Prognostic analysis of MDA5-associated clinically amyopathic dermatomyositis with interstitial lung disease.

OBJECTIVE: To investigate the prognostic factors of patients with anti-melanoma differentiation-associated gene 5 (MDA5) positive clinically amyopathic dermatomyositis (CADM) and interstitial lung disease (ILD). METHODS: A retrospective analysis was conducted on clinical data of 125 patients with anti-MDA5 + CADM-ILD collected from 10 branches in eastern China between December 2014 and December 2022. Prognostic factors were analyzed using χ2 test, Log-rank test, COX and logistic regression analysis. RESULTS: In this cohort, 125 anti-MDA5 + CADM-ILD patients exhibited a rapidly progressive interstitial lung disease (RPILD) incidence of 37.6%, and an overall mortality rate of 24.8%. One patient was lost to follow-up. After diagnosis of RPILD, a mortality rate of 53.2% occurred in patients died within 3 months, and that of 5.6% appeared in those who survived for more than 3 months. Multiple factor analysis revealed that C-reactive protein (CRP) ≥ 10 mg/L (p = 0.01) and recombinant human tripartite motif containing 21 (Ro52) (+) (p = 0.003) were associated with a higher risk of RPILD in anti-MDA5 + CADM-ILD patients; CRP ≥ 10 mg/L (p = 0.018) and the presence of RPILD (p = 0.003) were identified as the factors influencing survival time in these patients, while arthritis was the protective factor (p = 0.016). CONCLUSION: Patients with anti-MDA5 + CADM-ILD will have a higher mortality rate, and the initial 3 months after diagnosis of RPILD is considered the risk window for the dismal prognosis. Patients with CRP ≥ 10 mg/L, Ro52 (+) and RPILD may be related to a shorter survival time, while patients complicated with arthritis may present with relatively mild conditions.

Elevated serum B-cell activator factor levels predict rapid progressive interstitial lung disease in anti-melanoma differentiation associated protein 5 antibody positive dermatomyositis.

BACKGROUND: Rapid progressive interstitial lung disease (RP-ILD) is the leading cause of anti-melanoma differentiation associated protein 5 antibody positive dermatomyositis (anti-MDA5+DM) related death. Elevated serum B-cell activating factor (BAFF) levels have been implicated in connective tissue diseases associated ILD. Here, we evaluate whether BAFF could be a prognostic biomarker for predicting RP-ILD in anti-MDA5+DM patients. METHODS: Serums were collected from 39 patients with anti-MDA5+DM (20 with RP-ILD and 19 with non-RP-ILD), 20 antisynthase syndrome (ASS) patients and 20 healthy controls (HC). BAFF concentration was measured by an enzyme-linked immunosorbent assay. RESULTS: Serum BAFF level was higher in anti-MDA5+DM patients than those in ASS patients and HC (3882.32 ± 1880.09 vs. 2540.89 ± 1403.04 and 2486.28 ± 767.97 pg/mL, p = 0.0056 and 0.0038, respectively). Within anti-MDA5+DM groups, RP-ILD patients exhibited higher BAFF concentration than non-RP-ILD group (4549.78 ± 1839.97 vs. 3297.28 ± 1794.69 pg/mL, p = 0.04). The BAFF concentration was positively correlated with levels of C-reactive protein (CRP), dehydrogenase (LDH) and cytokeratin (CK) in anti-MDA5+DM patients (r = 0.350, p = 0.035; r = 0.393, p = 0.016; r = 0.518, p = 0.001; respectively). The best cut-off value of BAFF concentration was 2971.5 pg/mL by ROC curve (AUC area = 0.690, p = 0.045) and BAFF > 2971.5 pg/mL was an independent risk factor for RP-ILD using multivariate analysis (OR = 9.389, 95% CI = 1.609-54.769; p = 0.013). CONCLUSIONS: Serum BAFF could be a useful prognostic biomarker for early detecting RP-ILD risk in anti-MDA5+DM patients.

Rapidly progressive interstitial lung disease risk prediction in anti-MDA5 positive dermatomyositis: the CROSS model.

Background: The prognosis of anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+DM) is poor and heterogeneous. Rapidly progressive interstitial lung disease (RP-ILD) is these patients' leading cause of death. We sought to develop prediction models for RP-ILD risk in anti-MDA5+DM patients. Methods: Patients with anti-MDA5+DM were enrolled in two cohorts: 170 patients from the southern region of Jiangsu province (discovery cohort) and 85 patients from the northern region of Jiangsu province (validation cohort). Cox proportional hazards models were used to identify risk factors of RP-ILD. RP-ILD risk prediction models were developed and validated by testing every independent prognostic risk factor derived from the Cox model. Results: There are no significant differences in baseline clinical parameters and prognosis between discovery and validation cohorts. Among all 255 anti-MDA5+DM patients, with a median follow-up of 12 months, the incidence of RP-ILD was 36.86%. Using the discovery cohort, four variables were included in the final risk prediction model for RP-ILD: C-reactive protein (CRP) levels, anti-Ro52 antibody positivity, short disease duration, and male sex. A point scoring system was used to classify anti-MDA5+DM patients into moderate, high, and very high risk of RP-ILD. After one-year follow-up, the incidence of RP-ILD in the very high risk group was 71.3% and 85.71%, significantly higher than those in the high-risk group (35.19%, 41.69%) and moderate-risk group (9.54%, 6.67%) in both cohorts. Conclusions: The CROSS model is an easy-to-use prediction classification system for RP-ILD risk in anti-MDA5+DM patients. It has great application prospect in disease management.

Proteomic profiling identifies SPP1 associated with rapidly progressive interstitial lung disease in anti-MDA5-positive dermatomyositis.

BACKGROUND: Anti-melanoma differentiation-associated gene five antibody positive (MDA5+) dermatomyositis (DM) is significantly associated with rapidly progressive interstitial lung disease (RP-ILD). Early detection of RP-ILD remains a major challenge. This study aims to identify and validate prognostic factors for RP-ILD in MDA5+ DM patients. METHODS: Plasma samples from 20 MDA5+ DM patients and 10 healthy controls (HC) were collected for proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The proteins of interest were validated in independent samples (20 HC, 20 MDA5+ DM with RP-ILD, and 20 non-RP-ILD patients) with enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 413 differentially expressed proteins (DEPs) were detected between the MDA5+ DM patients and HC. When comparing DEPs between RP-ILD and non-RP-ILD patients, 79 proteins were changed in RP-ILD patients, implicating acute inflammatory response, coagulation, and complement cascades. Six candidate biomarkers were confirmed with ELISA. Secreted phosphoprotein 1 (SPP1), serum amyloid A1 (SAA1), and Kininogen 1 (KNG1) concentrations were significantly elevated in RP-ILD patients than those in non-RP-ILD patients and HC. In the different clinical subgroups, SPP1 was particularly elevated in the high-risk RP-ILD subgroup of MDA5+ DM. CONCLUSION: This study provides novel insights into the pathogenesis of RP-ILD development in MDA5+ DM and suggests the plasma protein SPP1 could serve as a potential blood biomarker for RP-ILD early warning.

Characteristics of iron (hydr)oxides and Cr(VI) retention mechanisms in soils from tropical and subtropical areas of China.

Though both iron (hydr)oxides and soil organic matter (SOM) significantly influence heavy metal behaviors in soils, studies on the characteristics of natural minerals and the synergic effects of the two on Cr(VI) transformation are limited. This study investigated Cr(VI) retention mechanisms in four soils from tropical and subtropical regions of China based on a comprehensive characterization of Fe (hydr)oxides. These soils exhibited varying quantities of hematite, ferrihydrite and goethite, with distinct Al substitution levels and varied exposed crystallographic facets. Adsorption experiments revealed a positive correlation between Fe (hydr)oxide content and Cr(VI) fixation amount on colloid, which was influenced by the mineral types, Al substitution levels and facet exposures. Further, Cr(VI) was sequestered on soil by adsorption and reduction. In soils enriched with crystalline Fe (hydr)oxides, Cr(VI) reduction was primarily governed by SOM, while in soils enriched with poorly crystalline Fe (hydr)oxides, mineral-associated Fe(II) also contributed to Cr(VI) reduction. Aging experiments demonstrated that SOM and mineral-associated Fe(II) expedited Cr (VI) passivation and diminished the Cr leaching. These results improve our understanding of natural Fe (hydr)oxide structures and their impact on Cr(VI) behavior in soils, and shed light on complex soil-contaminant interactions and remediation of Cr(VI) polluted soils.

[Interaction and Transport Characteristics of Lead and Cadmium in Different Soil-wheat Systems].

In this study, four groups of lead(Pb) and cadmium(Cd) combined treatments with different concentration ratios were set up in Hailun black soil, Xianning brown-red soil, and Changwu Heilu soil, and wheat(Zhengmai 9023) was planted for a five-month pot experiment to analyze the Pb-Cd interaction behavior on heavy metal bioaccumulation in wheat under three soil-wheat systems. The low pH brown-red soil had the highest water-soluble Cd and Pb contents with significant Pb-Cd interactions in the soil, whereas the black soil with high organic matter and Heilu soil with high calcium carbonate content exhibited lower Cd and Pb activities. Among the three soils, wheat height and dry weight showed the poorest growth performance in the Heilu soil, but the wheat height increased by 2.68-8.49 cm compared with that in the control under the Pb-Cd combined treatment, whereas Pb-Cd interaction had the least effect on wheat height and dry weight in black soil and inhibited the growth of wheat in the brown-red soil. In the transport process of Cd or Pb in wheat, Pb-Cd interaction showed quite different effects in the three soil-wheat systems. Under the 125 mg·kg-1 and 250 mg·kg-1 Pb treatments, the Pb content in wheat grain planted in brown-red soil significantly increased by 73.2% and 19.1% with the addition of Cd, respectively, and therefore there was a synergistic effect between Pb and Cd. Under the 0.3 mg·kg-1 and 0.6 mg·kg-1 Cd treatments, the Cd content in wheat grains planted in black soil decreased by 51% and 33% with the addition of Pb, respectively; therefore, there was an antagonist effect between Pb and Cd. In the Heilu soil, a synergistic effect of Cd on Pb transport in wheat leaves was only observed under high Pb treatment. Therefore, pH and organic matter content were the key factors that determined the interaction behavior of Pb and Cd. The wheat food security risk of Pb and Cd combined pollution was higher than that of single metal pollution in acidic brown-red soil and lower in high organic matter black soil, whereas the interaction of Pb and Cd had little impact on the wheat food security risk of alkaline Heilu soil.

Integrating bioinformatic resources to identify characteristics of rheumatoid arthritis-related usual interstitial pneumonia.

BACKGROUND: Rheumatoid arthritis (RA) is often accompanied by a common extra-articular manifestation known as RA-related usual interstitial pneumonia (RA-UIP), which is associated with a poor prognosis. However, the mechanism remains unclear. To identify potential mechanisms, we conducted bioinformatics analysis based on high-throughput sequencing of the Gene Expression Omnibus (GEO) database. RESULTS: Weighted gene co-expression network analysis (WGCNA) analysis identified 2 RA-positive related modules and 4 idiopathic pulmonary fibrosis (IPF)-positive related modules. A total of 553 overlapped differentially expressed genes (DEG) were obtained, of which 144 in the above modules were further analyzed. The biological process of "oxidative phosphorylation" was found to be the most relevant with both RA and IPF. Additionally, 498 up-regulated genes in lung tissues of RA-UIP were screened out and enriched by 7 clusters, of which 3 were closely related to immune regulation. The analysis of immune infiltration showed a characteristic distribution of peripheral immune cells in RA-UIP, compared with IPF-UIP in lung tissues. CONCLUSIONS: These results describe the complex molecular and functional landscape of RA-UIP, which will help illustrate the molecular pathological mechanism of RA-UIP and identify new biomarkers and therapeutic targets for RA-UIP in the future.

Solutions for an efficient arsenite oxidation and removal from groundwater containing ferrous iron.

Manganese (Mn) oxides are extensively used to oxidize As(III) present in ground, drinking, and waste waters to the less toxic and more easily removable As(V). The common presence of multiple other cations in natural waters, and more especially of redox-sensitive ones such as Fe2+, may however significantly hamper As(III) oxidation and its subsequent removal. The present work investigates experimentally the influence of Mn(III) chelating agents on As(III) oxidation process in such environmentally relevant complex systems. Specifically, the influence of sodium pyrophosphate (PP), an efficient Mn(III) chelating agent, on As(III) oxidation by birnessite in the presence of Fe(II) was investigated using batch experiments at circum-neutral pH. In the absence of PP, competitive oxidation of Fe(II) and As(III) leads to Mn oxide surface passivation by Fe(III) and Mn(II/III) (oxyhydr)oxides, thus inhibiting As(III) oxidation. Addition of PP to the system highly enhances As(III) oxidation by birnessite even in the presence of Fe(II). PP presence prevents passivation of Mn oxide surfaces keeping As and Fe species in solution while lower valence Mn species are released to solution. In addition, reactive oxygen species (ROS), tentatively identified as hydroxyl radicals (•OH), are generated under aerobic conditions through oxygen activation by Fe(II)-PP complexes, enhancing As(III) oxidation further. The positive influence of Mn(III) chelating agents on As(III) oxidation most likely not only depend on their affinity for Mn(III) but also on their ability to promote formation of these active radical species. Finally, removal of As(V) through sorption to Fe (oxyhydr)oxides is efficient even in the presence of significant concentrations of PP, and addition of such Mn(III) chelating agents thus appears as an efficient way to enhance the oxidizing activity of birnessite in large-scale treatment for arsenic detoxification of groundwaters.

Postoperative intermittent pneumatic compression for preventing venous thromboembolism in Chinese lung cancer patients: a randomized clinical trial.

BACKGROUND: Postoperative lung cancer patients belong to the high-risk group for venous thromboembolism (VTE). The standardized preventive measures for perioperative VTE in lung cancer are not perfect, especially for the prevention and treatment of catheter-related thrombosis (CRT) caused by carried central venous catheters (CVCs) in lung cancer surgery. PATIENTS AND METHODS: This study included 460 patients with lung cancer undergoing video-assisted thoracic surgery (VATS) in our center from July 2020 to June 2021. Patients were randomized into two groups, and intraoperatively-placed CVCs would be carried to discharge. During hospitalization, the control group was treated with low-molecular-weight heparin (LMWH), and the experimental group with LMWH + intermittent pneumatic compression (IPC). Vascular ultrasound was performed at three time points which included before surgery, before discharge, and one month after discharge. The incidence of VTE between the two groups was studied by the Log-binomial regression model. RESULTS: CRT occurred in 71.7% of the experimental group and 79.7% of the control group. The multivariate regression showed that the risk of developing CRT in the experimental group was lower than in the control group (Adjusted RR = 0.889 [95%CI0.799-0.989], p = 0.031), with no heterogeneity in subgroups (P for Interaction > 0.05). Moreover, the fibrinogen of patients in the experimental group was lower than control group at follow-up (P = 0.019). CONCLUSION: IPC reduced the incidence of CRT during hospitalization in lung cancer patients after surgery. TRIAL REGISTRATION: No. ChiCTR2000034511.

How different is the remediation effect of biochar for cadmium contaminated soil in various cropping systems? A global meta-analysis.

Cadmium (Cd) poses great threats to human health as a major contaminant in agricultural soil. Biochar shows great potential in the remediation of agricultural soil. However, it remains unclear whether the remediation effect of biochar on Cd pollution is affected by various cropping systems. Here, this study used 2007 paired observations from 227 peer-reviewed articles and employed hierarchical meta-analysis to investigate the response of three types of cropping systems to the remediation of Cd pollution by using biochar. As a result, biochar application significantly reduced the Cd content in soil, plant roots and edible parts of various cropping systems. The decrease in Cd level ranged from 24.9% to 45.0%. The feedstock, application rate, and pH of biochar as well as soil pH and cation exchange capacity were dominant factors for Cd remediation effect of biochar, and their relative importance all exceeded 37.4%. Lignocellulosic and herbal biochar were found to be suitable for all cropping systems, while the effects of manure, wood and biomass biochar were limited in cereal cropping systems. Furthermore, biochar exhibited a more long-lasting remediation effect on paddy soils than on dryland. This study provides new insights into the sustainable agricultural management of typical cropping systems.

Prediction of cadmium bioavailability in the rice-soil system on a county scale based on the multi-surface speciation model.

Relative to total cadmium (Cd) content, bioavailable Cd in paddy soil is regarded as a more reasonable indicator for the risk of Cd bioaccumulation in rice. However, there is still a lack of approach to accurately predict the content of bioavailable Cd in paddy soil due to its heterogeneity and complexity. Here, multi-surface speciation model (MSM) was employed to predict the bioavailable Cd and Cd immobilization effect. Moreover, a precise remediation strategy was designed based on screening and scenario simulation of the sensitive factors with MSM. The results demonstrated that MSM can well predict Cd bioaccumulation risk in rice. The contribution of pH to Cd bioavailability was quantified under three analysis scenarios, accounting for 87.51% of the total variance of bioavailable Cd. In addition, the pH alert value (6.31 ± 0.52) for Cd risk was acquired for each rice field on a county scale. A precise map for the application amount of lime materials was constructed by taking CaCO3 (3.38-15.75 t ha-1) as a recommended economical and green immobilization agent. This study provides a potentially effective approach for risk assessment of Cd contamination in rice and important reference for precise Cd remediation in paddy soil.

Generic CD-MUSIC-eSGC model parameters to predict the surface reactivity of iron (hydr)oxides.

The surface reactivity of iron (hydr)oxides plays a crucial role in controlling their interfacial reactions, for which various surface complexation models have been developed. The diversity of mineralogical properties of iron (hydr)oxides has resulted in a redundancy of model parameters, which hampers the modeling of iron (hydr)oxides in soils and sediments, where goethite, hematite and ferrihydrite dominate the iron (hydr)oxide mass fraction. To capture their combined surface reactivity, optimized generic protonation parameters of the Charge Distribution-Multisite Complexation (CD-MUSIC) extended-Stern-Gouy-Chapman (eSGC) model were derived by reanalyzing literature datasets and tested with some newly synthesized iron (hydr)oxides. It was observed that the proton and monovalent ion affinity constants of the different iron (hydr)oxides were located in a narrow range. For the singly- and triply-coordinated hydroxyl sites the obtained generic log(affinity constants) were 8.3 and 11.7 for the protonation reaction and -0.5 for the reaction with the monovalent background ions. Their combination with fixed site densities of singly-/triply-coordinated hydroxyl sites of 3.45/2.70, 5.00/2.50, and 5.80/1.40 sites/nm2 for goethite, hematite, and ferrihydrite, respectively, provided good results. The Stern layer capacitances of the inner and outer Stern layers were set equal and could be acquired by an empirical correlation with the sample specific surface area (SSA). The CD-MUSIC-eSGC model with the generic model parameters enables good quality predictions of the proton reactivity of iron (hydr)oxides in 1:1 electrolyte solutions regardless of the sample heterogeneity. The advantages of the generic CD-MUSIC-eSGC model are twofold: (1) protonation of iron (hydr)oxides can be described without making use of spectroscopic measurements and proton titrations, and (2) the model calculations are greatly simplified.

Efficacy and safety of tofacitinib in Chinese patients with active psoriatic arthritis: a phase 3, randomised, double-blind, placebo-controlled study.

OBJECTIVES: Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, were evaluated in a 6-month, double-blind, phase 3 study in Chinese patients with active (polyarthritic) psoriatic arthritis (PsA) and inadequate response to ≥1 conventional synthetic disease-modifying antirheumatic drug. METHODS: Patients were randomised (2:1) to tofacitinib 5 mg twice daily (N=136) or placebo (N=68); switched to tofacitinib 5 mg twice daily after month (M)3 (blinded). PRIMARY ENDPOINT: American College of Rheumatology (ACR50) response at M3. Secondary endpoints (through M6) included: ACR20/50/70 response; change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI); ≥75% improvement in Psoriasis Area and Severity Index (PASI75) response, and enthesitis and dactylitis resolution. Safety was assessed throughout. RESULTS: The primary endpoint was met (tofacitinib 5 mg twice daily, 38.2%; placebo, 5.9%; p<0.0001). M3 ACR20/ACR70/PASI75 responses, and enthesitis and dactylitis resolution rates, were higher and HAQ-DI reduction was greater for tofacitinib 5 mg twice daily versus placebo. Incidence of adverse events (AEs)/serious AEs (M0-3): 68.4%/0%, tofacitinib 5 mg twice daily; 75.0%/4.4%, placebo. One death was reported with placebo→tofacitinib 5 mg twice daily (due to accident). One serious infection, non-serious herpes zoster, and lung cancer case each were reported with tofacitinib 5 mg twice daily; four serious infections and one non-serious herpes zoster case were reported with placebo→tofacitinib 5 mg twice daily (M0-6). No non-melanoma skin cancer, major adverse cardiovascular or thromboembolism events were reported. CONCLUSION: In Chinese patients with PsA, tofacitinib efficacy was greater than placebo (primary and secondary endpoints). Tofacitinib was well tolerated; safety outcomes were consistent with the established safety profile in PsA and other indications. TRIAL REGISTRATION NUMBER: NCT03486457.

Coexistence of Anti-Ro52 Antibodies in Anti-MDA5 Antibody-Positive Dermatomyositis Is Highly Associated With Rapidly Progressive Interstitial Lung Disease and Mortality Risk.

OBJECTIVE: Interstitial lung disease (ILD) is a common extramuscular complication contributing to significant morbidity and mortality in patients with dermatomyositis (DM) who are positive for antimelanoma differentiation-associated gene 5 antibody (anti-MDA5+). We conducted this study to investigate the association of anti-Ro52 antibodies with clinical characteristics and prognosis in patients with anti-MDA5+ DM. METHODS: We assessed a cohort of 246 patients with anti-MDA5+ DM. To calculate hazard ratios and 95% CIs for rapidly progressive ILD (RP-ILD) and death while controlling for potential confounders, variables selected by univariate Cox regression analysis were included in a multivariate Cox regression model with the stepwise forward-selection method. A 2-tailed analysis with P < 0.05 was considered to be statistically significant. RESULTS: A total of 246 patients with anti-MDA5+ DM were enrolled; 70 patients were male, and the patient group had an average age of 53.1 (12.4) years. Anti-Ro52 was present in 64.2% (158/246) patients. Patients with anti-MDA5+ DM who were positive for anti-Ro52 had a higher rate of RP-ILD (log-rank P < 0.001) and a higher mortality rate (log-rank P = 0.01). For patients with anti-MDA5+ DM who were positive for anti-Ro52, those with a short disease course and high inflammation were at increased risk of RP-ILD and death. The appearance of active rash was an independent protective factor of death. CONCLUSION: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5+ DM, and their coexistence correlated with a higher rate of RP-ILD and mortality. Patients with a short disease course, with increased inflammation, and without rash were more likely to have a poor prognosis.

Identification of Three Different Phenotypes in Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis Patients: Implications for Prediction of Rapidly Progressive Interstitial Lung Disease.

OBJECTIVE: There is substantial heterogeneity among the phenotypes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis (DM), hindering disease assessment and management. This study aimed to identify distinct phenotype groups in patients with anti-MDA5+ DM and to determine the utility of these phenotypes in predicting patient outcomes. METHODS: A total of 265 patients with anti-MDA5+ DM were retrospectively enrolled in the study. An unsupervised hierarchical cluster analysis was performed to characterize the different phenotypes. RESULTS: Patients were stratified into 3 clusters characterized by markedly different features and outcomes. Cluster 1 (n = 108 patients) was characterized by mild risk of rapidly progressive interstitial lung disease (RPILD), with the cumulative incidence of non-RPILD being 85.2%. Cluster 2 (n = 72 patients) was characterized by moderate risk of RPILD, with the cumulative incidence of non-RPILPD being 73.6%. Patients in cluster 3 (n = 85 patients), which was characterized by a high risk of RPILD and a cumulative non-RPILD incidence of 32.9%, were more likely than patients in the other 2 subgroups to have anti-Ro 52 antibodies in conjunction with high titers of anti-MDA5 antibodies. All-cause mortality rates of 60%, 9.7%, and 3.7% were determined for clusters 3, 2, and 1, respectively (P < 0.0001). Decision tree analysis led to the development of a simple algorithm for anti-MDA5+ DM patient classification that included the following 8 variables: age >50 years, disease course of <3 months, myasthenia (proximal muscle weakness), arthritis, C-reactive protein level, creatine kinase level, anti-Ro 52 antibody titer, and anti-MDA5 antibody titer. This algorithm placed patients in the appropriate cluster with 78.5% accuracy in the development cohort and 70.0% accuracy in the external validation cohort. CONCLUSION: Cluster analysis identified 3 distinct clinical patterns and outcomes in our large cohort of anti-MDA5+ DM patients. Classification of DM patients into phenotype subgroups with prognostic values may help physicians improve the efficacy of clinical decision-making.

Time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients: a cohort study of 272 cases in China.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 positive (anti-MDA5+) DM has a close relationship with rapidly progressive interstitial lung disease (RPILD) and is associated with high mortality. However, data regarding the time-dependent risk of RPILD and deaths during disease progression are limited. We conducted this study to investigate whether the risk of RPILD and death were time-dependent or not in anti-MDA5+ DM. METHODS: We assessed a cohort of 272 patients with anti-MDA5+ DM. The clinical characteristics of patients with anti-MDA5+ were collected, and COX regression was used to analyse independent risk factors for RPILD and death. We also described changes in risk of RPILD and death over time and their potential clinical implications. RESULTS: There were 272 anti-MDA5+ DM patients enrolled in this study. According to the multivariate cox regression analysis, short disease course, high CRP level, anti-Ro52 positive and anti-MDA5 titre (++∼+++) were independent risk factors of RPILD. High creatine kinase level, high CRP level and RPILD were independent risk factors for death, and >90% RPILD and 84% mortality occurred in the first 6 months after disease onset. Notably, the first 3 months is a particularly high-risk period, with 50% of RPILD and 46% of deaths occurring. Hazards regarding RPILD and mortality diminished over time during a median follow-up of 12 months. CONCLUSION: These results suggest significant, time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients, providing a cut-off time window to estimate disease progression and poor prognosis.

Environmental implications of interaction between humic substances and iron oxide nanoparticles: A review.

Goethite, hematite, ferrihydrite, and other iron oxides bind through various sorption reactions with humic substances (HS) in soils creating nano-, micro-, and macro-aggregates with a specific nature and stability. Long residence times of soil organic matter (SOM) have been attributed to iron-humic substance (Fe-HS) complexes due to physical protection and chemical stabilization at the organic-mineral interface. Humic acids (HA) and fulvic acids (FA) contain many acidic functional groups that interact with Fe oxides through different mechanisms. Due to the numerous interactions between mineral Fe and natural SOM, much research has led into a better identification and definition of HS. In this review, we first focus on the surface colloidal properties of Fe oxides and their reactivity toward HS. These minerals can be efficiently identified by usual techniques, such as XRD, FTIR spectroscopy, XAS, Mössbauer, diffuse reflectance spectroscopies (DRS), HRTEM, ATM, NanoSIMS. Second, we present the recent state of art regarding the adsorption/precipitation of HS onto iron mineral surfaces and their effects on binding metalloid and trace elements. Finally, we consider future research directions based on recent scientific literature, with particular focus on the ability of Fe nano-particles to increase Fe bioavailability, improve carbon sequestration, reduce greenhouse gas emissions, and decrease the impact of persistent organic and inorganic pollutants. The methodology in this field has rapidly developed over the last decade. However, new procedures to estimate the nature of Fe-HA bonds will be important contributions in clarifying the role of natural iron oxides in soil for carbon stabilization.

Alamandine, a new member of the renin-angiotensin system (RAS), attenuates collagen-induced arthritis in mice via inhibiting cytokine secretion in synovial fibroblasts.

Alamandine is a novel component of the renin-angiotensin system (RAS) as well as an important biologically active peptide. It has predominantly been studied in cardiovascular context. However, its role in rheumatoid arthritis (RA) remains unknown. Here we illustrated its effects on inflammatory cytokines production by synovial fibroblasts from RA and pathological changes in collagen-induced arthritis (CIA) mice. Alamandine (0.1, 1 and 10 µg/ml) did not affect the survival of the synovial fibroblasts, but decreased the migration and proinflammatory cytokines expression in TNF-α (10 ng/ml) stimulated cells in vitro. Additionally, alamandine selectively decreased phosphorylated-JNK expression induced by TNF-a stimulation in RA FLS. DBA/1 J mice were induced arthritis by a primary injection with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 21). Mice were then given alamandine intraperitoneally in saline (50 µg/kg/day) from days 21-42. Histology and multiplex immunobead assay showed that alamandine treatment inhibited the development of arthritis and reduced the joint damage. This effect was accompanied by the reduced inflammatory cytokines (IL-6, IL-23, IFN-γ) mRNA expression in local joints, the decreased TNF-α, IL-6, IL-17 and the increased IL-10 levels in the serum from alamandine administrated CIA mice. In conclusion, alamandine attenuates the development of arthritis by suppressing inflammatory cytokines expression in RA synovial fibroblasts via MAPK signaling pathway, suggesting a potential therapeutic role for RA.

Human SLE variant NCF1-R90H promotes kidney damage and murine lupus through enhanced Tfh2 responses induced by defective efferocytosis of macrophages.

OBJECTIVES: We previously identified a hypomorphic variant, p.Arg90His (p.R90H) of neutrophil cytosolic factor 1 (NCF1, a regulatory subunit of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 complex), as an putative causal variant for systemic lupus erythematosus (SLE), and established a knock-in (KI) H90 variant in the C57BL/6 background to study how this variant promotes lupus development. METHODS: Wild type (WT) and KI littermates were assessed for immune profiles and lupus-like features. Disease activity and renal damage of patients with SLE were assessed by systemic lupus erythematosus disease activity index (SLEDAI) and renal items of systemic lupus international collaborating clinics (SLICC), respectively. RESULTS: Compared with WT littermates, 5-week-old homozygous KI mice had reduced oxidative burst, splenomegaly, elevated type I interferon (IFN-I) scores, increased ratios of splenic follicular T helper 2 (Tfh2) to either T follicular regulatory (Tfr) or Tfh1 cells, increased ANA+ follicular, germinal centre and plasma cells without spontaneous kidney disease up to 1 year of age. Pristane treatment exacerbated the immune dysregulation and induced IFN-I-dependent kidney disease in 36-week-old H90 KI female mice. Decreased efferocytosis of macrophages derived from KI mice and patients with homozygous H90 SLE promoted elevated ratios of Tfh2/Tfr and Tfh2/Tfh1 as well as dysregulated humoral responses due to reduced voltage-gated proton channel 1 (Hv1)-dependent acidification of phagosome pH to neutralise the decreased electrogenic effect of the H90 variant, resulting in impaired maturation and phagosome proteolysis, and increased autoantibody production and kidney damage in mice and patients with SLE of multiple ancestries. CONCLUSIONS: A lupus causal variant, NCF1-H90, reduces macrophage efferocytosis, enhances Tfh2 responses and promotes autoantibody production and kidney damage in both mice and patients with SLE.

Up-Regulated Interleukin-10 Induced by E2F Transcription Factor 2-MicroRNA-17-5p Circuitry in Extrafollicular Effector B Cells Contributes to Autoantibody Production in Systemic Lupus Erythematosus.

OBJECTIVE: Elevated interleukin-10 (IL-10) levels in patients with systemic lupus erythematosus (SLE) have B cell-promoting effects, contributing to autoantibody production and tissue damage. We aimed to characterize up-regulated IL-10+ B cell subsets and dysregulated IL10 expression in SLE B cells for new therapeutic options. METHODS: Proportions of Th10 and IL-10+ B cell subsets in peripheral blood mononuclear cells (PBMCs) were assessed using flow cytometry. The IL10 3'-untranslated region (3'-UTR) dual-luciferase vector was constructed and cotransfected with small interfering RNA (siRNA), microRNA (miRNA) mimics, or miRNA inhibitors into Raji cells. Transcript levels were quantified using TaqMan assays. RESULTS: Culture conditions that induced IL-10+ Breg cells in healthy controls resulted in expansion of IL-10+ double-negative 2 (DN2; IgD-CD27-CD21-CD11c+) B cells in SLE PBMCs. Proportions of IL-10+ DN2, but not those of IL-10- DN2, correlated with disease activity and levels of antibodies to double-stranded DNA (dsDNA) (r = 0.60, P = 0.03 for cohort 1; r = 0.38, P = 0.03 for cohort 2), and were associated with high levels or seropositivity of anti-Sm (P = 0.03 for cohort 1; P = 0.01 for cohort 2) and IgG anticardiolipin (P < 0.01 for cohort 1; P = 0.02 for cohort 2) in SLE patients from 2 cohorts, of mainly African American subjects (cohort 1) and of Asian subjects (cohort 2). Proportions of Th10 (CD45RA-CXCR5-CXCR3+PD-1high CD4+) cells correlated with IL-10+ DN2 frequencies (r = 0.60, P < 0.01 for cohort 2), antinuclear antibody titers (r = 0.52, P = 0.01 for cohort 2), and proteinuria levels (r = 0.72, P < 0.01 for cohort 2) in SLE patients. Screening of predicted IL10 3'-UTR-targeting miRNAs in SLE B cells identified miRNA-17-5p (miR-17-5p) and miR-20a-5p, with their levels inversely correlated with IL10 (r = -0.47, P < 0.01 for miR-17-5p; r = -0.37, P = 0.03 for miR-20-5p) and transcription factor E2F2 (r = -0.48, P = 0.04 for miR-17-5p; r = -0.45, P = 0.05 for miR-20-5p). In Raji cells, knockdown of E2F2 expression resulted in increased levels of miR-17-5p and miR-20a-5p and decreased IL10 messenger RNA (mRNA) and protein levels, and overexpression and inhibition of miR-17-5p down-regulated and up-regulated, respectively, IL10 mRNA levels, suggesting regulation of IL10 expression by an E2F2-miR-17-5p loop. CONCLUSION: IL-10 promotes extrafollicular autoimmune responses in patients with active SLE, which might be dampened by targeting the E2F2-miR-17-5p circuitry.