate the effects of terlipressin on renal perfusion in patients with septic shock.Materials and Methods This pilot study enrolled patients with septic shock in the intensive care unit of the tertiary hospital from September 2019 to May 2020. We randomly assigned patients to terlipressin and usual care groups using a 1:1 ratio. Terlipressin was intravenously pumped at a rate of 1.3 μg/kg/hour for 24 h. We monitored renal perfusion using renal contrast-enhanced ultrasound (CEUS). The primary outcome was peak sonographic signal intensity (a renal perfusion parameter monitored by CEUS) at 24 h after enrollment.Results 22 patients were enrolled in this study with 10 in the terlipressin group and 12 in the usual care group. The baseline characteristics of patients between the two groups were comparable. The peak sonographic signal intensity at 24 h after enrollment in the terlipressin group (60.5 ± 8.6 dB) was significantly higher than that in the usual care group (52.4 ± 7.0 dB; mean difference, 7.1 dB; 95% CI, 0.4–13.9; adjusted p = .04). Patients in the terlipressin group had a lower time to peak, heart rates, norepinephrine dose, and a higher stroke volume at 24 h after enrollment. No significant difference in the urine output within 24 h and incidence of acute kidney injury within 28 days was found between the two groups.Conclusions Terlipressin improves renal perfusion, increases stroke volume, and decreases norepinephrine dose and heart rates in patients with septic shock.

Yellow fever virus (YFV) infection is a major public concern that threatens a large population in South America and Africa. No specific anti-YFV drugs are available till now. Here, we report that rifapentine is a potent YFV inhibitor in various cell lines by high-throughput drugs screening, acting at both cell entry and replication steps. Kinetic test and binding assay suggest that rifapentine interferes the viral attachment to the target cells. The application of YFV replicon and surface plasmon resonance assay indicates that rifapentine suppresses viral replication by binding to the RNA-dependent RNA polymerase (RdRp) domain of viral nonstructural protein NS5. Further molecular docking suggests that it might interact with the active centre of RdRp. Rifapentine significantly improves the survival rate, alleviates clinical signs, and reduces virus load and injury in targeted organs both in YFV-infected type I interferon receptor knockout A129−/− and wild-type C57 mice. The antiviral effect in vivo is robust during both prophylactic intervention and therapeutic treatment, and the activity is superior to sofosbuvir, a previously reported YFV inhibitor in mice. Our data show that rifapentine may serve as an effective anti-YFV agent, providing promising prospects in the development of YFV pharmacotherapy.

Abstract Background Previously identified phenotypes of acute respiratory distress syndrome (ARDS) have been limited by a disregard for temporal dynamics. We aimed to identify longitudinal phenotypes in ARDS to test the prognostic and predictive enrichment of longitudinal phenotypes, and to develop simplified models for phenotype identification. Methods We conducted a multi-database study based on the Chinese Database in Intensive Care (CDIC) and four ARDS randomized clinical trials (RCTs). We employed latent class analysis (LCA) to identify longitudinal phenotypes using 24-hourly data from the first four days of invasive ventilation. We used the Cox regression model to explore the association between time-varying respiratory parameters and 28-day mortality across phenotypes. Phenotypes were validated in four RCTs, and the heterogeneity of treatment effect (HTE) was investigated. We also constructed two multinomial logistical regression analyses to develop the probabilistic models. Findings A total of 605 ARDS patients in CDIC were enrolled. The three-class LCA model was identified and had the optimal fit, as follows: Class 1 (n = 400, 66.1% of the cohort) was the largest phenotype over all study days, and had fewer abnormal values, less organ dysfunction and the lowest 28-day mortality rate (30.5%). Class 2 (n = 102, 16.9% of the cohort) was characterized by pulmonary mechanical dysfunction and had the highest proportion of poorly aerated lung volume, the 28-day mortality rate was 47.1%. Class 3 (n = 103, 17% of the cohort) was correlated with extra-pulmonary dysfunction and had the highest 28-day mortality rate (56.3%). Time-varying mechanical power was more significantly associated with 28-day mortality in Class 2 patients compared to other phenotypes. Similar phenotypes were identified in four RCTs. A significant HTE between phenotypes and treatment strategies was observed in the ALVEOLI (high PEEP vs. low PEEP) and the FACTT trials (conservative vs. liberal fluid management). Two parsimonious probabilistic models were constructed to identify longitudinal phenotypes. Interpretation We identified and validated three novel longitudinal phenotypes for ARDS patients, with both prognostic and predictive enrichment. The phenotypes of ARDS can be accurately identified with simple classifier models, except for Class 3.

ABSTRACTThe potential future burden of COVID-19 is determined by the level of susceptibility of the population to infection. The protective effect provided by those previously infected diminishes over several months, while individuals with mixed immunity have the highest degree and persistence of protection. This study aimed to clarify the vaccination status of COVID-19 patients with hypertension and to analyze the characteristics and risk factors of non-vaccinated patients to protect this vulnerable population in the future. The study ultimately enrolled 4576 hypertensive patients with Omicron infection from April 6, 2022, to May 15, 2022. Among them, 3556 patients (77.7%) had received at least one dose of vaccine, and 2058 patients (45.0%) received a booster dose. In the multivariate logistic analysis, male (OR 1.328, 95% CI 1.138–1.550, p

Although the Berlin definition of acute respiratory distress syndrome (ARDS), 2012 has been widely used in clinical practice, issues have occasionally been raised regarding various criteria since it was proposed. High-flow nasal oxygen (HFNO) is widely used for effective respiratory support in acute respiratory failure. As patients who do not require ventilation but meet the Berlin criteria have similar characteristics to those with ARDS, the definition of ARDS may be broadened to include patients receiving HFNO. As the PaO2/FiO2 under-recognizes the diagnosis of ARDS, a SpO2/FiO2 value of ≤315 may be considered instead of a PaO2/FiO2 value of ≤300 for diagnosing the condition in resource-constrained settings. In this context, patients with severe COVID-19 always meet other criteria for ARDS except for 7-day acute onset. Therefore, the timeframe for the onset of ARDS may be extended to up to 14 days. An expanded definition of ARDS may allow early identification of patients with less severe diseases and facilitate testing and application of new therapies in patients with a high risk of poor outcomes. Here, we discuss the major controversies regarding the extension of the ARDS definition with a view to improving clinical implementation and patient outcomes.

Background: To describe the current status of aerosol therapy during mechanical ventilation (MV) and the practice, knowledge, and beliefs about aerosol therapy in physicians working in the intensive care unit (ICU) in China. Methods: A physician self-administered questionnaire-based cross-sectional survey was carried out from January 2019 to July 2019. An electronic questionnaire was designed, and physicians who worked regularly in ICUs across several hospitals were contacted through WeChat. Answers to all questions and the general characteristics of physicians who answered the questionnaire were collected and analyzed. Results: A total of 2203 medical staff who regularly worked in the ICUs completed this questionnaire (9.0% missing data); 87.7% of the participants were doctors. Most respondents claimed that they often administered aerosolization therapy. Ultrasonic atomizer (50.7%) and jet nebulizer (48.6%) were the most commonly used atomization devices. Bronchodilators (65.8%) and steroids (66.3%) were the most frequently aerosolized drugs during MV. During nebulization, ventilator settings were never changed by 32.7% of respondents. Only 49.1% of respondents knew the appropriate place for a nebulizer. Further, 62.7% of respondents using heated humidifiers reported turning them off during nebulization. Specific knowledge about droplet size and nebulization yield was poor. Respondents from tertiary hospitals and those with higher technical title or work experience tended to have better accuracy than those from primary hospitals or with lower technical titles (P

Laboratory analysis of returned Chang’E-5 samples from the lunar surface show their hydroxyl contents to be on the weak end of lunar hydration features.

SARS-CoV-2 Omicron variant is significantly different from all the previous variants and has rapidly replaced other variants as the dominant variant across the globe. An easily obtained, inexpensive, and rapid marker is needed to predict the negative conversion time (NCT) of nucleic acid in nonsevere COVID-19 patients infected by the Omicron variant. This retrospective study enrolled 226 patients infected by the Omicron variant between April 23, 2022, and May 16, 2022. The median age of the patients was 61 (interquartile range (IQR), 48–70) years, and 56.2% were male. 84 patients (37.2%) had at least one comorbidity, and 49 patients (21.7%) were classified into the moderate illness group. 145 patients (64.2%) received at least one dose of vaccine, in which 67 patients (29.6%) received a booster dose of vaccine. The median duration of NCT was 8 (IQR, 7–11) days. Univariate Cox analyses found that high NLR (>2.22), aged ≥65 years, vaccination, and moderate illness were significantly related to the NCT of nucleic acid. Multivariate Cox regression analysis showed that high NLR (NLR > 2.22, hazard ratio (HR):0.718, 95% CI: 0.534–0.964, p = 0.028) and vaccination (vaccinated ≥1 dose, HR: 1.536, 95% CI: 1.147–2.058, p = 0.004) were independently associated with NCT of nucleic acid. NLR is a rapid, simple, and useful prognostic factor for predicting NCT of nucleic acid in nonsevere COVID-19 patients with the Omicron variant. In addition, vaccination may also play a valuable role in predicting the NCT of nucleic acid.

BackgroundPrevious studies usually identified patients who benefit the most from prone positioning by oxygenation improvement. However, inconsistent results have been reported. Physiologically, pulmonary dead space fraction may be more appropriate in evaluating the prone response. As an easily calculated bedside index, ventilatory ratio (VR) correlates well with pulmonary dead space fraction. Hence, we investigated whether the change in VR after prone positioning is associated with weaning outcomes at day 28 and to identify patients who will benefit the most from prone positioning.Materials and methodsThis retrospective cohort study was performed in a group of mechanically ventilated, non-COVID ARDS patients who received prone positioning in the ICU at Zhongda hospital, Southeast University. The primary outcome was the rate of successful weaning patients at day 28. Arterial blood gas results and corresponding ventilatory parameters on five different time points around the first prone positioning were collected, retrospectively. VR responders were identified by Youden’s index. Competing-risk regression models were used to identify the association between the VR change and liberation from mechanical ventilation at day 28.ResultsOne hundred and three ARDS patients receiving prone positioning were included, of whom 53 (51%) successfully weaned from the ventilator at day 28. VR responders were defined as patients showing a decrease in VR of greater than or equal to 0.037 from the baseline to within 4 h after prone. VR responders have significant longer ventilator-free days, higher successful weaning rates and lower mortality compared with non-responders at day 28. And a significant between-group difference exists in the respiratory mechanics improvement after prone (P < 0.05). A linear relationship was also found between VR change and compliance of the respiratory system (Crs) change after prone (r = 0.32, P = 0.025). In the multivariable competing-risk analysis, VR change (sHR 0.57; 95% CI, 0.35–0.92) was independently associated with liberation from mechanical ventilation at day 28.ConclusionVentilatory ratio decreased more significantly within 4 h after prone positioning in patients with successful weaning at day 28. VR change was independently associated with liberation from mechanical ventilation at day 28.

Abstract Background Prolonged ventilatory support is associated with poor clinical outcomes. Partial support modes, especially pressure support ventilation, are frequently used in clinical practice but are associated with patient–ventilation asynchrony and deliver fixed levels of assist. Neurally adjusted ventilatory assist (NAVA), a mode of partial ventilatory assist that reduces patient–ventilator asynchrony, may be an alternative for weaning. However, the effects of NAVA on weaning outcomes in clinical practice are unclear. Methods We searched PubMed, Embase, Medline, and Cochrane Library from 2007 to December 2020. Randomized controlled trials and crossover trials that compared NAVA and other modes were identified in this study. The primary outcome was weaning success which was defined as the absence of ventilatory support for more than 48 h. Summary estimates of effect using odds ratio (OR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with accompanying 95% confidence interval (CI) were expressed. Results Seven studies (n = 693 patients) were included. Regarding the primary outcome, patients weaned with NAVA had a higher success rate compared with other partial support modes (OR = 1.93; 95% CI 1.12 to 3.32; P = 0.02). For the secondary outcomes, NAVA may reduce duration of mechanical ventilation (MD = − 2.63; 95% CI − 4.22 to − 1.03; P = 0.001) and hospital mortality (OR = 0.58; 95% CI 0.40 to 0.84; P = 0.004) and prolongs ventilator-free days (MD = 3.48; 95% CI 0.97 to 6.00; P = 0.007) when compared with other modes. Conclusions Our study suggests that the NAVA mode may improve the rate of weaning success compared with other partial support modes for difficult to wean patients.

Coronavirus disease 2019 (COVID-19) may rapidly worsen respiratory failure, thereby leading to death. COVID-19-induced respiratory failure exhibits some atypical characteristics, silent hypoxemia, and high lung compliance. Some histopathological changes associated with COVID-19-induced respiratory failure differ from those of classic acute respiratory distress syndrome (ARDS). However, compared with classical ARDS, COVID-19-induced respiratory failure has a similar timing of onset, clinical syndromes, radiological profile, and mortality rate in the intensive care unit (ICU). Respiratory failure induced by COVID-19 is a type of ARDS and is currently underdiagnosed. This condition stretches the definition of classic ARDS; therefore, an updated definition is warranted.

BackgroundThe convalescent plasma of patients who recover from coronavirus disease 2019 (COVID-19) contains high titers of neutralizing antibodies, which has potential effects on the viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and improving the prognosis of patients with COVID-19. The goal of this study was to clarify the effects of convalescent plasma therapy on the 60-day mortality and negative conversion rate of SARS-CoV-2 during the hospitalization of patients with severe and life-threatening COVID-19 infection.MethodsThis was a retrospective, case-matched cohort study that involved patients with severe COVID-19 infections. The patients who received convalescent plasma therapy were matched by age, sex, diabetes, hypertension, heart failure, the onset of symptoms to hospital admission, respiratory support pattern, lymphocyte count, troponin, Sequential organ failure assessment (SOFA), glucocorticoid, and antiviral agents to no more than three patients with COVID-19 who did not receive convalescent plasma therapy. A Cox regression model and competing risk analysis were used to evaluate the effects of convalescent plasma therapy on these patients.ResultsTwenty-six patients were in the convalescent plasma therapy group, and 78 patients were in the control group. Demographic characteristics were similar in both groups, except for the SOFA score. Convalescent plasma therapy did not improve 60-day mortality [hazard ratio (HR) 1.44, 95% CI 0.82–2.51, p = 0.20], but the SARS-CoV-2 negative conversion rate for 60 days after admission was higher in the convalescent plasma group (26.9 vs. 65.4%, p = 0.002) than in the control. Then, a competing risk analysis was performed, which considered events of interest (the negative conversion rate of SARS-CoV-2) and competing events (death) in the same model. Convalescent plasma therapy improved events of interest (p = 0.0002).ConclusionConvalescent plasma therapy could improve the SARS-CoV-2 negative conversion rate but could not improve 60-day mortality in patients with severe and life-threatening COVID-19 infection.Clinical Trial NumberThe study was registered at ClinicalTrials.gov (NCT04616976).

Abstract To investigate the relationships between LncRNA NNT-AS1, CRP, PCT and their interactions and the refractory mycoplasma pneumoniae pneumonia (RMPP) in children. Serum levels of LncRNA NNT-AS1 of RMPP and non-RMPP (NRMPP) patients were detected by real-time PCR, and were analyzed together with serum c-reactive protein (CRP) and procalcitonin (PCT). Correlations between LncRNA NNT-AS1 and CRP and PCT were analyzed by Pearson correlation test. The ROC curve was used to analyze the potential of LncRNA NNT-AS1, CRP and PCT as biomarkers for predicting RMPP. Logistic regression crossover model and the Excel compiled by Andersson et al. were used to analyze the interactions among the biomarkers. We found that LncRNA NNT-AS1, CRP and PCT were all highly expressed in patients with RMPP. LncRNA NNT-AS1 could positively correlate with the expressions of CRP and PCT, and jointly promote the occurrence of RMPP. The combined diagnosis of LncRNA NNT-AS1, CRP and PCT could predict the occurrence of RMPP.

We previously reported that sputum induction was more sensitive than throat swabs for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in two convalescent coronavirus disease 2019 (COVID-19) patients; however, the value and safety of induced sputum testing require further study. We conducted a prospective multi-center cross-sectional study to compare induced sputum to throat swabs for SARS-CoV-2 detection. Confirmed COVID-19 patients from six hospitals in six cities across China who received one or more negative RT-PCR result for SARS-CoV-2 were enrolled, and paired specimens (induced sputum and throat swabs; 56 cases) were assayed. In three paired samples, both the induced sputum and throat swabs were positive for SARS-CoV-2. The positive rate for induced sputum was significantly higher than for throat swabs both overall (28.6% vs 5.4%, respectively; p

BackgroundVitamin D deficiency is a common condition in critically ill patients. A high dose of vitamin D3 can rapidly restore vitamin D levels. The aim of this meta-analysis was to synthesize the results from up-to-date randomized control trials (RCT) and validate the effect of vitamin D3 in critically ill patients.Study MethodsSeveral databases, including PubMed, Web of Science, EMBASE, and the Cochrane Central database, were searched up to December 4th, 2020. All RCTs that investigated the use of a high dose of vitamin D3 in critically ill patients and reported mortality data were included in the meta-analysis. The primary outcome was the mortality truncated to day 28 and day 90.ResultsA total of 10 RCTs enrolling 2058 patients were finally included. The use of a high dose of vitamin D3 in critically ill patients could not decrease the mortality truncated to day 28 (RR 0.93, 95% CI 0.78–1.11, P = 0.43) or day 90 (RR 0.91, 95% CI 0.79–1.05, P = 0.21). A high dose of vitamin D3 could significantly reduce the ventilator days (MD −9.38, 95%CI −13.44 to −5.31, P < 0.001), but there were no statistic difference in length of ICU stay (MD −2.76, 95% CI −6.27 to 0.74, P = 0.12) and hospital stay (MD −2.42, 95% CI −6.21 to 1.36, P = 0.21). No significant difference was observed in adverse events between the vitamin D3 group and the placebo group.ConclusionThe use of high dose vitamin D3 was not associated with decreased mortality in critically ill patients, but could significantly reduce the ventilator days.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42020179195.

PurposeFor men suspected of having prostate cancer (PCa), the transrectal ultrasound (TRUS)-guided systematic biopsy (SB) was performed. MRI/TRUS fusion guided-targeted biopsy (MRI-TB) could enhance PCa detection, allowing sampling of sites at higher risk which were not obvious with TRUS alone. The aim of this systematic review and meta-analysis was to compare the detection rates of prostate cancer by MRI-TB or MRI-TB plus SB versus SB, mainly for diagnosis of high-risk PCa.MethodsA literature Search was performed on PubMed, Cochrane Library, and Embase databases. We searched from inception of the databases up to January 2021.ResultsA total of 5831 patients from 26 studies were included in the present meta-analysis. Compared to traditional TRUS-guided biopsy, MRI-TB had a significantly higher detection rate of clinically significant PCa (RR=1.27; 95%CI 1.15-1.40; p

Abstract Background Sepsis remains a leading cause of death in critically ill patients. It is well known that mesenchymal stem cells (MSCs) are a promising therapy partly due to their paracrine-mediated immunoregulatory function. Previous study demonstrated that transforming growth factor-beta1 (TGF-β1) is an important cytokine secreted by MSCs and that it participates in MSC-mediated macrophage phenotype switch from pro-inflammatory to pro-resolution. In addition, the transformation of macrophage phenotype may be a potential treatment for sepsis. However, the therapeutic effect of overexpressing TGF-β1 in MSCs (MSC-TGF-β1) on sepsis is not well understood. Therefore, this study aimed to evaluate the effects of TGF-β1 overexpressing MSCs on organ injury in cecal ligation and puncture (CLP)-induced septic mice and to detect the changes in macrophage phenotype during this process. Methods Mouse MSCs stably transfected with TGF-β1 were constructed and injected into CLP-induced septic mice via tail vein. After 24 h, the mice were sacrificed; then, the histopathology of the organ was evaluated by hematoxylin-eosin (H&E) staining. Inflammatory cytokines were detected by ELISA. Macrophage infiltration and phenotype transformation in the tissues were determined by immunohistochemistry and flow cytometry. In addition, we performed adoptive transfer of mouse peritoneal macrophage pretreated with TGF-β1 overexpressing MSCs in septic mice. Results We found that infusion of TGF-β1 overexpressing MSCs attenuated the histopathological impairment of the organ, decreased the pro-inflammatory cytokine levels and inhibited macrophage infiltration in tissues. TGF-β1 overexpressing MSCs induced macrophage phenotypes changed from pro-inflammatory to pro-resolution in inflammatory environment. The adoptive transfer of mouse peritoneal macrophages pretreated with TGF-β1 overexpressing MSCs also relieved organ damage in CLP-induced septic mice. Conclusion Under septic conditions, TGF-β1 overexpressing MSCs can enhance the therapeutic effects of MSCs on organ injury and inflammation as a result of reduced macrophage infiltration and induced macrophages transformation, the adoptive transfer of macrophages treated with TGF-β1 overexpressing MSCs also relieved organ damage. This will provide new hope for the treatment of sepsis.

Abstract Background Endothelial injury is one of the predominant pathophysiological characteristics of sepsis and is the major cause of sepsis-induced multiple organ failure. Endothelial pyroptosis is a fatal mechanism of endothelial injury in sepsis, and specific, effective therapies are lacking. Although hepatocyte growth factor (HGF) has been shown to have anti-apoptotic and anti-necrotic effects, whether it prevents pyroptosis to improve endothelial injury in sepsis remains unclear. Methods Recombinant HGF was intravenously injected into mice with sepsis caused by caecal ligation puncture (CLP). Histopathological examination and transmission electron microscopy (TEM) were used to measure lung vascular endothelial injury. Lipopolysaccharide (LPS) was transfected into EA.hy926 cells to induce endothelial pyroptosis, and the cells were treated with HGF in the presence of inhibitors of c-Met and mTOR, namely, PHA-665752 and rapamycin, respectively. The mTOR signalling pathway and mitochondrial physiology were assessed using Western blot and flow cytometry. Results Intravenous HGF effectively alleviated pulmonary vascular endothelial injury and acute lung injury in the septic mice. The TEM results of lung tissue revealed that HGF attenuated pulmonary vascular endothelial pyroptosis, which was confirmed in vitro. Transfected LPS induced the pyroptosis of EA.hy926 cells and damaged their paracellular permeability, and these effects were ameliorated by treating the cells with recombinant HGF. The protective effect of HGF against pyroptosis was dependent on c-Met/mTOR signalling. mTOR activation effectively protected mitochondrial physiology and decreased reactive oxygen species (ROS) production in EA.hy926 cells in vitro. Conclusions These results demonstrated that HGF protected mitochondrial physiology by activating mTOR signalling to partially ameliorate endothelial pyroptosis and attenuate vascular endothelial injury and acute lung injury in sepsis animal model.

Abstract Background T helper 17 cells (Th17)/regulatory T cells (Treg), as subtypes of CD4+ T cells, play an important role in the inflammatory response of acute respiratory distress syndrome (ARDS). However, there is still a lack of effective methods to regulate the differentiation balance of Th17/Treg. It was proven that mesenchymal stem cells (MSCs) could regulate the differentiation of CD4+ T cells, but the mechanism is still unclear. TGFβ1, a paracrine cytokine of MSCs, could also regulate the differentiation of Th17/Treg but is lowly expressed in MSCs. Therefore, mouse MSCs (mMSCs) overexpressing TGFβ1 were constructed by lentivirus transduction and intratracheally transplanted into LPS-induced ARDS mice in our study. The aim of this study was to evaluate the therapeutic effects of mMSCs overexpressing TGFβ1 on inflammation and immunoregulation by impacting the Th17/Treg balance in LPS-induced ARDS mice. Methods mMSCs overexpressing TGFβ1 were constructed using lentiviral vectors. Then, mouse bone-marrow-derived MSCs (mBM-MSC) and mBM-MSC-TGFβ1 (mBM-MSC overexpressing TGFβ1) were transplanted intratracheally into ARDS mice induced by lipopolysaccharide. At 3 and 7 days after transplantation, the mice were sacrificed, and the homing of the mMSCs was assayed by ex vivo optical imaging. The relative numbers of Th17 and Treg in the lungs and spleens of mice were detected by FCM. IL-17A and IL-10 levels in the lungs of mice were analysed by western blot. Permeability and inflammatory cytokines were evaluated by analysing the protein concentration of BALF using ELISA. Histopathology of the lungs was assessed by haematoxylin and eosin staining and lung injury scoring. Alveolar lung fibrosis was assessed by Masson’s trichrome staining and Ashcroft scoring. The mortality of ARDS mice was followed until 7 days after transplantation. Results The transduction efficiencies mediated by the lentiviral vectors ranged from 82.3 to 88.6%. Overexpressing TGFβ1 inhibited the proliferation of mMSCs during days 5–7 (p 0.05). Compared to that in the LPS + mBM-MSC-NC group mice, engraftment of mMSCs overexpressing TGFβ1 led to much more differentiation of T cells into Th17 or Treg (p 0.05). Conclusion MSCs overexpressing TGFβ1 could regulate lung inflammation and attenuate lung injuries by modulating the imbalance of Th17/Treg in the lungs of ARDS mice.

Abstract Background Mesenchymal stem cells (MSCs) have been shown to alleviate acute lung injury (ALI) and induce the production of regulatory dendritic cells (DCregs), but the potential link between these two cell types remains unclear. The goal of this study was to investigate the effect and mechanism of MSC-induced regulatory dendritic cells in ALI mice. Material/methods In vivo experiments, C57BL/6 wild-type male mice were sacrificed at different times after intratracheal injection of LPS to observe changes in lung DC maturation and pathological damage. MSCs, DCregs or/and carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled DCs were administered to the mice by tail vein, and flow cytometry was performed to measure the phenotype of lung DCs and T cells. Lung injury was estimated by the lung wet weight/body weight ratio and histopathological analysis. In vitro, Western blotting or flow cytometry was used to detect the expression of Notch ligand or receptor in MSCs or DCs after coculture or LPS stimulation. Finally, in vivo and in vitro, we used the Notch signaling inhibitor DAPT to verify the effect of the Notch pathway on MSC-induced DCregs and their pulmonary protection. Results We showed significant accumulation and maturation of lung DCs 2 h after intratracheal injection of LPS, which were positively correlated with the lung pathological injury score. MSC treatment alleviated ALI lung injury, accompanied by a decrease in the number and maturity of classical DCs in the lungs. CFSE-labeled DCs migrated to the lungs of ALI mice more than those of the normal group, and the elimination of CFSE-labeled DCs in the blood was slower. MSCs inhibited the migration of CFSE-labeled DCs to the lung and promoted their elimination in the blood. DCregs, which are obtained by contact coculture of mDCs with MSCs, expressed reduced levels of MHCII, CD86, CD40 and increased levels of PD-L1, and had a reduced ability to stimulate lymphocyte proliferation and activation (expression of CD44 and CD69). mDCs expressing Notch2 significantly increased after coculture with MSCs or rhJagged1, and MSCs expressed more Jagged1 after LPS stimulation. After stimulation of mDCs with recombinant Jagged1, DCs with low expression of MHCII, CD86 and CD40 were also induced, and the effects of both rhJagged1 and MSCs on DCs were blocked by the Notch inhibitor DAPT. Intra-airway DAPT reversed the inhibitory effect of mesenchymal stem cells on DC recruitment to the lungs and its maturation. Conclusions Our results suggested that the recruitment and maturation of lung DCs is an important process in early ALI, MSCs attenuate LPS-induced ALI by inducing the production of DCregs by activating Notch signaling.

Abstract Background We aimed to synthesize up-to-date trials to validate the effects of neuromuscular blocking agent (NMBA) use in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Methods Several databases including PubMed, EMBASE, Web of Science, and Cochrane Central Register were searched up to November 14, 2019. All randomized trials investigating the use of NMBAs in patients with moderate-to-severe ARDS and reporting mortality data were included in the meta-analysis. The primary outcome was mortality, and the secondary outcomes were clinical outcomes, including respiratory physiological parameters, incidence of barotrauma, ICU-free days, and ventilation-free days. Results A total of 7 trials enrolling 1598 patients were finally included in this meta-analysis. The results revealed that the use of NMBAs in moderate-to-severe ARDS could significantly decrease the mortality truncated to day 28 (RR 0.74, 95% CI 0.56 to 0.98, P = 0.03) and day 90 (RR 0.77, 95% CI 0.60 to 0.99, P = 0.04). NMBA use could significantly decrease the incidence of barotrauma (RR 0.56, 95% CI 0.36 to 0.87, P = 0.009). No significant difference was observed in ICU-free days or ventilation-free days between the NMBA and control groups. Conclusion The use of NMBAs could significantly decrease mortality in moderate-to-severe ARDS patients and decrease the incidence of barotrauma during mechanical ventilation. However, more large-scale randomized trials are needed to further validate the effect of NMBA use in ARDS.

BackgroundThe benefits of intravenous immunoglobulin administration are controversial for critically ill COVID-19 patients.MethodsWe analyzed retrospectively the effects of immunoglobulin administration for critically ill COVID-19 patients. The primary outcome was 28-day mortality. Inverse probability of treatment weighting (IPTW) with propensity score was used to account for baseline confounders. Cluster analysis was used to perform phenotype analysis.ResultsBetween January 1 and February 29, 2020, 754 patients with complete data from 19 hospitals were enrolled. Death at 28 days occurred for 408 (54.1%) patients. There were 392 (52.0%) patients who received intravenous immunoglobulin, at 11 (interquartile range (IQR) 8, 16) days after illness onset; 30% of these patients received intravenous immunoglobulin prior to intensive care unit (ICU) admission. By unadjusted analysis, no difference was observed for 28-day mortality between the immunoglobulin and non-immunoglobulin groups. Similar results were found by propensity score matching (n = 506) and by IPTW analysis (n = 731). Also, IPTW analysis did not reveal any significant difference between hyperinflammation and hypoinflammation phenotypes.ConclusionNo significant association was observed for use of intravenous immunoglobulin and decreased mortality of severe COVID-19 patients. Phenotype analysis did not show any survival benefit for patients who received immunoglobulin therapy.

Background. Regulatory T cell (Treg)/T helper (Th) 17 skewing is important in the development of acute respiratory distress syndrome (ARDS). Immunomodulatory effects of mesenchymal stem cell- (MSC-) secreted transforming growth factor- (TGF-) β1 on CD4+ T cells are environment-sensitive and lack discussion in hypoxic and inflammatory conditions. Methods. Mouse splenic CD4+ T cells were precoated with anti-CD3 (5 μg/ml) and anti-CD28 (2 μg/ml) overnight. RAW264.7 cells were added as antigen-presenting cells (APCs). T cells with and without RAW264.7 cells were treated with various LPS concentrations of 0, 10, 100, and 1000 ng/ml or/and at hypoxia condition of 5% O2. Based on LPS (100 ng/ml) and hypoxia conditions (5% O2) as stimuli, MSCs were set as direct coculture or indirect coculture by transwell system. Anti-TGF-β1 neutralization antibody was added to explore the role of TGF-β1 among the soluble factors secreted by MSCs; miR-155 overexpression of CD4+ T cells was performed by transfection, and then, cells were added to the MSC-CD4+ T cell coculture system in hypoxic- and LPS-stimulated condition. After 48 hours, cells or supernatants were collected for detection of frequency of Treg and Th17 subsets, CD4+ T cell apoptosis and proliferation capacity assay by flow cytometry, secretion of INF-γ, IL-17A, IL-21, TGF-β1, and IL-10 by ELISA, and levels of miR-155, Rorc, Foxp3, and Ptpn2 mRNA expression of CD4+ T cells by RT-PCR. Results. MSCs could restore skewed Treg/Th17 induced by LPS and hypoxia compared to groups without MSCs with increased secretion of TGF-β1, IL-10, and IL-17A (P

Abstract Background Mesenchymal stem cells (MSCs) have been shown to alleviate acute lung injury (ALI) via paracrine hepatocyte growth factor (HGF) and to induce the differentiation of dendritic cells (DCs) into tolerogenic dendritic cells (DCregs) and participate in the immune response. However, whether MSCs induce the production of DCregs by secreting HGF to alleviate early ALI remains unclear. We observed that the protective effect of mouse bone marrow-derived MSCs against lipopolysaccharide (LPS)-induced ALI was achieved by inducing mature DCs (mDCs) to differentiate into DCregs, and its mechanism is related to the activation of the HGF/Akt pathway. Methods MSCs or MSCs with overexpression or knockdown of HGF were cocultured with DCs derived from mouse bone marrow using a Transwell system for 3 days. Moreover, we used MSCs or MSCs with overexpression or knockdown of HGF to treat LPS-induced ALI mice for 24 h. Flow cytometry was performed to measure the phagocytosis, accumulation, and maturation of DCs, as well as proliferation of T cells. Lung injury was estimated by lung wet weight to body weight ratio (LWW/BW) and histopathological analysis. Furthermore, we used the Akt inhibitor MK-2206 in a coculture system to elucidate the role of the HGF/Akt pathway in regulating the differentiation of DCs into regulatory DCs and relieving lung injury in early ALI mice. Results Immature DCs (imDCs) were induced to mature after 24 h of LPS (50 ng/ml) stimulation. MSCs or HGF induced the differentiation of mDCs into regulatory DCs characterized by low expression of MHCII, CD86, and CD40 molecules, strong phagocytic function, and the ability to inhibit T cell proliferation. The effect of MSCs on DCregs was enhanced with the increase in HGF secretion and was weakened with the decrease in HGF secretion. DCregs induced by recombinant HGF were attenuated by the Akt inhibitor MK-2206. Lung DC aggregation and mDC ratio increased in LPS-induced ALI mice, while treatment with MSCs decreased lung DC aggregation and maturation and alleviated lung pathological injury. High expression of the HGF gene enhanced the above effect of MSCs, while decreased expression of HGF weakened the above effect of MSCs. Conclusions MSCs alleviate early ALI via paracrine HGF by inducing mDCs to differentiate into regulatory DCs. Furthermore, the mechanism of HGF-induced differentiation of mDCs into DCregs is related to the activation of the Akt pathway.

Background: Acute respiratory failure (ARF) is a commonly distressing condition in critically ill patients. Its early recognition and treatment may improve clinical outcomes. Mounting evidence suggests that lung ultrasound (LUS) could be an alternative to chest X-ray (CXR) or computed tomography (CT) for the diagnosis of ARF in critically ill patients. This meta-analysis aimed to determine whether LUS can be an alternative tool used to investigate the cause of ARF or thoracic pathologies associated with the diagnosis of ARF in critically ill patients.Method: A systematic literature search of the PubMed, Web of Science, Embase, and Cochrane Library databases was conducted from inception to March 2020. Two researchers independently screened studies investigating the accuracy of LUS with CXR or CT for adult critically ill patients with ARF. Data with baseline, true positives, false positives, false negatives, and true negatives were extracted. The study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The pooled sensitivity and specificity were obtained using a bivariate model.Results: Eleven studies, including 1,232 patients, were included in the meta-analysis. Most studies were of low quality. LUS had a pooled sensitivity of 92% (95% confidence interval [CI]: 85–96) and a pooled specificity of 98% (95% CI: 94–99). The area under the summary receiver operating characteristic curve was 98% (95% CI: 97–99). The sensitivity and specificity of LUS to identify different pathological types of ARF were investigated. For consolidation (1,040 patients), LUS had a sensitivity of 89% and a specificity of 97%. For pleural effusion (279 patients), LUS had a pooled sensitivity of 95% and a specificity of 99%. For acute interstitial syndrome (174 patients), LUS had a pooled sensitivity of 95% and a specificity of 91%.Conclusions: LUS is an adjuvant tool that has a moderate sensitivity and high specificity for the diagnosis of ARF in critically ill patients.Systematic Review Registration: The study protocol was registered with PROSPERO (CRD42020211493).