Prevalence and clinical profiles of primary sclerosing cholangitis in China: Data from electronic medical records and systematic literature retrieval.

BACKGROUND & AIMS: Epidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China. METHODS: We identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model. RESULTS: A total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence. CONCLUSION: Our study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.

Changing spectrum and mortality disparities of etiology of liver cirrhosis in Beijing, China.

Liver cirrhosis remains a major health concern globally, but its epidemiology and etiology evolve with time. However, the changing pattern in etiology and cause of liver-related mortality for patients with cirrhosis are not fully elucidated. Herein, our aim was to characterize the temporal trend of the etiological spectrum and evaluate the impact of etiology on liver-related death among patients with compensated cirrhosis (CC) in Beijing, China. Clinical profiles of patients with CC discharged between January 2008 and December 2015 were retrieved from the Beijing hospital discharge database. The mortalities of different etiologies of cirrhosis were calculated. The risks of readmission and liver-related death associated with etiologies were evaluated by the Cox regression model. A total of 23 978 cirrhotic patients were included. The predominant cause was hepatitis B virus (HBV) (58.93%), followed by alcohol (21.35%), autoimmune (14.85%), miscellaneous etiologies (3.55%), and hepatitis C virus (HCV) (1.32%). From 2008 to 2015, the proportion of HBV-related cirrhosis decreased to 28.11%. Meanwhile, the proportions of autoimmune- and miscellaneous-related cirrhosis increased to 28.54% and 13.11%. The risk of liver-related death ranked the highest in patients with miscellaneous cirrhosis, followed by HBV-related cirrhosis, alcohol-related cirrhosis, autoimmune-related cirrhosis, and HCV-related cirrhosis. The 5-year rates of liver-related death were 22.56%, 18.99%, 18.77%, 16.01%, and 10.76%, respectively. HBV-related cirrhosis caused the highest risk of hepatocellular carcinoma (HCC)-related death, whereas alcohol- and miscellaneous-related cirrhosis caused higher risks of decompensation (DC)-related death than HBV-related cirrhosis, with hazard ratios of 1.35 (95% confidence interval [CI]: 1.24-1.48) and 1.20 (95% CI: 1.03-1.40), respectively. HBV remained a common cause of liver cirrhosis but gradually decreased. Mortality disparities existed in etiologies, with higher risks of HCC-related death in HBV-related cirrhosis, and DC-related death in alcohol- and miscellaneous-related cirrhosis.

"Treat-all" Strategy for Patients with Chronic Hepatitis B Virus Infection in China: Are We There Yet?

Chronic hepatitis B remains the primary cause of liver-related events in China. The World Health Organization set a goal to eliminate viral hepatitis as a public health threat by 2030. However, achieving this goal appears challenging due to the current low rates of diagnosis and treatment. The "Treat-all" strategy, which proposes treating all patients with detectable hepatitis B virus (HBV) DNA or even all patients with positive HBsAg, has been suggested to simplify anti-HBV treatment. In 2022, the Chinese Society of Hepatology and the Chinese Society of Infectious Diseases updated the guidelines for the prevention and treatment of chronic hepatitis B in China, expanding antiviral indications and simplifying the treatment algorithm. According to this latest guideline, nearly 95% of patients with detectable HBV DNA are eligible for antiviral treatment. This review aimed to provide a detailed interpretation of the treatment indications outlined in the Chinese Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2022) and to identify gaps in achieving the "Treat-all" strategy in China.

Molecular characterization of SPATA6 and association of its SNPs with testicular size in sheep.

The testis is an important organ for maintaining fertility in males, and testis size is positively correlated with ejaculate volume, sperm motility, thus fertility. Spermatogenesis-associated 6 (SPATA6) is an evolutionarily conserved testis-specific gene reported in many species. However, the effect of SPATA6 expression levels on testicular development and the effect of single nucleotide polymorphisms (SNPs) on testis and epididymis phenotype in sheep have not been studied. The purpose of the research was to investigate the expression profile of SPATA6 and its effect on testicular development and to confirm the effect of SNPs on the testis and epididymis phenotype. In this study, we detected a 1245bp coding sequence (CDS) of SPATA6 and encoded 414 amino acids. The expression levels of SPATA6 were significantly higher in the testis than in other tissues and gradually increased with testis development. Moreover, the expression level in the large testis was significantly higher than that in the small testis at six months. A total of 11 SNPs were detected in the coding region of SPATA6 by cDNA-pooling sequencing and improved multiplex ligation detection reaction (iMLDR) methods. Correlation analysis showed that SNP2 (c. 3631C > G) significantly affected left epididymis weight (LEW) and right epididymis weight (REW), and SNP10 (c. 937 A > G) significantly affected REW. And the combined genotype of SNP1 (c. 4245 G > A) and SNP2 significantly affected REW. The current study concluded that SPATA6 plays an important role in testicular development and the SNPs significantly associated with the epididymis phenotype can provide molecular markers for the early selection of high-fertility Hu sheep.

SNPS within the SLC27A6 gene are highly associated with Hu sheep fatty acid content.

Fatty acids (FA) are an important factor affecting meat quality and human health, and the important role of the solute carrier family 27 member 6 (SLC27A6) in FA metabolism has been demonstrated in several species. However, the expression profile of the SLC27A6 in different tissues and the effect of its polymorphism on FA in sheep are currently unknown. This study aimed to explore the differences in FAs in the longissimus dorsi (LD) of 1,085 Hu sheep, the expression profile of SLC27A6, and confirm the effect of single nucleotide polymorphisms (SNPs) on FA phenotypes. We found that many FA phenotypes differ significantly across different seasons, and winter promoted the deposition of polyunsaturated fatty acids (PUFA). The mRNA expression level of SLC27A6 in the lung was significantly higher than that in the heart, testis, and LD. A total of 16 SNPs were detected in the SLC27A6, and 14 SNPs were successfully genotyped by improved multiplex ligase detection reaction (iMLDR) technology. Correlation analysis showed that 7 SNPs significantly affected at least one FA phenotype. Among them, SNP14 contributes to the selection of lamb with low saturated fatty acid content and high PUFA content. Combined genotypes also significantly affected a variety of beneficial FAs such as C18:3n3, C20:4n6, C22:6n3, and monounsaturated fatty acids. This study suggests that SLC27A6 plays an important role in FA metabolism and SNPs that are significantly associated with FA phenotype could be used as potential molecular markers for later targeted regulation of FA profiles in sheep.

Preliminary genetic parameter estimates of meat quality traits in Hu sheep.

Because substantial numbers of Chinese consumers are prepared to pay for tender and quality lamb, meat quality traits are becoming more relevant for breeding programs for Chinese sheep breeds. The current study estimated heritabilities and genetic correlations for 13 meat quality traits recorded on lamb loins from Hu sheep. Heritability estimates ranged from 0.04 ± 0.06 for meat redness at 45 min to 0.57 ± 0.10 for drip loss, with most of the meat quality traits having moderate heritabilities. Positive genetic correlations were observed among meat color traits. Intramuscular fat (IMF) was genetically correlated with most meat quality traits, indicating that increasing IMF can favor meat pH, color, and tenderness, but would lead to increased cooking loss. Direct selection to increase IMF of loins is recommended to be included in breeding programs for Hu sheep, as it was more efficient than indirect selection on the other meat quality traits. The genetic parameters presented in this preliminary study provide valuable genetic information needed to design a breeding program aimed at improving the quality of lamb meat from Hu sheep.

Fish swim bladders as valve leaflets enhance the durability of transcatheter aortic valve replacement devices.

Transcatheter aortic valve replacement (TAVR) has emerged as an effective therapy for inoperable patients with severe aortic stenosis (AS). However, calcification-induced limited durability restricts its application. Fish swim bladders (FSB), which are resistant to calcific degeneration, offer a viable solution to this challenge. In this study, we developed a new TAVR device using FSB as the valve leaflet. Furthermore, the in vitro durability, in vivo performance, and size selection of this TAVR device were assessed by an experimental study and finite element analysis. A self-expandable TAVR device was fabricated by suturing the FSB films into a 23 mm nitinol alloy frame. Further, hemodynamic performance, such as effective orifice area, transvalvular pressure difference and regurgitant fraction, the durability was tested by the pulsatile flow test and accelerated fatigue test, according to the ISO 5840-3. The effect of release size on hydrodynamic performance was also investigated. Finally, the in vivo performance of the TAVR device were examined using a porcine implantation model. The results showed that the strength of the FSB films satisfied the requirements for valve leaflets. The hemodynamic performance of the FSB TAVR device met the requirements of ISO 5840-3 standards. After 400 million cycles, the FSB showed no fiber loss, torn, perforation, or other valve failure phenomena. In porcine models, the devices were well-positioned, functioned well with no stenosis immediately after the operation. Collectively, we successfully developed a TAVR device with FSB as valve leaflets that exhibited good fatigue resistance. STATEMENT OF SIGNIFICANCE: The source of material for the leaflets of commercialized biological heart valves (BHVs) is mainly bovine pericardium, but this material suffers the following problems: large and uneven thickness of the material, the presence of α-Gal and Neu5Gc antigens, and the susceptibility to structural valve degradation (SVD). New material for BHVs leaflets is rarely reported. In this study, we prepared a transcatheter aortic valve (TAV) and performed long-term in vitro and short-term in vivo studies using fish swim bladder (FSB) as the leaflets. The study confirmed that FSB TAV device can complete 400 million fatigue tests and maintain the good morphology of the leaflets, and that it still maintains good functionality after a certain amount of compression, indicating that FSB is a promising material for leaflets.

Neonatal Amino Acids and Acylcarnitines Associated With Maternal Blood Glucose Levels Throughout Pregnancy: Insights From the Beijing Birth Cohort Study.

OBJECTIVE: To determine the association between maternal blood glucose patterns throughout pregnancy and neonatal amino acids and acylcarnitines. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study involving 11,457 singleton pregnant women without preexisting diabetes from the Beijing Birth Cohort Study, along with their neonates born between July 2021 and October 2022 in Beijing, China. Distinct maternal glucose trajectories were identified using a latent class model based on blood glucose levels across the three trimesters, and their association with neonatal circulating metabolites, including 11 amino acids and 33 acylcarnitines, was examined, adjusting for potential confounding factors. RESULTS: Three distinct groups of maternal glucose trajectories were identified: consistent normoglycemia (n = 8,648), mid-to-late gestational hyperglycemia (n = 2,540), and early-onset hyperglycemia (n = 269). Mid-to-late gestational hyperglycemia was associated with decreased levels of amino acids (alanine, arginine, ornithine, and proline) involved in the arginine and proline metabolism and urea cycle pathway, as well as increased levels of C4DC+C5-OH and decreased level of C6DC and C10:1. Early-onset hyperglycemia was associated with elevated levels of free acylcarnitine and C4DC+C5-OH and a decreased level of C10:1, involved in the fatty acid oxidation pathway. However, these associations were primarily observed in male neonates rather than in female neonates. CONCLUSIONS: Our findings revealed a significant link between maternal glucose trajectories throughout pregnancy and neonatal arginine and proline metabolism, urea cycle pathway, and fatty acid oxidation pathway. These results highlight the importance of maintaining optimal blood glucose levels throughout pregnancy to promote healthy neonatal metabolic outcomes.

Liver fibrosis showed a two-phase regression rate during long-term anti-HBV therapy by three-time biopsies assessments.

BACKGROUND: Evidence has proven that liver fibrosis or even cirrhosis can be reversed by anti-HBV treatment. However, the difference of fibrosis regression rates in short-term and long-term antiviral therapy remain unclear. Therefore, we aimed to identify the dynamic changes in fibrosis regression rate in patients with three-time liver biopsies during 5 years antiviral therapy. METHODS: CHB patients with three times of liver biopsies (baseline, after 1.5-year and 5-year antiviral therapy) from a prospective cohort were enrolled. All patients were biopsy-proved Ishak stage ≥ 3 at baseline (n = 92). Fibrosis regression was defined as Ishak stage decreased ≥ 1 or predominantly regressive categorized by P-I-R score. RESULTS: Totals of 65.2% (60/92) and 80.4% (74/92) patients attained fibrosis regression after 1.5-year and 5-year therapy, respectively. Median HBV DNA level declined from 6.5 log IU/ml (baseline) to 0 log IU/ml (1.5 years and 5 years, P < 0.001). The mean level of Ishak fibrosis stage in all patients decreased from stage 4.1 (baseline) to 3.7 (1.5 years) then 3.2 (5 years). Fibrosis regression rates were 0.27 stage/year between baseline to year 1.5 and 0.14 stage/year between year 1.5 and year 5. Furthermore, for patients who attained fibrosis regression after 5-year antiviral therapy, the two-phase regression rates were 0.39 stage/year (0 year-1.5 years) and 0.20 stage/year (1.5 years-5 years). This two-phase feature of regression rate was further confirmed by fully-quantification assessment of liver fibrosis based on SHG/TPEF. CONCLUSION: During the 5 years of long-term antiviral treatment, liver fibrosis rapidly regresses in the first 1.5 years before slowing down in the following 3.5 years.

Add-on immunosuppressive therapy may benefit selected patients with primary biliary cholangitis and autoimmune phenomena.

Background: Mildly elevated levels of transaminase and/or immunoglobulin G (IgG) are common in patients with primary biliary cholangitis (PBC). It is still unclear whether adding immunosuppressive therapy to ursodeoxycholic acid (UDCA) benefits those patients who are not fulfilling the diagnostic criteria of PBC with autoimmune hepatitis (AIH) features. Objectives: To assess the efficacy of adding immunosuppressive therapy to UDCA for patients with PBC and autoimmune phenomena but not fulfilling the diagnostic criteria of PBC with AIH features. Design: This is a retrospective-prospective cohort study in a tertiary medical center. Methods: Patients with PBC and autoimmune phenomena were defined by the elevation of IgG and/or transaminase but did not fulfill the diagnostic criteria of PBC with AIH features. We grouped these patients based on with and without add-on immunosuppressive therapy and balanced their baseline characteristics using inverse probability treatment weighting (IPTW). Results: A total of 652 patients with PBC and autoimmune phenomena were included, with a median follow-up of 4.08 years. After IPTW, the pseudo sample size in the add-on therapy and monotherapy groups was 558 and 655, respectively. After 1 year of observation, patients in the add-on therapy group had a higher biochemical response rate (normalization of transaminase and IgG levels) (49% versus 17%, p < 0.001). Furthermore, add-on therapy improved the transplant-free survival in the subgroup of patients with PBC and transaminase ⩾3 × upper limit of normal (ULN) or IgG ⩾1.3 × ULN (p = 0.033). Conclusion: Add-on immunosuppressive therapy may improve the normalization rates of transaminase and IgG levels in all patients with PBC and mildly elevated transaminase and IgG levels and the long-term outcomes in the subgroup of the patients with transaminase ⩾3 × ULN or IgG ⩾1.3 × ULN.

A look at add-on immunosuppressive therapy in primary biliary cholangitis patients Adding immunosuppressive therapy may enhance the normalization of ALT, AST and IgG levels in all PBC patients with mild elevation and improve long-term outcomes in those with more severe elevation of ALT, AST and IgG. These findings contribute to our understanding of treatment options for PBC patients with autoimmune phenomena.

SERK3A and SERK3B could be S-nitrosylated and enhance the salt resistance in tomato seedlings.

Salinity hinders plant growth and development, resulting in reduced crop yields and diminished crop quality. Nitric oxide (NO) and brassinolides (BR) are plant growth regulators that coordinate a plethora of plant physiological responses. Nonetheless, the way in which these factors interact to affect salt tolerance is not well understood. BR is perceived by the BR receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1) and its co-receptor BRI1-associated kinase 1 (BAK1) to form the receptor complex, eventually inducing BR-regulated responses. To response stress, a wide range of NO-mediated protein modifications is undergone in eukaryotic cells. Here, we showed that BR participated in NO-enhanced salt tolerance of tomato seedlings (Solanum lycopersicum cv. Micro-Tom) and NO may activate BR signaling under salt stress, which was related to NO-mediated S-nitrosylation. Further, in vitro and in vivo results suggested that BAK1 (SERK3A and SERK3B) was S-nitrosylated, which was inhibited under salt condition and enhanced by NO. Accordingly, knockdown of SERK3A and SERK3B reduced the S-nitrosylation of BAK1 and resulted in a compromised BR response, thereby abolishing NO-induced salt tolerance. Besides, we provided evidence for the interaction between BRI1 and SERK3A/SERK3B. Meanwhile, NO enhanced BRI1-SERK3A/SERK3B interaction. These results imply that NO-mediated S-nitrosylation of BAK1 enhances the interaction BRI1-BAK1, facilitating BR response and subsequently improving salt tolerance in tomato. Our findings illustrate a mechanism by which redox signaling and BR signaling coordinate plant growth in response to abiotic stress.

Validation of the revised electronic version of RUCAM for diagnosis of DILI in Chinese patients.

BACKGROUND AIMS: The Revised Electronic Causality Assessment Method (RECAM), a computerized update of the Roussel Uclaf Causality Assessment Methodology (RUCAM), was recently proposed. In this study, we validated and compared the utility of the RECAM and RUCAM in Chinese patients with a single conventional or herbal agent-induced liver injury. METHODS: In this retrospective multicenter cohort of well-established DILI and non-DILI patients from 5 centers in China, the diagnostic performance of the RUCAM and RECAM was compared by AUC analysis. The consistency was evaluated by weighted kappa. The major causes of discrepancy were explored. RESULTS: A total of 481 DILI and 100 non-DILI patients were included. In total, 62.6% of the DILI cases were induced by conventional agents, and 37.4% were induced by herbs. The RECAM had relatively higher AUC than RUCAM for overall [0.947 (0.926-0.964) vs. 0.867 (0.836-0.893), p=0.0016], conventional agents [0.923 (0.890-0.949) vs. 0.819 (0.775-0.858), p=0.0185], and herbs [0.972 (0.941-0.989) vs.0.911 (0.866-0.944), p=0.0199]. Latency, scores associated with hepatitis B, and hepatotoxicity information of the insulting drugs were the 3 main causes for the inconsistency between RECAM and RUCAM scores. CONCLUSIONS: The RECAM had relatively better diagnostic performance than RUCAM, with a higher AUC for Chinese DILI patients. Timely updates of the LiverTox category and refinement of serum markers to exclude hepatitis B activity would further improve the applicability of RECAM in areas where the use of herbs and resolution of past HBV infections are common.

Understanding the unique mechanism of ferroptosis: a promising therapeutic target.

Ferroptosis is an iron-dependent form of regulated cell death and is characterized by high concentrations of intracellular lipid peroxide and a redox imbalance in the cells. Ferroptosis shows distinct morphological and biological features compared with other prominent mechanisms of programmed cell death. The distinct characteristics of ferroptosis include the dysfunction of the lipid peroxide repair enzyme glutathione peroxidase 4, the presence of ferrous iron overload, and the lipid peroxidation of polyunsaturated fatty acids. Several other metabolic pathways (including iron, lipid, and amino acid metabolism) and ferritinophagy, as well as transcription factors, can modulate ferroptosis. However, to date, the molecular mechanism of ferroptosis has not been elucidated. This review outlines the discovery, characterization, regulatory mechanisms, and crosstalk of ferroptosis. Further, we have noted the controversial elements in the ferroptosis-related mechanisms. Our inferences may provide a partial reference for developing strategies to regulate ferroptosis.