PM2.5 Causes Increased Bacterial Invasion by Affecting HBD1 Expression in the Lung.

Our research addresses the critical environmental issue of a fine particulate matter (PM2.5), focusing on its association with the increased infection risks. We explored the influence of PM2.5 on human beta-defensin 1 (HBD1), an essential peptide in mucosal immunity found in the airway epithelium. Using C57BL/6J mice and human bronchial epithelial cells (HBE), we examined the effects of PM2.5 exposure followed by Pseudomonas aeruginosa (P. aeruginosa) infection on HBD1 expression at both mRNA and protein levels. The study revealed that PM2.5's toxicity to epithelial cells and animals varies with time and concentration. Notably, HBE cells exposed to PM2.5 and P. aeruginosa showed increased bacterial invasion and decreased HBD1 expression compared to the cells exposed to P. aeruginosa alone. Similarly, mice studies indicated that combined exposure to PM2.5 and P. aeruginosa significantly reduced survival rates and increased bacterial invasion. These harmful effects, however, were alleviated by administering exogenous HBD1. Furthermore, our findings highlight the activation of MAPK and NF-κB pathways following PM2.5 exposure. Inhibiting these pathways effectively increased HBD1 expression and diminished bacterial invasion. In summary, our study establishes that PM2.5 exposure intensifies P. aeruginosa invasion in both HBE cells and mouse models, primarily by suppressing HBD1 expression. This effect can be counteracted with exogenous HBD1, with the downregulation mechanism involving the MAPK and NF-κB pathways. Our study endeavors to elucidate the pathogenesis of lung infections associated with PM2.5 exposure, providing a novel theoretical basis for the development of prevention and treatment strategies, with substantial clinical significance.

Machine learning-based identification of cuproptosis-related markers and immune infiltration in severe community-acquired pneumonia.

BACKGROUND: Severe community-acquired pneumonia (SCAP) is one of the world's most common diseases and a major etiology of acute respiratory distress syndrome (ARDS). Cuproptosis is a novel form of regulated cell death that can occur in various diseases. METHODS: Our study explored the degree of immune cell infiltration during the onset of severe CAP and identified potential biomarkers related to cuproptosis. Gene expression matrix was obtained from GEO database indexed GSE196399. Three machine learning algorithms were applied: The least absolute shrinkage and selection operator (LASSO), the random forest, and the support vector machine-recursive feature elimination (SVM-RFE). Immune cell infiltration was quantified by single-sample gene set enrichment analysis (ssGSEA) scoring. Nomogram was constructed to verify the applicability of using cuproptosis-related genes to predict the onset of severe CAP and its deterioration toward ARDS. RESULTS: Nine cuproptosis-related genes were differentially expressed between the severe CAP group and the control group: ATP7B, DBT, DLAT, DLD, FDX1, GCSH, LIAS, LIPT1, and SLC31A1. All 13 cuproptosis-related genes were involved in immune cell infiltration. A three-gene diagnostic model was constructed to predict the onset of severe CAP: GCSH, DLD, and LIPT1. CONCLUSION: Our study confirmed the involvement of the newly discovered cuproptosis-related genes in the progression of SCAP.

The evaluation of next-generation sequencing assisted pathogenic detection in immunocompromised hosts with pulmonary infection: A retrospective study.

INTRODUCTION: Pulmonary infections are frequent in immunocompromised hosts (ICH), and microbial detection is difficult. As a new method, next-generation sequencing (NGS) may offer a solution. OBJECTIVES: This study aimed to assess the impact of NGS-assisted pathogenic detection on the diagnosis, treatment, and outcomes of ICH complicated by pulmonary infection and radiographic evidence of bilateral diffuse lesions. METHODS: This study enrolled 356 patients with ICH complicated by pulmonary infection that were admitted to Zhongshan Hospital, Fudan University, from November 17, 2017, to November 23, 2018, including 102 and 254 in the NGS and non-NGS groups, respectively. Clinical characteristics, detection time, rough positive rate, effective positive rate, impact on anti-infective treatment plan, 30-day/60-day mortality, and in-hospital mortality were compared. RESULTS: NGS-assisted pathogenic detection reduced detection time (28.2 h [interquartile range (IQR) 25.9-29.83 h] vs. 50.50 h [IQR 47.90-90.91 h], P < 0.001), increased positive rate, rate of mixed infection detected, effective positive rate, and proportion of antibiotic treatment modification (45.28% vs. 89.22%, 4.72% vs. 51.96%, 21.65% vs. 64.71%, 16.54% vs. 46.08%, P < 0.001). The NGS group had a significantly lower 60-day mortality rate (18.63% vs. 33.07%, P = 0.007). The difference in the Kaplan-Meier survival curve was significant (P = 0.029). After multivariate logistic regression, NGS-assisted pathogenic detection remained a significant predictor of survival (OR 0.189, confidence interval [CI], 0.068-0.526). CONCLUSION: NGS-assisted pathogenic detection may improve detection efficiency and is associated with better clinical outcomes in these patients.

Shh and Olig2 sequentially regulate oligodendrocyte differentiation from hiPSCs for the treatment of ischemic stroke.

Rationale: Demyelination is a major component of white matter injury, characterized by oligodendrocyte (OL) death and myelin sheath loss, which result in memory loss and cognitive impairment in the context of ischemic stroke. Accumulating evidence has shown that OLs can be generated by the direct activation of defined transcription factors (TFs) in human induced pluripotent stem cells (hiPSCs); however, the rapid acquisition of single TF-induced OL progenitor cells (OPCs) as cell therapy for ischemic stroke remains to be thoroughly explored. Methods: A stable, chemically defined protocol was used to generate a substantial number of transplantable and functional OLs through the partial inhibition of sonic hedgehog (Shh) activity by GANT61 during neural induction from hiPSCs and sequential induction of TF Olig2 overexpression. Transcriptome and metabolome analyses further revealed a novel molecular event in which Olig2 regulates OL differentiation from hiPSC-derived neural progenitor cells (NPCs). Olig2-induced NG2+ OPCs (Olig2-OPCs) were then evaluated for their therapeutic potential in cell-based therapy for ischemic stroke. Results: GANT61 treatment resulted in a motor neuron (MN)-OL fate switch during neural induction, and induced overexpression of Olig2 accelerated oligodendroglial lineage cell specification. Olig2-OPCs expressed typical oligodendroglial lineage marker genes, including NKX2.2, CSPG4, and ST8SIA1, and displayed superior ability to differentiate into mature OLs in vitro. Mechanistically, Olig2-OPCs showed increased gene expression of the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, and activated CEPT1-mediated phospholipogenesis. Functionally, inhibiting PPARγ and knocking down CEPT1 further compromised the terminal differentiation of Olig2-OPCs. Most importantly, when transplanted into a rat model of transient middle cerebral artery occlusion (tMCAO), Olig2-OPCs efficiently promoted neurological functional recovery by reducing neuronal death, promoting remyelination, and rescuing spatial memory decline. Conclusions: We developed a stable, chemically defined protocol to generate OPCs/OLs with partial inhibition of Shh activity by GANT61 from hiPSCs and sequentially induced the expression of the single TF Olig2. Olig2-OPC transplantation may be an ideal alternative approach for ischemic stroke rehabilitation therapy.

CoQ10 enhances the efficacy of airway basal stem cell transplantation on bleomycin-induced idiopathic pulmonary fibrosis in mice.

BACKGROUND: Recent studies have demonstrated that airway basal stem cells (BCs) transplantation can ameliorate bleomycin-induced idiopathic pulmonary fibrosis (IPF) through lung regeneration promotion. However, BCs under oxidative stress in the alveolar microenvironment are poor in survival, causing unsatisfied efficacy of BCs transplantation. In this study, we investigated whether Coenzyme Q10(CoQ10) counteracts oxidative stress in the alveolar microenvironment, thus improved the efficacy of BCs transplantation for IPF treatment. METHODS: The protective effects of CoQ10 on H2O2-induced BCs apoptosis and cytoplasmic reactive oxygen species (ROS) level were tested by flow cytometry in vitro. The therapeutic effects of BCs combined with CoQ10 were compared to a single BCs transplantation protocol in IPF treatment after 2 weeks and were evaluated by parameters including changes of body weight and survival rate, as well as various levels of pulmonary inflammation, α-SMA expression and hydroxyproline (HYP) in IPF mouse lung tissues. RESULTS: CoQ10 preincubation with BCs (10 mM, 24 h) significantly reduced the late apoptosis of BCs and the number of oxidative stressful BCs as a result of H2O2 stimulation (1 mM, 6 h) in vitro. IPF mouse model was constructed through bleomycin (5 mg/kg) intratracheal instillation. Bleomycin-induced IPF mice showed weight loss continuously and mortality increased progressively during modeling. Serious pulmonary inflammatory cell infiltration, collagen fiber proliferation, and collagen protein deposition were observed in lung tissues of IPF mice. Though BCs transplantation alone improved indicators above in bleomycin-induced IPF mice to some extent, the combination with CoQ10 improved the transplantation efficacy and obtained better therapeutic effects. CONCLUSION: CoQ10 blocked H2O2-induced apoptosis of BCs and ROS production in vitro, and enhanced the efficacy of BCs transplantation against bleomycin-induced IPF in mice.

Association between risk of venous thromboembolism and mortality in patients with COVID-19.

OBJECTIVES: To investigate the association of risk of venous thromboembolism with 30-day mortality in COVID-19 patients. METHODS: A total of 1030 COVID-19 patients were retrospectively collected, with baseline data on demographics, sequential organ failure assessment (SOFA) score, and VTE risk assessment models (RAMs), including Padua prediction score (PPS), International Medical Prevention Registry (IMPROVE), and Caprini. RESULTS: Thirty-day mortality increased progressively from 2% in patients at low VTE risk to 63% in those at high risk defined by PPS. Similar findings were observed in IMPROVE and Caprini scores. Progressive increases in VTE risk were also associated with higher SOFA score. High risk of VTE was independently associated with mortality regardless of adjusted gender, smoking status and some comorbidities, with hazard ratios of 29.19, 37.37 and 20.60 for PPS, IMPROVE and Caprini RAM, respectively (P < 0.001 for all comparisons). The predictive accuracy of PPS (area under curve (AUC) 0.900), IMPROVE (AUC 0.917), or Caprini (AUC 0.861) RAM for risk of hospitalized mortality was unexpectedly strong. CONCLUSIONS: We established that the presence of a high risk of VTE identifies a group of COVID-19 patients at higher risk for mortality. Furthermore, there is a high accuracy of VTE RAMs to predict mortality in these patients.

Synergistic anti-tumor effect of anti-PD-L1 antibody cationic microbubbles for delivery of the miR-34a gene combined with ultrasound on cervical carcinoma.

This study explored the synergistic effect of anti-PD-L1 antibody cationic microbubbles (MBs) for delivery of the miR-34a gene combined with ultrasound in inhibiting the cervical cancer. H&E stain, TUNEL, immunohistochemistry and RT-PCR were used to detect the change of apoptosis regulatory factors, and immunofluorescence, Flow cytometry and LDH assays were applied to evaluate the changing of immunomodulatory. In this experiment the PD-L1 Ab/miR-34a-MBs were prepared successfully. The cell targeting assay showed that U14 cells were surrounded by the PD-L1 Ab/miR-34a-MBs and microbubbles had well contrast imaging capability in vivo. With the irradiation power was 1 W/cm2 and the irradiation time was 25 s, the gene transfection efficiency was the highest using EGFP plasmid lorded microbubbles. In vivo anti-tumor assays, the PD-L1 Ab/miR-34a-MBs showed a great potential in inhibiting tumor growth with a TGI of >50%. PD-L1 Ab/miR-34a-MBs treatment enhanced the anti-tumor effect compared with that induced by PD-L1 Ab or miR-34a alone. Firstly, PD-L1 Ab/miR-34a-MBs could gather miR-34a with high-concentration aggregation and releasing around the cervical cancer, which takes a significant role in promoting apoptosis by downregulated Bcl-2 and upregulated Bax. Furthermore, combination therapy was found to augment the activation of T lymphocytes proliferation and increase CD8+ T cells infiltration, to enhance antitumor immune killing effect. The anti-PD-L1 antibody microbubbles for delivery miR-34a gene with ultrasound were considered to be a promising combination therapy regimen via initiating apoptotic mechanism of the tumor and anti-tumor immune regulation.

DVT incidence and risk factors in critically ill patients with COVID-19.

Few data are available on the incidence of deep vein thrombosis (DVT) in critically ill COVID-19 with thrombosis prophylaxis. This study retrospectively included 88 patients in the ICU with critically ill COVID-19 at Jinyintan Hospital in Wuhan, China. All patients underwent compression ultrasonography for identifying DVT. Firth logistic regression was used to examine the association of DVT with sex, age, hypoalbuminemia, D-dimer, and SOFA score. The median (interquartile range [IQR]) age and SOFA score of 88 patients were 63 (55-71) years old and 5 (4-6), respectively. Despite all patients receiving guideline-recommended low-molecular-weight heparin (LMWH) thromboprophylaxis, the incidence of DVT was 46% (95% CI 35-56%). Proximal DVT was recognized in 9% (95% CI 3-15%) of the patients, while 46% (95% CI 35-56%) of patients had distal DVT. All of the proximal DVT combined with distal DVT. Risk factors of DVT extension occurred in all distal DVT patients. As Padua score ≥ 4 or IMPROVE score ≥ 2, 53% and 46% of patients had DVT, respectively. Mortality was higher in patients with acute DVT (30%) compared with non-DVT (17%), but did not reach statistical significance. Hypoalbuminemia (odds ratio [OR], 0.17; 95% CI 0.06-0.05, P = 0.001), higher SOFA score (OR per IQR, 2.07; 95% CI 1.38-3.39, P = 0.001), and elevated D-dimer (OR per IQR, 1.04; 95% CI 1.03-1.84, P = 0.029) were significant DVT risk factors in multivariable analyses. High incidence of DVT was identified in patients with critically ill COVID-19, despite the use of guideline-recommended pharmacologic thromboprophylaxis. The presence of hypoalbuminemia, higher SOFA score, and elevated D-dimer were significantly independent risk factors of DVT. More effective VTE prevention and management strategies may need to be addressed.

Derivation and validation of a prognostic model for predicting in-hospital mortality in patients admitted with COVID-19 in Wuhan, China: the PLANS (platelet lymphocyte age neutrophil sex) model.

BACKGROUND: Previous published prognostic models for COVID-19 patients have been suggested to be prone to bias due to unrepresentativeness of patient population, lack of external validation, inappropriate statistical analyses, or poor reporting. A high-quality and easy-to-use prognostic model to predict in-hospital mortality for COVID-19 patients could support physicians to make better clinical decisions. METHODS: Fine-Gray models were used to derive a prognostic model to predict in-hospital mortality (treating discharged alive from hospital as the competing event) in COVID-19 patients using two retrospective cohorts (n = 1008) in Wuhan, China from January 1 to February 10, 2020. The proposed model was internally evaluated by bootstrap approach and externally evaluated in an external cohort (n = 1031). RESULTS: The derivation cohort was a case-mix of mild-to-severe hospitalized COVID-19 patients (43.6% females, median age 55). The final model (PLANS), including five predictor variables of platelet count, lymphocyte count, age, neutrophil count, and sex, had an excellent predictive performance (optimism-adjusted C-index: 0.85, 95% CI: 0.83 to 0.87; averaged calibration slope: 0.95, 95% CI: 0.82 to 1.08). Internal validation showed little overfitting. External validation using an independent cohort (47.8% female, median age 63) demonstrated excellent predictive performance (C-index: 0.87, 95% CI: 0.85 to 0.89; calibration slope: 1.02, 95% CI: 0.92 to 1.12). The averaged predicted cumulative incidence curves were close to the observed cumulative incidence curves in patients with different risk profiles. CONCLUSIONS: The PLANS model based on five routinely collected predictors would assist clinicians in better triaging patients and allocating healthcare resources to reduce COVID-19 fatality.

Corticosteroid therapy for coronavirus disease 2019-related acute respiratory distress syndrome: a cohort study with propensity score analysis.

BACKGROUND: The impact of corticosteroid therapy on outcomes of patients with coronavirus disease 2019 (COVID-19) is highly controversial. We aimed to compare the risk of death between COVID-19-related ARDS patients with corticosteroid treatment and those without. METHODS: In this single-center retrospective observational study, patients with ARDS caused by COVID-19 between January 20, 2020, and February 24, 2020, were enrolled. The primary outcome was 60-day in-hospital death. The exposure was prescribed systemic corticosteroids or not. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for 60-day in-hospital mortality. RESULTS: A total of 382 patients [60.7 ± 14.1 years old (mean ± SD), 61.3% males] were analyzed. The median of sequential organ failure assessment (SOFA) score was 2.0 (IQR 2.0-3.0). Of these cases, 94 (24.6%) patients had invasive mechanical ventilation. The number of patients received systemic corticosteroids was 226 (59.2%), and 156 (40.8%) received standard treatment. The maximum dose of corticosteroids was 80.0 (IQR 40.0-80.0) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was 7.0 (4.0-12.0) days in total. In Cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within 60 days after adjusting for age, sex, SOFA score at hospital admission, propensity score of corticosteroid treatment, comorbidities, antiviral treatment, and respiratory supports (HR 0.42; 95% CI 0.21, 0.85; p = 0.0160). Corticosteroids were not associated with delayed viral RNA clearance in our cohort. CONCLUSION: In this clinical practice setting, low-dose corticosteroid treatment was associated with reduced risk of in-hospital death within 60 days in COVID-19 patients who developed ARDS.

Ultrasound targeting of microbubble-bound anti PD-L1 mAb to enhance anti-tumor effect of cisplatin in cervical cancer xenografts treatment.

AIMS: Anti-PD-L1 monoclonal antibody (mAb)-conjugated ultrasound (US) lipid-shelled microbubbles (PD-L1-MBs) were successfully synthesized to investigate whether that PD-L1-MBs could enhance anti-tumor effect in combination therapy with cisplatin (CDDP) under ultrasound mediation. MAIN METHODS: Based on affinity between biotin and streptavidin, we prepared microbubbles conjugated with anti-PD-L1 mAb by membrane hydration and mechanical oscillation. A subcutaneous tumor model was established to test the anti-tumor effect and immunological activity of this combination therapy. Bax and Bcl-2 expression were detected by RT-qPCR and Immunohistochemistry. Cells undergoing apoptosis in tissue section were determined by TUNEL. Proliferation of splenocytes was analyzed by Flow cytometry. A cytotoxic T lymphocyte assay was performed by CTL. Expression of PD-L1 and CD8 in tissue section was examined by immunologfluorescence. Expression of IFN-γ, TNF-α, CD86 and CD80 was also detected by RT-qPCR. KEY FINDINGS: We observed that the growth of the subcutaneous tumor was significantly slower in combined group than that in the group treated with either drug or microbubbles. Moreover, higher antitumor activity was observed in the combined group than that in cisplatin alone, which could be reflected by the number of apoptotic cells in tumor tissues and over expression of bax in the combined group. This combination treatment also exhibited a better immunological activity, increasing the infiltration of CD8+ T cells and the expression of several revelant cytokines. SIGNIFICANCE: The ultrasound lipid-shelled PD-L1-MBs may enhance anti-tumor effects of cisplatin by blocking the PD-L1 site and improving immune function.

The association between monocytic myeloid-derived suppressor cells levels and the anti-tumor efficacy of anti-PD-1 therapy in NSCLC patients.

Monocytic myeloid-derived suppressor cells (M-MDSCs), granulocytic MDSC (G-MDSCs) and regulatory T cells (Tregs) inhibit adaptive anti-tumor immunity and undermine the efficacy of anti-PD-1 therapy. However, the impact of anti-PD-1 treatment on these immunosuppressive cells has not been clearly defined in non-small cell lung cancer (NSCLC). In this retrospective study, 27 advanced NSCLC patients were divided into partial response (PR), stable disease (SD), and progressive disease (PD) groups. The impact of anti-PD-1 therapy on circulating Tregs, G-MDSCs, and M-MDSCs was assessed by flow cytometer. Here, we found that anti-PD-1 treatment boosted circulating Tregs levels, which presented the most remarkable augment during the first two therapeutic cycles, in NSCLC patients. In contrast, anti-PD-1 therapy did not overall change G-MDSCs and M-MDSCs levels. However, the PR group had a higher baseline level of M-MDSCs, which exhibited a significant decrease after the first cycle of anti-PD-1 treatment. Besides, M-MDSCs levels in the PR group were maintained at a low level in the following therapeutic cycles. Consistently, Tregs levels robustly increased in the syngeneic tumor model after anti-mouse PD-1 Ab treatment. Accordingly, M-MDSCs neutralization by anti-mouse ly6c Ab enhanced the anti-tumor efficacy of anti-PD-1 therapy in mice. Finally, the decreased M-MDSCs levels were associated with the enhanced effector CD8+ T cells expansion in the PR group and mice. In conclusion, anti-PD-1 therapy upregulates Tregs levels in NSCLC patients, and the M-MDSC levels are associated with the anti-tumor efficacy of anti-PD-1 treatment. Neutralization of M-MDSCs may be a promising option to augment anti-PD-1 therapy efficacy in NSCLC.

Ribavirin therapy for severe COVID-19: a retrospective cohort study.

The aim of this study was to compare ribavirin therapy versus supportive therapy only for patients with severe coronavirus disease 2019 (COVID-19). A total of 115 patients with laboratory-confirmed COVID-19 were retrospectively analysed. All patients received supportive care as well as regular laboratory and clinical monitoring. The 115 patients comprised 44 patients who received intravenous ribavirin (treatment group) and 71 who did not (control group). Baseline laboratory and clinical characteristics were similar between the two groups. The negative conversion time for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR in the ribavirin group was 12.8 ± 4.1 days compared with 14.1 ± 3.5 days in the control group (P = 0.314). Moreover, 7/41 patients (17.1%) in the ribavirin group died compared with 17/69 (24.6%) in the control group (P = 0.475). Adverse effects were similar between the two groups. In conclusion, in patients with severe COVID-19, ribavirin therapy is not associated with improved negative conversion time for SARS-CoV-2 test and is not associated with an improved mortality rate. Further assessment in designed randomised controlled trials is recommended.

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China.

Importance: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated. Objective: To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died. Design, Setting, and Participants: Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020. Exposures: Confirmed COVID-19 pneumonia. Main Outcomes and Measures: The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed. Results: Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72). Conclusions and Relevance: Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.

2019 novel coronavirus of pneumonia in Wuhan, China: emerging attack and management strategies.

An ongoing outbreak of 2019-nCoV pneumonia was first identified in Wuhan, Hubei province, China at the end of 2019. With the spread of the new coronavirus accelerating, person-to-person transmission in family homes or hospitals, and intercity spread of 2019-nCoV occurred. At least 40,261 cases confirmed, 23,589 cases suspected, 909 cases death and 3444 cases cured in China and worldwide 24 countries confirmed 383 cases being diagnosed, 1 case death in February 10th, 2020. At present, the mortality of 2019-nCoV in China is 2.3%, compared with 9.6% of SARS and 34.4% of MERS reported by WHO. It seems the new virus is not as fatal as many people thought. Chinese authorities improved surveillance network, made the laboratory be able to recognize the outbreak within a few weeks and announced the virus genome that provide efficient epidemiological control. More comprehensive information is required to understand 2019-nCoV feature, the epidemiology of origin and spreading, and the clinical phenomina. According to the current status, blocking transmission, isolation, protection, and alternative medication are the urgent management strategies against 2019-nCoV.

Lung-Resident Mesenchymal Stem Cells Promote Repair of LPS-Induced Acute Lung Injury via Regulating the Balance of Regulatory T cells and Th17 cells.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Mesenchymal stem cells (MSCs) have been shown to improve ALI, and the imbalance of regulatory T cells (Tregs) and Th17 cells is associated with mortality in ALI/ARDS patients. However, whether administration of lung-resident MSC (LRMSC) improves lung injury and regulates the balance of Tregs and Th17 cells remains unknown. An ALI animal model was induced by LPS, and PBS or LRMSC were administered via tail vein after 4 h. LRMSC were subsequently detected in the lungs by a live imaging system (Berthold LB983, Germany). Lung morphology; lung wet-to-dry weight ratio; and total protein concentration, inflammatory cells, and cytokines in bronchoalveolar lavage fluid (BALF) and plasma were determined. The percentage of Tregs in lung and spleen, and of Th17 cells in lung and blood, were also evaluated. The results showed that LRMSC not only attenuated histopathological damage but also mediated the downregulation of lung wet-to-dry weight ratio and the reduction of total protein concentration and inflammatory cells in BALF. LRMSC also decreased inflammatory cytokines in both BALF and plasma and increased KGF-2 and surfactant protein C (SPC) expression in the lung. Flow cytometry revealed the upregulation of Tregs and the downregulation of Th17 cells, and the increase in the ratio of Tregs and Th17 cells. The live imaging system showed that LRMSC migrated to and were retained in the injured area. In conclusion, the results indicated that administration of LRMSC attenuates LPS-induced ALI via upregulating the balance of Tregs and Th17 cells.

Neutrophil-to-lymphocyte ratio as a prognostic marker in acute respiratory distress syndrome patients: a retrospective study.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is the leading cause of high mortality in intensive care units (ICUs) worldwide. An effective marker for prognosis in ARDS is particularly important given the absence of effective treatment strategies aside from small tidal volume ventilation. Previous studies identified an association between the neutrophil-to-lymphocyte ratio (NLR) and prognosis in critical patients. In this study, we explored the prognostic and predictive value of the NLR in ARDS patients. METHODS: We retrospectively included 275 ARDS patients treated at a single institute from 2008 to 2015. After excluding patients with chronic lung disease, acute myocardial infarction and missing data, 247 patients were ultimately included in the analysis. Clinical characteristics and experimental test data, including the NLR, were collected from medical records at 24 hours after the ARDS diagnosis. Independent prognostic factors were determined by multivariate Cox regression analysis. Subgroup stratification was performed according to different factors, and the continuous factors were divided according to the median values. RESULTS: The NLR in survivors was significantly lower than that in non-survivors (P<0.001). We took the median NLR value as the cut-off point and further divided all patients into a high NLR group (NLR >14) and a low NLR group (NLR ≤14). We found that an NLR >14 was associated with a shorter overall survival (OS) (P=0.005). In the multivariate Cox regression model, we further identified an NLR >14 as an independent prognostic factor for OS [hazard ratio (HR) 1.532, (95% CI, 1.095-2.143), P=0.013]. Subgroup analysis showed that the prognostic value of the NLR was higher in hypertensive patients (P=0.009) and in patients with low red blood cell specific volume (P=0.013), high sodium (P=0.002) and high creatinine levels (P=0.017). CONCLUSIONS: The NLR is potentially a predictive prognostic biomarker in ARDS patients.

Noninvasive ventilation on mortality of acute respiratory distress syndrome.

[Purpose] The aim of this study was to assess the efficacy of noninvasive ventilation (NIV) in acute respiratory distress syndrome (ARDS). [Subjects and Methods] The clinical data of 58 patients with ARDS that required mechanical ventilation in two intensive care units (ICU) was reviewed. [Results] Endotracheal intubation was performed in 55.17% of the total patients and in 39.53% of the patients who received NIV treatment. The APACHE II score for patients who only received IV was significantly higher than those who only underwent NIV (25.67 ± 5.30 vs. 18.12 ± 7.20). However, there were no significant differences in 28-day/90-day survival rates, duration of mechanical ventilation, and length of ICU stay between these two groups. For patients from a NIV-to-IV group, the APACHE II scores before endotracheal intubation were higher than the scores from IV patients (26.12 ± 4.08 vs. 21.94 ± 6.10). The 90-day survival rate in the NIV-to-IV group was significantly lower than that of the IV-only group (23.5% vs. 73.3%), although there was no difference in the 28-day survival rate between the two groups. [Conclusion] The application of NIV reduces the percentage of patients requiring endotracheal intubation.

Synthesis, in vitro and in vivo evaluation of new norcantharidin-conjugated hydroxypropyltrimethyl ammonium chloride chitosan derivatives as polymer therapeutics.

New norcantharidin-conjugated hydroxypropyltrimethyl ammonium chloride chitosan derivatives (NCTD-HACCs) were synthesized and characterized by (1)H NMR, Fourier-transform infrared spectroscopy (FT-IR), and wide-angle X-ray diffraction (WAXD). Two NCTD-HACCs with different degrees of substitution (DS) (12.2% and 24.8%) were obtained, which had good water solubility. NCTD was released from the NCTD-HACCs via hydrolysis, faster in pH 5.0 than pH 7.4 and presenting one biphasic drug release pattern with rapid release at the initial stage and slow release later. Fluorescence microscope and flow cytometry analysis demonstrated that the NCTD-HACC was endocytosized into MGC80-3 cells and the uptaken amount increased as incubation time. Compared with free NCTD, the NCTD-HACCs showed lower in vitro anti-tumor activity against human gastric cancer MGC80-3 cells, but higher in vivo tumor growth inhibition in S180 tumor-bearing mice. The in vivo near-infrared (NIR) fluorescence real-time imaging result showed the fluorescence intensity in tumor was much higher than that in heart, liver, spleen and lung (except kidney) after i.v. injection of the FITC-labeled NCTD-HACC2, indicating specific accumulation of the NCTD-HACC in tumor.