A Retrospective, Nested Case-Control Study to Develop a Biomarker-Based Model for ARDS Diagnostics.

BACKGROUND: Several biomarkers could be intercalated with traditional measures to improve ARDS diagnostics. METHODS: There were 211 ICU patients enrolled in this retrospective, nested case-control study. Participants were divided into an ARDS (n = 79) and non-ARDS (n = 132) groups, according to the Berlin criteria. Patient characteristics, vital signs, and laboratory tests were collected within three hours of admission. CC16, Ang-2, sRAGE, HMGB1, and SPD were measured within three hours and again at 24 hours, after admission to ICU. Receiver Operating Characteristic curves and multivariate logistic regression analyses were applied for predictive purposes. RESULTS: C-reactive protein (CRP), NT-proBNP, and pH values were intercalated with five established ARDS indicators, and the PaO2/FiO2 ratio. Only four potential indicators were analyzed, with CRP having high diagnostic value. Areas under curve (AUC) were as follows: CC16 (AUC: 0.752; 95% CI 0.680 - 0.824), Ang-2 (AUC: 0.695; 95% CI 0.620 - 0.770), HMGB1 (AUC: 0.668; 95% CI 0.592 - 0.744), sRAGE (AUC: 0.665; 95% CI 0.588 - 0.743), CRP (AUC: 0.701; 95% CI 0.627 - 0.776). No single indicator improved upon the PaO2/FiO2 ratio which had an AUC: 0.844 (95% CI 0.789 - 0.898). However, when the binary logistic model was transformed and the model was constructed, the AUC increased from 0.647 (95% CI 0.568 - 0.726) to 0.911 (95% CI 0.864 - 0.946). Among the combinations tested, PaO2/FiO2 + CRP + Ang-2 + CC16 + HMGB1 resulted in the highest AUC of 0.910 (95% CI 0.863 - 0.945), although there are other factors which must be considered. CONCLUSIONS: A combination of biomarkers could enhance ARDS diagnostics, which has obvious ramifications for patient care and prognosis. It may be possible to develop a predictive ARDS nomogram; however, of the combinations tested here, we tentatively recommend PaO2/FiO2 + CRP + Ang-2 + CC16 + HMGB1. This is because of the cost implications in contrast with benefit involved in utilizing the more elaborate model. Further health economics research is required to consider the opportunity cost for emergency care policy.

The therapeutic effect of stem cells from human exfoliated deciduous teeth on a rat model of tracheal fistula.

BACKGROUND: Tracheal fistulas (TF) can be dangerous and even fatal in patients. The current treatment is really challenging. Previous studies reported that mesenchymal stem cells (MSCs) could be used to treat respiratory tract fistulas. Stem cells from human exfoliated deciduous teeth (SHED) are considered to be MSC-like cells that may also have the potential to treat the tracheal fistulas. In this study, we investigated the therapeutic effects of SHED in rat tracheal fistula models. METHODS: A total of 80 SD rats were randomly divided into five groups: a sham-operated group, a local PBS group (L-PBS), an intravenous PBS group (I-PBS), a local SHED treatment group (L-SHED), and an intravenous SHED treatment group (I-SHED). The L-SHED and I-SHED groups were given a topical application around the fistula or an intravenous injection of 1*107 SHED via the tail vein, respectively, while the L-PBS and I-PBS groups were given an equivalent volume of PBS through local or intravenous administration. A stereomicroscope was used to observe fistula healing on the 2nd, 3rd, and 5th days following transplantation. On the 7th day, the survival of SHED was observed by immunofluorescence. The pathology of the lungs and fistulas was observed by hematoxylin and eosin (H&E) and Masson staining. The expression levels of the Toll-like receptor 4 (TLR4), interleukin (IL)-1ß, IL-33, and IL-4 were measured using immunohistochemistry. The expression levels of TLR4, high mobility group box 1 (HMGB1), and myeloid differentiation factor 88 (MYD88) were studied using western blotting. On day 14, airway responsiveness of rats was detected and analyzed. RESULTS: Fistula healing in the L-SHED and I-SHED groups was faster than that in their respective PBS groups after transplantation. The fistula diameters in the L-SHED and I-SHED groups were significantly smaller than those in the L-PBS and I-PBS groups on the 3rd day. Moreover, the phenomenon of fibroblast proliferation and new blood vessel growth around the fistula seemed more pronounced in the L-SHED and I-SHED groups. Although no discernible difference was found in airway responsiveness after SHED treatment, the degree of inflammation in the lungs was reduced by intravenous SHED treatment. However, there was no significant reduction in lung inflammation by local SHED treatment. The expression levels of IL-1ß and IL-33 were decreased in the I-SHED group, while IL-4 was elevated compared with the I-PBS group. Interestingly, intravenous SHED treatment inhibited the activation of HMGB1/TLR4/MYD88 in the lung tissues of TF rats. CONCLUSIONS: SHED transplantation accelerated the rate of fistula healing in rats. Intravenous SHED treatment reduced lung inflammation. Thus, SHED may have potential in the treatment of tracheal fistula, providing hope for future therapeutic development for TF.

[The research progress on the registration database of out-of-hospital cardiac arrest].

Out-of-hospital cardiac arrest (OHCA) with high mortality and disable rate is a public health problem of common concern all over the world. In order to improve the survival rate of OHCA, developed countries such as Europe and the United States have established regional and even national OHCA registration database for continuous monitoring and quality improvement of OHCA, identifying the weaknesses in each link of the survival chain, and evaluating effective measures to enhance the survival rate. At present, China still lacks of registration database that can comprehensively collect the information of OHCA and effectively reflect the treatment status and research direction of OHCA. In order to shorten the huge gap of OHCA survival rate between China and developed countries such as Europe and the United States, we should learn from the experience of foreign registration databases and establish OHCA registration database suitable for China's national conditions, so as to promote the improvement of OHCA survival rate in China. This paper presents several major OHCA registry databases of the internationally recognized,such as cardiac arrest registry to enhance survival (CARES), resuscitation outcomes consortium (ROC), European registry of cardiac arrest (EuReCa), Pan-Asian resuscitation outcomes registry (PAROS), and Australian resuscitation outcome consortium (Aus-ROC), aims to provide a reference for promoting the construction of the cardiac arrest registration database in China.

[Hierarchical first aid training scheme for elementary and middle school students: the practices from the construction of "Baoan Model" social emergency medicine training].

OBJECTIVE: To share the implementation experience of hierarchical first aid training scheme for elementary and middle school students in Baoan District of Shenzhen City and evaluate its effect of training. METHODS: During August 2018 and August 2019, elementary and middle schools students who participated in the first aid training held by emergency rescue training center of Baoan District were enrolled. Baseline information including the number of students, the number of attending tutors, the number of cardiopulmonary resuscitation (CPR) training models, automated external defibrillator (AED) models were recorded. According to hierarchical levels of three age, students received different courses with content from simple to hard: the course of elementary school students was consisting of dialing 120, smart animation on how to identify accidental damage, demonstration of AED and Hemlick techniques, CPR practise (40 minutes). The course of junior high school students was consisted of how to dial 120, how to identify accidental damage and simple disposal, application of CPR and AED, practice CPR and AED and Hemlick techniques (90 minutes). The course of high school students was consisted of how to dial 120, identify accidental damage and right disposal, identification of out-of-hospital cardiac arrest, the key-point of CPR and AED, practice CPR and AED, Hemlick techniques and hemostatic bandage (120 minutes). At the end of course, elementary school students were voluntary for skill assessment; junior high school students only were compulsory for skill assessment in small classes but not required in large classes, just for demonstration; additionally, the whole high school students were compulsory for skill assessment. The characteristics of first aid training students at different levels were collected in order to compare the differences on the usage of CPR training model and AED training model, the distribution of emergency resource, the ratio for passing examination. RESULTS: A total of 12 896 students and 2 086 training instructors took parted in 200 lists of first aid training courses, 8 557 CPR models and 8 493 AED models were used. On average, there are 65.27±5.61 students in each session, and 10.52±10.43 training instructors. There are 43.09±19.06 CPR training models and 42.77±18.61 AED training models. The mean ratio of student to tutor was 6.07±1.47, student to CPR model was 1.54±1.02, and student to AED model was 1.54±1.03. In the end of course, 10 494 students participated in the examination with the participation rate of 81.37%; 10 114 students passed the examination with the passing rate of 96.38%. Hierarchical analysis showed: compare to elementary school students, the average number of junior high school students in every training session significantly increased (cases: 69.94±8.77 vs. 58.69±6.12, P < 0.05), but the average number of high school students in every training session significantly decreased (cases: 57.35±5.79 vs. 58.69±6.12, P < 0.05). The proportion of instructors in junior high school students' training significantly reduced (5.94±1.39 vs. 6.48±2.02, P < 0.05). The examination ratio of junior high school students and high school students was increased significantly [81.07% (6 667/8 224), 100% (2 313/2 313) vs. 64.18% (1 514/2 359), both P < 0.05], but the ratio of passing the examination was significantly reduced [95.47% (6 365/6 667), 96.88% (2 241/2 313) vs. 99.60%(1 508/1 514), both P < 0.01]. This might be related to the low difficulty of elementary school students' assessment and the low proportion of compulsory examination. CONCLUSIONS: Hierarchical scheme is feasible for first aid training in elementary and middle school students, the content of course should be desighed from easy to hard. Synchronously, sufficient training instructors and training models should be equipped to ensure the quality.

The rCC16 Protein Protects Against LPS-Induced Cell Apoptosis and Inflammatory Responses in Human Lung Pneumocytes.

OBJECTIVE: Our previous clinical study showed that low lung levels of CC16 strongly influence the occurrence and development of ARDS. The aim of the present study was to evaluate the therapeutic effect of rCC16 on LPS-induced inflammation in A549 cells and to determine its mechanism. METHODS: Cell apoptosis and inflammation was induced by LPS stimulation. The cytotoxic effect of rCC16 was evaluated using the MTT assay. Cytokine levels were determined using enzyme-linked immunosorbent assays. The molecular mechanism of rCC16 was investigated by analyzing relevant signaling pathways. RESULTS: The LPS treatment of A549 cells significantly decreased cell viability, increased the levels of the apoptotic proteins Bax, Bak and Cleaved Caspase-3, the secretion of inflammatory cytokines, and the expression levels of TLR4, p-NF/κB, MAPK proteins. While the levels of Bcl-2, p-AKT, p-mTOR, p-ERK1/2, NF/κB, p-AMPK, and p-p38 were significantly decreased in LPS-treated A549 cells. Our experimental results also confirmed that rCC16 inhibited LPS-induced apoptosis, promoted A549 cell proliferation by activating the PI3K/AKT/mTOR/ERK1/2 pathway, and inhibited the release of certain inflammatory factors, especially HMGB1, through dephosphorylation and inactivation of the TLR4/NF-κB/AMPK signaling pathways. CONCLUSION: These results highlight the potential utility of CC16 as an important cytokine for the prevention or treatment of inflammation and show that CC16 may play an important role in the future clinical treatment of ARDS.

Renal dysfunction reduces the diagnostic and prognostic value of serum CC16 for acute respiratory distress syndrome in intensive care patients.

BACKGROUND: Contradictory results regarding changes in serum club cell protein 16 (CC16) levels in patients with acute respiratory distress syndrome (ARDS) have been reported, challenging the value of CC16 as a diagnostic and prognostic marker for ARDS. We have also observed increased serum CC16 levels in patients with renal dysfunction (RD). Therefore, the present study aimed to determine whether RD affects the diagnostic performance of CC16 for ARDS in intensive care unit (ICU) patients. METHODS: We measured serum CC16 concentrations in 479 ICU patients, who were categorized into six groups according to their diagnoses: control, acute kidney injury (AKI), chronic kidney disease (CKD), ARDS, ARDS+AKI, and ARDS+CKD. The sensitivity, specificity, and cutoff values for serum CC16 were assessed by receiver operating characteristic curve analysis. RESULTS: Serum CC16 concentrations were higher in the ARDS group than in the control group, and in ARDS patients with normal renal function, serum CC16 could identify ARDS and predict survival outcomes at 7 and 28 days. However, serum CC16 levels were similar among the ARDS+AKI, ARDS+CKD, AIK, and CKD groups. Consequently, in patients with AKI and/or CKD, the specificity of CC16 for diagnosing ARDS or ARDS+RD decreased from 86.62 to 2.82% or 81.70 to 2.12%, respectively. Consistently, the CC16 cutoff value of 11.57 ng/ml in patients with RD differed from the established values of 32.77-33.72 ng/ml with normal renal function. Moreover, the predictive value of CC16 for mortality in ARDS+RD patients was lost before 7 days but regained by 28 days. CONCLUSION: RD reduces the diagnostic specificity, diagnostic cutoff value, and predictive value for 7-day mortality of serum CC16 for ARDS among ICU patients.

[Research progress of sepsis-induced acute kidney injury].

OBJECTIVE: Acute kidney injury (AKI) is a common complication in patients with sepsis, with poor prognosis and high mortality. The pathogenesis of sepsis-induced acute kidney injury (SAKI) is closely related to renal hemodynamic abnormalities, inflammatory injury and adaptive mechanism. It is insufficient for previous criteria based on urine output and creatinine to the early diagnosis of SAKI. The emergence of new biomarkers may make up for deficiencies in early diagnosis. And significant progress has also been made in the treatment of SAKI. The aim of this article was to review the researches on pathophysiology, early diagnosis and treatment of SAKI and provides some help for clinical staff to understand SAKI.

Diagnostic and prognostic values of Club cell protein 16 (CC16) in critical care patients with acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a critical condition characterized by bilateral pulmonary infiltrates and severe hypoxemia. This study aimed to evaluate the diagnostic and prognostic values of Club cell protein 16 (CC16) in critical care patients with ARDS. METHODS: In this retrospective observational study, 83 patients with ARDS and 129 non-ARDS patients on ICU admission were enrolled. The differences in serum CC16 and other laboratory indicators between two groups were analyzed. The sensitivity, specificity, positive and negative predictive values, and accuracy of CC16 as a diagnostic marker on ICU admission were determined by receiver operating characteristic (ROC) curve analysis. The correlation between serum CC16 levels and the severity of ARDS as quantified by PaO2 /FiO2 ratio were further assessed. CC16 levels were compared between survivors and non-survivors. The relationships between CC16 levels and duration of ICU and hospitalization were evaluated. RESULTS: The serum CC16 levels in ARDS patients were significantly higher than that in non-ARDS patients (54.44±19.62 vs 24.13±12.32 ng/mL, P=.001). ROC analysis showed that the sensitivity, specificity, positive predictive value, and negative predictive value were 90.4%, 79.8%, 74.2%, and 92.8%, respectively, when the cut-off value was set at 33.3 ng/mL. CC16 levels were correlated with the severity of ARDS. The serum CC16 levels were significantly greater in non-survivors than in survivors from the ARDS group. CC16 levels were associated with ICU stay but not hospital stay. CONCLUSIONS: CC16 may serve as a diagnostic and stratification marker for ARDS. However, it provided limited prognostic information for ARDS.

Inhibition of RHO Kinase by Fasudil Attenuates Ischemic Lung Injury After Cardiac Arrest in Rats.

Lung injury is a common complication after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), and Rho kinase (ROCK) may be involved in the process of this injury. In this study, we aimed to study the effects of ROCK inhibition by fasudil on lung injury induced by asphyxial CA and CPR in rats. A total of 130 rats were randomized into three groups: Sham, Control, and Fasudil intervention group. Animals in the Fasudil intervention group were intraperitoneally administered with 10 mg/kg of the drug, 1 h before inducing CA. Rats in the Control group received equivalent volume of saline and were subjected to the same experimental procedures with as the Fasudil group. Blood was collected and lungs were harvested at 3, 6, 12, 24, and 48 h after return of spontaneous circulation (ROSC) for blood gas and biochemical analysis. Fasudil significantly increased the partial pressure of oxygen and pH in arterial blood, as well as attenuated lung histological injury and lung edema after ROSC. Additionally, it significantly decreased lung inflammatory response (decreased levels of tumor necrosis factor-α and interleukin-6, and myeloperoxidase activity) and oxidative stress (decreased malonaldehyde level and increased superoxide dismutase activity) after ROSC. Using western blot analysis, we found that fasudil inhibited both isoforms ROCK1 and ROCK2, and intercellular adhesion molecule-1; nevertheless, it increased vascular endothelial cadherin protein expression after ROSC. Our study suggested that the Rho kinase signaling pathway is critical for CA-induced lung injury and fasudil has protective effects on lung injury after CA and CPR.

[Advances in biomarkers of ARDS].

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is a common diseases in critical ill patients, which is an acute-onset hypoxic condition with radiographic bilateral lung infiltration. And it can be divided into two phases in pathophysiology: an acute exudative phase combining diffuse alveolar damage and lung edema followed by a later fibro proliferative phase. The early prediction and risk assessment of patients with ARDS is still very poor in the clinical. In recent years, researchers gradually focus their research on exploration of biomarkers of ARDS. The article mainly aims to sum up the development of biomarkers exploration.

Apoptosis and surfactant protein-C expression inhibition induced by lipopolysaccharide in AEC II cell may associate with NF-κB pathway.

Lipopolysaccharide (LPS), a Gram-negative bacterial outer membrane component, is one of the major causes of septic shock. Herein we investigate LPS-induced apoptosis of rat alveolar epithelial type II cells (AEC II) and the effects of LPS on surfactant protein-C (SP-C) expression in AEC II, along with the possible molecular mechanisms. LPS exposure impaired cell viability and increased apoptosis of AEC II significantly in concentration-dependent manner embodied in increased caspase-3 expression and the activity of caspase-3. Simultaneously, our results also indicated that LPS inhibited surfactant protein-C (SP-C) expression in AEC II. Mechanistic studies revealed that LPS treatment significantly increased the expression of NF-κB p50, NF-κB p65 and IKKß proteins as well as induced IκB-α phosphorylation. Moreover, pretreatment with IKK inhibitor IKK-16 or NF-κB inhibitor PDTC ameliorated LPS-caused alterations in cleaved caspase-3 expression, the activity of caspase-3 and SP-C expression. Taken together, these results demonstrate that LPS can induce apoptosis of AEC II and decrease SP-C expression partly through activating the NF-κB pathway.