Differences in sex- and age-associated mortality in patients with anti-MDA5-positive dermatomyositis.

OBJECTIVES: The effect of sex and age on the outcomes of patients with anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (MDA5+ DM) remains unclear. This study aimed to investigate the impact of sex and age on the prognosis of patients with MDA5+ DM. METHODS: We included 251 patients (women, 156; men, 95), who were newly diagnosed with MDA5+ DM between 2014 and 2021. The outcome was 6-month all-cause mortality after the diagnosis of interstitial lung disease. Cox regression analysis was used to assess the mortality. Adjusted restricted cubic spline analysis was performed to explore the non-linear relationship between age and outcomes. RESULTS: The 6-month mortality rates of women and men were 36.5% and 46.3%, respectively. Multivariate Cox regression revealed that ≥60 years of age was significantly associated with the risk of death (hazard ratio, 2.43; 95% confidence interval, 1.02-5.78). The trend of the risk of 6-month mortality in men was relatively flat until 54 years and increased rapidly afterwards (hazard ratio, 1.14; 95% confidence interval, 1.01-1.29). In contrast, the 6-month mortality rate showed a low linear increasing trend with age among females. CONCLUSIONS: Patients with MDA5+ DM, who received contemporary treatment, had unfavourable outcomes. The 6-month mortality risk increased with age, particularly in male patients aged >54 years.

Forced vital capacity predicts the survival of interstitial lung disease in anti-MDA5 positive dermatomyositis: a multi-centre cohort study.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) positive DM is a life-threatening disease often complicated with rapidly progressive interstitial lung disease (ILD). This study aimed to establish and validate a clinical prediction model for 6-month all-cause mortality in Chinese patients with anti-MDA5 positive DM-ILD. METHODS: We conducted a retrospective observational study using a single-centre derivation cohort and a multicentre validation cohort. Hospitalized DM patients with positive anti-MDA5 antibody and ILD course ≤3 months on admission were included. Patients' baseline characteristics were described and compared between the deceased and survivors by univariable Cox regression. Optimal cut-off values were defined by the 'survminer' R package for significant continuous variables. Independent prognostic factors were determined by the final multivariable Cox regression model chosen by backward stepwise algorithm, which could be reproduced in both cohorts. The Kaplan-Meier survival analyses based on the derived predictor were conducted. RESULTS: A total of 184 and 81 eligible patients were included with a cumulative 40.8 and 40.7% 6-month mortality in the derivation and validation cohorts, respectively. Based on multivariable Cox regression, the prognostic factor at baseline was identified and validated as three-category forced vital capacity (FVC)%: FVC% ≥50%, FVC% <50%, unable to perform. This significantly distinguishes three risk stages with mortalities of 15.3, 46.8, 97.4% in the derivation cohort, and 14.9, 58.3, 86.4 in the validation cohort, respectively (all P <0.05). CONCLUSION: The validated FVC%-based categorical predictor in anti-MDA5 positive DM-ILD is helpful for risk stratification in clinical practice and might facilitate cohort enrichment for future trials.

The Development of Vanadyl Phosphate Cathode Materials for Energy Storage Systems: A Review.

Various cathode materials have been proposed for high-performance rechargeable batteries. Vanadyl phosphate is an important member of the polyanion cathode family. VOPO4 has seven known crystal polymorphs with tunneled or layered frameworks, which allow facile cation (de)intercalations. Two-electron transfer per formula unit can be realized by using VV /VIV and VIV /VIII redox couples. The electrochemical performance is closely related to the structures of VOPO4 and the types of inserted cations. This Review outlines the crystal structures of VOPO4 polymorphs and their lithiated phases. The research progress of vanadyl phosphate cathode materials for different energy storage systems, including lithium-ion batteries, sodium-ion batteries, potassium-ion batteries, multivalent batteries, and supercapacitors, as well as the related mechanism investigations are summarized. It is hoped that this Review will help with future directions of using vanadyl phosphate materials for energy storage.

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort.

OBJECTIVES: To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. RESULTS: Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). CONCLUSIONS: Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice.

Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model.

OBJECTIVES: To identify the predictive clinical characteristics and establish a prediction model for the progression of mild interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). METHODS: Patients with SSc from two independent prospective cohorts were included in this observational study. All patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria, had mild ILD at baseline diagnosed by High-Resolution Computed Tomography (HRCT), available baseline and ≥1 annual follow-up pulmonary function tests and no concomitant pulmonary hypertension or airflow obstruction. ILD progression was defined as a relative decrease in forced vital capacity (FVC)%≥15%, or FVC%≥10% combined with diffusing capacity for carbon monoxide %≥15% at 1-year follow-up. Candidate predictors for multivariate logistic regression were selected by expert opinion based on clinical significance. A prediction model for ILD progression was established in the derivation cohort and validated in the multinational validation cohort. RESULTS: A total of 25/98 and 25/117 patients with SSc showed ILD progression in the derivation cohort and the validation cohort, respectively. Lower SpO2 after 6 min walk test (6MWT) and arthritis ever were identified as independent predictors for ILD progression in both cohorts. The optimal cut-off value of SpO2 after 6MWT for predicting ILD progression was determined as 94% by receiver operating characteristic curve analysis. The derived SPAR model combining both predictors (SPO2 and ARthritis) increased the prediction rate from 25.5% to 91.7% with an area under the curve (95% CI) of 0.83 (0.73 to 0.93). CONCLUSIONS: The evidence-based SPAR prediction model developed in our study might be helpful for the risk stratification of patients with mild SSc-ILD in clinical practice and cohort enrichment for future clinical trial design.

The critical role of IL-6 in the pathogenesis of Takayasu arteritis.

OBJECTIVES: To investigate T cell subsets and immune cytokine profiles in untreated Takayasu arteritis (TAK) patients and the underlying immunopathological mechanism. METHODS: We enrolled 50 untreated TAK patients and 40 age-matched controls (20 healthy controls, 20 untreated SLE patients). Enzyme-linked immunosorbent assays (ELISAs) were used to define cytokine profiles in all patients, and flow cytometry was performed for 9 TAK patients and 12 healthy controls. Hematoxylin and eosin (Handamp;E) staining and immunohistochemistry (IHC) were performed in aortic tissues of 9 TAK and 9 atherosclerosis patients; clinical data were also collected. RESULTS: Circulating CD4(+) T cells were more frequent in TAK patients (p<0.05). Frequencies of Th1, Th2, and Th17 cells were higher, whereas Treg cells were reduced in TAK. Significantly higher levels of IL-6 and lower levels of IFN-γ, IL-4, and IL-17 were detected in TAK patients (p<0.05). By H & E staining, thickened vascular walls with proliferation of collagen fibre were observed in most patients. Inflammatory sites with infiltrating macrophages, lymphocytes, and neutrophils were located in adventitia. IHC revealed T cells (mainly CD4(+) T cells) in vascular lesions. Additionally, IL-6 was positive throughout the vascular wall in most specimens, whereas IFN-γ, IL-12, and IL-17 were detected in inflammatory sites of active patients. IL-6 levels were positively related to ESR, CRP, and Kerr scores (p<0.05). CONCLUSIONS: Significantly increased levels of IL-6 were detected in peripheral blood and aortic tissues of untreated patients. IL-6 might be a sensitive biomarker to assess disease activity and could be critical in the immunopathogenesis of TAK.

Anti-synthetase syndrome is associated with a higher risk of hospitalization among patients with idiopathic inflammatory myopathy and COVID-19.

Background: Data with fine granularity about COVID-19-related outcomes and risk factors were still limited in the idiopathic inflammatory myopathies (IIMs) population. This study aimed to investigate clinical factors associated with hospitalized and severe COVID-19 in patients with IIMs, particularly those gauged by myositis-specific antibodies. Methods: This retrospective cohort study was conducted in the Renji IIM cohort in Shanghai, China, under an upsurge of SARS-CoV-2 omicron variant infections from December 2022 to January 2023. Clinical data were collected and analyzed by multivariable logistic regression to determine risk factors. High-dimensional flow cytometry analysis was performed to outline the immunological features. Results: Among 463 infected patients in the eligible cohort (n=613), 65 (14.0%) were hospitalized, 19 (4.1%) suffered severe COVID-19, and 10 (2.2%) died. Older age (OR=1.59/decade, 95% CI 1.18 to 2.16, p=0.003), requiring family oxygen supplement (2.62, 1.11 to 6.19, 0.028), patients with anti-synthetase syndrome (ASyS) (2.88, 1.12 to 7.34, 0.027, vs. other dermatomyositis), higher IIM disease activity, and prednisone intake >10mg/day (5.59, 2.70 to 11.57, <0.001) were associated with a higher risk of hospitalization. Conversely, 3-dose inactivated vaccination reduced the risk of hospitalization (0.10, 0.02 to 0.40, 0.001, vs. incomplete vaccination). Janus kinase inhibitor (JAKi) pre-exposure significantly reduced the risk of severe COVID-19 in hospitalized patients (0.16, 0.04 to 0.74, 0.019, vs. csDMARDs). ASyS patients with severe COVID-19 had significantly reduced peripheral CD4+ T cells, lower CD4/CD8 ratio, and fewer naive B cells but more class-switched memory B cells compared with controls. Conclusion: ASyS and family oxygen supplement were first identified as risk factors for COVID-19-related hospitalization in patients with IIMs. JAKi pre-exposure might protect IIM patients against severe COVID-19 complications.

Zinc-dual-halide complexes suppressing polyhalide formation for rechargeable aqueous zinc-halogen batteries.

Aqueous zinc-halogen batteries suffer from poor coulombic efficiency and short cycle life owing to the formation and dissolution of polyhalides in electrolytes. Herein, we apply a zinc-dual-halide complex strategy to confine free halides and suppress polyhalide formation. The high stabilities of zinc-dual-halide complexes are identified to be essential for effective confinement. The resulting Zn-Br2 and Zn-I2 cells deliver excellent rate capability and cycling stability, as well as high coulombic efficiency and energy efficiency.

Ferroptosis signaling promotes the release of misfolded proteins via exosomes to rescue ER stress in hepatocellular carcinoma.

Dysfunction of the ubiquitin‒proteasome system can induce sustained endoplasmic reticulum stress (ERS) and subsequent cell death. However, malignant cells have evolved multiple mechanisms to evade sustained ERS. Therefore, identification of the mechanisms through which tumor cells develop resistance to ERS is important for the therapeutic exploitation of these cells for drug-resistant tumors. Herein, we found that proteasome inhibitors could induce ERS, activate ferroptosis signaling, and thereby induce the adaptive tolerance of tumor cells to ERS. Mechanistically, the activation of ferroptosis signaling was found to promote the formation and secretion of exosomes containing misfolded and unfolded proteins, which resulted in rescuing ERS and promoting tumor cell survival. The inhibition of ferroptosis signaling synergized with bortezomib, a clinically used proteasome inhibitor, to suppress the viability of hepatocellular carcinoma cells in vitro and in vivo. The present findings reveal that ERS resistance can be driven by an ERS-ferroptosis signaling-exosome pathway and have important clinical implications for intracellular signaling, ER homeostasis and drug-resistant cancer therapy.

A High Potential Polyanion Cathode Material for Rechargeable Mg-Ion Batteries.

The development of Mg-ion batteries is hindered by the lack of cathode materials that allow facile and reversible Mg2+ intercalation at high potential. Herein, the authors present a polyanion cathode material of K2 (VO)2 (HPO4 )2 (C2 O4 )⋅4.5H2 O (KVPCH) for Mg-ion batteries. The inductive effect of polyanions ensures the high redox potential of the vanadium centers. In addition, the material contains structural water located between the layers. It helps with Mg2+ desolvation at the electrode-electrolyte interface and facilitates its diffusion in the structure, as confirmed by experimental analysis and theoretical calculations. Thanks to those factors, the KVPCH electrode presents excellent Mg storage capability at room temperature. It delivers 121 mAh g-1 capacity at 1C with a high average discharge potential of 0.16 V versus Ag/Ag+ (3.2 V vs Mg/Mg2+ ). A capacity retention of 87% is realized after 1500 cycles at 5C. A rocking-chair Mg-ion full cell is also demonstrated with the KVPCH cathode and a MoOx anode, which achieves 46 mAh g-1 capacity (based on the total active material mass of two electrodes). This work would bring effective paths for the design of cathode materials for Mg-ion batteries.

An Anti-Aromatic Covalent Organic Framework Cathode with Dual-Redox Centers for Rechargeable Aqueous Zinc Batteries.

Covalent organic frameworks (COFs) are promising cathode candidates with high structural stability. However, they contain redox inactive linkages and experience low redox potential. Herein, a full anti-aromatic microporous COF cathode material of TAQ-BQ is designed for aqueous zinc batteries. The anti-aromatic conjugation effectively lowers the energy level of the lowest unoccupied molecular orbital as revealed by theoretical calculations, which corresponds to an elevated redox potential. Besides, the structure contains imino active sites at the linkages, in addition to carbonyl at the active parts. As a result, the TAQ-BQ cathode exhibits a voltage of 1.53 V/1.54 V and between 1.35 and 0.45 V in zinc cells. It delivers 208 mAh g-1 capacity at 0.1 A g-1 and maintains 136 mAh g-1 at 2 A g-1. Stable cycling is realized for 1000 cycles with 87% capacity retention. The co-de/insertion of Zn2+ and protons is identified for energy storage. Our work reveals the promises of COF cathode materials for aqueous zinc batteries.

Trisomy 8 Associated Clonal Cytopenia Featured With Acquired Auto-Inflammation and Its Response to JAK Inhibitors.

Objects: It has been recognized the nexus between trisomy 8 and auto-inflammatory features in myelodysplasia syndrome (MDS). Recent research about VEXAS syndrome proved clonal hematopoiesis could interfere with innate immune system far before occurrence of hematological malignancies. We reported a case series of clonal cytopenia with auto-inflammatory features in trisomy 8 patients. Methods: A total of six patients with isolated trisomy 8 excluded from MDS was retrospectively collected from the Department of Rheumatology, Renji Hospital, Shanghai. The clinical presentations and treatment outcomes were presented. Results: We report patients with trisomy 8 shared the auto-inflammatory features of recurrent fever, arthralgia, gastrointestinal involvement, and elevated inflammatory markers, especially hyperferritinemia, in addition to hematological findings such as macrocytic anemia and cytopenia of other lineages but without myelodysplasia. The symptoms of this disorder responded to the treatment of glucocorticoids but difficult to taper. JAK inhibitors were introduced to four patients with enhanced response along with glucocorticoids sparing effect and good tolerance. Conclusion: Clonal cytopenia harboring trisomy 8 presenting with auto-inflammatory features was identified. JAK inhibitor may be a promising anti-inflammatory option.

Major infections in newly diagnosed systemic lupus erythematosus: an inception cohort study.

OBJECTIVE: To evaluate the risk of major infections and the relationship between major infections and mortality in patients with newly diagnosed SLE. METHODS: A newly diagnosed (<3 months) hospitalised Systemic Lupus Inception Cohort (hSLIC) in our centre during 1 January 2013 and 1 November 2020 was established. All patients were followed up for at least 1 year or until death. Patient baseline characteristics were collected. Major infection events were recorded during follow-up, which were defined as microbiological/clinical-based diagnosis treated with intravenous antimicrobials. The cohort was further divided into a training set and a testing set. Independent predictors of major infections were identified using multivariable logistic regression analysis. Kaplan-Meier survival analyses were conducted. RESULTS: Among the 494 patients enrolled in the hSLIC cohort, there were 69 documented episodes of major infections during the first year of follow-up in 67 (14%) patients. The major infection events predominantly occurred within the first 4 months since enrolment (94%, 65/69) and were associated with all-cause mortality. After adjustments for glucocorticoid and immunosuppressant exposure, a prediction model based on SLE Disease Activity Index >10, peripheral lymphocyte count <0.8×109/L and serum creatinine >104 µmol/L was established to identify patients at low risk (3%-5%) or high risk (37%-39%) of major infections within the first 4 months. CONCLUSIONS: Newly onset active SLE is susceptible to major infections, which is probably due to underlying profound immune disturbance. Identifying high-risk patients using an appropriate prediction tool might lead to better tailored management and better outcome.

The back-deposition of dissolved Mn2+ to MnO2 cathodes for stable cycling in aqueous zinc batteries.

The Mn2+ dissolution of MnO2 cathode materials causes rapid capacity decay in aqueous zinc batteries. We herein show that the dissolved Mn2+ can be deposited back to the cathode with the aid of a suitable conductive agent. The active material is thus retained for energy storage, and this MnO2/Mn2+ redox process also provides capacity. In the Mn2+ free ZnSO4 electrolyte, MnO2 delivers 325 mA h g-1 capacity at 0.1 A g-1, and 90.4% capacity retention is achieved after 3000 cycles at 5 A g-1. Our work demonstrates an effective strategy to realize stable cycling of MnO2 cathodes in aqueous zinc batteries without Mn2+ additives.