Mean Blood Glucose Level During ICU Hospitalization is a Strong Predictor of the Mortality of COVID-19.

Objective: To investigate the potential prognostic value of mean blood glucose (MBG) in hospital for prognosis of COVID-19 adult patients in the intensive unit care unit (ICU). Methods: A single-site and retrospective study enrolled 107 patients diagnosed as COVID-19 from department of critical care medicine in the Second Xiangya Hospital between October 2022 and June 2023. Demographic information including glucose during ICU hospitalization, comorbidity, clinical data, types of medications and treatment, and clinical outcome were collected. The multivariate logistic and cox regression was used to explore the relationship between blood glucose changes and clinical outcomes of COVID-19 during ICU stay. Results: In total, 107 adult patients confirmed with COVID-19 were included. Multivariate logistic regression results showed an increase in MBG was associated with ICU mortality rate. Compared with normal glucose group (MBG <= 7.8 mmol/L), the risk of ICU mortality, 7-day mortality and 28-day mortality from COVID-19 were significantly increased in high glucose group (MBG >7.8mmol/L). Conclusion: MBG level during ICU hospitalization was strongly correlated to all-cause mortality and co-infection in COVID-19 patients. These findings further emphasize the importance of overall glucose management in severe cases of COVID-19.

ARDS in solid organ transplant recipients hospitalized for COVID-19 based on the 2023 new definition.

BACKGROUND: Solid organ transplant recipients (SOTRs) are more likely to suffer complications after being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). OBJECTIVES: We aimed to describe the clinical features of SOTRs infected with SARS-CoV-2 and to assess independent risk factors associated with the development of acute respiratory distress syndrome (ARDS) following COVID-19 infection in SOTRs based on the new ARDS definition. METHODS: 358 SOTRs infected with SARS-CoV-2 were recruited and divided into two groups, patients with ARDS (n = 81) and patients without ARDS (n = 277). Demographic data, initial laboratory findings, therapeutic measures, and outcome indicators were compared between the two groups. The association between the onset of ARDS and related factors was analyzed using a logistic regression model. A nomogram was created to estimate the probability of developing ARDS. RESULTS: Approximately 22.6 % (81/358) of hospitalized SOTRs infected with SARS-CoV-2 developed ARDS. In comparison to patients without ARDS, those with ARDS presented with more underlying conditions, decreased lymphocyte counts and serum albumin levels, but increased levels of leukocytes, serum creatinine, nitrogen urea, uric acid, and inflammatory markers. Cerebrovascular disease, leukocyte counts, albumin levels, and IL-6 levels were independent risk factors for the development of ARDS in this population. Furthermore, a nomogram prediction model was created utilizing the aforementioned factors to facilitate early prediction of ARDS, exhibiting an AUC (area under curve) of 0.81. CONCLUSIONS: Cerebrovascular disease, leukocyte counts, albumin levels, and IL-6 levels were independent risk factors for the development of ARDS following COVID-19 infection in SOTRs.

Y-tube assisted coprecipitation synthesis of iron-based Prussian blue analogues cathode materials for sodium-ion batteries.

Prussian blue analogues possess numerous advantages as cathode materials for sodium-ion batteries, including high energy density, low cost, sustainability, and straightforward synthesis processes, making them highly promising for practical applications. However, during the synthesis, crystal defects such as vacancies and the incorporation of crystal water can lead to issues such as diminished capacity and suboptimal cycling stability. In the current study, a Y-tube assisted coprecipitation method was used to synthesize iron-based Prussian blue analogues, and the optimized feed flow rate during synthesis contributed to the successful preparation of the material with a formula of Na1.56Fe[Fe(CN)6]0.90□0.10·2.42H2O, representing a low-defect cathode material. This approach cleverly utilizes the Y-tube component to enhance the micro-mixing of materials in the co-precipitation reaction, featuring simplicity, low cost, user-friendly, and the ability to be used in continuous production. Electrochemical performance tests show that the sample retains 69.8% of its capacity after 200 cycles at a current density of 0.5C (1C = 140 mA g-1) and delivers a capacity of 71.9 mA h g-1 at a high rate of 10C. The findings of this research provide important insights for the development of high-performance Prussian blue analogues cathode materials for sodium-ion batteries.

P75NTR+CD64+ neutrophils promote sepsis-induced acute lung injury.

Patients suffering from sepsis-induced acute lung injury (ALI) exhibit a high mortality rate, and their prognosis is closely associated with infiltration of neutrophils into the lungs. In this study, we found a significant elevation of CD64+ neutrophils, which highly expressed p75 neurotrophin receptor (p75NTR) in peripheral blood of mice and patients with sepsis-induced ALI. p75NTR+CD64+ neutrophils were also abundantly expressed in the lung of ALI mice induced by lipopolysaccharide. Conditional knock-out of the myeloid lineage's p75NTR gene improved the survival rates, attenuated lung tissue inflammation, reduced neutrophil infiltration and enhanced the phagocytic functions of CD64+ neutrophils. In vitro, p75NTR+CD64+ neutrophils exhibited an upregulation and compromised phagocytic activity in blood samples of ALI patients. Blocking p75NTR activity by soluble p75NTR extracellular domain peptide (p75ECD-Fc) boosted CD64+ neutrophils phagocytic activity and reduced inflammatory cytokine production via regulation of the NF-κB activity. The findings strongly indicate that p75NTR+CD64+ neutrophils are a novel pathogenic neutrophil subpopulation promoting sepsis-induced ALI.

Scalable Synthesis of a Porous Micro Si/Si-Ti Alloy Anode for Lithium-Ion Battery from Recovery of Titanium-Blast Furnace Slag.

The extensive utilization of Si-anode-based lithium-ion batteries faces obstacles due to their substantial volume expansion, limited intrinsic conductivity, and low initial Coulombic efficiency (ICE). In this study, we present a straightforward, cost-effective, yet scalable method for producing a porous micro Si/Si-Ti alloy anode. This method utilizes titanium-blast furnace slag (TBFS) as a raw material and combines aluminothermic reduction with acid etching. By adjusting the Al:TBFS ratio, the specific surface area of the material can be facilely tailored, ranging from 25.89 to 43.23 m2 g-1, enhancing the ICE from 78.2 to 85.5%. The incorporation of the Si-Ti alloy skeleton and porous structure contributes to the enhanced cyclic stability (capacity retention from 50.7 to 96.9%) and conductivity (Rct from 107.7 to 76.6 Ω). The Si/Si-Ti anode exhibits excellent electrochemical performance, including delivering a specific capacity of 1161 mAh g-1 at 200 mA g-1 after 200 cycles and 1112 mAh g-1 at 500 mA g-1 after 100 cycles, with an improved ICE of 81.2%. This study introduces a successful methodology for designing novel Si anodes from recycling waste materials, providing valuable insights for future advancements in this area.

The role of NLRP3 inflammasome in sepsis: A potential therapeutic target.

Sepsis is the host immune imbalance following infection and leads to organ dysfunction, with highly complicated pathophysiology. To date, sepsis still lacks effective therapies with high mortality rates. Recently, numerous studies have highlighted the potential of NLRP3 inflammasome as a therapeutic target during sepsis. NLRP3 inflammasome is a protein complex that could induce the activation of caspase-1 and the following release of pro-inflammatory cytokines such as IL-1ß and IL-18. It was demonstrated that NLRP3 inflammasome was involved in the development and progression of sepsis. In contrast, inhibition of NLRP3 inflammasome activation could mitigate the inflammatory response, protect organ function, and improve outcomes and mortality. This paper illustrated the activation pathways of the NLRP3 inflammasome and its possible molecular mechanisms in the pathophysiology of sepsis. Meanwhile, the beneficial effects of inhibiting NLRP3 activation in sepsis-related organ damage were also presented. In addition, the diverse role of NLRP3 inflammasome in bacterial clearance was addressed. Of note, several herbal extracts targeting NLRP3 inflammasome in the treatment of sepsis were emphasized. We hope that this paper could provide a basis for further drug research targeting NLRP3 inflammasome.

The differences in virus shedding time between the Delta variant and original SARS-CoV-2 infected patients.

Background: The worldwide epidemic of Coronavirus Disease 2019 (COVID-19) has evolved into multiple variants. The Delta variant is known for its ability to spread and replicate, while data are limited about the virus shedding time in patients infected by the Delta variant. Methods: 56 Delta variant and 56 original SARS-CoV-2 infected patients from Hunan, China, matched according to age and gender divided into two groups and compared the baseline characteristics and laboratory findings with appropriate statistical methods. Results: Patients infected with the Delta variant had significantly fewer symptoms of fever (p < 0.001), fatigue (p = 0.004), anorexia (p < 0.001), shortness of breath (p = 0.004), diarrhea (p = 0.006), positive pneumonia rate of chest CT (p = 0.019) and chest CT ground glass opacities (p = 0.004) than those of patients with the original SARS-CoV-2. Patients of the Delta variant group had a significantly longer virus shedding time [41.5 (31.5, 46.75) vs. 18.5 (13, 25.75), p < 0.001] compared with the original SARS-CoV-2 group. The correlation analyses between the virus shedding time and clinical or laboratory parameters showed that the virus shedding time was positively related to the viral strain, serum creatinine and creatine kinase isoenzyme, while negatively correlated with lymphocyte count, total bilirubin and low-density lipoprotein. Finally, the viral strain and lymphocyte count were thought of as the independent risk factors of the virus shedding time demonstrated by multiple linear regression. Conclusion: COVID-19 patients infected with the Delta variant exhibited fewer gastrointestinal symptoms and prolonged virus shedding time than those infected with the original SARS-CoV-2. Delta variant and fewer lymphocyte were correlated with prolonged virus shedding time.

Retrograde Drilling and Bone Graft for Hepple Stage V Subchondral Bone Lesion of Talus Using 3D Image-Based Navigation-Assisted Endoscopic Technique.

BACKGROUND: Retrograde drilling remains technically challenging, because of the difficulty of identifying the accurate location of cysts during surgery. This study's aim was to evaluate the 3-dimensional (3D) image-based surgical navigation-assisted endoscopic retrograde drilling technique for subchondral bone lesions of the talus. METHODS: From March 2017 to June 2020, a total of 21 cases with Hepple stage V subchondral bone lesions of the talus were treated with 3D image-based surgical navigation-assisted endoscopic retrograde drilling and bone graft technique. Arthroscopic views were categorized per Pritsch classifications. The correlation between the drilled tunnel with preoperative cystic lesions were assessed under postoperative computer tomographic (CT) scans. The American Orthopaedic Foot & Ankle Society (AOFAS) scores, visual analog scale (VAS) scores, and Foot and Ankle Ability Measure (FAAM) sports scales were evaluated at the preoperative and final consultation. All complications were recorded. RESULTS: On postoperative CT scans, in 20 cases (95.2%), the drilled tunnel was judged to have been in the center of previous cysts. Only 9 cases (42.9%) showed intact normal cartilage (grade 0, group A); 12 cases (57.1%) had intact, but soft, cartilage (grade I, group B). The median follow-up time was 24 (24, 30) months, and at final follow-up, there were no significant differences between the mean AOFAS and VAS scores in both groups (89.0 ± 6.4 vs 88.3 ± 7.0 and 1 vs 0.5) or postoperative FAAM sports scales (28.2 ± 2.2 vs 26.6 ± 4.9, P = .363). Two patients had revision surgery in group B. CONCLUSION: The 3D image-based surgical navigation-assisted endoscopic retrograde drilling and bone graft technique for the subchondral bone lesions of the talus in this small case series showed encouraging results. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study.

BACKGROUND: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. METHODS: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. RESULTS: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. CONCLUSIONS: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Environmental-friendly and effectively regenerate anode material of spent lithium-ion batteries into high-performance P-doped graphite.

Recycling graphitefrom spentlithium-ionbatteries has been largely ignored.In the present work, we propose a novel purification process, which modifies the structure of graphite through phosphoric acid leaching-calcination to obtain high-performance phosphorus (P)-doped graphite (LG-temperature) and lithium phosphate products. The content analysis of X-ray photoelectron spectroscopy (XPS), X-ray fluorescence (XRF) and scanning electron microscope focused ion beam (SEM-FIB) indicates that the LG structure is deformed by the doped P atom. The results of In-situ fourier transform infrared spectroscopy (In-situ-FTIR), density functional theory (DFT) calculation and XPS analysis show that the surface of the leached spent graphite contains rich oxygen groups, which react with phosphoric acid at high temperatures and form stable C-O-P and C-P bonds, making it easier to form stable solid electrolyte interface (SEI) layer. The increase of layer spacing is confirmed by X-ray diffraction (XRD), Raman and transmission electron microscope (TEM), which is conducive to the formation of efficient Li+ transport channels. What is more, Li/LG-800 cells possess high reversible specific capacities of 359, 345, 330 and 289 mA h g-1 at 0.2C, 0.5C, 1C and 2C, respectively. After100cyclesat0.5C, the specific capacityis as high as 366 mAh g-1, demonstrating the outstanding reversibility and cycle performance. This study proves and highlights a promising recovery route for exhausted lithium-ion batteries anodes, making complete recycling possible.

Leukadherin-1 inhibits NLRP3 inflammasome by blocking inflammasome assembly.

Aberrant activation of the NLRP3 inflammasome has been implicated in the occurrence and development of many inflammatory diseases, and thus potent inhibitors of the NLRP3 inflammasome should be explored. An antitumor agent, Leukadherin-1 (LA-1), tested in phase 1/2 clinical trials, has been reported to exert anti-inflammatory properties by blocking the NF-κB pathway. However, the effects of LA-1 on the NLRP3 inflammasome have not been conclusively determined. In this study, we found that at lower doses (below 1 µM) ex vivo, LA-1 blocked NLRP3 inflammasome activation without affecting NF-κB signaling. Accordingly, 1 mg/Kg LA-1 strongly inhibited the release of NLRP3-dependent cytokine, but only slightly inhibited NLRP3-independent-cytokines secretion in endotoxemia and alleviated NLRP3-dependent peritonitis in vivo. Mechanistically, LA-1 had no effects on ion flux or mitochondrial injury. Instead, it inhibited NLRP3 inflammasome assembly by suppressing ASC oligomerization, blocking NLRP3 self-assembly, and reducing interactions of NLRP3 with ASC and NEK7. Therefore, LA-1 inhibits NLRP3 inflammasome activation, implying that it is a potential treatment option for NLRP3-associated diseases.

ZBP1 and heatstroke.

Heatstroke, which is associated with circulatory failure and multiple organ dysfunction, is a heat stress-induced life-threatening condition characterized by a raised core body temperature and central nervous system dysfunction. As global warming continues to worsen, heatstroke is expected to become the leading cause of death globally. Despite the severity of this condition, the detailed mechanisms that underlie the pathogenesis of heatstroke still remain largely unknown. Z-DNA-binding protein 1 (ZBP1), also referred to as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, was initially identified as a tumor-associated and interferon (IFN)-inducible protein, but has recently been reported to be a Z-nucleic acid sensor that regulates cell death and inflammation; however, its biological function is not yet fully understood. In the present study, a brief review of the main regulators is presented, in which the Z-nucleic acid sensor ZBP1 was identified to be a significant factor in regulating the pathological characteristics of heatstroke through ZBP1-dependent signaling. Thus, the lethal mechanism of heatstroke is revealed, in addition to a second function of ZBP1 other than as a nucleic acid sensor.

The Potential of NLRP3 Inflammasome as a Therapeutic Target in Neurological Diseases.

NLRP3 (NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome is the best-described inflammasome that plays a crucial role in the innate immune system and a wide range of diseases. The intimate association of NLRP3 with neurological disorders, including neurodegenerative diseases and strokes, further emphasizes its prominence as a clinical target for pharmacological intervention. However, after decades of exploration, the mechanism of NLRP3 activation remains indefinite. This review highlights recent advances and gaps in our insights into the regulation of NLRP3 inflammasome. Furthermore, we present several emerging pharmacological approaches of clinical translational potential targeting the NLRP3 inflammasome in neurological diseases. More importantly, despite small-molecule inhibitors of the NLRP3 inflammasome, we have focused explicitly on Chinese herbal medicine and botanical ingredients, which may be splendid therapeutics by inhibiting NLRP3 inflammasome for central nervous system disorders. We expect that we can contribute new perspectives to the treatment of neurological diseases.

The Association Between Alveolar-Arterial Oxygen Tension Difference and the Severity of COVID-19 in Patients.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) emerged as a global pandemic and resulted in a significantly high death toll. Therefore, there is an urgent need to find a potential biomarker related to the disease severity that can facilitate early-stage intervention. METHODS: In the present study, we collected 242 laboratory-confirmed COVID-19-infected patients. The patients were grouped according to the alveolar to arterial oxygen tension difference (PA-aO2) value of COVID-19 infection after admission. RESULTS: Among the 242 laboratory-confirmed COVID-19- infected patients, 155 (64.05%) had an abnormal PA-aO2 value on admission. Compared with the normal PA-aO2 group, the median age of the abnormal PA-aO2 group was significantly older (p = 0.032). Symptoms such as fever, cough, and shortness of breath were more obvious in the abnormal PA-aO2 group. The proportion of severe events in the abnormal PA-aO2 group was higher than the normal PA-aO2 group (10.34% vs. 23.23%, p = 0.013). The abnormal PA-aO2 group had a higher possibility of developing severe events compared with the normal PA-aO2 group (HR 2.622, 95% CI 1.197-5.744, p = 0.016). After adjusting for age and common comorbidities (hypertension and cardiovascular disease), the abnormal PA-aO2 group still exhibited significantly elevated risks of developing severe events than the normal PA-aO2 group (HR 2.986, 95% CI 1.220-7.309, p = 0.017). Additionally, the abnormal PA-aO2 group had more serious inflammation/coagulopathy/fibrinolysis parameters than the normal PA-aO2 group. CONCLUSION: Abnormal PA-aO2 value was found to be common in COVID-19 patients, was strongly related to severe event development, and could be a potential biomarker for the prognosis of COVID-19 patients.

Reliability and validity test and application of the Chinese version of the Feeling of Satisfaction with Inhaler. / ä¸­æ–‡ç‰ˆå¸å ¥è¯ç‰©æ»¡æ„åº¦é‡è¡¨çš„ä¿¡æ•ˆåº¦æ£€éªŒåŠåº”ç”¨.

OBJECTIVES: Inhaler satisfaction is an important factor affecting inhaler adherence and the efficacy of inhalers in chronic airway diseases. Using a scientific and effective method to assess patients' satisfaction with inhalers is of great significance for improving clinical outcomes. The Feeling of Satisfaction with Inhaler-10 (FSI-10) is specifically designed to assess patients' inhaler satisfaction in chronic airway diseases, but the application research on this scale is not available in China. This study aims to evaluate the reliability and validity of the Chinese version of FSI-10, describe the current status of inhaler satisfaction and discuss the associated variables in Chinese patients with chronic airway disease. METHODS: Based on the English version of FSI-10, items of the Chinese version of FSI-10 were determined after forward⁃backward translation and cultural adaption. Totally, 322 patients with chronic obstructive pulmonary disease (COPD) and asthma were enrolled from the Second Xiangya Hospital of Central South University from June to October 2022. We collected associated clinical variables and inhaler satisfaction using the Chinese version of FSI-10. The content validity of the scale was expressed by content validity index (CVI) and the construct validity was analyzed by exploratory factor analysis (EFA). The reliability of the scale was expressed by Cronbach's α coefficient, the split-half reliability and test-retest reliability. A multivariate logistic regression was conducted to examine variables related to inhaler satisfaction. RESULTS: The reliability and validity analysis showed that the CVI was 0.983. One factor was extracted from the Chinese version of FSI-10 and the cumulative variance contribution rate was 73.114%. The Cronbach's α of the scale was 0.913, the Guttman's half-reliability coefficient was 0.905, and the test-retest reliability was 0.727 (P<0.001). In addition, the total score of the scale for patients was 38.92±4.26 points and the proportion of high satisfaction (the score of FSI-10≥40) in patients with COPD was significantly lower than that in asthma patients (71.3% vs 87.9%, P<0.01). Older age (age≥70 years) was a risk factor of lower inhaler satisfaction and asthma diagnosis was a protective factor. CONCLUSIONS: The Chinese version of FSI-10 has good reliability and validity in patients with COPD and asthma, which may be further promoted and applied in patients with chronic airway disease in China. Doctors should regularly evaluate the inhaler satisfaction of patients with chronic airway diseases, especially for those elder or with severe symptoms and a long course of illness.

Fulvic-polyphosphate composite embedded in ZnO nanorods (FA-APP@ZnO) for efficient P/Zn nutrition for peas (Pisum sativum L.).

A nano-fertilizer (FA-APP@ZnO) was designed and prepared based on the copolymer of fulvic acid (FA) and ammonium polyphosphate (APP) with ZnO nanorods embedded, to tackle the antagonism between phosphorus (P) and zinc (Zn) in fertilization. FA-APP@ZnO was confirmed to revert the precipitability of H2PO4 - and Zn2+ into a synergistic performance, where FA and APP can disperse ZnO nanorods, and in return, ZnO catalyzes the hydrolysis of the absorbed APP. The hydrolysis rate constant of pyrophosphates consequently increased 8 times. The dry biomass of pea (Pisum sativum L.) under the FA-APP@ZnO hydroponics for 7 days increased by 119%, as compared with the situation employing the conventional NH4H2PO4 and ZnSO4 compound fertilizer. Moreover, the uptake of seedlings for P and Zn was enhanced by 54% and 400%, respectively. The accelerated orthophosphate release due to ZnO catalysis and the well-dispersed ZnO nanorods enabled by APP met the urgent demand for P and Zn nutrients for peas, especially at their vigorous seedling stage. This work would provide a new idea for constructing nano-platforms to coordinate the incompatible P and Zn nutrients for the improvement of agronomic efficiency.

Prevention and treatment of ventilator-associated pneumonia in COVID-19.

Ventilator-associated pneumonia (VAP) is the most common acquired infection in the intensive care unit. Recent studies showed that the critical COVID-19 patients with invasive mechanical ventilation have a high risk of developing VAP, which result in a worse outcome and an increasing economic burden. With the development of critical care medicine, the morbidity and mortality of VAP remains high. Especially since the outbreak of COVID-19, the healthcare system is facing unprecedented challenges. Therefore, many efforts have been made in effective prevention, early diagnosis, and early treatment of VAP. This review focuses on the treatment and prevention drugs of VAP in COVID-19 patients. In general, prevention is more important than treatment for VAP. Prevention of VAP is based on minimizing exposure to mechanical ventilation and encouraging early release. There is little difference in drug prophylaxis from non-COVID-19. In term of treatment of VAP, empirical antibiotics is the main treatment, special attention should be paid to the antimicrobial spectrum and duration of antibiotics because of the existence of drug-resistant bacteria. Further studies with well-designed and large sample size were needed to demonstrate the prevention and treatment of ventilator-associated pneumonia in COVID-19 based on the specificity of COVID-19.

Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling.

Sepsis is a life-threatening syndrome with disturbed host responses to severe infections, accounting for the majority of death in hospitalized patients. However, effective medicines are currently scant in clinics due to the poor understanding of the exact underlying mechanism. We previously found that blocking caspase-11 pathway (human orthologs caspase-4/5) is effective to rescue coagulation-induced organ dysfunction and lethality in sepsis models. Herein, we screened our existing chemical pools established in our lab using bacterial outer membrane vesicle (OMV)-challenged macrophages, and found 7-(diethylamino)-1-hydroxy-phenothiazin-3-ylidene-diethylazanium chloride (PHZ-OH), a novel phenothiazinium-based derivative, was capable of robustly dampening caspase-11-dependent pyroptosis. The in-vitro study both in physics and physiology showed that PHZ-OH targeted AP2-associated protein kinase 1 (AAK1) and thus prevented AAK1-mediated LPS internalization for caspase-11 activation. By using a series of gene-modified mice, our in-vivo study further demonstrated that administration of PHZ-OH significantly protected mice against sepsis-associated coagulation, multiple organ dysfunction, and death. Besides, PHZ-OH showed additional protection on Nlrp3-/- and Casp1-/- mice but not on Casp11-/-, Casp1/11-/-, Msr1-/-, and AAK1 inhibitor-treated mice. These results suggest the critical role of AAK1 on caspase-11 signaling and may provide a new avenue that targeting AAK1-mediated LPS internalization would be a promising therapeutic strategy for sepsis. In particular, PHZ-OH may serve as a favorable molecule and an attractive scaffold in future medicine development for efficient treatment of bacterial sepsis.

Impaired interferon-γ signaling promotes the development of silicosis.

Silicosis is caused by inhalation of crystalline silica dust particles and known as one of the most serious occupational diseases worldwide. However, little is known about intrinsic factors leading to disease susceptibility. Single-cell sequencing of bronchoalveolar lavage fluid cells of mine workers with silicosis and their co-workers who did not develop silicosis revealed that the impaired interferon (IFN)-γ signaling in myeloid cells was strongly associated with the occurrence of silicosis. Global or myeloid cell-specific deletion of interferon γ receptor (IFN-γR) markedly enhanced the crystalline silica-induced pulmonary injury in wild-type but not in NLRP3 deficient mice. In vitro, IFN-γ priming of macrophages suppressed the crystalline silica-induced NLRP3 inflammasome activation partly by inducing the formation of spacious phagosomes with relatively reduced ratio of crystalline silica/phagosomal areas volumes to resistant crystalline silica-induced lysosomal membrane damage. Thus, these findings provide molecular insights into the intricate mechanisms underlying innate immunity-mediated host responses to environmental irritants.

The Association Between FT3 With the Outcome and Inflammation/Coagulopathy/Fibrinolysis of COVID-19.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused substantial threats to people's physical health and lives, claiming the lives of over 5 million people worldwide. It is imperative to identify the disease severity and intervene with effective therapy as early as possible. Previous studies have shown that low free triiodothyronine (FT3) may possess the predictive value on COVID-19 prognosis. Methods: In this retrospective cohort study, 15-day clinical and laboratory data of 186 hospitalized patients of COVID-19 after admission were analyzed. Groups were based on the disease severity of COVID-19, survival or non-survival, and presence or absence of euthyroid sick syndrome (ESS). Categorical variables were compared with the chi-square test or Fisher's exact test. Continuous variables were tested by Wilcoxon rank-sum test for the non-normal distribution. Spearman correlations were used to assess the correlations between FT3 with clinic parameters of multiple time points. Results: The non-survival patients had significant lower levels of FT3 (3.24 ± 0.42 vs. 4.19 ± 0.08 pmol/L, p < 0.05) and thyroid-stimulating hormone (TSH) (0.69 ± 0.19 vs. 2.32 ± 0.2 uIU/ml, p < 0.05), and the FT3 of severe patients was significantly lower than that of non-severe patients (3.67 ± 0.14 vs. 4.33 ± 0.09 pmol/L, p < 0.05). Fifty-nine cases of COVID-19 patients were diagnosed with ESS. Compared with non-ESS patients, those with ESS were older and had higher proportions of fever, shortness of breath, hypertension, diabetes, severe disease, and mortality. In addition, the correlation analysis between FT3 and clinical parameters showed that FT3 were positively related to the lymphocyte count and albumin and negatively correlated with C-reactive protein, erythrocyte sedimentation rate, and D-dimer at all time points in the first 15 days after admission. Conclusion: Low FT3 had a significant predictive value on the prognosis of COVID-19 patients, and FT3 was significantly related with clinic parameters of inflammation/coagulopathy/fibrinolysis.