In 2022， Hainan provincial government launched the project for the prevention and control of viral hepatitis with the goals of a hepatitis B screening rate of 90%， a diagnostic rate of 90%， and a treatment rate of 80% among people aged 18 years and above by the year 2025， and the main intervention measures include population-based prevention， case screening， antiviral therapy， and health management. As of December 31， 2024， a total of 6.875 million individuals in the general population had been screened for hepatitis B， with a screening rate of 95.6%. A total of 184 710 individuals with positive HBsAg were identified， among whom 156 772 were diagnosed through serological reexamination， resulting in a diagnostic rate of 84.9%. A total of 50 742 patients with chronic hepatitis B were identified， among whom 42 921 had hepatitis B-specific health records established for health management， with a file establishment rate of 84.6%. A total of 31 553 individuals received antiviral therapy， with a treatment rate of 62.2%. A total of 2.503 million individuals at a high risk of hepatitis C were screened， among whom 4 870 tested positive for HCV antibody and 3 858 underwent HCV RNA testing， resulting in a diagnostic rate of 79.2%， and 1 824 individuals with positive HCV RNA were identified， among whom 1 194 received antiviral therapy， with a treatment rate of 65.5%. In addition， 159 301 individuals with negative HBsAg and anti-HBs and an age of 20 — 40 years were inoculated with hepatitis B vaccine free of charge. Through the implementation of the project for the prevention and control of viral hepatitis， a large number of hepatitis patients have been identified， treated， and managed in the province within a short period of time， which significantly accelerates the efforts to eliminate the crisis of viral hepatitis.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist approved for diabetes and obesity, has shown significant potential in treating metabolic dysfunction-associated steatotic liver disease (MASLD). However, its systematic molecular regulation and mechanisms remain underexplored. In this study, a mouse model of MASLD was developed using a high-fat diet (HFD), followed by Lira administration. Proteomics and glycoproteomics were analyzed using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS), while potential molecular target analysis was conducted via quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Our results revealed that Lira treatment significantly reduced liver weight and serum markers, including alanine aminotransferase (ALT) and others, with glycosylation changes playing a more significant role than overall protein expression. The glycoproteome identified 255 independent glycosylation sites, emphasizing the impact of Lira on amino acid, carbohydrate metabolism, and ferroptosis. Simultaneously, proteomic analysis highlighted its effects on lipid metabolism and fibrosis pathways. 21 signature molecules, including 7 proteins and 14 N-glycosylation sites (N-glycosites), were identified as potential targets. A Lira hydrogel formulation (Lira@fibrin (Fib) Gel) was developed to extend drug dosing intervals, offering enhanced therapeutic efficacy in managing chronic metabolic diseases. Our study demonstrated the importance of glycosylation regulation in the therapeutic effects of Lira on MASLD, identifying potential molecular targets and advancing its clinical application for MASLD treatment.

Moyamoya disease (MMD) is a chronic progressive cerebrovascular disease, and extracranial-intracranial revascularization is the most commonly treatment for MMD. With the continuous development of imaging techniques, the perioperative monitoring methods for MMD patients have gradually become more diverse. However, Doppler ultrasound still holds an important position due to its convenience and non-invasiveness. This article reviews the role of Doppler ultrasound in the perioperative assessment of patients with MMD.

Objective:To study the survival and prognostic factors for the recurrent extracranial malignant germ cell tumors (MGCTs) in children, and to explore feasible salvage treatment.Methods:A retrospective study.Pediatric patients with recurrent extracranial MGCTs diagnosed in Shanghai Children′s Medical Center between January 2010 and January 2020 were retrospectively recruited.Comprehensive treatment regimens included surgery, chemotherapy and radiation.Kaplan-Meier survival analysis and Cox regression model were employed to analyze the survival and prognostic factors for children with recurrent extracranial MGCTs.Results:A total of 172 children with extracranial MGCTs were treated, including 21 (12.2%) recurrent cases.The median time of MGCT recurrence after the end of the first treatment was 11 months.Finally, 19 patients were recruited after excluding 2 non-eligible cases, including 10 boys and 9 girls with the age at recurrence of 26 (8-170) months.The follow-up time was 57 (13-122) months.Salvage chemotherapy, complete resection and radiotherapy were performed in 16, 14 and 4 patients, respectively.The 4-year overall survival (4yr-OS) rate was (82.5±9.2)%(19 cases). The 4yr-OS rate was significantly higher in patients managed with surgery but without adjuvant chemotherapy at the initial treatment (13 cases) than those managed with chemotherapy at the initial treatment (6 cases)[(92.3±7.4)% vs.(60.0%±21.9)%, P=0.002]. Univariant and Cox multivariant regression analyses showed that failure to achieve the normal range of alpha fetoprotein after 3 cycles of chemotherapy significantly influenced the survival of recurrent extracranial MGCTs. Conclusions:For patients with recurrent extracranial MGCTs, comprehensive treatment approaches like complete surgical resection, chemotherapy, and radiotherapy offer a favorable survival rate.Specifically, recurrent and re-treated patients who initially received surgery alone without adjuvant chemotherapy have a higher survival rate compared to those who received chemotherapy during the initial treatment.

Objective:To investigate the expression of miRNA-144 in the peripheral blood of patients with type 2 diabetes foot ulcer (DFU) and its correlation with the pathogenesis of the disease.Methods:A total of 106 patients with DFU admitted to the General Hospital of the Western Theater Command of the Chinese People′s Liberation Army from March 2020 to June 2022 were retrospectively selected as the observation group, and 106 patients with type 2 diabetes mellitus (T2DM) who did not have DFU admitted to our hospital during the same period were selected as the control group. According to the median expression level of miRNA-144 in peripheral blood of DFU patients as the segmentation point, 106 patients in the observation group were divided into low expression group and high expression group. We compared the clinical data of the observation group and the control group, and analyzed the relationship between different levels of miRNA-144 expression and clinical characteristics of DFU patients; A multivariate analysis was conducted on the factors related to the occurrence and development of the disease course in DFU patients, and a column chart model was constructed for model validation.Results:The course of diabetes, fasting blood glucose (FPG), erythrocyte sedimentation rate (ESR), glycosylated hemoglobin (HbA 1c), white blood cell count (WBC), C-reactive protein (CRP), corticotropin releasing hormone (CRH), interleukin-6 (IL-6), adrenaline (E), norepinephrine (NE), cortisol (Cor) and miRNA-144 expression levels in the observation group were significantly higher than those in the control group, while transcutaneous partial pressure of oxygen (TcPO 2), ankle brachial index (ABI), triglyceride (TG) and hemoglobin (Hb) were significantly lower than those in the control group, the difference was statistically significant (all P<0.05). There were statistically significant differences in foot ulcer healing rate, Wagner grading, and ulcer course between the high expression group of miRNA-144 and the low expression group of DFU patients after 8 weeks (all P<0.05). Multivariate regression analysis showed that the duration of diabetes>5 years, HbA 1c>8.5%, TcPO 2<60 mmHg, CRP>10 mg/L, Cor>190 μg/L, and miRNA-144 expression level>35 were independent risk factors for the occurrence of DFU in T2DM patients. The total score of 315 points after constructing the nomogram prediction model for the above factors, and the corresponding probability of occurrence and development of DFU was 72.56%. Conclusions:The expression level of miRNA-144 in the peripheral blood of DFU patients is significantly related to the occurrence and development of the disease course, and the course of diabetes and the changes of HbA 1c, TcPO 2, CRP, Cor levels are independent risk factors for the occurrence and development of DFU, which should be focused on clinically.

Objective:To evaluate the association between N-acylsphingosine amide hydrolase 1 (ASAH1) and pyroptosis during acute lung injury (ALI) in septic mice.Methods:Forty SPF-grade healthy male C57BL/6 mice, aged 6-8 weeks, weighing 18-23 g, were divided into 4 groups ( n=10 each) by a random number table method: sham operation group (Sham group), ALI group, HCFU solvent+ ALI group (HA group) and ASAH1 inhibitor HCFU+ ALI group (AA group). The abdominal cavity was only opened in Sham group, and cecal ligation puncture was performed in ALI, HA and AA groups. HCFU solvent 0.2 ml was intraperitoneally injected at 2 h before operation in HA group, and HCFU 10 mg/kg was intraperitoneally injected at 2 h before operation in AA group. The mice were sacrificed at 24 h under deep anesthesia, the eyeballs were removed to collect the blood, the bronchoalveolar lavage fluid (BALF) was collected, and lung tissues and blood samples were collected for microscopic examination of the pathological changes (using HE staining) which were scored and for determination of concentrations of protein in BALF (by BCA method), concentrations of interleukin-1beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNF-α) in BALF (by enzyme-linked immunosorbent assay), and expression of NOD-like receptor thermoprotein structural domain-related protein 3 (NLRP3) in lung tissues (by Western blot), gasdermin D protein (GSDMD), ASAH1 and cysteine protease-1 (caspase-1) (by Western blot). The wet/dry lung weight (W/D) ratio was calculated. Results:Compared with Sham group, the lung injury score, W/D ratio and concentrations of protein in BALF, IL-1β, IL-6 and TNF-α in serum were significantly increased, and the expression of NLRP3, GSDMD and caspase-1 in lung tissues was up-regulated in ALI, HA and AA groups, and the expression of ASAH1 was significantly up-regulated in ALI and HA groups ( P<0.05). Compared with ALI and HA groups, the lung injury score, W/D ratio, and concentrations of protein in BALF, IL-1β, IL-6 and TNF-α in serum were significantly increased, the expression of NLRP3, GSDMD and caspase-1 in lung tissues was up-regulated, and the expression of ASAH1 was down-regulated in AA group ( P<0.05 or 0.01). Conclusions:ASAH1 is involved in the endogenous protective mechanism underlying ALI in septic mice, which may be related to the inhibition of cell pyroptosis.

Objectives:To explore the clinicopathological characteristics and prognostic risk factors in differentiated thyroid cancer (DTC) patients with lung metastasis.Methods:Patients of differentiated thyroid cancer with lung metastasis in Tianjin Medical University Cancer Institute & Hospital were enrolled from Jan 1, 2010 to Dec 31, 2016. The clinicopathological characteristics and risk factors affecting the prognosis were analyzed retrospectively.Results:A total of 65 DTC patients with lung metastasis were collected in this study, including 56 patients with papillary thyroid carcinoma and 9 patients with follicular thyroid carcinoma; 23 patients died and 42 patients survived. Median follow-up time was 99.4 months. There were 18 males, 47 females. Age 14-73 years, median age 51.0 years. High incidence of DTC lung metastasis was 50-59 years for males and 40-49 years for females. Based on AJCC 8th edition TNM staging, there were 37 patients in stage Ⅱ (age <55 years) and 28 patients in stage Ⅳb (age ≥55 years). The number of 131Ⅰ treatments performed ranged from 1 to 13 times, with a mean of 3.9 times. Firty-five patients were with lung metastasis alone, and 10 patients with lung metastasis and distant metastasis in other organs. Eleven patients suffered from hypoparathyroidism after 131Ⅰ treatment. COX multifactorial regression analysis found that age was independent risk factor affecting prognosis, multiple organs distant metastasis and pathologic subtype were relative risk factors affecting prognosis. There was no correlation between gender, number of 131Ⅰ treatments and poor prognosis. Conclusions:DTC has a high survival even with the occurrence of lung metastasis, but the prognosis is poor when combined with multi-organ metastasis. Age and multiple organ distant metastatic are independent risk factors affecting prognosis.

Objective:To evaluate and screen the regimens of tigecycline intraventricular injection in extensively drug resistant Acinetobacter baumannii (XDRAB) intracranial infection based on Monte Carlo simulation and pharmacokinetic/pharmacodynamic (PK/PD) model.Methods:Nine patients with XDRAB intracranial infection confirmed as having susceptibility to tigecycline or polymyxin antimicrobials from January 1, 2018 to December 31, 2023 were screened from electronic medical record system in Second Affiliated Hospital of Shandong First Medical University. WHONET software was used to extract pathogen susceptibility data isolated from cerebrospinal fluid samples. Minimum inhibitory concentration (MIC) of tigecycline against XDRAB was analyzed by drug susceptibility test; different regimens for intraventricular tigecycline injection were designed based on MIC: 2 mg/12 h, 3 mg/12 h, 4 mg/12 h, 5 mg/12 h, 6 mg/12 h, and 10 mg/12 h, with drug concentration of 0.5 mg/mL or 1.0 mg/mL once a day. Target value of PK/PD index was set as ?C max/MIC≥8; Monte Carlo was used to simulate the compliance of PK/PD index of tigecycline with different MIC against XDRAB for different dosed regimens (probability of target attainment [PTA] and cumulative fraction of response [CFR]); the best regiment was selected (screening basis: PTA≥90% or CFR≥90%). Results:(1) A total of 27 strains of pathogenic bacteria from 9 patients were extracted from drug susceptibility test, in which MIC of tigecycline against XDRAB was 55.56% for 2 mg/L, 25.93% for 4 mg/L, and 18.52% for 8 mg/L. (2) When the drug concentration was 0.5 mg/mL or 1.0 mg/mL, respectively, all 6 regimens had PTA>90% at 2 mg/L MIC; 5 regimens, except for 2 mg/12 h, had PTA>90% at 4 mg/L MIC; regimens of 5 mg/12 h, 6 mg/12 h, and 10 mg/12 h could achieve PTA>90% at 8 mg/L MIC. (3) When the drug concentration was 0.5 mg/mL, regimens of 4 mg/12 h, 5 mg/12 h, 6 mg/12 h, and 10 mg/12 h could achieve CFR>90%; when the drug concentration was 1 mg/mL, regimens of 4 mg/12 h, 5 mg/12 h, 6 mg/12 h, and 10 mg/12 h could achieve CFR>92%.Conclusion:In intraventricular tigecycline injection for XDRAB intracranial infection, 2 mg/12 h regimen is available in 2 mg/L MIC, 3 mg/12 h regimen is available in 4 mg/L MIC, and 5 mg/12 h regimen is available in 8 mg/L MIC, with either 0.5 mg/mL or 1 mg/mL concentration.

Objective:To observe the effects of warming needle therapy combined with the modified Hua Tan Tong Luo Tang(decoction for dissipating phlegm and unblocking collaterals)on post-stroke cognitive impairment due to obstruction of wind-phlegm. Methods:A total of 78 patients who met the inclusion criteria were randomly assigned to an observation group and a control group,with 39 patients in each group.Both groups received conventional treatment.The control group was additionally treated with the modified Hua Tan Tong Luo Tang,while the observation group received warming needle therapy in addition to the treatment given to the control group.Scores on the mini-mental state examination(MMSE),Montreal cognitive assessment(MoCA),and activities of daily living(ADL)were assessed before and after treatment.Adverse reactions and clinical efficacy were analyzed and compared between the two groups after treatment. Results:The total effective rate was 82.1%in the observation group and 61.5%in the control group,showing statistical significance between the two groups(P<0.05).After treatment,the MMSE,MoCA,and ADL scores of both groups were significantly higher than those before treatment within each group(P<0.05).Notably,the scores in the observation group were higher than those in the control group(P<0.05).No adverse reactions occurred in either group during the treatment period. Conclusion:Based on the conventional treatment,compared to modified Hua Tan Tong Luo Tang alone,warming needle therapy combined with the modified Hua Tan Tong Luo Tang showed superior clinical efficacy in treating post-stroke cognitive impairment due to obstruction of wind-phlegm,and this combined therapy also showed high safety.