To summarize Prof. ZHANG Zhiyuan's clinical experience in using large doses of Fuzi （Aconiti Lateralis Radix Praeparata）. The effect of Fuzi is based on its acrid and hot propoerties， warming and invigorating yang qi and running without guard. The application of large doses of Fuzi can be categorized into raw and processed， with common dosage ranging from 30 g to 60 g of raw Fuzi， and 15 g to 30 g， 30 g to 60 g of processed Fuzi. The quantity-effect relationship of the large dose of Fuzi is summarized as 15 g to 30 g of processed Fuzi could warm water， warm yang and eliminate timidity， as the treatment of asthma with deficiency cold phlegm， edema of yang deficiency， and panic and timidity of yang deficiency； 30 g to 60 g of processed Fuzi could tonify fire， warm the meridians and collaterals， assist yang to dispel cold and relieve pain， as the treatment of coldness in the limbs， abdominal pain， pain in the joints of the limbs， and loose stools due to deficient yang qi and exuberant internal yin cold； 30 g to 60 g raw Fuzi could restore yang to save from collapse， as the treatment of yang depletion after profuse sweating and vomiting. At the same time， different dosages of Fuzi were flexibly paired with other medicines， i.e.， 15 g to 30 g of processed Fuzi was paired with Mahuang （Ephedrae Herba） and Xixin （Asari Radix et Rhizoma） to assist yang to dispel coldness， 30 g to 60 g of processed Fuzi was paired with Baizhu （Atractylodis macrocephalae rhizoma） or Wuzhuyu （Euodiae Fructus） to warm yang and dispel dampness， and 30 g to 60 g of raw Fuzi was paired with Shanzhuyu （Corni Fructus） to tonify both yin and yang.

Background Manganese is an essential trace element for the human body and maintains normal development of many organs including the brain. However, long-term exposure to a high manganese environment or excessive manganese intake will lead to manganese poisoning and result in neurological diseases, and currently no effective treatment plan is available. Objective To develop an animal model for subchronic manganese exposure and assess the impact of Dendrobium nobile Lindl. alkaloids (DNLA) on manganese associated behavioral and hippocampal effects in rats. Methods Fifty male SPF SD rats were randomly allocated into a control group (0.9% normal saline by intraperitoneal injection), two experimental groups [7.5 mg·kg⁻¹ (low) or 15 mg·kg⁻¹ (high) of MnCl₂·4H₂O by intraperitoneal injection], and two DNLA antagonistic groups [15 mg·kg⁻¹ MnCl₂·4H₂O by intraperitoneal injection then either 20 mg·kg⁻¹ (low) or 40 mg·kg⁻¹ (high) DNLA by oral administration]. All groups of rats were adminaistered 5 d per wek, once a day, for consecutive 13 weeks. Following modeling, neurobehavioral assessments were conducted using open field, Morris water maze, and Y maze. Inductively coupled plasma mass spectrometry (ICP-MS) was utilized to measure manganese levels in the blood and brain tissues of the rats, and hematoxylin-eosin (HE) staining was employed to examine neuronal morphological changes in the hippocampal tissues of the rats. Results The neurobehavioral tests revealed that the manganese-exposed rats exhibited decreased total movement distance, prolonged central zone dwelling time, and reduced motor activity in the open field test, indicating tendencies toward depression and anxiety (P<0.05). In the Y-maze test, the mean exploration distance in the novel arm, the number of entries into the novel arm, and the time spent in the novel arm of the managanses-exposed rats were all reduced, while the latency period increased, suggesting impaired spatial exploration and learning-memory functions (P<0.05). In the Morris water maze navigation test, the escape latency was significantly longer in the manganese-exposed rats compared to the control group, and the number of platform crossings decreased in the spatial probe test, indicating a significant decline in spatial learning and memory (P<0.05). The ICP-MS analysis showed elevated manganese concentrations in the blood and hippocampus of the exposed rats (P<0.05), and the histopathological observation revealed hippocampal damage. Following the DNLA intervention, the manganese-exposed rats showed increased total movement distance and reduced central zone dwelling time in the open field test (P<0.05). In the Y-maze test, the mean exploration distance in the novel arm, the number of entries into the novel arm, and the time spent in the novel arm increased, while the latency period decreased, suggesting alleviation of anxiety and improved exploratory behavior (P<0.05). In the Morris water maze test, the escape latency gradually shortened, and both the number of platform crossings and the percentage of time spent in the target quadrant increased, indicating improved spatial learning and memory (P<0.05). Additionally, the manganese levels in the blood and hippocampus decreased (P<0.05), and the hippocampal pathological changes were partially restored. Conclusion DNLA demonstrates the ability to counteract multiple neurotoxic effects following the elevation of manganese levels in the blood and hippocampal tissues of rats induced by subchronic manganese exposure. Specifically, DNLA is shown to ameliorate the behavioral alterations observed in rats after manganese exposure, and mitigate the hippocampal damage in manganese-exposed rats.

Alzheimer’s disease (AD) is a neurodegenerative disease that has become increasingly serious with the aging of human society. It has become an important factor that hinders the development of society, making early diagnosis and intervention of great significance. In recent years, with the continuous development of computer technology, deep learning has shown superior performance in processing AD big data, identifying effective detection indices, and improving detection accuracy. In this paper, the research progress of deep learning in early diagnosis of AD in areas such as neuroimaging data, electroencephalogram, blood and genetic data, and multimodal fusion data was mainly introduced. Common deep learning models were summarized, and future research directions in this field were discussed.

Objective:To compare the assay and related substance detection methods of erythromycin lactobionate in the Chinese Pharmacopoeia 2020(ChP),USP 2023(USP),JP18(JP),BP2023(BP)and EP 11.0(EP),investigate the differences between the test results obtained from 7 batches of erythromycin lactobionate for injection samples by using ChP and BP methods and thus provide a reference for the improvement of specification of erythromycin lactobionate.Methods:The differences of test methods and limits under the items of assay and related substances of erythromycin lactobionate in the above five pharmacopoeias were listed and compared.The related substances and contents of erythromycin lactobionate for injection samples from different manufactures were tested with methods stated in ChP and BP,and then compared and analyzed.Results:The items of related substances were determined by high performance liquid chromotographic methods in the ChP,EP and BP.The test methods and limits in the EP and BP were the same,which were different from that in ChP.The related substances were not determined in the USP and JP.There are obvious differences between the chromatographic methods and limits for the items of related substances in the ChP and BP,i.e.,BP contains 7 specific impuri-ties,while ChP contains only 2 specific impurities.The limits for any other impurity and the total amount of impurities were lower in the BP than those in the ChP.The antibiotic microbiological assay was used as the test method for the item of assay in the ChP,USP and JP based on different bacterial strains,which was different from the chromatographic method used in the BP.Based on the different methods of the ChP and BP,the related substances and content determination results of 7 batches of erythromycin lactobionate for injection samples met the acceptance criteria.The detection efficiency of BP related substances inspection method for specific impurities and total impurities were significantly higher than that of the ChP method.Conclusion:The BP method is superi-or to the ChP method in the detection of erythromycin lactobionate and erythromycin lactobionate for injection related substances.In terms of content determination,the external standard method adopted by BP is feasible to replace the antibiotic microbiological assay adopted by the ChP.Related substances and content determination methods adopted by the BP can provide an important reference for the revision and improvement of erythromycin lactobionate standard in the ChP.

The leukocyte immunoglobulin-like receptor LILRB4(ILT3 or CD85k),a member of the immunosuppressive re-ceptor family,is expressed predominantly on the cell membranes of immune cells of myeloid origin,and exerts an immunosuppressive effect in immune regulation by activating either the autoinhibitory motif(ITIM)or by inhibiting Fc receptor activation motif(ITAM).In tumors,activation of LILRB4 receptor generates an immunosuppressive tumor microenvironment that assists in tumor invasion and metastasis,and in inflammatory diseases,LILRB4 is expressed on a variety of cells,such as monocytes,macrophages,mast cells,etc.,and attenuates inflammatory responses.Currently,LILRB4 has become a therapeutic target for tumors and various inflammatory diseases,and anti-LILRB4 monoclonal antibodies against acute myeloid leukemia(AML)have entered clinical trials.This review dis-cusses LILRB4 in terms of its structural distribution,signaling,therapeutic targets,and new drug development.

Objective:To explore the facilitators and barriers in implementing the orthokeratology lens-wearing education guidance program from the perspectives of children, their families, and medical and nursing staff.Methods:Based on phenomenological research, purposive sampling was used to select five medical workers, 18 children wearing orthokeratology lenses and family members from the Optometry Center of Peking University Third Hospital as interviewees for semi-structured interviews. Colaizzi's 7-step method was used to analyze interview data.Results:Two themes (facilitators and barriers) were extracted, among which facilitators included two sub-themes (strong demand for educational guidance, trust in medical and nursing staff), and barriers consisted of two sub-themes (patient factors, external support factors) .Conclusions:In promoting the educational guidance intervention program for wearing orthokeratology lenses, medical and nursing staff need to fully play the role of facilitators, analyze and solve barriers, and ultimately promote the smooth implementation of the intervention program.

Objective To explore the analgesic initiation mechanism of three-manipulation and three-acupoint tuina in model rats with minor chronic constriction injury(CCI).Methods Fifty-six SD rats were divided randomly into eight groups:normal group,sham group,model 1 group,model 2 group,tuina 1 group,tuina 2 group,tuina 1+transient receptor potential vanilloid-1(TRPV1)antagonist group,and tuina 2+transient receptor potential ankyrin 1(TRPA1)antagonist group.The model,tuina,and tuina+antagonist groups were established with minor CCI models.The tuina and tuina+antagonist groups received the three-method three-point intervention(point method,dial method,kneading method,Yinmen point,Chengshan point,Yanglingquan point)7 days after modeling.The model and sham groups were subjected to grasping restraint,and the normal group received no intervention.After the respective interventions,each group was tested for changes in mechanical withdrawal threshold(MWT)and thermal withdrawal latency(TWL)to detect different types of pain.The nitric oxide(NO)content of the dorsal root ganglion(DRG)was determined by the nitrate reductase method,and changes in protein and gene expression levels of components of the TRPV1/TRPA1-NO-cGMP-protein kinase G(PKG)signaling pathway in the DRG of each group were determined by enzyme-linked immunosorbent assay,Western blot,and qPCR.Results Compared with the model group,MWT and TWL were prolonged in the tuina 1 and tuina 2 groups.Expression levels of TRPV1,TRPA1,NO,soluble guanylate cyclase-β,cGMP,and PKG1 in the DRG were significantly decreased in the tuina 1,tuina 2,tuina 1+TRPV1 antagonist,and tuina 2+TRPA1 antagonist groups.Conclusions Tuina can effectively improve the symptoms of thermal and mechanical hyperalgesia caused by peripheral nerve injury after one-time intervention.Tuina can exert immediate and continuous analgesic effects via the TRPV1/TRPA1-NO-cGMP-PKG signaling pathway.

The aim of this study is to investigate the effect of Dahuang Fuzi decoction(DHFZT)on the killing effect of natural killer(NK)cells and the growth of lung cancer xenografts in mice.Lewis lung cancer xenograft model was constructed,and the mice were randomly divided to the normal saline group,low and high concentrations of DHFZT groups.The growth of lung cancer xenografts in mice in the control group,low and high concentration of DHFZT treatment groups was detected.The levels of IFN-y,IL-2 and IL-10 were detected by ELISA.The killing effect of NK cells was detected by calcein release assay.The release of CD107α was detected by flow cytometry.The expression of activated receptors and the tumor cell surface ligands were detected in the con-trol group and DHFZT treatment groups.The results showed that the xenografts of Lewis mice in the DHFZT treatment groups were grown slower than that in the control group in a dose depend-ent manner(P＜0.05).Compared with the control groups,the levels of IL-2 and IFN-y in tumor tissues were increased in DHFZT treatment groups(P＜0.05),but no significant changes in IL-10.Calcein release assay showed that the killing efficiency of NK cells in the DHFZT treatment groups was increased(P＜0.05).The secretion level of IFN-y in the culture supernatant was increased by DHFZT treatment(P＜0.05).DHFZT treatment increased the expression level of CD107α of NK cells.The expression of MIC A/B on the surface of A549 and H1299 cells was up-regulated by DHFZT treatment,but not the expression of inhibitory ligand HLA-ABC.The results showed that DHFZT enhanced the killing effect of NK cells on mouse lung cancer cells by up-reg-ulating the expression of MIC A/B,increasing the secretion of IFN-y and CD107α.Hence,these re-sults indicated that DHFZT suppresses the lung cancer growth potential through regulating the killing effect of NK cells.

Objective:To examine the correlation between serum 25-hydroxyvitaminD [25(OH)D] levels and all-cause mortality risk among adult women in the United States.Methods:Data for this retrospective cohort study were obtained from the National Health and Nutrition Examination Survey 2011—2016. A total of 6 452 women with complete data were enrolled and the end point event was all-cause mortality. The subjects were categorized into four groups based on serum 25(OH)D levels: severe deficiency group [25(OH)D<25.0 nmol/L, n=285], deficiency group [25(OH)D 25.0-49.9 nmol/L, n=1 695], insufficient group [25(OH)D 50.0-74.9 nmol/L, n=2 119], and sufficient group [25(OH)D≥75.0 nmol/L, n=2 353]. The serum 25 (OH) D level was included in cox proportional hazards model as a continuous variables and a categorical variables, respectively, to estimate the risk of all-cause mortality. Cox regression model based on restricted cubic splines was used to observe the curve relationship between the continuous change of serum 25(OH)D and the risk of all-cause mortality. A two-piecewise linear regression model was used to analyze the saturation threshold effect and examine the correlation between serum 25(OH)D levels and all-cause mortality risk among adult women in the United States. Results:A total of 6 452 women were enrolled. The mean level of serum 25(OH)D was (68.2±31.6) nmol/L, and only 36.5% (2 353/6 452) of the women had sufficient vitamin D. During the follow-up time of (5.8±1.8) years, 375 women died, and the all-cause mortality rate of 5.8%. After multivariate adjustment, for every 10 nmol/L increase in serum 25(OH)D level, the risk of all-cause mortality was reduced by 5% ( HR=0.95, 95% CI: 0.91-0.98) ( P<0.05). Compared with serum 25(OH)D severe deficiency group, the risk of all-cause mortality in 25(OH)D sufficient group was 54% lower ( HR=0.46, 95% CI: 0.29-0.75) ( P<0.05, Ptrend<0.001). The association between serum 25(OH)D levels and all-cause mortality risk exhibited an L-shaped curve ( P=0.007) and the inflection point was 128.5 nmol/L; when the serum level of 25(OH)D was less than 128.5 nmol/L, for every 10 nmol/L increase in 25(OH)D, the risk of all-cause mortality was reduced by 8% ( HR=0.92, 95% CI: 0.88-0.96) ( P<0.001). Conclusion:High serum 25(OH)D concentrations are non-linearly associated with low risk of all-cause mortality. These findings suggest that maintaining adequate vitamin D status may lower mortality risk in American women individuals.

Objective:To investigate the association between metabolically healthy overweight/obesity(MHO) and risk of new-onset diabetes among Chinese adults.Methods:This study was a secondary analysis of a retrospective cohort study recruiting 117 056 Chinese adults who received a health check at the Rich Healthcare Group from 2010 to 2016.Participants were classified into metabolically healthy non-obesity(MHNO), MHO, metabolically unhealthy non-obesity(MUNO), and metabolically unhealthy overweight/obesity(MUO) group according to body mass index and metabolic status at baseline. Kaplan-Meier method(log-rank test) was used to estimate the cumulative incidence of diabetes in each group. The Cox proportional hazards model was employed to estimate the hazard ratios( HR and 95% CI) for diabetes incidence across different obesity metabolic phenotype groups, followed by subgroup analysis. Results:A total of 117 056 Chinese adults were enrolled and the prevalence of MHO was 24.3%. During the follow-up time of (3.1±1.0) years, 2 685 new-onset diabetes adults occurred, resulting in a cumulative incidence rate of 2.3%. The cumulative incidences of MHNO, MHO, MUNO and MUO groups were 0.5%, 1.6%, 4.8%, and 7.9%, respectively, and there was a statistical difference ( χ2=1 224.164, P<0.001). Cox proportional hazards model showed that after adjusting for sex, age, fasting plasma glucose, smoking, alcohol drinking, and diabetes family history, the risk of new-onset diabetes in MHO group was 2.19 folds of MHNO group(95% CI 1.89-2.55). Additionally, the HR for diabetes in MUNO and MUO groups were 2.25(95% CI 1.93-2.64)and 3.00(95% CI 2.61-3.45). Conclusion:The MHO phenotype was significantly associated with an increased risk of new-onset diabetes in Chinese adults.