Multi-target analgesics with minimal side effects and high efficacy are a key research focus in addressing the global pain crisis. Using a molecular networking approach, five pairs of potent analgesic alkaloid enantiomers were isolated from the roots of Anacyclus pyrethrum (A. pyrethrum). Their structures were elucidated by comprehensive spectroscopic data analysis, including LR-HSQMBC and ¹H-¹⁵N HMBC, quantum ¹³C NMR DP4+ and ECD calculations, and single-crystal X-ray diffraction analysis. Anacyphrethines A (1) and B (2) are highly conjugated and polymethylated 6/6/6/6/5/7/5/5-fused octacyclic tetraazabic alkaloids possessing an unprecedented 8,14,18,24-tetraaza-octacyclo[16.8.2.1^1,23.0^4,28.0^5,17.0^9,16.0^11,15.0^21,27] nonacosane motif. Their biosynthetic pathways are proposed involving key aldol, hydroamination, and Schiff base reactions. All isolates showed potent analgesic effects in vivo. Even at a lower dose of 0.2 mg/kg, (±)-1 and (+)-1 still exhibited more potent analgesic activities than morphine. Interestingly, the racemic mixture (±)-1 showed stronger analgesic effect than either pure enantiomer alone at higher doses of 5 and 1 mg/kg; while, (±)-1 showed significant analgesic activities comparable to (+)-1 at lower doses of 0.2 and 0.04 mg/kg. (+)-1 had stronger analgesic effect than (-)-1 at five tested does. Further tests on 44 analgesic-related targets demonstrated that (+)-1 showed significant inhibitory effects against many ion channels such as TRPM8, Kv1.2, Kv1.3, and Ca_v2.1 with IC₅₀ values of 1.10 ± 0.26, 4.20 ± 0.07, 2.20 ± 0.24, and 10.40 ± 0.69 μmol/L, respectively, while (-)-1 primarily inhibited TRPC6, Kv1.2, and Kv1.3 ion channels with IC₅₀ values of 0.81 ± 0.05, 0.91 ± 0.04, and 1.50 ± 0.13 μmol/L, respectively, without affecting the opioid receptors, suggesting their non-opioid analgesic potentials. The molecular dockings provided structural guidance to develop potent non-opioid analgesics.

Objective:To investigate the clinical effectiveness of autologous hamstring tendon reconstruction with preserved synovial sheath combined with remnant suture in the treatment of anterior cruciate ligament (ACL) tears.Methods:A retrospective study was conducted to analyze the clinical data of 38 patients with ACL tear who had been admitted to Department of Sports Medicine, The Fourth Hospital of Wuhan from January 2016 to July 2020. There were 30 males and 8 females, with an age of (25.4±7.2) years. By the typing of MRI Sherman tear locations (MSTL) for anterior cruciate ligament, 7 cases were Type I and 31 cases type II. A total of 18 patients underwent single bundle reconstruction of autologous hamstring tendon combined with remnant suture (group A), and the other 20 patients underwent conventional reconstruction to clean the synovial sheath of ACL (group B). The operation time,Tenger scores, Lysholm scores, International Knee Documentation Committee (IKDC) subjective score and side-to-side differences in relaxation at pre- operation, 1 year and 2 years after operation, as well as ACL healing of the affected knee at 2 years after operation, were observed and compared between the 2 groups. The graft synovial coverage was evaluated by secondary arthroscopy in some cases.Results:There was no significant difference in the preoperative general data between the 2 groups, indicating comparability ( P>0.05). All patients were followed up for (38.5±8.4) months. No surgical site infection or knee stiffness occurred in the 2 groups after operation, and 2 patients in each group developed intermuscular venous thrombosis at a lower limb. There was no significant difference in operation time between the 2 groups ( P>0.05). There were significant differences in Tenger score [(6.3±1.6) points versus (4.7±1.7) points], Lysholm score [(93.4±4.2) points versus (85.9±4.3) points] and IKDC subjective score [(89.1±2.9) points versus (81.2±2.9) points] between group A and group B at 1 year after operation ( P<0.05), but there was no significant difference in Tenger score, Lysholm score or IKDC subjective score between the 2 groups at 2 years after operation ( P>0.05). There was no significant difference in side-to-side difference in relaxation between the 2 groups at 1 year or 2 years after operation ( P>0.05). MRI evaluation at 2 years after operation showed no recurrent rupture or no sign of impingement between the graft and the intercondylar fossa in either group. Conventional secondary arthroscopy for 2 patients in group A and 3 patients in group B revealed better synovial coverage in group A. Conclusion:In the treatment of ACL tears of MSTL types I and II, compared with conventional reconstruction to clean the synovial sheath of ACL, autologous hamstring tendon reconstruction with preserved synovial sheath combined with remnant suture can lead to better functional recovery at 1 year after operation, though there is no significant difference in function at 2 years after operation.

Objective: To compare the transcriptomic profiles between three distinct metabolic dysfunction⁃associat⁃mal murine model that more closely resembles human MASH progression . Methods: Forty 8 ⁃week⁃old male C57BL/6J mice were randomly assigned to either a control group fed normal chow diet ( NCD) or one of three MASH model groups receiving high⁃fat high⁃cholesterol diet (HFHCD) , choline⁃deficient high⁃fat diet (CDHFD) ,from three randomly selected mice per group were collected for mRNA sequencing ( mRNA⁃seq) analysis . Mean⁃bases . Overlap of functional profiles was analyzed by gene set enrichment analysis (GSEA) profiles to compare the mouse transcriptome with that of human patients at different stages of the disease . Additionally , Pearson ′s correla⁃tion analysis was used to explore the correlation between gene expression of murine models and human MASH . Results: Seven commonly up⁃regulated genes (Col1a1 , Smoc2 , Col6a1 , Gpx3 , Col16a1 , Spp1 and Crtap) were de⁃ways involving steatosis , hepatocellular injury and fibrosis were detected in the three MASH models at the pathway level . HFHCD and MCD might share more common traits . In comparing gene expression and pathway profiles be⁃tween different murine models and patients with different stages of MASH , all three murine MASH models showed a closer resemblance to the human progressive stages of MASH . Notably , the transcriptomic features of the CDHFD model were more consistent with those of human MASH . Conclusion There are certain similarities and differences among the transcriptional profiles of the three MASH models . The MASH models are more similar to the advanced stage of MASH in human patients . Compared to the other two models , the CDHFD model ′ s transcriptome profile more closely resembles human MASH .

Objective The study intends to develop a multi－dimensional specific scale for the primary family caregivers of cancer patients,verify its reliability and validity,and reveal the burden level of the primary family caregivers of cancer patients.Methods This study investigated the primary family caregivers of cancer patients by questionnaire survey in Harbin of two medical institutions,finally we recalled 571 valid questionnaires.The study used SPSS 27.0 and AMOS 28.0 software to conduct reliability and validity analysis.The critical value of the burden score was determined by the quartile method to evaluate the burden level.Results The revised scale includes 21 items in 5 dimensions.The Cronbach's α coefficient range of the total scale and each dimension of the scale was 0.798~0.922,the Omega coefficient range was 0.806~0.918,and the split－half reliability range was 0.753~0.862.The average variance extracted(AVE)value and composite reliability(CR)value of the five dimensions of the scale meet the criteria,and the correlation coefficient between each dimension is less than the square root of AVE.Based on the critical value,there are 54.8%of carers suffer from moderate or heavy burdens.Among them,the financial burden and the care burden have the highest scores.Conclusion It shows that the burden scale for primary family caregivers of cancer patients has good reliability and validity.There are more than half of carers suffer from relatively heavy burden.Policymakers should draw up policies to support economic medical expense reimbursement and last comfort service.

Objective The study intends to develop a multi－dimensional specific scale for the primary family caregivers of cancer patients,verify its reliability and validity,and reveal the burden level of the primary family caregivers of cancer patients.Methods This study investigated the primary family caregivers of cancer patients by questionnaire survey in Harbin of two medical institutions,finally we recalled 571 valid questionnaires.The study used SPSS 27.0 and AMOS 28.0 software to conduct reliability and validity analysis.The critical value of the burden score was determined by the quartile method to evaluate the burden level.Results The revised scale includes 21 items in 5 dimensions.The Cronbach's α coefficient range of the total scale and each dimension of the scale was 0.798~0.922,the Omega coefficient range was 0.806~0.918,and the split－half reliability range was 0.753~0.862.The average variance extracted(AVE)value and composite reliability(CR)value of the five dimensions of the scale meet the criteria,and the correlation coefficient between each dimension is less than the square root of AVE.Based on the critical value,there are 54.8%of carers suffer from moderate or heavy burdens.Among them,the financial burden and the care burden have the highest scores.Conclusion It shows that the burden scale for primary family caregivers of cancer patients has good reliability and validity.There are more than half of carers suffer from relatively heavy burden.Policymakers should draw up policies to support economic medical expense reimbursement and last comfort service.

Objective:To investigate the clinical effectiveness of autologous hamstring tendon reconstruction with preserved synovial sheath combined with remnant suture in the treatment of anterior cruciate ligament (ACL) tears.Methods:A retrospective study was conducted to analyze the clinical data of 38 patients with ACL tear who had been admitted to Department of Sports Medicine, The Fourth Hospital of Wuhan from January 2016 to July 2020. There were 30 males and 8 females, with an age of (25.4±7.2) years. By the typing of MRI Sherman tear locations (MSTL) for anterior cruciate ligament, 7 cases were Type I and 31 cases type II. A total of 18 patients underwent single bundle reconstruction of autologous hamstring tendon combined with remnant suture (group A), and the other 20 patients underwent conventional reconstruction to clean the synovial sheath of ACL (group B). The operation time,Tenger scores, Lysholm scores, International Knee Documentation Committee (IKDC) subjective score and side-to-side differences in relaxation at pre- operation, 1 year and 2 years after operation, as well as ACL healing of the affected knee at 2 years after operation, were observed and compared between the 2 groups. The graft synovial coverage was evaluated by secondary arthroscopy in some cases.Results:There was no significant difference in the preoperative general data between the 2 groups, indicating comparability ( P>0.05). All patients were followed up for (38.5±8.4) months. No surgical site infection or knee stiffness occurred in the 2 groups after operation, and 2 patients in each group developed intermuscular venous thrombosis at a lower limb. There was no significant difference in operation time between the 2 groups ( P>0.05). There were significant differences in Tenger score [(6.3±1.6) points versus (4.7±1.7) points], Lysholm score [(93.4±4.2) points versus (85.9±4.3) points] and IKDC subjective score [(89.1±2.9) points versus (81.2±2.9) points] between group A and group B at 1 year after operation ( P<0.05), but there was no significant difference in Tenger score, Lysholm score or IKDC subjective score between the 2 groups at 2 years after operation ( P>0.05). There was no significant difference in side-to-side difference in relaxation between the 2 groups at 1 year or 2 years after operation ( P>0.05). MRI evaluation at 2 years after operation showed no recurrent rupture or no sign of impingement between the graft and the intercondylar fossa in either group. Conventional secondary arthroscopy for 2 patients in group A and 3 patients in group B revealed better synovial coverage in group A. Conclusion:In the treatment of ACL tears of MSTL types I and II, compared with conventional reconstruction to clean the synovial sheath of ACL, autologous hamstring tendon reconstruction with preserved synovial sheath combined with remnant suture can lead to better functional recovery at 1 year after operation, though there is no significant difference in function at 2 years after operation.

Objective To investigate the pathological damage to and inflammation of different intestinal segments in a rat model of severe hemorrhage,and to explore the effect of polarization of intestinal macrophage on the pathophysiology of intestinal inflammation.Methods Male Wistar rats were randomly divided into two groups:the sham operation group and hemorrhage group.In the hemorrhage group,40％of the total blood volume was lost in 25-30 minutes,while in the sham operation group,only the femoral artery and vein were intubated without bleeding.The rats were killed at 0,3,6,12 and 24 hours.The entire intestine was isolated quickly,and sections of the intestine were cut at the duodenum,jejunum,ileocecal junction,colon and rectum for histopathological evaluation.ELISA was adopted to determine related inflammation factors while multi-color immunohistochemistry was used to calculate macrophage surface markers.The data was statistically analyzed.Results(1)Compared with the sham group,there was no significant difference in colon histology at 3 h and 6 h,but significant difference was detected in rectum scores only at 24 h.The scores of other intestinal segments were significantly different at each time point.The severity of ileocecal and colonic lesions after bleeding increased with time.The duodenum,jejunum and ileocecum were more critically injured at 3 h than the rectum at 6 h.The injury to the duodenum,jejunum,ileum and colon was much more pronounced than to the rectum at 12 h.(2)The expressions of TNF-α and IL-1β in the rectum were increased significantly at 12 h post operation.The expressions of IL-1β,TNF-α in the jejunum increased obviously at 3 h and 6 h,respectively.(3)Three hours after severe bleeding,the level of macrophages in the jejunum and ileocececal area increased significantly,and the percentage of M1 macrophages was higher.After 6 hours,the proportion of M2 macrophages in the jejunum and M1 macrophages decreased significantly.After 3 hours,the percentage of M1 macrophages in the colon decreased,but that of M2 macrophages increased.The proportion of M2 polarized macrophages in the duodenum and rectum increased at 3 h after severe bleeding but decreased at 6 h.Conclusion Pathological damage to intestinal sections after bleeding varies depending on the time,and is correlated with the inflammatory level of macrophages.

Abstract: Objective　To understand the current epidemic status of echinococcosis in non-endemic areas of Xinjiang and provide a scientific basis for the local prevention and control of echinococcosis. Methods A cross-sectional study was conducted to investigate the prevalence of echinococcosis in non-epidemic areas of Xinjiang: Tianshan District, Shayibake District, Shule County in Kashgar Prefecture, and Hotan City in Hotan Prefecture of Urumqi City. From each surveyed county (city/district), three townships with higher numbers of reported echinococcosis cases from 2016 to 2020 were selected. Subsequently, three administrative villages with the highest number of reported echinococcosis cases were chosen as survey points from each township. A total of 9 administrative villages were investigated in each county (city/district). In the surveyed village, abdominal B-ultrasound screening was carried out for permanent residents aged three years and older, with suspected cases further tested for echinococcosis antibodies in blood using ELISA. In each survey village, at least 20 fecal samples from domestic dogs and, if present, at least 10 fecal samples from stray dogs were collected and tested for Echinococcus antigens. In the designated slaughterhouse of the surveyed townships, a random sample of 100 sheep or cattle raised in the township was selected on the spot, and their organs were examined by naked eyes, and the suspected diseased organs were detected by PCR. Results Among the four survey counties (cities/districts), 6 020 people underwent ultrasound screening for echinococcosis, with 7 positive cases detected, resulting in a detection rate of 0.12% (7/6 020). The detection rates of Tianshan District, Shayibake District, Shule County, and Hotan City were 0.26 % (4/1 512), 0.14 % (2/1 475), 0 (0/1 499), and 0.07% (1/1 534), respectively, all of which were cystic echinococcosis patients. A total of 1 474 dog fecal samples were detected, with an infection rate of 0.68% (10/1 474). The infection rates for domestic dogs and stray dogs were 0.84% (9/1 076) and 0.25% (1/398) respectively; there was no statistically significant difference between the two (χ2=0.74, P>0.05). A total of 2 095 livestock were surveyed, with an overall infection rate of 2.67% (56/2 095). The infection rates for sheep and cattle were 2.94% (46/1 564) and 1.88% (10/531) respectively, with a statistically significant difference between the two (χ2=6.99, P<0.01). Conclusions No human or dog infections were found in Shule County, which needs to be confirmed by in-depth epidemiological investigation and analysis of previously reported cases. Echinococcosis was found among humans, dogs, and livestock in Tianshan District, Shayibake District, and Hotan City, providing preliminary evidence of circulation history and transmission conditions of echinococcosis. It should be comprehensively considered to determine whether or not to incorporate into the epidemiologic area of echinococcosis to carry out systematic prevention and control.

Objective : To analyze the overall survival( OS) of sequential osimertinib treatment in patients with epidermal growth factor receptor(EGFR) exon 20 T790M mutant advanced non⁃small cell lung cancer(NSCLC) and risk factors of the efficacy of sequential osimertinib treatment. Methods : The data of 138 advanced NSCLC patients with acquired EGFR exon 20 T790M mutation who took sequential osimertinib as second⁃line treatment. KaplanMeier variable was used for survival analysis. The Log⁃rank method was used for univariate analysis. The COX risk regression model was used for multivariate analysis. The survival status and influencing factors of patients treated with sequential osimertinib were analyzed. Results : At the last follow⁃up , 99 of the 138 patients died. Median progression free survival (PFS1)of first⁃line of first⁃ or second⁃generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR⁃TKIs) was 11 months (95% CI: 10. 1 - 11. 9) ; median PFS2 of osimertinib was 10 months (95% CI: 8. 5 - 11. 5) ; The median PFS with sequential osimertinib treatment was 24 months(95% CI: 21. 7 -26. 3) , the median OS was 32 months(95% CI: 28. 9 - 35. 1) . In univariate and multivariate analysis , PFS1 was an independent prognostic factor for PFS and OS(P < 0. 001) . Conclusion Sequential osimertinib treatment for advanced NSCLC patients with acquired EGFR exon 20 T790M mutation achieved good PFS(24 months) and OS (32 months) .

Objective Based on the gene expression omnibus(GEO)database,bioinformatics methods were employed to analyze the expression characteristics of hypoxia-related differentially expressed genes(HRDEGs)in ischemic stroke,and key genes were screened,to provide important support for a deeper understanding of ischemic stroke.Methods The GSE16561 and GSE58294 datasets were downloaded from the GEO database,and Python software was used for data integration.The Combat method was employed to eliminate batch effects while retaining disease grouping characteristics.Principal component analysis was conducted to reduce dimensionality of the data before and after batch effect removal,and intraclass correlation coefficient(ICC)testing was performed on the ischemic stroke and normal control groups.Gene set enrichment analysis(GSEA)and single-sample GSEA were conducted on the merged and batch effects eliminated dataset,with a nominal P-value(NOM P-val)＜0.05 and false discovery rate P-value(FDR P-val)＜0.25 used as criteria to select significantly different gene sets.Differential expression genes between the ischemic stroke samples and normal control samples after merging and eliminating batch effects of the GSE16561 and GSE58294 datasets were identified using R software,with an absolute value of log2 gene expression fold change(FC)≥0.58 and adjusted P-value(Padj)＜0.05 as selection criteria.Intersection with hypoxia-related genes obtained from the National Center for Biotechnology Information(NCBI)in the United States yielded the HRDEGs.Gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)enrichment analyses were performed on the HRDEGs,and the STRING database was used to construct a protein-protein interaction network of differentially expressed genes.The top 10 key genes were filtered using Cytoscape 3.8 software.Results The ICC analysis results showed excellent consistency in the ischemic stroke and normal control samples after batch effect removal,with ICC values of 0.94 and 0.98 for the GSE16561 and GSE58294datasets,respectively.GSEA results demonstrated significant enrichment of 34 gene sets in the stroke samples in the newly merged and batch effects removed dataset from GSE16561 and GSE58294,leading to the identification of 404 differentially expressed genes(all with Padj＜0.05),including 354 upregulated genes and 50 downregulated genes.Intersection with hypoxia-related genes yielded 64 HRDEGs.GO enrichment analysis indicated significant enrichment of HRDEGs in vesicle lumen,cytoplasmic vesicle lumen,secretory granule lumen,with molecular functions such as amide binding,peptide binding,phospholipid binding,and enzyme inhibitor activity.These genes are primarily involved in the positive regulation of cytokine production,regulation of immune response,response to bacterium-derived molecules,and response to lipopolysaccharide,among other biological processes.KEGG enrichment analysis revealed enrichment of HRDEGs in pathways related to lipid and atherosclerosis,Salmonella infection,neutrophil extracellular trap formation,nucleotide-binding oligomerization domain-like receptor signaling pathway,protein glycosylation in cancer,tuberculosis,and necroptosis.Based on the protein-protein interaction network,10 key genes were identified,including arginase1(ARG1),caspase1(CASP1),interleukin1 receptor type 1(IL-1R1),integrin subunit alpha M(ITGAM),matrix metalloproteinase9(MMP9),prostaglandin-endoperoxide synthase 2(PTGS2),signal transducer and activator of transcription 3(STAT3),Toll-like receptor2(TLR2),TLR4,and TLR8.Conclusion This study has identified 10 key genes associated with ischemic stroke and hypoxia through bioinformatics mining,which maybe provid potential targets for subsequent research and diagnostic and therapeutic interventions.