Association of red cell distribution width/albumin ratio and in hospital mortality in patients with atrial fibrillation base on medical information mart for intensive care IV database.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia. The ratio of red cell distribution width (RDW) to albumin has been recognized as a reliable prognostic marker for poor outcomes in a variety of diseases. However, the evidence regarding the association between RDW to albumin ratio (RAR) and in hospital mortality in patients with AF admitted to the Intensive Care Unit (ICU) currently was unclear. The purpose of this study was to explore the association between RAR and in hospital mortality in patients with AF in the ICU. METHODS: This retrospective cohort study used data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database for the identification of patients with atrial fibrillation (AF). The primary endpoint investigated was in-hospital mortality. Multivariable-adjusted Cox regression analysis and forest plots were utilized to evaluate the correlation between the RAR and in-hospital mortality among patients with AF admitted to ICU. Additionally, receiver operating characteristic (ROC) curves were conducted to assess and compare the predictive efficacy of RDW and the RAR. RESULTS: Our study included 4,584 patients with AF with a mean age of 75.1 ± 12.3 years, 57% of whom were male. The in-hospital mortality was 20.3%. The relationship between RAR and in-hospital mortality was linear. The Cox proportional hazard model, adjusted for potential confounders, found a high RAR independently associated with in hospital mortality. For each increase of 1 unit in RAR, there is a 12% rise in the in-hospital mortality rate (95% CI 1.06-1.19). The ROC curves revealed that the discriminatory ability of the RAR was better than that of RDW. The area under the ROC curves (AUCs) for RAR and RDW were 0.651 (95%CI: 0.631-0.671) and 0.599 (95% CI: 0.579-0.620). CONCLUSIONS: RAR is independently correlated with in hospital mortality and in AF. High level of RAR is associated with increased in-hospital mortality rates.

HCC prediction models in chronic hepatitis B patients receiving entecavir or tenofovir: a systematic review and meta-analysis.

BACKGROUND: Our study aimed to compare the predictive performance of different hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B patients receiving entecavir or tenofovir, including discrimination, calibration, negative predictive value (NPV) in low-risk, and proportion of low-risk. METHODS: We conducted a systematic literature research in PubMed, EMbase, the Cochrane Library, and Web of Science before January 13, 2022. The predictive performance was assessed by area under receiver operating characteristic curve (AUROC), calibration index, negative predictive value, and the proportion in low-risk. Subgroup and meta-regression analyses of discrimination and calibration were conducted. Sensitivity analysis was conducted to validate the stability of the results. RESULTS: We identified ten prediction models in 23 studies. The pooled 3-, 5-, and 10-year AUROC varied from 0.72 to 0.84, 0.74 to 0.83, and 0.76 to 0.86, respectively. REAL-B, AASL-HCC, and HCC-RESCUE achieved the best discrimination. HCC-RESCUE, PAGE-B, and mPAGE-B overestimated HCC development, whereas mREACH-B, AASL-HCC, REAL-B, CAMD, CAGE-B, SAGE-B, and aMAP underestimated it. All models were able to identify people with a low risk of HCC accurately. HCC-RESCUE and aMAP recognized over half of the population as low-risk. Subgroup analysis and sensitivity analysis showed similar results. CONCLUSION: Considering the predictive performance of all four aspects, we suggest that HCC-RESCUE was the best model to utilize in clinical practice, especially in primary care and low-income areas. To confirm our findings, further validation studies with the above four components were required.

Age and Serum Creatinine Can Differentiate Wilson Disease Patients with Pseudonormal Ceruloplasmin.

Methods: We retrospectively screened individuals with serum Cp ≥ 140 mg/L from 1032 WD patients who were hospitalised for the first time. Logistic regression analyses were performed in a case-control study between the WD cohort and another liver disease cohort to explore the independent risk factors for WD diagnosis and establish a regression model to identify them. The follow-up medical records of the WD cohort were subjected to mixed-effects model analysis in a longitudinal study to discover factors associated with Cp normalisation. Results: Eighty-six WD patients and their 353 medical records and another 98 non-WD liver disease patients were included in the present study. Cp normalisation was significantly associated with the copper burden and liver function indexes, such as urinary copper, γ-glutamyltransferase, and albumin (p ≤ 0.001). Logistic regression analysis showed that age and serum creatinine (p ≤ 0.001) were independent risk factors associated with WD. The AUC value of the regression model in the total cohort was 0.926 (p ≤ 0.001). At a cutoff value of ≥0.617 and ≥-1, the positive and negative predictive values were both 90.8% for WD. Conclusion: Increased serum Cp in WD patients is related to excessive copper burden and hepatic injury, and common tests can effectively distinguish WD patients from other liver injury patients.

Indole-3-carbinol ameliorates necroptosis and inflammation of intestinal epithelial cells in mice with ulcerative colitis by activating aryl hydrocarbon receptor.

Ulcerative colitis (UC) is a disease characterized by inflammation and disruption of the intestinal epithelial barrier. Necroptosis plays a critical role in disease progression. Indole-3-carbinol (I3C), a natural dietary agonist of aryl hydrocarbon receptor (AHR), has shown alleviating effects on UC. However, its mechanisms of action have not been comprehensively elucidated. Therefore, we aimed at investigating the protective role of I3C in DSS-induced colitis mice models. I3C significantly ameliorated body weight loss, colon length shortening and colonic pathological damage in colitis mice, reduced disease activity index (DAI) and histological (HI) scores, as well as alleviated colonic necroptosis and inflammation. In vitro, I3C attenuated necroptosis and inflammation of colonoids and NCM460 cells. AHR, activated by I3C, inhibits activation of receptor-interacting protein kinase 1 (RIPK1) and the subsequent assembly of necrosome in a time-dependent manner, as well as suppressing NF-κB activation and decreasing TNF-α, IL-1ß, IL-6 and IL-8 expression. Silencing of AHR aggravated necroptosis and inflammation of NCM460 cells, and did not be ameliorated by I3C. Furthermore, AHR activation induces the expression of inhibitor of apoptosis proteins (IAPs) and the ubiquitination of RIPK1. In conclusion, I3C exerts a protective effect in DSS-induced colitis mice models by alleviating the necroptosis and inflammation of IECs through activating AHR.

Incidence of malnutrition and changes in phosphocalcic metabolism in perioperative liver transplantation patients -a retrospective study in a tertiary children's hospital in China.

BACKGROUND: The primary aim of the study was to assess the nutritional status of pediatric liver transplant outpatients in nutrition clinic, particularly the nutritional status of their bones.  METHODS: One hundred thirty-eight pediatric liver transplant outpatients, who had visited the nutrition clinic in Shanghai Children's Medical Center between January 2017 and December 2019, were recruited. The bone mineral density (BMD) z-scores were determined by dual energy X-ray absorptiometry (DXA). Nutritional assessment was performed, and their corresponding height-for-age z-scores (HAZs)/weight-for-age z-scores (WAZs)/BMI-for-age z-scores (BMIZs) were obtained. RESULTS: A total of 138 patients came to our nutrition outpatient clinic, including 68 boys (49.3%) and 70 girls (50.7%). The median age was 0.87y (0.68y, 1.71y). Among these patients, 44 (31.9%) had acute malnutrition with WAZ/BMIZ value -1.14 (-2.38, -0.18), 55 (38.4%) had chronic malnutrition with HAZ value -1.51 (-2.39, -0.38), and 96 (69.6%) had a BMD lower than normal. The BMD z-score was significantly correlated with the WAZ/BMIZ value (Spearman's correlation coefficient = 0.334, p < 0.001). A total of 37 infants re-visited the nutrition clinic for a follow-up after (147 ± 127) days. The WAZ/BMIZ value of the re-visiting patients and the BMD z-score of the re-visiting patients were significantly improved compared to those of the first-visit patients (p = 0.004 and p = 0.001 respectively). CONCLUSIONS: There were different rates of malnutrition before and after liver transplantation. At the same time, BMD Z-score and serum vitamin D level of patients decreased. There was a significant correlation between BMD z-scores and WAZ/BMIZ values. Proper and professional nutrition guidance significantly improved the WAZ/BMIZ-values and BMD Z-score of liver transplantation patients.

The role of fibrosis index FIB-4 in predicting liver fibrosis stage and clinical prognosis: A diagnostic or screening tool?

This review evaluates the ability of the fibrosis index based on four factors (FIB-4) identifying fibrosis stages, long-time prognosis in chronic liver disease, and short-time outcomes in acute liver injury. FIB-4 was accurate in predicting the absence or presence of advanced fibrosis with cut-offs of 1.0 and 2.65 for viral hepatitis B, 1.45 and 3.25 for viral hepatitis C, 1.30 (<65 years), 2.0 (≥65 years), and 2.67 for non-alcoholic fatty liver disease (NAFLD), respectively, but had a low-to-moderate accuracy in alcoholic liver disease (ALD) and autoimmune hepatitis. It performed better in excluding fibrosis, so we built an algorithm for identifying advanced fibrosis by combined methods and giving work-up and follow-up suggestions. High FIB-4 in viral hepatitis, NAFLD, and ALD was associated with significantly high hepatocellular carcinoma incidence and mortality. Additionally, FIB-4 showed the ability to predict high-risk varices with cut-offs of 2.87 and 3.91 in cirrhosis patients and predict long-term survival in hepatocellular carcinoma patients after hepatectomy. In acute liver injury caused by COVID-19, FIB-4 had a predictive value for mechanical ventilation and 30-day mortality. Finally, FIB-4 may act as a screening tool in the secondary prevention of NAFLD in the high-risk population.

Assessment of nutritional status in paediatric outpatients using bioelectrical impedance analysis and anthropometric z-scores.

AIM: To investigate paediatric outpatients' nutritional status using bioelectrical impedance analysis and anthropometric z-scores. METHODS: A retrospective data analysis of tertiary paediatric hospital outpatients from 2017 to 2019 was conducted. Patients were categorised into three groups (non-illness, illness and simple obesity) according to clinical diagnoses. The nutritional status was evaluated using anthropometric and bioelectrical impedance analysis. In addition, body composition measurements of patients in three subgroups of the illness group and age- and gender-matched healthy controls were compared. RESULTS: A total of 2015 paediatric outpatients were enrolled. According to body mass index z-scores, undernutrition prevalence among participants was 14.0% (non-illness group, 21.3%; illness group, 11.4%). Body composition measurements indicated that 41.6% of participants had a low fat-free mass index, and the proportions of participants with a low fat-free mass index in the non-illness, illness and simple obesity groups were 48.4, 47.0 and 10.7%, respectively. Compared with healthy controls, the haematology and oncology subgroup had a significantly lower fat-free mass index and fat mass index; the nephrology and rheumatology subgroup had significantly lower height-for-age z-scores but higher fat mass index; and the gastroenterology subgroups had lower fat mass index, fat-free mass index and body mass index z-scores. CONCLUSIONS: The results suggested the low fat-free mass index prevalence was greater than the low body mass index z-score prevalence among paediatric outpatients, and body composition parameters varied across different illnesses. Body composition analysis is recommended in nutrition clinics for accurate paediatric outpatient nutritional assessment, thereby providing timely individualised nutritional interventions.

ACEI/ARB use and risk of infection or severity or mortality of COVID-19: A systematic review and meta-analysis.

The effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on the risk of COVID-19 infection and disease progression are yet to be investigated. The relationship between ACEI/ARB use and COVID-19 infection was systematically reviewed. To identify relevant studies that met predetermined inclusion criteria, unrestricted searches of the PubMed, Embase, and Cochrane Library databases were conducted. The search strategy included clinical date published until May 9, 2020. Twelve articles involving more than 19,000 COVID-19 cases were included. To estimate overall risk, random-effects models were adopted. Our results showed that ACEI/ARB exposure was not associated with a higher risk of COVID-19 infection (OR = 0.99; 95 % CI, 0-1.04; P = 0.672). Among those with COVID-19 infection, ACEI/ARB exposure was also not associated with a higher risk of having severe infection (OR = 0.98; 95 % CI, 0.87-1.09; P = 0.69) or mortality (OR = 0.73, 95 %CI, 0.5-1.07; P = 0.111). However, ACEI/ARB exposure was associated with a lower risk of mortality compared to those on non-ACEI/ARB antihypertensive drugs (OR = 0.48, 95 % CI, 0.29-0.81; P = 0.006). In conclusion, current evidence did not confirm the concern that ACEI/ARB exposure is harmful in patientswith COVID-19 infection. This study supports the current guidelines that discourage discontinuation of ACEIs or ARBs in COVID-19 patients and the setting of the COVID-19 pandemic.

A system dynamics modelling simulation based on a cohort of hepatitis B epidemic research in east China community.

Hepatitis B constitutes a severe public health challenge in China. The Community-based Collaborative Innovation hepatitis B (CCI-HBV) project is a national epidemiological study of hepatitis B and has been conducting a comprehensive intervention in southern Zhejiang since 2009.The comprehensive intervention in CCI-HBV areas includes the dynamic hepatitis B screening in local residents, the normalised treatment for hepatitis B infections and the upcoming full-aged hepatitis B vaccination. After two rounds of screening (each round taking for 4 years), the initial epidemiological baseline of hepatitis B in Qinggang was obtained, a coastal community in east China. By combining key data and system dynamics modelling, the regional hepatitis B epidemic in 20 years was predicted.There were 1041 HBsAg positive cases out of 12 228 people in Round 1 indicating HBV prevalence of 8.5%. Of the 13 146 people tested in Round 2, 1171 people were HBsAg positive, with a prevalence of 8.9%. By comparing the two rounds of screening, the HBV incidence rate of 0.192 per 100 person-years was observed. By consulting electronic medical records, the HBV onset rate of 0.533 per 100 person-years was obtained. We generated a simulated model to replicate the real-world situation for the next two decades. To evaluate the effect of interventions on regional HBV prevalence, three comparative experiments were conducted.In this study, the regional hepatitis B epidemic in 20 years was predicted and compared with HBV prevalence under different interventions. Owing to the existing challenges in research methodology, this study combined HBV field research and simulation to provide a system dynamics model with close-to-real key data to improve prediction accuracy. The simulation also provided a prompt guidance for the field implementation.

H3 relaxin inhibits the collagen synthesis via ROS- and P2X7R-mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose.

Excessive production of reactive oxygen species (ROS) and P2X7R activation induced by high glucose increases NLRP3 inflammasome activation, which contributes to the pathogenesis of diabetic cardiomyopathy. Although H3 relaxin has been shown to inhibit cardiac fibrosis induced by isoproterenol, the mechanism has not been well studied. Here, we demonstrated that high glucose (HG) induced the collagen synthesis by activation of the NLRP3 inflammasome, leading to caspase-1 activation, interleukin-1ß (IL-1ß) and IL-18 secretion in neonatal rat cardiac fibroblasts. Moreover, we used a high-glucose model with neonatal rat cardiac fibroblasts and showed that the activation of ROS and P2X7R was augmented and that ROS- and P2X7R-mediated NLRP3 inflammasome activation was critical for the collagen synthesis. Inhibition of ROS and P2X7R decreased NLRP3 inflammasome-mediated collagen synthesis, similar to the effects of H3 relaxin. Furthermore, H3 relaxin reduced the collagen synthesis via ROS- and P2X7R-mediated NLRP3 inflammasome activation in response to HG. These results provide a mechanism by which H3 relaxin alleviates NLRP3 inflammasome-mediated collagen synthesis through the inhibition of ROS and P2X7R under HG conditions and suggest that H3 relaxin represents a potential drug for alleviating cardiac fibrosis in diabetic cardiomyopathy.

NLRP3 inflammasome activation in liver cirrhotic patients.

AIMS: NLRP3 inflammasome activation is involved in the mechanism of liver cirrhosis. In this study, we investigated the levels of plasma IL-1ß and IL-18 and their relationship to component traits in patients with liver cirrhosis, and NLRP3 inflammasome expression in liver of patients with liver cirrhosis. METHODS: A total of 75 patients with liver cirrhosis and 41 age-matched healthy control subjects were enrolled in this study. NLRP3 inflammasome expression and activation were measured in liver of patients with liver cirrhosis. Plasma IL-1ß and IL-18 levels were examined by ELISA in patients with liver cirrhosis. RESULTS: Plasma IL-1ß and IL-18 levels were also significantly higher in patients with liver cirrhosis than in control subjects. Plasma IL-18 levels were significantly positively associated with Child-Pugh classification, IL-1ß levels, diastolic blood pressure, aspartate aminotransferase, total bilirubin, direct bilirubin, activated partial thromboplastin timealk and aline phosphatase. Plasma IL-18 levels were significantly negatively associated with albumin. NLRP3 and cleaved caspase-1 expression were increased in the livers of patients with cirrhosis compared with the livers of control subjects. CONCLUSIONS: Plasma IL-1ß and IL-18 levels were higher in plasma in patients with liver cirrhosis than in control subjects, and plasma IL-18 levels were significantly positively associated with Child-Pugh classification and IL-1ß levels. In addition, NLRP3 and cleaved caspase-1 expression were increased in the livers of patients with cirrhosis.

H3 Relaxin Protects Against Myocardial Injury in Experimental Diabetic Cardiomyopathy by Inhibiting Myocardial Apoptosis, Fibrosis and Inflammation.

BACKGROUND/AIMS: Apoptosis, fibrosis and NLRP3 inflammasome activation are involved in the development of diabetic cardiomyopathy (DCM). Human recombinant relaxin-3 (H3 relaxin) is a novel bioactive peptide that inhibits cardiac injury; however, whether H3 relaxin prevents cardiac injury in rats with DCM and the underlying mechanisms are unknown. METHODS: To investigate the effect of H3 relaxin on DCM, we performed a study using H3 relaxin treatment in male Sprague-Dawley (SD) rats with streptozotocin (STZ)-induced diabetes (DM). We measured apoptosis, fibrosis and NLRP3 inflammasome markers in the rat hearts four and eight weeks after the rats were injected with STZ (65 mg/kg) by western blot analysis. Subsequently, 2 or 6 weeks after the STZ treatment, the rats were treated with H3 relaxin [2 µg/kg/d (A group) or 0.2 µg/kg/d (B group)] for 2 weeks. Cardiac function was evaluated by echocardiography to determine the extent of myocardial injury in the DM rats. The protein levels of apoptosis, fibrosis and NLRP3 inflammasome markers were used to assess myocardial injury. In addition, we determined the plasma levels of IL-1ß and IL-18 using a Milliplex MAP Rat Cytokine/Chemokine Magnetic Bead Panel kit. RESULTS: The protein expression of cleaved caspase-8, caspase-9 and caspase-3 as well as fibrosis markers increased at 4 and 8 weeks in the STZ-induced diabetic hearts compared with the levels in the control group. Furthermore, the NLRP3 inflammasome was substantially activated in STZ-induced diabetic hearts, leading to increased IL-1ß and IL-18 levels. Compared with the DM group, the A group exhibited substantially better cardiac function. The protein levels of apoptosis markers were attenuated by H3 relaxin, indicating that H3 relaxin inhibited myocardial apoptosis in the hearts of diabetic rats. The protein expression of fibrosis markers was inhibited by H3 relaxin. Additionally, the protein expression and activation of the NLRP3 inflammasome were also effectively attenuated by H3 relaxin. CONCLUSIONS: This study is the first to demonstrate that H3 relaxin plays an anti-apoptotic, anti-fibrotic and anti-inflammatory role in DCM.

Alterations of relaxin and its receptor system components in experimental diabetic cardiomyopathy rats.

High glucose induces apoptosis of cardiomyocytes and fibrosis of cardiac fibroblasts, contributing to diabetic cardiomyopathy. In this work, we explore the production of relaxin alterations and the significance of their receptor system components in the hearts of experimental diabetic cardiomyopathy rats. We measured rat relaxin-1 (equivalent to human relaxin-2), relaxin-3, RXFP1 and RXFP3 mRNA expression in the hearts of experimental diabetic cardiomyopathy rats. Neonatal rat ventricular myocytes (NRVMs) and cardiac fibroblasts were treated with 5.5 mmol/l normal glucose (NG) and 33 mmol/l high glucose (HG) for 0, 6, 12, 24, 48 and 72 h. Rat relaxin-1, relaxin-3, RXFP1 and RXFP3 mRNA expression were determined by real-time PCR. In the present study, we offer the first evidence that Relaxin-1 mRNA significantly increased and Relaxin-3 mRNA expression decreased at 4 and 8 weeks after STZ in the hearts of diabetic rats. In addition, significant down regulation of the mRNA expression of RXFP1 and RXFP3 was observed at 4 w after STZ; however, the mRNA expression levels of RXFP1 and RXFP3 were increased at 8 weeks after STZ. Apoptotic NRVMs induced by high glucose generate a decreased level of relaxin-1 and RXFP1. In HG-administered cardiac fibroblasts, Relaxin-1 mRNA was significantly increased and relaxin-3 mRNA was significantly decreased. Additionally, the mRNA expression of RXFP1 was decreased, and the mRNA expression of RXFP3 was increased. This results showed that an important role of relaxin-2, relaxin-3 and their receptors system in the regulation of diabetic cardiomyopathy.

Characterization of the intestinal microbiome of Hirschsprung's disease with and without enterocolitis.

Hirschsprung's disease (HD) is a congenital malformation of the gastrointestinal tract characterized by the absence of the distal enteric nervous system. Hirschsprung-associated enterocolitis (HAEC) is severe life threatening complication of HD. The disease pathogenesis is still unclear, but evidences suggest that the intestinal microbiota may play important role in the development of HD and HAEC. Because microbial abundance and diversity might differ in HD patients with enterocolitis, we sought to generate comparative metagenomic signatures to characterize the structure of the microbiome in HD patients with and without enterocolitis. Our experimental design is to enroll four HD patients (two with enterocolitis and two without enterocolitis). The microbiome was characterized by 16S rRNA gene, and the data obtained will be used to taxonomically classify and compare community structure among different samples. We found that the structure of the microbiome within HAEC patients are differ from those without enterocolitis. This study helps us to understand microbial contributions to the etiology of Hirschsprung-associated enterocolitis.

Emerging function of main RNA methylation modifications in the immune microenvironment of digestive system tumors.

Digestive system tumors have been reported in more than 25% of all cancer cases worldwide, bringing a huge burden on the healthcare system. RNA methylation modification-an important post-transcriptional modification-has become an active research area in gene regulation. It is a dynamic and reversible process involving several enzymes, such as methyltransferases, demethylases, and methylation reader proteins. This review provides insights into the role of three major methylation modifications, namely m6A, m5C, and m1A, in the development of digestive system tumors, specifically in the development of tumor immune microenvironment (TIME) of these malignancies. Abnormal methylation modification affects immunosuppression and antitumor immune response by regulating the recruitment of immune cells and the release of immune factors. Understanding the mechanisms by which RNA methylation regulates digestive system tumors will be helpful in exploring new therapeutic targets.

Connectome-based prediction of cognitive performance in patients with temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) patients often exhibit varying degrees of cognitive impairments. This study aims to predict cognitive performance in TLE patients by applying a connectome-based predictive model (CPM) to whole-brain resting-state functional connectivity (RSFC) data. METHODS: A CPM was established and leave-one-out cross-validation was employed to decode the cognitive performance of patients with TLE based on the whole-brain RSFC. RESULTS: Our findings indicate that cognitive performance in TLE can be predicted through the internal and network connections of the parietal lobe, limbic lobe, and cerebellum systems. These systems play crucial roles in cognitive control, emotion processing, and social perception and communication, respectively. In the subgroup analysis, CPM successfully predicted TLE patients with and without focal to bilateral tonic-clonic seizures (FBCTS). Additionally, significant differences were noted between the two TLE patient groups and the normal control group. CONCLUSION: This data-driven approach provides evidence for the potential of predicting brain features based on the inherent resting-state brain network organization. Our study offers an initial step towards an individualized prediction of cognitive performance in TLE patients, which may be beneficial for diagnosis, prognosis, and treatment planning.

Clinical Significance of a Novel Vasculogenic Mimicry-Based Prognostic Model in Hepatocellular Carcinoma.

BACKGROUND: Vasculogenic mimicry, a novel neovascularization pattern of aggressive tumors, is associated with poor clinical outcomes. OBJECTIVE: The aim of this research was to establish a new model, termed VC score, to predict the prognosis, Tumor Microenvironment (TME) components, and immunotherapeutic response in Hepatocellular Carcinoma (HCC). METHODS: The expression data of the public databases were used to develop the prognostic model. Consensus clustering was performed to confirm the molecular subtypes with ideal clustering efficacy. The high- and low-risk groups were stratified utilizing the VC score. Various methodologies, including survival analysis, single-sample Gene Set Enrichment Analysis (ssGSEA), Tumor Immune Dysfunction and Exclusion scores (TIDE), Immunophenoscore (IPS), and nomogram, were utilized for verification of the model performance and to characterize the immune status of HCC tissues. GSEA was performed to mine functional pathway information. RESULTS: The survival and immune characteristics varied between the three molecular subtypes. A five-gene signature (TPX2, CDC20, CFHR4, SPP1, and NQO1) was verified to function as an independent predictive factor for the prognosis of patients with HCC. The high-risk group exhibited lower Overall Survival (OS) rates and higher mortality rates in comparison to the low-risk group. Patients in the low-risk group were predicted to benefit from immune checkpoint inhibitor therapy and exhibit increased sensitivity to immunotherapy. Enrichment analysis revealed that signaling pathways linked to the cell cycle and DNA replication processes exhibited enrichment in the high-risk group. CONCLUSIONS: The VC score holds the potential to establish individualized treatment plans and clinical management strategies for patients with HCC.

Prognostic and immune predictive roles of a novel tricarboxylic acid cycle-based model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. Since the tricarboxylic acid cycle is widely involved in tumor metabolic reprogramming and cuproptosis, investigating related genes may help to identify prognostic signature of patients with HCC. Data on patients with HCC were sourced from public datasets, and were divided into train, test, and single-cell cohorts. A variety of machine learning algorithms were used to identify different molecular subtypes and determine the prognostic risk model. Our findings revealed that the risk score (TRscore), based on the genes OGDHL, CFHR4, and SPP1, showed excellent predictive performance in different datasets. Pathways related to cell cycle and immune inflammation were enriched in the high-risk group, whereas metabolism-related pathways were significantly enriched in the low-risk group. The high-risk group was associated with a greater number of mutations of detrimental biological behavior and higher levels of immune infiltration, immune checkpoint expression, and anti-cancer immunotherapy response. Low-risk patients demonstrated greater sensitivity to erlotinib and phenformin. SPP1 was mainly involved in the interaction among tumor-associated macrophages, T cells, and malignant cells via SPP1-CD44 and SPP1-(ITGA5 + ITGB1) ligand-receptor pairs. In summary, our study established a prognostic model, which may contribute to individualized treatment and clinical management of patients with HCC.

Cost-effectiveness of different intervention strategies of human immunodeficiency virus in Zhejiang, China: a Model Study From 2023 to 2052.

OBJECTIVE: :Mass screening for human immunodeficiency virus (HIV) and preexposure prophylaxis (PrEP) may be effective measures for reducing the probability of HIV transmission. Our study aimed to determine the cost-effectiveness of preliminary screening in the general population, PrEP for HIV-negative spouses in serodiscordant couples, or both approaches in Zhejiang Province. DESIGN: :From a policy-maker's perspective, a Markov model was constructed to compare 4 strategies over a 30-year horizon. METHODS: :In the Markov model, the implementation intensities of the strategies varied from 50% to 100%. Different strategies were evaluated by the reduction of unfavorable clinical outcomes, saved life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). RESULTS: :The PrEP-Screening strategy reduced the most unfavorable clinical outcomes and saved the most LYs and QALYs from 2023 to 2052. It always gained the maximum QALYs and NMB, while its ICER was always lower than the willingness-to-pay (WTP). The NMB of the PrEP-Screening strategy gradually increased as the implementation intensity increased. CONCLUSIONS: :With adequate manpower and policies, we suggest implementing the PrEP-Screening strategy in Zhejiang Province, suggesting that the broader the population coverage of the strategy, the better. In addition, the PrEP strategy is an alternative.

Unraveling the mechanisms of NK cell dysfunction in aging and Alzheimer's disease: insights from GWAS and single-cell transcriptomics.

Background: Aging is an important factor in the development of Alzheimer's disease (AD). The senescent cells can be recognized and removed by NK cells. However, NK cell function is gradually inactivated with age. Therefore, this study used senescence as an entry point to investigate how NK cells affect AD. Methods: The study validated the correlation between cognition and aging through a prospective cohort of the National Health and Nutrition Examination Survey database. A cellular trajectory analysis of the aging population was performed using single-cell nuclear transcriptome sequencing data from patients with AD and different ages. The genome-wide association study (GWAS) cohort of AD patients was used as the outcome event, and the expression quantitative trait locus was used as an instrumental variable. Causal associations between genes and AD were analyzed by bidirectional Mendelian randomization (MR) and co-localization. Finally, clinical cohorts were constructed to validate the expression of key genes. Results: A correlation between cognition and aging was demonstrated using 2,171 older adults over 60 years of age. Gene regulation analysis revealed that most of the highly active transcription factors were concentrated in the NK cell subpopulation of AD. NK cell trajectories were constructed for different age populations. MR and co-localization analyses revealed that CHD6 may be one of the factors influencing AD. Conclusion: We explored different levels of AD and aging from population cohorts, single-cell data, and GWAS cohorts and found that there may be some correlations of NK cells between aging and AD. It also provides some basis for potential causation.