Protein Profiles and Novel Molecular Biomarkers of Schizophrenia Based on 4D-DIA Proteomics.

Schizophrenia is a severe psychological disorder. The current diagnosis mainly relies on clinical symptoms and lacks laboratory evidence, which makes it very difficult to make an accurate diagnosis especially at an early stage. Plasma protein profiles of schizophrenia patients were obtained and compared with healthy controls using 4D-DIA proteomics technology. Furthermore, 79 DEPs were identified between schizophrenia and healthy controls. GO functional analysis indicated that DEPs were predominantly associated with responses to toxic substances and platelet aggregation, suggesting the presence of metabolic and immune dysregulation in patients with schizophrenia. KEGG pathway enrichment analysis revealed that DEPs were primarily enriched in the chemokine signaling pathway and cytokine receptor interactions. A diagnostic model was ultimately established, comprising three proteins, namely, PFN1, GAPDH and ACTBL2. This model demonstrated an AUC value of 0.972, indicating its effectiveness in accurately identifying schizophrenia. PFN1, GAPDH and ACTBL2 exhibit potential as biomarkers for the early detection of schizophrenia. The findings of our studies provide novel insights into the laboratory-based diagnosis of schizophrenia.

Early systemic anticoagulation reduces hospital readmission in acute necrotizing pancreatitis patients: A retrospective cohort study.

BACKGROUND: Early systemic anticoagulation (SAC) is a common practice in acute necrotizing pancreatitis (ANP), and its impact on in-hospital clinical outcomes had been assessed. However, whether it affects long-term outcomes is unknown. This study aimed to evaluate the effect of SAC on 90-day readmission and other long-term outcomes in ANP patients. METHODS: During January 2013 and December 2018, ANP patients admitted within 7 days from the onset of abdominal pain were screened. The primary outcome was 90-day readmission after discharge. Cox proportional-hazards regression model and mediation analysis were used to define the relationship between early SAC and 90-day readmission. RESULTS: A total of 241 ANP patients were enrolled, of whom 143 received early SAC during their hospitalization and 98 did not. Patients who received early SAC experienced a lower incidence of splanchnic venous thrombosis (SVT) [risk ratio (RR) = 0.40, 95% CI: 0.26-0.60, P < 0.01] and lower 90-day readmission with an RR of 0.61 (95% CI: 0.41-0.91, P = 0.02) than those who did not. For the quality of life, patients who received early SAC had a significantly higher score in the subscale of vitality (P = 0.03) while the other subscales were all comparable between the two groups. Multivariable Cox regression model showed that early SAC was an independent protective factor for 90-day readmission after adjusting for potential confounders with a hazard ratio of 0.57 (95% CI: 0.34-0.96, P = 0.04). Mediation analysis showed that SVT mediated 37.0% of the early SAC-90-day readmission causality. CONCLUSIONS: The application of early SAC may reduce the risk of 90-day readmission in the survivors of ANP patients, and reduced SVT incidence might be the primary contributor.

Auricular Vagal Nerve Stimulation Inhibited Central Nerve Growth Factor/Tropomyosin Receptor Kinase A/Phospholipase C-Gamma Signaling Pathway in Functional Dyspepsia Model Rats With Gastric Hypersensitivity.

OBJECTIVE: Functional dyspepsia (FD), which has a complicated pathophysiologic process, is a common functional gastrointestinal disease. Gastric hypersensitivity is the key pathophysiological factor in patients with FD with chronic visceral pain. Auricular vagal nerve stimulation (AVNS) has the therapeutic effect of reducing gastric hypersensitivity by regulating the activity of the vagus nerve. However, the potential molecular mechanism is still unclear. Therefore, we investigated the effects of AVNS on the brain-gut axis through the central nerve growth factor (NGF)/ tropomyosin receptor kinase A (TrkA)/phospholipase C-gamma (PLC-γ) signaling pathway in FD model rats with gastric hypersensitivity. MATERIALS AND METHODS: We established the FD model rats with gastric hypersensitivity by means of colon administration of trinitrobenzenesulfonic acid on ten-day-old rat pups, whereas the control rats were given normal saline. AVNS, sham AVNS, K252a (an inhibitor of TrkA, intraperitoneally), and K252a + AVNS were performed on eight-week-old model rats for five consecutive days. The therapeutic effect of AVNS on gastric hypersensitivity was determined by the measurement of abdominal withdrawal reflex response to gastric distention. NGF in gastric fundus and NGF, TrkA, PLC-γ, and transient receptor potential vanilloid 1 (TRPV1) in the nucleus tractus solitaries (NTS) were detected separately by polymerase chain reaction, Western blot, and immunofluorescence tests. RESULTS: It was found that a high level of NGF in gastric fundus and an upregulation of the NGF/TrkA/PLC-γ signaling pathway in NTS were manifested in model rats. Meanwhile, both AVNS treatment and the administration of K252a not only decreased NGF messenger ribonucleic acid (mRNA) and protein expressions in gastric fundus but also reduced the mRNA expressions of NGF, TrkA, PLC-γ, and TRPV1 and inhibited the protein levels and hyperactive phosphorylation of TrkA/PLC-γ in NTS. In addition, the expressions of NGF and TrkA proteins in NTS were decreased significantly after the immunofluorescence assay. The K252a + AVNS treatment exerted a more sensitive effect on regulating the molecular expressions of the signal pathway than did the K252a treatment. CONCLUSION: AVNS can regulate the brain-gut axis effectively through the central NGF/TrkA/PLC-γ signaling pathway in the NTS, which suggests a potential molecular mechanism of AVNS in ameliorating visceral hypersensitivity in FD model rats.

Prevalence of central obesity among the elderly with different body mass indexes in Xuhui District， Shanghai / 上海预防医学

ObjectiveTo investigate the prevalence and influencing factors of overweight， obesity and central obesity among elderly residents in Xuhui District， and to analyze the epidemiological status of central obesity in elderly people with different body mass indexes. MethodsThe third round of health status and health service utilization monitoring data in Xuhui District was used. The information collected from questionnaire survey and physical examination were analyzed. SPSS 20.0 software was used for χ2 test， trend χ2 test and multinominal logistic regression analysis. Results5 096 survey subjects were included. The prevalence of overweight， general obesity， and central obesity in the residents aged 60 and above in Xuhui District were 34.3%， 6.5%， and 29.2%， respectively. There was gender difference in the rates of overweight， obesity， and central obesity among the residents. The overweight and central obesity rates in males were higher than those in females， while the obesity rate was lower than that in females （P<0.05）. Multinominal logistic regression analysis showed that in comparison with the normal weight non-central obesity group drinking only at party （OR=1.729， 95%CI： 1.184‒2.525）， and hypertension （OR=1.637， 95%CI： 1.305‒2.053）， were highly associated with normal weight with central obesity. Aged 60‒ years （OR=1.589， 95%CI： 1.190‒2.120）， aged 70‒ years （OR=1.763， 95%CI： 1.327‒2.342）， male （OR=1.379， 95%CI： 1.134‒1.676）， hypertension （OR=2.231， 95%CI： 1.878‒2.649）， former smokers （OR=1.437， 95%CI： 1.027‒2.011）， drinking at party only （OR=1.491， 95%CI： 1.107‒2.006）， and drinking ≥3 times per week （OR=1.611， 95%CI： 1.116‒2.325）， were highly associated with overweight combined with central obesity. Aged 60‒ years （OR=3.817， 95%CI： 2.251‒6.474）， aged 70‒ years （OR=3.084， 95%CI： 1.838‒5.175）， hypertension （OR=3.683， 95%CI： 2.753‒4.929）， diabetes （OR=2.085， 95%CI： 1.511‒2.878）， former smokers （OR=1.835， 95%CI： 1.043‒3.226）， were highly associated with compound obesity. Central obesity was found in the elderly residents with different BMI categories， and the rate of central obesity increased with the increase of BMI grade. ConclusionThe prevalence of overweight， obesity and central obesity among the elderly aged 60 years and above in Xuhui District is not optimistic. Attention should be paid to the elderly under 80 years old who are with hypertension and/or diabetes， alcohol consumption， low educational level and not doing physical exercise. Especially for the central obesity population with normal BMI， measures should be taken to prevent and intervene the occurrence of obesity and related diseases.

Combination of Ranibizumab and Dexamethasone intravitreal implant for macular edema secondary to retinal vein occlusion / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To compare the differences in the efficacy and safety of combination of intravitreal dexamethasone(Ozurdex)and ranibizumab or monotherapy of ranibizumab in eyes with macular edema secondary to retinal vein occlusion(RVO-ME).METHODS: Patients diagnosed with non-ischemic RVO-ME by fluorescein fundus angiography in our hospital from June 2020 to December 2022 were selected. All patients were initially treated with intravitreal injection of ranibizumab(0.5 mg), and 42 patients(42 eyes)who had central retinal thickness(CRT)≥300 μm after 2 wk were included. They were randomly divided into combined treatment group and monotherapy group. The combined treatment group(21 eyes)received Ozurdex intravitreal injection immediately, while the monotherapy group(21 eyes)was treated with ranibizumab intravitreal injection by 3+pro re nata(PRN). The changes of best corrected visual acuity(BCVA), CRT, and intraocular pressure before and at 2 wk, 1, 2, 3, 4, 5, and 6 mo after treatment were recorded, and the ocular or systemic complications were observed.RESULTS:The BCVA and CRT of all patients at 2 wk, 1, 2, 3, 4, 5, and 6 mo after treatment were significantly better than those before treatment(all P&#x0026;#x003C;0.01). There were statistical significance in the BCVA and CRT between two groups at 2 and 3 mo after treatment(all P&#x0026;#x003C;0.05). The most significant increase of BCVA in the combined treatment group occurred at 2 mo after treatment. The mean recurrence time of macular edema in the monotherapy group was 1.45±0.53 mo, with 4.21±0.78 injection times of ranibizumab. None of the patients showed serious complications after treatment. The most common complications in the combined treatment group were subconjunctival hemorrhage and elevated intraocular pressure, which were manageable with topical ocular hypotensive agents, and no patient required antiglaucoma or cataract surgery.CONCLUSION: Compared with monotherapy of ranibizumab, intravitreal injection of dexamethasone combined with ranibizumab can significantly improve the visual acuity and effectively reduce the macular edema in the treatment of RVO-ME, with a long duration of efficacy and less intravitreal injection of drugs.

An Enhancer LncRNA Regulates NFE2 Expression and Proliferation in Human Leukemic K562 Cells / 生物化学与生物物理进展

ObjectiveTranscription factor NFE2 was observed abnormal expression in myeloproliferative neoplasm (MPN) patients. However, how NFE2 is transcriptionally regulated remains ambiguous. This study aims to explore the elements and molecular mechanisms involved in the transcriptional regulation of NFE2. MethodsActive enhancers were predicted by public NGS data and conformed experimentally via dual luciferase reporter assay. After that, PRO-seq and GRO-seq data was used to detect enhancer RNAs transcribed from these enhancers. RACE was utilized to clone the full length enhancer RNA (eRNA) transcripts, and RT-qPCR was used to measure their expression in different leukemia cell lines as well as the transcript levels during induced differentiation. Finally, to investigate the molecular function of the eRNA, overexpression and knockdown of the eRNA via lentivirus system was performed in K562 cells. ResultsWe identified three enhancers regulating NFE2 transcription, which located at -3.6k, -6.2k and +6.3k from NFE2 transcription start site (TSS) respectively. At the -3.6k enhancer, we cloned an eRNA transcript and characterized that as a lncRNA which was expressed and located in the nucleus in three types of leukemia cell lines. When this lncRNA was overexpressed, expression of NFE2 was upregulated and decreases of K562 cell proliferation and migration ability were observed. While knocking down of this lncRNA, the level of NFE2 decreases correspondingly and the proliferation ability of K562 cells increases accordingly. ConclusionWe identified an enhancer lncRNA that regulates NFE2 transcription positively and suppresses K562 cell proliferation.

Application of droplet digital PCR in etiological diagnosis of severe acute pancreatitis patients with suspected bloodstream infection / 中国感染控制杂志

Objective To explore the value of droplet digital polymerase chain reaction(ddPCR)in the etiological diagnosis of severe acute pancreatitis(SAP)patients with suspected bloodstream infection(BSI).Methods SAP patients admitted to the department of critical care medicine in a hospital July to September 2022 were enrolled.When BSI was suspected,venous blood was collected for both ddPCR detection and blood culture(BC)with antimi-crobial susceptibility testing(AST)simultaneously.The time required for two detection methods was recorded,and the detection results of ddPCR and BC were compared.The etiological diagnostic efficacy of ddPCR was calculated,and the correlation between the value of pathogen load detected by ddPCR and the level of infection parameters was explored.Results A total of 22 patients were included in the analysis,and 52 venous blood specimens were collec-ted for detection.BC revealed 17 positive specimens(32.7％)and 29 pathogenic strains,while ddPCR showed 41 positive specimens(78.8％)and 73 pathogenic strains.Detection time required for ddPCR was significantly lower than that of BC([0.16±0.03]days vs[5.92±1.20]days,P＜0.001).Within the detection range of ddPCR and taking BC results as the gold standard,the sensitivity and specificity of ddPCR were 80.0％and 28.6％,respective-ly.With the combined assessment of BSI based on non-blood specimen microbial evidence within a week,the sensi-tivity and specificity of ddPCR detection increased to 91.9％and 76.9％,respectively.ddPCR detected resistance genes of blaKPC,blaNDM/IMP,VanA/VanM,and mecA from 19,9,6,and 5 specimens,respectively.Correlation analysis showed a positive correlation between pathogen load and levels of C-reactive protein as well as procalcitonin(r=0.347,0.414,P＜0.05).Conclusion As a supplementary detection method for BC in BSI diagnosis,ddPCR has the advantages of higher sensitivity and shorter detection time,and is worthy of further exploration in clinical application.

The value of CT three-dimensional reconstruction combined with serum carbohydrate antigen 19-9 and carcinoembryonic antigen detection in the diagnosis and resectability evaluation of hilar cholangiocarcinoma / 中国基层医药

Objective:To investigate the value of three-dimensional reconstruction combined with serum carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) detection in the diagnosis and resectability evaluation of hilar cholangiocarcinoma (HCCA) before resectable lymph node metastasis.Methods:A total of 65 patients with suspected HCCA who were treated at Yiwu Central Hospital from June 2019 to June 2022 were included in the observation group. Thirty healthy people who concurrently underwent physical examinations in the same hospital were included in the control group. All participants underwent a CT three-dimensional reconstruction examination. Simultaneously, the automatic electrochemiluminescence immunoassay analyzer was used to measure serum levels of CA19-9 and CEA. The outcomes of percutaneous transhepatic cholangiography were used as the "gold standard". The consistency between CT three-dimensional reconstruction, CA19-9 detection, and CEA detection, either individually or combined, and the "gold standard" in the diagnosis of HCCA was evaluated.Results:Serum levels of CA19-9 and CEA in the observation group were (62.71 ± 10.63) U/mL and (62.71 ± 10.63) ng/mL, respectively, which were significantly higher than those in the control group [(12.37 ± 7.39) U/mL, (1.31 ± 0.97) ng/mL, t = 23.43, 11.59, both P < 0.05). The levels of CA19-9 [(71.69 ± 12.37) U/mL] and CEA [(8.89 ± 3.51) ng/mL] in patients with HCCA who had lymph node metastasis were significantly higher than those in patients with HCCA who had no lymph node metastasis [CA19-9 (56.78 ± 10.16) U/mL, CEA (6.45 ± 2.11) ng/mL, t = 4.14, 2.76, both P < 0.05].Compared with histopathological examination, the accuracy of CT three-dimensional reconstruction in typing was 85.00%. According to the "gold standard" diagnosis, CT three-dimensional reconstruction, CA19-9 detection, and CEA detection, alone and their combination, successfully detected HCCA in 22 cases (55.00%), 26 cases (65.00%), 31 cases (77.50%), and 38 cases (95.00%), respectively. The detection rate of HCCA was the highest when CT three-dimensional reconstruction, CA19-9 detection, and CEA detection were combined, and the difference was statistically significant ( χ2 = 18.15, P < 0.05). Compared with CT three-dimensional reconstruction (AUC: 0.808), CA19-9 detection (AUC: 0.721), and CEA detection (AUC: 0.703) individually, their combination (AUC: 0.913) had the highest value in the diagnosis of HCCA (all P < 0.05). Conclusion:CT three-dimensional reconstruction, CA19-9 detection, and CEA detection have a certain diagnostic value for HCCA, but the combination of CT three-dimensional reconstruction with the detection of serum levels of CA19-9 and CEA has a higher diagnostic value for HCCA, providing an effective reference for the preoperative evaluation of the resectability of HCCA in the clinic.

Retrospective analysis of serum protein electrophoresis screening for monoclonal gammopathy in 533 989 cases / 中华检验医学杂志

Objective:To compare the distribution differences of serum protein electrophoresis (SPE) among different gender and age individuals, and to explore the clinical application of SPE screening monoclonal gammopathy.Methods:A retrospective analysis was conducted based on the SPE results obtained from 533 989 cases enrolled from January 2018 to December 2019 at Zhongshan Hospital Affiliated to Fudan University. Among these patients, 435 479 inpatients were from departments of hematology, nephrology, spinal surgery, endocrinology, and rheumatology and immunology; and 98 510 were apparently healthy individuals. The distributions of albumin, α1 globulin, α2 globulin, β1 globulin, β2 globulin and γ globulin in different gender and age groups (≤20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, ≥91 years old) were compared. A total of 10 014 cases were selected by immunofixation electrophoresis (IFE). The positive detection rates of different SPE bands and IFE bands were analyzed. The sensitivity and specificity of SPE methods were determined according to IFE results as the gold standard.Results:No significant difference was examined in the proportion of SPE bands between different genders ( P>0.05). There were statistically significant differences in the proportion of albumin bands between apparently healthy individuals and hospitalized patients at different ages (apparently healthy individuals: F=5.12, P<0.05, inpatients: F=4.18, P<0.05), and all of them decreased with the increase of age. The proportion of γ globulin bands increased with age (apparently healthy individuals: F=1.34, P<0.05; inpatients: F=1.24, P<0.05). The sensitivity of SPE was 69% (2 098/3 051), and the specificity was 97% (6 721/6 963). Compared with IFE method, the positive detection rate of monoclonal gammopathy was significantly different (χ2=5 049.94, P<0.05). The positive rate of monoclonal gammopathy in γ globulin region (21.11%, 2 114/10 014) was higher than that in β globulin region (3.28%, 328/10 014) (χ2=90.74, P<0.05) and β-γ globulin region (1.63%, 163/10 014) (χ2=44.34, P<0.05). IgG and IgM bands are common in γ globulin region. Among them, IgG-κ type accounted for 94.1% (995/1 058), IgG-λ type accounted for 94.8% (690/728), IgM-κ type accounted for 89.2% (222/249), IgM-λ accounted for 83.8% (62/74). IgA bands are common in β region, of which IgA-κ accounted for 49.8% (103/207) and IgA-λ accounted for 51.6% (149/289). The positive rate of monoclonal gammopathy of IgG-κ type was the highest (10.57%, 1 058/10 014), and the positive rate of monoclonal gammopathy of IgM-λ type was the lowest (0.74%, 74/10 014). Conclusions:With increasing age, the proportion of albumin band in SPE decreased and the proportion of γ globulin band increased. IgG and IgM type monoclonal gammopathy is mostly found in the gamma region, with a higher detection rate in IgG type. IgA type monoclonal gammopathy is mostly found in the β region, with a lower detection rate.

Characteristics and distribution of monoclonal gammopathy in clinical patients: a single-center study / 中华检验医学杂志

Objective:To investigate the characteristics and distribution of monoclonal gammopathy in clinical patients.Methods:A total of 936 171 patients (508 449 males and 427 722 females) who received capillary zone electrophoresis in Zhongshan Hospital Affiliated to Fudan University from January 2012 to December 2021 were selected, from which 14 945 patients with abnormal bands were screened as the study subjects, including 10 173 males and 4 772 females and the age 21-102 (65±13) years old. According to the age, patients were divided into 8 groups: 21-30 years old (168 cases), 31-40 years old (405 cases), 41-50 years old (1 326 cases), 51-60 years old (3 068 cases), 61-70 years old (4 985 cases), 71-80 years old (3 288 cases), 81-90 years old (1 519 cases), and≥91 years old (186 cases). The diagnostic results of the 14 945 patients with abnormal bands were collected and were divided into tumor group (5 196 cases) and non-tumor disease group (9 749 cases) according to the presence of tumor. The distribution of abnormal bands in different gender, age, and disease groups were retrospectively analyzed. Among the 14 945 patients, 4 988 cases underwent immunofixation electrophoresis, excluding 336 negative cases and 412 cases of double clonal bands reaction, and 4 240 patients with monoclonal immunoglobulin (M protein) reaction were selected as the study subjects, including 2 794 males and 1 446 females aged 21-102 (67±12) years old. They were divided into 8 groups according to the age: 21-30 years old (18 cases), 31-40 years old (91 cases), 41-50 years old (364 cases), 51-60 years old (862 cases), 61-70 years old (1 455 cases), 71-80 years old (904 cases), 81-90 years old (486 cases), and≥91 years old (60 cases). The diagnostic results and immunoglobin subtypes (IgA-κ, IgA-λ, IgG-κ, IgG-λ, IgM-κ, IgM-λ, κ, λ) of patients were collected, and the distribution of monoclonal gammopathy in different gender, age and disease groups were retrospectively analyzed.Results:Among 936 171 patients, 14 945 cases showed abnormal bands in electropherograms with a detection rate of 1.60%; the detection rates of abnormal bands in males and females were 2.00% (10 173/508 449) and 1.12% (4 772/427 722), respectively, with a statistically significant difference ( P<0.01). There was a significant difference in the detection rate of abnormal bands among different age groups ( P<0.01); among them, the highest detection rate of abnormal band in group of ≥91 years old was 5.98%, and the ratio of male to female was 1.67∶1. Among the 14 945 cases of abnormal bands, patients aged 51-60, 61-70 and 71-80 accounted for 20.53% (3 068 cases), 33.36% (4 985 cases) and 22.00% (3 288 cases), respectively, and the differences among the age groups were statistically significant (χ 2=115.82, P<0.01). In the tumor group, the top 3 tumors with abnormal bands were plasmacytoma with 1 123 cases, lymphoma with 289 cases, and leukemia with 49 cases. The detection rate of abnormal bands in electropherograms of plasmacytoma was 89.92% (1 123/1 249), which was higher than that in lymphoma and leukemia [6.73% (289/4 296) and 6.40% (49/766), respectively, P<0.01]. Among 4 240 patients with positive M protein, the proportion of 51-60, 61-70 and 71-80 years old patients were 20.33% (862/4 240), 34.32% (1 455/4 240) and 21.32% (904/4 240), respectively, and the differences among age groups were statistically significant ( P<0.01). The results of M protein types showed that the proportion of IgG-κ type was the highest in both genders, with 32.28% (902/2 794) in males and 34.30% (496/1 446) in females. In the 21-30, 31-40, and 41-50 age groups, the proportion of IgG-λ was the highest, which were 38.89% (7/18), 36.26% (33/91) and 34.07% (124/364) in these groups respectively. However, the proportions of IgG-κ were the highest in either of the 51-60, 61-70, 71-80, 81-90 and ≥91 years old groups, which were 33.87% (292/862), 34.16% (497/1 455), 31.53% (285/904), 34.57% (168/486), 28.33% (17/60), respectively, and the differences among all age groups and gender groups had statistical significance ( P<0.01). Among patients with positive M protein in the tumor group, plasmacytoma accounted for 14.22% (603/4 240), followed by lymphoma 6.30% (267/4 240); among non-tumor diseases, M proteinemia accounted for the highest proportion (7.24%, 307/4 240), followed by pulmonary infection (5.47%, 232/4 240). Conclusions:The detection rate of abnormal bands in capillary zone electrophoresis may increase with age, and is higher in males than in females in the same age group; different malignant tumor diseases can also show abnormal bands in capillary zone electrophoresis, but they are still mainly hematological tumors. Among the positive results of M protein, 61-70 years old group accounts for the highest proportion; the most common type of monoclonal gammopathy is IgG type; in the age group of 21-50 years, the proportion of IgG-λ type is the highest; in the group of >50 years old, the proportion of IgG-κ type is the highest; in the diagnosis of positive monoclonal gammopathy, the top 3 diseases are all hematological diseases, including plasmacytoma, monoclonal gammopathies and lymphoma.

Risk factor analysis for adverse prognosis of the fetal ventricular septal defect (VSD).

BACKGROUND: Ventricular septal defect (VSD) is the most common subtype of congenital heart disease. In the present study, we aimed to determine whether chromosome aberration was associated with the occurrence of VSD and evaluate the association of VSD size, location and chromosome aberration with adverse outcomes in the Chinese fetuses. METHODS: Fetuses with VSD and comprehensive follow-up data were included and evaluated retrospectively. Medical records were used to collect epidemiological data and foetal outcomes. For VSD fetuses, conventional karyotype and microarray analysis were conducted. After adjusting confounding factors by using multivariable logistic regression analyses, the association between chromosome variations and VSD occurrence was explored. The association between defect size, location and chromosome aberrations and adverse foetal outcomes was also investigated. RESULTS: Chromosome aberration was the risk factor for VSD occurrence, raising 6.5-fold chance of developing VSD. Chromosome aberration, peri-membranous site and large defect size of VSD were significant risk factors of adverse fetal outcome. Chromosome aberrations, including pathogenic copy number variations (CNVs) and variations of uncertain significance (VUS), were both risk factors, increasing the risk of the adverse fetal outcome by 55.9 times and 6.7 times, respectively. The peri-membranous site would increase 5.3-fold risk and defects larger than 5 mm would increase the 7.1-fold risk for poor fetal outcome. CONCLUSIONS: The current investigation revealed that chromosomal abnormalities, large defects, and the peri-membranous site were all risk factors for poor fetal outcomes. Our study also indicated that chromosome aberration was one of risk factors for the VSD occurrence.

Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis.

AIMS: Diabetic cardiomyopathy (DC) is one of serious complications of diabetic patients. This study investigated the biological function of activating transcription factor 4 (ATF4) in DC. METHODS AND RESULTS: Streptozotocin-treated mice and high glucose (HG)-exposed HL-1 cells were used as the in vivo and in vitro models of DC. Myocardial infarction (MI) was induced by left coronary artery ligation in mice. Cardiac functional parameters were detected by echocardiography. Target molecule expression was determined by real time quantitative PCR and western blotting. Cardiac fibrosis was observed by haematoxylin and eosin and Masson's staining. Cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelling. Activities of superoxide dismutase, glutathione peroxidase, and levels of malonic dialdehyde and reactive oxygen species were used to assess oxidative stress damage. Molecular mechanisms were evaluated by chromatin immunoprecipitation, dual luciferase assay, and co-immunoprecipitation. ATF4 was up-regulated in the DC and MI mice (P < 0.01). Down-regulation of ATF4 improved cardiac function as evidenced by changes in cardiac functional parameters (P < 0.01), inhibited myocardial collagen I (P < 0.001) and collagen III (P < 0.001) expression, apoptosis (P < 0.001), and oxidative stress (P < 0.001) in diabetic mice. Collagen I (P < 0.01) and collagen III (P < 0.01) expression was increased in MI mice, which was reversed by ATF4 silencing (P < 0.05). ATF4 depletion enhanced viability (P < 0.01), repressed apoptosis (P < 0.001), oxidative damage (P < 0.001), and collagen I (P < 0.001), and collagen III (P < 0.001) expression of HG-stimulated HL-1 cells. ATF4 transcriptionally activated Smad ubiquitin regulatory factor 2 (Smurf2, P < 0.001) to promote ubiquitination and degradation of homeodomain interacting protein kinase-2 (P < 0.001) and subsequently caused inactivation of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 pathway (P < 0.001). The inhibitory effects of ATF4 silencing on HG-induced apoptosis (P < 0.01), oxidative injury (P < 0.01), collagen I (P < 0.001), and collagen III (P < 0.001) expression were reversed by Smurf2 overexpression. CONCLUSIONS: ATF4 facilitates diabetic cardiac fibrosis and oxidative stress by promoting Smurf2-mediated ubiquitination and degradation of homeodomain interacting protein kinase-2 and then inactivation of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 pathway, suggesting ATF4 as a treatment target for DC.

[Clinical Outcome and Risk Factors of Treatment Failure of Peritoneal Dialysis Associated Peritonitis Caused by Klebsiella Pneumoniae:A Multicenter Study].

Objective To investigate the treatment outcomes,prognosis,and risk factors of treatment failure of peritoneal dialysis associated peritonitis (PDAP) caused by Klebsiella pneumoniae,and thus provide clinical evidence for the prevention and treatment of this disease. Methods The clinical data of PDAP patients at four peritoneal dialysis centers from January 1,2014 to December 31,2019 were collected retrospectively.The treatment outcomes and prognosis were compared between the patients with PDAP caused by Klebsiella.pneumoniae and that caused by Escherichia coli.Kaplan-Meier method was employed to establish the survival curve of technical failure,and multivariate Logistic regression to analyze the risk factors of the treatment failure of PADP caused by Klebsiella pneumoniae. Results In the 4 peritoneal dialysis centers,1034 cases of PDAP occurred in 586 patients from 2014 to 2019,including 21 cases caused by Klebsiella pneumoniae and 98 cases caused by Escherichia coli.The incidence of Klebsiella pneumoniae caused PDAP was 0.0048 times per patient per year on average,ranging from 0.0024 to 0.0124 times per patient per year during 2014-2019.According to the Kaplan-Meier survival curve,the technical failure rate of Klebsiella pneumoniae caused PDAP was higher than that of Escherichia coli caused PDAP (P=0.022).The multivariate Logistic regression model showed that long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP (OR=1.082,95%CI=1.011-1.158,P=0.023).Klebsiella pneumoniae was highly sensitive to amikacin,meropenem,imipenem,piperacillin,and cefotetan,and it was highly resistant to ampicillin (81.82%),cefazolin (53.33%),tetracycline (50.00%),cefotaxime (43.75%),and chloramphenicol (42.86%). Conclusion The PDAP caused by Klebsiella pneumoniae had worse prognosis than that caused by Escherichia coli,and long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP.

Efficacy of traditional Chinese medicine combined with 131I in the treatment of Graves hyperthyroidism / 中华核医学与分子影像杂志

Objective:To explore the value of traditional Chinese medicine combined with 131I in the treatment of Graves hyperthyroidism. Methods:From March 2020 to July 2021, 90 patients (39 males, 51 females, age (33.2±7.0) years) with Graves hyperthyroidism who were diagnosed and treated in Changshu No.2 People′s Hospital were retrospectively analyzed. Patients were randomly divided into 3 groups ( n=30 in each group), including group A who received treatment of antithyroid drugs (ATD), group B who received treatment of traditional Chinese medicine, and group C who received treatment of 131I combined with traditional Chinese medicine. Thyroid function indicators and inflammatory indicators before treatment and 1, 3, and 6 months after treatment were determined, including free triiodothyronine (FT 3), free thyroxine (FT 4), thyroid stimulating hormone (TSH) and TSH receptor antibody (TRAb), and C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). One-way analysis of variance and χ2 test were used to analyze data. Results:The levels of FT 3, FT 4, TSH, TRAb, CRP, IL-6 and TNF-α in group A, B and C before treatment and 1, 3, 6 months after treatment were significantly different ( F values: 193.27-906.11, all P<0.05). The total effective rate in group C (100.0%, 30/30) was significantly higher than that in group A (86.7%, 26/30) or group B (83.3%, 25/30; χ2 values: 8.24, 9.83, P values: 0.006, 0.037), while there was no significant difference between group A and group B ( χ2=3.02, P=0.124). The incidence of adverse reactions in group B (46.7%, 14/30) was significantly higher than that in group A (30.0%, 9/30; χ2=6.59, P=0.042). And the incidence of adverse reaction in group C (13.3%, 4/30) was significantly lower than that in group A or group B ( χ2 values: 12.05, 7.20, P values: 0.004, 0.038). Conclusion:The curative effect of 131I combined with traditional Chinese medicine is effective and reliable, suggesting that clinical researches should be carried out together and perfected.

Meta-analysis of efficacy and safety of cabozantinib in the treatment of advanced thyroid cancer / 中国药房

OBJECTIVE To review the efficacy and safety of cabozantinib in the treatment of advanced thyroid cancer. METHODS Retrieved from PubMed， the Cochrane Library， Embase， ClinicalTrials.gov， Wanfang data， VIP， CNKI and China Clinical Trials Registry， randomized controlled trials （RCTs） about cabozantinib （trial group） versus placebo （control group） were collected from the inception to Nov. 2022. After literature screening， data extraction and quality evaluation， meta-analysis was performed by using RevMan 5.4 software. RESULTS A total of 4 RCTs were included involving 588 patients. The results of the meta-analysis showed that the progression free survival （PFS） [HR＝0.24， 95%CI （0.19，0.31）， P＜0.000 01]， objective response rate （ORR） [RR＝31.46， 95%CI （6.32，156.75）， P＜0.000 1]， the incidence of grade 3-4 adverse event （AE） [RR＝2.15，95%CI （1.76，2.61），P＜0.000 01]， severe adverse event [RR＝1.78，95%CI （1.11，2.83），P＝0.02]， diarrhea [RR＝3.29，95%CI（1.62， 6.66），P＝0.001]， palmar-plantar erythrodysesthesia syndrome [RR＝28.19，95%CI （12.25，64.88），P＜0.000 01]， and hypertension [RR＝6.50，95%CI （3.90，10.83），P＜0.000 01] in trial group were significantly higher than control group； there was no statistical significance in overall survival （OS） [HR＝0.83，95%CI （0.67，1.02）， P＝0.07] or the incidence of fatigue [RR＝1.25，95%CI （0.78，1.98），P＝0.35] between the two groups. Subgroup analysis showed that PFS and ORR in patients with differentiated thyroid carcinoma （DTC） and medullary thyroid carcinoma （MTC） in the trial group were significantly higher than control group （P＜ 0.05）. There was no significant difference in OS of DTC and MTC patients in the trial group compared with the control group （P＞ 0.05）. CONCLUSIONS Cabozantinib can prolong PFS and increase ORR in patients with advanced thyroid cancer， but the incidence of AE is high.

Pathogenic characterization of Klebsiella pneumoniae resistant to carbapenems and polymyxin / 中华预防医学杂志

Objective: Analysis and investigation of pathogenic characteristics of polymyxin-and carbapenem-resistant Klebsiella pneumoniae (PR-CRKP). Methods: A total of 23 PR-CRKP strains isolated from clinical specimens from the General Hospital of Southern Theater Command from March 2019 to July 2021 were retrospectively collected, Whole-genome sequencing was performed on 23 PR-CRKP strains, resistance genes were identified by comparison of the CARD and the ResFinder database, high-resolution typing of PR-CRKP strains was analyzed by core genomic multilocus sequencing (cgMLST) and single nucleotide polymorphism (SNP); polymyxin resistance genes were determined by PCR and sequencing. Results: All PR-CRKP strains were KPC-2 producing ST11 types. cgMLST results showed that the evolutionary distance between the PR-CRKP strains and Klebsiella pneumoniae in mainland China was 66.44 on average, which is more closely related than foreign strains; the 23 PR-CRKP strains were divided into 3 main subclusters based on SNP phylogenetic trees, with some aggregation among Clade 2-1 in the isolation department and date. The two-component negative regulatory gene mgrB has seven mutation types including point mutations, different insertion fragments and different insertion positions. Conclusion: The close affinity of PR-CRKP strains indicate the possibility of nosocomial clonal transmission and the need to strengthen surveillance of PR-CRKP strains to prevent epidemic transmission of PR-CRKP.

Exploration and practice of hierarchical training model for improving professional ability of primary pediatricians / 中华医学教育探索杂志

At present, the routine specialized training for primary pediatricians (focusing on theoretical learning of public subjects) cannot meet the needs of primary pediatricians. In order to promote the development of children's medical care at the grassroots level and improve the quality, medical and clinical research abilities of regional pediatric medical personnel, the Children's Hospital of Chongqing Medical University has designed and built a "hierarchical training model for improving the professional ability of pediatricians" from the aspects of training objectives, training contents, training methods, construction and evaluation of training programs, and quality control. In addition, the 8-month "Pediatric Professional Basic Training" and the 9-month "Pediatric Professional Ability Improvement Training" were respectively carried out in Xianyang Children's Hospital. In the "Professional Basic Training", 88 trainees were comprehensively evaluated after training, 53 of whom were qualified or above. In the "Ability Improvement Training", 26 of the 29 students actually participated in the evaluation and reached the qualified level or above. Learners provided feedbacks that they have effectively improved their own knowledge structure, expanded their clinical diagnosis and treatment thinking and clinical research ideas, and provided some guidance for clinical work.

Pediatric clinical teaching reform based on early clinical teaching concept: taking the course of "New Medical Professional Experience Social Practice" as an example / 中华医学教育探索杂志

In order to implement the teaching philosophy of "early clinical, multiple clinical, and repeated clinical", this study takes the "New Medical Professional Experience Social Practice" as a research course, analyzes the reform of pediatric clinical teaching, and evaluates the teaching effectiveness through classroom interviews and post-class questionnaire surveys. The results showed that through the combination of online and offline learning and multiple evaluation models, it was found that students with more hands-on teaching content in offline teaching were more interested and evaluated. Eight-year students had higher participation in offline teaching than five-year students, and 8-year students also rated online teaching higher than five-year students. A total of 151 [84.36%(151/179)] students have learned about the clinical work of pediatricians through this course. The reform of pediatric clinical teaching based on the concept of early clinical teaching can achieve the teaching goal of early clinical practice and early contact for medical students.

P450-mediated dehydrotyrosine formation during WS9326 biosynthesis proceeds via dehydrogenation of a specific acylated dipeptide substrate

WS9326A is a peptide antibiotic containing a highly unusual N-methyl-E-2-3-dehydrotyrosine (NMet-Dht) residue that is incorporated during peptide assembly on a non-ribosomal peptide synthetase (NRPS). The cytochrome P450 encoded by sas16 (P450Sas) has been shown to be essential for the formation of the alkene moiety in NMet-Dht, but the timing and mechanism of the P450Sas-mediated α,β-dehydrogenation of Dht remained unclear. Here, we show that the substrate of P450Sas is the NRPS-associated peptidyl carrier protein (PCP)-bound dipeptide intermediate (Z)-2-pent-1'-enyl-cinnamoyl-Thr-N-Me-Tyr. We demonstrate that P450Sas-mediated incorporation of the double bond follows N-methylation of the Tyr by the N-methyl transferase domain found within the NRPS, and further that P450Sas appears to be specific for substrates containing the (Z)-2-pent-1'-enyl-cinnamoyl group. A crystal structure of P450Sas reveals differences between P450Sas and other P450s involved in the modification of NRPS-associated substrates, including the substitution of the canonical active site alcohol residue with a phenylalanine (F250), which in turn is critical to P450Sas activity and WS9326A biosynthesis. Together, our results suggest that P450Sas catalyses the direct dehydrogenation of the NRPS-bound dipeptide substrate, thus expanding the repertoire of P450 enzymes that can be used to produce biologically active peptides.

Glucose and serum deprivation under hypoxia treatment inducing oxidative stress and apoptosis in rat bone marrow mesenchymal stem cells through inhibition of Nrf2 signaling pathway / 解剖学报

Objective To investigate the effects of glucose and serum deprivation under hypoxia(GSDH)treatment on oxidative stress and apoptosis in rat bone marrow mesenchymal stem cells (BMSCs), so to provide an experimental support for improving the therapeutic efficacy of BMSCs. Methods The cell injury model was established by hypoxia (1% O