Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

Laparoscopic subtotal cholecystectomy (LSC) has been a safe and viable alternative to conversion to laparotomy in cases of severe cholecystitis. The objective of this study is to determine the utility of intraoperative choledochoscopy in LSC for the exploration of the gallbladder, cyst duct, and subsequent stone clearance of the cystic duct in cases of severe cholecystitis. A total of 72 patients diagnosed with severe cholecystitis received choledochoscopy-assisted laparoscopic subtotal cholecystectomy (CALSC). A choledochoscopy was performed to explore the gallbladder cavity and/or cystic duct, and to extract stones using a range of techniques. The clinical records, including the operative records and outcomes, were subjected to analysis. No LSC was converted to open surgery, and no bile duct or vascular injuries were sustained. All stones within the cystic duct were removed by a combination of techniques, including high-frequency needle knife electrotomy, basket, and electrohydraulic lithotripsy. A follow-up examination revealed the absence of residual bile duct stones, with the exception of one common bile duct stone, which was extracted via endoscopic retrograde cholangiopancreatography. In certain special cases, CALSC may prove to be an efficacious treatment for the management of severe cholecystitis. This technique allows for optimal comprehension of the situation within the gallbladder cavity and cystic duct, facilitating the removal of stones from the cystic duct and reducing the residue of the non-functional gallbladder remnant.

BACKGROUND: The combination of immune checkpoint inhibitors and chemotherapy (ICI + Chemo) shows promise in treatment of recurrent or metastatic nasopharyngeal carcinoma (RM-NPC), but some patients received limited benefit and the prognostic factors of the treatments remain unclear. Furthermore, ICIs efficacy in subsequent treatments needs further evaluation. METHODS: A systematic search on PubMed, Embase, the Cochrane Library, and major conference proceedings was conducted to identify relevant studies for meta-analysis. The study was designed to compare ICI + Chemo with chemotherapy in first-line treatment and identify efficacy predictors, and to evaluate ICIs alone in subsequent-line treatment for RM-NPC, with a focus on progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs). RESULTS: Fifteen trials involving 1928 patients were included. Three trials compared ICI + Chemo with chemotherapy as a first-line treatment, while 12 trials evaluated ICIs alone in subsequent-line treatment of RM-NPC patients. First-line ICI + Chemo showed superior PFS (hazard ratio [HR] = 0.52, 95% confidence interval [CI], 0.43-0.63; P <0.001) and ORR (risk ratio [RR] = 1.14, 95% CI, 1.05-1.24; P <0.001) compared to chemotherapy, without increased AEs (RR = 1.01, 95% CI, 0.99-1.03; P = 0.481). Neither programmed death-ligand 1 (PD-L1) nor other factors predicted the efficacy of ICI + Chemo vs . chemotherapy. Subsequent-line ICIs alone had a median PFS of 4.12 months (95% CI, 2.93-5.31 months), an ORR of 24% (95% CI, 20-28%), with grade 1-5/grade 3-5 AEs at 79%/14%. However, ICIs alone were associated with significantly shorter PFS (HR = 1.31, 95% CI, 1.01-1.68; P = 0.040) than chemotherapy alone. CONCLUSIONS ICI + Chemo confers superior survival benefits compared to chemotherapy in first-line RM-NPC treatment, independent of PD-L1 expression or other factors. However, ICIs alone demonstrate a manageable safety profile but do not surpass chemotherapy in efficacy for subsequent-line treatment.
Humans ; Immune Checkpoint Inhibitors/adverse effects* ; Nasopharyngeal Carcinoma/drug therapy* ; Nasopharyngeal Neoplasms/drug therapy* ; Neoplasm Recurrence, Local/drug therapy*

Purpose: The aim of this study was to investigate the feasibility of an intelligent handheld ultrasound (US) device for assisting non-expert general practitioners (GPs) in detecting carotid plaques (CPs) in community populations. Methods: This prospective parallel controlled trial recruited 111 consecutive community residents. All of them underwent examinations by non-expert GPs and specialist doctors using handheld US devices (setting A, setting B, and setting C). The results of setting C with specialist doctors were considered the gold standard. Carotid intima-media thickness (CIMT) and the features of CPs were measured and recorded. The diagnostic performance of GPs in distinguishing CPs was evaluated using a receiver operating characteristic curve. Inter-observer agreement was compared using the intragroup correlation coefficient (ICC). Questionnaires were completed to evaluate clinical benefits. Results: Among the 111 community residents, 80, 96, and 112 CPs were detected in settings A, B, and C, respectively. Setting B exhibited better diagnostic performance than setting A for detecting CPs (area under the curve, 0.856 vs. 0.749; P<0.01). Setting B had better consistency with setting C than setting A in CIMT measurement and the assessment of CPs (ICC, 0.731 to 0.923). Moreover, measurements in setting B required less time than the other two settings (44.59 seconds vs. 108.87 seconds vs. 126.13 seconds, both P<0.01). Conclusion Using an intelligent handheld US device, GPs can perform CP screening and achieve a diagnostic capability comparable to that of specialist doctors.

Purpose: The aim of this study was to investigate the feasibility of an intelligent handheld ultrasound (US) device for assisting non-expert general practitioners (GPs) in detecting carotid plaques (CPs) in community populations. Methods: This prospective parallel controlled trial recruited 111 consecutive community residents. All of them underwent examinations by non-expert GPs and specialist doctors using handheld US devices (setting A, setting B, and setting C). The results of setting C with specialist doctors were considered the gold standard. Carotid intima-media thickness (CIMT) and the features of CPs were measured and recorded. The diagnostic performance of GPs in distinguishing CPs was evaluated using a receiver operating characteristic curve. Inter-observer agreement was compared using the intragroup correlation coefficient (ICC). Questionnaires were completed to evaluate clinical benefits. Results: Among the 111 community residents, 80, 96, and 112 CPs were detected in settings A, B, and C, respectively. Setting B exhibited better diagnostic performance than setting A for detecting CPs (area under the curve, 0.856 vs. 0.749; P<0.01). Setting B had better consistency with setting C than setting A in CIMT measurement and the assessment of CPs (ICC, 0.731 to 0.923). Moreover, measurements in setting B required less time than the other two settings (44.59 seconds vs. 108.87 seconds vs. 126.13 seconds, both P<0.01). Conclusion Using an intelligent handheld US device, GPs can perform CP screening and achieve a diagnostic capability comparable to that of specialist doctors.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Objective To clone and express the heat shock cognate protein 20 (SjHsc20) of Schistosoma japonicum, and to preliminarily investigate its biological characteristics. Methods The target fragment of the SjHsc20 gene was amplified using PCR assay and cloned into the pET-28a(+) expression plasmid to generate the recombinant expression vector pET-28a(+)-SjH-sc20, which was then transformed into Escherichia coli BL21 (DE3) competent cells. The recombinant SjHsc20 (rSjHsc20) protein was induced with isopropyl β-D-thiogalactopyranoside (IPTG) and purified, and the expression of the rSjHsc20 protein was checked with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The immunogenicity of the rSjHsc20 protein was detected using Western blotting, and the transcriptional levels of SjHsc20 were quantified in S. japonicum worms at different developmental stages and in male and female adult worms using real-time quantitative PCR (RT-qPCR) assay. Thirty female BALB/c mice at ages 6 to 8 weeks were divided into three groups, including the rSjHsc20 immunization group, the PBS control group, and the ISA 206 adjuvant group, of 10 mice in each group. Mice in the rSjHsc20 immunization group were subcutaneously immunized with 20 μg rSjHsc20 on days 1, 15 and 31, and animals in the PBS control group were subcutaneously injected with the same volume of PBS on days 1, 15 and 31, while mice in the ISA 206 adjuvant group were subcutaneously immunized with the same volume of ISA 206 adjuvant on days 1, 15 and 31, respectively. All mice in each group were infected with (40 ± 2) S. japonicum cercariae via the abdomen 14 day following the last immunization. Levels of serum specific IgG and its subtypes IgG1 and IgG2 antibodies against rSjHsc20, and the serum titers of anti-rSjHsc20 antibody were detected in mice using indirect enzyme-linked immunosorbent assay (ELISA). All mice were sacrifice 42 days post-infection, and S. japonicum worms were collected from the hepatic portal vein and counted. The eggs per gram (EPG), worm burden reductions and egg burden reductions were estimated to evaluate the protective efficacy of the rSjHsc20 protein. Results The SjHsc20 gene had an open reading frame (ORF) with 756 bp in length and encoded 252 amino acids, and the rSjHsc20 protein had a relative molecular mass of approximately 29 kDa. The rSjHsc20 protein was recognized by the serum of mice infected with S. japonicum and the serum of mice immunized with the rSjHsc20 protein, indicating that rSjHsc20 had a good immunogenicity. There was a significant difference in the transcriptional levels of the SjHsc20 gene among the 7-day (1.001 4 ± 0.065 7), 12-day (2.268 3 ± 0.129 2), 21-day (1.378 5 ± 0.160 4), 28-day (1.196 4 ± 0.244 0), 35-day (1.646 3 ± 0.226 1), 42-day worms of S. japonicum (1.758 0 ± 0.611 1) (F = 38.45, P < 0.000 1), and the transcriptional level of the SjHsc20 gene was higher in the 12-day worms than in worms at other developmental stages (all P values < 0.000 1). The serum levels of anti-rSjHsc20 IgG antibody were 0.106 6 ± 0.010 7, 0.108 3 ± 0.010 4, and 0.553 2 ± 0.069 1 in the PBS control group, ISA 206 adjuvant group, and rSjHsc20 immunization group following the last immunization, respectively, and the serum levels of IgG1 antibody were 0.137 3 ± 0.054 0, 0.181 1 ± 0.096 8, and 1.765 8 ± 0.221 1, while the levels of IgG2a antibody were 0.280 3 ± 0.197 6, 0.274 0 ± 0.146 3, and 1.560 4 ± 0.106 0, respectively. There were significant differences in the serum levels of anti-rSjHsc20 IgG (F = 397.70, P < 0.000 1), IgG1 (F = 401.00, P < 0.000 1) and IgG2a antibodies (F = 229.70, P < 0.000 1) among the three groups, and the serum levels of anti-rSjHsc20 IgG, IgG1 and IgG2a antibodies were higher in the rSjHsc20 immunization group than in the PBS control group and the ISA 206 adjuvant group (all P values < 0.000 1). There was a significant difference in the IgG1/IgG2a ratio among the rSjHsc20 immunization group (1.177 2 ± 0.143 6), the PBS control group (0.428 4 ± 0.199 8) and the ISA 206 adjuvant group (0.559 9 ± 0.181 1) (F = 43.97, P < 0.000 1), and the IgG1/IgG2a ratio was > 1 in the rSjHsc20 immunization group, which was higher than in the PBS control group and the ISA 206 adjuvant group (both P values < 0.000 1). The titers of serum anti-rSjHsc20 antibody were all above 1∶16 384 in the rSjHsc20 immunization group following immunizations on days 1, 15 and 31, indicating that the rSjHsc20 protein had a strong immunogenicity. The mean worm burdens were (16.60±5.75), (15.80±5.58) worms per mouse and (14.40±5.75) worms per mouse in the PBS control group, the ISA 206 adjuvant group and the rSjHsc20 immunization group 42 days post-infection with S. japonicum cercariae (F = 0.50, P > 0.05), and the EPG were 68 370 ± 22 690, 67 972 ± 19 502, and 41 075 ± 13 251 in the PBS control group, the ISA 206 adjuvant group and the rSjHsc20 immunization group (F = 4.55, P < 0.05), with lower EPG in the PBS control group and the ISA 206 adjuvant group than in the rSjHsc20 immunization group (both P values < 0.05). Immunization with the rSjHsc20 protein resulted in a worm burden reduction of 13.25% and an egg burden reduction of 39.92% relative to the PBS control group. Conclusions SjHsc20 is successfully cloned and expressed, and the rSjHsc20 protein induces partial immunoprotective effects in mice, which provides a basis for deciphering the biological functions of SjHsc20 and assessing the potential of SjH-sc20 as a vaccine candidate.

Objective: To investigate the characteristics and HIV confirmed positive status among individuals attending HIV voluntary counseling and testing (VCT) clinics in Inner Mongolia Autonomous Region, so as to provide the basis for enhancing interventions targeting high-risk populations for AIDS. Methods: Demographic information, reasons for consultation, consulting institutions, and HIV antibody testing data of individuals attending VCT clinics in Inner Mongolia Autonomous Region from 2019 to 2023 were collected through the VCT database of the Chinese Center for Disease Control and Prevention. The characteristics of individuals attending VCT were described. Factors affecting HIV confirmed positive among VCT clinic attendees were analyzed using a multivariable logistic regression model. Results: A total of 249 919 individuals attended VCT clinics in Inner Mongolia Autonomous Region from 2019 to 2023, including 128 069 males (51.24%) and 121 850 females (48.76%). The majority of attendees were aged 25-<35 years, accounting for 92 445 cases (36.99%). Among them, 785 cases were confirmed as HIV positive, with a positivity rate of 0.31%. Multivariable logistic regression analysis revealed that males (OR=4.787, 95%CI: 3.562-6.434), 45-<65 years of age (45-<55 years, OR=7.723, 95%CI: 1.786-33.406; 55-<65 years, OR=7.689, 95%CI: 1.757-33.653), being unmarried (OR=2.143, 95%CI: 1.580-2.906), junior high school education or below (OR=1.147, 95%CI: 1.042-2.430), having the history of high-risk behaviors or exposure risks (commercial heterosexual behaviors, OR=2.717, 95%CI: 1.707-4.324; non-commercial non-fixed heterosexual behaviors, OR=5.421, 95%CI: 3.763-7.809; homosexual behaviors, OR=70.774, 95%CI: 48.409-103.473; having an HIV-positive spouse/fixed partner/mother, OR=100.024, 95%CI: 62.490-160.100; drug injection, OR=5.366, 95%CI: 2.213-13.014), and seeking general hospitals or traditional Chinese medicine hospitals (OR=1.973, 95%CI: 1.650-2.360) were associated with a higher risk of HIV confirmed positive. Conclusions HIV confirmed positive among individuals attending VCT clinics in Inner Mongolia Autonomous Region is associated with gender, age, marital status, educational level, reasons for consultation, and consulting institutions. It is recommended to strengthen health education and targeted interventions for high-risk populations to reduce the risk of HIV infection.

ObjectiveTo investigate the influence of histone deacetylase 3 (HDAC3) on the occurrence, development of psoriasis-like inflammation in mice, and the relative immune mechanisms. MethodsHealthy C57BL/6 mice aged 6-8 weeks were selected and randomly divided into 3 groups: control group (Control), psoriasis model group (IMQ), and HDAC3 inhibitor RGFP966-treated psoriasis model group (IMQ+RGFP966). One day prior to the experiment, the back hair of the mice was shaved. After a one-day stabilization period, the mice in Control group was treated with an equal amount of vaseline, while the mice in IMQ group was treated with imiquimod (62.5 mg/d) applied topically on the back to establish a psoriasis-like inflammation model. The mice in IMQ+RGFP966 group received intervention with a high dose of the HDAC3-selective inhibitor RGFP966 (30 mg/kg) based on the psoriasis-like model. All groups were treated continuously for 5 d, during which psoriasis-like inflammation symptoms (scaling, erythema, skin thickness), body weight, and mental status were observed and recorded, with photographs taken for documentation. After euthanasia, hematoxylin-eosin (HE) staining was used to assess the effect of RGFP966 on the skin tissue structure of the mice, and skin thickness was measured. The mRNA and protein expression levels of HDAC3 in skin tissues were detected using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB), respectively. Flow cytometry was employed to analyze neutrophils in peripheral blood and lymph nodes, CD4⁺ T lymphocytes, CD8⁺ T lymphocytes in peripheral blood, and IL-17A secretion by peripheral blood CD4⁺ T lymphocytes. Additionally, spleen CD4⁺ T lymphocyte expression of HDAC3, CCR6, CCR8, and IL-17A secretion levels were analyzed. Immunohistochemistry was used to detect the localization and expression levels of HDAC3, IL-17A, and IL-10 in skin tissues. ResultsCompared with the Control group, the IMQ group exhibited significant psoriasis-like inflammation, characterized by erythema, scaling, and skin wrinkling. Compared with the IMQ group, RGFP966 exacerbated psoriasis-like inflammatory symptoms, leading to increased hyperkeratosis. The psoriasis area and severity index (PASI) skin symptom scores were higher in the IMQ group than those in the Control group, and the scores were further elevated in the IMQ+RGFP966 group compared to the IMQ group. Skin thickness measurements showed a trend of IMQ+RGFP966>IMQ>Control. The numbers of neutrophils in the blood and lymph nodes increased sequentially in the Control, IMQ, and IMQ+RGFP966 groups, with a similar trend observed for CD4⁺ and CD8⁺ T lymphocytes in the blood. In skin tissues, compared with the Control group, the mRNA and protein levels of HDAC3 decreased in the IMQ group, but RGFP966 did not further reduce these expressions. HDAC3 was primarily located in the nucleus. Compared with the Control group, the nuclear HDAC3 content decreased in the skin tissues of the IMQ group, and RGFP966 further reduced nuclear HDAC3. Compared with the Control and IMQ groups, RGFP966 treatment decreased HDAC3 expression in splenic CD4⁺ and CD8⁺ T cells. RGFP966 treatment increased the expression of CCR6 and CCR8 in splenic CD4⁺ T cells and enhanced IL-17A secretion by peripheral blood and splenic CD4⁺ T lymphocytes. Additionally, compared with the IMQ group, RGFP966 reduced IL-10 protein levels and upregulated IL-17A expression in skin tissues. ConclusionRGFP966 exacerbates psoriatic-like inflammatory responses by inhibiting HDAC3, increasing the secretion of the cytokine IL-17A, and upregulating the expression of chemokines CCR8 and CCR6.

OBJECTIVE To investigate the epidemiological characteristics of hospital-associated infections caused by multidrug-resistant organisms(MDROs)among the burn wound patients so as to provide bases for taking tar-geted control measures.METHODS A systematic search was conducted in the worldwide database for nosocomial outbreaks,PubMed and CNKI databases so as to summarize and analyze the data regarding to outbreaks of MDROs hospital-associated infections among burn wound patients.RESULTS A total of 61 incidents of MDROs hospital-associated infections outbreaks among the burn wound patients were included,involving 2 293 patients from 21 countries and regions,50(81.97％)of which were reported for the infection sites or colonization sites in-volving burn wound,12(19.67％)involving the respiratory tract,10(16.39％)involving the bloodstream infec-tions.Methicillin-resistant Staphylococcus aureus(28 incidents,45.90％)was dominant among the pathogens causing the infections,followed by multidrug-resistant Acinetobacter baumannii(17 incidents,27.87％)and multidrug-resistant Pseudomonas aureus(9 incidents,14.75％).52 incidents(82.25％)of outbreaks were reported the contact as the major transmission mode.The suspected sources of the outbreaks included the patients(37 incidents,28.46％),health care workers(30 incidents,23.08％),ward environments(28 incidents,21.54％),medical equipments(19 incidents,30.56％),drainage systems(6 incidents,4.62％).The major pre-vention and control measures included environmental cleaning and disinfection,screening of colonization in patients and health care workers,isolation of patients with infections and hand hygiene;8 incidents were taken the measure of closing the ward.CONCLUSIONS The outbreaks of MDROs infections in the burn wound patients are mostly associated with the high frequently contact environments,medical equipments and hand hygiene of health care workers.In view of the peculiarities of the burn wound patients,it is feasible to take the targeted measures based on the summarized prevention and control combinations for MDROs so as to prevent the outbreak of hospital-asso-ciated infections.