Objective To analyze the effect of the activation rate of peripheral blood monocytes on the recovery of patients after liver transplantation and to initially explore the possible influencing factors for differences in monocyte activation rates. Methods A total of 139 patients who underwent orthotopic liver transplantation from September 2020 to June 2023 at Department of Liver Surgery and Transplantation of Zhongshan Hospital, Fudan University were selected. The proportion of CD14^＋HLA-DR^＋ monocytes in peripheral blood was defined as the monocyte activation rate. The difference in monocyte activation rates between postoperative day 7 (POD7) and postoperative day 1 (POD1) was calculated as Δ, and patients were divided into Δ＞0 group (n＝73) and Δ＜0 group (n＝66). The two groups were compared in terms of complete blood count, liver and kidney function, coagulation indicators, infection indicators, ICU length of stay, total length of hospitalization, and 90-day mortality. Changes in the proportions of different monocytes subsets (Mo0, Mo1, Mo2, and Mo3) and HLA-DR expression in peripheral blood on POD1 and POD7 were detected using flow cytometry. Results The ICU length of stay in the Δ＜0 group was significantly longer than that in the Δ＞0 group (18[12, 26] days vs 14[10, 20.5] days, P＝0.018). On POD1, the proportion of Mo0 in the Δ＞0 group was significantly lower than that in the Δ＜0 group (P＜0.05); on POD7, the proportion of Mo0 in the Δ＞0 group was significantly lower than that in the Δ＜0 group (P＜0.001), while the proportions of Mo1, Mo2, and Mo3 were significantly higher than those in the Δ＜0 group (P＜0.001). Compared to POD1, the HLA-DR expression level of Mo0 in peripheral blood of patients with liver transplantation significantly decreased on POD7 (P＜0.01), while there was no significant difference in HLA-DR expression levels of Mo1, Mo2, and Mo3. Conclusions Increased proportion of Mo0 (CD14^lowCD16⁻HLA-DR^low) among peripheral blood monocyte subsets may be one of the influencing factors for the differences in monocyte activation rates in patients with liver transplantation. The difference in monocyte activation rate can serve as a new clinical indicator for assessing changes in the immune status and postoperative recovery of patients with liver transplantation.

BACKGROUND:Eucommia ulmoides has a certain osteogenic effect,which can promote the proliferation and differentiation of osteoblasts.However,it is unclear whether Eucommia ulmoides has effects on alveolar bone formation and Wnt/β-Catenin signaling pathway. OBJECTIVE:To investigate the mechanism by which Eucommia ulmoides promotes alveolar bone formation in ovariectomized rats based on the Wnt/β-Catenin signaling pathway. METHODS:Sixty female Sprague-Dawley rats were selected and randomly divided into five groups:blank control group,sham-operation group,model group,low-dose group Eucommia ulmoides group,and high-dose Eucommia ulmoides group,with twelve rats in each group.Osteoporosis animal models were constructed by bilateral oophorectomy in the model group and the low-dose and high-dose Eucommia ulmoides groups.The sham-operation group underwent the same method to remove adipose tissue of equal mass around the bilateral ovaries.Three months after surgery,the low-and high-dose Eucommia ulmoides groups were given 2.1 g/kg/d and 4.2 g/kg/d Eucommia ulmoides by gavage,respectively.The sham-operation group and model group were given the same amount of physiological saline by gavage.After 12 weeks of drug intervention,the changes in alveolar bone mass of rats in each group were observed through Micro-CT;hematoxylin-eosin staining was used to observe the pathological structural changes of alveolar bone in rats;enzyme linked immunosorbent assay was used to detect the expression levels of alkaline phosphatase and osteocalcin in the serum of rats;western blot was used to detect the expression levels of β-Catenin and Frizzled9 receptor proteins in the alveolar bone of rats;and real-time fluorescence quantitative PCR was used to detect the expression of osteocalcin,Runt-related transcription factor 2(Runx2),alkaline phosphatase,β-catenin,and frizzled9 mRNAs in alveolar bone tissues of rats. RESULTS AND CONCLUSION:Compared with the blank control group,bone volume fraction,trabecular number,trabecular thickness,and bone mineral density were reduced in the model group(P＜0.05),and trabecular separation was elevated(P＜0.05).Pathological observation showed that the arrangement of trabeculae was disordered and irregular,the trabeculae were thinned or broken,and the marrow cavity was enlarged in the model group,with a significant reduction in bone volume;the level of alkaline phosphatase in the serum was increased(P＜0.05),and the level of osteocalcin was decreased(P＜0.05);mRNA expression of alkaline phosphatase,osteocalcin,Runx2,β-catenin,and frizzled9 were decreased(P＜0.05);protein expression of β-Catenin and Frizzled9 was decreased(P＜0.05).Compared with the model group,the low-and high-dose Eucommia ulmoides groups showed an increase in bone volume fraction,trabecular number,trabecular thickness,and bone mineral density(P＜0.05)and a decrease in trabecular separation(P＜0.05).In the low-and high-dose Eucommia ulmoides groups,bone trabeculae were slightly aligned and thickened,with a significant increase in bone mass.Compared with the model group,the serum level of alkaline phosphatase was reduced(P＜0.05)and the serum level of osteocalcin was elevated(P＜0.05)in the low-and high-dose Eucommia ulmoides groups.Compared with the model group,the mRNA expression of alkaline phosphatase,osteocalcin,Runx2,β-catenin,and frizzled9 were increased in the low-and high-dose Eucommia ulmoides groups(P＜0.05).Compared with the model group,the protein expression of Frizzled9 was increased in the low-dose Eucommia ulmoides group(P＜0.05),while the protein expression of β-Catenin and Frizzled9 was increased in the high-dose Eucommia ulmoides group(P＜0.05).Compared with the low-dose Eucommia ulmoides group,the high-dose Eucommia ulmoides group had a more significant improvement in the above indexes.To conclude,Eucommia ulmoides can effectively promote the alveolar bone formation,and its mechanism of action might be related to the activation of the Wnt/β-catenin signaling pathway.

Phase Ⅰ clinical trials play a crucial role in the research and development of new drugs, serving as the initial studies to assess their safety, tolerability, effectiveness, and pharmacokinetic properties in humans. These trials involve uncertainties regarding safety and efficacy. Comprehensive management of all aspects of phase Ⅰ clinical trials for anti-tumor drugs is crucial to protect the rights and safety of participants. This article provides an in-depth analysis of the key points and precautions necessary for effective quality control throughout the process. The analysis is informed by guidelines such as the “Good Clinical Practice for Drugs” “Key Points and Judgment Principles for Drug Registration Verification” “Key Points and Judgment Principles for Supervision and Inspection of Drug Clinical Trial Institutions” and the standard operating procedures for quality control of the center. Topics discussed include informed consent, inclusion criteria, experimental drugs, biological samples, adverse events, and serious adverse events. The goal is to standardize quality control in phase Ⅰ clinical trials of anti-tumor drugs, ensure the authenticity and reliability of clinical trial data, and protect the rights and safety of participants.

Objective: To explore the association between negative life events and smartphone addiction among middle school students, so as to provide theoretical support and practical guidance for prevention and intervention of smartphone addiction among middle school students. Methods: Using cluster sampling, 8 890 students were selected to survey from 27 junior high schools and 3 senior high schools in a district of Shenzhen in 2022 (baseline) and 2023 (followup). Data were collected through selfresigned questionnaires on basic information, the Smartphone Addiction Scale-Short Version, and the Adolescent Selfrating Life Events Checklist. Mixedeffects models were employed to analyze the association. Results: Compared to 2022, the punishment scores of middle school students in 2023 [1.00 (0.00, 6.00) and 1.00 (0.00, 6.00)] decreased (Z=4.27), while the scores of interpersonal stress, learning stress and adaptation [4.00(0.00, 8.00), 4.00(0.00, 8.00); 4.00(1.00, 8.00), 5.00(2.00, 9.00); 2.00 (0.00, 6.00), 3.00 (0.00, 7.00)] increased (Z=-3.04, -8.36, -6.80) (P<0.01). Mixedeffects models revealed a positive doseresponse relationship between negative life events and smartphone addiction (OR=1.08-1.17, P<0.01). Stepwise regression showed independent positive effects of interpersonal stress (OR=1.05), academic stress (OR=1.03), and adaptation stress (OR=1.11) on smartphone addiction (P<0.01). Subgroup analysis of nonaddicted students in 2022 confirmed persistent associations for academic stress (OR=1.03) and adaptation (OR=1.07) (P<0.01). Conclusion Negative life events exhibit a positive doseresponse relationship with smartphone addiction, particularly interpersonal stress, academic stress, and adaptationrelated events.

Objective: To explore the potential causal association between adolescent compulsive behaviour and smartphone addiction based on longitudinal data, so as to provide reference for the establishment of adolescent smartphone addiction interventions. Methods: A preliminary survey and follow-up were conducted on 8 907 middle and high school students in a district of Shenzhen in 2022 and 2023, respectively. Compulsive behaviours were measured by using the Mental Health Inventory for Middle School Students-60 Items (MMHI-60), smartphone addiction was assessed by using the Smartphone Addiction Scale-Short Version ( SAS- SV), and the associations between compulsive behaviours and smartphone addiction were analysed by using multilevel mixed-effects models and subgroup analyses. Results: Smartphone addiction detection rates among middle school students were significantly associated with genders, father s education level, mother s education level, study load subgroups, and whether or not they were single-parent families, and there were statistical differences ( χ 2=17.21-175.34, P <0.05). Students with compulsive behaviours were 2.98 times more likely to develop smartphone addiction than those without compulsive behaviours ( OR=2.98, 95%CI=2.77-3.22, P <0.05). Subgroup analysis of middle school students without smartphone addiction in the first year found that compulsive behaviours significantly predicted smartphone addiction ( OR= 1.76 , 95%CI=1.54-2.01, P <0.05). Conclusion There is a potential causal association between obsessive-compulsive behaviours and smartphone addiction in middle school students, and obsessive-compulsive behaviours in middle school students could significantly predicted the occurrence of smartphone addiction.

ObjectiveTo investigate the possible mechanism of action of Xibining Formula （膝痹宁） for cartilage damage in knee osteoarthritis （KOA） through the cyclic guanosine-adenosine monophosphate synthase （cGAS）- stimulator of interferon genes （STING） signaling pathway. MethodsFifty C57BL/6J mice were randomly divided into five groups （10 per group）， sham operation group， KOA model group， low-dose Xibining Formula group， high-dose Xibining Formula group， and high-dose Xibining Formula + agonist group. The KOA models were constructed using the destabilization of the medial meniscus （DMM） method in all groups but the sham surgery group. Two weeks after surgery， the low- and high-dose Xibining Formula groups were administered Xibining Formula at doses of 3.58 g/（kg·d） and 14.32 g/（kg·d） respectively via gavage. The high-dose Xibining Formula + agonist group received 14.32 g/（kg·d） of Xibining Formula via gavage followed by an intraperitoneal injection of Vadimezan （DMXAA） at 25 mg/kg. The sham surgery group and the KOA model group mice were given an equivalent volume of normal saline at 5 ml/（kg·d） via gavage， once daily for four consecutive weeks. Serum levels of tumor necrosis factor-alpha （TNF-α）， interleukin-1β （IL-1β）， and interleukin-6 （IL-6） were measured by ELISA； pathological changes in cartilage tissue were observed using hematoxylin-eosin （HE） staining and Safranin O-Fast Green staining. Pathological changes were scored according to the Mankin scoring system； the levels of cartilage tissue matrix regulation-related indicators such as matrix metalloproteinase 3 （MMP3）， matrix metalloproteinase 13 （MMP13）， a disintegrin and metalloproteinase with thrombospondin motifs 5 （ADAMTS）， type-Ⅱ collagen （CⅡ） and aggregated proteoglycan （Aggrecan）， and also cGAS-STING pathway-related protein and mRNA expression levels were detected by Western blot and qPCR methods. ResultsCompared with the sham surgery group， the KOA model group showed severe cartilage edge destruction， significantly increased Mankin scores， significantly decreased protein and mRNA expression levels of COLⅡ and Aggrecan， and significantly increased protein and mRNA expression levels of cGAS， STING， MMP3， MMP13， and ADAMTS5 （P＜0.01）. Compared with the control group， serum level of IL-6， IL-1β， TNF-α in all the intervented groups decreased （P＜0.01）， while compared with high-dose Xibining Formula group， level of IL-6， IL-1β， and TNF-α in low-dose Xibining Formula group and high-dose Xibining Formula + agonist group increased （P＜0.01）. Compared with the KOA model group， all the intervention groups exhibited alleviated cartilage pathological changes， signi-ficantly reduced Mankin scores， significantly increased protein and mRNA expression levels of COLⅡ and Aggrecan， and significantly decreased protein and mRNA expression levels of cGAS， STING， MMP3， MMP13， and ADAMTS5 （P＜0.01）. Compared with high-dose Xibining Formula group， high-dose Xibining Formula + agonist group showed cartilage edge destruction， significantly increased Mankin scores， significantly decreased protein and mRNA expression levels of COLⅡ and Aggrecan， and increased protein and mRNA expression levels of cGAS， STING， MMP3， MMP13， and ADAMTS5 （P＜0.01）. ConclusionXibining Formula may improve KOA cartilage damage by inhibiting the cGAS-STING signaling pathway， decreasing matrix degradation-related proteins， and elevating matrix composition-related proteins.

Objective To analyze the clinical efficacy of valve surgeries for infective endocarditis and the affecting factors, and compare the early- and long-term postoperative outcomes of different surgery approaches. Methods The patients with infective endocarditis who underwent valve replacement/valvuloplasty in our hospital from 2010 to 2022 were retrospectively collected. The clinical data of the patients were analyzed. Results A total of 343 patients were enrolled, including 197 patients with mechanical valve replacement, 62 patients with bioprosthetic valve replacement, and 84 patients with valvuloplasty. There were 238 males and 105 females with an average age of (44.2±14.8) years. Single-valve endocarditis was present in 200 (58.3%) patients, and multivalve involvement was present in 143 (41.7%) patients. Sixty (17.5%) patients had suffered thrombosis before surgery, including cerebral embolisms in 32 patients. The mean follow-up time was (60.6±43.8) months. Early mortality within one month after the surgery occurred in 17 (5.0%) patients, while later mortality occurred in 19 (5.5%) patients. Eight (2.3%) patients underwent postoperative dialysis, 13 (3.8%) patients suffered postoperative stroke, 6 patients underwent reoperation, and 3 patients suffered recurrence of infective endocarditis. Smoking (P=0.002), preoperative embolisms (P=0.001), duration of surgery (P=0.001), and postoperative dialysis (P=0.001) were risk factors for early mortality, and left ventricular ejection fraction ≥60% (P=0.022) was protective factor for early mortality. New York Heart Association classification Ⅲ-Ⅳ (P=0.010) and ≥3 valve procedures (P=0.028) were risk factors for late mortality. The rate of composite endpoint events was significantly lower in the valvuloplasty group than that in the valve replacement group. Conclusion For patients with infective endocarditis, smoking and preoperative embolisms are associated with high postoperative mortality, multiple-valve surgery is associated with a poorer prognosis, and valvuloplasty has advantages over valve replacement and should be attempted in the surgical management of patients with infective endocarditis.

OBJECTIVE To investigate the intervention effect of kushenol F （KSC-F） on ulcerative colitis （UC） mice. METHODS Totally 30 male C57BL/6J mice were randomly divided into the normal group， model group， positive drug group （sulfasalazine， 703 mg/kg）， KSC-F 50 mg/kg group （KSC-F50 group）， and KSC-F 100 mg/kg group （KSC-F100 group）， with 6 mice in each group. Except for the normal group， the mice in the remaining groups were given 3% dextran sulfate sodium solution continuously for 7 days to induce UC model. Concurrently， administration groups received corresponding drug solution intragastrically， once a day， for 10 consecutive days. During the experiment， the changes in body weight and bowel movements of the mice were observed. Disease activity index scoring was performed after the last administration. The histopathological morphology of colonic tissue was examined. The levels of inflammatory factors in the serum and colon tissue were measured. Additionally， the mRNA expression of inflammatory factors， and the protein expressions of inflammation-related proteins [interleukin-1β （IL-1β）， forkhead box O1（FOXO1）， phosphoinositide 3-kinase（PI3K）， phosphorylated PI3K（p-PI3K）， p38 mitogen-activated protein kinase（p38 MAPK）， phosphorylated p38 MAPK（p-p38 MPAK） and phosphorylated protein kinase B（p- Akt）] were determined in colonic tissue. RESULTS KSC-F could alleviate weight loss and colonic tissue damage in UC mice. KSC- F reduced the levels of IL-1β， IL-6， IL-8 and tumor necrosis factor-α （TNF-α） in serum， as well as IL-1β， IL-6， IL-17 and TNF- α in colonic tissue to varying degrees and increased the levels of IL-10 in both serum and colonic tissue （P＜0.05 or P＜0.01）. Moreover， KSC-F decreased the expression levels of IL-1β， IL-17 and TNF-α mRNA， as well as p-PI3K， p-p38 MAPK， and p- Akt proteins in colonic tissue to varying degrees， and increased the expression levels of IL-10 mRNA and FOXO1 protein in colonic tissue （P＜0.05 or P＜0.01）. CONCLUSIONS KSC-F effectively alleviates UC symptoms in mice by inhibiting PI3K， Akt and p38 MAPK activation， mitigating the release of pro-inflammatory factors such as IL-1β， IL-6， TNF- α，promoting the anti-inflammatory factor IL-10 secretion， and reducing inflammation-induced colonic tissue damage.

Background Acute cadmium (Cd) exposure can cause damage to multiple tissues, with the kidney being the primary target organ. The development of Cd-induced acute kidney injury involves complex mechanisms, in which autophagy and oxidative stress play crucial roles. Objective To investigate the effect of 10-hydroxy-2-decenoic acid (10-HDA) on kidney injury in mice exposed to cadmium, and provide experimental basis for studying the pathogenesis and prevention of Cd poisoning. Methods Thirty-five male C57BL/6 mice were divided into 7 groups (each of 5 mice): control group (normal saline, intraperitoneal injection), CdCl₂ group (4 mg·kg⁻¹, intraperitoneal injection), intervention groups ( 4 mg·kg⁻¹ CdCl₂, intraperitoneal Injection + 50, 100, 150, or 200 mg·kg⁻¹ 10-HDA, oral gavage), and 10-HDA group (150 mg·kg⁻¹, oral gavage). All treatments were given for 14 d. Twenty-four hours after the last infection, physiological indicators [blood urea nitrogen (BUN), creatinine (CRE), malondialdehyde (MDA), and superoxide dismutase (SOD)], histopathological indicators, autophagy-related proteins (Atg7, Atg5, Beclin-1, and LC3), and mitochondrial autophagy-related proteins (PINK1 and Parkin) were detected to examine the effect of 10-HDA on kidney injury caused by CdCl₂. Results Compared with the control group, the body weight of mice in the CdCl₂ group was significantly reduced (P<0.01); compared with the CdCl₂ group, the body weight of mice after intervention with different concentrations of 10-HDA was significantly increased (P<0.01). CdCl₂ significantly increased BUN and CRE in the serum samples compared with the control group (P<0.01), which was significantly reduced to varying degrees after 100, 150, and 200 mg·kg⁻¹ 10-HDA intervention (P<0.01). MDA significantly increased and SOD significantly decreased in the renal cortex following CdCl₂ administration compared with the control group (P<0.01), which was resolved following 10-HDA administration at different concentrations (P<0.01). In histopathological studies, 10-HDA restored injured kidney tissues induced by CdCl₂. The expression levels of autophagy proteins Atg7 and LC3-II/I were significantly increased (P<0.05), and the expression level of Beclin-1 was significantly decreased (P<0.05) in the CdCl₂ group compared with the control group. The expression levels of Atg7 were reduced to varying degrees after treatment with designed concentrations of 10-HDA, the expression levels of LC3-II/I were also reduced in the 50, 150, and 200 mg·kg⁻¹ 10-HDA intervention groups, and the expression levels of Beclin-1 were increased in the 50, 100, and 150 mg·kg⁻¹ 10-HDA intervention groups (P<0.05). The expression levels of PINK1 and Parkin in the CdCl₂ group and the 50 mg·kg⁻¹ 10-HDA intervention group were lower than those in the control group (P<0.01). Compared with the CdCl₂ group, the expression levels of PINK1 increased to varying degrees after 100, 150, and 200 mg·kg⁻¹ 10-HDA intervention, and the expression levels of Parkin increased in all 10-HDA intervention groups (P<0.01). Conclusion The intervention using 10-HDA can lessen acute kidney injury caused by CdCl₂, reduce the expression of autophagy-related proteins, and increase the expression of mitochondrial autophagy-related proteins.

OBJECTIVE To investigate the improvement effects of 3，5，6，7，8，3′，4′-heptamethoxyflavone （HMF） of Fructus Aurantii on rats with damp blockage of the middle energizer. METHODS The rats were randomly divided into normal group， model group， positive control group （Raceanisodamine tablet， 1 mg/kg）， HMF low-dose， medium-dose and high-dose groups （0.3， 0.6， 0.9 mg/kg）， with 7 rats in each group. Except for the normal group， the other groups were modeled by internal and external composite factors. After successful modeling， the rats in each group were given the corresponding drug or normal saline， once a day， for 14 days. The general behavioral states such as dietary intake， water intake and mental state of the rats were observed， and the fecal water content rate and saliva flow rate were measured. Hematoxylin-eosin （HE） staining was used to observe the pathological and morphology in gastric and small intestinal tissues of rats. The plasma content of aldosterone was detected， and the expression of aquaporins （AQP3） in the gastric tissue of rats was determined. RESULTS Compared with the normal group， the dietary intake and water intake of the model group rats were significantly decreased （P＜0.01）， the fecal water content rate， salivary flow rate， plasma content of aldosterone and the expression of AQP3 in gastric tissue were increased significantly （P＜0.01）. Gastric tissue injury invaded the mucosal muscle layer， resulting in mucosal muscle layer rupture； pathological and morphological changes such as small intestinal villous erosion and glandular structure destruction were observed in the small intestine. Compared with the model group， the dietary intake and water intake of rats were increased in HMF groups； fecal water content rate， salivary flow rate， plasma content of aldosterone， the expression of AQP3 in gastric tissue were decreased， most of the above differences were statistically significant （P＜0.05 or P＜0.01）. The pathological and morphological changes in the gastric and small intestine tissues of rats had been improved to varying degrees. CONCLUSIONS HMF of Fructus Aurantii with dry property HMF could improve the symptoms of rats with damp blockage of middle energizer， the mechanism of which may be associated with reducing the content of plasma aldosterone and down-regulating the expression of gastric AQP3.