The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use （ICH） issued the ICH E6（R3）： Guideline for Good Clinical Practice on January 14， 2025， which will enhance the speed and quality of global clinical trials， including those in China. As the ethical， scientific and quality standards for global drug clinical trials， the highlights of the revision in the ICH E6 （R3） include encouraging innovation to improve efficiency and quality， motivating research participants to participate in the design and implementation of clinical trials throughout the process， emphasizing quality originating from design and based on the quality management of risks， as well as underlining proportionality and standalone chapter to data governance. ICH E6 （R3） adopts an appendix and appendix structure， enabling future revisions to be more convenient and efficient. ICH E6 （R3） restructures the principles section， adding two new principles and reducing the total from 13 to 11， while incorporating extensive explanatory notes. Major revisions also encompass multiple aspects， including regular review by ethics committees to ensure the safety， rights and interests， and well-being of research participants； diversification of informed consent methods， refinement of its processes， and clarification of detailed rules for minors’ consent； qualifications， authorization， and oversight of investigators and their service providers； risk-proportionate design and implementation by sponsors； joint data governance by investigators and sponsors； and the addition and revision of terms， along with updates to three appendices. The design， implementation， and review of drug clinical trials in China are increasingly aligning with international standards. ICH E6 （R3） will accelerate the revision of China’s Guideline for Good Clinical Practice， promote the speed and quality of drug research and development， and further facilitate the internationalization of China’s new drug research and development.

Objective:To evaluate the prevalence, potential risk factors, and correlation between coronary and peripheral microvascular dysfunction in heart failure with non-reduced ejection fraction (nHFrEF) patients.Methods:This was a prospective registry study. nHFrEF patients admitted to Zhongshan Hospital affiliated with Fudan University from December 2021 to December 2023 were enrolled. According to coronary flow reserve (CFR) or reactive congestion index (RHI), enrolled patients were divided into coronary microvascular endothelial dysfunction (CMD) group (CFR<2.5) and no CMD group (CFR≥2.5) or peripheral microvascular endothelial dysfunction (MED) group (RHI<1.67) and no MED group (RHI≥1.67). Patients′ general information, laboratory and auxiliary examination data were collected. Univariate and multivariate logistic regression were used to analyze the influencing factors of CMD and MED in nHFrEF patients, and Spearman correlation analysis was used to evaluate the correlation between MED and CMD.Results:A total of 142 nHFrEF patients were enrolled, aged 69.0 (59.0, 74.0) years, with a male proportion of 66.9% (95/142). The grouping results were as follows: (1) According to CFR, there were 73 cases in the CMD group and 69 cases in the no CMD group; (2) According to RHI, there were 57 cases in the MED group and 85 cases in the no MED group. The prevalence of CMD and MED in this study was 51.4% (73/142) and 40.1% (57/142), respectively. Univariate logistic regression analysis showed that increased heart rate, chronic kidney disease, atrial fibrillation, elevated N-terminal pro-B type natriuretic peptide levels, and increased urinary albumin/creatinine ratio were risk factors for CMD, while increased RHI was a protective factor for CMD; Atrial fibrillation is a risk factor for MED, while increased CFR is a protective factor for MED. Incorporating clinically significant variables from univariate analysis into multivariate analysis, the results showed that increased heart rate and elevated RHI remained risk and protective factors for CMD, respectively; increased CFR remains a protective factor for MED. Spearman correlation analysis showed that CFR was negatively correlated with lg urinary albumin/creatinine ratio, lg cardiac troponin T, lg N-terminal pro-B type natriuretic peptide, and heart rate; RHI is positively correlated with CFR.Conclusions:The prevalence of CMD and MED in nHFrEF patients is high, and the two have a certain positive correlation. Increased heart rate and RHI are risk and protective factors for CMD, respectively, while increased CFR is a protective factor for MED. MED may be a potential therapeutic target for nHFrEF patients.

OBJECTIVE The regression equation of cognitive impairment in patients with obstructive sleep apnea hypopnea syndrome(OSAHS)was constructed based on Logistic regression analysis,to lay a foundation for the prevention of cognitive impairment in OSAHS patients.METHODS A total of 302 OSAHS patients admitted to Huai'an First People's Hospital from October 2022 to October 2024 were selected for the study,and the cognitive impairment group(n=83)and the non-cognitive impairment group(n=219)were included according to the occurrence of cognitive impairment.The status quo of OSAHS patients complicated with cognitive impairment was analyzed,univariate and multivariate Logistic regression was used to analyze the early warning factors of OSAHS combined with cognitive impairment,regression equation was established,and receiver operating characteristic(ROC)curve was drawn to analyze the predictive value of regression equation on OSAHS combined with cognitive impairment.RESULTS Among 302 OSAHS patients,83 cases were complicated with cognitive impairment(27.48%).Multivariate Logistic analysis showed that age increase,physical exercise<3 times/week,apnea hypopnea index increase,longest apnea duration prolongation,serum levels of neuropeptide Y(NPY)increase were early warning factors of OSAHS combined with cognitive impairment.The increase of minimum blood oxygen saturation and serum gamma-aminobutyric acid(GABA)were protective factors of OSAHS combined with cognitive impairment(P<0.05).The above factors were included in the regression equation:logit(P)=-1.875+age×0.059+physical exercise<3 times/week×0.041+apnea hypopnea index×0.031+longest apnea duration×0.073-minimum blood oxygen saturation×0.081+NPY×0.043-GABA×0.049.The regression equation was evaluated,and the likelihood ratio of Chi-square=7.632,DF=7,P<0.001,the regression equation was statistically significant.Patients with OSAHS combined with cognitive impairment were included as positive,while those OSAHS without cognitive impairment were included as negative.The ROC curve for predicting OSAHS combined with cognitive impairment was drawn according to the regression equation.The results showed that when logit(P)>2.02,the area under the curve(AUC)was 0.896.The diagnostic sensitivity and specificity were 85.54%and 83.56%respectively.CONCLUSION OSAHS patients with cognitive impairment were not optimistic,early warning factors included increasing age,less than 3 times/week of physical exercise,increased apnea hypopnea index,prolonged longest apnea time,elevated serum NPY,protective factors included elevated minimum blood oxygen saturation and elevated serum GABA,the regression equation constructed on this basis had good predictive value.

Objective:To analyze the genetic characteristics of coxsackievirus A16 (CVA16) related to hand, foot and mouth disease (HFMD) in Jiaxing from 2021 to 2023, and understand the biological and molecular evolutionary characteristics of CVA16 in this city.Methods:Real-time fluorescent quantitative PCR was used to detect enterovirus and its types in collected HFMD case samples. At the same time, virus isolation and cultivation were performed on positive samples using RD cells. Then high-throughput sequencing of the whole genome was performed on 23 strains of CVA16 identified from the isolated samples. Finally we obtained its whole genome sequence. DNAStar, MEGA 6.0, Simplot 3.5.1 and other bioinformatics software were used to compare and analyze the sequences, construct the phylogenetic tree of VP1 region, and realize the genotype composition. And these software were also used to analyze the homology of the whole genome nucleotide sequence and the encoded amino acids, while know well the amino acid mutation sites and gene recombination in the main regions.Results:The results showed that among the 1 836 HFMD specimens tested from 2021 to 2023, 1 432 (78.00%, 1 432/1 836) were positive for enterovirus general genes, of which 263 were positive for CVA16, accounting for 18.37% (263/1 432) of the confirmed positive cases. Twenty-three CVA16 strains were sequenced and all of them were B1 subtype, of which 6 strains belong to B1b and 17 strains belong to B1a, with B1a being dominant. B1a strains in Jiaxing showed genetic relatedness to strains isolated in Beijing, Yunnan, Guangzhou, Jiangsu and other places in 2018 to 2023, as well as strains from Vietnam, Thailand, and Australia from 2015 to 2017. B1b strains exhibited consistent amino acid mutations of L23M in the VP1 region and V217I in the VP2 region, while B1a strains exhibited amino acid mutations of S14N/D, T164K, and V251I in the VP1 region and R41H in the VP3 region. Compared with the prototype strain, the 23 strains of CVA16 in Jiaxing accumulated the largest number of amino acid mutations in the coding region, with 28 and 50 mutations in the VP1 and 3D regions, respectively. The recombination patterns of B1a and B1b strains were slightly different, with B1a type showing recombination with CVA8 in the 5′-UTR region instead of CVA4, B1a was similar to enterovirus A71 in most of P2 and P3 regions, and recombined with CVA5 in the 3D region of P3.Conclusions:The prevalent strain of CVA16 in Jiaxing may share a common trend of co-circulation and evolution with those in other provinces. The recombination mainly occurs in the 5′-UTR region and non-structural protein coding regions of P2 and P3. Continuous molecular surveillance of CVA16 is in need, and whole-genome sequencing can help understand the genetic variation, evolution, and recombination of strains.This information will provide a more robust basis for the monitoring and early warning, vaccine development, and prevention and control efforts against HFMD.

Oral adenoid cystic carcinoma(OACC)is one of the malignant tumors from the oral cavity,with strong invasion and infiltration ability,and poor prognosis for patients.Studies have shown that epigenetic mechanisms such as DNA methylation,histone modification,non-coding RNAs,and chromatin remodeling are involved in regulating the occurrence,development,invasion,and me-tastasis of OACC.The in-depth research of epigenetic regulatory mechanisms has important clinical significance for the prevention,di-agnosis,and targeted therapy of OACC.This article reviews the epigenetic regulatory mechanisms and new advances in therapeutic re-search of OACC.

Oral adenoid cystic carcinoma(OACC)is one of the malignant tumors from the oral cavity,with strong invasion and infiltration ability,and poor prognosis for patients.Studies have shown that epigenetic mechanisms such as DNA methylation,histone modification,non-coding RNAs,and chromatin remodeling are involved in regulating the occurrence,development,invasion,and me-tastasis of OACC.The in-depth research of epigenetic regulatory mechanisms has important clinical significance for the prevention,di-agnosis,and targeted therapy of OACC.This article reviews the epigenetic regulatory mechanisms and new advances in therapeutic re-search of OACC.

Objective:To analyze the genetic characteristics of coxsackievirus A16 (CVA16) related to hand, foot and mouth disease (HFMD) in Jiaxing from 2021 to 2023, and understand the biological and molecular evolutionary characteristics of CVA16 in this city.Methods:Real-time fluorescent quantitative PCR was used to detect enterovirus and its types in collected HFMD case samples. At the same time, virus isolation and cultivation were performed on positive samples using RD cells. Then high-throughput sequencing of the whole genome was performed on 23 strains of CVA16 identified from the isolated samples. Finally we obtained its whole genome sequence. DNAStar, MEGA 6.0, Simplot 3.5.1 and other bioinformatics software were used to compare and analyze the sequences, construct the phylogenetic tree of VP1 region, and realize the genotype composition. And these software were also used to analyze the homology of the whole genome nucleotide sequence and the encoded amino acids, while know well the amino acid mutation sites and gene recombination in the main regions.Results:The results showed that among the 1 836 HFMD specimens tested from 2021 to 2023, 1 432 (78.00%, 1 432/1 836) were positive for enterovirus general genes, of which 263 were positive for CVA16, accounting for 18.37% (263/1 432) of the confirmed positive cases. Twenty-three CVA16 strains were sequenced and all of them were B1 subtype, of which 6 strains belong to B1b and 17 strains belong to B1a, with B1a being dominant. B1a strains in Jiaxing showed genetic relatedness to strains isolated in Beijing, Yunnan, Guangzhou, Jiangsu and other places in 2018 to 2023, as well as strains from Vietnam, Thailand, and Australia from 2015 to 2017. B1b strains exhibited consistent amino acid mutations of L23M in the VP1 region and V217I in the VP2 region, while B1a strains exhibited amino acid mutations of S14N/D, T164K, and V251I in the VP1 region and R41H in the VP3 region. Compared with the prototype strain, the 23 strains of CVA16 in Jiaxing accumulated the largest number of amino acid mutations in the coding region, with 28 and 50 mutations in the VP1 and 3D regions, respectively. The recombination patterns of B1a and B1b strains were slightly different, with B1a type showing recombination with CVA8 in the 5′-UTR region instead of CVA4, B1a was similar to enterovirus A71 in most of P2 and P3 regions, and recombined with CVA5 in the 3D region of P3.Conclusions:The prevalent strain of CVA16 in Jiaxing may share a common trend of co-circulation and evolution with those in other provinces. The recombination mainly occurs in the 5′-UTR region and non-structural protein coding regions of P2 and P3. Continuous molecular surveillance of CVA16 is in need, and whole-genome sequencing can help understand the genetic variation, evolution, and recombination of strains.This information will provide a more robust basis for the monitoring and early warning, vaccine development, and prevention and control efforts against HFMD.

Objective:To evaluate the prevalence, potential risk factors, and correlation between coronary and peripheral microvascular dysfunction in heart failure with non-reduced ejection fraction (nHFrEF) patients.Methods:This was a prospective registry study. nHFrEF patients admitted to Zhongshan Hospital affiliated with Fudan University from December 2021 to December 2023 were enrolled. According to coronary flow reserve (CFR) or reactive congestion index (RHI), enrolled patients were divided into coronary microvascular endothelial dysfunction (CMD) group (CFR<2.5) and no CMD group (CFR≥2.5) or peripheral microvascular endothelial dysfunction (MED) group (RHI<1.67) and no MED group (RHI≥1.67). Patients′ general information, laboratory and auxiliary examination data were collected. Univariate and multivariate logistic regression were used to analyze the influencing factors of CMD and MED in nHFrEF patients, and Spearman correlation analysis was used to evaluate the correlation between MED and CMD.Results:A total of 142 nHFrEF patients were enrolled, aged 69.0 (59.0, 74.0) years, with a male proportion of 66.9% (95/142). The grouping results were as follows: (1) According to CFR, there were 73 cases in the CMD group and 69 cases in the no CMD group; (2) According to RHI, there were 57 cases in the MED group and 85 cases in the no MED group. The prevalence of CMD and MED in this study was 51.4% (73/142) and 40.1% (57/142), respectively. Univariate logistic regression analysis showed that increased heart rate, chronic kidney disease, atrial fibrillation, elevated N-terminal pro-B type natriuretic peptide levels, and increased urinary albumin/creatinine ratio were risk factors for CMD, while increased RHI was a protective factor for CMD; Atrial fibrillation is a risk factor for MED, while increased CFR is a protective factor for MED. Incorporating clinically significant variables from univariate analysis into multivariate analysis, the results showed that increased heart rate and elevated RHI remained risk and protective factors for CMD, respectively; increased CFR remains a protective factor for MED. Spearman correlation analysis showed that CFR was negatively correlated with lg urinary albumin/creatinine ratio, lg cardiac troponin T, lg N-terminal pro-B type natriuretic peptide, and heart rate; RHI is positively correlated with CFR.Conclusions:The prevalence of CMD and MED in nHFrEF patients is high, and the two have a certain positive correlation. Increased heart rate and RHI are risk and protective factors for CMD, respectively, while increased CFR is a protective factor for MED. MED may be a potential therapeutic target for nHFrEF patients.

Objective:To study the value of coronary flow reserve (CFR) via dynamic single photon emission computed tomography (D-SPECT) in evaluating coronary microcirculation dysfunction (CMD) in patients with heart failure.Methods:A prospective research method was adopted. One hundred and ninety-four patients with heart failure from September 2019 to September 2020 in Zhongshan Hospital, Fudan University were selected. The patients were tested for CFR using D-SPECT, and CFR<2 was defined as CMD. The general data were recorded, including age, gender, body mass index (BMI), blood pressure, heart rate, smoking history, New York Heart Association (NYHA) heart function classification, comorbidities and medication situation. The laboratory test results were recorded, including blood urea nitrogen, blood creatinine, blood uric acid, estimated glomerular filtration rate (eGFR), high-sensitivity C-reactive protein (hs-CRP), cardiac troponin T (cTnT) and N terminal pro B type natriuretic peptide (NT-proBNP). The left atrial diameter (LAD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septal thickness (IVST), pulmonary artery systolic pressure (PASP) and left ventricular ejection fraction (LVEF) were measured by cardiac ultrasound. After discharge, patients were followed up in outpatient or telephone contact, with the primary endpoint event being a composite endpoint consisting of cardiovascular death and heart failure readmission. Multiple linear regression analysis was used to analyze the risk factors of CFR. The Kaplan-Meier survival curve was draw, and the log-rank test was used to evaluate the effect of CFR on prognosis.Results:Among 194 patients, 133 patients had CMD (CMD group), and the incidence of CMD was 68.56%; 61 patients did not have CMD (non-CMD group). There were no statistical differences in gender composition, BMI, smoking history proportion, blood pressure, heart rate, hypertension rate, atrial fibrillation rate, diabetes mellitus rate, renal dysfunction rate, medication situation, LAD, LVEDD, IVST, PASP, blood urea nitrogen, blood creatinine, blood uric acid, eGFR and hs-CRP between two groups ( P>0.05). The age, rate of NYHA heart function classification Ⅲ to Ⅳ grade, rate of myocardial infarction or revascularization history, LVESD, cTnT and NT-proBNP in CMD group were significantly higher than those in non-CMD group: (60.7 ± 14.0) years old vs. (55.9 ± 15.8) years old, 54.89% (73/133) vs. 26.23% (16/61), 22.56% (30/133) vs. 1.64% (1/61), (48.8 ± 13.1) mm vs. (44.6 ± 11.4) mm, 0.023 (0.015, 0.046) μg/L vs. 0.015 (0.010, 0.023) μg/L and 1 591 (751, 3 409) ng/L vs. 1 132 (288, 1 860) ng/L, the LVEF was significantly lower than that in non-CMD group: (40.9 ± 14.2)% vs. (45.5 ± 14.1)%, and there were statistical differences ( P<0.05 or <0.01). Multiple linear regression analysis result showed that the cTnT was an risk factor of CFR ( β = - 0.18, 95% CI - 0.82 to - 0.06, P = 0.025). The median followed up time was 230 (136 to 330) d, 10 patients were lost to follow-up, with 58 patients in CMD group completing follow-up and 126 patients in the non-CMD group. The incidences of primary endpoint event and heart failure readmission in CMD group were significantly higher than those in non-CMD group: 23.02% (29/126) vs. 3.45% (2/58) and 15.87% (20/126) vs. 3.45% (2/58), and there were statistical differences ( P<0.01); there was no statistical difference in incidence of cardiovascular death between two groups ( P>0.05). Kaplan-Meier survival curve analysis result showed that the event free survival rate in CMD group was significantly lower than that in non-CMD group, and there was statistical difference (log-rank χ2 = 11.92, P<0.01). Conclusions:CMD is highly prevalent in patients with heart failure, and it is associated with poor prognosis. Improving CMD for improving coronary microcirculation may be potential targets for the treatment of heart failure.

Objective To investigate the interventional effect and mechanism of a novel ampelopsis hydrogel on dampness-heat accumulation syndrome of gouty arthritis. Methods A total of 90 patients with gouty arthritis who met the diagnostic criteria of western medicine and were differentiated as damp-heat accumulation syndrome of traditional Chinese medicine(TCM) were randomly divided into treatment group, control group and blank group, with 30 patients in each group. The blank group was treated with etoricoxib only, the control group was treated with etoricoxib combined with ampelopsis hydrogel, and the treatment group was treated with etoricoxib combined with external application of ampelopsis hydrogel. The clinical efficacy, time to symptom improvement, safety, comfort, changes in syndrome scores of TCM, serum inflammatory factors[C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), erythrocyte sedimentation rate (ESR)], NF-κB signaling pathway-related proteins, Visual Analogue Scale (VAS) scores for pain, and joint mobility were compared among the three groups before and after treatment. Results The total effective rates in the treatment group and control group were 93.33% and 90.00%, respectively, which were higher than 70.00% in the blank group (P < 0.05). The time for improvement of pain, redness, tenderness, and limited joint mobility in the treatment group was shorter than that in the control group and blank group (P < 0.05). After 7 days of treatment, the TCM syndrome score in the treatment group was lower than that in the control group and blank group, and the levels of serum CRP, TNF-α, and ESR and the expressions of NF-κB signalingpathway-related proteins P50 and P65 in the treatment group and control group were lower than those in the blank group (P < 0.05). After 7 days of treatment, the VAS score in the treatment group was lower than that in the control group and blank group, and the comfort score in the treatment group was higher than that in the control group (P < 0.05). There was no significant difference in the incidence of adverse reactions among the three groups (P>0.05). Conclusion The effect of ampelopsis hydrogel in treating gouty arthritis is better than that of ampelopsis paste, and its mechanism may be related to the regulation of the NF-κB pathway and inhibition of inflammatory factor expression. The hydrogel is easy to use, hygienic, and comfortable, and is expected to become a safe, effective, and convenient external medicine for gouty arthritis.