Endothelial Cell-Derived Extracellular Vesicles Promote Aberrant Neutrophil Trafficking and Subsequent Remote Lung Injury.

The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis-induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single-cell RNA sequencing (scRNA-seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis-associated ARDS and is positively correlated with disease severity. Mechanically, scRNA-seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta-1 (KPNB1), promoting abluminal-to-luminal neutrophil rTEM. Additionally, EC-derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC-derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis-associated lung injury.

Dynamic decline of lymphocytes predicts extracorporeal membrane oxygenation-related infections: a retrospective observational study.

Background: Limited data are available regarding the current microbiological characteristics of extracorporeal membrane oxygenation (ECMO)-related infections in intensive care units (ICUs) in China. This retrospective study aimed to determine the epidemiology, risk factors and impact on the outcome of ECMO-related infections. Methods: A retrospective observational study from January 2014 to December 2019 was performed, and adult patients receiving ECMO support for more than 48 hours were included in this study. The primary outcome was the incidence rate of ECMO-related infection. Clinical data were recorded, and risk factors associated with an increased risk of ECMO-related infection were analyzed. Results: A total of 174 adult patients who received ECMO and underwent ECMO for 1,670 days were included in this study. Forty-six patients (26.4%) developed ECMO-related infections, corresponding to 27.5 first episodes/1,000 ECMO days. The most common ECMO-related infection observed was ventilator-associated pneumonia (VAP). Infected patients had longer durations of mechanical ventilation {20.2 [interquartile range (IQR), 12.6, 30.7] vs. 9.0 (IQR, 5.8, 14.7) days, P<0.001}, ECMO support [11.6 (IQR, 8.1, 17.3) vs. 7.6 (IQR, 5.6, 9.7) days, P<0.001] and hospital stays (28.2±20.7 vs. 22.0±15.6 days, P<0.001). The factors independently associated with ECMO-related infection were a dynamic decrease in lymphocyte count [adjusted odds ratio (OR) =3.578, 95% confidence interval (CI): 2.175-4.906, P<0.001] and ECMO duration (adjusted OR =1.207, 95% CI: 1.096-1.330, P<0.001). Compared to patients without infection, infected patients had greater hospital mortality (39.1% vs. 78.3%, P<0.001) and 90-day mortality (40.6% vs. 87.0%, P<0.001). ECMO-related infections were associated with worse outcomes (adjusted Kaplan-Meier curve, log rank test P<0.001). Conclusions: Patients supported by ECMO had a high risk of developing ECMO-related infection. The most common ECMO-related infection observed was VAP. A dynamic decrease in lymphocyte counts was significantly associated with an increased risk of ECMO-related infection.

Prolonged vs shorter awake prone positioning for COVID-19 patients with acute respiratory failure: a multicenter, randomised controlled trial.

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.

Integrated multi-omics profiling landscape of organising pneumonia.

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.

Carbon performance analysis of upgraded wastewater treatment plants in key control areas of the Ziya River Basin in China.

Wastewater treatment plants (WWTPs) are one of the largest sources of greenhouse gas (GHG) emissions, and they are also one of the largest energy consumption industries in urban systems. With the progression of upgrading and standard-rising, WWTPs both directly and indirectly increase carbon emissions from the increased investments in facilities and usages in electricity as well as chemical agents. Here, we collected operational data from 15 WWTPs in the key control areas of the Ziya River Basin in North China and accounted for the changes in carbon performance at different technical upgrade methods. Results showed that the average carbon emission performance increased by 0.487 kg CO2/m3 after the upgrade. Carbon emissions from electricity consumption, chemical usage, biochemical process and sludge treatment accounted for 42%, 17%, 24%, and 17% of the total improvement in carbon emission performance, respectively. Reducing energy consumption, regulating chemical use and sludge comprehensive utilization are the key to carbon emission reduction. It further proposes that the development of wastewater treatment discharge standards should fully consider the comprehensive utilization of water quality classification. Regions with favorable natural conditions should make full use of their advantages by adopting economically feasible, low-energy-consuming technologies such as constructed wetlands, which offer carbon sequestration and landscaping benefits. This study provides guidance on the selection of technological pathways for pollution reduction and carbon mitigation in the wastewater treatment industry and on achieving sustainable water resource utilization.

Fibrinogen binding to histones in circulation protects against adverse cellular and clinical outcomes.

BACKGROUND: Circulating histones are released by extensive tissue injury or cell death and play important pathogenic roles in critical illnesses. Their interaction with circulating plasma components and the potential roles in the clinical setting are not fully understood. OBJECTIVES: We aimed to characterize the interaction of histones with fibrinogen and explore its roles in vitro, in vivo, and in patient samples. METHODS: Histone-fibrinogen binding was assessed by electrophoresis and enzyme-linked immunosorbent assay-based affinity assay. Functional significance was explored using washed platelets and endothelial cells in vitro and histone-infusion mouse models in vivo. To determine clinical translatability, a retrospective single-center cohort study was conducted on patients requiring intensive care admission (n = 199) and validated in a cohort of hospitalized patients with COVID-19 (n = 69). RESULTS: Fibrinogen binds histones through its D-domain with high affinity (calf thymus histones, KD = 18.0 ± 5.6 nM; histone 3, KD = 2.7 ± 0.8 nM; and histone 4, KD = 2.0 ± 0.7 nM) and significantly reduces histone-induced endothelial damage and platelet aggregation in vitro and in vivo in a histone-infusion mouse model. Physiologic concentrations of fibrinogen can neutralize low levels of circulating histones and increase the cytotoxicity threshold of histones to 50 µg/mL. In a cohort of patients requiring intensive care, a histone:fibrinogen ratio of ≥6 on admission was associated with moderate-severe thrombocytopenia and independently predicted mortality. This finding was validated in a cohort of hospitalized patients with COVID-19. CONCLUSION: Fibrinogen buffers the cytotoxic properties of circulating histones. Detection and monitoring of circulating histones and histone:fibrinogen ratios will help identify critically ill patients at highest risk of adverse outcomes who might benefit from antihistone therapy.

Overactivated MX1 Positive Natural Killer Cells Promote the Progression of Sepsis-Induced Acute Respiratory Distress Syndrome.

Background: Natural killer (NK) cells are key regulators of immune defense in sepsis-induced acute respiratory distress syndrome (ARDS), yet the characteristics of NK cell clusters in ARDS remain poorly understood. Methods: A prospective and observational study enrolled septic patients with ARDS or not was conducted to determine the percentage of NK cells via flow cytometry. The transcriptomes of peripheral blood mononuclear cells (PBMCs) from healthy controls, patients with sepsis only, and patients with sepsis-induced ARDS were profiled. Vitro experiments were performed to confirm the mechanism mediating MX1+NK cell infiltration. Results: A total of 115 septic patients were analyzed, among whom 63 patients developed ARDS and 52 patients did not. Decreased NK percentages were found in sepsis with ARDS patients (%, 7.46±4.40 vs 11.65±6.88, P=0.0001) compared with sepsis-only patients. A lower percentage of NK cells showed a significant increase in 28-day mortality. Single-cell sequencing analysis revealed distinct characteristics of NK cells in sepsis-induced ARDS, notably the identification of a unique cluster defined as MX1+NK cells. Flow cytometry analysis showed an elevated percentage of MX1+NK cells specifically in individuals with sepsis-induced ARDS, compared with patients with sepsis only. Pseudo-time analysis showed that MX1+NK cells were characterized by upregulation of type I interferon-induced genes and other pro-inflammatory genes. MX1+NK cells can respond to type I interferons and secrete type I interferons themselves. Ligand-receptor interaction analysis also revealed extensive interaction between MX1+NK cells and T/B cells, leading to an uncontrolled inflammatory response in ARDS. Conclusion: MX1+NK cells can respond to type I interferons and secrete type I interferons themselves, promoting the development of sepsis-induced ARDS. Interfering with the infiltration of MX1+NK cells could be a therapeutic approach for this disease. Due to the limited sample size, a larger sample size was needed for further exploration.

Prognostic value of time-varying dead space estimates in mechanically ventilated patients with acute respiratory distress syndrome.

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.

Endothelial cell-derived extracellular vesicles expressing surface VCAM1 promote sepsis-related acute lung injury by targeting and reprogramming monocytes.

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.

CIRP increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TLR4-IL-2 signaling in the late phase of sepsis.

BACKGROUND: T helper (Th) cell imbalances have been associated with the pathophysiology of sepsis, including the Th1/Th2 and Th17/T regulatory cells (Treg) paradigms. Cold-inducible RNA-binding protein (CIRP), a novel damage-associated molecular pattern (DAMP) was reported that could induce T cell activation, and skew CD4+ T cells towards a Th1 profile. However, the effect and underlying mechanisms of CIRP on Th17/Treg differentiation in sepsis still remains unknown. METHODS: A prospective exploratory study including patients with sepsis was conducted. Blood samples were collected from patients on days 0, 3 and 7 on admission. The serum CIRP and peripheral blood Treg/Th17 percentage was determined by ELISA and flow cytometry. CD4+ T cells from the spleen and lymph nodes of mice with experimental sepsis were collected after treatment with normal saline (NS), recombinant murine CIRP (rmCIRP) and C23 (an antagonist for CIRP-TLR4) at late stage of sepsis. RNA-seq was conducted to reveal the pivotal molecular mechanism of CIRP on Treg/Th17 differentiation. Naïve CD4+ T cell was isolated from the Tlr4 null and wildtype mice in the presence or absence rmCIRP and C23 to confirmed above findings. RESULTS: A total of 19 patients with sepsis finally completed the study. Serum CIRP levels remained high in the majority of patients up to 1 week after admittance was closely associated with high Treg/Th17 ratio of peripheral blood and poor outcome. A univariate logistic analysis demonstrated that higher CIRP concentration at Day 7 is an independent risk factor for Treg/Th17 ratio increasing. CIRP promotes Treg development and suppresses Th17 differentiation was found both in vivo and in vitro. Pretreated with C23 not only alleviated the majority of negative effect of CIRP on Th17 differentiation, but also inhibited Treg differentiation, to some extent. Tlr4 deficiency could abolish almost all downstream effects of rmCIRP. Furthermore, IL-2 is proved a key downstream molecules of the effect CIRP, which also could amplify the activated CD4+ T lymphocytes. CONCLUSIONS: Persistent high circulating CIRP level may lead to Treg/Th17 ratio elevated through TLR4 and subsequent active IL-2 signaling which contribute to immunosuppression during late phases of sepsis.

Development and validation of a deep interpretable network for continuous acute kidney injury prediction in critically ill patients.

Early detection of acute kidney injury (AKI) may provide a crucial window of opportunity to prevent further injury, which helps improve clinical outcomes. This study aimed to develop a deep interpretable network for continuously predicting the 24-hour AKI risk in real-time and evaluate its performance internally and externally in critically ill patients. A total of 21,163 patients' electronic health records sourced from Beth Israel Deaconess Medical Center (BIDMC) were first included in building the model. Two external validation populations included 3025 patients from the Philips eICU Research Institute and 2625 patients from Zhongda Hospital Southeast University. A total of 152 intelligently engineered predictors were extracted on an hourly basis. The prediction model referred to as DeepAKI was designed with the basic framework of squeeze-and-excitation networks with dilated causal convolution embedded. The integrated gradients method was utilized to explain the prediction model. When performed on the internal validation set (3175 [15 %] patients from BIDMC) and the two external validation sets, DeepAKI obtained the area under the curve of 0.799 (95 % CI 0.791-0.806), 0.763 (95 % CI 0.755-0.771) and 0.676 (95 % CI 0.668-0.684) for continuousAKI prediction, respectively. For model interpretability, clinically relevant important variables contributing to the model prediction were informed, and individual explanations along the timeline were explored to show how AKI risk arose. The potential threats to generalisability in deep learning-based models when deployed across health systems in real-world settings were analyzed.

Clinical characteristics and predictors of delayed discharge among children with SARS­CoV­2 Omicron variant infection.

The present study investigated the epidemiology and clinical characteristics of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant and determined the risk factors for delayed discharge or release from isolation for pediatric patients in Quanzhou, China in 2022. There were 145, 254 and 23 patients in the asymptomatic, mildly symptomatic and moderately symptomatic categories, respectively. The proportion of pediatric patients in the moderately symptomatic category increased with increasing age. No child aged <1 year and 9.02% of patients aged 13-18 years were in the moderately symptomatic category. The proportion of patients with asymptomatic infection did not differ significantly by vaccination status. The median days until the first negative conversion of viral RNA was 11 days, and the median hospitalization duration was 16 days. Most symptoms appeared in the upper respiratory tract. Notably, ~33.23% of patients showed elevated aspartate aminotransferase levels. C-reactive protein and interleukin-6 (IL-6) levels, and lymphocyte counts were consistently lower in asymptomatic patients than those in in symptomatic patients. Adjusted logistic regression analyses indicated that IL-6 levels and time to the first negative conversion of viral RNA were independent risk factors for delayed discharge. The area under the curve of the regression model for predicting delayed discharge was 0.760. In conclusion, these results could facilitate the formulation of global epidemic prevention policies for pediatric patients.

Epidemiological and clinical features of SARS-CoV-2 Omicron variant infection in Quanzhou, Fujian province: a retrospective study.

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 < 18 years and 18-59 years. The median hospitalization duration was 17 days. Among the 2,541 patients, 43.52% had a clear history of close contact. The vaccination rate was 87.92%, and the percentage of asymptomatic infections was higher in vaccinated than in unvaccinated patients. Moreover, patients with underlying diseases, including hypertension and diabetes mellitus, had more moderate infections than those without underlying diseases. The three most common clinical manifestations were fever, dry cough, and sore throat. The albumin-to-globulin (A/G) ratio and lymphocyte count decreased in cases with mild and moderate infections, while procalcitonin, erythrocyte sedimentation rate, interleukin-6, D-dimer, and C4 levels increased. Advanced age, non-vaccination, and underlying comorbid diseases were high-risk factors for disease progression in patients. However, dynamic monitoring of blood routine parameters, A/G ratio, and inflammatory indicators facilitated the prediction of disease progression.

Immune dysregulation in sepsis: experiences, lessons and perspectives.

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.

Development of genomic phenotype and immunophenotype of acute respiratory distress syndrome using autophagy and metabolism-related genes.

Background: Distinguishing 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. Methods: Transcription 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. Results: A 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. Conclusion: This 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.

Effects of early versus delayed application of prone position on ventilation-perfusion mismatch in patients with acute respiratory distress syndrome: a prospective observational study.

BACKGROUND: Prone position has been shown to improve oxygenation and survival in patients with early acute respiratory distress syndrome (ARDS). These beneficial effects are partly mediated by improved ventilation/perfusion (V/Q) distribution. Few studies have investigated the impact of early versus delayed proning on V/Q distribution in patients with ARDS. The aim of this study was to assess the regional ventilation and perfusion distribution in early versus persistent ARDS after prone position. METHODS: This is a prospective, observational study from June 30, 2021, to October 1, 2022 at the medical ICU in Zhongda Hospital, Southeast University. Fifty-seven consecutive adult patients with moderate-to-severe ARDS ventilated in supine and prone position. Electrical impedance tomography was used to study V/Q distribution in the supine position and 12 h after a prone session. RESULTS: Of the 57 patients, 33 were early ARDS (≤ 7 days) and 24 were persistent ARDS (> 7 days). Oxygenation significantly improved after proning in early ARDS (157 [121, 191] vs. 190 [164, 245] mm Hg, p < 0.001), whereas no significant change was found in persistent ARDS patients (168 [136, 232] vs.177 [155, 232] mm Hg, p = 0.10). Compared to supine position, prone reduced V/Q mismatch in early ARDS (28.7 [24.6, 35.4] vs. 22.8 [20.0, 26.8] %, p < 0.001), but increased V/Q mismatch in persistent ARDS (23.8 [19.8, 28.6] vs. 30.3 [24.5, 33.3] %, p = 0.006). In early ARDS, proning significantly reduced shunt in the dorsal region and dead space in the ventral region. In persistent ARDS, proning increased global shunt. A significant correlation was found between duration of ARDS onset to proning and the change in V/Q distribution (r = 0.54, p < 0.001). CONCLUSIONS: Prone position significantly reduced V/Q mismatch in patients with early ARDS, while it increased V/Q mismatch in persistent ARDS patients. Trial registration ClinicalTrials.gov (NCT05207267, principal investigator Ling Liu, date of registration 2021.08.20).

Factors associated with COVID-19 vaccination coverage in hypertensive patients with Omicron infection in Shanghai, China.

The 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 < .001), age (60-69 years vs.18-49 years) (OR 0.348, 95% CI 0.270-0.448, p < .001), age (≥70 years vs.18-49 years) (OR 0.130, 95% CI 0.100-0.169, p < .001), diabetes mellitus (OR 0.553, 95% CI 0.463-0.661, p < .001), chronic pulmonary diseases (OR 0.474, 95% CI 0.260-0.863, p = .015), chronic kidney disease (OR 0.177, 95% CI 0.076-0.410, p < .001), and cancer (OR 0.225, 95% CI 0.094-0.535, p = .001) were associated with vaccinated status. The vaccine coverage rate, especially the booster vaccine, was low for hypertensive patients with Omicron infection. Females, increasing age, and coexisting chronic diseases were associated with more inadequate vaccine coverage in hypertensive COVID-19 patients. Targeted interventions are required to address the under-vaccination of diverse hypertensive populations.

Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Vaccination for Negative Conversion Time of Nucleic Acid in Nonsevere COVID-19 Patients Infected by SARS-CoV-2 Omicron Variant.

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.

Combination of NK and Other Immune Markers at Early Phase Stratify the Risk of Sepsis Patients: A Retrospective Study.

Purpose: Immune dysfunction plays a pivotal role in sepsis pathogenesis. Previous studies have revealed the crucial role of T cells and human leukocyte antigen-DR (HLA-DR) in sepsis. However, the function of natural killer (NK) cells remains unclear. This study aimed to investigate whether NK cells are associated with sepsis prognosis. In addition, we aimed to explore the interrelation and influence between NK and other immunological features in patients with sepsis. Patients and Methods: This retrospective, observational study included patients with sepsis from two hospitals in mainland China. The clinical characteristics and immune results during the early phase were collected. Patients were classified according to the level of immune cells to analyze the relationship between immunological features and 28-day mortality. Results: A total of 984 patients were included in this study. Non-survivors were older and had lower levels of lymphocytes, monocytes, NK cells, HLA-DR, and T cells. Patients were classified into eight groups according to their levels of NK cells, HLA-DR, and T cells. Only patients with decreased NK and T cell counts showed a significant increase in 28-day mortality. An increase in CD8+ T cells was correlated with the alleviation of 28-day mortality only among patients with high NK cell levels. Conclusion: This study provides novel insights into the association between NK cells and 28-day mortality as well as the interrelation between NK cells and other immune cells in sepsis. The relationship between CD8+ T cells and 28-day mortality in sepsis is dependent on NK cell count.

Impact of renal complications on outcome in adult patients with acute fulminant myocarditis receiving venoarterial extracorporeal membrane oxygenation: an analysis of nationwide CSECLS database in China.

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 < 0.001) compared with those without. The development of renal complications was related to a 3.12-fold increase risk of 30-day mortality (adjusted OR 3.120, 95%CI 1.002-6.577, P = 0.049). Increasing age (adjusted OR1.025, 95% CI 1.008-1.298, P = 0.040) and higher SOFA score (adjusted OR 1.162, 95%CI 1.012-1.334, P = 0.034) were independent risk factors of renal complications. CONCLUSIONS: Our findings demonstrated that patients with AFM receiving VA-ECMO at high risk of developing renal complications. Advancing age and higher SOFA score was associated with increased risk of developing renal complications. The onset of renal complications was significantly associated with 30-day mortality.