Association between triglyceride glucose index and cognitive decline: A meta-analysis.

BACKGROUND: The triglyceride glucose (TyG) index, a novel surrogate indicator for insulin resistance (IR), is believed to be associated with various diseases. However, its connection with cognitive decline remains controversy. METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science, and Medline databases were systematically searched up to October 2023 to assess the association between the TyG index and the risk of cognitive decline. Effect estimates and 95 % confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Our review included 3 cohort studies and 9 case-control/cross-sectional studies with a total of 5,603,350 participants. In comparison to a low TyG index, a higher TyG index was connected to an elevated risk of cognitive decline (RR/HR = 1.14, 95 % CI [1.11, 1.17], P < 0.05; OR = 1.75, 95 % CI [1.34, 2.29], P < 0.05). Furthermore, the dose-response analysis from the case-control/cross-sectional studies revealed a 1.42 times higher risk of cognitive decline per 1 mg/dl increment of the TyG index (OR = 1.42, 95 % CI [1.19, 1.69], P < 0.05). LIMITATIONS: The inclusion of observational studies in the meta-analysis demonstrated a lower hierarchy of evidence compared to randomized controlled trials. Moreover, we incorporated a restricted number of studies and identified significant heterogeneity among them, potentially attributed to the presence of numerous confounding variables. CONCLUSION: TyG index is related to cognitive decline. In view of some of the limitations of this study, further research will be necessary to confirm this relationship.

Type 1 diabetes mellitus and non-alcoholic fatty liver disease: a two-sample Mendelian randomization study.

Background: NAFLD (Nonalcoholic fatty liver disease) is becoming an increasingly common cause of chronic liver disease. Metabolic dysfunction, overweight/obesity, and diabetes are thought to be closely associated with increased NAFLD risk. However, few studies have focused on the mechanisms of NAFLD occurrence in T1DM. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal association between T1DM and NAFLD with/without complications, such as coma, renal complications, ketoacidosis, neurological complications, and ophthalmic complications. Multiple Mendelian randomization methods, such as the inverse variance weighted (IVW) method, weighted median method, and MR-Egger test were performed to evaluate the causal association of T1DM and NAFLD using genome-wide association study summary data from different consortia, such as Finngen and UK biobank. Results: We selected 37 SNPs strongly associated with NAFLD/LFC (at a significance level of p < 5 × 10-8) as instrumental variables from the Finnish database based on the T1DM phenotype (8,967 cases and 308,373 controls). We also selected 14/16 SNPs based on with or without complications. The results suggest that the genetic susceptibility of T1DM does not increase the risk of NAFLD (OR=1.005 [0.99, 1.02], IVW p=0.516, MR Egger p=0.344, Weighted median p=0.959, Weighted mode p=0.791), regardless of whether complications are present. A slight causal effect of T1DM without complications on LFC was observed (OR=1.025 [1.00, 1.03], MR Egger p=0.045). However, none of the causal relationships were significant in the IVW (p=0.317), Weighted median (p=0.076), and Weighted mode (p=0.163) methods. Conclusion: Our study did not find conclusive evidence for a causal association between T1DM and NAFLD, although clinical observations indicate increasing abnormal transaminase prevalence and NAFLD progression in T1DM patients.

Alfosbuvir plus Daclatasvir for Treatment of Chronic Hepatitis C Virus Infection in China.

INTRODUCTION: A pan-genotypic and effective treatment regimen for patients with chronic hepatitis C virus (HCV) infection remains an unmet medical need in China. Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. We conducted a phase 3 study to evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV infection. METHODS: All patients received 600 mg alfosbuvir tablets plus 60 mg daclatasvir tablets once daily for 12 weeks. The primary endpoint was sustained virological response 12 weeks after the end of treatment (SVR12). A follow-up visit was done at week 4 and 12, and those who achieved SVR12 were followed up at post-treatment week 24. RESULTS: Of the 326 patients who received at least one dose of the study drug, 320 (98.2% [95% confidence interval (CI): 96.5%-99.5%]) achieved sustained virological response at post-treatment week 12 (SVR12), which was superior to the historical SVR12 rate of 88% (p < 0.0001). The SVR12 rates were similar regardless of most baseline characteristics. The most common adverse event (AE) (≥ 10%) was hypercholesterolemia. Serious adverse events (SAEs) were reported in 25 (7.7%) patients, none of which was judged to be related to the study drug. The majority of AEs were mild to moderate in severity. CONCLUSIONS: Alfosbuvir plus daclatasvir for 12 weeks was highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3, or 6, suggesting that this regimen could be a promising option for HCV treatment in China irrespective of genotype. TRIAL REGISTRATION: ClinicalTrial.gov identifier, NCT04070235.

Cellular and molecular insights into incomplete immune recovery in HIV/AIDS patients.

Highly active antiretroviral therapy (ART) can effectively inhibit virus replication and restore immune function in most people living with human immunodeficiency virus (HIV). However, an important proportion of patients fail to achieve a satisfactory increase in CD4+ T cell counts. This state is called incomplete immune reconstitution or immunological nonresponse (INR). Patients with INR have an increased risk of clinical progression and higher rates of mortality. Despite widespread attention to INR, the precise mechanisms remain unclear. In this review, we will discuss the alterations in the quantity and quality of CD4+ T as well as multiple immunocytes, changes in soluble molecules and cytokines, and their relationship with INR, aimed to provide cellular and molecular insights into incomplete immune reconstitution.

A genetic variant in IL-6 lowering its expression is protective for critical patients with COVID-19.

Critical coronavirus disease 2019 (COVID-19) is associated with high mortality and potential genetic factors have been reported to be involved in the development of critical COVID-19. We performed a genome-wide association study to identify the genetic factors responsible for developing critical COVID-19. 632 critical patients with COVID-19 and 3021 healthy controls from the Chinese population were recruited. First, we identified a genome-wide significant difference of IL-6 rs2069837 (p = 9.73 × 10-15, OR = 0.41) between 437 critical patients with COVID-19 and 2551 normal controls in the discovery cohort. When replicated these findings in a set of 195 patients with critical COVID-19 and 470 healthy controls, we detected significant association of rs2069837 with COVID-19 (p = 8.89 × 10-3, OR = 0.67). This variant surpassed the formal threshold for genome-wide significance (combined p = 4.64 × 10-16, OR = 0.49). Further analysis revealed that there was a significantly stronger expression of IL-6 in the serum from patients with critical COVID-19 than in that from patients with asymptomatic COVID-19. An in vitro assay showed that the A to G allele changes in rs2069837 within IL-6 obviously decreased the luciferase expression activity. When analyzing the effect of this variant on the IL-6 in the serum based on the rs2069837 genotype, we found that the A to G variation in rs2069837 decreased the expression of IL-6, especially in the male. Overall, we identified a genetic variant in IL-6 that protects against critical conditions with COVID-19 though decreasing IL-6 expression in the serum.

Dynamic blood single-cell immune responses in patients with COVID-19.

The 2019 coronavirus disease (COVID-19) outbreak caused by the SARS-CoV-2 virus is an ongoing global health emergency. However, the virus' pathogenesis remains unclear, and there is no cure for the disease. We investigated the dynamic changes of blood immune response in patients with COVID-19 at different stages by using 5' gene expression, T cell receptor (TCR), and B cell receptors (BCR) V(D)J transcriptome analysis at a single-cell resolution. We obtained single-cell mRNA sequencing (scRNA-seq) data of 341,420 peripheral blood mononuclear cells (PBMCs) and 185,430 clonotypic T cells and 28,802 clonotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies. In addition, we used three control samples. We found expansion of dendritic cells (DCs), CD14+ monocytes, and megakaryocytes progenitor cells (MP)/platelets and a reduction of naïve CD4+ T lymphocytes in patients with COVID-19, along with a significant decrease of CD8+ T lymphocytes, and natural killer cells (NKs) in patients in critical condition. The type I interferon (IFN-I), mitogen-activated protein kinase (MAPK), and ferroptosis pathways were activated while the disease was active, and recovered gradually after patient conditions improved. Consistent with this finding, the mRNA level of IFN-I signal-induced gene IFI27 was significantly increased in patients with COVID-19 compared with that of the controls in a validation cohort that included 38 patients and 35 controls. The concentration of interferon-α (IFN-α) in the serum of patients with COVID-19 increased significantly compared with that of the controls in an additional cohort of 215 patients with COVID-19 and 106 controls, further suggesting the important role of the IFN-I pathway in the immune response of COVID-19. TCR and BCR sequences analyses indicated that patients with COVID-19 developed specific immune responses against SARS-CoV-2 antigens. Our study reveals a dynamic landscape of human blood immune responses to SARS-CoV-2 infection, providing clues for therapeutic potentials in treating COVID-19.

Efficacy and Safety of All-oral Emitasvir and Sofosbuvir in Patients with Genotype 1b HCV Infections without Cirrhosis.

Background and Aims: Emitasvir is a new type of hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor, and the data of phase 2 trial has shown emitasvir-sofosbuvir to have good safety and tolerance. We conducted this phase 3 trial to further verify the efficacy and safety. Methods: We evaluated the antiviral activity and safety of a 12-week regimen of emitasvir phosphate (100 mg) combined with sofosbuvir (400 mg) once daily in non-cirrhotic patients with genotype 1 HCV infection. The primary endpoint was a sustained virological response at 12 weeks (SVR12) after the end of treatment. Results: Of the 362 patients enrolled in the trial, 39.8% were male, 99.2% had HCV genotype 1b, 0.8% had genotype 1a and 79.8% were treatment-naïve. The average age was 47.2 years. All patients completed the treatment and follow-up. All 3 patients with genotype 1a achieved SVR. Two genotype 1b treatment-naïve patients experienced virologic relapse. The rate of SVR12 was 99.7% (358/359), and SVR24 was 99.4% (357/359) in genotype 1b. Overall, 36.2% had resistance-associated substitutions (RASs) in NS5A and 98.3% had RASs in NS5B at baseline. The RASs at baseline had no effect on the rates of response. Serious adverse events were reported in 16 patients and were not related to emitasvir-sofosbuvir. Most adverse events did not require therapy. Conclusions: The 12 weeks of treatment with emitasvir-sofosbuvir was a highly efficient and safe treatment for a wide range of patients with HCV genotype 1b infection without cirrhosis, who had not been treated or who had been treated with interferon-based regimen previously.

Comparison of different samples for 2019 novel coronavirus detection by nucleic acid amplification tests.

An ongoing outbreak of severe respiratory pneumonia associated with the 2019 novel coronavirus has recently emerged in China. Here we report the epidemiological, clinical, laboratory and radiological characteristics of 19 suspect cases. We compared the positive ratio of 2019-nCoV nucleic acid amplification test results from different samples including oropharyngeal swab, blood, urine and stool with 3 different fluorescent RT-PCR kits. Nine out of the 19 patients had 2019-nCoV infection detected using oropharyngeal swab samples, and the virus nucleic acid was also detected in eight of these nine patients using stool samples. None of positive results was identified in the blood and urine samples. These three different kits got the same result for each sample and the positive ratio of nucleic acid detection for 2019-nCoV was only 47.4% in the suspect patients. Therefore, it is possible that infected patients have been missed by using nucleic acid detection only. It might be better to make a diagnosis combining the computed tomography scans and nucleic acid detection.

Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China.

Background and Aims: Ravidasvir (RDV) is a new generation pangenotypic hepatitis C virus (HCV) NS5A inhibitor, with high barrier to baseline resistance-associated species. This is the first phase 2/3 study conducted in Mainland China confirming the efficacy and safety of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks in treatment-naïve noncirrhotic patients with genotype 1 infection in a large population. Methods: In this multicenter, randomized, double-blinded, placebo-controlled phase 2/3 trial (NCT03362814), we enrolled 424 treatment-naïve, noncirrhotic adult HCV genotype 1 patients. All patients were randomized at 3:1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day (body weight <75/≥75 kg) (n = 318) or placebo (n = 106) for 12 weeks. The primary end-point was the rate of sustained virologic response 12 weeks after the end of treatment, and the safety was evaluated and compared between treatment and placebo groups. Results: The overall rate of sustained virological response at 12 weeks after treatment is 99% (306/309, 95%, CI: 97%-100%) under per protocol set analysis. All patients harboring baseline NS5A resistance-associated species in the treatment group (76/76, per protocol set) achieved sustained virological response at 12 weeks after treatment. No treatment-related serious adverse events were reported. Laboratory abnormalities showed mild or moderate severity (grade 1 and grade 2) in liver function tests. Conclusions: In treatment-naïve, noncirrhotic HCV Chinese patients infected with HCV genotype 1, all-oral regimen of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks was highly efficacious, safe, and well tolerated.

Prognostic Significance of Elevated Cholestatic Enzymes for Fibrosis and Hepatocellular Carcinoma in Hospital Discharged Chronic Viral Hepatitis Patients.

Chronic viral hepatitis (CVH) is the root cause of liver fibrosis and subsequent hepatocellular carcinoma (HCC). We conducted a cross-sectional, observational study based on medical records and primary data collection from patients with CVH who were admitted in five hospitals across China between February and September 2013 to determine the prevalence of elevated cholestatic enzymes (ALP and/or GGT above ULN) in discharged Chinese patients with CVH as a primary outcome and secondarily evaluated the relationship of these enzymes with fibrosis and disease severity. Majority of the patients (56%) had cholestatic enzyme elevation at discharge, with high prevalence of liver fibrosis (37.6% vs. 20.1%, p < 0.001) and cirrhosis (Child-Pugh B: 56.9% vs. 48.7%; Child-Pugh C: 17.4% vs. 12.5%; p < 0.001) in addition to significantly higher odds of liver fibrosis (OR 1.54; p = 0.024) and a trend towards higher odds of moderate-to-severe cirrhosis (OR 1.24; p = 0.317) compared to those who had normal enzyme levels. Elevated cholestatic enzyme levels serve as important prognosticators of liver fibrosis in CVH patients. Therefore, pre-discharge testing of cholestatic enzymes is recommended to identify CVH patients and provide prophylactic care.

Transient elastography in clinical detection of liver cirrhosis: A systematic review and meta-analysis.

BACKGROUND/AIMS: Transient elastography is a noninvasive method for measuring liver fibrosis. This meta-analysis assesses the diagnostic performance of transient elastography of detecting liver cirrhosis in patients with liver disease. PATIENTS AND METHODS: We searched MEDLINE, Cochrane, EMBASE databases until Jan 31, 2015, using the following search terms: elastography and liver cirrhosis. Included studies assessed patients with a diagnosis of liver cirrhosis, with an index test of transient elastography, and with the reference standard being a histopathological exam by liver biopsy. Sensitivity analysis and assessment of risk of bias and publication bias were performed. RESULTS: Fifty-seven studies were included in the meta-analysis with a total of 10,504 patients. The pooled estimate for the sensitivity of transient elastography for detecting liver fibrosis was 81% and the specificity was 88%. The imputed diagnostic odds ratio (DOR) was 26.08 and the area under the receiver-operating characteristic (AUROC) curve was 0.931. CONCLUSION: Our findings indicate that transient elastography shows good sensitivity, specificity and a high accuracy for detecting liver cirrhosis. Transient elastography can be used as an additional method for the clinical diagnosis of liver fibrosis and cirrhosis.

NLRP3 Activation Was Regulated by DNA Methylation Modification during Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (Mtb) infection activates the NLRP3 inflammasome in macrophages and dendritic cells. Much attention has been paid to the mechanisms for regulation of NLRP3 against Mtb. However, whether epigenetic mechanisms participated in NLRP3 activation is still little known. Here we showed that NLRP3 activation was regulated by DNA methylation modification. Mtb infection promoted NLRP3 activation and inflammatory cytokines expression. NLRP3 promoter was cloned and subsequently identified by Dual-Luciferase Reporter System. The results showed that NLRP3 promoter activity was decreased after methylation by DNA methylase Sss I in vitro. Meanwhile, DNA methyltransferases inhibitor DAC could upregulate the expression of NLRP3. Furthermore, promoter region of NLRP3 gene was demethylated after Mtb H37Rv strain infection. These data revealed that DNA methylation was involved in NLRP3 inflammasome activation during Mtb infection and provided a new insight into the relationship between host and pathogens.

Will Sofosbuvir/Ledipasvir (Harvoni) Be Cost-Effective and Affordable for Chinese Patients Infected with Hepatitis C Virus? An Economic Analysis Using Real-World Data.

BACKGROUND: Little is known on the cost-effectiveness of novel regimens for hepatitis C virus (HCV) compared with standard-of-care with pegylated interferon (pegIFN) and ribavirin (RBV) therapy in developing countries. We evaluated cost-effectiveness of sofosbuvir/ledipasvir for 12 weeks compared with a 48-week pegIFN-RBV regimen in Chinese patients with genotype 1b HCV infection by economic regions. METHODS: A decision analytic Markov model was developed to estimate quality-adjusted-life-years, lifetime cost of HCV infection and incremental cost-effectiveness ratios (ICERs). SVR rates and direct medical costs were obtained from real-world data. Parameter uncertainty was assessed by one-way and probabilistic sensitivity analyses. Threshold analysis was conducted to estimate the price which can make the regimen cost-effective and affordable. RESULTS: Sofosbuvir/ledipasvir was cost-effective in treatment-experienced patients with an ICER of US$21,612. It varied by economic regions. The probability of cost-effectiveness was 18% and 47% for treatment-naive and experienced patients, and it ranged from 15% in treatment-naïve patients in Central-China to 64% in treatment-experienced patients in Eastern-China. The price of 12-week sofosbuvir/ledipasvir treatment needs to be reduced by at least 81% to US$18,185 to make the regimen cost-effective in all patients at WTP of one time GDP per capita. The price has to be US$105 to make the regimen affordable in average patients in China. CONCLUSION: Sofosbuvir/ledipasvir regimen is not cost-effective in most Chinese patients with genotype 1b HCV infection. The results vary by economic regions. Drug price of sofosbuvir/ledipasvir needs to be substantially reduced when entering the market in China to ensure the widest accessibility.

Fibroscan improves the diagnosis sensitivity of liver fibrosis in patients with chronic hepatitis B.

The aim of the present study was to investigate the diagnostic accuracy of Fibroscan for liver fibrosis in patients with chronic hepatitis B (CHB) with alanine aminotransferase (ALT) levels <2 times the upper normal limit. A total of 263 consecutive patients with CHB and ALT levels <2 times the upper normal limit were enrolled in the present study. Liver biopsies and liver stiffness measurements (LSM) were conducted. Receiver operating characteristic (ROC) analysis was used to determine the predictive ability of LSM for the development of liver fibrosis in patients with stage S1, S2 and S3 liver fibrosis. Bivariate Spearman rank correlation analysis was performed in order to determine the association between liver stiffness value, which was measured by Fibroscan, and liver fibrosis stage, which was measured by liver biopsy. The liver stiffness value was found to be positively correlated with the liver fibrosis stage (r=0.522, P<0.001) and necroinflammatory activity (r=0.461, P<0.001), which was measured by liver biopsy. The optimal cut-off value in the patients with stage S1, S2 and S3 liver fibrosis was 5.5, 8.0 and 10.95 kPa, respectively. The area under the ROC curve for the prediction of the development of liver fibrosis in these patients was 0.696, 0.911 and 0.923, respectively. The threshold of the optimal cut-off value exhibited a high sensitivity and specificity. The results of the present study suggested that Fibroscan may improve the sensitivity of the diagnosis of liver fibrosis in patients with CHB and ALT levels <2 times the upper normal limit, and that this sensitivity may increase with the progression of liver fibrosis.

Hepatic actinomycosis: report of one case and analysis of 32 previously reported cases.

Hepatic actinomycosis is rare, with few published cases. There are no characteristic clinical manifestations, and computed tomography (CT) shows mainly low-density images, making clinical diagnosis difficult, and leading to frequent misdiagnosis as primary liver cancer, metastatic liver cancer or liver abscess. Diagnosis normally requires examination of both the aetiology and pathology. This article reports one male patient aged 55 who was hospitalized because of repeated upper abdominal pain for more than 2 mo. He exhibited no chills, fever or yellow staining of the skin and sclera, and examination revealed no positive signs. The routine blood results were: haemoglobin 110 g/L, normal numbers of leukocytes and neutral leukocytes, serum albumin 32 g/L, negative serum hepatitis B markers and hepatitis C antibodies, normal tumour markers (alpha-fetoprotein and carcinoembryonic antigen). An abdominal CT scan revealed an 11.2 cm × 5.8 cm × 7.4 cm mass with an unclear edge in the left liver lobe. The patient was diagnosed as having primary liver cancer, and left lobe resection was performed. The postoperative pathological examination found multifocal actinomycetes in the hepatic parenchyma, which was accompanied by chronic suppurative inflammation. A focal abscess had formed, and large doses of sodium penicillin were administered postoperatively as anti-infective therapy. This article also reviews 32 cases reported in the English literature, with the aim of determining the clinical features and treatment characteristics of this disease, and providing a reference for its diagnosis and treatment.

[Comparison of liver pathohistological and clinical characteristics between chronic HBV carriers and chronic hepatitis B patients with mild elevation in ALT].

OBJECTIVE: To compare the liver pathohistological and clinical features between chronic HBV carriers and chronic hepatitis B patients with mild elevated in ALT. METHODS: 128 patients were divided into 3 groups according to the ALT: group A: ALT is less than or equal to 0.5*ULN, group B: 0.5*ULN less than ALT is less than or equal to 1*ULN, group C: 1*ULN less than ALT less than 2*ULN. The age, sex, serum HBV DNA, HBeAg status, expression of HBcAg in liver, thickness of spleen, breadth of portal vein ,blood stream speed of protal vein, right liver obliqua diameter, grade of liver inflammation and stage of liver fibrosis were compared in the three groups. RESULTS: Among 128 patients, 57(44.5%) patients had G1 hepatitis and 71 (55.5%) had G2 hepatitis, no G0 hepatitis was found in these patients; 72 patients (56.3%) had S1 fibrosis, 30 (23.4%) patients had S2 fibrosis, and 26 (20.3%) patients did not have liver fibrosis. The liver inflammation in group C was more aggravated than that in group A (P less than 0.05). And there were significant differences in thickness of spleen and right liver obliqua diameter between group C and group A, as well as between group C and B (P all less than 0.01). With the aggravating of liver inflammation, the serum ALT, thickness of spleen, breadth of portal vein and expression of HBcAg in liver were increased obviously (P less than 0.05). With the aggravating of liver fibrosis, the thickness of spleen, breadth of portal vein, right liver obliqua diameter and HBeAg negative patients were increased obviously, while the blood stream speed of portal vein was decreased obviously (P less than 0.01). CONCLUSION: Among the chronic HBV infection patients whose ALT less than 2*ULN, there were 55.5% patients had G2 of liver inflammation and 23.4% patients had S2 of liver fibrosis. The serum ALT, thickness of spleen, breadth and blood stream speed of portal vein, right liver obliqua diameter and expression of HBcAg in liver are associated with pathohistological changes in these patients.