Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective:To investigate the postoperative prosthesis position and early clinical efficacy of 3D printing patient-specific instrumentation (PSI)-assisted unicompartmental knee arthroplasty (UKA).Methods:The clinical data of 15 patients (17 knees, PSI group) with medial compartment knee osteoarthritis who underwent PSI-assisted UKA in the Second Affiliated Hospital, the Air Force Medical University from May to August 2023 were retrospectively analyzed, matched with fifteen patients (17 knees, non-PSI group) with medial compartment knee osteoarthritis undergoing conventional UKA. The differences in the prosthesis placement positions in the postoperative X-ray films between the two groups were compared, including the coronal varus-valgus angles of the tibial and femoral prostheses, the sagittal posterior inclination angle of the tibial prosthesis, the flexion-extension angle of the femoral prosthesis, and the height of the reconstructed joint line. The indicators related to the lower limb alignment (including the femoral valgus angle, the lateral femoral angle, the hip-knee-ankle angle, and the femur-tibia angle) and the range of motion of the knee joint before and after the operation were compared. The Oxford knee score (OKS), American Knee Society (AKS) knee score and function score, and the visual analogue scale (VAS) were used to evaluate the clinical effects of the two groups.Results:In the PSI group, the coronal varus-valgus angle of the tibial prosthesis was 1.6°±0.3° after the operation, and the sagittal posterior inclination angle was 5.7°±0.8°. The coronal varus-valgus angle of the femoral prosthesis was -0.5°±1.5°, and the sagittal flexion-extension angle was 4.0°±1.9°. In the non-PSI group, the corresponding angles were 2.3°±0.6°, 4.5°±1.0°, 1.4°±1.5°, and 7.3°±2.2° respectively with significant differences between the two groups ( P<0.05). The OKS of the PSI group before and after the operation were 26.5±1.8 and 38.6±4.1 points respectively. The AKS knee score were 56.9±8.6 and 89.2±7.2 points. The AKS function score were 70.1±4.2 and 77.5±9.4 points. The VAS were 4.5±3.7 and 2.3±0.3 points, and the range of motion of the knee joint were 115.2°±4.8° and 125.9°±4.6° with significant differences ( P<0.05). The OKS of the non-PSI group before and after the operation were 25.3±6.2 and 38.2±3.5 points respectively. The AKS knee score were 50.6±9.3 and 84.5±6.6 points. The AKS function score were 73.4±3.9 and 77.2±4.8 points. The VAS were 5.8±2.4 and 2.5±1.6 points, and the range of motion of the knee joint were 113.6°±6.7° and 122.3°±5.0° with significant differences ( P<0.05). There were inter-group differences in the AKS knee score and the range of motion of the knee joint after the operation between the two groups with significant differences ( P<0.05). Conclusion:PSI guides-assisted UKA can effectively correct the lower limb alignment of patients and improve knee joint function with good short-term efficacy. Compared with conventional UKA, PSI guides-assisted UKA is less time-consuming with higher precision in prosthesis installation position and fewer post-operative complications.

Objective To explore the effect of intermittent fasting combined with diversified management mode on weight loss of overweight and obese people. Methods A total of 120 overweight and obese patients were selected as research objects, and randomly divided into control group (n=60) and experimental group (n=60). The control group was given intermittent fasting, and the experimental group was given diversified management mode on the basis of the control group. Waist circumference, body mass, body mass index (BMI), waist-to-hip ratio and blood lipid level were compared between the two groups; the scores of hunger, satiety, satisfaction and the incidence of adverse reactions were compared between the two groups. Results After intervention, waist circumference, body mass, BMI, waist-to-hip ratio, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in the experimental group were significantly lower, and high-density lipoprotein cholesterol (HDL-C) was significantly higher than that in the control group (P < 0.05). After intervention, the hunger score of the experimental group was significantly lower, and the satiety score and satisfaction score were significantly higher than those of the control group (P < 0.05). The total incidence of adverse reactions in the experimental group was 6.67%, which was significantly lower than 20.00% in the control group (P < 0.05). Conclusion The application of intermittent fasting combined with diversified management mode in overweight and obese people is better, which can improve the relevant clinical indicators and blood lipid levels, and has high safety.

Objective:To evaluate the role of NF-E2-related factor 2 (Nrf2)/heme oxygenase (HO-1) signaling pathway in reduction of endotoxin-induced acute lung injury (ALI) by esketamine and the relationship with NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in mice.Methods:SPF male wild-type (WT) and Nrf2 knockout (KO) C57BL/6J mice, aged 6-8 weeks, weighing 20-25 g, were divided into 3 groups ( n=6 each) using a random number table method: control group (WT+ C group, KO+ C group), ALI group (WT+ ALI group, KO+ ALI group) and ALI+ esketamine group (WT+ ALI+ E group, KO+ ALI+ E group). ALI model was developed by injection of lipopolysaccharide (LPS) 15 mg/kg via the tail vein. Esketamine 10 mg/kg was intraperitoneally injected at 30 min after LPS injection, and 6 h later the medication was repeated for one time in WT+ ALI+ E and KO+ ALI+ E groups, while the equal volume of normal saline was given in the other groups. The mice were anesthetized at 12 h after LPS injection, and blood samples were obtained by cardiac puncture for determination of serum interleukin-1beta (IL-1β) and IL-18 concentrations, and bilateral lung tissues were also obtained for examination of the pathological changes of lung tissues(with the light microscope) which were scored and for determination of the content of reduced glutathione (GSH) and expression of Nrf2, HO-1 and NLRP3 inflammasome-mediated pyroptosis-related proteins (NLRP3, apoptosis-associated speck-like protein containing a CARD[ASC], pro-caspase-1, cleaved-caspase-1, gasdermin D[GSDMD]) (by Western blot). Results:Compared with the corresponding C group (WT+ C group or KO+ C group), the lung injury score and concentrations of IL-1β and IL-18 were significantly increased, the content of GSH in lung tissues was decreased, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was up-regulated in WT+ ALI group and KO+ ALI group ( P<0.05), and the expression of Nrf2 and HO-1 was significantly up-regulated in WT+ ALI group( P<0.05). Compared with the corresponding ALI group (WT+ ALI group or KO+ ALI group), the lung injury score and concentrations of IL-1β and IL-18 were significantly decreased, the content of GSH in lung tissues was increased, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was down-regulated in WT+ ALI+ E group and KO+ ALI+ E group ( P<0.05), and Nrf2 and HO-1 expression was significantly up-regulated in WT+ ALI+ E group( P<0.05). Compared with WT+ ALI+ E group, the lung injury score and concentrations of IL-1β and IL-18 were significantly increased, the content of GSH in lung tissues was decreased, the expression of Nrf2 and HO-1 was down-regulated, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was up-regulated in KO+ ALI+ E group ( P<0.05). Conclusions:The mechanism by which esketamine reduces endotoxin-induced ALI may be related to activation of Nrf2/HO-1 signaling pathway, thus inhibiting NLRP3 inflammasome-mediated pyroptosis in mice.

Objective:To investigate the relationship between lymph node metastases and the prognosis of uterine cervical cancer patients diagnosed at Ⅲ C1p after abdominal surgery. Methods:The clinical data of 350 uterine cervical cancer patients preoperatively confirmed as 2018 International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰ B-Ⅱ A who underwent abdominal hysterectomy followed by postoperative concurrent chemoradiotherapy between January 2012 and December 2019 at Subei People's Hospital of Jiangsu Province were retrospectively analyzed, and there were 81 patients postoperatively diagnosed at stage Ⅲ C1p. Kaplan-Meier method was used to analyze the survival of patients stratified by different factors, and multivariate Cox proportional risk model was used to analyze the factors affecting the prognosis of patients. Results:Among 81 uterine cervical cancer patients diagnosed at stage Ⅲ C1p after abdominal surgery, 79 cases were successfully followed up. Kaplan-Meier analysis showed that patients with parametrial infiltration, the number of metastatic lymph nodes > 2, metastatic lymph node rate > 20 and common iliac lymph node metastasis had worse disease-free survival (DFS) and the overall survival (OS) (all P < 0.05). Multivariate Cox proportional analysis showed that the number of metastatic lymph nodes > 2 ( HR = 5.38,95% CI 1.30-22.20, P = 0.020) was an independent risk factor for OS; the number of metastatic lymph nodes >2 ( HR = 5.99, 95% CI 1.45-24.77, P = 0.013), common iliac lymph node metastasis ( HR = 4.91, 95% CI 1.17-20.55, P = 0.029) were independent risk factors for DFS. Conclusion:Lymph node metastasis may be associated with the prognosis of uterine cervical cancer patients diagnosed at stage Ⅲ C1p after abdominal surgery. The number of metastatic lymph nodes > 2 is a adverse influencing factor for OS and DFS.

Objective:To evaluate the influence of telomerase reverse transcriptase (TERT) promoter mutation on radioiodine uptake status of radioactive iodine refractory papillary thyroid cancer (RAIR-PTC) and radioiodine therapy response by analyzing the mutation frequency of TERT promoter in RAIR-PTC.Methods:A total of 37 patients with RAIR-PTC (15 males, 22 females, age (49.8±16.1) years) and 40 PTC patients with effective radioiodine therapy (13 males, 27 females, age (39.8±10.9) years) between January 2005 and June 2020 in JiangYuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine were retrospectively analyzed. TERT promoter mutation and B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation of patients were observed. The differences across genotype patterns on radioiodine uptake status and therapy response were compared. The Fisher′s exact test and independent-sample t test were used for data analysis. Results:The incidence rate of TERT promoter mutation in the RAIR-PTC group was 40.54% (15/37, all C228T), which was significantly higher than that in the effective radioiodine therapy group (0, 0/40; P<0.001). No statistically significant difference was found for the mutation rate of BRAF V600E between the RAIR group (64.86%, 24/37) and the effective radioiodine therapy group (72.50%, 29/40; P=0.858). Patients with TERT promoter mutation were older ( t=3.76, P=0.001) and the non-intake rate of radioiodine in distant metastases of those patients was higher ( P=0.037). Furthermore, 2/3 of patients who received targeted therapies and 3/4 deaths had TERT promoter mutation. Among 35 patients with negative thyroglobulin antibody (TgAb), 11/14 of patients with TERT mutation had a rising stimulated thyroglobulin (sTg), while the percentage of the non-TERT mutation group was 57.1% (12/21; P=0.357). Conclusion:The TERT promoter mutation rate is significantly increased in RAIR-PTC patients and can serve as a prognostic predictor in RAIR.

Objective:To evaluate delayed laparoscopic cholecystectomy (DLC) after percutaneous transhepatic gallbladder drainage (PTGBD) in acute cholecystitis.Methods:Clinical data of 64 patients who were diagnosed moderate (grade Ⅱ) acute cholecystitis by the 2018 Tokyo Guidelines in acute phase and underwent delayed LC at our hospital from Jan 2018 to Jan 2021 were compared between two groups ie PTGBD treatment (21 cases)in acute stage before DLC and DLC without PTGBD group (43 cases). The difficulty score of TG18 was used to evaluated every surgical procedure of the cases by reviewing the operation videos.Results:Patients in DLC after PTGBD group had a longer hospital stay and operation time, more blood lose and higher difficulty score than the DLC without PTGBD group(all P<0.05). There was no statistically significant difference in the conversion rate and morbidity rate between the two groups( P>0.05). Conclusion:This study fails to show there is any if ever benefit of PTGBD before DLC over DLC without PTGBD in the management of Grade Ⅱ acute cholecystitis.

Objective To understand the situation of cancer screening of community residents and its association with the knowledge of cancer core knowledge, and to provide reference for the formulation of secondary cancer prevention measures. Methods A cross-sectional survey was conducted among 2 037 residents aged 18-79 who lived in Bao 'an District, Shenzhen. Multivariate Logistic regression analysis was used to investigate the relationship between core knowledge and cancer screening behavior after adjusting for age, gender, education, marriage, occupation and smoking. Results The cancer screening rate of community residents was 28.10%, and the screening rate of middle-aged and elderly people aged 40-79 was 33.50 %.The proportion of ^“not very well understanding^”, ^“partial understanding^” and ^“basic understanding^” of the core knowledge of cancer were 43.91%, 42.33% and 13.76%, respectively, which was higher than that of the non-participants. Multivariate analysis showed that the women, the higher the level of education of college/university or above and the higher the level of knowledge of cancer prevention core knowledge, the higher the probability of participating in cancer screening was OR (95%CI ) : 2.40 (1.86-3.12), 1.65 (1.29-2.10), 1.38 (1.18 - 1.62), respectively. Conclusion The proportion of cancer screening in community residents needs to be improved, and the degree of core knowledge of cancer is closely related to cancer screening behavior. It is suggested to increase the publicity and education of the core knowledge of cancer, and at the same time, carry out the health education of secondary cancer prevention for the key population such as men and people with low education level, so as to improve the proportion of ^“early detection, early diagnosis and early treatment^” of cancer.

BACKGROUND: The 2019 novel coronavirus disease (COVID-19) has had a massive impact on public health, resulting in sudden dietary and behavioral habit changes. Frontline epidemic prevention workers play a pivotal role against COVID-19. They must face high-risk infection conditions, insufficient anti-epidemic material supplies, mental pressure, and so on. COVID-19 seriously affects their dietary and behavioral habits, and poor habits make them more susceptible to COVID-19. However, their baseline dietary and behavioral habits before COVID-19 and their willingness to change these habits after the outbreak of COVID-19 remain unclear for these workers in China. This study aimed to explore the baseline dietary and behavioral habits of frontline workers and their willingness to change these habits after the outbreak of the epidemic; in addition, susceptible subgroups were identified by stratified analyses as targets of protective measures to keep them from being infected with COVID-19. METHODS: A cross-sectional study was conducted through an online questionnaire using a sample of 22,459 valid individuals living in China, including 9402 frontline epidemic prevention workers. RESULTS: Before COVID-19, 23.9% of the frontline epidemic prevention workers reported a high-salt diet, 46.9% of them reported a high frequency of fried foods intake, and 50.9% of them smoked cigarettes. After the outbreak of COVID-19, 34.6% of them expressed a willingness to reduce salt intake, and 43.7% of them wanted to reduce the frequency of pickled vegetables intake. A total of 37.9% of them expressed a willingness to decrease or quit smoking, and 44.5% of them wanted to increase sleep duration. Significant differences in the baseline dietary and behavioral habits and the willingness to change their habits were observed between frontline epidemic prevention workers and other participants. Among the frontline epidemic prevention workers with poor dietary and behavioral habits before COVID-19, frontline epidemic prevention experience was a promoting factor for adopting worse dietary and behavioral habits, including those in the high-salt intake subgroup (OR, 2.824; 95% CI, 2.341-3.405) and the 11-20 cigarettes/day subgroup (OR, 2.067; 95% CI, 1.359-3.143). CONCLUSIONS The dietary and behavioral habits of frontline epidemic prevention workers were worse than that those of other participants before COVID-19. They had a greater willingness to adopt healthy dietary and behavioral habits after experiencing the outbreak of COVID-19. However, frontline epidemic prevention workers with poor dietary and behavioral habits before COVID-19 continued in engage in these poor habits. Dietary and behavioral intervention policies should be drafted to protect their health, especially frontline epidemic prevention workers with poor habits at baseline.
Adult ; COVID-19/psychology* ; China/epidemiology* ; Cross-Sectional Studies ; Diet/standards* ; Female ; Health Behavior ; Health Knowledge, Attitudes, Practice ; Health Personnel/psychology* ; Humans ; Male ; Risk Reduction Behavior ; SARS-CoV-2 ; Surveys and Questionnaires

Objective:To evaluate the effect of dexmedetomidine mixed with dexamethasone on efficacy of ropivacaine for popliteal sciatic nerve block in the patients undergoing ankle surgery.Methods:A total of 120 patients of either sex, aged 30-64 yr, with body mass index of 19.6-29.7 kg/m 2, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, undergoing elective ankle surgery, were divided into 4 groups ( n=30 each) by a random number table method: control group (group C), dexmedetomidine group (group DD), dexamethasone group (group DM), and dexmedetomidine plus dexamethasone group (group DD+ DM). In group C, 0.5% ropivacaine 30 ml was injected around the popliteal sciatic nerve guided by ultrasound combined with a nerve stimulator.Dexmedetomidine 1 μg/kg, dexamethasone 10 mg and dexmedetomidine 1 μg/kg plus dexamethasone 10 mg were added to 0.5% ropivacaine in group DD, group DM and group DD+ DM, respectively.The analgesic time, consumption of sufentanil and adverse reactions were recorded after popliteal sciatic nerve block. Results:Compared with group C, the analgesic time was significantly prolonged, the consumption of sufentanil was reduced, and the incidence of nausea and vomiting was decreased in group DD, group DM and group DD+ DM ( P<0.05). Compared with group DD and group DM, the analgesic time was significantly prolonged, and the consumption of sufentanil was reduced in group DD+ DM ( P<0.05). No itching, drowsiness, hypotension, bradycardia or respiratory depression occurred in each group. Conclusion:Dexmedetomidine mixed with dexamethasone can effectively enhance the efficacy of ropivacaine for popliteal sciatic nerve block in the patients undergoing ankle surgery.