Association between triglyceride-glucose index and carotid atherosclerosis in patients with psoriatic arthritis.

OBJECTIVE: To investigate the association of the triglyceride-glucose (TyG) index with atherosclerotic risk among patients with PsA. METHODS: This cross-sectional study included 165 consecutive PsA patients receiving carotid ultrasonography with integrated TyG index, calculated as ln [fasting triglycerides (mg/dl) × fasting glucose (mg/dl)/2]. Logistic regression models were applied to analyse the association of TyG index as continuous variables and tertiles with carotid atherosclerosis and carotid artery plaque. Fully adjusted model included sex, age, smoking, BMI, comorbidities and psoriatic-related variables. RESULTS: Overall, PsA patients with carotid atherosclerosis had substantially higher TyG index than those without [8.82 (0.50) vs 8.54 (0.55), P = 0.002]. The frequency of carotid atherosclerosis was increased with increases in TyG index tertiles, showing 14.8%, 34.5%, 44.6% for tertile 1, 2 and 3, respectively (P = 0.003). Multivariate logistic analyses showed that each 1-unit increase in TyG index was significantly associated with prevalent carotid atherosclerosis [unadjusted odds ratio (OR) 2.65 (1.39-5.05); fully adjusted OR 2.69 (1.02-7.11)]. Compared with patients in tertile 1 of TyG index, the unadjusted and fully adjusted OR for occurrence of carotid atherosclerosis were 4.64 (1.85-11.60) and 5.10 (1.54-16.93) in patients in tertile 3. Similarly, higher prevalent carotid artery plaque was observed with increasing TyG index [unadjusted OR 3.11 (1.54-6.26); fully adjusted OR 3.61 (1.15-11.38)] or in tertile 3 vs tertile 1 [unadjusted OR 10.20 (2.83-36.82); fully adjusted OR 17.89 (2.88-111.11)]. Additionally, TyG index provided incremental predictive capacity beyond established risk factors, shown by an increase in discrimination ability (all P < 0.001). CONCLUSIONS: TyG index was positively correlated with the burden of atherosclerosis in PsA patients, independent of traditional cardiovascular risk factors and psoriatic-related factors. These findings suggest that TyG index may be a promising atherosclerotic marker for the PsA population.

Single-Cell RNA Sequencing and Assay for Transposase-Accessible Chromatin Using Sequencing Reveals Cellular and Molecular Dynamics of Aortic Aging in Mice.

OBJECTIVE: The impact of vascular aging on cardiovascular diseases has been extensively studied; however, little is known regarding the cellular and molecular mechanisms underlying age-related vascular aging in aortic cellular subpopulations. Approach and Results: Transcriptomes and transposase-accessible chromatin profiles from the aortas of 4-, 26-, and 86-week-old C57/BL6J mice were analyzed using single-cell RNA sequencing and assay for transposase-accessible chromatin sequencing. By integrating the heterogeneous transcriptome and chromatin accessibility data, we identified cell-specific TF (transcription factor) regulatory networks and open chromatin states. We also determined that aortic aging affects cell interactions, inflammation, cell type composition, dysregulation of transcriptional control, and chromatin accessibility. Endothelial cells 1 have higher gene set activity related to cellular senescence and aging than do endothelial cells 2. Moreover, construction of senescence trajectories shows that endothelial cell 1 and fibroblast senescence is associated with distinct TF open chromatin states and an mRNA expression model. CONCLUSIONS: Our data provide a system-wide model for transcriptional and epigenetic regulation during aortic aging at single-cell resolution.

Roughening for Strengthening and Toughening in Monolayer Carbon Based Composites.

Three-dimensional (3D) aggregation of graphene is dramatically weak and brittle due primarily to the prevailing interlayer van der Waals interaction. In this report, motivated by the recent success in synthesis of monolayer amorphous carbon (MAC) sheets, we demonstrate that outstanding strength and large plastic-like strain can be achieved in layered 3D MAC composites. Both surface roughening and the ultracompliant nature of MACs count for the high strength and gradual failure in 3D MAC. Such properties are not seen when intact graphene or multiple stacked MACs are used as building blocks for 3D composites. This work demonstrates a counterintuitive mechanism that surface roughening due to initial defects and low rigidity may help to realize superb mechanical properties in 3D aggregation of monolayer carbon.

An AKT/PRMT5/SREBP1 axis in lung adenocarcinoma regulates de novo lipogenesis and tumor growth.

Protein kinase B (AKT) hyperactivation and de novo lipogenesis are both common in tumor progression. Sterol regulatory element-binding protein 1 (SREBP1) is the master regulator for tumor lipid metabolism, and protein arginine methyltransferase 5 (PRMT5) is an enzyme that can catalyze symmetric dimethyl arginine (SDMA) modification of the mature form of SREBP1 (mSREBP1) to induce its hyperactivation. Here, we report that SDMA-modified mSREBP1 (mSREBP1-SDMA) was overexpressed and correlated with Ser473-phosphorylated AKT (AKT-473P) expression and poor patient outcomes in human lung adenocarcinomas. Furthermore, patients with AKT-473P and mSREBP1-SDMA coexpression showed the worst prognosis. Mechanistic investigation revealed that AKT activation upregulated SREBP1 at both the transcriptional and post-translational levels, whereas PRMT5 knockdown reversed AKT signaling-mediated mSREBP1 ubiquitin-proteasome pathway stabilization at the post-translational level. Meanwhile, AKT activation promoted nuclear PRMT5 to the cytoplasm without changing total PRMT5 expression, and the transported cytoplasmic PRMT5 (cPRMT5) induced by AKT activation showed a strong mSREBP1-binding ability. Immunohistochemical assay indicated that AKT-473P and mSREBP1-SDMA were positively correlated with cPRMT5 in lung adenocarcinomas, and high cPRMT5 levels in tumors were associated with poor patient outcomes. Additionally, PRMT5 knockdown reversed AKT activation-induced lipid synthesis and growth advantage of lung adenocarcinoma cells both in vitro and in vivo. Finally, we defined an AKT/PRMT5/SREBP1 axis involved in de novo lipogenesis and the growth of lung cancer. Our data also support that cPRMT5 is a potential therapeutic target for hyperactive AKT-driven lung adenocarcinoma.

Dynamical trajectory of glucocorticoids tapering and discontinuation in patients with rheumatoid arthritis commencing glucocorticoids with csDMARDs: a real-world data from 2009 to 2020.

OBJECTIVE: To unravel the dynamical trajectory and features of glucocorticoids (GC) tapering and discontinuation in patients with rheumatoid arthritis (RA) commencing GC with concomitant conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). METHODS: We used data from longitudinal real-world Treat-to-TARget in RA cohort. Patients with RA who started GC and contaminant csDMARDs therapy were included. The changes in GC dose and disease activity were evaluated. GC discontinuation rate was analysed using Kaplan-Meier analysis. The relapse profile within 6 months after GC discontinuation was also analysed. RESULTS: A total of 207 patients with RA were included. During a median follow-up of 38.6 months, 124 patients discontinued GC. The median prednisolone dose of 10 (5-10) mg/day at initiation was reduced by 50% in the first 6 months and then more slowly, to zero by 48 months eventually. The cumulative probabilities of GC discontinuation were 9.7%, 26.6%, 48.0% and 58.6% at month 6, years 1, 2 and 3, with calculated median time to GC cessation of 27 months. In 110 DMARD-naïve patients, the corresponding cumulative probabilities of GC discontinuation were, respectively, 12.7%, 30.0%, 50.9% and 60.6%, with calculated median time to GC cessation of 24 months. Of the 124 patients who discontinued GC, adding other csDMARDs or concomitant csDMARDs increment was documented in 28.2% of them. Approximately half of 124 patients were in clinical remission at GC discontinuation. Within 6 months after GC withdrawal, 79.1% (91/115) of patients maintained relapse free. CONCLUSIONS: In patients with RA commencing GC besides csDMARDs, GC is feasibly discontinued with favourable control of disease activity in real-life setting, mostly without short-term flare. But the withdrawal time is far from reaching the recommended time frame, indicating the gap between real-world practice and current guidelines.

Low-dose glucocorticoids should be withdrawn or continued in systemic lupus erythematosus? A systematic review and meta-analysis on risk of flare and damage accrual.

OBJECTIVE: To assess the risk of flare and damage accrual after discontinuation of low-dose glucocorticoids (GCs) in SLE. METHODS: We performed a comprehensive literature search of the PubMed, Embase, Cochrane Library and Scopus databases from inception to July 2020 for studies concerning relapses/damage accrual in SLE patients. Pooled incidence rates of flare and time to flare with their 95% CIs after GC withdrawal were calculated. The summary risk ratio (RR) and 95% CI of flare/organ damage accrual risk were computed using a random- or fixed-effects model. RESULTS: A total of 738 SLE patients with GC discontinuation in 17 publications were eligible for the final analysis. In the primary meta-analysis, the pooled incidence of flare was 24% (95% CI 21, 27) and 13% (95% CI 8, 18) for global and major flares, respectively. Pooled time to flare was 21.08 months (95% CI 9.32, 32.85). In the secondary meta-analysis, GC discontinuation showed an increased risk of flare compared with GC continuation [RR 1.38 (95% CI 1.01, 1.89)], but the risk of major flares was not increased [RR 1.77 (95% CI 0.40, 7.83)]. Moreover, GC withdrawal was associated with a borderline risk reduction in the SLICC/ACR damage index increase compared with GC continuation [RR 0.64 (95% CI 0.38, 1.09)]. CONCLUSION: GC discontinuation leads to a slightly increased risk of flare, however, no increase in major flare and a borderline reduction of risk in further damage in SLE patients. Baseline screening for candidate patients and long-term follow-up after GC withdrawal are needed to reliably evaluate the organ damage increase.

Maternal and neonatal outcomes in pregnant women with psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

OBJECTIVE: Psoriasis and PsA are inflammatory diseases that affect women in their reproductive years. We aimed to investigate whether maternal psoriasis and PsA are associated with adverse pregnancy outcomes. METHODS: We searched multiple electronic databases from inception to 3 August 2020, and reference lists of selected articles. Observational studies reporting at least one pregnancy outcome in women with psoriasis or PsA with a comparator of general population or healthy subjects were included. Data were pooled by random-effects models and expressed as odds ratio (OR) and 95% CI. RESULTS: Overall, 16 studies were included in the meta-analysis. The pooled analyses showed pregnant women with psoriatic diseases have a significantly higher risk of adverse maternal outcomes compared with the general population [caesarean delivery: 1.33 (1.17, 1.52); preterm birth: 1.32 (1.15, 1.52); (pre)eclampsia: 1.28 (1.14, 1.43); gestational diabetes: 1.19 (1.10, 1.30); gestational hypertension: 1.30 (1.18, 1.44)]. However, no statistically increased risks of fetal complications were observed in women with psoriatic diseases [small for gestational age: 1.02 (0.93, 1.11); low birth weight: 1.15 (0.93, 1.42); congenital malformations: 1.03 (0.93, 1.14); Apgar score <7: 1.07 (0.81, 1.39); neonatal mortality: 1.13 (0.90, 1.43); stillbirth: 1.19 (0.95, 1.50)]. Subgroup analysis found similar results in women with either psoriasis or PsA regarding maternal outcomes, and the magnitude of risk estimates seems to be greater in PsA, though without statistical difference. CONCLUSIONS: Pregnant women with psoriasis and PsA have excess risk of adverse maternal events, but not adverse neonatal events. Close monitoring of the mothers' clinical status before and during pregnancy is decidedly required in daily practice.

Mortality in patients with primary Sjögren's syndrome: a systematic review and meta-analysis.

OBJECTIVE: It remains debated whether patients with primary Sjögren's syndrome (pSS) are at greater risk of mortality. We aimed to determine the magnitude of all-cause mortality risk in patients with pSS compared with the general population through a systematic review and meta-analysis. METHODS: We searched PubMed, EMBASE and Cochrane Library for studies published from inception to October 2020. Stata meta-analysis software was used to calculate the pooled risk estimates for mortality (standardized mortality ratio, SMR). RESULTS: Our search identified 2796 articles, of which 14 studies with 14 584 patients were eventually included for the analysis. A total of 902 deaths were observed. Overall, we found a 1.46-fold increased risk of death in pSS patients when compared with the general population [meta-standardized mortality ratio (SMR): 1.46, 95% CI: 1.10, 1.93]. Subgroup analyses showed that mortality risks were higher in European countries (meta-SMR: 1.55, 95% CI: 1.04, 2.33), in retrospective studies (meta-SMR: 1.50, 95% CI: 1.09, 2.05), in studies based on referral cohorts (meta-SMR: 1.55, 95% CI: 1.04, 2.30), in studies that enrolled >500 patients (meta-SMR: 1.70, 95% CI: 1.11, 2.61) and in studies with follow-up time longer than 8 years (meta-SMR: 1.55, 95% CI: 0.87, 2.77). Significantly greater mortality risk was found in patients with older age, male gender, vasculitis, interstitial lung disease, low complements, positive anti-La/SSB and cryoglobulinaemia. CONCLUSION: The existing data indicated ∼50% increase of mortality among patients with pSS compared with the general population. More attention should be paid to those patients with poor prognostic factors.

Mucosal chemokine CXCL17: What is known and not known.

CXCL17, the last described chemokine, has recently been found to be abundantly and specifically expressed in mucosal sites, while its receptor is still not well determined. Accumulative studies indicate that CXCL17 could potentially exhibit chemotactic, anti-inflammatory, antimicrobial activities under multiple biological conditions. However, the mechanism by which it contributes to the physiological and pathological processes within specific mucosal tissues is still far from being fully elucidated. In this present review, we therefore summarize the current available evidence of CXCL17 with specific emphasis on its biological role and pathophysiological significance, in order to aid in the advancement of CXCL17-related studies.

A clinically practical radiomics-clinical combined model based on PET/CT data and nomogram predicts EGFR mutation in lung adenocarcinoma.

OBJECTIVES: This study aims to develop a clinically practical model to predict EGFR mutation in lung adenocarcinoma patients according to radiomics signatures based on PET/CT and clinical risk factors. METHODS: This retrospective study included 583 lung adenocarcinoma patients, including 295 (50.60%) patients with EGFR mutation and 288 (49.40%) patients without EGFR mutation. The clinical risk factors associated with lung adenocarcinoma were collected at the same time. We developed PET/CT, CT, and PET radiomics models for the prediction of EGFR mutation using multivariate logistic regression analysis, respectively. We also constructed a combined PET/CT radiomics-clinical model by nomogram analysis. The diagnostic performance and clinical net benefit of this risk-scoring model were examined via receiver operating characteristic (ROC) curve analysis while the clinical usefulness of this model was evaluated by decision curve analysis (DCA). RESULTS: The ROC analysis showed predictive performance for the PET/CT radiomics model (AUC = 0.76), better than the PET model (AUC = 0.71, Delong test: Z = 3.03, p value = 0.002) and the CT model (AUC = 0.74, Delong test: Z = 1.66, p value = 0.098). Also, the PET/CT radiomics-clinical combined model has a better performance (AUC = 0.84) to predict EGFR mutation than the PET/CT radiomics model (AUC = 0.76, Delong test: D = 2.70, df = 790.81, p value < 0.001) or the clinical model (AUC = 0.81, Delong test: Z = 3.46, p value < 0.001). CONCLUSIONS: We demonstrated that the combined PET/CT radiomics-clinical model has an advantage to predict EGFR mutation in lung adenocarcinoma. KEY POINTS: • Radiomics from lung tumor increase the efficiency of the prediction for EGFR mutation in clinical lung adenocarcinoma on PET/CT. • A radiomic nomogram was developed to predict EGFR mutation. • Combining PET/CT radiomics-clinical model has an advantage to predict EGFR mutation.

Modifiable lifestyle and environmental factors associated with onset of psoriatic arthritis in patients with psoriasis: A systematic review and meta-analysis of observational studies.

BACKGROUND: Psoriatic arthritis (PsA) is a progressive joint disease associated with psoriasis. OBJECTIVES: To investigate the association of modifiable lifestyle and environmental factors with PsA risk among people with psoriasis. METHODS: We conducted a systematic search of PubMed, Embase, and Cochrane Library through May 2, 2020, for observational studies reporting lifestyle or environmental factors for PsA onset in patients with psoriasis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were combined using a random-effects model. RESULTS: We included 16 studies comprising 322,967 individuals. Obesity and being overweight were associated with an increased PsA risk in patients with psoriasis (OR, 1.75 [95% CI, 1.42-2.16] and OR, 1.50 [95% CI, 1.08-2.09], respectively), with an increase of approximately 6% for each kg/m2 rise in body mass index (OR, 1.06; 95% CI, 1.03-1.10). The presence of PsA was associated with a history of physical trauma (OR, 1.33; 95% CI, 1.16-1.54) or fracture (OR, 1.46; 95% CI, 1.22-1.74). No significant associations were observed regarding alcohol consumption (OR, 0.99; 95% CI, 0.88-1.13), smoking (OR, 0.89; 95% CI, 0.75-1.06), female hormonal exposure (OR, 1.45; 95% CI, 0.95-2.20), and psychologically traumatic events. LIMITATIONS: Inherent limitations in the included observational studies. CONCLUSIONS: Several lifestyle and environmental factors are associated with PsA onset among patients with psoriasis. These findings indicate that such risk may be modified with lifestyle changes or avoidance of physical trauma in people with psoriasis.

Frequencies and predictors of the Lupus Low Disease Activity State and remission in treatment-naïve patients with systemic lupus erythematosus.

OBJECTIVES: To evaluate the attainability of Lupus Low Disease Activity State (LLDAS) and definitions of remission in SLE (DORIS) in a treatment-naïve cohort of SLE. METHODS: LLDAS5 was defined as LLDAS with a prednisone dose ≤5 mg/day. There were four definitions in DORIS: clinical remission on treatment (RONT), complete RONT, clinical remission off treatment (ROFT) and complete ROFT. The treatment-naïve patients from Peking University First Hospital SLE cohort were enrolled. The time to each state and their annual cumulative probabilities were estimated. The frequencies of patients who achieved each component of LLDAS or DORIS during follow-up were determined. The predictors of time to each state were identified. RESULTS: A total of 218 patients were included, with a median follow-up of 4.48 years. Respectively, 190 (87.2%), 160 (73.4%), 148 (67.9%), 94 (43.1%), 23 (10.6%) and 18 (8.3%) patients achieved LLDAS, LLDAS5, clinical RONT, complete RONT, clinical ROFT and complete ROFT. The median time to LLDAS, LLDAS5, clinical RONT and complete RONT were 1.4, 2.3, 2.6 and 4.7 years, respectively. Positive anti-dsDNA, RP and anaemia were significantly associated with prolonged time to LLDAS, LLDAS5 or clinical RONT. CONCLUSION: Our data confirmed that LLDAS is an attainable early treatment target for SLE. Though with more difficulty, RONT can be achieved in two-thirds of our patients. ROFT may not be an ideal treatment target at present as it is only attained in few patients.

A meta-analysis of biologic therapies on risk of new or recurrent cancer in patients with rheumatoid arthritis and a prior malignancy.

OBJECTIVES: To explore the risk of new and recurrent cancer in adult RA patients with prior malignancy and subsequently exposed to biologic therapies. METHODS: Separate searches were performed of PubMed, EMBASE and Cochrane Library and conference proceedings for observational studies reporting cancer incidence or recurrence in patients with RA and prior malignancy treated with biologics and conventional synthetic DMARDs (csDMARDs). Mantel-Haenszel fixed-effects method was conducted to calculate relative risk and 95% CI. RESULTS: A total of 12 studies involving 13 598 patients and 32 473 patient-years of follow-up were included (10, 3 and 1 studies for TNF inhibitors [TNFi], rituximab and anakinra, respectively). The crude incidence of new and recurrent cancer per 1000 patient-years were 34.4 for TNFi, 32.3 for rituximab, 32.3 for anakinra and 31.8 for csDMARDs. In the quantitative meta-analysis, biologics were not associated with an increased risk of new or recurrent cancer compared with csDMARDs in patients with RA and prior cancer (TNFi: relative risk = 0.95, 95% CI = 0.83, 1.09; rituximab: relative risk = 0.89, 95% CI = 0.52, 1.53). Secondary analyses of stratification of cancer types, the interval between initiation of TNFi and prior cancer diagnosis, and duration of TNFi exposure, found similar results. CONCLUSION: Compared with csDMARDs, there is no increased risk of developing cancer overall or some specific subtypes in RA patients with a prior cancer receiving biologics. More investigations are warranted to explore the risk of cancer development in individual cancer as well as to determine optimal time to initiate biologic therapy after the diagnosis of cancer or completion of cancer treatment.

Pretreatment serum neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios: Two tumor-related systemic inflammatory markers in patients with thymic epithelial tumors.

OBJECTIVES: To understand underlying changes in pretreatment serum inflammatory markers associated with thymic epithelial tumors (TETs) development. METHODS: A retrospective analysis of 113 TETs patients who underwent 18-fluorine fluorodeoxyglucose (18F-FDG) positron emission tomography combined computed tomography (PET/CT) one to two weeks before tumor resection or biopsy was performed. Pretreatment serum neutrophil, monocyte, platelet, and lymphocyte counts, and fibrinogen and C-reaction protein (CRP) concentrations were measured one day before surgery or biopsy. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) were calculated by dividing corresponding cells counts by lymphocyte counts, respectively. The maximum standard uptake value (SUVmax) of 18F-FDG of primary TETs was applied to reflect tumor glycolytic activity. The student's t-test, one-way ANOVA analysis, Chi-square test, receiver operating characteristic curve analysis, and Logistic regression analysis were used for statistical analysis. RESULTS: The serum NLR and MLR were significantly higher in TETs patients than in healthy volunteers (P both ≤ 0.001). High serum NLR and MLR were related to the thymic carcinomas (TCs) subtype, elevated Masaoka-Koga (M-K) tumor stage, and metastasis of TETs (P all < 0.005). High serum NLR and MLR were also associated with high SUVmax values of TETs (P all < 0.005), with increasingly differences between groups as the cut-off values defining low-SUVmax and high-SUVmax groups increased. With the medium cutoff of NLR, MLR, and SUVmax of 3.07, 0.25, and 8.00 respectively, the high NLR and MLR levels were significantly associated with high SUVmax level of TETs (P both < 0.005). Moreover, the incidences of co-high SUVmax/NLR and co-high SUVmax/MLR were higher in TETs patients older than 55 years, with TCs, in M-K stage IV, and with metastasis (P all < 0.05). Both the co-high SUVmax/NLR and co-high SUVmax/MLR increased the risk of TETs metastasis (P both < 0.001), while the co-high SUVmax/MLR was also an independent risk factor for TETs metastasis (odds ratio: 3.92, 95% confidence interval: 1.02-15.12, P = 0.047). CONCLUSION: Pretreatment serum NLR and MLR of TETs patients are two tumor-progression- and tumor-glycolysis-related inflammatory markers. Enhanced tumor glycolytic activity and associated systemic inflammatory reaction may play a synergistic role in TETs metastasis.

Correlation between combining 18F-FDG PET/CT metabolic parameters and other clinical features and ALK or ROS1 fusion in patients with non-small-cell lung cancer.

PURPOSE: Our study intended to explore the association between combining 18F-FDG PET/CT metabolic parameters and other clinical features and anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS1) fusion in non-small-cell lung cancer (NSCLC). METHODS: Eight hundred and six patients with wild-type epidermal growth factor receptor (EGFR) mutation were screened for ALK or ROS1 fusion and subjected to 18F-FDG PET/CT prior to treatment at our hospital. The associations between ALK or ROS1 fusion and clinical characteristics and the PET/CT parameters were analyzed. Multivariate logistic regression analysis was performed to explore independent deterministic factors associated with ALK and ROS1 fusion. RESULTS: Eighty-two patients (11.7%) with ALK fusion were found. Multivariate analysis demonstrated that high pSUVmax ≥ 10.6, low primary tumor lesion glycolysis (pTLG) < 101.8, young age, nonsmoker status, and high carcinoembryonic antigen (CEA) level correlated with ALK fusion in NSCLC. The receiver operating characteristic (ROC) curve yielded the area under curve (AUC) values of 0.603 and 0.873 for high pSUVmax alone and the combination of the five factors, respectively. Twenty-six patients (5.6%) with ROS1 fusion were found. Multivariate analysis revealed that high pSUVmax ≥ 8.8, young age, and nonsmoker status correlated with ROS1 fusion in NSCLC. The ROC curve yielded AUC values of 0.662 and 0.813 for high pSUVmax alone and the combination of the three factors, respectively. CONCLUSION: The study indicated that combining 18F-FDG PET/CT metabolic parameters and other clinical parameters were correlated with ALK and ROS1 mutation in NSCLC patients and may help to refine the process of optimal patient selection to gene test for targeted therapy.

Effect of statin use on cardiovascular events and all-cause mortality in immune-mediated inflammatory diseases: A systematic review and meta-analysis involving 148,722 participants.

BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are associated with an increased risk of premature cardiovascular disease and all-cause mortality. Given lipid-lowering and anti-inflammatory properties, statins theoretically provide greater survival benefits for patients with IMIDs. OBJECTIVE: We aimed to evaluate the impact of statin on all-cause mortality and cardiovascular risk in patients with IMIDs, and examine whether the effect varies between primary prevention and secondary prevention. METHODS: We systematically searched PubMed, EMBASE and Cochrane Library to identify eligible studies evaluating the association between statin use and all-cause mortality or cardiovascular events in IMIDs. Data were pooled using fixed-effects or random-effects meta-analysis according to I2 and pooled hazard ratios (HRs) and 95 % confidence intervals (CIs) were used as summary statistic. RESULTS: Our meta-analysis included 12 studies that comprised 148,722 patients with IMIDs (57,670 statin users, 91,052 statin non-users) contributing more than 840,113 patient-years. In pooled analysis, statin initiation was associated with 28 % decreased risk of all-cause mortality (random-effects: meta-HR 0.72, 95 % CI 0.65-0.80), 23 % decreased risk of major adverse cardiovascular events (fixed-effects: meta-HR 0.72, 95 % CI 0.62-0.83). Subgroup analysis of patients with rheumatoid arthritis showed similar results (fixed-effects: meta-HR 0.77, 95 % CI 0.67-0.89 for all-cause mortality; meta-HR 0.75, 95 % CI 0.63-0.88 for major adverse cardiovascular events). Furthermore, the protective role of statin in decreasing mortality was stronger in patients receiving statin for primary prevention of cardiovascular diseases than that for secondary prevention (fixed-effects: meta-HR 0.64, 95 % CI 0.59-0.70; meta-HR 0.84, 95 % CI 0.80-0.89, respectively), although both were statistically significant. Additional analysis yielded similar benefit from statin usage between females and males regarding mortality. CONCLUSION: Statin use was associated with lower risks of mortality and cardiovascular events, with greater benefits for primary prevention in those IMIDs patients without prior cardiovascular disease.

Hepatitis B virus X protein promotes liver cell pyroptosis under oxidative stress through NLRP3 inflammasome activation.

OBJECTIVE: Hepatitis B virus X protein (HBx) is a pivotal factor for HBV-induced hepatitis. Herein, we sought to investigate HBx-mediated NLR pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis under oxidative stress. METHODS: The effect of HBx on the NLRP3 inflammasome was analyzed by enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence in hepatic HL7702 cells. Pyroptosis was evaluated by western blotting, lactate dehydrogenase release, propidium iodide staining, and transmission electron microscopy. NLRP3 expression in the inflammasome from liver tissues was assessed by immunohistochemistry. RESULTS: In hydrogen peroxide (H2O2)-stimulated HL7702 cells, HBx triggered the release of pro-inflammatory mediators apoptosis-associated speck-like protein containing a CARD (ASC), interleukin (IL)-1ß, IL-18, and high-mobility group box 1 (HMGB1); activated NLRP3; and initiated pro-inflammatory cell death (pyroptosis). HBx localized to the mitochondria, where it induced mitochondrial damage and production of mitochondrial reactive oxygen species (mitoROS). Treatment of HL7702 cells with a mitoROS scavenger attenuated HBx-induced NLRP3 activation and pyroptosis. Expression levels of NLRP3, ASC, and IL-1ß in liver tissues from patients were positively correlated with HBV DNA concentration. CONCLUSIONS: The NLRP3 inflammasome was activated by elevated mitoROS levels and mediated HBx-induced liver inflammation and hepatocellular pyroptosis under H2O2-stress conditions.

Minor components of micropapillary and solid subtypes in lung invasive adenocarcinoma (≤ 3 cm): PET/CT findings and correlations with lymph node metastasis.

OBJECTIVE: To investigate the PET/CT findings in lung invasive adenocarcinoma with minor components of micropapillary or solid contents and its association with lymph node metastasis. MATERIALS AND METHODS: A total of 506 lung invasive adenocarcinoma (≤ 3 cm) patients who underwent a PET/CT examination and resection surgery were included. According to the proportion of solid/micropapillary components, the patients were classified into three groups: solid/micropapillary-negative (SMPN) (n = 258), solid/micropapillary-minor (SMPM; > 5% not predominant) (n = 158) and solid/micropapillary-predominant (SMPP; > 5% most dominant) (n = 90). The patients' PET/CT findings, including SUVmax, MTV, TLG and CT characteristics, and other clinical factors were compared by one-way ANOVA test. Logistic regression analysis was done to identify the most predictive findings for lymph node metastasis. RESULTS: The value of SUVmax, MTV, TLG and tumor size was highest in SMPP group, followed by SMPM and SMPN group (P < 0.001).The areas under the curve for SUVmax, MTV and TLG for node metastasis were 0.822, 0.843 and 0.835, respectively. Univariate analysis found that the SMPP and SMPM group had more lymph node metastasis than the SMPN group (P < 0.001). Furthermore, the lymph node metastasis group had higher CEA, SUVmax, MTV, TLG, tumor size and more pleural invasion (P < 0.001). Logistic regression analysis found that SMPP pathological type, SMPM pathological type, higher CEA and male patients were risk factors for lymph node metastasis (P < 0.01). CONCLUSIONS: Lung invasive adenocarcinoma with micropapillary or solid contents had higher SUVmax, MTV, TLG and tumor size and was associated with lymph node metastasis, even if they were not predominant.

Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: To investigate the effect of Janus kinase inhibitors (Jakinibs) on cardiovascular risk in adult patients with rheumatoid arthritis (RA) via a meta-analysis of randomised controlled trials (RCTs). METHODS: PubMed, Embase and Cochrane library were thoroughly searched for RCTs reporting safety issues in patients with RA receiving Jakinibs, from inception to October 2018. The primary and secondary outcomes were all cardiovascular events (CVEs) and major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs). OR and 95% CI were calculated using the Mantel-Haenszel fixed-effect method. RESULTS: 26 RCTs randomising 11 799 patients were included. No significant difference was observed regarding all CVEs risk following Jakinibs usage in general (OR 1.04 (0.61 to 1.76), p = 0.89), tofacitinib (OR 0.63 (0.26 to 1.54), p = 0.31), baricitinib (OR 1.21 (0.51 to 2.83), p = 0.66), upadacitinib (OR 3.29 (0.59 to 18.44), p = 0.18), peficitinib (OR 0.43 (0.07 to 2.54), p = 0.35) or decernotinib (OR 1.12 (0.13 to 10.11), p = 0.92). Likewise, there was no significant difference for Jakinibs treatment overall regarding occurrence of MACEs (OR 0.80 (0.36 to 1.75), p = 0.57) or VTEs (OR 1.16 (0.48 to 2.81), p = 0.74). Dose-dependent impact of Jakinibs on the risks of all CVEs, MACEs and VTEs was not observed in tofacitinib (5 mg vs 10 mg), upadacitinib (15 mg vs 30 mg), whereas baricitinib at 2 mg was found to be safer than 4 mg in all CVEs incidence (OR 0.19 (0.04 to 0.88), p = 0.03). CONCLUSION: The existing evidence from RCTs indicated no significant change in cardiovascular risk for Jakinib-treated patients with RA in a short-term perspective, but postmarketing data are sorely needed to ascertain their cardiovascular safety, especially at the higher dose, due to increased risk of thromboembolism events for both tofacitinib and baricitinib at higher dosage.

Trends in the activity of rheumatoid arthritis as the consequence of treat-to-target strategy: eight-year data from 2009 to 2016.

OBJECTIVES: To investigate the trends in the activity of rheumatoid arthritis (RA) over the past 8 years and evaluate the value of treat-to target (T2T) strategy in daily practice. METHODS: All the medical records of RA patients from 2009 to 2016 were retrospectively reviewed. Disease activity scores at obtained visits were measured by DAS28-CRP, DAS28-ESR, SDAI and CDAI. To display trends over years, both mean and time-adjusted methods were applied in calculation of annual disease activity and remission rate. Disease activity and remission rate were also compared before and after the year 2011 when application of T2T strategy was initiated in our centre. Furthermore, a sub-cohort study including T2T and non-T2T period groups was conducted with outcome of cumulative percentage of remission and time to achieve first remission during the first year follow-up. RESULTS: In total, 1,001 patients with 6,944 clinical visits were included. Over an eight-year period, significant improvements were witnessed in disease activity and remission rate, measured by all four indices (p<0.0001). More patients achieved lower disease activity and higher remission rates after T2T adherence in 2011 compared to those in the years 2009 and 2010 (p<0.0001). Moreover, sub-cohort study revealed that more patients (49.3-73.2% vs. 19.1-34.5%, OR=2.4-3.0) achieved remission with a shorter median time compared with the non-T2T period group (p<0.0001), particularly in DAS28-CRP (21 vs. >52 weeks), DAS28-ESR (37 vs. >52 weeks). CONCLUSIONS: Over the past 8 years, the RA activity has substantially decreased and T2T strategy was directly attributable to the favourable changes in clinical practice.