Driven by the growing practical need to accelerate drug development and the continuous innovation of trial design in recent years， the number of protocol amendments during clinical trials have gradually increased， and the changed contents have become more flexible and complex， which significantly heightens the difficulty of ethical review on amendments. Against this backdrop， it is of great importance to fully leverage the role and responsibilities of ethics committees， effectively control clinical trial risks， and ensure subject safety. This paper analyzed development trends of protocol amendments in recent years， sorted out requirements for protocol amendments in Chinese regulations and guiding principles， and examined difficulties of amendment ethical review in practical work. Based on these， targeted strategies and recommendations were proposed， namely， strengthening the integration with scientific review， enhancing the formal review， adjusting the scope of review according to approval notifications， and adopting appropriate review methods， with a view to providing insights and references for the management of the amendment ethical review in drug clinical trials.

Chronic post-surgical pain (CPSP) is a common long-term complication following lung surgery. Its high incidence significantly impacts patients’ quality of life and functional recovery, and imposes a substantial socioeconomic burden. This consensus aims to systematically establish a standardized integrated Chinese and Western medicine diagnostic and treatment framework for chronic post-lung surgery pain (CPLSP). Based on the latest domestic and international evidence-based medical research and multidisciplinary clinical experience, the working group comprehensively elaborates on core issues regarding CPLSP, including its definition, epidemiology, pathogenesis, clinical assessment, Western medical treatment, traditional Chinese medicine (TCM) treatment, and integrated strategies. The consensus emphasizes a patient-centered approach, adhering to the principles of multimodality, individualization, and stepwise management, highlighting the synergistic advantages of integrating Chinese and Western medicine throughout the entire perioperative management cycle encompassing "perioperative anti-inflammation, acute analgesia, and chronic rehabilitation." Through systematic literature retrieval and evidence integration, a total of 9 core recommendations were established to provide scientifically sound and clinically practical guidance.

The AP2/ERF transcription factor family is a class of transcription factors widely present in plants, playing a crucial role in regulating flowering, flower development, flower opening, and flower senescence. Based on transcriptome data from flower, leaf, and stem samples of two Lonicera macranthoides varieties, 117 L. macranthoides AP2/ERF family members were identified, including 14 AP2 subfamily members, 61 ERF subfamily members, 40 DREB subfamily members, and 2 RAV subfamily members. Bioinformatics and differential gene expression analyses were performed using NCBI, ExPASy, SOMPA, and other platforms, and the expression patterns of L. macranthoides AP2/ERF transcription factors were validated via qRT-PCR. The results indicated that the 117 LmAP2/ERF members exhibited both similarities and variations in protein physicochemical properties, AP2 domains, family evolution, and protein functions. Differential gene expression analysis revealed that AP2/ERF transcription factors were primarily differentially expressed in the flowers of the two L. macranthoides varieties, with the differentially expressed genes mainly belonging to the ERF and DREB subfamilies. Further analysis identified three AP2 subfamily genes and two ERF subfamily genes as potential regulators of flower development, two ERF subfamily genes involved in flower opening, and two ERF subfamily genes along with one DREB subfamily gene involved in flower senescence. Based on family evolution and expression analyses, it is speculated that AP2/ERF transcription factors can regulate flower development, opening, and senescence in L. macranthoides, with ERF subfamily genes potentially serving as key regulators of flowering duration. These findings provide a theoretical foundation for further research into the specific functions of the AP2/ERF transcription factor family in L. macranthoides and offer important theoretical insights into the molecular mechanisms underlying floral phenotypic differences among its varieties.
Plant Proteins/chemistry* ; Gene Expression Regulation, Plant ; Transcription Factors/chemistry* ; Lonicera/classification* ; Flowers/metabolism* ; Phylogeny ; Gene Expression Profiling ; Multigene Family

Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t _{1/2, cornea} = 1.11 h; t _{1/2, meibomian glands} = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

This study established a droplet digital PCR(ddPCR)EvaGreen assay and probe methods for Schistosoma japonicum detection,and evaluated their application in detecting early infections in the S.japonicum host oncomelania and mice.Primers and corresponding probes for both ddPCR methods were designed and synthesized,and plasmids containing target sequences were constructed.The sensitivity of the two methods was tested through detection of the corresponding plasmids,and infectious and mixed oncomelania genomic DNA.Their specificity was evaluated by the detection of genomic DNA of negative oncomelania,Schistosoma mansoni,Clonorchis sinensis,Spirometra mansoni,and S.japonicum(as a positive control).The ddPCR probe method was evaluated by detection of early infection of oncomelania exposed tomiracidium with various ratios and incubation times,and the early migration and distribution of cercaria or schistosomula in mouse hosts infected with 200 cercaria via abdominal skin contact.According to standard curves constructed through the detection of plasmid serial dilutions,the regression equation for the EvaGreen assay was y=-0.839 9x+7.050 9,with a correlation coefficient R2=0.988 1,and the regression equation for the probe method was y=-1.047 5x+7.255 1,with a correlation coefficient R2=0.999 8.The lowest limit of plasmid detection with the probe method was between 38.94 cp/μL and 194.74 cp/μL.Both methods successfully detected positive reactions in the genomic DNA samples of infectious oncomelania at concentrations above 0.002 ng/μL and in the genomic DNA of each group of oncomelania mixtures.No significant differences between probe methods were observed in the detection values in the control group and the genomic DNA of negative oncomelania,S.mansoni,C.sinensis,and S.mansoni.However,the detection value of genomic DNA of negative oncomelania(291 ng/μL)with the EvaGreen assay was(20.3±4.39)cp/μL,a value significantly higher than the(1.5±0.1)cp/μL observed in the control group.For detection of early infection in oncomelania,the probe method detected Schistosoma japonicum DNA after 30 s incubation at room temperature with a≥5∶1 ratio of miracidium to oncomelania;the detection value peaked after a short time(5 min),and the peak value showed a fold increase similar to the increase in the miracidium to oncomelania ratio.Detection of early stage infection in mice with the probe method revealed that the schistosomula entered the lungs on day 2 and the liver on day 4,and continually migrated within the organs with abundant blood supply(spleen,kidney,and brain)in the first 9 days;moreover,a tendency toward ectopic parasitism was observed in the heart and pancreas on day 9,and a constantly negative control level was observed in the testes.The ddPCR probe method was more accurate and specific than the EvaGreen assay in the detection of plasmids,and infectious and mixed oncomelania,and the latter showed non-specific reactions in negative oncomelania detection.In a practical application,the probe method was demonstrated to be sensitive,to effectively reflect the early infection of oncomelania,and to reveal schistosomula migration and distribution in multiple organs of infected mice.

Objective:To evaluate the radiological and functional outcomes of moderate to severe hallux valgus patients with enlarged distal metatarsal articular angle (DMAA) underwent modified Chevron osteotomy.Methods:The clinical data of patients with moderate and severe hallux valgus with increased distal metatarsal joint angle who accepted surgery operation in the Department of Foot and Ankle Surgery of Yantaishan Hospital from October 2020 to December 2022 were retrospectively analyzed. All patients underwent modified Chevron osteotomy. Taking the proximal end of the metatarsal head centre as the osteotomy apex, the vertical arm osteotomy line in the sagittal plane made an angle of ≤80° with the metatarsal stem, the horizontal plane was inclined to the lateral distal end of the metatarsal head by about 10°, and the sagittal plane metatarsal arm osteotomy line made an angle of ≥90° with the vertical arm osteotomy line; at the proximal osteotomy surface, another cuneiform bone with its base on the medial and its apex on the lateral was resected. The deformity correction was insufficient and Akin osteotomy was performed in combination. Weil osteotomy was performed in combination with metatarsalgia. Radiological assessment including the hallux valgus angle (HVA), intermetatarsal angle (IMA), DMAA, the joint congruity angle (JCA), forefoot bone width and soft tissue width was performed preoperatively and at last follow-up postoperatively. American Orthopedic Foot and Ankle Society/hallux metatarsophalangeal-interphalangeal scale (AOFAS/HMIS) was used for clinical and functional evaluation, total score from 0 to 100, with higher scores indicating better function.Visual analogue scale (VAS) was used for pain valuation, total score from 0 to 10, with higher scores indicating more pain. A questionnaire survey on patient satisfaction was conducted at the last follow-up. Shapiro-Wilk test was used for normal distribution test, and measurement data following normal distribution were represented as Mean±SD. Paired t-test was used for comparison before and after operation. Other indicators conformed to non-normal distribution were denoted by M( Q1, Q3) and were tested by Wilcoxon signed-rank test. P<0.05 was considered statistically significant. Results:Fifty-two feet of 48 patients (5 males, 43 females; mean age (52.4±14.9) years; range, 24 to 78 years) were enrolled. Before the operation, 8 feet combined with metatarsalgia, among them, 7 feet underwent modified Chevron+ Akin+ Weil osteotomy, and 1 foot underwent modified Chevron+ Weil osteotomy. Among the 44 feet without metatarsalgia, 11 feet underwent modified Chevron osteotomy and 33 feet underwent modified Chevron+ Akin osteotomy. The mean follow-up time was 17.8 months (12-24 months). The HVA angle decreased from 38.30°±7.59° before surgery to 10.00°±5.73° at the last follow-up; the IMA angle decreased from 16.08°(12.89°, 18.24°) to 4.81°(3.62°, 7.57°); the DMAA angle decreased from 18.35°(13.03°, 27.47°) to 4.52°(2.68°, 7.09°); JCA decreased significantly from 15.93°(10.25°, 23.06°) to 3.56°(1.71°, 6.98°); forefoot bone width decreased from (90.05±6.12) mm to (82.75±5.01) mm; forefoot soft tissue width decrease from 102.25(96.77, 107.15) mm to 98.08(91.01, 100.60) mm; the VAS decreased from 6(5.5, 7) points to 0(0, 0) points; the score according to the AOFAS/HMIS forefoot was increased from 49(42, 52.5) points to 90(83.5, 95) points; which were statistically significant compared with that before the operation (all P<0.01). There was no statistically significant difference in the first metatarsal length before the operation and at the last follow-up [54.60(52.86, 56.42) mm vs. 54.29(51.85, 56.35) mm, P>0.05]. In the post-operative period, there were 8 feet had limited metatarsophalangeal joint movement, 3 feet had limited interphalangeal joint movement, 5 feet had limited movement in both joints, which did not affect walking and function; 3 feet of partial recurrence of hallux valgus, 2 feet of screw irritation pain, 1 foot of cystic degeneration of the first metatarsal head, and no complications such as metastatic metatarsalgia. The satisfaction survey showed that the satisfaction rate of patients with the orthopedic effect was 90.4% (47/52). Conclusion:The modified Chevron osteotomy is effective in the treatment of moderate to severe hallux valgus with enlarged DMAA. Careful intraoperative operation and standardized postoperative rehabilitation training can reduce complications.

Objective To investigate the relationship between platelet distribution width(PDW)and coronary artery calcification(CAC)in overweight and obese populations.Methods Clinical and chest CT data of 10 838 subjects with overweight or obesity(body mass index[BMI]≥24 kg/m2)were retrospectively analyzed.The subjects were divided into CAC group(n=4 237)and non-CAC group(n=6 601)based on CAC scores obtained from chest CT.The relationship between PDW and CAC in overweight and obese populations was analyzed after controlling confounding variables.A threshold effect analysis was conducted using a two-stage logistic model to find the non-linear inflection point.Subgroup analyses and interaction tests were conducted to validate the stability of the relationship between PDW and CAC.Results Non-linear relationship was observed between PDW and CAC risk in overweight and obese populations.The risk of CAC decreased with the increase of PDW which ≤17.80％(OR=0.82),but increased with the increase of PDW(OR=1.04)which＞17.80％.Subgroup analysis showed that the relationship between PDW and CAC remained stable in subgroups of different genders,BMI(＜28 kg/m2,≥28 kg/m2)and hypertension(all P＞0.05).Compared with aged＜40 years or ≥60 years subgroups,under the same PDW,aged≥40 and＜60 years subgroups had higher risk of CAC(interaction P=0.015).Conclusion Nonlinear relationship existed between PDW and CAC in overweight and obese populations.Both excessively high and low PDW were risk factors of CAC.

AIM To establish an HPLC-MS/MS method for the simultaneous residue determination of 11 plant growth regulators(PGRs)in Renshen Guben preparations,and to conduct a risk assessment.METHODS The analysis was performed on a 40 ℃ thermostatic ACQUITY UPLC ? Waters HSS T3 column(2.1 mm×100 mm,1.8 μm),with the mobile phase of acetonitrile-0.1％formic acid(containing 5 mmol/L ammonium formate)flowing at 0.30 mL/min in a gradient elution manner,and electro spray ionization was employed in both positive and negative ion scanning,with multiple reaction monitoring mode.The chronic and acute exposure risk values of the detected PGRs were calculated and assessed based on residue levels,health guidance values,and exposure estimates.RESULTS Eleven PGRs exhibited good linear relationships within their own ranges(R2 ≥ 0.990),whose average recoveries were 70.0％-120.0％,with RSDs all below 12.0％.In both oral liquid and pill forms,mepiquat chloride showed the highest average residue levels,while sodium 5-nitroguaiacolate exhibited the highest acute risk value(0.765 7,0.908 1)and chronic risk value(0.023 1,0.027 0).CONCLUSION Although PGRs residues are detected in Renshen Guben preparations,all levels remained within safe limits.

Through network pharmacology and molecular docking technology, combined with in vitro experiment verification, we explored the mechanism of action of Porana racemosa Roxb. (PRA) in the treatment of rheumatoid arthritis (RA), and provided a modern pharmacological basis for the treatment of RA by PRA. The potential target of chemical components in the analyzed moth rattan was predicted by Swiss Target Prediction database; OMIM, GeneCards, TTD and Disgenet databases were used to search the disease targets of RA; the protein interaction (PPI) network and medicine-composition-target network were constructed using STRING database and Cytoscape software; GO (gene ontology) functional enrichment and KEGG (kyoto encyclopedia of genes and genomes) pathway analysis were carried out using DAVID database, and molecular docking software was used to dock the potentially active ingredients of PRA and core targets; finally, MH7A cells were selected for cell viability, scratch healing and mRNA expression level analysis of key genes to explore the effects of PRA and their potentially active ingredients on the proliferation, migration and apoptosis of MH7A cells. In this study, a total of 628 potentially active ingredient targets, 1 890 RA targets and 235 intersection targets were identified. It was screened that the potentially active ingredients of RA treatment by PRA were ethylcaffeate, N-p-coumaroyltyramine, 9,12,15-octadecatrienoic acid, methyl ester and so on, and the core targets involved tumor necrosis factor (TNF), matrix metalloproteinase 9 (MMP9), prostaglandin-endoperoxide synthase 2 (PTGS2) and so on. 1 200 GO entries and 166 KEGG pathway entries were obtained from the enrichment analysis; molecular docking results showed that N-p-coumaroyltyramine and ethylcaffeate had good binding activity with TNF, MMP9, cysteine-aspartate protease 3 (CASP3), PTGS2, B-cell lymphoma 2 (BCL2) proteins. In vitro experiments showed that PRA, ethylcaffeate and N-p-coumaroyltyramine could inhibit the proliferation, migration and invasion of MH7A cells, up-regulate the expression of apoptosis-related gene CASP3 mRNA, and down-regulate the expression of MMP9, PTGS2 and BCL2 mRNA, and it can also down-regulate the expression of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) mRNA and PI3K and p-AKT proteins. This study preliminarily revealed that the treatment of RA by PRA may be related to proliferation, migration, invasion, apoptosis and regulation of PI3K/AKT signaling pathway.