Anti-Ro52 antibodies are associated with the prognosis of adult idiopathic inflammatory myopathy-associated interstitial lung disease.

OBJECTIVES: In the present study, we aimed to assess the prevalence and clinical significance of anti-Ro52 antibodies in a cohort of patients with idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) with different myositis-specific autoantibodies (MSAs). METHODS: A cohort of 267 IIM-ILD patients, including 62 patients with PM, 126 patients with DM and 79 patients with clinically amyopathic DM (CADM) were retrospectively analysed in this study. Clinical and laboratory findings, pulmonary function tests (PFTs), HRCT patterns and treatment information were compared between patients with and without anti-Ro52 antibodies. The association between prognosis and anti-Ro52 antibodies was also evaluated based on different MSA subgroups. RESULTS: Anti-Ro52 antibodies were more frequent in patients with anti-MDA5 (62.1%, P < 0.01) and anti-Jo1 (64.9%, P < 0.01) antibodies than in those with other MSAs. The proportion of patients with anti-Jo1 antibodies was higher in the anti-Ro52 antibody-positive group than in the anti-Ro52 antibody-negative group. Patients with anti-Ro52 antibodies were more likely to exhibit the Gottron sign than the anti-Ro52 antibody-negative group (P < 0.001). Furthermore, it was a predictive factor for rapid progression interstitial lung disease (RP-ILD) (P = 0.001) and was also associated with a higher mortality rate (log-rank test, P = 0.001). Furthermore, RP-ILD was more frequently exhibited in anti-MDA5- and anti-Ro52-positive patients. Moreover, anti-Ro52 antibody positivity was closely associated with a higher mortality rate in anti-MDA5-ILD patients (log-rank test, P < 0.05). CONCLUSIONS: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5 and anti-Jo1 antibodies. Within all patients with IIM-ILD, those with anti-Ro52 autoantibodies had a higher frequency of RP-ILD and a poorer prognosis, especially in the anti-MDA5 antibody subgroup.

Cytokeratin 19 fragment is associated with severity and poor prognosis of interstitial lung disease in anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: In the present study, we aimed to assess the clinical significance of cytokeratin 19 fragment (CYFRA21-1) in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-interstitial lung disease (MDA5-DM-ILD). METHODS: A total of 73 MDA5-DM-ILD patients were retrospectively analysed in this work. Their clinical characteristics, including clinical manifestations, laboratory findings, peripheral blood lymphocyte subsets and lung function, were compared between patients with acute/subacute interstitial pneumonia (A/SIP) and chronic interstitial pneumonia (CIP). The level of serum CYFRA21-1 was also compared between the above-mentioned two groups of patients, and its association with the clinical features and mortality of MDA5-DM-ILD was also evaluated. RESULTS: Of the 73 MDA5-DM-ILD patients, 26 patients exhibited the A/SIP pattern. The level of serum CYFRA21-1 was higher in MDA5-DM patients with A/SIP compared with the CIP group (P = 0.009). Lower oxygenation index (OI), CD3+CD4+ T cell counts and percentage of CD3+CD4+ cells were also observed in MDA5-DM patients with A/SIP compared with the CIP group. Higher serum CYFRA21-1, lower OI, and lower zone consolidation were associated with a higher risk of A/SIP in MDA5-DM-ILD. In addition, 38 decedents with MDA5-DM-ILD exhibited a greater level of CYFRA21-1 compared with 35 survivors (P < 0.001). Furthermore, it was a prognostic factor and also associated with a higher mortality rate (log-rank test, P < 0.001). CONCLUSIONS: CYFRA21-1 could be a useful serum indicator associated with occurrence of A/SIP in MDA5-DM-ILD. Moreover, it was associated with a poor survival in MDA5-DM-ILD patients.

Analyses of Short Chain Branches in Polyolefins with Improved 1H NMR Spectroscopy.

Polyolefin microstructures, for example, short chain branching (SCB) and short chain branch distribution (SCBD), have a direct impact on properties and thus ultimately influence end-use applications. The 1H NMR approach to analyze SCB and SCBD is particularly useful when only a limited amount of sample is available, for example, polyolefin film layers or the fractions from polyolefin separation techniques, such as gel permeation chromatography (GPC), crystallization elution fractionation (CEF), high temperature liquid chromatography (HTLC), and thermal gradient interaction chromatography (TGIC). In this paper, we discuss the best approach to find a good decoupling frequency and propose an improved 1H pulse sequence with homonuclear decoupling for better measuring SCB. With this new pulse it is possible to reach a S/N of 10 (level of quantification) for the methyl signal from SCB in an ethylene-hexene copolymer (EH, 3.6 mol % H) in 3.5 min with 0.5 µg of sample. We also show an easy method to calculate SCB/1000C and demonstrate the proper use of heteronuclear single quantum coherence (HSQC) to measure SCB in a complicated system. A very quick approach to examine the presence of a small amount of LDPE in a polyolefin sample is also suggested, which can reduce NMR acquisition time from a couple of days to a few minutes.

Polyolefin Analyses with a 10 mm Multinuclear NMR Cryoprobe.

Polyolefins are important and broadly used materials. Their molecular microstructures have direct impact on macroscopic properties and dictate end-use applications. 13C NMR is a powerful analytical technique used to characterize polyolefin microstructures, such as long-chain branching (LCB), but it suffers from low sensitivity. Although the 13C sensitivity of polyolefin samples can be increased by about 5.5 times with a cryoprobe, when compared with a conventional broadband observe (BBO) probe, further sensitivity enhancement is in high demand for studying increasingly complex polyolefin microstructures. Toward this goal, distortionless enhancement by polarization transfer (DEPT) and refocused insensitive nuclei enhanced by polarization transfer (RINEPT) are explored. The use of hard, regular, and new short adiabatic 180° 13C pulses in DEPT and RINEPT is investigated. It is found that RINEPTs perform better than DEPTs and a sensitivity enhancement of 3.1 can be achieved with RINEPTs. The results of RINEPTs are further analyzed with statistics software JMP and recommendations for optimal usage of RINEPTs are suggested. An example of analyzing saturated chain ends in an ethylene-octene copolymer sample with a hard 180° 13C RINEPT pulse is demonstrated. It is shown that the experimental time can be further reduced in half because of faster proton relaxation, where the total experimental time is about 580 times shorter when compared to using a conventional method and a 10 mm BBO probe. A naturally abundant nitrogen-containing polyolefin is analyzed using 1H-15N HMBC and, to our knowledge, is the first 1H-15N HMBC presented in the field of polyolefin characterization. The relative amount of similar nitrogen-containing structures is quantified by two-dimensional integration of 1H-15N HMBC. Two pragmatic technical challenges related to using high-sensitivity NMR cryoprobes are also addressed: (1) A new 1H decoupling sequence Bi_Waltz_65_256pl is proposed to address decoupling artifacts in 13C{1H} NMR spectra which contain a strong 13C signal with a high signal-to-noise ratio (S/N). (2) A simple pulse sequence that affords zero-slope spectral baselines and quantitative results is presented to address acoustic ringing that is often associated with high-sensitivity cryoprobe use.

Associations of Serological Biomarkers of sICAM-1, IL-1ß, MIF, and su-PAR with 3-Month Mortality in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

OBJECTIVE: To investigate prognostic values of serum biomarkers of soluble intercellular adhesion molecule 1 (sICAM-1), macrophage migration inhibitor factor (MIF), interleukin 1ß (IL-1ß), and soluble urokinase plasminogen activator receptor (su-PAR) in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). METHODS: From August 2017 to November 2019, 122 consecutive IPF patients treated in our center were classified as stable IPF and AE-IPF based on the newly published international guidelines. Serum levels of four biomarkers at admission were measured by the enzyme-linked immunosorbent assay (ELISA). The primary endpoint was 3-month mortality. The log-rank test and logistic regression analysis were used to evaluate the effects of these biomarkers for survival in patients with AE-IPF. Cox proportional hazards analysis was performed to evaluate the prognostic values of serological biomarkers and clinical data. RESULTS: Eighty-one patients were diagnosed with stable IPF, and 41 AE-IPF patients were enrolled in the study. Serum levels of sICAM-1 (p < 0.001), IL-1ß (p < 0.001), MIF (p < 0.001), and su-PAR (p < 0.001) in patients with IPF were significantly increased compared to those in healthy controls. All the four biomarkers were elevated in patients with AE-IPF compared to those with stable IPF. The 3-month mortality in AE-IPF was 56.1% (23/41). Increased levels of MIF (p = 0.01) and IL-1ß (>5 pg/mL, p = 0.033) were independent risk factors for 3-month mortality in patients with AE-IPF. CONCLUSIONS: We showed the higher serum levels of IL-1ß, and MIF had prognostic values for 3-month mortality in AE-IPF. This study provided a clue to promote our understanding in the pathogenesis of the disease.

Correlation between serum bilirubin levels and the severity as well as the prognosis of idiopathic pulmonary fibrosis.

Bilirubin exerts antioxidant activity that has been associated with respiratory diseases. However, the relationship between serum bilirubin levels and idiopathic pulmonary fibrosis (IPF) is not clear. Therefore, in this study, we evaluated the relationship between serum bilirubin levels and the severity as well as the prognosis of IPF. One hundred and forty-six patients with IPF and 69 healthy individuals as the control group were enrolled as a derivation cohort. Routine blood examination and pulmonary function tests were performed and serum bilirubin levels were measured. To validate the value of serum bilirubin levels to predict the survival of patients with IPF, 40 additional IPF patients were included as a validation cohort. IPF patients were followed-up. Patients with IPF had significantly lower levels of serum total bilirubin (TBIL) and direct bilirubin (DBIL) than those in the control group (P < 0.05). Patients with acute exacerbation of IPF (AE-IPF) had significantly lower levels of serum TBIL and IBIL than those in patients with stable IPF (P < 0.05). The area under the receiver operating characteristic curve (AUROC) of serum TBIL levels for the prediction of the incidence of AE-IPF was 0.72 (95% CI: 0.56-0.87, P = 0.0057). The best cutoff value of serum TBIL level to predict the survival of patients with IPF was 8.8 µmol/l (AUC = 0.75, 95% CI: 0.64-0.87, P = 0.022). The log-rank test showed a significant difference in survival between the two groups (TBIL ≤8.8 µmol/l and TBIL >8.8 µmol/l) in derivation and validation cohort. Cox multiple regression analysis indicated that serum TBIL levels were an independent prognostic factor for IPF prognosis (HR = 0.582, P = 0.026). Serum TBIL levels might be useful for reflecting the severity and predicting the survival of patients with IPF.

SPOCK1 contributes to the third-generation EGFR tyrosine kinase inhibitors resistance in lung cancer.

INTRODUCTION: Explanation of the mechanism of resistance to third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the development of a novel strategy for drug resistance are imperative in third-generation EGFR-TKIs-resistant non-small cell lung cancer (NSCLC). SPOCK1 was found to be abnormally expressed in various tumors including lung cancer, however, there was no study focused on the role of SPOCK1 in third-generation EGFR-TKIs resistant lung cancer cells. METHODS AND RESULTS: We investigated the roles of SPOCK1 in NSCLC with third-generation EGFR-TKIs resistance. We showed that SPOCK1 was upregulated in the osimertinib-resistant lung cancer cells and knockdown of SPOCK1 inhibits osimertinib-resistant cells growth and overcomes resistance. Furthermore, we demonstrated that the SPOCK1 was higher in clinical NSCLC specimens compared with the normal lung tissues, and the higher expression of SPOCK1 correlated with poor prognosis. In addition, the overexpression of SPOCK1 in NSCLC tissues was positively correlated with MMP11 and TGFß1. CONCLUSION: Our study suggested that SPOCK1 could be an independent prognostic factor in NSCLC and would be a candidate for target therapy in osimertinib-resistant lung tumors.

Acute exacerbations of fibrosing interstitial lung disease associated with connective tissue diseases: a population-based study.

BACKGROUND: Acute exacerbation (AE) is the major cause of morbidity and mortality in patients with idiopathic pulmonary fibrosis (IPF). AEs also occur in other forms of fibrosing interstitial lung disease (fILD). The clinical features and prognosis of AE patients with connective tissue diseases (CTDs) associated-ILD has not been fully described. METHODS: We retrospectively reviewed 177 patients with either IPF or a characterized CTD-ILD admitted to Nanjing Drum Tower Hospital with an AE from January 2010 to December 2016. RESULTS: The study cohort included 107 subjects with AE-IPF and 70 cases with AE-CTD-ILD. Female gender, prior use of corticosteroid and immunosupressants, lower serum albumin, higher D-dimer level, TLC% pred, survival, and treatment with immunosupressants and caspofungin were more common in the CTD-ILD group (all p<0.05). The incidences of AE-CTD-ILD and AE-IPF were similar in our single center (p = 0.526). TLC% pred was the risk factor for AE after ILD diagnosis for 1 year in CTD patients (p = 0.018). Log-rank tests showed patients with CTD-ILD had a significantly lower mortality rate compared with IPF patients after AEs (p = 0.029). No significant difference in survival was noted among CTD subgroups (p = 0.353). The survival was negatively correlated with WBC count, LDH and CT score, (p = 0.006, p = 0.013 and p = 0.035, respectively), and positively correlated with PaO2/FiO2 ratio (p<0.001) in the CTD-ILD group. WBC count and PO2/FiO2 ratio were the independent predictors for survival in AE-CTD-ILD after adjusting for other clinical variates in Cox regression Models (p = 0.038 and p < 0.001, respectively). CONCLUSIONS: The clinical characteristics of patients with AE-CTD-ILD differed from those with AE-IPF, while AE incidences were similar between the two groups. Subjects with AE-CTD-fILD tended to have a better prognosis, and WBC count and PO2/FiO2 ratio were the independent survival predictors for these patients.

Carnosol protects against spinal cord injury through Nrf-2 upregulation.

BACKGROUND: Carnosol is an ortho-diphenolic diterpene with excellent antioxidant potential. The present study was designed to identify the protective role of carnosol against spinal cord injury (SCI)-induced oxidative stress and inflammation in Wistar rats. METHODS: In the present study, oxidative stress status was determined through estimating total antioxidant capacity, total oxidant status, lipid peroxide content, protein carbonyl and sulfhydryl levels, reactive oxygen species (ROS), antioxidant status (superoxide-dismutase, catalase, glutathione, glutathione peroxidase, glutathione-S-transferase). Inflammatory effects were determined by analyzing the expression of NF-κB and COX-2 through Western blot analysis. Further, carnosol-mediated redox homeostasis was analyzed by determining p-AKT and Nrf-2 levels. RESULTS: SCI resulted in a significant increase in oxidative stress status through increased ROS generation, total oxidant levels, lipid peroxide content, protein carbonyl and sulfhydryl levels. The antioxidant status in SCI rats was significantly reduced, indicating imbalance in redox status. In addition, the expression of NF-κB and COX-2 was significantly upregulated, while p-AKT and Nrf-2 levels were downregulated in SCI rats. However, treatment with carnosol showed a significant enhancement in the antioxidant status with concomitant decline in oxidative stress parameters. Further, carnosol treatment regulated the key proteins in inflammation and redox status through significant downregulation of NF-κB and COX-2 levels and upregulation of p-AKT and Nrf-2 expression. CONCLUSION: Thus, the present study shows for the first time on the protective role of carnosol against SCI-induced oxidative stress and inflammation through modulating NF-κB, COX-2 and Nrf-2 levels in Wistar rats.

Increased cardiac index attenuates septic acute kidney injury: a prospective observational study.

BACKGROUND: The relationship between cardiac output and septic acute kidney injury (AKI) remains unclear. The purpose of this study was to assess the association between the cardiac index (CI) and the renal outcomes in patients with septic shock. METHODS: A one-year prospective cohort study was performed in the surgical and medical ICU of a teaching hospital in Nanjing, China. Twenty-nine septic shock patients who required early goal-directed fluid resuscitation were consecutively included. Pulse indicator continuous cardiac output (PiCCO) device was used to measure hemodynamic parameters before and after early goal-directed therapy (EGDT). Based on CI changes after EGDT, patients were assign to the CI increased group or the CI constant group, respectively. The incidence of poor renal outcome, which was defined as AKI on admission without recovery in following three days or new onset AKI within 28 days, was recorded. We investigated whether an increased CI was associated with a better renal outcome. RESULTS: After EGDT, there were 16 patients in the CI increased group and 13 patients in the CI constant group. The incidence of poor renal outcome was lower in CI increased group than in the CI constant group (6% vs. 62%; P = 0.003) with a relative risk of 0.10. The logistic regression showed that the CI percent change was associated with renal outcome, with an odd ratio of 0.003 (P = 0.056) after adjustment of possible confounding factors. The CI percent change would predict a good renal outcome (AU ROC 0.739, P = 0.012) with moderate accuracy (sensitivity 75% and specificity 89%) when using a 10% cut-off value from Youden index. The CI percent change was also positively correlated with creatinine clearance (CCr) after EGDT (ρ = 0.548; P = 0.002). CONCLUSIONS: The increased CI after EGDT was a protective factor for kidney in patients with septic shock. A CI increased above 10% could be potentially used to predict development and reversibility of AKI in septic shock patients. TRIAL REGISTRATION: Clinicaltrials.gov:NCT01862588 (May 13, 2013).

Effects of terlipressin on microcirculation of small bowel mesentery in rats with endotoxic shock.

BACKGROUND: Septic shock is still related to unacceptably high morbidity and mortality. Microcirculatory alteration has been demonstrated to be one important reason associated with this evolution. Vasoactive drugs are often used to restore adequate arterial pressure and tissue perfusion in septic shock. To define the roles of different drugs, the effects of terlipressin (TP) on the microcirculation of small bowel mesentery in rats with endotoxic shock were evaluated and compared with those of norepinephrine (NE). METHODS: Twenty-five adult male Wistar rats were randomized to the control (n = 5), TP (n = 10), and NE (n = 10) groups. After endotoxic shock was induced by intravenous lipopolysaccharide administration for 30 min, rats in the NE and TP groups were infused with saline 5 mL/kg/h and simultaneously given NE 4 µg/kg/min or TP 8 µg/kg/h. The mean arterial pressure, heart rate, blood gas analysis, and microvascular blood flow images of small bowel mesentery were recorded. RESULTS: After fluid resuscitation and vasopressor infusion, the mean arterial pressure was restored to the baseline values in the NE and TP groups. In the TP group, the heart rate was significantly lower compared with the NE group (P = 0.013). The proportion of perfused vessels and the microvascular flow index (MFI) were significantly increased; furthermore, the heterogeneity index of small vessels was markedly decreased in both the interventional groups with respect to the control group. Compared with the NE group, the MFI was significantly higher (P < 0.05) and the heterogeneity index was significantly lower (P < 0.05) in the TP group. CONCLUSIONS: Both TP and NE improved hemodynamic and microcirculatory alterations in rats with endotoxic shock. Compared with NE, TP was more effective in promoting MFI and improving the heterogeneity of small bowel mesentery in rats.

Effect of high-dose intravenous methylprednisolone pulse (IVMP) therapy in the survival of patients with anti-melanoma differentiation-associated gene 5-related rapidly progressive interstitial lung disease: a retrospective analysis.

OBJECTIVES: To assess the impacts of high-dose intravenous methylprednisolone pulse (IVMP) therapy in survival and the occurrences of treatment-related infection of patients with anti-melanoma differentiation-associated gene 5 antibody-related rapidly progressive interstitial lung disease (MDA5-RPILD). METHODS: Patients with MDA5-RPILD from June 2017 to August 2022 in our hospital were retrospectively reviewed. IVMP therapy was defined as intravenous methylprednisolone (mPSL) 0.5g/day for 3 consecutive days during hospitalization or 7 days prior to admission and patients were divided into IVMP group and non-IVMP group based on who had ever received IVMP therapy. All-cause mortality and the incidence of adverse events during treatment were compared between the two groups. RESULTS: Sixty-four patients with MDA5-RPILD were enrolled. Among them, twenty-three (35.9%) patients had ever received IVMP therapy. The overall mortality was comparable between IVMP and non-IVMP group (IVMP group: 22/23, 95.7% vs. non-IVMP group: 38/41, 92.7%, p=0.11). And the incidence of treatment-related infections was also close (IVMP group: 21/23, 91.3% vs. non-IVMP group: 32/41, 78.0%, p=0.30). After adjustment for gender, age, smoking history, duration from symptom onset to diagnosis, and combination with steroid-sparing agent treatment, the Cox proportional hazards model showed that IVMP therapy was not associated with an improved survival (adjusted HR 1.10; 95% CI 0.57-2.13; p=0.77). CONCLUSION: Our study showed that the survival benefits and adverse events were comparable between IVMP-treated and untreated MDA5-RPILD patients. Future prospective trials are needed to investigate the optimal treatment regimen in MDA5-RPILD. Key Points • This observational study found that IVMP therapy may be not associated with an improved outcome in patients with MDA5-RPILD. • Treatment-related infections are common; however, the incidence of treatment-related infections had no difference between IVMP and non-IVMP group.

Dynamic change of lymphocytes associated with short-term prognosis in anti-MDA5-positive dermatomyositis with interstitial lung disease: a multicenter retrospective study.

Lymphopenia is a unique manifestation of anti-MDA5 positive dermatomyositis with interstitial lung disease (MDA5 + DM-ILD). This study aimed to investigate the relationship between dynamic changes in peripheral lymphocytes and short-term prognosis in patients of MDA5 + DM-ILD. Two hundred sixty-three MDA5 + DM-ILD patients were divided into different groups according to lymphocyte count and death or survival within 1 month, then the differences in clinical features and outcomes were compared. Associations between lymphocytes and risk of death within 1 month were also investigated in different lymphocyte groups using Cox proportional hazard models. A generalized additive mixed model (GAMM) was established to analyze the dynamic changes of lymphocytes in the death 1-month group. Lymphocytes of the patients who died within 1 month were significantly lower than survivors by different lymphocyte grouping methods, and the total lymphocytes showed a gradually decreasing trend in non-survivors. And the difference between survivors and non-survivors was more obvious over time. The lowest tertile of baseline lymphocytes as a reference, the hazard ratios for death within 1 month in the highest tertile were 0.497 (95% CI 0.26-0.949, P for trend = 0.033) after adjustment for potential confounders. GAMM analysis found a mean daily decrease of lymphocytes (0.034 × 10^9/L) after admission in death 1-month patients. Low baseline lymphocytes and gradually declined lymphocytes are both associated with a high risk of death within 1 month. However dynamic changes in lymphocytes can better reflect the disease status and better predict the short-term prognosis than baseline lymphocytes in MDA5 + DM-ILD patients. Key points •Low baseline lymphocytes and gradually decreased trend along time correlated with poor short-term prognosis in MDA5 + DM-ILD patients. •Dynamic changes of lymphocytes can better reflect the disease status and better predict the 1-month prognosis than baseline lymphocytes in MDA5 + DM-ILD patients. •Generalized additive mixed model (GAMM) analysis found that in 1-month non-survivors, peripheral blood lymphocytes decreased by 0.034 × 10^9/L per day, while the lymphocytes in survivors gradually increased.

Pretreatment mortality risk prediction model in patients with polymyositis/dermatomyositis-associated interstitial lung disease.

OBJECTIVES: Risk prediction for patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) is challenging due to heterogeneity in the disease course. We aimed to develop a mortality risk prediction model for PM/DM-ILD. METHODS: This prognostic study analysed patients with PM/DM-ILD admitted to Nanjing Drum Hospital from 2016 to 2021. The primary outcome was mortality within 1 year. We used a least absolute shrinkage and selection operator (LASSO) logistic regression model to identify predictive laboratory indicators. These indicators were used to create a laboratory risk score, and we developed a mortality risk prediction model by incorporating clinical factors. The evaluation of model performance encompassed discrimination, calibration, clinical utility and practical application for risk prediction and prognosis. RESULTS: Overall, 418 patients with PM/DM-ILD were enrolled and randomly divided into development (n=282) and validation (n=136) cohorts. LASSO logistic regression identified four optimal features in the development cohort, forming a laboratory risk score: C reactive protein, lactate dehydrogenase, CD3+CD4+ T cell counts and PO2/FiO2. The final prediction model integrated age, arthralgia, anti-melanoma differentiation-associated gene 5 antibody status, high-resolution CT pattern and the laboratory risk score. The prediction model exhibited robust discrimination (area under the receiver operating characteristic: 0.869, 95% CI 0.811 to 0.910), excellent calibration and valuable clinical utility. Patients were categorised into three risk groups with distinct mortality rates. The internal validation, sensitivity analyses and comparative assessments against previous models further confirmed the robustness of the prediction model. CONCLUSIONS: We developed and validated an evidence-based mortality risk prediction model with simple, readily accessible clinical variables in patients with PM/DM-ILD, which may inform clinical decision-making.

Diagnostic finding on high-resolution computed tomography (HRCT) predicts a good response to pirfenidone in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating condition, with a life expectancy of 2 to 5 years after diagnosis. Pirfenidone is a drug that has been shown to reduce the decline in forced vital capacity (FVC). We sought to identify whether different patterns on high-resolution computed tomography (HRCT) have different clinical effects through a retrospective comparison of baseline values and changes in pulmonary function tests (PFTs) after treatment with pirfenidone. We retrospectively analyzed data from IPF patients treated with pirfenidone at Nanjing Drum Tower Hospital in Jiangsu Province, China. According to the HRCT pattern, the patients were divided into usual interstitial pneumonitis (UIP) and possible UIP groups. Baseline clinical characteristics and changes every 6 months in the PFTs during the follow-up period were compared between the 2 groups. A total of 65 consecutive patients were enrolled. According to the HRCT pattern, patients were clustered into the UIP group (n = 46) and possible UIP group (n = 19). No difference was observed in the baseline PFTs ratio between the 2 groups. The FVC values of the 2 groups were not significantly different at the initial treatment and at 6 and 12 months after pirfenidone treatment (P = .081, 0.099, and 0.236, respectively). The improvement in % diffusion capacity of the lung for carbon monoxide (%DLCO) was higher in the possible UIP group after 6 and 12 months of pirfenidone treatment (P = .149, 0.026, and 0.025, respectively). The annual decrease in FVC was not significantly different between the 2 groups, and the annual decrease in %DLCO in the UIP group was significantly higher than that in patients with the possible UIP type (-7.767 ±â€…12.797 vs 0.342 ±â€…20.358, P < .05). These results indicate that patients with IPF with a possible UIP pattern on HRCT showed indications of a good response to pirfenidone.

Effects of membrane-type PBLs on the expression of TNF-α and IL-2 in pulmonary tissue of SD rats after LPS-induced acute lung injury.

BACKGROUND: As the first target organ, the lungs usually display symptoms of acute lung injury (ALI). Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-2, are crucial in triggering the systemic inflammatory response syndrome and the subsequent cascading effects. Therefore, the inhibition of the release of inflammatory mediators has become an important strategy for the prevention and treatment of ALI. OBJECTIVES: To evaluate the preventive and therapeutic effects of transmembrane peripheral blood leukocytes (PBLs) on lipopolysaccharide (LPS)-induced ALI and its mechanism. MATERIAL AND METHODS: Sixty Sprague Dawley rats were randomly divided into experimental and control groups. The animal model was established through intravenous injection of LPS. Plasmid PBLs were dissolved in a saline solution and injected into the experimental group of rats in different doses (0.1 mg, 0.2 mg and 0.3 mg per rat) using the in situ injection method. After injecting the PBL solution, the rats were killed after 12 h, 24 h, 36 h, or 48 h. The expression of microRNA (miRNA)-25 and miRNA-223 was detected using the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Tumor necrosis factor alpha and IL-2 levels in bronchoalveolar lavage fluid (BALF) were detected with an enzyme-linked immunosorbent assay (ELISA). The expressions of TNF-α and IL-2 proteins in lung tissue were detected using western blotting. RESULTS: The expression of miRNA-25 was upregulated in tissues and BALF in a doseand time-dependent manner, while miRNA-223 was downregulated. The differences were statistically significant compared to the control group (p < 0.05). The TNF-α and IL-2 levels in the BALF of rats in the experimental group were increased in a dose-dependent manner compared to the control group (p < 0.05). In the presence of PBLs, the expressions of TNF-α, IL-2, miRNA, and proteins were inhibited. Thus, PBLs were found to alleviate pulmonary tissue damage. CONCLUSIONS: In summary, PBLs have a protective effect on rats with ALI through the downregulation of TNF-α and IL-2 expression.

ZLN005 improves the protective effect of mitochondrial function on alveolar epithelial cell aging by upregulating PGC-1α.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging. Methods: Western blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H2O2) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed. Results: The Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H2O2-induced cell senescence by enhancing the expression of PGC-1α. Conclusions: These results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

[Effect of Xuebijing injection treatment on acute respiratory distress syndrome: a multicenter prospective randomized control clinical trial].

OBJECTIVE: To assess the therapeutic effect of Xuebijing injection on adult patients with acute respiratory distress syndrome (ARDS). METHODS: A multicenter prospective randomized control study was conducted at 10 intensive care units in Jiangsu province. A total of 172 early ARDS patients were randomly divided into Xuebijing treatment and control groups. All patients received routine therapy of ARDS while additional Xuebijing injection 100 ml was administered in the treatment group intravenously for 7 days. Lung injury score, acute physiology and chronic health evaluation II (APACHE II) score, multiple organ dysfunction score (MODS) and PaO2/FiO2 of the patients was recorded before and after treatment. Mortality at 28 days and the duration of mechanical ventilation were compared between two groups. RESULTS: Ninety-one patients were assigned to receive Xuebijing injection and 81 patients as control; Mortality at Days 28 and 90, the duration of mechanical ventilation and ventilation free days showed no difference between two groups (P > 0.05). PaO2/FiO2 improved after randomization versus pre-treatment in all patients. There was no significant difference between two groups. Murray scores were not significantly different between two groups. In a subgroup analysis of patients with pulmonary infection, pulmonary contusion and extra-pulmonary cause, two groups had no difference in mortality at Day 28, mortality at Day 90, the duration of mechanical ventilation, ventilation free days and days of ICU stay (P > 0.05). CONCLUSION: The treatment of Xuebijing injection early in course of ARDS does not improve the mortality of ARDS patients. But it may improve lung function and oxygenation. Further studies are warranted.

[Use of extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome: a meta-analysis].

OBJECTIVE: To evaluate the effects of extracorporeal membrane oxygenation (ECMO) on mortality in adult patients with acute respiratory distress syndrome (ARDS). METHODS: Literature concerning randomized controlled trials (RCTs), case-control studies and prospective cohort studies from January 1966 to July 2011 on ECMO for the treatment of ARDS patients was retrieved by electronic and manual search. Meta-analysis of the use of ECMO in the treatment of ARDS patients was conducted using the methods recommended by the Cochrane Collaboration's software RevMan 5.0. RESULTS: Three papers reporting RCTs and 6 papers concerning observational cohort studies of using ECMO in patients with severe ARDS were enrolled for analysis. Meta-analysis of the 3 RCTs (310 patients, 159 of them treated with ECMO) revealed ECMO did not decrease the mortality of ARDS patients [odds ratio (OR)=0.75, 95% confidence interval (95%CI) 0.45-1.24, P = 0.27]. Meta-analysis of the all 9 studies (1058 patients, 386 of them treated with ECMO) revealed ECMO increased the mortality of ARDS patients (OR=1.58, 95%CI 0.94-2.67, P = 0.08). CONCLUSION: There is no evidence to prove that ECMO is beneficial in adult patients with ARDS, therefore further investigation with a large sample of high quality RCT is warranted.

Do clinical trials affect anxiety, depression, and quality of life in the caregivers of patients with cancer?

Objective: To investigate the effect of clinical trials on anxiety, depression, and the quality of life experienced by the family caregivers (FCs) of cancer patients. Materials and methods: We screened the FCs of patients who were participating in clinical trials and FCs of patients who were not participating in clinical trials [group FCs-GCP (FG) and group FCs-non-GCP (FNG) at Cancer Center of West China Hospital]. We assessed the anxiety, depression, and quality of life of the FCs using the Hospital Anxiety and Depression Scale and SF-12. The demographic characteristics of FCs and patients were analyzed. Results: The prevalences of anxiety and depression showed no significant difference between FG and FNG (46.3 vs. 51.5%, P = 0.604; 36.6 vs. 51.5%, P = 0.131, respectively). Physical Component Scores (PCS) were 48.87 ± 7.67 for FG and 48.01 ± 8.12 for FNG (P = 0.618) while Mental Component Scores (MCS) were 48.92 ± 7.78 and 44.89 ± 11.42, respectively (P = 0.031). The anxiety of FCs was positively associated with patients' advanced disease (HR 4.292 [1.409, 13.072], P = 0.010) and initial treatment (HR 3.105 [1.014, 9.515], P = 0.047). Depression was positively related to advanced disease (HR 3.347 [1.140, 9.832], P = 0.028), and negatively related to patients participating in clinical trials (HR 0.421 [0.180, 0.985], P = 0.046) and the education degree of FCs (HR 0.355 [0.149, 0.843], P = 0.019). MCS was positively associated with patients participating in clinical trials (ß = 5.067, 95% CI [0.817, 9.317], P = 0.020) and negatively associated with advanced disease (ß = -8.055, 95% CI [-19.804, 6.528], P = 0.002). Conclusion: The FCs of the cancer patients who participated in clinical trials showed a comparable worrying situation of anxiety and depression to the FCs of regular cancer patients. This indicates that more concern and attention should be given to this population, and further study on them is warranted.