Pathological Priors Inspired Network for Vertebral Osteophytes Recognition.

Automatic vertebral osteophyte recognition in Digital Radiography is of great importance for the early prediction of degenerative disease but is still a challenge because of the tiny size and high inter-class similarity between normal and osteophyte vertebrae. Meanwhile, common sampling strategies applied in Convolution Neural Network could cause detailed context loss. All of these could lead to an incorrect positioning predicament. In this paper, based on important pathological priors, we define a set of potential lesions of each vertebra and propose a novel Pathological Priors Inspired Network (PPIN) to achieve accurate osteophyte recognition. PPIN comprises a backbone feature extractor integrating with a Wavelet Transform Sampling module for high-frequency detailed context extraction, a detection branch for locating all potential lesions and a classification branch for producing final osteophyte recognition. The Anatomical Map-guided Filter between two branches helps the network focus on the specific anatomical regions via the generated heatmaps of potential lesions in the detection branch to address the incorrect positioning problem. To reduce the inter-class similarity, a Bilateral Augmentation Module based on the graph relationship is proposed to imitate the clinical diagnosis process and to extract discriminative contextual information between adjacent vertebrae in the classification branch. Experiments on the two osteophytes-specific datasets collected from the public VinDr-Spine database show that the proposed PPIN achieves the best recognition performance among multitask frameworks and shows strong generalization. The results on a private dataset demonstrate the potential in clinical application. The Class Activation Maps also show the powerful localization capability of PPIN. The source codes are available in https://github.com/Phalo/PPIN.

Preoperative albumin-alkaline phosphatase ratio affects the prognosis of patients undergoing hepatocellular carcinoma surgery.

BACKGROUND: The correlation between the preoperative albuminalkaline phosphatase ratio (AAPR) and the prognosis of hepatocellular carcinoma (HCC) patients after radical resection is still not comprehensive. OBJECTIVE: This study aims to observe the correlation between preoperative AAPR and the prognosis of HCC patients after radical resection. METHODS: We constructed a retrospective cohort study and included 656 HCC patients who underwent radical resection. The patients were grouped after determining an optimum AAPR cut-off value. We used the Cox proportional regression model to assess the correlation between preoperative AAPR and the prognosis of HCC patients after radical resection. RESULTS: The optimal cut-off value of AAPR for assessing the prognosis of HCC patients after radical resection was 0.52 which was acquired by using X-tile software. Kaplan-Meier analysis curves showed that a low AAPR (⩽ 0.52) had a significantly lower rate of overall survival (OS) and recurrence-free survival (RFS) (P< 0.05). Multiple Cox proportional regression showed that an AAPR > 0.52 was a protective factor for OS (HR = 0.66, 95%CI 0.45-0.97, p= 0.036) and RFS (HR = 0.70, 95% CI 0.53-0.92, p= 0.011). CONCLUSIONS: The preoperative AAPR level was related to the prognosis of HCC patients after radical resection and can be used as a routine preoperative test, which is important for early detection of high-risk patients and taking personalized adjuvant treatment.

The Role of Metabolic Dysfunction-Associated Fatty Liver Disease in Developing Chronic Kidney Disease: Longitudinal Cohort Study.

BACKGROUND: The association between metabolic dysfunction-associated fatty liver disease (MAFLD) and chronic kidney disease (CKD) is unclear. OBJECTIVE: This longitudinal cohort study aimed to test whether MAFLD plays an important role in the development of CKD. METHODS: This cohort study included 41,246 participants who had undergone 3 or more health examinations from 2008 to 2015 at the People's Hospital of Guangxi Zhuang Autonomous Region, China. Participants were categorized into 2 groups according to whether they presented with or without MAFLD. The occurrence of new-onset CKD was stated as either an estimated glomerular filtration rate of <60 mL/min per 1.73 m2 or a higher level of albuminuria during their follow-up appointment. The association between MAFLD and CKD was evaluated using a Cox regression method. RESULTS: Of the 41,246 participants, 11,860 (28.8%) were diagnosed with MAFLD. Over the course of the 14-year follow-up (median 10.0 years), 5347 (13%) participants experienced a new incident of CKD (135.73 per 10,000 person-years). MAFLD was discovered as an important risk factor for new incidents of CKD (hazard ratio 1.18, 95% CI 1.11-1.26) by using the multivariable Cox proportional hazard regression model. When stratified by gender, the adjusted hazard ratio for the incidence of CKD in men and women with MAFLD were 1.16 (95% CI 1.07-1.26) and 1.32 (95% CI 1.18-1.48), respectively. According to the subgroup analysis results, after adjusting for confounding factors, the MAFLD-related CKD risk was greater in men aged <60 years (Pinteraction=.001) and in those with combined dyslipidemia (Pinteraction=.02), but this relationship was not found in women (all Pinteraction>.05). CONCLUSIONS: MAFLD plays an important role in the development of new incidents of CKD in the long run. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200058543; https://www.chictr.org.cn/showproj.html?proj=153109.

Sex Differences in the Impact of Metabolic Dysfunction-associated Fatty Liver Disease on the of Patients with Hepatocellular Carcinoma After Radical Resection.

Background: International experts have put forward a new definition for metabolic dysfunction-associated fatty liver disease (MAFLD). Nonetheless, sex differences in MAFLD function in hepatocellular carcinoma (HCC) survival is still unknown. Therefore, the current work focused on exploring the gender-specific association of MAFLD effect on prognosis after radical resection of liver cancer. Methods: The long-term prognostic outcomes of 642 HCC patients undergoing hepatectomy were analyzed retrospectively. To calculate overall survival (OS) and recurrence-free survival (RFS), Kaplan-Meier (KM) curve was plotted. Further, using Cox proportional model to explore the prognostic factors. Sensitivity analysis was performed using propensity score matching (PSM) to balance the confounding bias. Results: For MAFLD patients, median OS and RFS times were 6.8 years and 6.1 years, respectively, compared to 8.5 years and 2.9 years in non-MAFLD patients. KM curve shown that compare with non-MAFLD patients, MAFLD patients had a higher survival rate in men, but had a lower survival rate in women (P<0.05). Multivariate analysis showed that MAFLD was significantly risk factor with mortality in the female (HR = 5.177, 95%CI: 1.475-18.193). However, MAFLD was not related to RFS This correlation was consistent after PSM analysis. Conclusions: MAFLD can improve the mortality of women undergoing radical resection for liver cancer, which independently estimate disease prognosis but is not related to recurrence-free survival.

The relationship between metabolic dysfunction-associated fatty liver disease and the incidence rate of extrahepatic cancer.

Background: The associations between metabolic dysfunction-associated fatty liver disease (MAFLD) and cancer development, especially extrahepatic cancers, are unknown. The aims of the current study were to investigate the cancer incidence rates of MAFLD and analyze the associations between MAFLD and the development of cancers. Methods: This historical cohort study included participants who underwent ultrasonographic detection of hepatic steatosis at a tertiary hospital in China from January 2013 to October 2021. MAFLD was diagnosed in accordance with The International Expert Consensus Statement. Cox proportional hazards regression modeling was used to assess the associations between MAFLD and the development of cancers. Results: Of the 47,801 participants, 16,093 (33.7%) had MAFLD. During the total follow-up of 175,137 person-years (median 3.3 years), the cancer incidence rate in the MAFLD group was higher than that in the non-MAFLD group [473.5 vs. 255.1 per 100,000 person-years; incidence rate ratio 1.86; 95% confidence interval (CI) 1.57-2.19]. After adjustment for age, gender, smoking status, and alcohol status, MAFLD was moderately associated with cancers of the female reproductive system/organs (labium, uterus, cervix, and ovary) [hazard ratio (HR) 2.24; 95% CI 1.09-4.60], thyroid (HR 3.64; 95% CI 1.82-7.30), and bladder (HR 4.19; 95% CI 1.15-15.27) in the total study cohort. Conclusion: MAFLD was associated with the development of cancers of the female reproductive system/organs (labium, uterus, cervix, and ovary), thyroid, and bladder in the total study cohort.

Metabolic dysfunction-associated fatty liver disease can significantly increase the risk of chronic kidney disease in adults with type 2 diabetes.

AIMS: This study is to explore the relationship between metabolic dysfunction-associated fatty liver disease (MAFLD) and chronic kidney disease (CKD) among populations with type 2 diabetes through longitudinal cohort study. METHODS: 3,627 subjects who had received at least three health examinations between 2008 and 2015 were included. CKD was stated as subjects with an eGFR < 60 mL/min per 1·73 m2 or the occurrence of 2 or more proteinuria during their follow-up. RESULTS: After median of 10·0 years follow up, 837 (23·1%) developed CKD (244·7 per 10,000 person-years; 95 % CI, 228.4 - 261·8). MAFLD ([HR] 1·46; 95 % CI 1·26-1·70, P < 0.001) acts as an important risk factor of developing CKD. After adjusting for confounding factors, this association was consistent (HR 1·30; 95 % CI 1·11-1·53, P < 0.001). In stratified analysis, subjects aged < 60 years were likely to have greater risk of MAFLD-related CKD (HR 1·58 and 1·03; 95 % CI 1·28-1·95 and 0·79-1·33, P < 0.001 in both cases, respectively). CONCLUSIONS: The risk of developing CKD in type 2 diabetes adults with MAFLD was higher, especially if they are below 60 years old. This study underscores the importance of early prevention strategies for MAFLD to reduce the occurrence of CKD in type 2 diabetes adults.

Prevalence and clustering of cardiovascular risk factors among resident of coastal areas in Qinzhou, Guangxi, China.

OBJECTIVE: We aimed to estimate the prevalence of CRFs and investigate its associated social-economic factors among adults in coastal areas of Qinzhou, Guangxi. METHODS: A representative sample of 1836 participants aged 20 to 70 years was included in Qinzhou, Guangxi in 2020. Data were collected by the questionnaire, anthropometric and laboratory measurements. The prevalence of CRFs, including hypertension, dyslipidemia, diabetes, overweight or obesity, alcohol consumption, and smoking were calculated by standardization. The multivariate logistic regression analysis was performed to explore the independent factors associated with the presence of CRFs. RESULTS: The age-standardized prevalence of hypertension, dyslipidemia, diabetes, overweight or obesity alcohol consumption, and smoking was 42.7%, 39.5%, 0.9%, 38.5%, 18.4% and 15.7%, respectively. The prevalence of clustering of at least one and at least two cardiovascular disease risk factors were 82.2% and 45.3% in total. There were differences in the aggregation of cardiovascular risk factors among different age, education, and income levels. There appeared higher clustering of at least one and at least two CRFs among adults with lower education level, higher income level and those elderly. CONCLUSIONS: Compared with other regions in China, a higher prevalence of CRFs exists among adults in Guangxi and several social-economic factors were associated with the presence of CRFs. These findings suggest that we should implement effective measures to control the CRFs, to reduce the risk of cardiovascular disease in adults.

Design, Synthesis and Biological Evaluation of Novel and Potent Protein Arginine Methyltransferases 5 Inhibitors for Cancer Therapy.

Protein arginine methyltransferases 5 (PRMT5) is a clinically promising epigenetic target that is upregulated in a variety of tumors. Currently, there are several PRMT5 inhibitors under preclinical or clinical development, however the established clinical inhibitors show favorable toxicity. Thus, it remains an unmet need to discover novel and structurally diverse PRMT5 inhibitors with characterized therapeutic utility. Herein, a series of tetrahydroisoquinoline (THIQ) derivatives were designed and synthesized as PRMT5 inhibitors using GSK-3326595 as the lead compound. Among them, compound 20 (IC50: 4.2 nM) exhibits more potent PRMT5 inhibitory activity than GSK-3326595 (IC50: 9.2 nM). In addition, compound 20 shows high anti-proliferative effects on MV-4-11 and MDA-MB-468 tumor cells and low cytotoxicity on AML-12 hepatocytes. Furthermore, compound 20 possesses acceptable pharmacokinetic profiles and displays considerable in vivo antitumor efficacy in a MV-4-11 xenograft model. Taken together, compound 20 is an antitumor compound worthy of further study.

PCAN: Pixel-wise classification and attention network for thoracic disease classification and weakly supervised localization.

Automatic chest X-ray (CXR) disease classification has drawn increasing public attention as CXR is widely used in thoracic disease diagnosis. Existing classification networks typically employ a global average pooling layer to produce the final feature for the subsequent classifier. This limits the classification performance owing to the characteristics of lesions in CXR images, including small relative sizes, varied absolute sizes, and different occurrence locations. In this study, we propose a pixel-wise classification and attention network (PCAN) to simultaneously perform disease classification and weakly supervised localization, which provides interpretability for disease classification. The PCAN comprises a backbone network for extracting mid-level features, a pixel-wise classification branch (pc-branch) for generating pixel-wise diagnoses, and a pixel-wise attention branch (pa-branch) for producing pixel-wise weights. The pc-branch is capable of explicitly detecting small lesions, and the pa-branch is capable of adaptively focusing on different regions when classifying different thoracic diseases. Then, the pixel-wise diagnoses are multiplied with the pixel-wise weights to obtain the disease localization map, which provides the sizes and locations of lesions in a manner of weakly supervised learning. The final image-wise diagnosis is obtained by summing up the disease localization map at the spatial dimension. Comprehensive experiments conducted on the ChestX-ray14 and CheXpert datasets demonstrate the effectiveness of the proposed PCAN, which has great potential for thoracic disease diagnosis and treatment. The source codes are available at https://github.com/fzfs/PCAN.

Discovery of the First Selective IDO2 Inhibitor As Novel Immunotherapeutic Avenues for Rheumatoid Arthritis.

Indoleamine 2,3-dioxygenase 2 (IDO2), a closely related homologue of well-studied immunomodulatory enzyme IDO1, has been identified as a pathogenic mediator of inflammatory autoimmunity in preclinical models. Therapeutic targeting IDO2 in autoimmune diseases has been challenging due to the lack of small-molecule IDO2 inhibitors. Here, based on our previously developed IDO1/IDO2 dual inhibitor, guided by the homology model of the IDO2 structure, we discovered compound 22, the most potent inhibitor targeting IDO2 with good in vitro inhibitory activity (IDO2 IC50 = 112 nM). Notably, treatment with 22 alleviated disease severity and reduced inflammatory cytokines in both the collagen-induced arthritis (CIA) mice model and adjuvant arthritis (AA) rat model. Our study offered for the first time a selective small-molecule IDO2 inhibitor 22 with IC50 at the nanomolar level, which may be used not only as a candidate compound for the treatment of autoimmune diseases but also as a tool compound for further IDO2-related mechanistic study.

Value of CSF-Cl, CSF-GS, CSF-MALB, and CSF-ADA in Differential Diagnosis of Secondary Hydrocephalus.

Objectives: To investigate the value of cerebrospinal fluid chloride (CSF-Cl), cerebrospinal fluid glucose (CSF-GS), cerebrospinal fluid microalbumin (CSF-MALB), and cerebrospinal fluid adenosine deaminase (CSF-ADA) in the differential diagnosis of secondary hydrocephalus. Methods: 103 patients with secondary hydrocephalus treated in our hospital from January 2018 to April 2022 were selected. According to different types, it is divided into the hemorrhagic hydrocephalus group and tumor hydrocephalus group. By detecting the levels of inflammatory factors such as CSF-Cl, CSF-GS, CSF-MALB, and CSF-ADA in the two groups, we can analyze the value of these inflammatory factors in the differential diagnosis of secondary hydrocephalus. Results: The level of CSF-MALB in the hemorrhagic hydrocephalus group was significantly higher than that in the tumor hydrocephalus group, and the difference between the two groups was statistically significant (P < 0.05). There was no significant difference in the levels of CSF-Cl, CSF-GS, and CSF-ADA between the two groups (P > 0.05). The area under ROC curve (AUC) of CSF-Cl, CSF-GS, CSF-MALB, and CSF-ADA in the differential diagnosis of secondary hydrocephalus was 0.438, 0.553, 0.750, and 0.542, respectively, sensitivity was 15.1%, 45.3%, 79.2%, and 18.9%, respectively, and specificity was 96.0%, 80.0%, 80.0%, and 94.0%, respectively. Conclusions: The inflammatory reaction of hemorrhagic hydrocephalus was significantly greater than that of tumor hydrocephalus. Moreover, CSF-MALB is closely related to the pathogenesis of hemorrhagic hydrocephalus. At the same time, CSF-MALB can be used as a good index for rapid differential diagnosis of secondary hydrocephalus.

Endothelial microparticles exert differential effects on functions of Th1 in patients with acute coronary syndrome.

BACKGROUND: Endothelial microparticles (EMPs) can be involved in inflammatory process, blood coagulation, and regulation of vascular function. However, it remains unclear whether EMPs participate in the pathogenesis of ACS. The purpose of this study is to investigate the impact of EMPs on Th1/Th2 development and functions in vitro. METHODS: Eight-five patients were allocated into SAP group (n=27), UAP group (n=28), and AMI group (n=30). Twenty hospitalized patients with normal coronary angiography were recruited as controls. The frequency of EMPs, IFN-γ, and IL-4 levels were measured, and the correlation between EMPs and Th1/Th2 cytokine was analyzed. PBMCs isolated from patients with ACS were treated in vitro with EMPs. This was followed by flow cytometry for Th1/Th2 counts, real-time PCR and western blotting for T-bet and GATA mRNA and protein expression, and ELISA for IFN-γ, TNF-α, IL-4, and IL-10. RESULTS: This study proved that the frequency of EMPs was significantly increased in ACS patients. There was a significant positive correlation between EMPs and IFN-γ. EMPs could significantly upregulate the differentiation and function of Th1 through increasing the expression of T-bet mRNA and protein. Furthermore, this study also indicated that EMP treatment in vitro could promote the expression of TNF-α, which exerts adverse effects on the pathogenesis and progression of atherosclerosis. CONCLUSIONS: EMPs may be involved in the immune and inflammatory processes that take part in artery atherosclerosis and that they do so by regulating Th1/Th2 differentiation and function. They may play an important role in the pathogenesis of coronary atherosclerosis and plaque instability.