The ethical review of clinical research on rare diseases is crucial in ensuring the scientific validity of the research and the rights and interests of the subjects. Starting from the definition of rare diseases， this paper analyzed the current situation of domestic and international regulations and ethical review in clinical research on rare diseases. It also explored the key elements of ethical review from the two dimensions of scientific and ethical aspects of clinical research， including research objectives， methods， risk and benefit assessment， researcher qualifications， research infrastructure， informed consent process， data security and privacy protection， and protection of vulnerable groups such as children. Regarding the ethical review of clinical research on rare diseases， strategies can be adopted such as strengthening the training of ethics review personnel， conducting multi-center collaborative reviews， and focusing on the long-term safety of trials， to improve the quality of ethical review， protect the safety of the subjects， and ensure the efficiency and quality of clinical research.

ObjectiveBased on ultra performance liquid chromatography-mass spectrometry（UPLC-MS） and non-targeted metabolomics technology to discuss the central regulatory effect of Chaishao Liujuntang on chronic atrophic gastritis（CAG） rats with liver-depression and spleen-deficiency， and to look for the correlation between cerebral cortex， hypothalamus and metabolic status of gastric tissues. MethodA CAG rat model with liver-depression and spleen-deficiency was established by chemical induction， hunger and satiety disorders， chronic restraint and tail clamping stimulation， lasting for 16 weeks. Twenty-eight Wistar rats were randomly divided into a blank group of 8 rats and a model group of 20 rats. After the completion of modeling， 4 rats in the model group were taken to observe the pathological changes of gastric mucosa. The remaining model rats were randomly divided into a model group of 8 rats and a Chaishao Liujuntang group of 8 rats. Chaishao Liujuntang group rats were given 5.1 g·kg^-1 by gavage， and the remaining rats were given equal volume sterilized water by gavage for 4 weeks. Macroscopic characteristics， behavioral indicators and histopathological changes of the gastric mucosa of rats in each group were observed and compared. UPLC-MS non-targeted metabolomics was used to explore the metabolic regulation effect of Chaishao Liujuntang on the cerebral cortex， hypothalamus and stomach tissues of CAG rats with liver-depression and spleen-deficiency. Pearson correlation coefficient method was used to analyze the correlation between different tissue metabolites. ResultCompared with the model group， the macroscopic characteristics of rats in Chaishao Liujuntang group were improved， such as hair color， mental state and stool properties， and the number of times of crossing and standing in the open field experiment was significantly increased， and the static time of forced swimming was significantly reduced（P<0.01）， and the gastric mucosa atrophy was reduced. The metabolic data from the cerebral cortex of rats in each group identified a total of 3 common potential biomarkers， but not enriched in pathways， 26 common potential biomarkers were identified in the hypothalamus， and the key metabolic pathways involved were mainly enriched in purine metabolism， glycerol phospholipid metabolism， D-glutamine and D-glutamic acid metabolism. Seventeen common potential biomarkers were identified in the stomach， and the key metabolic pathways involved were mainly enriched in thiamine metabolism， valine， leucine and isoleucine biosynthesis， and taurine and taurine metabolism. Correlation analysis of metabolites in different tissues revealed that multiple amino acids and their derivatives mediated metabolic connections between the cerebral cortex， hypothalamus and stomach of rats. ConclusionThe metabolic disorders in the cerebral cortex， hypothalamus and stomach of CAG rats with liver-depression and spleen-deficiency have their own characteristics， mainly manifested by changes in the content of glycerol phospholipids， fatty acids and bile acid metabolites. Moreover， Chaishao Liujuntang may play a central regulatory role in CAG rats with liver-depression and spleen-deficiency by correcting the metabolic disorders of amino acids.

Objective To investigate the role of miRNAs in maternal amniotic fluid exosomes in development of isolated ventriculomegaly(VM)in fetuses.Methods Amniotic fluid samples were collected from 9 cases of moderate isolated VM and 8 normal control cases to extract exosomal miRNA,and miRNA sequencing technique was used to identify differentially expressed miRNAs between the two groups.Three miRNAs with significant differential expression between the two groups,whose high expression was associated with VM,were selected for verification with RT-qPCR.Dual luciferase reporter assays were used to verify the regulatory effect of miR-122-5p on its predicted target genes AKT3 and CCDC88C.Gene ontology(GO)and KEGG pathway analyses were performed to explore the possible roles of the top 40 significant differential miRNAs in the pathophysiology of VM.Results We identified a total of 272 differentially expressed miRNAs in VM cases,including 43 up-regulated and 229 down-regulated miRNAs.The target genes of these differential miRNAs were associated with DNA and transcription factor binding,transmembrane transporter and nucleic acid binding transcription factor activity,and cell developmental process.These miRNAs were mostly enriched in the MAPK,cGMP-PKG and Wnt signaling pathways.Verification with RT-qPCR showed that miR-122-5p expression level was significantly lower in VM group than in the control group(P<0.05),which was consistent with miRNA sequencing results;let-7b-5p expression level was significantly lower in VM group,which was contrary to miRNA sequencing result.Dual luciferase reporter assays showed that miR-122-5p was not capable of regulating AKT3 or CCDC88C expressions.Conclusions The highly abundant differentially expressed miRNAs in maternal amniotic fluid exosomes play important roles in the occurrence of fetal VM possibly by regulating the MAPK,PI3K-Akt,Wnt and cGMP-PKG signaling pathways.

Objective To investigate the role of miRNAs in maternal amniotic fluid exosomes in development of isolated ventriculomegaly(VM)in fetuses.Methods Amniotic fluid samples were collected from 9 cases of moderate isolated VM and 8 normal control cases to extract exosomal miRNA,and miRNA sequencing technique was used to identify differentially expressed miRNAs between the two groups.Three miRNAs with significant differential expression between the two groups,whose high expression was associated with VM,were selected for verification with RT-qPCR.Dual luciferase reporter assays were used to verify the regulatory effect of miR-122-5p on its predicted target genes AKT3 and CCDC88C.Gene ontology(GO)and KEGG pathway analyses were performed to explore the possible roles of the top 40 significant differential miRNAs in the pathophysiology of VM.Results We identified a total of 272 differentially expressed miRNAs in VM cases,including 43 up-regulated and 229 down-regulated miRNAs.The target genes of these differential miRNAs were associated with DNA and transcription factor binding,transmembrane transporter and nucleic acid binding transcription factor activity,and cell developmental process.These miRNAs were mostly enriched in the MAPK,cGMP-PKG and Wnt signaling pathways.Verification with RT-qPCR showed that miR-122-5p expression level was significantly lower in VM group than in the control group(P<0.05),which was consistent with miRNA sequencing results;let-7b-5p expression level was significantly lower in VM group,which was contrary to miRNA sequencing result.Dual luciferase reporter assays showed that miR-122-5p was not capable of regulating AKT3 or CCDC88C expressions.Conclusions The highly abundant differentially expressed miRNAs in maternal amniotic fluid exosomes play important roles in the occurrence of fetal VM possibly by regulating the MAPK,PI3K-Akt,Wnt and cGMP-PKG signaling pathways.

Objective:To investigate the serum level of fatty acid binding protein 1 (FABP1) and its relationship with Helicobacter pylori (Hp) infection in patients with gastric cancer. Methods:Forty gastric cancer patients (gastric cancer group) who were hospitalized in Affiliated Hospital of Qinghai University from August 2021 to August 2022 were selected as the research subjects, and 40 physical examination subjects during the same period were selected as the normal control group and 40 chronic atrophic gastritis patients were selected as the CAG group. The Hp infection were detected by 13C breath test, and the levels of serum FABP1 were detected by enzyme-linked immunosorbent assay. The Hp infection status, serum FABP1 levels, and the relationship between the two in the three groups of study subjects were analyzed. And the relationships between the level of serum FABP1 and the clinicopathological features of gastric cancer patients were analyzed. The diagnostic value of serum FABP1, CA19-9, CA72-4 and combined test of 3 indexes were evaluated by receiver operating characteristic (ROC) curve. Results:The Hp infection rates in the control group, CAG group, and gastric cancer group were 32.50% (13/40), 55.00% (22/40), and 60.00% (24/40), respectively, with a statistically significant difference ( χ2=6.87, P=0.032). Among them, the Hp infection rate in the control group was compared with that in the gastric cancer group, with a statistically significant difference ( P<0.05), and there were no statistically significant differences between the CAG group and the control group, the gastric cancer group (both P>0.05). The levels of serum FABP1 in the control group, CAG group, and gastric cancer group were [63.47 (37.53, 71.59) ] ng/ml, [65.26 (51.15, 79.67) ] ng/ml, and [72.84 (53.44, 82.25) ] ng/ml, respectively, with a statistically significant difference ( H=6.62, P=0.037). Among them, there was a statistically significant difference between the control group and the gastric cancer group ( H=19.93, P=0.031), while there were no statistically significant differences between the CAG group and the control group, the gastric cancer group ( H=1.50, P=0.133; H=1.09, P=0.277). Among all study subjects, the levels of serum FABP1 in the Hp positive group ( n=59) and Hp negative group ( n=61) were [77.05 (68.90, 83.54) ] ng/ml and [47.80 (37.76, 63.32) ] ng/ml, respectively, with a statistically significant difference ( Z=7.45, P<0.001). In the control group, the levels of FABP1 in the serum of Hp positive and Hp negative persons were [77.34 (68.84, 86.31) ] ng/ml and [39.79 (36.83, 63.75) ] ng/ml, respectively, with a statistically significant difference ( Z=4.46, P<0.001). In the CAG group, the levels of FABP1 in the serum of Hp positive and Hp negative patients were [76.51 (65.30, 80.97) ] ng/ml and [49.34 (39.92, 59.41) ] ng/ml, respectively, with a statistically significant difference ( Z=4.32, P<0.001). In the gastric cancer group, the levels of FABP1 in the serum of Hp positive and Hp negative patients were [77.15 (72.62, 84.13) ] ng/ml and [50.57 (44.54, 68.97) ] ng/ml, respectively, with a statistically significant difference ( Z=4.32, P<0.001). There were significant correlations between the serum level of FABP1 and smoking ( t=2.54, P=0.015), tumor diameter ( t=2.23, P=0.035), and lymph node metastasis ( t=3.22, P=0.003) in gastric cancer patients. And there were no significant correlations between FABP1 and gender ( t=0.98, P=0.333), age ( t=1.60, P=0.117), alcohol consumption ( Z=0.10, P=0.925), tumor site ( F=1.06, P=0.356), degree of differentiation ( t=0.61, P=0.545), the depth of infiltration ( t=1.41, P=0.166), distant metastasis ( Z=1.96, P=0.050) and TNM staging ( Z=0.66, P=0.508). ROC curve analysis showed that the area under the curve (AUC) of serum FABP1 for gastric cancer diagnosis was 0.62, 95% CI: 0.51-0.72, the sensitivity and specificity were 57.50% and 68.70%, respectively; the AUC of CA19-9 for gastric cancer diagnosis was 0.89, 95% CI: 0.83-0.95, the sensitivity and specificity were 77.50%, 86.30%, respectively; the AUC of CA72-4 for gastric cancer diagnosis was 0.88, 95% CI: 0.81-0.94, the sensitivity and specificity were 70.00%, 93.70%, respectively; the AUC of combined test of 3 indexes for gastric cancer diagnosis was 0.91, 95% CI: 0.82-0.97, the sensitivity and specificity were 67.50% and 95.00%, respectively. Conclusion:The Hp infection rate of gastric cancer patients is higher than that of the health examiners, the serum FABP1 level of gastric cancer patients is higher than that of the healthy health examiners, the serum FABP1 level of Hp positive persons is higher than that of Hp negative persons, and Hp infection and FABP1 level may have a common carcinogenic mechanism in the occurrence and development of gastric cancer.

The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.
Antigens, CD19/therapeutic use* ; Antineoplastic Agents/pharmacology* ; Humans ; Immunotherapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; T-Lymphocytes

Clinical research of artificial intelligence (AI) medical devices is one of the most important links in the process of AI medical devices product development. This paper discusses the key elements of the ethical review of clinical research of artificial intelligence medical devices and the four aspects including strengthening the legislative construction and supervision, strengthening the capacity building of the ethics committee, improving the ethical review system and system construction, expanding platform construction and strengthening regional linkage that can improve the quality of ethical review in the future, protect the safety of subjects, and ensure the efficiency and quality of clinical research.

Objective:To investigate the effect of preoperative pulmonary hypertension (PH) on right ventricular function in patients with heart transplantation(HTx) one year after surgery.Methods:A total of 120 patients who underwent HTx in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2017 to January 2020 were retrospectively recruited.According to the mean pulmonary arterial pressure (mPAP) obtained by preoperative right heart catheterization, the research subjects were divided into the pulmonary hypertension group (PH group, n=81) and without pulmonary hypertension group (NPH group, n=39). Conventional echocardiographic indices of right ventricular function such as right ventricular area change (RV-FAC), tricuspid annular plane systolic excursion (TAPSE), tricuspid lateral annular systolic velocity (S′), and two-dimensional speckle tracking imaging (2D-STI) strain parameters including right ventricular global longitudinal strain (RV-GLS), right ventricular free wall longitudinal strain (RV-FWLS) were obtained to assess the right ventricular function of grafted hearts. The echocardiographic parameters one year after the operation of the two groups were analyzed to compare the differences in right ventricular function and their correlation with preoperative mPAP. Results:The grafted heart RV-GLS and RV-FWLS were significantly decreased in the PH group (all P<0.01), while RV-FAC, TAPSE, and S′ were similar between the two groups (all P>0.05). RV-FWLS and RV-GLS correlated with preoperative hemodynamic parameter mPAP( rs=-0.46, -0.54; all P<0.05)while RV-FAC, TAPSE, and S′ were not significantly correlated with mPAP (all P>0.05). Conclusions:Preoperative PH correlates with right ventricular function in HTx patients 1 year after the operation. The absolute values of RV-FWLS and RV-GLS in HTx patients with preoperative PH decrease 1 year after the operation. 2D-STI is more sensitive than conventional echocardiography to monitor the changes in right ventricular function in HTx patients after the operation.

Objective:To analyze the impact of COVID-19 epidemic on syphilis case reporting in China, and provide evidence to evaluate the epidemic situation of syphilis and strengthen the prevention and control of syphilis during COVID-19 epidemic.Methods:The data were collected from the National Notifiable Infectious Disease Reporting System of China Information System for Disease Control and Prevention, National STD Management Information System, and the "nCov2019" R package of github website. The changes of reported cases of syphilis before and during COVID-19 epidemic in China were analyzed. Joinpoint regression model was established by using the reported case number of syphilis from 2010 to 2018, the data in 2019 was used for validation, and the number of syphilis cases in 2020 and 2021 was predicted. The impact of COVID-19 epidemic on the number of syphilis cases was evaluated with calculating the percentage error (PE) between actual number and predicted number of syphilis cases reported.The correlation between reported cases of syphilis and COVID-19 was analyzed by Spearman's correlation analysis. The softwares of Joinpoint 4.9.1.0 and SPSS 18.0 were used for statistical analysis.Results:In 2020 and 2021, the reported cases of syphilis in China decreased significantly by 13.32% and 10.41%, respectively, compared with 2019 (before COVID-19 epidemic), and the reported cases of syphilis in 2021 increased by 3.36% compared with 2020. The reported cases of syphilis in 2020 and 2021 decreased by 17.95% and 20.41%, respectively, compared with predicted numbers. From January to March 2020, the reported monthly case number of syphilis was completely negatively correlated with the confirmed case number of COVID-19 ( r s=-1.00, P<0.001). In the provinces with different scales of COVID-19 epidemic, there was also a negative correlation between the monthly reported case number of syphilis and confirmed case number of COVID-19 (all P<0.05). Conclusions:In China, the change of reported cases of syphilis was closely associated with COVID-19 epidemic in 2020 and 2021. Due to the influence of COVID-19 epidemic, the number of reported cases of syphilis decreased significantly, but it should not be thought that syphilis incidence will become a decline trend in the future. It is necessary to carefully and scientifically assess the changes in syphilis epidemic.