Intentions of healthcare seeking and self-isolation for MPOX among men who have sex with men in China: a national cross-sectional study.

Linking identified MPOX cases to care is essential for MPOX control. This study aims to investigate the intentions of healthcare seeking and self-isolation for MPOX among men who have sex with men (MSM) in China. A cross-sectional online survey was conducted in early August 2023 in China. Respondents were recruited by community-based organizations (CBOs), collecting information on demographics, health status, behavioural and psychological characteristics. Univariate and multivariate logistic regression analyses were performed to examine the predictors of intentions to seek healthcare and self-isolate for MPOX within the MSM population. A total of 7725 participants were recruited, with a median age of 30 years. 92.21% of the participants would seek healthcare for MPOX-like symptoms, but only 52.50% intended to self-isolate if diagnosed. Intentions to seek healthcare were lower among those with MPOX-like symptoms in the past 3 months (standardized prevalence ratio (SPRs) = 0.82, 95% CI: 0.74-0.89) and the willingness to self-isolate was reduced among those diagnosed with MPOX in the past 3 months (SPRs = 0.65, 95% CI: 0.48-0.87). Participants free of sexually transmitted infections (STIs) and those aware of their HIV status were more likely to seek healthcare and self-isolate than those with STIs or unaware of their HIV status. Regular followers of MPOX information and those perceiving a low risk of infection were more inclined to take preventive measures. These findings highlight the need for targeted MPOX prevention strategies for high-risk groups and the importance of addressing barriers in infectious disease prevention response.

Utilization of post-exposure prophylaxis potentially contributed to the changes of risk behaviors among men who have sex with men in China.

Background: The HIV infection status among men who have sex with men (MSM) in China is a cause for concern. Post-exposure prophylaxis (PEP) serves as a highly effective biomedical preventive measure against HIV infection. Substantial evidence has established an association between PEP utilization and risk behaviors among MSM, but whether the utilization of PEP has an impact on risk behaviors remains unknown. This study sought to elucidate the impact of PEP usage on risk behaviors among MSM and provide recommendations for developing targeted HIV prevention programs. Methods: A cohort study was conducted in Qingdao, China, from April 2021 to January 2022. Participants were enlisted by volunteers from community-based organizations through a snowball sampling method. Face-to-face interviews were conducted to collect sociodemographic and behavioral information of participants. The study encompassed a retrospective investigation, baseline survey, and follow-up survey, representing periods before, during, and after PEP usage, respectively. Generalized estimating equations, fitting a Poisson regression model, were applied to scrutinize changes in risk behaviors of MSM during and after PEP usage, in comparison to before PEP usage. Results: A total of 341 MSM were recruited in the cohort study, with 179 individuals completing the follow-up survey. In comparison to before PEP usage, there was a significant increase in the proportion of Rush Popper usage (17.6% vs. 23.8% vs. 29.6%) and commercial sexual partners (10.9% vs. 17.6% vs. 21.8%) among MSM during and after PEP usage. Before PEP usage, 88.7% of MSM reported having ≥3 temporary sexual partners in the last 6 months. This proportion exhibited no significant change during PEP usage (91.8%), but it significantly increased to 97.8% after PEP usage (P < 0.05). Notably, there was a significant decrease in group sex during and after PEP usage compared to before PEP usage (30.8% vs. 21.4% vs. 21.2%). Conclusion: The utilization of PEP may impact risk behaviors among MSM, potentially leading to increased Rush Popper usage, temporary sexual partners, and commercial sexual partners after PEP usage, accompanied by a decrease in group sex. Further research is imperative to elucidate the impact of PEP utilization on MSM and develop targeted HIV prevention programs.

The impact of HIV self-testing on risk behaviors among men who have sex with men: a mixed-methods study.

Background: Men who have sex with men (MSM) have a high prevalence of HIV and a low rate of HIV testing in China. HIV self-testing (HIVST) presents a viable strategy for expanding HIV testing among MSM. However, the impact of HIVST on risk behaviors among MSM remains controversial. Our study sought to ascertain this impact. Methods: From April 2021 to January 2022, a mixed-methods study was conducted in Qingdao City, employing both quantitative and qualitative methodologies. The quantitative component entailed a cohort study among MSM who had used HIVST. Generalized estimating equations fitting Poisson regressions were used to analyze the changes in risk behaviors of MSM in short time after HIVST (ST-HIVST) and longer time after HIVST (LT-HIVST) compared to before HIVST. Subsequently, we conducted in-depth interviews with 18 MSM who completed the follow-up to delve deeper into the impact of HIVST on MSM. Results: A total of 410 MSM were recruited in the cohort, of whom 83 were lost to follow-up. Compared to before HIVST, there were no significant changes in risk behaviors in ST-HIVST (p > 0.05), while the proportion of recreational drugs abuse (20.7% vs. 33.3%), commercial sex (14.6% vs. 22.9%), and unprotected anal sex (95.9% vs. 98.5%) increased significantly in LT-HIVST (p < 0.05). Specific changes varied across demographic characteristics. According to qualitative interviews, MSM might have decreased risk perception and increased risk behaviors after HIVST. Conclusion: The use of HIVST may promote MSM to engage in risk behaviors. In the future, customized HIVST promotion programs need to be developed to expand HIV testing among MSM and simultaneously control their risk behaviors.

Temporal and Spatial Trends in HIV Positivity Rate for VCT Clinics - China, 2015-2022.

Introduction: Human immunodeficiency virus (HIV) voluntary counseling and testing (VCT) clinics play a critical role in identifying and diagnosing HIV cases. This study aimed to describe the trend of HIV positivity rate (HPR) among Chinese VCT clinics between 2015 and 2022. Methods: This study utilized data from the China Information System for Disease Control and Prevention to analyze the trend in the HPR for VCT clinics from 2015 to 2022. The HPR was calculated by dividing the number of newly-reported HIV cases by the number of HIV tests, multiplied by 100%. To identify temporal and spatial trends in the HPR, we employed joinpoint regression analysis and the Getis-Ord hotspot analysis. Results: From 2015 to 2022, VCT clinics in China performed a total of 22,075,386 HIV tests, leading to the identification of 260,353 HIV cases, resulting in a HPR of 1.18%. The HPR consistently declined over the study period, with an average annual percent change (AAPC) of -7.5% (95% confidence interval: -12.6%, -2.2%, P<0.05). The number of HPR hotspots also decreased from 41 in 2015 to 23 in 2022. These HPR hotspots were primarily located in Yunnan, Sichuan, Guangdong, and Guangxi provincial-level administrative divisions (PLADs). Among the 31 PLADs, 16 showed a significant decrease in HPR during the study period (AAPC<0, PAAPC<0.05). Conclusions: VCT clinics in China have played a significant role in identifying HIV cases. The declining HPR observed in these clinics may indicates the progress has been made in some degree in mitigating HIV among high-risk populations. Therefore, it is crucial to further improving the utilization of VCT clinics for HIV testing.

Implementing Routine HIV Screening in Hospitals: An Effective Practice to Expand HIV Testing - Xishuangbanna Prefecture, Yunnan Province, China, 2019-2020.

What is already known about this topic?: Research evidence is insufficient to suggest whether routine human immunodeficiency virus (HIV) screening in healthcare settings is effective in promoting greater awareness of HIV-positive status. What is added by this report?: This study found that, following the implementation of routine HIV screening in hospitals in Xishuangbanna Prefecture, Yunnan Province, there was a significant increase in the number of HIV screenings, positive results, and the positive rate of HIV screening in primary-level hospitals. What are the implications for public health practice?: Routine hospital-based HIV screening is effective in identifying HIV infections in areas with concentrated epidemics.

Leucine aminopeptidase 3:a promising serum biomarker candidate for nonalcoholic steatohepatitis diagnosis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a highly prevalent liver disease that lacks targeted therapeutic drugs and non-invasive diagnostic methods. Increasing evidence demonstrated that aberrant expression of leucine aminopeptidase 3 (LAP3) is involved in NASH. Herein, we aimed to investigate whether LAP3 can be a promising serum biomarker for NASH diagnosis. METHODS: Liver tissues and serum from NASH rats, serum from NASH patients, and liver biopsies from chronic hepatitis B (CHB) patients combined with NASH (CHB+NASH) were obtained to evaluate the LAP3 level. Correlation analysis was conducted to evaluate the association between LAP3 expression and clinical indexes in CHB patients and CHB+NASH patients. ROC curve analysis of LAP3 in the serum and liver was applied to assess whether LAP3 can be a promising biomarker for NASH diagnosis. RESULTS: LAP3 was significantly upregulated in serum and hepatocytes of NASH rats and patients with NASH. Correlation analysis revealed that LAP3 in the liver of CHB patients and CHB+NASH patients showed a strong positive correlation with lipidome indicators total cholesterol (TC) and triglyceride (TG), and liver fibrosis indicator hyaluronic acid (HA), which showed a negative correlation with the international normalized ratio of prothrombin coagulation (INR) and liver injury indicator aspartate aminotransferase (AST). For NASH, the diagnostic accuracy of ALT > LAP3 > AST, the sensitivity LAP3 (0.87) > ALT (0.5957) > AST (0.2941), the specificity AST (0.975) > ALT (0.9) > LAP3 (0.5). CONCLUSION: Our data urge that LAP3 can serve as a promising serum biomarker candidate for NASH diagnosis.

Awareness and use of HIV pre-exposure prophylaxis and factors associated with awareness among MSM in Beijing, China.

Human immunodeficiency virus (HIV) sexual transmission among men who have sex with men (MSM) has increased markedly in Beijing, China in the past decade. Pre-exposure prophylaxis (PrEP) is a highly efficacious biomedical prevention strategy that remarkably reduces HIV-transmission risk. This study examined PrEP awareness among MSM and the factors influencing it. From April to July 2021, respondent-driven sampling was used to conduct a cross-sectional survey among MSM in Beijing, China. Demographic, behavior, and awareness data regarding PrEP were collected. The factors influencing PrEP awareness were assessed using univariate and multivariable logistic regression. In total, 608 eligible responders were included in the study. Among the respondents, 27.9% had PrEP awareness, 3.3% had taken PrEP, and 57.9% expressed interest in receiving PrEP, if required. Greater odds of PrEP awareness were associated with higher education level (adjusted odds ratio [aOR] 3.525, 95% confidence interval [CI] 2.013-6.173, P < 0.0001), greater HIV-related knowledge (aOR 3.605, 95% CI 2.229-5.829, P < 0.0001), HIV testing (aOR 2.647, 95% CI 1.463-4.788, P = 0.0013), and sexually transmitted infections (aOR 2.064, 95% CI 1.189-3.584, P = 0.0101). Lower odds of PrEP awareness were associated with higher stigma score (aOR 0.729, 95% CI 0.591-0.897, P = 0.0029). The findings indicate sub-optimal awareness and low utilization of PrEP in Beijing and highlight PrEP inequities among MSM with stigma. Strengthening the training of peer educators in disseminating PrEP knowledge and reducing stigma are critical for improving PrEP awareness.

A doctor-nurse-patient mobile health management system effectively controls blood glucose in chinese patients with type 2 diabetes mellitus: a prospective study.

BACKGROUND: Coronavirus-2019 pandemic in China aroused increasing interest in telemedicine-supported glycaemic control. We hypothesize that age might influence usage and efficacy of telemedicine-supported glycaemic control. This study aims to measure the effects of a doctor-nurse-patient Mobile Health Management System (MHMS) for fasting plasma glucose (FPG) control in patients with type 2 diabetes mellitus (T2DM). METHODS: Four hundred sixty four patients with T2DM were recruited. A one-hour diabetes education provided to each patient and subsequent follow-ups arranged in the 1st, 2nd, 4th, 8th, and 12th week after enrollment were recorded in MHMS. The effectiveness of MHMS was defined as the proportion of patients achieving FPG target (below 126 mg/dL or 7.0mml/L). RESULTS: Among the enrolled 464 patients (age: 55.0 ± 13.7 years) who were divided into three groups: young (18-40 years), middle-aged (41-65 years) and elderly (> 65 years), 424 ones completed all follow-ups of 12 weeks. FPG decreased from 178.38 ± 95.04 to 117.90 ± 14.22 mg/dL in the young group, from 180.00 ± 91.08 to 122.94 ± 37.95 mg/dL in the middle-aged group, and from 174.24 ± 80.64 to 128.88 ± 23.4 mg/dL in the elderly group. The proportion of FPG-target-achieved patients increased from 46.2 to 90.4% in the young group, from 32.6 to 82.8% in the middle-aged group, and from 29.5 to 73.3% in the elderly group. The proportion of FPG-target-achieved patients between three age groups were statistically significant (P < 0.001). And the changes of proportion of FPG-target-achieved patients at different follow-up times were statistically significant (P = 0.037). Compared with the young group, the elderly group achieved poorer FPG level (P = 0.032). CONCLUSION: MHMS can help patients with T2DM lower FPG and improve proportion of FPG-target-achieved patients. Younger patients may achieve better glycaemic control than older patients. MHMS may serve multitudinous patients with T2DM to achieve adequate FPG self-management.

TGF-ß1 contributes to the hepatic inflammation in animal models with nonalcoholic steatohepatitis by Smad3/TLR2 signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is increasingly affecting human health and the economy worldwide due to various factors. Here, we found that the expression of TGF-ß1 and TLR2 was significantly up-regulated in liver samples from both rats and mice nonalcoholic steatohepatitis (NASH) models. By constructing corresponding cell model, we found that TGF-ß1 challenge can positively regulate the expression of TLR2 and p-Smad2/3, and the dual luciferase reporter gene system and EMSA assay confirmed the existence of Smad3 binding site (-916 ∼ -906) in the promoter region of TLR2. The overexpression and interference changes of Smad2/3 further verified the above experimental results. Taken together, these findings suggest that TGF-ß1 promotes TLR2 transcription and its target gene expression via Smad3, leading to malignant exacerbation of liver inflammation in NASH, which provides new insights into the treatment of NASH.

Curcumin improves insulin sensitivity in high-fat diet-fed mice through gut microbiota.

BACKGROUND: Insulin resistance precedes metabolic syndrome which increases the risk of type 2 diabetes and cardiovascular disease. However, there is a lack of safe and long-lasting methods for the prevention and treatment of insulin resistance. Gut microbiota dysbiosis can lead to insulin resistance and associated glucose and lipid metabolic dysfunction. Thus, the role of gut microbiota in metabolic diseases has garnered growing interest. Curcumin, the active ingredient of tropical plant Curcuma longa, has excellent prospects for the prevention and treatment of metabolic diseases. However, due to the extremely low bioavailability of curcumin, the mechanisms by which curcumin increases insulin sensitivity remains to be elucidated. This study aimed to elucidate the role of gut microbiota in mediating the effects of curcumin on improving insulin sensitivity in high-fat diet (HFD)-fed mice. METHODS: Glucose, insulin, and pyruvate tolerance were tested and hepatic triglycerides (TGs) content was measured in HFD-fed mice treated with curcumin (100 mg kg-1 d-1, p.o.) or vehicle for 4 weeks and aforementioned mice after gut microbiota depletion via antibiotic treatment for 4 weeks. Fecal microbiota transplantation (FMT) was conducted in endogenous gut microbiota-depleted HFD-fed mice. Glucose and lipid metabolic phenotypes were also measured in recipient mice colonized microbiota from vehicle- or curcumin-treated HFD-fed mice. The mechanisms underlying the effects of curcumin on increasing insulin sensitivity were testified by Western blotting, real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). RESULTS: Curcumin ameliorated HFD-induced glucose intolerance, insulin resistance, pyruvate intolerance, and hepatic TGs accumulation, while these effects were mediated by gut microbiota. Curcumin induced insulin-stimulated Akt phosphorylation levels in insulin-regulated peripheral tissues. The inhibitory effects of curcumin on the expressions of genes involved in hepatic gluconeogenesis and de novo lipogenesis were dependent on gut microbiota. Meanwhile, curcumin upregulated the expression of fibroblast growth factor 15 (FGF15) through gut microbiota. CONCLUSIONS: The effects of curcumin on promoting insulin sensitivity were dependent on gut microbiota in HFD-fed mice. Moreover, curcumin at least partly exerted its effects on increasing insulin sensitivity via FGF15 upregulation. This study provided new ideas on nutritional manipulations of gut microbiota for the treatment of metabolic diseases.

Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.

Objective : Our study aims to summarize and analyze the clinical characteristics of transient infantile hypertriglyceridemia (HTGTI) and variants in the glycerol-3-phosphate dehydrogenase 1 (GPD1) gene and the effect of HTGTI on the protein structure of GPD1. Methods: Retrospective analysis, using the general data, symptoms, signs, and auxiliary examinations, was performed on patients with HTGTI, which were confirmed by genetic testing in our hospital and reported cases online. The clinical data were analyzed using statistical and bioinformatic approaches. Results: A total of 31 genetically confirmed HTGTI patients were collected from our hospital and cases reported in the literature. The clinical manifestations showed the median age of onset was 6.0 (1.9, 12.0) months. All the patients had normal psychiatric status, but 22.6% of them presented growth retardation and short stature, 93.5% had hepatomegaly, and 16.1% had splenomegaly. Just a few children were reported with jaundice, cholestasis, and obesity (3.2-6.5%). The laboratory investigations showed that 96.8% of them had hypertriglyceridemia (HTG) with a median level of 3.1 (2.1, 5.5) mmol/L, but only 30.0% had returned to normal during follow-up. In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia. Upon abdominal imaging, all patients presented fatty liver and liver steatosis, with 66.7% of patients showing hepatic fibrosis. Statistical differences in triglyceride (TG) level were observed in the ≤6 months group compared with the older groups and in the 13 months to 6 years group with >6 years group (H = 22.02, P < 0.05). The restricted cubic spline model showed that severe HTG decreased in the early stage of infants to the normal level; however, it rebounded again to a mild or moderate level after the following days. The genetic test revealed that the main variant types of the GPD1 gene were missense variants (51.6%), followed by splicing variants (35.5%) and nonsense variants (12.9%). Of patients, 87.1% had homozygous variants, with the most frequent loci being c.361-1G > C and c.895G > A. Conclusion: The common manifestations of HTGTI were HTG, hepatomegaly, elevated liver transaminases, and hepatic steatosis in early infancy. However, the recurrence of aberrant HTG may pose long-term detrimental effects on HTGTI patients.

Catalytic degradation of amoxicillin from water by a combined system of ultrasound/H2O2/KI.

A new combined system of ultrasound (US)/ H2O2/KI was presented in this study for the degradation of amoxicillin (AMX). Various parameters that influencing the degradation efficiency, such as ultrasonic power, pH value of the solution, concentrations of H2O2 and KI, initial concentration of AMX were investigated. The maximum degradation efficiency of 84.1% in 60 min was obtained under the optimal conditions when the ultrasonic power was 195 W, the solution pH was 3.2, the concentrations of H2O2 and KI were 120 and 2.4 mmol/L, respectively. Results also showed US/H2O2/KI system possessed better degradation efficiency compared with that by using the systems of US alone, H2O2, US/H2O2, US/KI and H2O2/KI. The degradation reaction of AMX should be a very complex process, and the corresponding degradation pathways may change at different concentrations or under different reaction conditions. The results indicate that the combined system of US/ H2O2/KI has great potential applications for the treatment of wastewater containing antibiotics with high concentrations.

Estimating Changes in Population Size and Behavioral Characteristics in Men Who Have Sex With Men Between 2014 and 2019: Longitudinal Study.

BACKGROUND: Men who have sex with men (MSM) are at high risk for HIV infection. Accurate estimation of the population size and monitoring the risk sexual behavioral change of MSM is of great importance to develop targeted HIV prevention and interventions. OBJECTIVE: The goal of the research was accurate estimation of the population size and monitoring the risk sexual behavioral change of MSM. METHODS: Street interception investigation methods were conducted among males aged 16 years and older in selected sites in Shenzhen in 2014 and 2019. A population survey was used to estimate the population size of MSM. Logistic regression analysis was applied to evaluate the difference in behavioral characteristics in MSM from 2014 to 2019. RESULTS: In this study, we surveyed 10,170 participants in 2014, of whom 448 (4.41%, 95% CI 4.01%-4.80%) participants were men who have ever had sex with another man (MSMe) and 229 (2.25%, 95% CI 1.96%-2.54%) were men who had sex with another man in the previous 6 months (MSMa). A total of 10,226 participants were surveyed in 2019, of which 500 (4.90%, 95% CI 4.47%-5.31%) and 208 (2.03%, 95% CI 1.76%-2.31%) participants were MSMe and MSMa, respectively. The results showed that the population size of MSM who are active (MSMa) in Shenzhen was 155,469 (2.29%, 95% CI 2.28%-2.30%) in 2014 and 167,337 (2.05%, 95% CI 2.04%-2.06%) in 2019. It was estimated that there were about 12,005,445 (2.04%, 95% CI 2.04%-2.04%) MSMa in China in 2019. Compared with 2014, the MSMa in 2019 were more likely to seek sex partners through mobile phone apps and less likely to have male and female sex partners in addition to having inconsistent condom use and more than 6 sex partners in the previous 6 months. CONCLUSIONS: In Shenzhen, the proportion of MSMa among the general male population was lower in 2019 than in 2014, and the prevalence of HIV risk behavior was reduced in 2019. Although the preferred platform to find male sex partners among MSM has changed, intervention with high-HIV risk MSM could still help to reduce HIV risk behaviors among the whole MSM group. Because MSM prefer to seek sex partners through mobile phone apps, further study is needed to strengthen internet interventions with high-HIV risk MSM to curb the spread of HIV.

Association of HCV Prior Infection and Unprotected Sex on Subsequent HIV Acquisition Risk in the Era of Treatment as Prevention.

Backgrounds: Little was known about the impact of HCV prior infection on HIV transmission and acquisition. We aimed to explore whether HCV prior infection and its interactions with unprotected sex affected HIV acquisition. Methods: This study was conducted among HIV heterosexual serodiscordant couples whose index cases were receiving treatment during 2008-2014 in Zhumadian. At baseline, we collected information on demographics and medical history of ART use, CD4 count, and HIV viral load for index partners, and also HIV and HCV status for non-index partners. For each year's visit, we followed up on sexual behaviors among couples in the recent year and HIV seroconversion of non-index partners. Analyses of the Cox model and synergistic interaction were performed. Results: We identified 81 HIV seroconversions over 18,370.39 person-years, with the overall HIV seroconversion rate of 0.44 per 100 person-years. Couples, whose index cases were aged 50 years and above, had a baseline viral load >400 copies per ml and no AIDS-defining illness, and newly-initiated ART in the study period had a higher risk of HIV seroconversion. Unprotected sex and HCV prior infection showed a synergistic association with HIV acquisition risk (RERI = 3.65, SI = 0.48, AP = 2.24). Conclusion: Unprotected sex and HCV infection were independent risk factors associated with HIV acquisition. The coexistence of them might have a synergistic effect on the risk which needs further research.

Cholesterol-induced leucine aminopeptidase 3 (LAP3) upregulation inhibits cell autophagy in pathogenesis of NAFLD.

OBJECTIVES: Leucine aminopeptidase 3 (LAP3), an M1 member of leucine aminopeptidase, was reported to be significantly upregulated in serum of nonalcoholic fatty liver disease (NAFLD) patients. However, the underlying mechanisms of LAP3 in NAFLD pathogenesis are still unknown. We aim to investigate the role of LAP3 in NAFLD pathogenesis and explore whether LAP3 has the potential to be a candidate biomarker in serum for NAFLD diagnosis. METHODS: Liver tissues and serum from NASH rats, serum from patients with NAFLD were obtained to evaluate the LAP3 expression. Detection of GSSG/GSH, intracellular reactive oxygen species (ROS), and LC3 expression by elevation/ reduction of LAP3 expression to determine the role of LAP3 in NAFLD pathogenesis. Finally, the correlation analysis was conducted to evaluate the association between LAP3 expression and clinical indexes of NAFLD. RESULTS: LAP3 expression was upregulated in hepatocytes and serum in E3 rats with NASH after 6-month HFD feeding. Cholesterol (CHO) dramatically upregulated LAP3 in LO2 cells, and then lead to negative regulation of autophagy. Moreover, LAP3 levels were also significantly increased in NAFLD patients compared to healthy controls. Correlation analysis revealed that serum LAP3 levels were positively correlated with TG, γ-glutamyltranspeptidase (GGT), and fasting blood glucose levels, while there was a negative correlation with HDL levels. CONCLUSIONS: The cholesterol-dependent upregulation of LAP3 in hepatocytes plays a critical role in the pathogenesis of NAFLD via inhibiting autophagy. Moreover, LAP3 could serve as a potential novel candidate biomarker for the diagnosis of NAFLD.

Trends in suicide mortality among people with HIV after diagnosis during 2012-18: a retrospective, national cohort study in China.

BACKGROUND: Little is known about suicide mortality among people with HIV in low-income and middle-income countries. This study aimed to assess suicide mortality and its temporal change among people with HIV after diagnosis, then describe potential risk factors. METHODS: This nationwide, population-based cohort study used data from the China Information System for Disease Control and Prevention (CISDCP), which continually enrolled people diagnosed with HIV in mainland China. We included all people with HIV diagnosed between Jan 1, 2012, and Dec 31, 2018, who were aged 15 years or older at diagnosis. Follow-up started from the date of HIV diagnosis to the date of death, date of last follow-up visit, or Dec 31, 2018, whichever came first. Crude suicide mortality was calculated as the number of suicide deaths divided by person-years at risk in 2012-18 and compared by time after HIV diagnosis. Standardised mortality ratios (SMRs) were used to compare the relative risk of suicide deaths in people with HIV with the general population. We compared the trends of suicide mortality across three diagnosis year groups (2012-13, 2014-15, and 2016-18) using cumulative incidence curve of suicide. Competing-risk models were used to explore the potential risk factors of suicide. FINDINGS: 770 656 people diagnosed with HIV were included in the CISDCP database, 763 287 of whom were aged 15 years or older at diagnosis and had follow-up information available. During follow-up, 2825 (2·0%) of 144 729 all-cause deaths were due to suicide, with a mortality of 142·8 deaths by suicide per 100 000 person-years (95% CI 137·7-148·2). People with HIV were at an increased risk of suicide compared with the general population (SMR 20·9 [95% CI 20·2-21·7]). The greatest risk was during the first 3 months after diagnosis (SMR 98·1 [93·1-103·4]), which then decreased but was still elevated after the first year (SMR 9·2 [8·5-9·8]). Late diagnosis and never on antiretroviral therapy were independent risk factors for suicide. INTERPRETATION: Suicide mortality decreased during the study period, which coincided with improvement in access to care and treatment coverage. This study suggests the importance of targeted suicide prevention for people with HIV throughout the course of diagnosis and that the focus of efforts should be concentrated on the first 3 months after diagnosis. Our findings highlight the urgent need to integrate suicide screening and prevention in HIV care. FUNDING: Young Scholar Scientific Research Foundation of National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Pdcd4 promotes lipid deposition by attenuating PPARα-mediated fatty acid oxidation in hepatocytes.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes. The involvement of programmed cell death 4 (Pdcd4) in inflammation and metabolic diseases has been widely reported. However, the precise regulatory role of Pdcd4 in hepatocytic lipid metabolism and NAFLD is not well known. RESEARCH DESIGN AND METHODS: We established a high-fat diet-induced NAFLD (HFD-NAFLD) rat model and a free fatty acids (FFAs)-treated cell model, and analyzed the expression and distribution of PDCD4. The lentivirus for Pdcd4 knockout and the vector for Pdcd4 overexpression were used to alter Pdcd4 expression in BRL 3A cells. Thereafter, lipid accumulation, FA metabolic gene expression, and peroxisome proliferator-activated receptor alpha (Pparα)-dependent peroxisomal ß-oxidation-related gene expression, especially that of the critical transcription factors and enzymes acyl-CoA oxidases 1-3 (Acox1-3), were detected both at the mRNA and protein levels. RESULTS: PDCD4 expression increased and it was mainly distributed in hepatocyte nuclei of the HFD-NAFLD rats. as well as the FFAs-treated CBRH-7919 and BRL 3A cell lines. Pdcd4 knockout significantly suppressed FFAs-induced lipid accumulation, and Pdcd4 overexpression accelerated FFAs-induced lipid accumulation in hepatocytes. Mechanistically, Pdcd4 negatively regulated the expression Pparα and Acox1-3. In addition, rescue experiments confirmed that Pparα knockdown could attenuate the expression of Acox1-3 in Pdcd4 knockout cells, which ultimately restored lipid deposition to normal levels. PPARα expression decreased in the liver of the HFD-NAFLD rats. The enrichment of PDCD4 in hepatocyte nuclei correlated with lower PPARα expression after FFAs treatment in vitro. CONCLUSION: Our results indicate that the abundance of PDCD4 under high-fat conditions facilitates hepatocellular lipid accumulation by decreasing PPARα-dependent FA peroxisomal ß-oxidation.

Hepatic Reduction in Cholesterol 25-Hydroxylase Aggravates Diet-induced Steatosis.

BACKGROUND & AIMS: Cholesterol 25-hydroxylase (Ch25h), converting cholesterol to 25-hydroxycholesterol (25-HC), is critical in modulating cellular lipid metabolism and anti-inflammatory and antiviral activities. However, its role in nonalcoholic fatty liver disease remains unclear. METHODS: Ch25h expression was detected in livers of ob/ob mice and E3 rats fed a high-fat diet (HFD). Gain- or loss-of-function of Ch25h was performed using Ch25h+/+ (wild type [WT]) mice receiving AAV8-Ch25h or Ch25h knockout (Ch25h-/-) mice. WT mice fed an HFD were administered with 25-HC. The Ch25h-LXRα-CYP axis was measured in primary hepatocytes isolated from WT and Ch25h-/- mice. RESULTS: We found that Ch25h level was decreased in livers of ob/ob mice and E3 rats fed an HFD. Ch25h-/- mice fed an HFD showed aggravated fatty liver and decreased level of cytochrome P450 7A1 (CYP7A1), in comparison with their WT littermates. RNA-seq analysis revealed that the differentially expressed genes in livers of HFD-fed Ch25h-/- mice were involved in pathways of positive regulation of lipid metabolic process, steroid metabolic process, cholesterol metabolic process, and bile acid biosynthetic process. As gain-of-function experiments, WT mice receiving AAV8-Ch25h or 25-HC showed alleviated NAFLD, when compared with the control group receiving AAV8-control or vehicle control. Consistently, Ch25h overexpression significantly elevated the levels of primary and secondary bile acids and CYP7A1 but decreased those of small heterodimer partner and FGFR4. CONCLUSIONS: Elevated levels of Ch25h and its enzymatic product 25-HC alleviate HFD-induced hepatic steatosis via regulating enterohepatic circulation of bile acids. The underlying mechanism involves 25-HC activation of CYP7A1 via liver X receptor. These data suggest that targeting Ch25h or 25-HC may have therapeutic advantages against nonalcoholic fatty liver disease.

Induction of PDCD4 by albumin in proximal tubule epithelial cells potentiates proteinuria-induced dysfunctional autophagy by negatively targeting Atg5.

Autophagy dysfunction is a hallmark of type 1 diabetes. However, the precise molecular mechanism of proteinuria-induced dysfunctional autophagy remains unclear. Herein, we investigated the role of programmed cell death 4 (PDCD4) in the regulation of autophagy in the pathogenesis of diabetic kidney disease (DKD) in vivo and in vitro. RT-qPCR, immunohistochemistry (IHC), and western blotting demonstrated an upregulation of Pdcd4 mRNA and protein in streptozotocin (STZ)-induced DKD rats, as compared to the control. In addition, IHC and western blotting of a unilateral ureteral obstruction mouse model showed an upregulation of PDCD4 in the disease group, as compared to their respective controls. IHC analysis of kidney biopsy samples of human DKD patients showed an upregulation of PDCD4 compared to the control. Western blotting of the STZ-induced DKD rat tissues displayed a low microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, as compared to the control. It was found that albumin overload in cultured PTECs upregulated the expression of PDCD4 and p62 and decreased the expression of LC3-II and autophagy-related 5 (Atg5) proteins. The knockout of Pdcd4 in cultured PTECs could reduce albumin-induced dysfunctional autophagy, as evidenced by the recovery of Atg5 and LC3-II protein. The forced expression of PDCD4 could further suppress the expression of the crucial autophagy-related gene Atg5. Evidence suggests that endogenous PDCD4 promotes proteinuria-induced dysfunctional autophagy by negatively regulating Atg5. Therefore, PDCD4 may be a potential therapeutic target in DKD.

Inhibition of miR-188-5p alleviates hepatic fibrosis by significantly reducing the activation and proliferation of HSCs through PTEN/PI3K/AKT pathway.

Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR-188-5p is dysregulated during the process of HF. However, the role of miR-188-5p in HF remains unclear. This study investigated the potential role of miR-188-5p in HSCs and HF. Firstly, we validated the miR-188-5p expression in primary cells isolated from liver of carbon tetrachloride (CCl4 )-induced mice, TGF-ß1-induced LX-2 cells, livers from 6-month high-fat diet (HFD)-induced rat and 4-month HFD-induced mice NASH models, and human non-alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR-188-5p inhibitors to investigate the therapeutic effects of miR-188-5p inhibition in the HFD + CCl4 induced in vivo model and the potential role of miR-188-5p in the activation and proliferation of HSCs. This present study reported that miR-188-5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR-188-5p resulted in the up-regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR-188-5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR-188-5p suppressed the HF parameters, pro-fibrotic and pro-inflammatory genes, and fibrosis. Collectively, our results uncover the pro-fibrotic role of miR-188-5p. Furthermore, we demonstrated that miR-188-5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.