Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

Objective: To explore the role of outdoor activity in the relationship between infancy responsive caregiving trajectories and early childhood development, so as to provide a theoretical basis for the promotion of early child development. Methods: The study participants were drawn from the Shanghai Maternal-Child Pairs Cohort and 4 723 mother-child pairs who completed responsive caregiving questionnaires at 2, 6 and 12 months old were included. Questionnaires were used to assess children s responsive caregiving and average daily hours of outdoor activity at 2 years of age. The Age-Stage Questionnaire, Third Edition (ASQ-3) was used to evaluate children s development problems at 2-5 years old. Group based trajectory model was applied to fit infancy responsive caregiving trajectory. Modified Poisson regression was used to analyze associations between different responsive caregiving trajectory groups and child development, and moderating effects were tested for hours of outdoor activity. Results: Infancy responsive caregiving trajectories were categorized into general group ( n =3 871), declining group( n =160), and fluctuating group( n =646). After adjusting for confounding factors, such as parents educational level, annual household income, maternal progestation body mass index,maternal tobacco exposure during pregnancy,maternal anxiety and depression during pregnancy, maternal age at delivery,maternal gestational age,maternal mode of delivery, children s gender,children s birth weight, and duration of breastfeeding, the results of modified Poission regression analysis showed that compared with the general group, children at the age of 2 in declining and fluctuating group had increased risks of suspected developmental delays in communication, gross motor, fine motor, problem solving, and personal-social scales ( OR =1.41,1.31,1.35,1.23,1.21；1.07,1.08,1.08,1.09,1.06);but children only had increased risk of suspected developmental delays in communication of declining group ( OR =1.08), personal-social scales of fluctuating group ( OR =1.06) at 3-5 years of age ( P <0.05). At lower levels of outdoor activity, children in fluctuating group had reduced scores in communication ( β =-1.41), fine motor ( β =-2.34), problem solving ( β =-1.11) and personal-social scales ( β =-1.99) as compared to general group; and children in declining group had reduced scores in gross motor ( β =-4.78)( P <0.05). While at higher levels of outdoor activity, no differences were found between children in fluctuating, declining groups and those in general group in scores of different scales ( P >0.05). Conclusion Prolonged outdoor activity attenuates the adverse effects of declining and fluctuating trajectories of infancy responsive caregiving on early childhood development.

This paper aims to study the effect of Ziziphi Spinosae Semen extracts on chronic unpredictable mild stress(CUMS)-induced depression-like and insomnia behavior models of mice. The CUMS-induced depression-like and insomnia behavior model of mice was established by CUMS treatment for three weeks. The mice were randomly divided into control group, model group, positive drug diazepam group(2 mg·kg~(-1)), as well as low-dose group(1.95 g·kg~(-1)), medium-dose group(3.9 g·kg~(-1)), and high-dose group(7.8 g·kg~(-1)) of Ziziphi Spinosae Semen extracts, with 18 mice in each group. On the 15th day of modeling, the drug was administered intragastrically once a day for one week. Then, the pentobarbital sodium cooperative righting experiment, open field experiment, and elevated plus maze experiment were carried out, respectively. The contents of neurotransmitters 5-hydroxytryptamine(5-HT) and 5-hydroxyindoleacetic acid(5-HIAA) in serum and thalamus of mice, as well as the levels of corticotropin releasing hormone(CRH), adrenocorticotropic hormone(ACTH), and corticosterone(CORT) in serum, were determined by enzyme-linked immunosorbent assay(ELISA). The neuron damage in the hippocampus of mice was observed by hematoxylin-eosin(HE) staining and Nissl staining. Western blot was used to detect the expressions of tryptophan hydroxylase 2(TPH2), serotonin transporter(SERT), monoamine oxidase A(MAOA), five prime repressors under dual repression binding protein 1(Freud1), synaptic plasticity-related proteins [cellular gene FOS(C-FOS), postsynaptic density protein 95(PSD95), synapsin 1(SYN1), and activity-regulated cytoskeleton-associated gene(ARC)], blood-brain barrier(BBB) permeability-related proteins [zonula occludens 1(ZO-1), occludin, and claudin 1], inflammatory factors [NOD-, LRR-and pyrin domain-containing protein 3(NLRP3), apoptosis-associated speck-like protein(ASC), gasdermin D(GSDMD), caspase-3, and caspase-8], and antioxidant factors [nuclear factor erythroid 2-related factor 2(NRF2) and heme oxygenase 1(HO1)] in thalamic tissue of mice. The results indicated that compared with that in the model group, the sleep latency was significantly shortened, and the sleep duration was significantly prolonged in each dose group of Ziziphi Spinosae Semen extracts. The number of visits to the central area of the open field and the distance and time of visits were significantly increased in each dose group of Ziziphi Spinosae Semen extracts. In addition, the proportion of distance and time of entering the open arm area of the elevated plus maze was significantly increased in each dose group of Ziziphi Spinosae Semen extracts. The contents of 5-HT and 5-HIAA in serum and thalamus of mice increased to varying degrees in each dose group of Ziziphi Spinosae Semen extracts; the contents of CRH, ACTH, and CORT in serum of mice were significantly decreased. The protein expression of TPH2 was significantly increased. The protein expression of MAOA, SERT, and Freud1 was significantly decreased. Ziziphi Spinosae Semen extracts could also significantly reduce the protein expression of C-FOS but significantly increase the protein expression of PSD95, ARC, and SYN1. They could reduce the pathological damage of the hippocampus in mice and significantly increase the protein expression of ZO-1, occluding, and claudin 1. The protein expression of NLRP3, GSDMD, ASC, caspase-3, and caspase-8 in the thalamic tissue of mice was significantly decreased, and the protein expression of HO1 and NRF2 was significantly increased. In conclusion, Ziziphi Spinosae Semen extracts could effectively improve sleep disorders and depression-like behaviors in CUMS-induced model mice, which may be related to regulating the 5-HT anabolism process and hypothalamic-pituitary-adrenal(HPA) axis-related hormone levels, reducing pathological damage in the hippocampus, improving synaptic plasticity, repairing BBB integrity, and alleviating inflammatory response and oxidative stress damage.
Animals ; Ziziphus/chemistry* ; Mice ; Male ; Depression/psychology* ; Drugs, Chinese Herbal/administration & dosage* ; Sleep Initiation and Maintenance Disorders/psychology* ; Stress, Psychological/complications* ; Behavior, Animal/drug effects* ; Humans ; Disease Models, Animal

OBJECTIVE: To evaluate the association between erectile dysfunction (ED) and myocardial infarction (MI) using two sample Mendelian randomization. METHODS: A Mendelian randomization study was conducted using comprehensive data on ED and MI from extensive genome-wide association data. Using inverse variance weighted analysis for causal relationships, and correct for confounding factors using multivariate Mendelian randomization, the potential mediating effects were evaluated as well. Based on Genecard data, the genes related to ED and MI were identified. Molecular docking was used to reveal spontaneously bound drug molecules. RESULTS: Our study found that exposure to ED was a risk factor for MI (OR: 1.001 0, 95% CI: 1.000 2－1.001 8, P=0.017 7), which also held true in the validation dataset (OR: 1.028 5, 95% CI: 1.005 0－1.052 6, P=0.017 2). No statistically significant heterogeneity or horizontal pleiotropy was found. The results of reverse Mendelian randomization analysis showed any reverse causal relationship between ED and MI. In multivariate Mendelian randomization analysis, after excluding confounding factors (excluding triglycerides and high-density lipoprotein), the P-value remained less than 0.05, and the OR ranged from 1.000 1 to 1.000 7, indicating that ED was still a risk factor for MI. In the mediation analysis, it was found that the current mediation ratio of smoking to MI was 13.06%. In summary-data-based mendelian randomization analysis, it was found that the gene PTPN11 was a common target gene for MI and ED (OR=0.990, P<0.001). Subsequent molecular docking with sildenafil, clopidogrel, and dapoxetine could spontaneously bind to the PTPN11 gene receptor. CONCLUSION There is a causal relationship between ED and MI, with smoking as a potential mediating factor, and the gene PTPN11 being a co-target gene.
Humans ; Male ; Mendelian Randomization Analysis ; Myocardial Infarction/genetics* ; Erectile Dysfunction/complications* ; Risk Factors ; Genome-Wide Association Study ; Molecular Docking Simulation ; Polymorphism, Single Nucleotide

Objective To analyze the efficacy and safety of unilateral laminectomy and bilateral decompression under unilateral biportal endoscopy(UBE)and microendoscope(MED)in lumbar spinal stenosis.Methods 80 patients with lumbar spinal stenosis from January 2021 to December 2022 were selected and divided into two groups by numerical table method,the control group and the study group,and the number of cases was 40.The grouping method was random number table method.The control group was treated with unilateral laminectomy and bilateral decompression under MED,while the study group was treated with unilateral laminectomy and bilateral decompression under UBE.Operation time,intraoperative blood loss,Oswestry disability index(ODI)and visual analogue scale(VAS)of lumbago and leg pain were obtained before surgery,1,3 months after surgery and at the last follow-up,efficacy and complications were compared between the two groups.Result There were no significant differences in operative time and blood loss between the study group and the control group(P>0.05).1,3 months after surgery and at the last follow-up,ODI in both groups were lower than those before surgery(P<0.05),but there was no difference between the study group and the control group(P>0.05).The VAS of lumbago and leg pain in both groups were lower than those before surgery(P<0.05),at 1,3 months after surgery and the last follow-up,and the study group was significantly lower than the control group(P<0.05).The excellent and good rate of clinical treatment in the study group was 97.50%,and there was no difference compared with 92.50%in the control group(P>0.05).The complication rate of the study group was 2.50%,significantly lower than that of the control group(15.00%)(P<0.05).Conclusion Unilateral laminectomy and bilateral decompression under the UBE and MED have similar efficacy in the treatment of lumbar spinal stenosis,both of which can effectively promote functional recovery,but UBE can reduce pain more effectively and has fewer postoperative complications.

Objective To analyze the application effect and economic benefit of total parathyroidectomy(TPTX)+subcutaneous implantation of forearm(AT)+thymectomy in patients with secondary hyperparathyroidism(SHPT).Methods The clinical data of 110 patients with SHPT who were treated in our hospital from March 2018 to January 2021 were retrospectively analyzed.They were divided into medication group(50 cases,receiving cinacalcet combined with low-dose calcitriol)and operation group(60 cases,receiving TPTX+AT+thymectomy)according to different treatment regimens.The biochemical indexes,cardiac structure and function,clinical symptoms and quality of life of the two groups were compared before and after treatment for 24 months,and the complications,cost-effectiveness and recurrence rate of the two groups after operation were counted.Results After treatment,the levels of serum iPTH[(206.45±152.59)pg/ml],calcium[(2.05±0.26)mmol/L],phosphorus[(1.48±0.21)mmol/L],calcium-phosphorus product(3.02±0.69)and ALP[(102.03±30.25)U/L]in operation group were all lower Drug group[(721.32±325.36)pg/ml,(2.22±0.18)mmol/L,(1.91±0.22)mmol/L,(4.22±0.74),(140.62±27.15)U/L](P＜0.05);LVEF[(60.85±4.02)％]in operation group was higher than that in drug group[(55.58±3.84)％].LVED[(48.03±2.58)mm]and LVST[(9.85±0.76)mm]were lower than those in drug group[(51.02±3.65)mm,(11.12±0.86)mm](P＜0.05).The scores of bone pain,skin pruritus and restless legs syndrome in the operation group were lower than those of the medication group,and the KDTA score was higher than that of the medication group(P＜0.05).The total cost of treatment in the operation group[(4.06±1.42)million yuan]was not significantly different from that in the drug group[(3.46±1.85)million yuan](P＞0.05).The effective rate of iPTH reduction in operation group was 90.00％(54/60),which was higher than that in drug group(48.00％,24/50)(P＜0.05).The cost-effectiveness analysis showed that the CER of the drug group and the operation group were 7.21 and 4.51 respectively,and the operation treatment had more cost-effectiveness advantages.The incremental cost-effectiveness analysis shows that compared with the drug group,the operation group needs to increase the cost by 14,800 yuan for each additional patient effectively treated for SHPT(P＞0.05).There was no significant difference in the incidence of complications(13.33％VS 12.00％)and the recurrence rate(8.33％VS 4.00％)at 2 4 months after treatment between the operation group and the drug group(P＞0.0 5).Conclusion TPTX+AT+thymectomy can relieve the bone pain,reduce the iPTH level,correct the disorder of calcium and phosphorus metabolism,improve the heart function and structure,and improve the quality of life,and the cost-effectiveness is higher than SHPT of drug treatment,without increasing short-term recurrence rate.

Infectious diseases are the leading cause of death in children. Sepsis is a critical infectious disease that causes death in children globally, with a high morbidity and mortality rate. It poses a serious threat to children′s health. Early diagnosis has become the key to treating severe sepsis. The establishment of animal models of sepsis can help people better diagnose sepsis and take interventions to improve the prognosis of sepsis patients. This study reviews the types, advantages and disadvantages of existing animal models of sepsis and proposes the optimization of these models to provide a reference basis for the selection and optimization of experimental models and the promotion of the "reverse transformation" of sepsis into clinical practice.

Objective To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/-mice.Methods The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/-mice.Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers.Results Proteomic analysis showed that there were 43 significantly up-regulated and 58 sig-nificantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group.Among them,GBP2,TAOK3,TFR1 and UCP1 were biomarkers with great diagnostic potential.KEGG pathway enrichment analysis indicated that fer-roptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model.The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model.Conclusion Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferrop-tosis.Four potential biomarkers are selected for myocardial injury diagnosis,providing a new direction for sudden cardiac death(SCD)caused by hyperlipidemia combined with the restraint stress.

Objective To investigate the predictive value of the prognostic nutritional index(PNI)in all-cause mortality in pa-tients with acute and critical illness.Methods Acute and critically ill patients admitted to the Department of Emergency,Beijing Chao-yang Hospital,Capital Medical University,from March to July 2021 were selected as study subjects,and the relevant clinical data within 24h of their admission to the emergency department were collected and analyzed descriptively.The receiver operating characteristic(ROC)curve of PNI was drawn with all-cause mortality of patients within 28days as the endpoint,and the patients were divided into high PNI and low PNI groups according to the optimal cut-off value,and the clinical characteristics of the two groups were compared.Patients were divided into survival and death groups according to whether they died within 28days,and the clinical characteristics of the two groups were compared,and univariate and multivariate Logistic regression analysis was used to explore the risk factors for all-cause mortality within 28days in patients with acute and critical illness.Results A total of 603 patients were included,and the optimal cut-off value of PNI was 43.825,according to which all patients were divided into the high PNI group(n=334)and low PNI group(n=269),and it was found that the proportion of patients who all-cause mortality within 28days was significantly higher in the low PNI group than in the PNI group(P＜0.05).All patients died within 28days of admission to the emergency department in 127 cases,and the pro-portion of malnourished patients was significantly higher in the death group than that in the survival group(P＜0.05).Logistic regression analysis showed that malnutrition at admission to the emergency department screened by PNI was an independent risk factor for all-cause mortality within 28days in patients with acute and critical illness(OR=1.805,95％CI:1.157-2.817,P=0.009),and advanced age,low body mass index,and low hemoglobin levels were also independent risk factors for all-cause mortality within 28days.Conclu-sion Patients with acute and critical illness are at high risk of malnutrition,and malnutrition at admission to the emergency department,advanced age,low body mass index,and low hemoglobin levels screened by PNI are independent risk factors for all-cause mortality with-in 28 days.

Objective To evaluate the improvement in the quality of early postoperative recovery in patients undergoing cardiac valve surgery with remimazolam-based fast-track anesthesia,and to provide a reference for the clinical optimization of fast-track anesthesia and Enhanced Recovery After Surgery(ERAS)protocols.Methods We selected elective surgery patients undergoing median sternotomy for cardiac valve replacement and/or repair under general anesthesia with extracorporeal circulation.Based on routine anesthesia assessment and fast-track anesthesia suitability assessment,a total of 228 patients were strictly enrolled according to the inclusion and exclusion criteria and randomly divided into two groups:the Remimazolam group(n=114)and the Propofol group(n=114).Patients in the Remimazolam group were induced and maintained with remimazolam for anesthesia,while patients in the control group were administered propofol.We recorded the general information and surgical data of the patients;the QoR-15 scores before surgery(1 day preoperatively),1 day postoperatively,3 days postoperatively,and 1 day before discharge;as well as hemodynamic parameters at key time points after admission,the incidence of hypotension and bradycardia after anesthesia,the duration of surgery,anesthesia duration,postoperative mechanical ventilation time,ICU stay,postoperative hospital stay,and the incidence of perioperative cardiovascular adverse events and the incidence of early postoperative complications.Results There was no statistically significant difference in general data and QoR-15 scores between the two groups 1 day before surgery(P>0.05).The QoR-15 score of the Remima-zolam group 1 day before discharge was higher than that of the Propofol group,with a statistically significant differ-ence(P<0.05),but the difference was less than the minimum clinically important difference,which is less than 8,indicating no significant clinical benefit.One minute after intubation and one minute after skin incision,the heart rate in the Propofol group slowed down and the Mean Arterial Pressure(MAP)significantly decreased,with a statis-tically significant difference between the groups(P<0.05);there was no statistically significant difference in heart rate and MAP at other times.The incidence of intraoperative hypotension and bradycardia was lower in the Remima-zolam group than in the Propofol group,with a statistically significant difference(P<0.05).The duration of postop-erative mechanical ventilation,ICU stay,postoperative hospital stay,and the rate of re-intubation were all shorter in the Remimazolam group than in the Propofol group,and the success rate of fast-track anesthesia was higher in the Remimazolam group,with a statistically significant difference(P<0.05).There was no statistically significant difference in the incidence of perioperative complications between the two groups.Conclusions Compared with the commonly used intravenous anesthetic propofol,the remimazolam-based fast-track anesthesia regimen did not signifi-cantly improve the postoperative recovery quality scores in patients undergoing cardiac valve surgery.However,remimazolam had advantages in maintaining hemodynamic stability,increasing the success rate of fast-track anesthe-sia,shortening postoperative ICU stay and hospital stay,and is a viable intravenous anesthetic option for cardiac surgery patients.