OBJECTIVE To investigate the effect of pharmaceutical services guided by root cause analysis （RCA） in a problem-oriented manner combined with knowledge-attitude-practice （KAP） theory on reducing the incidence of protocol violations of investigational medicinal products in pediatric clinical trials. METHODS A total of 617 participants from 69 drug clinical trial projects conducted in our hospital from January 2016 to December 2020 were selected as the control group， and 868 participants from 72 drug clinical trial projects from January 2022 to December 2025 as the observation group. RCA was performed on the protocol violations of investigational medicinal product in the control group to identify the types and underlying causes. The control group received routine pharmaceutical services for drug clinical trials， while the observation group was provided with precision pharmaceutical services from the three dimensions of knowledge， attitude and practice on the basis of routine pharmaceutical services， according to the root causes identified by RCA. The occurrence of investigational medicinal products protocol violations was compared between the two groups. RESULTS The total incidence of protocol violations of investigational medicinal products， as well as the incidences of minor and major protocol violations， were all significantly lower in the observation group than in the control group （ P ＜0.001）. The main types of protocol violations in both groups included missed/under-/over-dosing of medications， non-adherence to administration time， failure to adjust dosage as required， and combined medication/vaccination in violation of the protocol. Regarding the responsible subjects of protocol violations， the incidences of protocol violations attributed to participants and their guardians as well as investigators and accidental factors were significantly lower in the observation group than in the control group （ P ＜0.001， P ＜0.001， P ＝0.025）. However， there were no statistically significant differences in the incidences of protocol violations caused by sponsor-related reasons between the two groups （ P ＞0.05）. CONCLUSIONS Pharmaceutical services led by pharmacists， based on problem-oriented RCA and combined with KAP theory， can effectively reduce the protocol violations of investigational medicinal products rate in pediatric clinical trials， thereby safeguarding the safety and rights of study participants.

Central serous chorioretinopathy(CSC)is a macular disease predominantly affecting young to middle-aged adults, characterized by serous retinal detachment in the posterior pole, leading to symptoms such as decreased central vision, visual distortion, and color changes. The disease has a certain degree of self-limitation but can recur. The pathogenesis is still uncertain and the treatment is controversial. Commonly used treatments include medication, retinal laser, photodynamic therapy(PDT)and vitreous anti-vascular endothelial growth factor(VEGF)therapy which have emerged in recent years, but the treatment of recurrent CSC is still tricky. The purpose of this article is to review the current therapeutic approaches regarding CSC, with a view to providing a reference for clinical treatment.

OBJECTIVE To evaluate the efficacy and safety of immune checkpoint inhibitors combined with neoadjuvant chemotherapy and adjuvant chemotherapy in the treatment of early-stage triple-negative breast cancer （TNBC）. METHODS A systematic search was conducted in PubMed， Embase， Cochrane Library， CNKI， and Wanfang Data to collect randomized controlled trials （RCT） on the use of immune checkpoint inhibitors combined with neoadjuvant chemotherapy and adjuvant chemotherapy （experimental group） versus neoadjuvant chemotherapy and adjuvant chemotherapy （control group） in the treatment of TNBC. After literature screening， data extraction and literature quality evaluation， meta-analysis was performed using Stata 17.0. RESULTS A total of 5 RCT involving 1 498 patients were included. The meta-analysis results showed that the pathological complete response rate （pCR） [RR＝1.34， 95%CI （1.09， 1.63）， P＝0.03]， pCR in patients with positive programmed death-1 （PD-1） and its ligand （PD-L1） [RR＝1.33， 95%CI （1.16， 1.51）， P＝0.01]， pCR in patients with positive lymph nodes [RR＝ 1.56， 95%CI （1.27， 1.93）， P＝0.01]， the incidence of grade 3-4 adverse events （AEs） [RR＝1.07， 95%CI （1.01， 1.14）， P＝ 0.04]， the incidence of serious AEs [RR＝1.57， 95%CI （1.31， 1.87）， P＝0.03]， and the incidence of treatment discontinuation due to AEs [RR＝1.45， 95%CI （1.19， 1.76）， P＝0.01] were significantly higher in the experimental group than control group. There were no statistically significant difference in pCR in patients with negative PD-1/PD-L1[RR＝ E-mail：biejun23@126.com 1.26， 95%CI （0.98， 1.62）， P＝0.08] and pCR in patients with negative lymph nodes [RR＝1.14， 95%CI （0.97， 1.33）， P＝0.17] between the two groups. CONCLUSIONS Immune checkpoint inhibitors combined with neoadjuvant chemotherapy and adjuvant chemotherapy demonstrates significant efficacy in early-stage TNBC patients， with more pronounced benefits observed in those who are PD-1/PD-L1 positive and lymph node- positive. However， the incidence of AEs is relatively high.

OBJECTIVE To compare the effects of leuprorelin and mifepristone on sex hormone levels， ovarian function， adverse reactions， and recurrence in patients with endometriosis （EMs） after surgery. METHODS A total of 178 patients who underwent surgical treatment for EMs in Ji’an Central People’s Hospital from September 2021 to September 2023 were randomly divided into the leuprorelin group and the mifepristone group， with 92 cases in each group. Medication was initiated on days 1 to 5 of the first menstrual cycle following surgery. Patients in the leuprorelin group received subcutaneous injections of Leuprorelin acetate microspheres， 3.75 mg per time， once every four weeks， for a total of 6 injections. Patients in the mifepristone group took 12.5 mg of Mifepristone capsules orally once daily for six consecutive months. Visual analog scale （VAS）， serum sex hormone levels [follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， and estradiol （E2）]， ovarian function indicators [anti- Müllerian hormone （AMH）， antral follicle count （AFC）]， and T helper 1 cell （Th1）/Th2 shift markers [interferon-γ （IFN-γ）， interleukin 2 （IL-2）， IL-4， and IL-10] were compared between the two groups before surgery and after treatment. Incidence and outcome of adverse reactions and recurrence within one year were also compared between the two groups. RESULTS There were no statistically significant differences in baseline indicators between the two groups before surgery （P＞0.05）. After treatment， both groups showed significantly lower VAS scores for chronic pelvic pain， dysmenorrhea and dyspareunia， and significantly reduced serum FSH， LH， E2， IL-4 and IL-10 levels compared to before surgery （P＜0.05）， while serum IFN-γ and IL-2 levels were significantly increased （P＜0.05）； the leuprorelin group showed significantly greater improvements than the mifepristone group in all these indicators （P＜0.05）. After treatment， serum AMH levels in both groups were significantly lower than before surgery levels， while AFC was significantly increased （P＜0.05）； the leuprorelin group had significantly higher serum AMH levels and more AFC compared to the mifepristone group （P＜0.05）. There were no significant differences in the incidence of adverse reactions and outcome rates between the two groups （P＞0.05）. During one year of follow-up after discontinuation， the recurrence rate in the leuprorelin group was significantly lower than in the mifepristone group （1.15% vs. 10.99%， P＜0.05）. CONCLUSIONS Both leuprorelin and mifepristone are effective therapeutic drugs for EMs， but the former has advantages in alleviating pain， regulating serum sex hormone levels， protecting ovarian function， regulating immune function and reducing recurrence rates.

OBJECTIVE To construct three-class （insufficient， normal， excessive） and two-class （insufficient， normal） models for predicting plasma concentration of valproic acid （VPA）， and compare the performance of these two models， with the aim of providing a reference for formulating clinical medication strategies. METHODS The clinical data of 480 patients who received VPA treatment and underwent blood concentration test at the Xi’an International Medical Center Hospital were collected from November 2022 to September 2024 （a total of 695 sets of data）. In this study， predictive models were constructed for target variables of three-class and two-class models. Feature ranking and selection were carried out using XGBoost scores. Twelve different machine learning algorithms were used for training and validation， and the performance of the models was evaluated using three indexes: accuracy， F1 score， and the area under the working characteristic curve of the subject （AUC）. RESULTS XGBoost feature importance scores revealed that in the three-class model， the importance ranking of kidney disease and electrolyte disorders was higher. However， in the two-class model， the importance ranking of these features significantly decreased， suggesting a close association with the excessive blood concentration of VPA. In the three-class model， Random Forest method performed best， with F1 score of 0.704 0 and AUC of 0.519 3 on the test set； while in the two-class model， CatBoost method performed optimally， with F1 score of 0.785 7 and AUC of 0.819 5 on the test set. CONCLUSIONS The constructed three-class model has the ability to predict excessive VPA blood concentration， but its prediction and model generalization abilities are poor； the constructed two-class model can only perform classification prediction for insufficient and normal blood concentration cases， but its model performance is stronger.

OBJECTIVES: The aim of this study is to determine the effect of cannabinoid receptor (CB) 2 inhibitor on desmoglein 3 (DSG3) expression in HaCaT cells co-cultured with pemphigus serum. METHODS: Immunohistochemical staining was used to compare CB expression in pemphigus patients and normal individuals. Enzyme-linked immunosorbent assay (ELISA) was employed to quantify the concentration of CB2 in the serum of pemphigus patients and normal individuals. A correlation analysis was performed to examine the relationship between the serum CB2 and DSG of pemphigus patients. The CCK-8 assay was used to evaluate the inhibitory effect of AM630 on HaCaT cells, and the half-maximal inhibitory concentration (IC₅₀) value was utilized to determine the experimental concentration. Serum from normal individuals (negative control group) and pemphigus patients (pemphigus group) was co-cultured with HaCaT cells at a 1∶1 ratio. HaCaT cells cultured in complete medium were used as the control group. HaCaT cells in the pemphigus group treated with AM630 were employed as the AM630 group. Real-time polymerase chain reaction (PCR) and Western blot were conducted to assess the expression levels of CB2, DSG3, and β-catenin. Cell dissociation experiments were conducted to evaluate the effect of AM630 on the adhesion of HaCaT cells. RESULTS: Immunohistochemistry revealed significant differences in CB2 expression between pemphigus and normal mucosa (P<0.000 1), but no difference was found in CB1 expression. ELISA analysis revealed a statistically significant difference in the expression levels of CB2 in the serum between normal individuals and pemphigus patients (P<0.001). The expression of CB2 in the serum of pemphigus patients exhibited a significant positive correlation with that of DSG3 (r=0.831, P=0.003). The CCK-8 assay indicated that the IC₅₀ of AM630 on HaCaT cells was 0.55 μmol/L. Real-time PCR and Western blot showed that the expression levels of CB2 and DSG3 increased in the pemphigus group, while the expression level of β-catenin decreased compared with that in the AM630 groups (P<0.05). CONCLUSIONS CB2 is highly expressed in oral mucosal pemphigus. AM630 inhibits overexpression of CB2 and DSG3 and underexpression of β-catenin levels, which can provide new therapeutic targets for pemphigus.
Humans ; Pemphigus/pathology* ; Receptor, Cannabinoid, CB2/metabolism* ; Desmoglein 3/metabolism* ; Acantholysis/metabolism* ; Mouth Mucosa/pathology* ; HaCaT Cells ; Coculture Techniques ; beta Catenin/metabolism*

Homeostasis and energy and substance metabolism reprogramming shape various tumor microenvironment to sustain cancer stemness, self-plasticity and treatment resistance. Aiming at them, a lipid-based pharmaceutical loaded with CaO₂ and glucose oxidase (GOx) (LipoCaO₂/GOx, LCG) has been obtained to disrupt calcium homeostasis and interfere with glycometabolism. The loaded GOx can decompose glucose into H₂O₂ and gluconic acid, thus competing with anaerobic glycolysis to hamper lactic acid (LA) secretion. The obtained gluconic acid further deprives CaO₂ to produce H₂O₂ and release Ca²⁺, disrupting Ca²⁺ homeostasis, which synergizes with GOx-mediated glycometabolism interference to deplete glutathione (GSH) and yield reactive oxygen species (ROS). Systematical experiments reveal that these sequential multifaceted events unlocked by Ca²⁺ homeostasis disruption and glycometabolism interference, ROS production and LA inhibition, successfully enhance cancer immunogenic deaths of breast cancer cells, hamper regulatory T cells (Tregs) infiltration and promote CD8⁺ T recruitment, which receives a considerably-inhibited outcome against breast cancer progression. Collectively, this calcium homeostasis disruption glycometabolism interference strategy effectively combines ion interference therapy with starvation therapy to eventually evoke an effective anti-tumor immune environment, which represents in the field of biomedical research.

Objective To develop an exercise rehabilitation program for the patients with upper limb lymphedema in order to provide standardised guidance for specialised management and nursing practice,and to promote the recovery of patients.Methods With the evidence-based methods,domestic and international literaturs were retrieved and the quality of the papers was evaluated.A research team was established to discuss and draft an initial version of the rehabilitation program for the patients with upper limb lymphedema.Delphi method was used to conduct two rounds of consultation with 15 experts in lymphedema between June and September 2023.According to the expert opinions,the exercise rehabilitation program for patients with upper limb lymphedema was finalised after screening and modification of the indicators.Results The final version of the exercise rehabilitation program for patients with upper limb lymphedema includes four tier-1 indicators(routine upper limb rehabilitation exercises,aerobic exercise,anti-resistance exercise and respiratory training),15 tier-2 indicators,and 33 tier-3 indicators.The positive response rate in both rounds of expert consultation was 100.00%,with the authority coefficient at 0.95.In the second round of expert consultation,it was founds that the importance of tier-3 indicators was from 3.93 to 5.00,with the rationality from 4.13 to 5.00 and the feasibility from 3.53 to 4.93.The coefficient of variation in tier-1 and tier-2 indicators was 0.00-0.17 and 0.07-0.23,respectively.The coefficients of variation of per tier-3 indicator in importance,rationality and feasibility were from 0.00 to 0.22,0.00 to 0.22 and 0.05 to 0.22,respectively.The Kendall's coefficient of concordance(W)for tier-1 and tier-2 indicators was 0.490 and 0.387,respectively.The Kendall's W of per tier-3 indicator in importance,rationality and feasibility was 0.427,0.311 and 0.530,respectively,with statistically significant differences(P<0.001).Conclusion The exercise rehabilitation program developed in this study is scientific,comprehensive and highly targeted.It provides a theoretical basis and practical guidance for exercise rehabilitation and nursing care of the patients with upper limb lymphedema.

Objective:To investigate the value of transabdominal bowel ultrasonography (TBUS) in evaluating the active phase of Crohn′s disease (CD) and its complications, and to compare the diagnostic efficacy of the international bowel ultrasound segmental activity score (IBUS-SAS) and the multidetector computed tomography enterography (MDCTE) score in the active phase.Methods:A totle of 103 CD patients who were admitted to the Nanjing Drum Tower Hospital from March 2021 to May 2023 were retrospectively analyzed. All patients underwent TBUS and MDCTE examinations. TBU parameters such as bowel wall thickness (BWT), color Doppler imaging signal (CDS), inflammatory fat (i-fat), and bowel wall stratification (BWS) were recorded. The patients were divided into the remission group and the active group based on the Crohn′s disease activity index. The latter group was further divided into the mild active group and the moderate-to-severe active group.Receiver operating characteristic curves (ROC) were plotted, and the diagnostic efficacy of TBUS parameters and two scoring systems in assessment of the active phase of CD was evaluated by sensitivity, specificity, area under the curve (AUC), and optimal cut-off values. Endoscopic or histopathological results were served as the gold standard for the diagnosis of intestinal strictures. The diagnostic efficacy of TBUS and MDCTE in CD complicated with intestinal stenosis were evaluated by ROC analysis. Spearman correlation analysis was performed to analyze the correlation between TBUS parameters, imaging scores, and clinical laboratory indicators such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and faecal calprotectin (FC).Results:In distinguishing the active phase and the remission phase of CD, BWT (a sensitivity of 85.7%, specificity of 90.9%, and cut-off value of 4.4 mm), CDS (a sensitivity of 95.7%, and specificity of 63.6%), IBUS-SAS (a sensitivity of 91.4%, specificity of 84.8%, and cut-off value of 23.8), and MDCTE score (a sensitivity of 77.1%, specificity of 75.8%, and cut-off value of 6.5) had high diagnostic efficacies. In distinguishing mild and moderate-severe active phases of CD, BWT, CDS and i-fat demonstrated high sensitivity (81.4%, 69.8% and 62.8%) and specificity (81.5%, 77.8% and 100.0%); IBUS-SAS (a sensitivity of 83.7%, specificity of 88.9%, and cut-off value of 40.0) and MDCTE score (a sensitivity of 83.7%, specificity of 85.2%, and cut-off value of8.5) had high diagnostic efficacy. In the diagnosis of CD complicated with intestinal stenosis, the AUC, sensitivity, specificity, and accuracy of MDCTE was 0.942, 94.0%, 94.3%, and 94.2%, respectively. The AUC, sensitivity, specificity, and accuracy of TBUS in the diagnosis of CD complicated with intestinal stenosis was 0.952, 96.0%, 94.3%, and 95.1%, respectively. The results of Spearman correlation analysis revealed that BWT, CDS, and i-fat have positively correlated with ESR, CRP, and FC ( r value: 0.252 to 0.451, all P<0.05). Conclusions:TBUS demonstrates good application value in evaluating the activity of CD and intestinal stenosis. IBUS-SAS has the potential application for precise assessment of CD activity.

Objective:To observe the effects of moxibustion at Shenshu(BL23)and Zusanli(ST36)on Toll-like receptor 4(TLR4)-myeloid differentiation factor 88(Myd88)signaling pathway-mediated inflammatory factors in the synovial tissue of ankle joints of rats with rheumatoid arthritis(RA),and to explore the molecular and biological mechanisms underlying the anti-inflammatory and analgesic effects.Methods:A total of 24 male Sprague-Dawley(SD)rats were randomly divided into a normal group,a model group,and a moxibustion group,with 8 rats in each group.The RA model was established with exposure to wind,cold,and damp environmental factors,along with Freund's complete adjuvant.After three days of modeling,mild moxibustion was applied to bilateral Shenshu(BL23)and Zusanli(ST36)in the moxibustion group using moxa sticks of 0.9 cm in diameter for 30 min each time,once a day for 14 d.Structural changes in the synovial tissue and cells were then observed using hematoxylin-eosin staining and transmission electron microscopy,while immunohistochemistry analysis was used to detect tumor necrosis factor(TNF)-α,interleukin(IL)-17,IL-1β,and IL-6 levels.Moreover,the protein expression levels of Myd88,TLR4,and transient potential receptor vanilloid type 1(TRPV1)in the synovial tissue were detected using Western blotting,while their mRNA expression levels were detected using reverse transcription-polymerase chain reaction.Finally,the levels of IL-1β,IL-2,IL-6,IL-17A,and TNF-α in rat serum were detected using enzyme-linked immunosorbent assay.Results:Compared to the normal group,the model group exhibited notable pathological synovial tissue damage,along with significantly higher IL-1β,IL-6,and TNF-α levels(P<0.01)and a slightly higher IL-17 content(P>0.05).Furthermore,the Myd88,TLR4,and TRPV1 protein and mRNA expression levels and serum IL-1β,IL-2,IL-6,IL-17A,and TNF-α levels were all significantly higher in the model group than in the normal group(P<0.01).Compared to the model group,the moxibustion group exhibited a lower degree of synovial tissue pathological damage,along with significantly lower IL-1β,IL-6,and TNF-α levels(P<0.05 or P<0.01)and a lower IL-17 content without statistical significance(P>0.05).Moreover,the Myd88,TLR4,and TRPV1 protein and mRNA expression levels,and serum IL-1β,IL-2,IL-6,IL-17A,and TNF-α levels were all significantly lower in the moxibustion group than in the model group(P<0.01 or P<0.05).Conclusion:Mild moxibustion at Shenshu(BL23)and Zusanli(ST36)can effectively inhibit TLR4-MyD88 signaling pathway-mediated inflammatory factor expression in the synovial tissue of ankle joints of RA rats.Furthermore,the effect of moxibustion on synovial tissue inflammation in RA rats may be attributed to TRPV1 channel activation.