Objective To design and synthesize dual-target antidepressant compounds possessing high-affinity binding to the serotonin 1A receptor(5-HT1A)and dual-site synergistic inhibition of the serotonin transporter(SERT).Methods Based on a dual-target synergistic mechanism,benzodioxolane derivatives were designed via scaffold hopping strategy before being synthesized.Their binding affinities to both targets were determined via competitive radioligand binding assays,and their binding modes were investigated using molecular docking.Results Eleven structurally novel target compounds were synthesized and structurally characterized by electrospray ionization mass spectrometry(ESI-MS)and nuclear magnetic resonance(NMR)spectroscopy.Compound 18b demonstrated dual nanomolar affinity for both the 5-HT1A receptor(Ki=2.72 nmol/L)and SERT(Ki=8.85 nmol/L).Molecular docking revealed that its inhibitory effect on SERT resulted from simultaneous occupation of the orthosteric site S1(Asp98 salt bridge)and the allosteric site S2(Arg104 rr-cation interaction),while its high affinity for 5-HT1A depended on the Asp116332 salt bridge anchor and π-π stacking with Phe362652.Conclusion The benzodioxolane-scaffold compounds designed and synthesized in this study exhibited functional synergy between simultaneous occupation of both the S1 and S2 sites of SERT and high-affinity binding to the 5-HT1Areceptor.Among them,compound 18b demonstrates superior activity and promises to be a lead compound for more investigation.

Objective:To compare the sustained virological response (SVR) and viral recurrence in patients with chronic hepatitis C (CHC) after antiviral treatment, and to further analyze the influencing factors of liver-related events (LRE).Methods:This was a retrospective cohort study. A total of 1 844 CHC patients who visited the Department of Infectious Diseases of Hainan General Hospital from January 1st, 2013 to December 31st, 2022 were included. After screening, 891 patients were selected and divided into direct-acting antiviral agent (DAA) treatment group, interferon treatment group and non-antiviral treatment group based on different intervention measures. Propensity score matching was performed, and SVR and viral recurrence were compared among the three groups. Statistical analysis was performed using the chi-square test, and multivariate Cox regression analysis was used to evaluate the risk factors for LRE.Results:The confirmed CHC patients showed an increasing trend year by year (average annual change percentage=19.97%, 95% confidence interval ( CI) 10.46% to 30.30%, t=4.32, P<0.001). After propensity score matching, the total sample size of 891 CHC patients was 451, including 100 in the interferon treatment group, 311 in the DAA treatment group, and 40 in the non-antiviral treatment group. In the interferon treatment group, 89 cases (89.00%) achieved SVR and nine cases (9.00%) had recurrence. In the DAA treatment group, 306 cases (98.39%) achieved SVR and 10 cases (3.22%) had recurrence. The differences were statistically significant ( χ2=17.84 and 6.22, respectively, both P<0.05). Cox multivariate regression analysis showed that age (hazard ratio ( HR)=1.065, 95% CI 1.028 to 1.104, P<0.001), alcohol consumption ( HR=3.034, 95% CI 1.302 to 7.071, P=0.010) were independent risk factors for LRE in CHC patients, while albumin ( HR=0.858, 95% CI 0.802 to 0.917, P<0.001), DAA treatment ( HR=0.267, 95% CI 0.103 to 0.692, P=0.007) were protective factors. In CHC patients receiving antiviral treatment, diabetes ( HR=6.719, 95% CI 2.242 to 20.137, P<0.001), total bilirubin ( HR=1.111, 95% CI 1.054 to 1.171, P<0.001) and viral recurrence ( HR=4.646, 95% CI 1.322 to 16.321, P=0.017) were independent risk factors for LRE. Conclusions:Compared with interferon treatment, DAA treatment has a significantly higher SVR rate and a lower recurrence rate. Age and alcohol consumption are independent risk factors for LRE, while higher albumin levels and DAA treatment are protective factors. In CHC patients receiving antiviral treatment, diabetes, viral recurrence, and total bilirubin are independent risk factors for LRE.

Objective:To compare the sustained virological response (SVR) and viral recurrence in patients with chronic hepatitis C (CHC) after antiviral treatment, and to further analyze the influencing factors of liver-related events (LRE).Methods:This was a retrospective cohort study. A total of 1 844 CHC patients who visited the Department of Infectious Diseases of Hainan General Hospital from January 1st, 2013 to December 31st, 2022 were included. After screening, 891 patients were selected and divided into direct-acting antiviral agent (DAA) treatment group, interferon treatment group and non-antiviral treatment group based on different intervention measures. Propensity score matching was performed, and SVR and viral recurrence were compared among the three groups. Statistical analysis was performed using the chi-square test, and multivariate Cox regression analysis was used to evaluate the risk factors for LRE.Results:The confirmed CHC patients showed an increasing trend year by year (average annual change percentage=19.97%, 95% confidence interval ( CI) 10.46% to 30.30%, t=4.32, P<0.001). After propensity score matching, the total sample size of 891 CHC patients was 451, including 100 in the interferon treatment group, 311 in the DAA treatment group, and 40 in the non-antiviral treatment group. In the interferon treatment group, 89 cases (89.00%) achieved SVR and nine cases (9.00%) had recurrence. In the DAA treatment group, 306 cases (98.39%) achieved SVR and 10 cases (3.22%) had recurrence. The differences were statistically significant ( χ2=17.84 and 6.22, respectively, both P<0.05). Cox multivariate regression analysis showed that age (hazard ratio ( HR)=1.065, 95% CI 1.028 to 1.104, P<0.001), alcohol consumption ( HR=3.034, 95% CI 1.302 to 7.071, P=0.010) were independent risk factors for LRE in CHC patients, while albumin ( HR=0.858, 95% CI 0.802 to 0.917, P<0.001), DAA treatment ( HR=0.267, 95% CI 0.103 to 0.692, P=0.007) were protective factors. In CHC patients receiving antiviral treatment, diabetes ( HR=6.719, 95% CI 2.242 to 20.137, P<0.001), total bilirubin ( HR=1.111, 95% CI 1.054 to 1.171, P<0.001) and viral recurrence ( HR=4.646, 95% CI 1.322 to 16.321, P=0.017) were independent risk factors for LRE. Conclusions:Compared with interferon treatment, DAA treatment has a significantly higher SVR rate and a lower recurrence rate. Age and alcohol consumption are independent risk factors for LRE, while higher albumin levels and DAA treatment are protective factors. In CHC patients receiving antiviral treatment, diabetes, viral recurrence, and total bilirubin are independent risk factors for LRE.

Objective: Progressive supranuclear palsy (PSP) involves a variety of visual symptoms that are thought to be partially caused by structural abnormalities of the retina. However, the relationship between retinal structural changes, disease severity, and intracranial alterations remains unknown. We investigated distinct retinal thinning patterns and their relationship with clinical severity and intracranial alterations in a PSP cohort. Methods: We enrolled 19 patients with PSP (38 eyes) and 20 age-matched healthy controls (40 eyes). All of the participants underwent peripapillary and macular optical coherence tomography. Brain 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography imaging were also performed in patients with PSP. We investigated the association between retinal thickness changes and clinical features, striatal dopamine transporter availability, and cerebral glucose metabolism. Results: The peripapillary retinal nerve fiber layer (pRNFL) and macula were significantly thinner in patients with PSP than in controls. The thickness of the superior sector of the pRNFL demonstrated a significant negative relationship with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III and Hoehn and Yahr staging scale scores. A significant negative correlation was found between outer inferior macular thickness and disease duration. Outer temporal macular thickness was positively correlated with Montreal Cognitive Assessment scores. In PSP, lower outer temporal macular thickness was also positively correlated with decreased dopamine transporter binding in the caudate. Conclusion The pRNFL and macular thinning may be candidate markers for monitoring disease severity. Additionally, macular thinning may be an in vivo indicator of nigrostriatal dopaminergic cell degeneration in PSP patients.

Platelet elevation is a rare manifestation in the peripheral blood of patients with chronic myeloid leukemia (CML). In this paper, we report for the first time a case of CML combined with cerebral hemorrhage manifested by abnormally elevated platelets. The patient had elevated platelets in the peripheral blood, showed normal coagulation function, and underwent intracranial hematoma removal due to cerebral hemorrhage. After the operation, bleeding from the operated area and other systems occurred, and the patient was diagnosed as having accelerated CML after combining bone marrow biopsy and genetic testing. His condition was controlled after administration of flumatinib through a jejunal tube. Based on this patient's experience, the feasibility ofadministering flumatinib via a jejunostomy tube was determined, which is the first report of its kind in China and abroad.This article summarizes the diagnosis and treatment process of this patient, with the aim of providing a warning and reference for clinicians.

Objective To construct SpyCatcher-mi3 nanoparticle vaccine delivery vectors,evaluate their role in enhancing the immunogenicity of the ovalbumin CD8+T-cell epitope peptide,OVA257-264,and determine its protective effect in a model which mice were immunized and subcutaneously challenged with E.G7-OVA tumor cells.Methods SpyCatcher-mi3 proteins were expressed by E.coli and purified by affinity chromatography and anion exchange chromatography sequentially.OVA257-264-SpyTag peptide was obtained by synthesis.The OVA257-264-mi3 nanoparticles were produced by the SpyTag/SpyCatcher system.The toxicity of OVA257-264-mi3 was evaluated using hemolysis assay,CCK-8 assay and mouse experiment.A total of 42 female SPF-grade C57BL/6 mice(6～8 weeks old,18～20 g)were randomly divided into OVA257-264-mi3,OVA257-264,and control groups,with 14 mice in each group.Then the mice in each group were immunized on days 0,14 and 28.In 14 d after the last immunization,the amounts of spot-forming cells(SFCs,indicating IFN-γ secreting cells in splenic lymphocytes)were determined using ELISpot assay to evaluate their immunogenicity.After the immunized mice were subcutaneously implanted with E.G7-OVA tumor cells,the antitumor effect of the vaccine in prophylactic xenograft tumor model was evaluate by observing tumor volumes with a caliper and tumor growth with MRI.Results Both SpyCatcher-mi3 and OVA257-264-mi3 could be self-assembled to form homogeneous and stable nanoparticles,with an average particle size of about 43.8 and 91.3 nm,respectively.The OVA257-264-mi3 was safe for in vitro and in vivo toxicity evaluation.The number of IFN--y secreting cells per 1 × 106 splenic lymphocytes reached 253 in the OVA257-264-mi3 group of mice,significantly higher than that in the OVA257-264 group and the Control group(P＜0.05).The tumor volume of mice in the OVA257-264-mi3 group was about 151.1 mm3 on day 22,which was significantly smaller than that of the OVA257-264 group and the Control group(P＜0.05),and the survival rate during the observation period reached 60％,which was significantly higher than that of the OVA257-264 groups(P＜0.05).Conclusion Nanoparticle vaccine OVA257-264-mi3 is successfully constructed,and it shows enhancing effect on the immunogenicity of the antigen epitope peptide,and exerts protective effect on prophylactic xenograft tumor model,providing a theoretical basis for the research of tumor neoantigen vaccines.

Objective:To investigate the surgical situations and perioperative outcome of pancreaticoduodenectomy in Jiangsu Province and the influencing factors for postoperative 90-day mortality.Methods:The retrospective case-control study was conducted. The clinicopathological data of 2 886 patients who underwent pancreaticoduodenectomy in 21 large tertiary hospitals of Jiangsu Quality Control Center for Pancreatic Diseases, including The First Affiliated Hospital of Nanjing Medical University, from March 2021 to December 2022 were collected. There were 1 732 males and 1 154 females, aged 65(57,71)years. Under the framework of the Jiangsu Provincial Pancreatic Disease Quality Control Project, the Jiangsu Quality Control Center for Pancreatic Diseases adopted a multi-center registration research method to establish a provincial electronic database for pancrea-ticoduodenectomy. Observation indicators: (1) clinical characteristics; (2) intraoperative and post-operative conditions; (3) influencing factors for 90-day mortality after pancreaticoduodenectomy. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(IQR), and comparison between groups was conducted using the Mann-Whitney U test. Count data were expressed as absolute numbers or constituent ratio, and comparison between groups was conducted using the chi-square test, continuity correction chi-square test and Fisher exact probability. Maximal Youden index method was used to determine the cutoff value of continuous variables. Univariate analysis was performed using the corresponding statistical methods based on data types. Multivariate analysis was performed using the Logistic multiple regression model. Results:(1) Clinical characteristics. Of the 2 886 patients who underwent pancreaticoduodenectomy, there were 1 175 and 1 711 cases in 2021 and 2022, respectively. Of the 21 hospitals, 8 hospitals had an average annual surgical volume of <36 cases for pancreaticoduodenectomy, 10 hospitals had an average annual surgical volume of 36-119 cases, and 3 hospitals had an average annual surgical volume of ≥120 cases. There were 2 584 cases performed pancreaticoduodenectomy in thirteen hospitals with an average annual surgical volume of ≥36 cases, accounting for 89.536%(2 584/2 886)of the total cases. There were 1 357 cases performed pancrea-ticoduodenectomy in three hospitals with an average annual surgical volume of ≥120 cases, accounting for 47.020%(1 357/2 886) of the total cases. (2) Intraoperative and postoperative conditions. Of the 2 886 patients, the surgical approach was open surgery in 2 397 cases, minimally invasive surgery in 488 cases, and it is unknown in 1 case. The pylorus was preserved in 871 cases, not preserved in 1 952 cases, and it is unknown in 63 cases. Combined organ resection was performed in 305 cases (including vascular resection in 209 cases), not combined organ resection in 2 579 cases, and it is unknown in 2 cases. The operation time of 2 885 patients was 290(115)minutes, the volume of intra-operative blood loss of 2 882 patients was 240(250)mL, and the intraoperative blood transfusion rate of 2 880 patients was 27.153%(782/2 880). Of the 2 886 patients, the invasive treatment rate was 11.342%(327/2 883), the unplanned Intensive Care Unit (ICU) treatment rate was 3.087%(89/2 883), the reoperation rate was 1.590%(45/2 830), the duration of postoperative hospital stay was 17(11)days, the hospitalization mortality rate was 0.798%(23/2 882), and the failure rate of rescue data in 2 083 cases with severe complications was 6.529%(19/291). There were 2 477 patients receiving postoperative 90-day follow-up, with the 90-day mortality of 2.705%(67/2477). The total incidence rate of complication in 2 886 patients was 58.997%(1 423/2 412). The incidence rate of severe complication was 13.970%(291/2 083). The comprehensive complication index was 8.7(22.6) in 2 078 patients. (3) Influencing factors for 90-day mortality after pancreaticoduodenectomy. Results of multivariate analysis showed that age ≥ 70 years, postoperative invasive treatment, and unplanned ICU treatment were independent risk factors for 90-day mortality after pancreaticoduodenectomy ( odds ratio=2.403, 2.609, 16.141, 95% confidence interval as 1.281-4.510, 1.298-5.244, 7.119-36.596, P<0.05). Average annual surgical volume ≥36 cases in the hospital was an independent protective factor for 90-day mortality after pancreaticoduodenectomy ( odds ratio=0.368, 95% confidence interval as 0.168-0.808, P<0.05). Conclusions:Pancreaticoduodenectomy in Jiangsu Province is highly con-centrated in some hospitals, with a high incidence of postoperative complications, and the risk of postoperative 90-day mortality is significant higher than that of hospitallization mortality. Age ≥ 70 years, postoperative invasive treatment, and unplanned ICU treatment are independent risk factors for 90-day motality after pancreaticoduodenectomy, and average annual surgical volume ≥36 cases in the hospital is an independent protective factor.

Objective To understand the testing performance of drug manufacturers and testing institute in Yunnan province by organizing proficiency testing of microbiological examination of non-sterile drugs,and to improve the testing performance and quality management level of participants by interpretation of unsatisfactory results.Methods According to the requirements of relevant China National Accreditation Service for Conformity Assessment (CNAS),preparation values of positive or negative was determined as assigned values for qualitative items,and the median value was as assigned value for enumeration items.Using robust statistical methods and Z-score for assessment,if all the 4 items were satisfactory,it would be assessed as overall satisfactory performance,and contrariwise,it would be assessed as unsatisfactory performance.If partial item were satisfactory,it would be assessed as partially satisfactory performance.Results 152 laboratories participated in this proficiency testing program,116 laboratories obtained satisfactory performance and the satisfactory rate was 76.31％;33 laboratories obtained partially satisfactory performance,and the partially satisfactory rate was 21.71％;3 laboratories obtained unsatisfactory performance and the unsatisfactory rate was 1.97％.To classify the participants with type,the satisfactory rate for drug control institute was 88.23％ and the satisfactory rate of drug manufacturers was 74.81％.Conclusion The testing performance of participating laboratories in microbiological examination of non-sterile drugs is generally good,which can ensure the smooth implementation of the program and the accuracy and effectiveness of the results.The testing capacity and quality management level of a few laboratories need to be improved.

Objective:To investigate the clinical effects of combined tissue flap transplantation in repairing giant chest wall defects.Methods:This study was a retrospective observational study. From August 2013 to December 2020, 31 patients with chest wall tumor or radiation ulcer after radical resection of chest wall tumor and conformed to the inclusion criteria were admitted to the Department of Breast Oncoplastic Surgery of Hunan Cancer Hospital, including 12 males and 19 females, aged 25-71 years. After resection of tumor or ulcer and wound debridement, the area of secondary chest wall defect was 300-600 cm 2 with length of 16-35 cm and width of 16-32 cm. According to the actual situation of the patients and the preoperative design, the chest wall defects were repaired with the flexible combination of perforator flaps and myocutaneous flaps from different donor sites, and the area of the combined tissue flap was 260-540 cm 2 with length of 20-30 cm and width of 13-20 cm. Free posteromedial thigh perforator flap+free anterolateral thigh myocutaneous flap were used in 2 patients, free deep inferior epigastric artery perforator flap+free anterolateral thigh myocutaneous flap were used in 5 patients, free deep inferior epigastric artery perforator flap+pedicled rectus abdominis myocutaneous flap+free anterolateral thigh myocutaneous flap were used in 7 patients, free deep inferior epigastric artery perforator flap+pedicled rectus abdominis myocutaneous flap+pedicled latissimus dorsi myocutaneous flap were used in 2 patients, and bilateral free anterolateral thigh myocutaneous flaps were used in 15 patients. For the remaining small area of superficial tissue defect after being repaired by combined tissue flaps, skin graft was used to repair or delayed local flap transfering was performed after the tissue flaps survived and edema subsided. The appropriate blood vessels in the donor and recipient sites were selected for anastomosis to reconstruct the blood supply of tissue flaps. The wounds in the donor sites of tissue flaps that can be directly sutured were sutured directly; for those that cannot be sutured directly, the skin grafting or delayed suture was performed. The anastomosis of blood vessels in the recipient sites, operation length, and postoperative hospital stay were recorded. The survivals of tissue flaps and skin grafts, the shape and texture of reconstructed chest wall, the wound healing, scar formation, and function of donor sites of tissue flaps, and the scar formation of the donor sites of skin grafts were observed after operation. Tumor recurrence and death of recurrent patients were followed up after operation. Results:The blood vessels in the recipient sites were anastomosed as follows: proximal internal thoracic vessels for 24 times, distal internal thoracic vessels for 12 times, trunk of thoracodorsal vessels for 4 times, anterior serratus branches of thoracodorsal vessels for 8 times, and thoracoacromial vessels for 12 times. The operation length was 6.0 to 8.5 hours, and the postoperative hospital stay was 9 to 21 days. Necrosis at the edge of partial tissue flaps occurred in 4 patients after operation, which healed after dressing change, and the tissue flaps and skin grafts of the other patients survived completely. The shape and texture of the reconstructed chest wall were good. Four patients had poor wound healing in the donor sites of abdominal tissue flaps, which healed after dressing change and local drainage. Only linear scar was left in the donor sites of all tissue flaps, and there was no obvious dysfunction in the donor sites of tissue flaps. Mild hypertrophic scar was left in the donor sites of skin grafts. During follow-up of 9 to 36 months after operation, 6 patients had tumor recurrence, and the recurrence time was 5 to 20 months after operation. After comprehensive treatment for patients with tumor recurrence, 3 patients died.Conclusions:Transplantation of combined tissue flaps in repairing the giant chest wall defects can shorten the time of total operation and hospital stay, and avoid multiple operations. After operation, patients had good chest wall appearance, with reduced tumor recurrence in patients with chest wall tumor.

Background: Femoral neck fractures (FNFs) comprise a large proportion of osteoporotic fractures in Asia. However, the full range of prognostic variables that affect prognosis remains unclear. Here, we aimed to determine whether the severity of bone defects at the fracture site and other variables impact the prognosis of displaced FNFs. Methods: We evaluated the incidence of FNF internal fixation failures at regular intervals after surgery in data collected retrospectively. Digital Imaging and Communications in Medicine (DICOM) magnetic resonance imaging data of the displaced FNFs of 204 patients (> 20 years old; mean age, 52.3 years; men, 55.4%) who underwent internal fixation were used to construct threedimensional (3D) virtual models of the femoral neck region. We calculated the position and volume of bone defect (VBD) using our independently developed algorithm and Mimics software. Each participant was followed up for at least 24 months; complications were noted and correlated with VBD and demographic and clinical variables. Results: On the basis of VBD values calculated from virtual reduction models, 57 patients were categorized as having a mild defect, 100 as having a moderate defect, and 47 as having a severe defect. Age (p = 0.046) and VBD (p < 0.001) were significantly correlated with internal fixation failure. Multivariate analysis revealed that severe bone defects were associated with internal fixation failure (adjusted odds ratio [aOR], 23.073; 95% confidence interval [CI], 2.791–190.732) and complications (aOR, 8.945; 95% CI, 1.829–43.749). In patients with a severe defect, bone grafting was inversely associated with internal fixation failure (aOR, 0.022; 95% CI, 0.002–0.268) and complications (aOR, 0.023; 95% CI, 0.002–0.299). Conclusions Bone defect severity was associated with internal fixation failure and other complications. For young adults with large VBDs, bone grafting of the defect can reduce the risk of internal fixation failure. These results provide useful new quantitative information for precisely classifying displaced FNFs and guiding subsequent optimal treatments.