Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China.

BACKGROUND: Within the normal range, elevated alanine aminotransferase (ALT) levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). AIM: To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively. METHODS: A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected. The incidence rate, cumulative times, and equally and unequally weighted cumulative effects of excess high-normal ALT levels (ehALT) were measured. Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD. RESULTS: A total of 83.13% of participants with MAFLD had normal ALT levels. The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group. Compared with those in the low-normal ALT group, the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651 [95% confidence interval (CI): 1.199-2.273] and 1.535 (95%CI: 1.119-2.106) in the third quartile and 1.616 (95%CI: 1.162-2.246) and 1.580 (95%CI: 1.155-2.162) in the fourth quartile, respectively. CONCLUSION: Most participants with MAFLD had normal ALT levels. Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

Network Pharmacology, Molecular Docking Analysis and Molecular Dynamics Simulation of Scutellaria baicalensis in the Treatment of Liver Fibrosis.

BACKGROUND: Traditional Chinese medicine Scutellaria Baicalensis (SB), one of the clinical firstline heat-clearing drugs, has obvious symptomatic advantages for hepatic fibrosis with dampness-heat stasis as its syndrome. We aim to predict and validate the potential mechanism of Scutellaria baicalensis active ingredients against liver fibrosis more scientifically and effectively. METHODS: The underlying mechanism of Scutellaria baicalensis in inhibiting hepatic fibrosis was studied by applying network pharmacology, molecular docking and molecular dynamics simulation. Expression levels of markers in activated Hepatic Stellate Cells (HSC) after administration of three Scutellaria baicalensis extracts were determined by Western blot and Real-time PCR, respectively, in order to verify the anti-fibrosis effect of the active ingredients Results: There are 164 common targets of drugs and diseases screened and 115 signaling pathways obtained, which were mainly associated with protein phosphorylation, senescence and negative regulation of the apoptotic process. Western blot and Real-time PCR showed that Scutellaria baicalensis extracts could reduce the expression of HSC activation markers, and Oroxylin A had the strongest inhibitory effect on it. Molecular docking results showed that Oroxylin A had high binding activity to target proteins. Molecular dynamics simulation demonstrates promising stability of the Oroxylin A-AKT1 complex over the simulated MD time of 200 ns. CONCLUSION: Scutellaria baicalensis active ingredients may inhibit HSC proliferation, reduce the generation of pro-inflammatory factors and block the anti-inflammatory effect of inflammatory signal transduction by inducing HSC apoptosis and senescence, thus achieving the effect of anti-fibrosis.

Epidemiological characteristics and dynamic transmissions of COVID-19 pandemics in Chinese mainland: A trajectory clustering perspective analysis.

BACKGROUND: The corona virus disease 2019 (COVID-19) pandemic has spread to more than 210 countries and regions around the world, with different characteristics recorded depending on the location. A systematic summarization of COVID-19 outbreaks that occurred during the "dynamic zero-COVID" policy period in Chinese mainland had not been previously conducted. In-depth mining of the big data from the past two years of the COVID-19 pandemics must be performed to clarify their epidemiological characteristics and dynamic transmissions. METHODS: Trajectory clustering was used to group epidemic and time-varying reproduction number (Rt) curves of mass outbreaks into different models and reveal the epidemiological characteristics and dynamic transmissions of COVID-19. For the selected single-peak epidemic curves, we constructed a peak-point judgment model based on the dynamic slope and adopted a single-peak fitting model to identify the key time points and peak parameters. Finally, we developed an extreme gradient boosting-based prediction model for peak infection cases based on the total number of infections on the first 3, 5, and 7 days of the initial average incubation period. RESULTS: (1) A total of 7 52298 cases, including 587 outbreaks in 251 cities in Chinese mainland between June 11, 2020, and June 29, 2022, were collected, and the first wave of COVID-19 outbreaks was excluded. Excluding the Shanghai outbreak in 2022, the 586 remaining outbreaks resulted in 1 25425 infections, with an infection rate of 4.21 per 1 00000 individuals. The number of outbreaks varied based on location, season, and temperature. (2) Trajectory clustering analysis showed that 77 epidemic curves were divided into four patterns, which were dominated by two single-peak clustering patterns (63.3%). A total of 77 Rt curves were grouped into seven patterns, with the leading patterns including four downward dynamic transmission patterns (74.03%). These curves revealed that the interval from peak to the point where the Rt value dropped below 1 was approximately 5 days. (3) The peak-point judgment model achieved a better result in the area under the curve (0.96, 95% confidence interval = 0.90-1.00). The single-peak fitting results on the epidemic curves indicated that the interval from the slow-growth point to the sharp-decline point was approximately 4-6 days in more than 50% of mass outbreaks. (4) The peak-infection-case prediction model exhibited the superior clustering results of epidemic and Rt curves compared with the findings without grouping. CONCLUSION: Overall, our findings suggest the variation in the infection rates during the "dynamic zero-COVID" policy period based on the geographic division, level of economic development, seasonal division, and temperature. Trajectory clustering can be a useful tool for discovering epidemiological characteristics and dynamic transmissions, judging peak points, and predicting peak infection cases using different patterns.

Multiple brain regions are involved in reaction to acute restraint stress in CYLD-knockout mice.

The lysine 63 deubiquitinase cylindromatosis (CYLD) is expressed at high levels in the brain and is considered to be involved in anxious and depressive behavior, cognitive inflexibility, and autism disorders. Previous research was limited in some brain regions, including the hippocampus, striatum, and amygdala. To better understand whether CYLD plays a role in adaptation to stress and which brain regions are involved, we analyzed the behavior of CYLD-knockout mice in the elevated plus maze (EPM) and light-dark box test (LDT) after acute restraint stress (ARS) and mapped their c-Fos immunoreactivity in brain sections. Here we report that CYLD deficiency leads to an unexpected reaction to ARS in mice, and is accompanied by significant neuronal activation of brain regions including the medial prefrontal cortex (mPFC), dorsal striatum (DS), nucleus accumbens (NAc), and basal lateral amygdala (BLA), but not ventral hippocampus (vHPC). Our findings show that CYLD participates in ARS-induced anxious behavior and that this involves multiple brain regions.

Prevalence, Association Relation, and Dynamic Evolution Analysis of Critical Values in Health Checkup in China: A Retrospective Study.

Objective: The critical values in health checkup play a key role in preventing chronic diseases and different types of cancer. This study aimed to analyze the prevalence, association relation, and dynamic evolution of critical values in health checkups at a large physical examination center in China. Methods: Herein, we chose 33,639 samples of physical examiners from January 2017 to December 2019. After strict exclusion processes, combined with the critical values in health checkup reporting data, 4,721 participants with at least one critical value were included. We first defined a critical value list for laboratory test, imaging, cervical cancer screening, electrocardiogram, and health checkup informed on site, and then performed a cross-sectional study to analyze the distribution and significance of critical values of 4,721 participants from different views and the association relation of 628 participants with more than one critical value and a retrospective cohort study to analyze the incidence and dynamic evolution of critical values based on 2,813 participants attending the physical examination from 2017 to 2019. Results: A total of 4,721 participants were included in the retrospective study. The prevalence of 10 critical values from 33,639 participants was over 0.6%. The critical values of obesity, hypertension, Glucose_T, Liver_T, Kidney_T, Lipid_T, Urine_T, and Head_CT were significantly increased in men (P < 0.05), whereas the results were the opposite for the Blood_T and Thyroid_US (P < 0.01). The prevalence trend of critical values increased along with age, where the prevalence of men was higher than that of women under 60 years old (P < 0.01), while the prevalence of women increased by four times and exceeded the prevalence of men above 70 years old. Association relation analysis identified 16 and 6 effective rules for men and women, respectively, where the critical values of Urine_T and Glucose_T played the central roles. Furthermore, a retrospective dynamic evolution analysis found that the incidence of new critical values was about 10%, the incidence of persistent critical values was about 50%, and that most of the effective evolution paths tended to no critical values for men and women. Conclusion: In conclusion, this study provides a new perspective to explore the population health status using the critical value reporting data in a physical examination center, which can assist in decision-making by health management at the population level and in the prevention and treatment of various types of cancer and chronic diseases at the individual level.

Performance of China's new medical licensing examination for rural general practice.

BACKGROUND: To evaluate the performance of China's new medical licensing examination (MLE) for rural general practice, which determines the number of qualified doctors who can provide primary care for China's rural residents, and to identify associated factors. METHODS: Data came from all 547 examinees of the 2017 MLE for rural general practice in Hainan province, China. Overall pass rates of the MLE and pass rates of the MLE Step 1 practical skills examination and Step 2 written exam were examined. Chi-square tests and multivariable logistic regression were used to identify examinee characteristics associated with passing Step 1 and Step 2, respectively. RESULTS: Of the 547 examinees, 68% passed Step 1, while only 23% of Step 1 passers passed Step 2, yielding an 15% (82 of 547) overall pass rate of the whole examination. Junior college medical graduates were 2.236 (95% CI, 1.127-4.435) times more likely to pass Step 1 than secondary school medical graduates. Other characteristics, including age, gender, forms of study and years of graduation, were also significantly associated with passing Step 1. In contrast, examinees' vocational school major and Step 1 score were the only two significant predictors of passing Step 2. CONCLUSIONS: Our study reveals a low pass rate of China's new MLE for rural general practice in Hainan province, indicating a relatively weak competency of graduates from China's alternative medical education. An effective long-term solution might be to improve examinees' clinical competency through mandating residency training for graduates of China's alternative medical education.

Microglial activation in the dorsal striatum participates in anxiety-like behavior in Cyld knockout mice.

CYLD lysine 63 deubiquitinase (CYLD), that is mainly involved in immune responses and inflammation, is expressed at high levels in the brain, especially in the dorsal striatum, but its physiological function of CYLD in the brain remains unexplored. The present study investigated the effect of Cyld gene knockout on behavior relevant to the dorsal striatum, such as motor activity and depression-like and anxiety-like behavior. Microglia and the pro-inflammatory cytokines including interleukin (IL)-1 ß and tumor necrosis factor (TNF)- α were evaluated in the dorsal striatum to elucidate the underlying mechanism. Cyld knockout (Cyld-/-) mice exhibited anxiety-like behavior, but not motor deficits or depression-like behavior. Microglia were activated and the mRNA levels of IL-1 ß and TNF- α were increased in the dorsal striatum of Cyld-/- mice compared to Cyld+/+ mice. The microglial modulator minocycline partially reversed the anxiety-like behavior, microglial activation and increase in IL-1 ß and TNF- α mRNA and protein levels in the dorsal striatum of Cyld-/- mice. Collectively, these results suggest that Cyld knockout leading to microglial activation promotes IL-1 ß and TNF- α expression and acts as a critical pathway in the pathophysiology of anxiety.