Background Gestational weight gain is closely related to maternal and infant health outcomes. Pregnant women are simultaneously exposed to four metals—lithium (Li), vanadium (V), uranium (U), and bismuth (Bi)—through inhalation of fine particulate matter and consumption of contaminated food and water. Existing studies suggest that exposure to these metals may be associated with gestational weight gain. However, no study has yet explored the complex relationships between exposure to mixtures of these four metals and weight gain at different stages of pregnancy. Objective To investigate the associations between mixed exposure to Li, V, U, and Bi in early pregnancy and the average weekly gestational weight gain during both early pregnancy and mid-to-late pregnancy. Methods This prospective study recruited eligible women in early pregnancy from an obstetrics clinic of a tertiary hospital in Jinan, China, between September 2021 and July 2023. Pre-pregnancy weight, current weight (at 11⁺⁰ to 13⁺⁶ weeks of gestation), and spot urine samples (≥5.0 mL) were collected at enrollment. Urinary concentrations of Li, V, Bi, and U were determined using inductively coupled plasma mass spectrometry. Participants were followed up in late pregnancy (≥28 weeks of gestation) to collect information on physical activity via questionnaire; weight measurements at the last antenatal visit (35⁺⁰ to 37⁺⁶ weeks of gestation) were obtained from the hospital information system. After adjusting for covariates, multiple linear regression and generalized additive models were used to assess the associations of individual metals with weekly weight gain in early pregnancy and in mid-to-late pregnancy. Bayesian kernel machine regression (BKMR) and quantile-based g-computation (Qgcomp) were applied to evaluate the joint effects of the metal mixture exposure on weekly weight gain at the two gestational stages. Results A total of 313 pregnant women were included. The geometric means of urinary Li, V, U, and Bi concentrations were 37.07, 0.20, 0.06, and 0.04 μg·L⁻¹, respectively; after creatinine adjustment, the corresponding values were 46.82, 0.25, 0.07, and 0.05 μg·g⁻¹ (Cr). The mean weekly gestational weight gain was (0.19±0.25) kg in early pregnancy and (0.53 ± 0.18) kg in mid-to-late pregnancy. Both multiple linear regression and generalized additive models showed that urinary V concentration was positively associated with average weekly gestational weight gain in early pregnancy, while no significant associations were found for other metals or for gestational weight gain in mid-to-late pregnancy. In the BKMR model with early-pregnancy weight gain as the outcome, V had the strongest association [posterior inclusion probability (PIP)=0.773]. When other metals were fixed at their medians, V showed a positive non-linear association with the outcome. A significant single-metal effect of V and its interaction with Li were observed. Compared with the 50th percentile of the metal mixture, the average weekly weight gain in early pregnancy increased by 0.016 (95%CI: 0.003, 0.029) and 0.018 (95%CI: 0.001, 0.036) at the 60th and 65th percentiles, respectively; conversely, at the 25th percentile, it decreased by 0.026 (95%CI: 0.002, 0.050). Overall, the joint effect of the metal mixture on early- pregnancy weight gain showed an upward trend. In the BKMR model for mid-to-late pregnancy gestational weight gain, all PIPs were<0.5, and no significant single-metal effects, interactions, or joint effects were identified. Qgcomp results confirmed a positive association between the metal mixture and early-pregnancy weight gain (b=0.031, 95%CI: 0.010, 0.051; P<0.01), with V contributing the highest positive weight (0.71). No significant association was found for weight gain in mid-to-late pregnancy (b=0.007, P=0.339). Conclusion Higher levels of co-exposure to the Li, V, Bi, and U metal mixture during early pregnancy may be associated with increased average weekly weight gain in early pregnancy. Among these metals, V exhibits a predominant role and appears to interact with Li. No association is observed between early-pregnancy metal mixture exposure and average weekly gestational weight gain in mid-to-late pregnancy. These findings suggest that monitoring and managing metal exposure during early pregnancy may be crucial for the rational regulation of gestational weight gain.

Aim To investigate the effect of Senecio scandens Buch.-Ham on inflammatory pain mediated by mast cell P2X7 receptor.Methods Using the ATP-induced foot inflammatory pain,immunofluores-cence and toluidine blue staining techniques were used to investigate whether Senecio scandens has inhibitory effect on P2X7 receptor on mast cells.Using the calci-um ion imaging experimental technology,to explore whether Senecio scandens inhibit the intracellular cal-cium ion enrichment caused by activation of P2X7 re-ceptor on mouse peritoneal mast cell.The whole-cell patch clamp technique was used to investigate whether senecio scandens could inhibit the inward current in-duced by activation of P2X7 receptor on mouse perito-neal mast cell.Results In vivo,Senecio scandens alle-viate ATP induced inflammatory pain(3.9 g·kg-1:P＜0.05),and significantly inhibited the infiltration of P2X7 receptor-positive mast cells(3.9 g·kg-1:P＜0.05).Knockout of mast cell can reduce the analgesic effect of Senecio scandens(3.9 g·kg-1:P=0.645).In vitro.The experiment results show that senecio scandens can significantly inhibit the calcium influx(300 mg·L-1:P＜0.05;1 g·L-1:P＜0.01;3 g·L-1:P＜0.01)and the inward current mediated by P2X7 receptor in mast cell(1 g·L-1:P＜0.01).Conclusion Senecio scandens alleviate inflammatory pain by inhibiting mast cell P2X7 receptor.

Currently,there are practical and technical difficulties in the construction of clinical ques-tions in the development of clinical practice guidelines.Clinicians or guideline developers seldom construct clin-ical questions based the actual case scenario,leading to some information loss between structured and actual clinical connotation.To overcome this challenge,we proposed a case-guided questions construction approach,and carried out case research and verification in the formulation of the guideline.We found that this method could more efficiently and scientifically assist the formulation of clinical questions,and provide reference for clinicians or guideline developers.

Objective:To investigate the situation of computed tomography(CT)equipment and socio economic development of various grades and classifications of medical institutions in Jiangsu Province,and to analyze the interrelationship between them.Methods:From October 20,2023 to November 20,2023,a questionnaire survey was conducted on imported and domestic CT equipment of various grades and classifications of medical institutions in 13 prefecture-level cities in Jiangsu Province through online questionnaire survey of"questionnaire star".The gross domestic product(GDP)of each prefecture-level city in Jiangsu province was used as an indicator of measuring the level of socio-economic development in the region.The CT number,the row number of detector,quality of image,the total examination case number of daily average and the daily average case number of single machine examination of medical institutions of various grades and classifications of 13 prefecture-level cities were used to conduct correlation analysis with GDP values of various districts.Results:A total of 910 questionnaires were distributed,and 512 questionnaires were retrieved.There were 482 valid questionnaires in the 512 questionnaires,and the valid rate was 94.15,which involved to 482 various grade and classification institutions of 13 prefecture-level cities in Jiangsu province.The number of imported and domestic CT equipment in the 13 prefecture-level cities of Jiangsu Province positively correlated with the GDP of each city(r=0.882,0.880,P<0.001).The number of imported CT equipment with 64 rows and more than 64 rows,and with less than 64 rows,and the number of domestic CT equipment with 64 rows and more than 64 rows,and with less than 64 rows all positively correlated with the GDP of each city(r=0.880,0.881,0.736,0.897,P<0.05).The total number of daily average of examinations for imported and domestic CT equipment of 13 prefecture-level cities positively correlated with the GDP of each city(r=0.774,0.814,P<0.05).There were no significant difference in the image quality and the daily average case number of single machine examination between the domestic CT equipment and the imported CT equipment(P>0.05).Conclusion:The medical institutions of city with high level of economic development have more quantitative and more high-end CT equipment,and the quality of image of domestic CT equipment is equal to that of imported CT equipment regardless of the high and low level of economic development.

AIM To investigate the effects of Xuesaitong Capsules(Panax notoginseng saponins)on ischemia/reperfusion injury in a mouse model of skin frostbite.METHODS The mice were randomly divided into the control group,the model group,the dexamethasone group(1 mg/kg),and the low-dose,medium-dose,and high-dose Xuesaitong Capsules groups(0.036,0.072,and 0.144 g/kg),with eight mice in each group.A frostbite model was established using a dry ice-cooled ceramic(ferrite)magnet.On the 2nd day after modeling,each group started its corresponding dosing by gavage for 14 consecutive days.The wound healing,histopathological changes,and serum levels of high-sensitivity C-reactive protein(hs-CRP),thromboxane B2(TXB2),6-keto-prostaglandin F1α(6-K-PGF1α),nitric oxide(NO)and endothelin(ET)were assessed using ELISA.The superoxide dismutase(SOD)activity and malondialdehyde(MDA)levels in skin tissues were measured biochemically.The protein expressions of tumor necrosis factor(TNF)-α,interleukin(IL)-1β,IL-6,Toll-like receptor(TLR)4 and phosphorylated nuclear factor-KB p65(p-NF-κB p65)in skin tissues were determined by Western blot.Additionally,LncRNA H19 mRNA expression in skin tissues was evaluated using RT-qPCR.RESULTS After the final administration,compared with the control group,the model group exhibited partial scab detachment,wound healing,and larger wound areas;hyperkeratosis with incomplete keratinization,detachment of the dermis and subcutaneous tissue,partial loss of appendages,subcutaneous edema,and dilated,congested,and hemorrhagic stromal vessels with extensive lymphocyte infiltration revealed by the histopathological examination;elevated serum levels of hs-CRP,TXB2,and ET(P＜0.05,P＜0.01);decreased 6-K-PGF1α and NO levels(P＜0.05,P＜0.01);reduced SOD activity in skin tissues(P＜0.01);increased MDA levels(P＜0.01);and upregulated protein expressions of TNF-α,IL-1β,IL-6,TLR4 and p-NF-κB p65,as well as LncRNA H19 mRNA expression(P＜0.05,P＜0.01).Compared with the model group,the group intervened with high-dose Xuesaitong Capsules displayed reduced wound areas(P＜0.01);decreased serum levels of hs-CRP,TXB2 and ET(P＜0.05,P＜0.01);increased 6-K-PGF1α and NO levels(P＜0.05,P＜0.01);enhanced SOD activity(P＜0.05,P＜0.01);reduced MDA level in skin tissues(P＜0.05,P＜0.01);and down-regulated TNF-α,IL-1β,IL-6,TLR4 and p-NF-κB p65 protein expressions and suppressed LncRNA H19 mRNA expression in skin tissues as well(P＜0.05,P＜0.01).CONCLUSION Xuesaitong Capsules alleviate ischemia/reperfusion injury in frostbite-injured mice by exerting anti-inflammatory and anti oxidative stress effects and restoring vascular endothelial function mediated by the downregulation of LncRNA H19 expression and inhibition of the TLR4/NF-κB signaling pathway.

This study was aimed at investigating the effects of demethylase fat mass and obesity-associated protein(FTO)and methyltransferase methyltransferase like protein 3(METTL3),key molecules in N6-methyladenosine(m6A)modification,on the replication and proliferation of Japanese encephalitis virus(JEV).Recombinant lentiviruses were generated by packaging the FTO and green fluorescent protein into lentiviral vectors.Neuro2a cells,a mouse neuroblastoma cell line,were infected with the lentivirus,and stable FTO-expressing cell lines were obtained through puromycin selection.Successful overexpression of FTO was confirmed through fluorescence microscopy,real-time quantitative PCR,and western blot analysis.When Neuro2a cells overexpressing FTO were infected with JEV,the overexpression of FTO decreased JEV replication in the cells,and increased the expression of interferon(IFN)and related molecules.Additionally,treatment of JEV-infected Neuro2a cells with the METTL3-specific inhibitor STM2457 resulted in a dose-dependent decrease in JEV replication and viral protein expression.These findings suggested that lowering m6A methylation levels inhibits JEV replication,thus shedding light on the regulatory role of methylation modification in JEV replication.

Objective To evaluate the efficacy and safety of a novel intravascular lithotripsy(IVL)balloon—Vesscrack shockwave balloon—for vascular preparation before stent implantation in patients with severe coronary artery calcification(CAC).Methods This was a prospective,single-arm,multicenter study conducted in China from June 2022 to October 2022.Patients with severe CAC were treated with the Vesscrack shockwave balloon for lesion preparation,followed by drug-eluting stent(DES)implantation.Of these,33 patients underwent optical coherence tomography(OCT).The primary endpoint was procedural success,defined as successful stent implantation with residual stenosis≤30％and the absence of in-hospital major adverse events,including cardiac death,target vessel-related myocardial infarction,or target lesion revascularization.Results A total of 170 patients[mean age:(65.9±7.9)years,116 males]were enrolled.After treatment with IVL and DES,the minimum lumen diameter increased significantly compared to baseline[(2.34±0.40)mm vs.(0.95±0.33)mm,P＜0.001],the degree of stenosis was significantly reduced[(13.24±6.60)％vs.(65.18±10.59)％,P＜0.001].Procedural success was achieved in 100％of cases,and device success was 98.8％.The 30-day patient-related cardiovascular clinical composite endpoint(POCE)rate was 0.0,with no target lesion failure,no confirmed or potential thrombotic events were observed.The shockwave energy generator demonstrated excellent stability and ease of use.Among the 33 patients assessed with OCT,after IVL intervention,the maximum calcified area of the lumen[(3.51±1.51)mm2 vs.(2.85±1.80)mm2,P＜0.001],and the minimum lumen area within the target lesion[(3.08±1.04)mm2 vs.(2.02±0.75)mm2,P＜0.001],and after DES intervention,the luminal area of the largest calcified site[(6.59±1.64)mm2 vs.(2.85±1.80)mm2,P＜0.001]and the minimum luminal area within the target lesion[(6.19±1.45)mm2 vs.(2.02±0.75)mm2,P＜0.001]were significantly increased,and the differences were statistically significant.Conclusions The Vesscrack shockwave balloon is effective and safe for vascular preparation in patients with severe CAC prior to stent implantation.It achieves significant calcified plaque modification,high procedural success rates,and minimal complications.

Objective To explore the long-term efficacy of percutaneous pulmonary valve implantation(PPVI)and the durability of the domestic self-expanding Venus P valve.Methods A total of 8 patients with post-surgical right ventricular outflow tract(RVOT)dysfunction,who were admitted to hospital from October 2014 to July 2016 and deemed anatomically suitable for PPVI with self-expanding valve,were included prospectively.Clinical,imaging,procedural and follow-up data were analyzed.The survival rates,perioperative and long-term complication rates,long-term efficacy of PPVI,and long-term function of Venus P in 8 patients were evaluated.The immediate procedural results were evaluated by clinical implant success rate,which is defined as successful valve implantation with echocardiography-assessed pulmonary regurgitation＜moderate and peak trans-pulmonary pressure gradient＜40 mmHg.Results A total of 8 patients were included,with 7 females,aged 14 to 36 years.The initial diagnosis included post-surgical Tetralogy of Fallot(5 cases),post-surgical Trilogy of Fallot(1 case),post-surgical Quadricuspid pulmonary valve stenosis(1 case)and post-surgical Double-Outlet Right Ventricle(1 case).The indications of PPVI included RVOT-pulmonary obstruction and regurgitation(1 case)and isolated regurgitation(7 cases).Clinical implant success was achieved in all of the 8 patients with firmly fixed valve,and there were no such complications as valve detachment,displacement or stent fracture.All patients experienced significant symptom relief after the procedure.The right ventricular end-diastolic volume index(RVEDVi)measured by CMR 6 months after PPVI showed a significant decrease compared to preprocedural values[(89.99±13.85)ml/m2 vs.(144.93±11.28)ml/m2,P=0.001].Postoperative pulmonary regurgitation were significantly improved or disappeared in all patients,and there was no statistically significant difference in the average peak pressure gradient measured by echocardiogram between preoperative and the latest follow-up[(23.25±8.39)mmHg vs.(18.75±6.28)mmHg,P=0.210].Over an average follow-up period of(9.25±0.71)years,1 case of infective endocarditis occurred 5 years after PPVI.During the follow-up,no death,deterioration of heart failure,malignant arrhythmia or other serious complications were observed.All patients completed 8-year follow-up,and 3 completed 10-year follow-up.All patients were graded as NYHA functional class one at the latest follow-up.Conclusions PPVI using the domestically produced self-expanding Venus P is safe and feasible for the treatment of patients with post-surgical RVOT dysfunction and suitable anatomy.Our study confirms the long-term efficacy and durability of Venus P from multiple perspectives,and no severe stent fracture occurred without pre-stent implantation in the native RVOT.

Objective:To investigate the pharmacological mechanism of Compound Xuanju Capsule in the treatment of erectile dysfunction(ED)by using network pharmacology and molecular docking technology.Methods:The active ingredients and targets of Compound Xuanju Capsule were screened using Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform(TCMSP).TTD,OMIM,DrugBank and GeneCards databases were used to obtain genes related to ED,and the union of the results was taken as the disease genes of ED.The common target of drug and disease was taken as the potential target of Compound Xuanju Capsule in ED,and the drug-disease interaction network was constructed by using Cytoscape software.The protein-protein interaction(PPI)network was constructed by using String database,which was then imported into Cytoscape to identify the key target.Based on the drug-disease intersection genes,GO and KEGG enrichment analyses were performed to predict the relevant signaling pathways and molecular mechanisms of Compound Xuanju Capsule for the treatment of ED.Autodock software was used to perform molecular docking between the active ingredients and the core targets.Results:Forty chemical components of Compound Xuanju Capsule were screened,and 239 predicted targets were obtained.A total of 1 907 ED-related genes were screened,and 97 common targets were identified between Compound Xuanju Capsule and ED,among which the core targets included EGFR,ESR1,HIF1A,PTGS2,and STAT3.The signaling pathways obtained by KEGG enrichment analysis included calcium signaling pathway,HIF-1 signaling pathway,PI3K-Akt signaling pathway,cGMP-PKG signaling pathway,relaxin signaling pathway,Serotonergic synapse signaling pathway.The molecular docking results showed that there were molecular binding sites between the key active ingredients and the core targets with strong binding activity.Conclusion:Compound Xuanju Capsule may treat ED through multi-target pathways such as anti-inflamnmato-ry and improving cellular oxidative stress.

Objective:To investigate the expression pattern of pan-TRK protein in colorectal cancers with NTRK gene fusion and mismatch repair deficient (dMMR) and to analyze its molecular pathological characteristics.Methods:A total of 117 dMMR colorectal cancers diagnosed in the Department of Pathology of Henan Provincial People′s Hospital, Zhengzhou, China from 2020 to 2023 were collected. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and DNA/RNA-based next-generation sequencing (NGS) were used to detect pan-TRK protein expression and fusion partner genes in tumors, and to further explore the correlation between pan-TRK staining patterns and partner genes.Results:IHC and FISH were performed successfully in formalin-fixed paraffin-embedded tissues from 117 dMMR colorectal cancer patients. There were 15 (15/117, 12.8%) cases with positive pan-TRK, including 6 cases with strong staining in tumor cell membrane and cytoplasm, 2 cases with weakly granular staining in tumor cytoplasm, 2 cases with moderate dot-like staining in near 5% tumor cell nuclei, 1 case with moderately to strongly granular staining in the cytoplasm and membrane of tumor cells, 1 case with moderately to weakly granular staining in about 60% of the tumor cells, 1 case with strongly staining in about 1% of the tumor cells, 1 case with moderately to strongly staining in about 3% of the tumor cells and 1 case with diffuse, moderate para-nuclear dot-like and weakly perinuclear granular staining. NTRK1 gene disruption was detected in 6 cases (6/117, 5.1%) and consistent with diffusely strong expression of pan-TRK. Based on DNA/RNA NGS, it was further confirmed that the 6 cases with NTRK1 gene disruption all carried TPM3-NTRK1 fusion gene, and all had high microsatellite instability and high tumor mutation burden. No KRAS, NRAS, BRAF V600E or TP53 gene mutations were detected. Four patients carried frame shift mutations in RNF43. Other molecular changes included 3 cases with ROS1 gene mutation, 2 cases with BRAC, ALK, and EGFR gene mutations, 2 cases with ATM gene mutation, and 2 cases with KIT gene mutation. These were missense/frame shift mutations that were associated with no clinical significance. The nine pan-TRK-positive cases without NTRK gene fusion detected with DNA-based NGS were further confirmed with RNA-based NGS, and no NTRK gene fusion was found. The sensitivity and specificity of NTRK gene fusion detected using IHC were 100.0% and 92.5%, respectively. The sensitivity and specificity of diffusely strong membranous/cytoplasmic staining were both 100.0%.Conclusions:Pan-TRK protein has various expression patterns in dMMR colorectal cancer. Its diffusely strong expression is highly suggestive of NTRK1 gene fusion. TPM3-NTRK1 gene fusion is a common form of NTRK gene fusion in dMMR colorectal cancer.