Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins.

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI-H1975 cells, and NCI-H1975-TM cells (IC50 = 0.009 µM, 0.49 µM and 3.24 µM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 µM and 0.63 µM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

Ultrathin layer TAFC on BiVO4 with ligand-to-metal charge transfer enhances built-in electric field for boosting photoelectrochemical water oxidation.

To reveal the mechanism of charge transfer between interfaces of BiVO4-based heterogeneous materials in photoelectrochemical water splitting system, the cocatalyst was grown in situ using tannic acid (TA) as a ligand and Fe and Co ions as metal centers (TAFC), and then uniformly and ultra-thinly coated on BiVO4 to form photoanodes. The results show that the BiVO4/TAFC achieves a superior photocurrent density (4.97 mA cm-2 at 1.23 VRHE). The charge separation and charge injection efficiencies were also significantly higher, 82.0 % and 78.9 %, respectively. From XPS, UPS, KPFM, and density functional theory calculations, Ligand-to-metal charge transfer (LMCT) acts as an electron transport highway in TAFC ultrathin layer to promote the concentration of electrons towards metal center, leading to an increase in the work function, which enhances the built-in electric field and further improves the charge transport. This study demonstrated that the LMCT pathway on TA-metal complexes enhances the built-in electric field in BiVO4/TAFC to promote charge transport and thus enhance water oxidation, providing a new understanding of the performance improvement mechanism for the surface-modified composite photoanodes.

Anthraquinone-based polymer modified BiVO4 photoanode with strong electron-withdrawing functional groups for boasting photoelectrochemical water oxidation.

The photoelectrochemical (PEC) performance ofBiVO4 is limited by sluggish water oxidation kinetics and severe carrier recombination. Herein, a novel high-performance BiVO4/NiFe-NOAQ photoanode is prepared by a simple one-step hydrothermal method, using BiVO4 and 1-Nitroanthraquinone (NOAQ) as raw materials. The BiVO4/NiFe-NOAQ photoanode has an excellent photocurrent density of 5.675 mA cm-2 at 1.23 VRHE, which is 3.35 times higher than that of the pure BiVO4 (1.693 mA cm-2) photoanode. The BiVO4/NiFe-NOAQ shows a significant improvement in charge separation efficiency (86.12 %) and charge injection efficiency (87.86 %). The improvement is ascribable to the NiFe-NOAQ form a type II heterojunction with BiVO4 to inhibit carrier recombination. More importantly, the kinetic isotope experiment suggests that the proton-coupled electron transfer (PCET) process can enhance the charge transfer of BiVO4/NiFe-NOAQ. The contact angle measurements show that modifying functional groups enhanced the hydrophilicity of BiVO4/NiFe-NOAQ, which can further accelerate the PCET process. The XPS and PL results as well as the tauc plot indicate that the strong electron-withdrawing ability of -NO2 which can promote the extension of π conjugation, results in more π electron delocalization and produces more efficient active sites, thus achieving efficient photoelectrochemical water oxidation.

Association of pulse pressure and aortic root diameter in elderly Chinese patients with chronic heart failure.

Background: High pulse pressure (PP) and aortic root diameter (AoD) are hallmarks of arterial stiffness or vascular aging and they are considered as risk factors for age-related cardiovascular disease, including heart failure (HF). However, the relationship between PP and AoD in patients with heart failure (HF) is uncertain. This study aimed to evaluate the relationship between PP and AoD in the middle-aged and the elderly with HF. Methods: A total of 1,027 Chinese middle-aged and elderly patients with HF, including HF with reduced ejection fraction (HFrEF), HF with mid-range EF (HFmrEF), and HF with preserved EF (HFpEF) were included in this study. Pearson correlation analysis was used to evaluate the relationship between PP and AoD in the three types of HF. Multiple linear regression analysis was performed to assess the factors that affected AoD. Multivariate logistic regression was performed to determine the association between the PP level quartiles and AoD. The results were validated in an independent dataset included a total of 378 consecutive patients with HFrEF hospitalized at the Pingtan Branch of Fujian Medical University Union Hospital (Fujian, China). Results: There was a positive correlation between PP and AoD in the middle-aged and the elderly with HFrEF. Multiple linear regression analysis revealed that PP, age, and body mass index (BMI) were independently correlated with AoD in HFrEF patients. In multivariate logistic regression analysis, an increased risk of aortic root dilation was observed in the highest quartile of the PP level compared with the lowest quartile. Age significantly interacted with PP (p = 0.047). A significant association between PP levels and AoD was only observed in patients ≥ 65 years old, but not in patients < 65 years old. In the validation dataset, PP was independently related to AoD in patients with HFrEF (ß = 0.205, p = 0.001). Conclusions: PP level was independently and positively associated with AoD, especially in the elderly with HFrEF, but not in patients with HFmrEF and HFpEF. Arterial stiffening or vascular aging may play a certain role in the elderly HFrEF patients.

Effects of acid and aluminum stress on seed germination and physiological characteristics of seedling growth in Sophora davidii.

Sophora davidii, a vital forage species, predominantly thrives in the subtropical karst mountains of Southwest China. Its resilience to poor soil conditions and arid environments renders it an ideal pioneer species for ecological restoration in these regions. This study investigates the influence of acidic, aluminum-rich local soil on the germination and seedling growth physiology of S. davidii. Experiments were conducted under varying degrees of acidity and aluminum stress, employing three pH levels (3.5 to 5.5) and four aluminum concentrations (0.5 to 2.0 mmol·L-1). The results showed that germination rate, germination index, and vigor index of S. davidii seeds were decreased but not significantly under slightly acidic conditions (pH 4.5-5.5), while strong acid (pH = 3.5) significantly inhibited the germination rate, germination index, and vigor index of white spurge seeds compared with the control group. Aluminum stress (≥0.5 mmol·L-1) significantly inhibited the germination rate, germination index, and vigor index of S. davidii seed. Moreover, the seedlings' root systems were sensitive to the changes of aluminum concentration, evident from significant root growth inhibition, characterized by root shortening and color deepening. Notably, under aluminum stress (pH = 4.3), the levels of malondialdehyde and proline in S. davidii escalated with increasing aluminum concentration, while antioxidant enzyme activities demonstrated an initial increase followed by a decline. The study underscores the pivotal role of cellular osmoregulatory substances and protective enzymes in combating aluminum toxicity in S. davidii, a key factor exacerbating growth inhibition in acidic environments. These findings offer preliminary theoretical insights for the practical agricultural utilization of S. davidii in challenging soil conditions.

The combination of maximum standardized uptake value and clinical parameters for improving the accuracy in distinguishing primary mediastinal lymphomas from thymic epithelial tumors.

Background: Anterior mediastinal masses are relatively uncommon, and mediastinal lymphomas are the malignancies most likely to be confused with thymic epithelial tumors (TETs). The aim of this study was to investigate whether the combination of 18fluorine-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) findings and clinical parameters is useful in differentiating lymphoma from TETs in anterior mediastinal masses. Methods: This retrospective study consecutively included 304 patients with anterior mediastinal masses (244 TETs and 60 lymphomas) who underwent 18F-FDG PET-CT 1 to 2 weeks before tumor resection or biopsy between August 2016 and March 2022. The correlations between the maximum standardized uptake value (SUVmax) of tumors and clinical parameters of patients with histology subtypes were analyzed. Receiver operating characteristic curve analysis was used to obtain the optimal cutoff values of age, lactate dehydrogenase (LDH), tumor size, and SUVmax to predict lymphoma. Logistic regression analysis was used to identify potential predictive factors for lymphoma. Results: Lymphoma was significantly associated with younger patient age, higher LDH level, larger tumor size, and higher SUVmax compared to TETs (P<0.001). In the modeling cohort, age ≤40.5 years, LDH level ≥197 U/L, tumor size ≥10.72 cm, and SUVmax ≥11.95 were identified as independent predictors for lymphoma with odds ratios of 20.14 [95% confidence interval (CI): 6.02-67.40; P<0.001], 4.89 (95% CI: 1.27-18.89; P=0.021), 8.82 (95% CI: 2.31-33.69; P=0.001), and 30.01 (95% CI: 6.59-136.72; P<0.001), respectively. The accuracy of age, LDH, tumor size, and SUVmax in predicting lymphoma was 84.8%, 67.8%, 85.2%, and 78.3% respectively. The combination of the four above parameters could improve the predictive accuracy to 89.1%, and in the validation cohort, this combination increased the predictive accuracy to 87.8%. Conclusions: SUVmax on 18F-FDG PET-CT has the potential ability to discriminate lymphomas from TETs in the diagnosis of anterior mediastinal masses, and the combination of SUVmax with clinical parameters can improve the diagnostic accuracy. This combination may therefore may be helpful in avoiding unnecessary operation in patients with anterior mediastinal lymphomas.

Association between disease-modifying antirheumatic drugs for rheumatoid arthritis and risk of incident dementia: a systematic review with meta-analysis.

BACKGROUND: Dysregulation of several inflammatory cytokines including tumour necrosis factor (TNF) in dementia patients has also been identified as a key factor in the pathogenesis of rheumatoid arthritis (RA). We aimed to investigate the association of disease-modifying antirheumatic drugs (DMARDs) therapy for RA with risk of incident dementia. METHODS: Electronic database searches of PubMed, EMBASE and Cochrane Library were performed. Observational studies that assessed the association of dementia with DMARDs in RA were included. Pooled risk ratios (RRs) with 95% CIs were used as summary statistic. The certainty of evidence was judged by using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Overall, 14 studies involving 940 442 patients with RA were included. Pooled RR for developing dementia was 0.76 (95% CI 0.72 to 0.80) in patients taking biological DMARDs overall versus those taking conventional synthetic DMARDs, with 24% for TNF inhibitors (RR 0.76, 95% CI 0.71 to 0.82), 24% for non-TNF biologics (RR 0.76, 95% CI 0.70 to 0.83), separately. There was a significant subgroup effect among different types of TNF inhibitors (RR 0.58 [95%CI 0.53 to 0.65], 0.65 [95% CI 0.59 to 0.72], 0.80 [95% CI 0.72 to 0.88] for etanercept, adalimumab, infliximab, respectively; p value between groups=0.002). However, compared with non-users of DMARDs or investigative treatment, no significant effect on dementia incidence was observed in those receiving conventional synthetic DMARDs overall (RR 0.84, 95% CI 0.59 to 1.20), methotrexate (RR 0.78, 95% CI 0.54 to 1.12), hydroxychloroquine (RR 0.95, 95% CI 0.63 to 1.44), except for sulfasalazine (RR 1.27, 95% CI 1.06 to 1.50). CONCLUSIONS: Biological DMARDs for RA are associated with decreased dementia risk, while protective effect is not observed in conventional synthetic DMARDs. Controlled clinical trials on TNF inhibitors are necessary to test their neuroprotective potentials.

Value of multi-center 18 F-FDG PET/CT radiomics in predicting EGFR mutation status in lung adenocarcinoma.

BACKGROUND: Accurate, noninvasive, and reliable assessment of epidermal growth factor receptor (EGFR) mutation status and EGFR molecular subtypes is essential for treatment plan selection and individualized therapy in lung adenocarcinoma (LUAD). Radiomics models based on 18 F-FDG PET/CT have great potential in identifying EGFR mutation status and EGFR subtypes in patients with LUAD. The validation of multi-center data, model visualization, and interpretation are significantly important for the management, application and trust of machine learning predictive models. However, few EGFR-related research involved model visualization and interpretation, and multi-center trial. PURPOSE: To develop explainable optimal predictive models based on handcrafted radiomics features (HRFs) extracted from multi-center 18 F-FDG PET/CT to predict EGFR mutation status and molecular subtypes in LUAD. METHODS: Baseline 18 F-FDG PET/CT images of 383 LUAD patients from three hospitals and one public data set were collected. Further, 1808 HRFs were extracted from the primary tumor regions using Pyradiomics. Predictive models were built based on cross-combination of seven feature selection methods and seven machine learning algorithms. Yellowbrick and explainable artificial intelligence technology were used for model visualization and interpretation. Receiver operating characteristic curve, classification report and confusion matrix were used for model performance evaluation. Clinical applicability of the optimal models was assessed by decision curve analysis. RESULTS: STACK feature selection method combined with light gradient boosting machine (LGBM) reached optimal performance in identifying EGFR mutation status ([area under the curve] AUC = 0.81 in the internal test cohort; AUC = 0.62 in the external test cohort). Random forest feature selection method combined with LGBM reached optimal performance in predicting EGFR mutation molecular subtypes (AUC = 0.89 in the internal test cohort; AUC = 0.61 in the external test cohort). CONCLUSIONS: Explainable machine learning models combined with radiomics features extracted from multi-center/scanner 18 F-FDG PET/CT have certain potential to identify EGFR mutation status and subtypes in LUAD, which might be helpful to the treatment of LUAD.

Droplet-Based Preparation of ZnO-nanostructure Array for Microfluidic Fluorescence Biodetection.

Nanostructure-enhanced biodetection is widely used for early diagnosis and treatment, which plays an essential role in improving the cure rates of cancer patients. ZnO nanostructure-based fluorescence immunoassay has been demonstrated to enable effective and sensitive detection of cancer biomarkers for their excellent biocompatibility, high electrical point, and unique fluorescence enhancement properties. Further optimization of such fluorescence detection technology is still in demand to meet the requirements of highly sensitive, multiplex detection, and user-friendly devices. Droplet microfluidics is a promising platform for high-throughput analysis of biological assays, and they have been intensively used in analytical chemistry and synthesis of nanoparticles. Here, we propose a simple droplet chip, where a static droplet array was successfully obtained for in situ growth of ZnO nanostructures with varied diameters by changing the entire growth time and replenishment interval. This device provides a novel and alternative approach for patterned growth of ZnO nanostructures and understanding the growth condition of ZnO nanostructures in static droplet, which offers some guidance toward the design of multiple fluorescence amplification platforms potentially for biosensing. As a demonstration, we used the patterned grown ZnO nanostructures for multiple detection of cancer biomarkers, achieving a low limit of detection as low as 138 fg/mL in the human α-fetoprotein assay and 218 fg/mL in the carcinoembryonic antigen assay with a large dynamic range of 8 orders. These results suggest that such multifunctional microfluidic devices may be useful tools for efficient fluorescence diagnostic assays.

Effects of Maize-Crop Rotation on Soil Physicochemical Properties, Enzyme Activities, Microbial Biomass and Microbial Community Structure in Southwest China.

Introducing cover crops into maize rotation systems is widely practiced to increase crop productivity and achieve sustainable agricultural development, yet the potential for crop rotational diversity to contribute to environmental benefits in soils remains uncertain. Here, we investigated the effects of different crop rotation patterns on the physicochemical properties, enzyme activities, microbial biomass and microbial communities in soils from field experiments. Crop rotation patterns included (i) pure maize monoculture (CC), (ii) maize-garlic (CG), (iii) maize-rape (CR) and (iv) maize-annual ryegrass for one year (Cir1), two years (Cir2) and three years (Cir3). Our results showed that soil physicochemical properties varied in all rotation patterns, with higher total and available phosphorus concentrations in CG and CR and lower soil organic carbon and total nitrogen concentrations in the maize-ryegrass rotations compared to CC. Specifically, soil fertility was ranked as CG > Cir2 > CR > Cir3 > CC > Cir1. CG decreased enzyme activities but enhanced microbial biomass. Cir2 decreased carbon (C) and nitrogen (N) acquiring enzyme activities and soil microbial C and N concentrations, but increased phosphorus (P) acquiring enzyme activities and microbial biomass P concentrations compared to CC. Soil bacterial and fungal diversity (Shannon index) were lower in CG and Cir2 compared to CC, while the richness (Chao1 index) was lower in CG, CR, Cir1 and Cir2. Most maize rotations notably augmented the relative abundance of soil bacteria, including Chloroflexi, Gemmatimonadetes and Rokubacteria, while not necessarily decreasing the abundance of soil fungi like Basidiomycota, Mortierellomycota and Anthophyta. Redundancy analysis indicated that nitrate-N, ammonium-N and microbial biomass N concentrations had a large impact on soil bacterial communities, whereas nitrate-N and ammonium-N, available P, soil organic C and microbial biomass C concentrations had a greater effect on soil fungal communities. In conclusion, maize rotations with garlic, rape and ryegrass distinctly modify soil properties and microbial compositions. Thus, we advocate for garlic and annual ryegrass as maize cover crops and recommend a two-year rotation for perennial ryegrass in Southwest China.

Association of Malnutrition Diagnosed Using Global Leadership Initiative on Malnutrition Criteria with Severe Postoperative Complications After Gastrectomy in Patients with Gastric Cancer.

Background: The purpose of this study was to investigate the relationship between malnutrition assessed by the Global Leadership Initiative on Malnutrition (GLIM) criteria and the occurrence of severe postoperative complications (SPCs) after gastrectomy in patients with gastric cancer. Methods: A total of 220 patients with gastric cancer were included in this retrospective study. According to the GLIM criteria, the first step was to use the Nutrition Risk Screening Score 2002 to conduct nutritional risk screening for patients and the second step was to diagnose and grade the severity of malnutrition in patients at risk of malnutrition. According to the Clavien-Dindo classification system, SPCs were defined as C-D Grade IIIa or higher. Results: Overall, 66 (30.0%) patients were diagnosed with malnutrition, including 32 (14.5%) with moderate malnutrition and 34 (15.5%) with severe malnutrition. The incidence of SPCs was 14.5%, and the most frequent postoperative event was anastomotic leakage. In the multivariate regression analysis, malnutrition was considered an independent risk factor for SPCs (P < .001). After adjusting for various factors, the grading association remained statistically significant. Compared with patients with normal nutrition, patients with moderate and severe malnutrition have a nearly 15-fold (OR = 15.682, 95% CI: 4.481-54.877, P < .001) and 20-fold (OR = 20.554, 95% CI: 5.771-73.202, P < .001) increased risk of developing SPCs, respectively. Conclusions: Malnutrition assessed by GLIM was an independent risk factor for SPCs in gastric cancer patients. Therefore, early identification of malnourished patients is crucial for timely implementation of nutritional treatment and reducing the occurrence of postoperative complications.

Predictive value of SUVmax in visceral pleural invasive lung adenocarcinoma with different diameters.

OBJECTIVES: This study aimed to investigate predictive visceral pleural invasion (VPI) occurrence value of the maximum standardized uptake value (SUVmax) in patients with lung adenocarcinoma (LA). PATIENTS AND METHODS: A total of 388 LA patients were divided into D1ab, D1c, D1, D2, D2a, D2b, D3, and all patient groups based on their tumor diameter (D). Patients were also classified into negative VPI (VPI-n) and positive VPI (VPI-p) groups according to VPI presence. SUVmax of patients was measured with 18F-fluorodeoxyglucose (FDG) by PET/computed tomography (18F-PET/CT). Receiver operating characteristic (ROC) analysis and the area under curve (AUC) of SUVmax were applied to determine optimal cut-off value for predicting VPI occurrence. RESULTS: There were significant differences in SUVmax between VPI-n and VPI-p groups ( P  < 0.05) at the same tumor diameter. SUVmax cut-off value and sensitivity (Se,%) of VPI occurrence in each group were following: D1ab was 3.79 [AUC = 0.764, P  < 0.001], Se86.11%; D1c was 5.47 (AUC = 0.706, P  < 0.001), Se 93.75%; D1 was 5.49 (AUC = 0.731, P  < 0.001), Se 79.76%; D2 was 7.36 (AUC = 0.726, P  < 0.001), Se81.67%. All patient group was 7.26 (AUC = 0.735, P  < 0.001), Se74.19%. CONCLUSION: In LA patients with the same diameter, SUVmax of the VPI-p group was significantly higher than that of the VPI-n group. The cut-off value of SUVmax for predicting VPI of T1 stage, T1 substages, and T2 stage LA could be determined through ROC curve. SUVmax measurement by PET/CT scan in stratified tumor size is helpful for predicting VPI occurrences of the physician.

The universal presence of poor prognostic factors based on EULAR recommendations: A real-world study in 1164 Chinese RA patients.

INTRODUCTION: Poor prognostic factors (PPFs) have been used in assisting therapeutic decision-making in rheumatoid arthritis (RA). There are no standard lists of PPFs for RA, and whether PPFs can guide RA treatment remains controversial. OBJECTIVES: To analyze the profile of PPF based on EULAR recommendations in RA patients and explore the necessity of considering these PPFs in adjusting therapy. METHODS: Prognostic factors including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), swollen joint count (SJC), early erosions, and response to first conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) therapy in 1164 RA patients were collected. The profile of PPFs was graphically displayed. The correlation between different PPFs was analyzed. RESULTS: Elevated ESR/CRP was presented in 746 (64%) patients, and positive RF/ACPA in 1021 (88%) patients. Two hundred and sixty-eight (23%) patients had≥4 swollen joints. Three hundred (26%) patients had moderate or high disease activity (MDA/HDA) despite csDMARD therapy. Failure of≥2 csDMARDs was found in 30% (224/740) of patients. One hundred and fifty-three out of 459 (33%) patients had early bone erosions, usually coexisted with other PPFs. Ninety-seven percent of RA patients had≥1 PPF. Being MDA/HDA≥3 months was significantly correlated with elevated ESR/CRP or high SJC, however uncorrelated with RF/ACPA positivity or early erosions. CONCLUSIONS: PPFs are universally present in RA patients. The reasonability of guiding treatment strategies just based on the presence or absence of PPFs requires further investigation. The categories of PPFs can be simplified and the role of different PPFs combinations in guiding treatment needs to be explored.

Changing epidemiology of cirrhosis from 2010 to 2019: results from the Global Burden Disease study 2019.

BACKGROUND: Liver cirrhosis is a significant yet largely preventable and underappreciated cause of global health loss. This study aimed to profile the global and regional burdens of liver cirrhosis between 2010 and 2019 and the contributions of various aetiologies. METHOD: Data on the incidence, mortality, and disability-adjusted life years (DALYs) of cirrhosis were obtained from the Global Burden of Disease 2019 study. The burden of cirrhosis was estimated by age, sex, region, aetiology, and socio-demographic index (SDI). The temporal trend was quantified using the annual percentage changes (APC.). RESULTS: Globally, there were 2.05 million new cases and 1.47 million deaths due to cirrhosis in 2019. From 2010 to 2019, the age-standardized incidence rate (ASIR) for cirrhosis increased slightly from 25.19 to 25.35 worldwide, while the age-standardized death rate (ASDR) and age-standardized DALYs (ASDALYs) decreased from 20.37 to 18.00 and 639.86 to 560.43, respectively. Cirrhosis incidence, mortality and DALYs were consistently higher in males than females. Stratification according to the socio-demographic index (SDI) revealed that low SDI countries had the highest ASDR and ASDALYs in 2019, while middle SDI countries had the highest ASIR. Regarding the aetiology of cirrhosis, hepatitis C accounted for the largest proportion of cirrhosis-related incidence (26.9%), death (26.8%) and DALYs (26.3%); however, non-alcoholic fatty liver disease (NAFLD) exhibited a rapidly growing cause of incident cirrhosis (+26.7%), cirrhosis-related death (+25.1%), and DALYs (+21.0%) worldwide during this period. The ASIR for NAFLD also significantly increased with APC 1.080 over the study period. CONCLUSIONS: Albeit the global burden of cirrhosis incidence increased from 2010 to 2019, cirrhosis-associated deaths and DALYs declined significantly. Notably, NAFLD exhibited the most significant increase as a contributor to cirrhosis worldwide.

Global burden of cirrhosis incidence increased from 2010 to 2019.Cirrhosis-associated death and DALYs declined significantly during this period.Non-alcoholic fatty liver disease (NAFLD) exhibited the most significant increase as a contributor to cirrhosis worldwide.

Exploring the correlation between HER2 alterations and 18F-FDG PET/CT metabolic parameters and their prognostic value in EGFR-negative non-small-cell lung cancer patients.

PURPOSE: Our study intended to explore the correlation between HER2 alterations and 18F-FDG PET/CT metabolic parameters and their prognostic value in EGFR-negative non-small-cell lung cancer (NSCLC) patients detected by next-generation sequencing (NGS). METHODS: NGS assay was performed in 1737 NSCLC patients, a total of 88 HER2 alterations and 176 negative HER2 with EGFR-negative patients were randomly selected for this study. RESULTS: When the HER2 status with EGFR-negative group was analyzed, multivariate analysis showed that smoking status, primary tumor SUVmax (pSUVmax) < 13.03 and stage were the independent deterministic factors of HER2 alterations. Multivariate cox regression analysis revealed that HER2 status, age, smoking status and stage were independent risk factors for overall survival (OS) in EGFR-negative NSCLC patients with different HER2 status. When the HER2 alterations group was separately analyzed, multivariate analysis demonstrated that low pSUVmax < 15.32 and histology were the independent deterministic factors of HER2 mutation. Multivariate cox regression analysis revealed that pSUVmax, smoking status, nodal involvement and treatment methods were independent risk factors for OS in EGFR-negative NSCLC patients with HER2 alterations. CONCLUSION: The study revealed that low pSUVmax was associated with HER2 alterations in EGFR-negative NSCLC patients, moreover HER2 mutation and HER2 amplification exhibited distinct 18F-FDG metabolic and clinical characteristics. Furthermore, it explored the prognostic value of HER2 alterations and 18F-FDG PET/CT metabolic parameters of pSUVmax in EGFR-negative NSCLC patients.

Prediction of flare following glucocorticoids withdrawal in rheumatoid arthritis patients with continuation of csDMARDs: a real-life study.

OBJECTIVE: To determine the risk factors for flare after glucocorticoids (GC) withdrawal in rheumatoid arthritis (RA) patients with undergoing conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS: RA patients who discontinued GC with continuation of csDMARD were selected from a longitudinal real-world cohort. Established RA was defined as disease duration over 12 months. Dissatisfied RA control was defined as the proportion of simplified disease activity index (SDAI)-based remission time to total time from GC initiation to discontinuation less than 50%. Logistic regression was used to analyze the independent risk factors for flare after GC discontinuation and results were expressed as odds ratio (OR). RESULTS: There were 115 eligible RA patients discounted GC with continuation of csDMARDs (methotrexate: 80%; hydroxychloroquine: 61%; csDMARDs combination: 79%). Of these, 24 patients experienced flare after GC discontinuation. Compared with relapse-free patients, flare patients were more likely to have established RA (75% vs 49%, p = 0.025), higher median cumulative prednisolone dosages (3.3 vs 2.2 g, p = 0.004), and higher proportion of dissatisfied RA control during GC usage (66% vs 33%, p = 0.038). In multivariate analysis, significantly increased flare risk was predicted by established RA (OR 2.93 [1.02-8.43]), cumulative prednisolone dose > 2.5 g (OR 3.69 [1.34-10.19]) and dissatisfied RA control (OR 3.00 [1.09-8.30]). Flare risk was increased with increases in number of risk factors with highest OR of 11.56 in patients with three risk factors (p for trend = 0.002). CONCLUSIONS: Flare following GC withdrawal is not common in RA patients with undergoing csDMARDs therapy. Established RA, higher cumulative GC dose and dissatisfied RA control before GC discontinuation are important factors associated with flare after GC withdrawal.

Incidence, mortality, and risk factors of acute kidney injury after immune checkpoint inhibitors: Systematic review and meta-analysis of real-world evidence.

BACKGROUND: To precisely quantify the incidence, mortality, and risk factors for acute kidney injury (AKI) following immune checkpoint inhibitor (ICI) treatment for cancer in real-world scenarios. METHODS: Comprehensive searches were performed on PubMed, EMBASE and the Cochrane library. Real-world observational studies reporting incidence, mortality and/or factors for AKI in ICI-treated patients were eligible. Odds ratio (OR) with 95% CI for potential predictors and hazard ratio (HR) with 95% CI for mortality risk associated with AKI were calculated using the random-effect model. RESULTS: Eighteen articles comprising 12,111 patients receiving ICI were finally eligible. The pooled incidence was 16.0% (95% CI 11.2%-20.8%; n = 15) for AKI following ICI therapies overall and 3.5% (95% CI 2.1%-4.9%; n = 8) for ICI-induced AKI. Patients who developed AKI during ICI therapies had 51% increased risk of death compared with those without (HR 1.51, 95% CI 1.07-2.14). Regarding risk factors, statistically increased risk for AKI during ICI therapies was observed with preexisting chronic kidney diseases (OR 1.86, 1.25-2.78), diabetes (OR 1.26, 1.04-1.53), and concomitant extrarenal immune-related adverse events (OR 2.53, 1.79-3.56). Ipilimumab (OR 2.18, 1.43-3.32), combined ICI therapies (OR 1.80, 1.14-2.83) and concomitant use of proton pump inhibitors (OR 1.97, 1.56-2.49), renin-angiotensin system inhibitors (OR 1.50, 1.05-2.14), diuretics (OR 1.69, 1.27-2.26) also significantly predicted the incident AKI. CONCLUSIONS: AKI episode is frequently observed during ICI exposure for cancer treatment, but ICI induced nephrotoxicity is only occasionally. Higher risk of AKI during ICI therapies was significantly associated with specific comorbidities, concomitant of certain drugs, ipilimumab and ICI combination therapies.

The Recent Outbreak of COVID-19 in China During the Omicron Variant Predominance: Clinical Features and Outcomes in Patients with Autoimmune Inflammatory Rheumatic Diseases.

INTRODUCTION: The impact of coronavirus disease 2019 (COVID-19) on vulnerable populations with autoimmune inflammatory rheumatic diseases (AIIRDs) has been variable with variants and of great concern. Here we report the clinical features, outcomes, and risk factors for infection and hospitalization in patients with AIIRDs in the first wave of infection in China in December 2022. METHODS: A real-world survey was conducted in Chinese patients with AIIRDs from 8 December 2022 to 13 January 2023. The survey was distributed via internet nationwide, clinic consultation, and to inpatients at a tertiary hospital in Beijing. Clinical features, outcomes, and vaccination status were collected. RESULTS: A total of 2005 patients with AIIRDs completed the survey. There were 1690 (84.3%) patients infected and only 48.2% of patients received COVID-19 vaccination. Most of the fully vaccinated patients received inactivated COVID-19 vaccines, including Sinovac (55.6%) and Sinopharm (27.2%), followed by recombinant subunit vaccine from Zhifei Longcom (2.0%). The independent protecting factors for infection were a time interval of less than 3 months from last vaccination (OR 0.53, p = 0.037) and rheumatoid arthritis (RA) as the underlying AIIRD (OR 0.62, p = 0.041). A total of 57 out of 1690 patients (3.4%) were hospitalized for COVID, with 46 (2.7%) experiencing severe/critical course and 6 deaths (0.4%). In multivariable logistic regression analysis, independent risk factors for hospitalization were age over 60 years (OR 11.52, p < 0.001), with comorbidity (OR 1.83, p = 0.045) and systemic lupus erythematosus (SLE) as the AIIRDs (OR 2.59, p = 0.036). Receiving booster vaccine was an independent protective factor for hospitalization (OR 0.53, 95% CI 0.30-0.98; p = 0.018). CONCLUSION: Hesitation for vaccination is common among Chinese patients with AIIRDs. The time from last vaccination of less than 3 months and having RA decreased the risk of COVID infection. Older age and having comorbidity or SLE increased the risk of hospitalization, while booster vaccination reduced the risk.

The Immune Landscape and Molecular Subtypes of Pediatric Crohn's Disease: Results from In Silico Analysis.

Pediatric Crohn's disease (CD) presents a distinct phenotype from adult-onset disease. A dysregulated immune response is critical in CD pathogenesis; thus, it is clinically important to describe immune cell alterations and to identify a new molecular classification for pediatric CD. To this end, in this study, a RNA-seq derived dataset GSE101794-which contains the expression profiles of 254 treatment-naïve pediatric CD samples, including CIBERSORTx and weighted gene-co-expression network analysis (WGCNA)-were performed to estimate the ratio of immune cells and to identify modules and genes related to specific immune cell infiltration, respectively. Hub genes derived from WGCNA were further employed to create a molecular classification using unsupervised K-means clustering. In the pediatric CD samples, it was found that M2 macrophages, CD4+ memory resting T cells, CD8+ T cells, and resting mast cells were the most prominent immune cells in intestinal tissues. Then, 985 up-regulated genes and 860 down-regulated genes were identified in samples with high immune cell infiltration. Of these differential genes, 10 hub genes (APOA1, CYB5A, XPNPEP2, SLC1A7, SLC4A6, LIPE, G6PC, AGXT2, SLC13A1, and SOAT2) were associated with CD8+T cell infiltration. Clinically, the higher expression of these 10 hub genes was strongly associated with an earlier age of CD onset and colonic-type CD. Furthermore, based on these key genes, pediatric CD could be classified into three molecular subtypes, displaying a different immune landscape. Altogether, this in silico analysis provides a novel insight into the immune signature of pediatric CD, and a new classification of pediatric CD is presented, which may help us develop more personalized disease management and treatments for pediatric CD.

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.