Monogenic diabetes is a type of diabetes characterized by single gene mutation. Due to its heterogeneity and overlap with type 1 and type 2 diabetes, it is difficult to be accurately diagnosed clinically. Correct diagnosis is essential for certain types of monogenic diabetes, however, there is still a lack of simple clinical criteria for selecting patients for genetic testing or even interpreting the results of genetic testing. The classification of monogenic diabetes (including maturity onset diabetes of the young, neonatal diabetes mellitus, mitochondrial diabetes mellitus and syndromic diabetes mellitus) and the clinical diagnosis and corresponding treatment methods of monogenic diabetes based on the new generation sequencing and clinical characteristics have been reviewed in present paper for providing theoretical basis for clinical diagnosis of physicians as well as help to individualize the treatment of patients with monogenic diabetes.

Objective To analyze the clinical features and pathological diagnosis of 3 cases of pineal region papillary tumor(PTPR), and review the related literature. Methods Three cases of PTPR patients were collected in the First Affiliated Hospital of Xinjiang Medical University from January 2012 to March 2021, and studied by HE staining and immunohistochemistry to observe its histological morphology and immunohistochemical phenotype. Combined with reviewing the relevant literature to understand the molecular characteristics of the disease and find potential therapeutic targets. Results The first symptom in the three PTPR patients were headache and intracranial hypertension. Histological examination showed that PTPR tumor cells formed a single-layer or stratified papillary structure surrounding the vascular. The distribution of the tumor cells had polarity, with more abundant cells near the vascular. Immunohistochemistry reveals strong reactivity for AE1/AE3, CAM5.2, cytokeratin 18 (CK18) and pair box 8(PAX8). The staining for vimentin (VIM) showed positive which is especially dense in cells near the vessel. The staining for nervous marker S-100 displayed diffuse positive in two cases while focal positive in the other one, while both glial fibrillary acidic protein(GFAP) and oligodendrocyte transcription-2 (OLIG-2) were negative in all the three cases. PTEN expression deficiency and p-Akt positive expression in the three cases. Literature reviews obtained 9 reports relevant to the molecular mechanism of PTPR, with 7 of them using genomic hybridization to detect chromosomal alterations in 29(29/62) patients, among which chromosome 10 loss and chromosome 8 gain were observed in 96.6%(28/29) cases and 57.1%(16/28) cases, respectively. Conclusions Exhibiting specific papillary structures, PTPR displayed specific immunohistochemical characteristics, which is helpful for diagnosis. PTEN protein deletion and positive expression of p-Akt and PAX8 suggested that PAX8, PTEN and PI3K/Akt/mTOR signal pathways played a potential role in the occurrence and development of PTPR and may become potential therapy targets.

Objective To evaluate the value of GeneXpert MTB/RIF Ultra (Xpert Ultra) in the early and rapid diagnosis of sputum and bronchoalveolar lavage fluid (BALF) samples in patients with smeared negative tuberculosis. Methods A total of 93 patients with sputum smear-negative suspected pulmonary tuberculosis who were admitted to Shandong Public Health Clinical Center from May 2020 to December 2021 were included in this study. Among them, 57 patients were clinically diagnosed as sputum smear-negative pulmonary tuberculosis and 36 patients were non-pulmonary tuberculosis. Sputum and BALF samples were collected from all patients, and Xpert Ultra, GeneXpert MTB/RIF (Xpert), BACTEC MGIT 960 culture (MGIT 960 culture) were performed. To evaluate the sensitivity, specificity and coincidence rate of various detection methods and their combined detection of sputum and bronchoalveolar lavage fluid samples in the diagnosis of smeared negative pulmonary tuberculosis. Results Taking clinical diagnosis as the reference standard, the sensitivity of sputum samples detected by Xpert Ultra for the diagnosis of smeared negative pulmonary tuberculosis was significantly higher than that of Xpert [56.14% (32/57) vs. 36.84% (21/57), P=0.039] and MGIT 960 culture [56.14% (32/57) vs. 33.33% (19/57), P=0.014]. The sensitivity of BALF samples detected by Xpert Ultra for the diagnosis of smeared negative pulmonary tuberculosis was significantly higher than that of Xpert [75.44% (43/57) vs. 56.14% (32/57),P=0.030] and MGIT 960 culture [75.44% (43/57) vs. 38.60% (22/57), P<0.01]. Three different methods of testing sputum samples, the area under the receiver operating characteristic curve (AUC) was the combination of the three elements (0.807)>Xpert Ultra+Xpert (0.798)>Xpert Ultra+MGIT 960 culture (0.789)>Xpert Ultra method (0.781)>Xpert (0.684)>MGIT 960 culture (0.667);Samples of BALF were examined, the AUC was the combination of the three elements (0.895)=Xpert Ultra+Xpert (0.895)>Xpert Ultra+MGIT 960 culture (0.877)=Xpert Ultra method (0.877)>Xpert (0.781)>culture method (0.693). Rifampicin resistance was not detected in the enrolled samples by the three detection methods. Conclusions Xpert Ultra has high clinical application value in the early and rapid diagnosis of smeared negative pulmonary tuberculosis, and the sensitivity of Xpert Ultra in the detection of BALF is higher than that of sputum sample, so the BALF sample is recommended as prior selection.

Currently, the bacillus Calmette-Guerin (BCG) is the only licensed vaccine against tuberculosis, but its protective effect is highly controversial. Therefore, it is particularly important to develop a new and effective tuberculosis vaccine. Meanwhile, with the in-depth understanding of the pathogenic mechanism of Mycobacterium tuberculosis and the continuous update of vaccine research and development technology, there will be a major breakthrough in tuberculosis vaccine. Considering the safety, economic cost and protective effect, multi-stage antigen subunit vaccine or multi-epitope vaccine has good application prospects. This paper systematically reviews the types and characteristics of current tuberculosis vaccines, and discuss the problems and challenges in four aspects: antigen selection, animal model selection, the evaluation indicators of vaccine efficacy and the population specificity in the research of new tuberculosis vaccines, which lays a theoretical foundation for the research of new tuberculosis vaccine.

Latent Mycobacterium tuberculosis infection (LTBI) is a reservoir for incident tuberculosis disease, and is a constant source of new patients. 5% to 10% of the LTBI patients will develop active tuberculosis in their lifetime, and the incidence rate is higher in high-risk population. The United Nations High-Level Meeting on Tuberculosis called for a focus on LTBI management to control in 2018, further could reduce the incidence of TB due to reactivation in patients with LTBI. This paper discusses the disease burden, epidemic status, patient management, and prevention strategies, providing reference for formulating LTBI prevention strategies in China.

Objective To investigate the effect and mechanism of berberine (BBR) on the activity and proliferation of hepatoma cells. Methods Normal human hepatocytes (MIHA) and human hepatoma cells (Hep3B, HepG2) were respectively divided into control group (high glucose) and different concentration (0, 12.5, 25, 50 μmol/L) of BBR groups (glucose-free). CCK-8 and clone formation experiment were used to explore the effect of BBR on the viability and clone formation. SYTOX Green nucleic acid stain was used to determine the cell death and flow cytometry to detect the changes in reactive oxygen species (ROS) levels in hepatoma cells. The changes of Nrf2 and its related proteins after BBR incubation were measured by Western blotting. We incubated the proteasome inhibitor MG132 and the protein synthesis inhibitor cycloheximide (CHX) with BBR to study its effect on the Nrf2 protein. We quantified the expressions of Nrf2 and HO-1 in Hep3B cells cultured with BBR using Quantitative real-time PCR (qRT-PCR). We established a tumor model by subcutaneous injection of Hep3B cells into nude mice. To observe the effect of BBR on tumor growth, we injected tumor-bearing nude mice in the BBR groups and the control group with BBR or the same amount of normal saline, respectively. We evaluated the effect of BBR on Nrf2 and its related proteins in vivo with HE and immunohistochemical staining. Results The viability of Hep3B and HepG2 cells decreased after BBR incubation in a glucose-free environment (P<0.05). No appreciable changes were observed in MIHA cell viability under the same experiment condition. BBR could inhibit clone formation and promote the death of hepatoma cells in a concentration-dependent manner (P<0.05). We observed an increase in the ROS and a decrease in Nrf2, HO-1, and c-Myc with no significant change in Keap1 in hepatoma cells after BBR treatment. While total GSK3β remained unchanged, the treatment-induced decrease in P-GSK3β (Ser9) decreased but increase in P-GSK3β (Tyr216). MG132 co-treatment reversed the BBR-induced reduction of Nrf2 protein while CHX enhanced the BBR-induced reduction of Nrf2 protein in hepatoma cells. BBR treatment-induced increase in Nrf2 mRNA and a decrease in HO-1 mRNA (P<0.05). BBR could significantly inhibit the growth of Hep3B cells in vivo in nude mice. BBR treatment increased tumor tissue necrosis and suppressed the expression of Nrf2 and c-Myc but did not affect the Keap1 level. Conclusions BBR could inhibit the activity and proliferation of hepatoma cells and promote cell death. In vivo experiments showed that BBR injection could significantly inhibit the growth of tumor cells and lead to increased necrosis of tumor cells. We verified that BBR may lead to the death of hepatoma cells through the non-Keap1-dependent Nrf2/GSK3β pathway. We infer that the degradation of Nrf2 protein through the ubiquitin-proteasome system by the non-Keap1-dependent Nrf2/GSK3β pathway, thereby reducing the anti-oxidative stress ability of tumor cells and leading to the death of hepatoma cells ultimately.

Objective To explore the relationship between perioperative hemoglobin (HGB) concentration and acute kidney injury (AKI) after pulmonary lobectomy. Methods Patients, who received selective pulmonary lobectomy under general anesthesia in Peking University First Hospital from July 2017 to December 2019, were recruited and divided into low HGB group (HGB<120.0 g/L; n=230) and normal group (HGB≥120.0 g/L, n=1522) according to the HGB concentration before surgery. And the primary endpoint was the incidence of AKI after surgery. Multivariate logistic regression model was used to analyze the influence of preoperative HGB, minimum HGB concentration during surgery and the decrease of HGB concentration after surgery on postoperative AKI. Results A total of 1752 patients were involved in the study, and the overall incidence of postoperative AKI was 2.3%. The incidence of AKI was significantly higher in low HGB group than in normal group [5.7% (13/230) vs. 1.8% (28/1522), RR=3.197, 95%CI 1.631-6.266, P=0.001]. Multivariate logistic regression analysis showed that the risk of postoperative AKI increased to 3.590 (95%CI 1.765-7.303, P<0.001) times if preoperative HGB concentration being lower than 120.0 g/L, and that the risk of postoperative AKI increased to 2.751 (95%CI 1.633-4.635, P<0.001) times for every 15.0 g/L reduction of preoperative HGB. Moreover, the independent risk factors involved preoperative eGFR <60 ml/ (min.1.73 m²), intraoperative infusion rate <5 ml/ (kg·h) and intraoperative urine output <0.8 ml/ (kg·h) (P<0.05). In addition, multivariate logistic regression models also showed that minimum HGB concentration during surgery (OR=0.933, 95%CI 0.780-1.114, P=0.442) and the decrease of HGB concentration after surgery (OR=0.900, 95%CI 0.630-1.287, P=0.565) were not independent risk factors of postoperative AKI. Conclusion Preoperative HGB <120.0 g/L is an independent risk factor of postoperative AKI after pulmonary lobectomy.

Objective To explore establish a risk prediction model for patients with nonvalvular atrial fibrillation (NVAF) after ablation based on serum miRNA levels. Methods A total of 389 NVAF patients who received ablative therapy in the Second Affiliated Hospital of Fujian Medical University from August 2018 to December 2020 were selected as the study objects. 70.0% (272 cases) were randomly selected as the training set, 20.0% (78 cases) as the test set, and 10.0% (39 cases) as the verification set. The patients were followed up for 1 year, and the Kaplan-Meier cumulative recurrence risk curve was drawn. According to the recurrence of patients during the follow-up period, the patients were divided into recurrence group and non-recurrence group. The factors influencing the risk of recurrence after ablation in the training set of NVAF patients were explored through univariate and multivariate analysis, and the prediction model of recurrence risk after ablation was constructed. The prediction efficiency of this model was further tested by the consistency index (C-index) and receiver operating characteristic (ROC) curve. Then the model effectiveness of the test set is verified. Results As of December 21, 2021, a total of 30 cases were lost to follow-up (18 cases in the training set, 10 cases in the test set, and 2 cases in the validation set), and 359 actual cases were finally included (254 cases in training set, 68 in test set, and 37 in validation set). Of which 58 cases recurred in training set, and the recurrence rate was 22.8%. The baseline epicardial adipose tissue (EAT) volume was higher in recurrent group than that in non-recurrent group (P<0.05). The levels of miRNA-21, miRNA-150 and miRNA-192-5p in relapse group before and at the end of follow-up were higher than those in non-recurrence group, while the levels of miRNA-29 were lower than those in non-recurrence group with statistical significance (P<0.05). Multivariate logistic analysis showed that EAT volume (OR=1.060, 95%CI 1.012-1.109), miRNA-192-5p (OR=1.759, 95%CI 1.135-2.726), miRNA-21 (OR=32.508, 95%CI 9.224-114.577), miRNA-150 (OR=18.704, 95%CI 5.513-63.456) are independent risk factors for recurrence after ablation, miRNA-29b (OR=0.166, 95%CI 0.049-0.560) are protective factors for recurrence after ablation (P<0.05). Based on the above factors, the recurrence risk prediction model predicted that the C-index of NVAF patients after ablation was 0.929 (95%CI 0.890-0.958). ROC curve results of verification set showed that the specificity and sensitivity of this model were 83.2% and 88.0%, and the optimal critical value of area under ROC curve (AUC) was 0.711. The test data showed that the sensitivity, specificity and accuracy of the model were 86.7%, 88.7% and 88.3%. Conclusion The post-NVAF ablation recurrence risk model constructed by EAT volume, miRNA-192-5p, miRNA-29b, miRNA-21, miRNA-150 and other factors has a high predictive value for the recurrence risk after NVAF ablation.

Objective To investigate the effects of GCN5-mediated histone H3 acetylation (ac) on the proliferation, apoptosis and inflammatory factors of lipopolysaccharide (LPS) -induced alveolar epithelial cells. Methods A549 cells were randomly divided into 6 groups: control group, LPS group, NC+LPS group, GCN5+LPS group, MB-3 (GCN5 inhibitor) +LPS group and GCN5+MB-3+LPS group. Expression levels of H3K9ac, H3K14ac, H3K23ac, GCN5, and cell viability, cell proliferation, apoptosis, levels of inflammatory factors were compared between different groups. Quantitative polymerase chain reaction (qPCR) was used to detect the GCN5 mRNA expression; CCK-8 kit was used to detect cell viability; Cell proliferation was detected by EdU assay; apoptosis was detected by flow cytometry. The expression of GCN5, H3K9ac, H3K14ac, H3K23ac, Caspase-3 and Bcl-2 proteins were detected by Western blotting. The levels of inflammatory factors [interleukin (IL) -1β, IL-6 and tumor necrosis factor (TNF) -α] were determined by enzyme-linked immunosorbent assay (ELISA). Results Compared with control group, the levels of H3K9ac, H3K14ac and H3K23ac were decreased, the mRNA and protein expression of GCN5 were down-regulated, and the cell viability and proliferation were decreased, cell apoptosis was increased, Caspase-3 protein expression was up-regulated while Bcl-2 was down-regulated, the levels of inflammatory factors were increased in LPS group (P<0.05). Compared with the LPS group, no significant changes existed in the levels of the mRNA and protein expression of GCN5 in NC+LPS group (P>0.05), the mRNA and protein expression of GCN5 were up-regulated, the levels of H3K9ac, H3K14ac and H3K23ac were increased, and the cell viability and proliferation were increased, cell apoptosis was decreased, Caspase-3 protein expression was down-regulated while Bcl-2 was up-regulated, the levels of IL-1β, IL-6 and TNF-α were decreased in GCN5+LPS group (P<0.05). Compared with GCN5+LPS group, the levels of H3K9ac, H3K14ac and H3K23ac were decreased, and the cell viability and proliferation were reduced, cell apoptosis was elevated, the levels of IL-1β, IL-6 and TNF-α were increased in GCN5+MB-3+LPS group (P<0.05). Conclusion GCN5 overexpression could resist LPS-induced injuries of alveolar epithelial cells such as abnormal proliferation and apoptosis and inflammatory factors production, which could be related to the increase of histone H3 acetylation level.

Objective To observe the pathological features of diabetic tubulopathy (DT) and analyze the relationship between interstitial fibrosis and tubular atrophy (IFTA) scores and poor disease prognosis. Methods The pathological types, basic data, laboratory examination indexes and follow-up of 121 patients diagnosed as diabetic tubulopathy by pathological biopsy from 2018-2021 at the Army Specialized Medical Center of Army Medical University were collected and retrospectively analyzed. The patients were divided into 3 groups according to the different IFTA scores: group 1 (n=20), group 2 (n=55), and group 3 (n=46). Adverse prognosis was based on the occurrence of endpoint events. Differences between clinical and laboratory data of each group were compared, and correlation analysis was performed between IFTA and glomerular injury, interstitial inflammation, renal artery vitreous lesion and renal arteriosclerosis. Cox regression analysis was used to assess the relationship between IFTA scores and endpoint events. Results The age of 121 DT patients was (53.0±10.2) years old, including 84 males and 37 females, and 99 cases of the 121 patients were with hypertension (81.8%). The incidence of nocturia, lower limb edema, proteinuria, and diabetic retinopathy increased with increasing IFTA score (P<0.01), and urinary microalbumin, urinary protein quantification, urinary albumin creatinine ratio (ACR), corrected urinary N-acyl-β-D-amino glucosidase (NAG), cystatin C (CYC), and blood creatinine levels showed increasing trend (P<0.01), and urinary creatinine (Ucr) and estimated glomerular filtration rate (eGFR) levels gradually decreased (P<0.01), but there was no statistically significant difference between the development of complications such as coronary heart disease, cerebrovascular disease, and chronic liver disease and high IFTA scores (P>0.05). Among pathological changes, IFTA score was strongly correlated with glomerular injury (r=0.503, P=0.000), and renal artery vitreous changes (r=0.329, P=0.007). There was a positive correlation between IFTA score and poor prognosis of patients (model-corrected P=0.021, HR=2.740, 95%CI 1.167-6.410), where the risk of adverse prognosis was 2.740 times higher in patients with IFTA score 3 than in patients with IFTA score 1. Conclusion Glomerular injury, renal artery vitreous degeneration, and renal arteriosclerosis scores were closely associated with IFTA scores in DT, and IFTA scores were closely associated with poor prognosis in DT patients.