[Establishment and validation of prediction models for human leukocyte antigen haplotypes and human leukocyte antigen genotypes].

Objective: To establish prediction models for human leukocyte antigen (HLA) haplotypes and HLA genotypes, and verify the prediction accuracy. Methods: The prediction models were established based on the characteristic of HLA haplotype inheritance and linkage disequilibrium (LD), as well as the invention patents and software copyrights obtained. The models include algorithm and reference databases such as HLA A-C-B-DRB1-DQB1 high-resolution haplotypes database, B-C and DRB1-DQB1 LD database, G group alleles table, and NMDP Code alleles table. The prediction algorithm involves data processing, comparison with reference data, filtering results, probability calculation and ranking, confidence degree estimation, and output of prediction results. The accuracy of the predictions was verified by comparing them with the correct results, and the relationship between prediction accuracy and the probability distribution and confidence degree of the predicted results was analyzed. Results: The HLA haplotypes and genotypes prediction models were established. The prediction algorithm included the prediction of A-C-B-DRB1-DQB1 haplotypes according to HLA-A, B, DRB1, C, DQB1 genotypes, the prediction of C and DQB1 high-resolution results according to A, B and DRB1 high-resolution results, and the prediction of A, B, DRB1, C and DQB1 high resolution results according to the A, B and DRB1 intermediate or low resolution results. Validation results of "Predicting A-C-B-DRB1-DQB1 haplotypes basing on HLA-A, B, DRB1, C, DQB1 genotypes" model: for 787 data, the accuracy was 94.0% (740/787) with 740 correct predictions, 34 incorrect predictions, and 13 instances with no predicted results. For 847 data, the accuracy was 100% (847/847). The 2 411 and 2 594 haplotype combinations predicted from 787 and 847 data were grouped according to confidence degree, the accuracy was 100% (48/48, 114/114) for a confidence degree of 1, 96.2% (303/315) and 97.8% (409/418) for a confidence degree of 2 respectively. Validation results of "Predicting A, B, DRB1 and C, DQB1 high-resolution genotypes basing on HLA-A, B, DRB1 high, intermediate, or low resolution genotypes" model: when predicting C and DQB1 high resolution genotypes basing on A, B, and DRB1 high resolution genotypes, 89.3% (1 459/1 634) of the predictions were correct. The accuracy for the top 2 predicted probability (GPP) ranking was 79.2% (1 156/1 459), and for the top 10, it was 95.0% (1 386/1 459). Furthermore, when GPP≥90% and GPP 50%-90%, the prediction accuracy was 81.3% (209/257) and 72.8% (447/614) respectively. The accuracy of predicting C and DQB1 high resolution genotypes basing on the results of A, B, and DRB1 high resolution genotypes from the China Marrow Donor Program was 87.0% (20/23). The accuracy of predicting A, B, DRB1, C, and DQB1 high resolution genotypes basing on the results of A, B, and DRB1 intermediate or low-resolution genotypes was 70.0% (7/10) and 52.5% (21/40) respectively. When predicting whether the patient is likely to have a HLA 10/10 matched donor, the accuracy of the top 2 GPP combinations with a proportion of ≥50% was 85.7% (6/7). Conclusions: When using A, B, DRB1, C, DQB1 genotypes to predict A-C-B-DRB1-DQB1 haplotype combinations, the results with a confidence degree of 1 and 2 are reliable. When predicting C and DQB1 genotypes according to A, B and DRB1 genotypes, the top 10 results ranked by GPP are reliable, and the top 2 results with GPP≥50% are more reliable.

[The impact of increased cardiac output induced by dobutamine on cerebral blood flow based on MRI 3D-pcASL technology].

Objective: To investigate the effect of increased cardiac output induced by dobutamine on cerebral blood flow (CBF) in healthy volunteers using magnetic resonance 3D-pseudo-continuous arterial spin labeling technology. Methods: A prospective study was conducted on 48 healthy volunteers recruited by handy sampling from June 2021 to January 2022. Physiological parameters before (at rest state) and after (under stress state) dobutamine-induced increase in cardiac output were analyzed. Quantitative CBF maps were generated by using arterial spin labeling difference imaging and proton density weighted reference image processing, and CBF changes under the rest and stress states were compared. Multivariable logistic regression model was used to analyze factors associated with reduced CBF. Results: A total of 48 subjects were included, with an age [M (Q1, Q3)] of 25.0 (24.0, 28.0) years, including 43 men and 5 women. Compared with the rest state, the CBF in the anterior cerebral artery [(36.2±6.9) vs (34.5±6.5) ml·(100 g)-1·min-1, P=0.006] and the middle cerebral artery perfusion area [(35.8±6.5) vs (34.1±6.4) ml·(100 g)-1·min-1, P=0.006] decreased under the stress state, however there was no statistically significant change in CBF in the posterior cerebral artery and the vertebral-basilar artery perfusion area (all P>0.05). Logistic regression analysis showed that the decrease in CBF in the anterior cerebral artery and middle cerebral artery supply regions during the stress state were correlated with an increase in diastolic blood pressure [OR (95%CI): 0.887 (0.796-0.989) and 0.895 (0.805-0.994), both P<0.05]. Conclusions: Dobutamine-induced increase in cardiac output leads to a decrease in CBF in anterior cerebral circulation but has no effect on posterior circulation. The increase in diastolic blood pressure is associated with decreased CBF under the stress state. Changes in CBF should be considered in the context of increased cardiac output.

[Detection of EWSR1 gene rearrangement by fluorescence in situ hybridization in bone and soft tissue tumors: clinical application evaluation and atypical signal analysis].

Objective: To investigate the clinical application of EWSR1 gene rearrangement by fluorescence in situ hybridization (FISH) in bone and soft tissue tumors and to analyze the cases with atypical signal pattern. Methods: The cases detected for EWSR1 gene rearrangement by FISH in Beijing Jishuitan Hospital, Capital Medical University from 2014 to 2021 were collected, and the value of detecting EWSR1 gene rearrangement for diagnosing bone and soft tissue tumors was analyzed. The cases with atypical positive signals were further analyzed by next generation sequencing (NGS). Results: FISH using EWSR1 break-apart probe kit was successfully performed in 97% (205/211) of cases, 6 cases failed. Four of the 6 failures were due to improper decalcification, 1 case due to signal overlap caused by thick slices, and 1 case due to signal amplification and disorder. EWSR1 gene rearrangements were positive in 122 cases (122/205, 59%), atypical positive signal in 8 cases (8/205, 4%), and negative in 75 cases (75/205, 37%). In cases testing positive, the percentage of positive cells ranged from 34% to 98%, with 120 cases (120/122, 98%) showing a positive cell percentage greater than 50%. Among the 205 successfully tested cases, 156 cases were histologically diagnosed as Ewing's sarcoma, of which 110 were positive (110/156, 71%), 7 were atypical positive (7/156, 4%), and 39 were negative (39/156, 25%). Nine cases were histologically diagnosed as clear cell sarcoma of soft tissue, of which 6 were positive (6/9), 1 was atypical positive (1/9), and 2 were negative (2/9). Five cases were histologically diagnosed as extraskeletal myxoid chondrosarcoma, of which 2 were positive (2/5) and 3 were negative (3/5). Three cases were histologically diagnosed as angiomatoid fibrous histiocytoma, of which 2 were positive (2/3) and 1 was negative (1/3). Two cases were histologically diagnosed as myoepithelioma of soft tissue, of which 1 was positive (1/2) and 1 was negative (1/2). One case was histologically diagnosed as olfactory neuroblastoma with a positive result. The 29 other tumor cases including osteosarcoma, synovial sarcoma, and malignant melanoma and others were all negative. Basing on histology as the standard for diagnosis and considering atypical positive cases as negative, comparing with the 29 cases of other tumors as control group, the sensitivity for diagnosing Ewing's sarcoma through the detection of EWSR1 gene rearrangement was 71%, and the specificity was 100%; the sensitivity for diagnosing clear cell sarcoma of soft tissue was 67%, and the specificity was 100%; the sensitivity for diagnosing extraskeletal myxoid chondrosarcoma was 40%, and the specificity was 100%; the sensitivity for diagnosing angiomatoid fibrous histiocytoma was 67%, and the specificity was 100%; the sensitivity for diagnosing myoepithelioma of soft tissue was 50%, and the specificity was 100%; the sensitivity for diagnosing olfactory neuroblastoma was 100%, and the specificity was 100%. Four of 8 cases with atypical positive signals analyzed by NGS showed EWSR1 rearrangement, including EWSR1::FLI1 in one case of Ewing sarcoma, EWSR1::NFATC2 in one case of EWSR1::NFATC2-rearranged sarcoma, EWSR1::ATF1 in one case of clear cell sarcoma of soft tissue and EWSR1::NR4A3 in one case of extraskeletal myxoid chondrosarcoma. Conclusions: Detection of EWSR1 rearrangement by FISH is of utmost significance in the diagnosis of bone and soft tissue tumors. Cases with atypical positive signals should be further scrutinized, correlating with their histomorphology and verifying by NGS if necessary.

[Canagliflozin can improve cardiac function in HFpEF rats partly by regulating ferroptosis].

Objective: To explore the effects of canagliflozin on cardiac function and its regulation of ferroptosis in rats with heart failure with preserved ejection fraction (HFpEF). Methods: Thirty-two 7-week-old Dahl salt-sensitive rats were selected and randomly divided into four groups: the control group (fed with low-salt diet), the HFpEF group (fed with high-salt diet), the canagliflozin 20 group (fed with high-salt diet and 20 mg·kg-1·d-1 canagliflozin), and the canagliflozin 30 group (fed with high-salt diet and 30 mg·kg-1·day-1 canagliflozin). Body weight and blood pressure of the rats in each group were monitored. Metabolic cage tests were conducted at the10th week of the experiment, and echocardiography was performed at the 12th week, after which the rats were killed. Blood and left ventricular samples were collected. HE staining, Masson staining, Prussian blue iron staining, and reactive oxygen species staining were performed to observe the cardiomyocyte size and shape, degree of interstitial fibrosis, iron staining, reactive oxygen species production under optical microscope. The ultrastructure of cardiomyocytes was observed under electron microscope. Western blotting and real-time fluorescent quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression levels of proteins and mRNA related to ferroptosis in left ventricular myocardial tissue of rats in each group. Results: After 1 week of adaptive feeding, all rats survived. Metabolic cage results showed that compared with control group, rats in the HFpEF group, canagliflozin 20 group and canagliflozin 30 group had more food intake, water intake and urine output, and lower body weight (all P<0.05). These changes were more pronounced in canagliflozin 20 group and canagliflozin 30 group than in HFPEF group, and only the body weight at the 12th week showed a statistically significant difference between canagliflozin 20 group and canagliflozin 30 group (P<0.05). The blood pressure of 6th week and 12th week, heart weight and left ventricular corrected mass of 12th week of rats in HFpEF group were higher than those in control group, canagliflozin 20 group and canagliflozin 30 group, while the ratio of early mitral valve peak velocity to late mitral valve peak velocity of 12th week was lower (all P<0.05). HE and Masson staining showed that compared to control group, the myocardial fibers in the left ventricular myocardial tissue of rats in HFpEF group were disordered, with larger cell diameter ((0.032±0.004) mm vs. (0.023±0.003) mm, P<0.05), irregular shape, obvious proliferation of interstitial collagen fibers, and higher collagen volume fraction (0.168±0.028 vs. 0.118±0.013, P<0.05). Compared with HFpEF group, rats in the canagliflozin 20 group and canagliflozin 30 had more orderly arranged myocardial fibers, more regular cardiomyocyte shape, smaller cell diameter, and lower collagen volume fraction (P<0.05). It was observed under electron microscopy that, compared to control group, most of the striated muscles in myocardial tissue of HFpEF group were broken, and the Z line and M line could not be clearly distinguished, some changes such as mitochondrial swelling, membrane thickening, cristae reduction or even disappearance occurred. In the canagliflozin 20 group and canagliflozin 30 group, the arrangement of striated muscles in the myocardial tissue of rats tended to be more regular, and the morphological changes of mitochondria were milder. Prussian blue iron staining results showed that the iron content in myocardial tissue of rats in HFpEF group was higher than that in control group, canagliflozin 20 group and canagliflozin 30 group. Reactive oxygen species staining results showed that the reactive oxygen species content in the myocardial tissue of rats in HFpEF group was higher than that of control group, canagliflozin 20 group and canagliflozin 30 group. Biochemical analysis of myocardial tissue showed that Fe2+ and malondialdehyde content in myocardial tissue of rats in HFpEF group were higher than those in control group, canagliflozin 20 group and canagliflozin 30 group, while glutathione content was lower (all P<0.05). Western blot and RT-qPCR detection results showed that compared to control group, rats in HFpEF group had higher expression levels of transferrin receptor 1 (protein relative expression level: 1.37±0.16 vs. 0.31±0.12), acyl-CoA synthetase long-chain family member 4 (protein relative expression level: 1.31±0.15 vs. 0.63±0.09) protein and mRNA, and lower expression levels of ferritin heavy chain 1 (protein relative expression level: 0.45±0.08 vs. 1.41±0.15) protein and mRNA (all P<0.05). There was no statistically significant difference in these indicators between canagliflozin 20 group and the canagliflozin 30 group (all P>0.05). There was no significant difference in levels of glutathione peroxidase 4 protein and mRNA expression in myocardial tissue of rats in four groups(P>0.05). Conclusion: Canagliflozin improves cardiac function in HFpEF rats by regulating the ferroptosis mechanism.

[Effects of canagliflozin on amino acid metabolism in atherosclerotic mice].

Objective: To explore the possible anti-atherosclerotic mechanisms of glucose co-transporter-2 inhibitor canagliflozin. Methods: ApoE-/-mice fed on Western diet were randomly assigned into the model group (n=10) and the canagliflozin group (n=10). C57BL/6J mice fed on normal diet were chosen as the control group (n=10). Mice in the canagliflozin group were gavaged with canagliflozin for 14 weeks. The presence and severity of atherosclerosis were evaluated with HE and oil red O stainings in aortic root section slices. PCR assay was performed to determine the mRNA expression levels of nitric oxide synthase. Hepatic transcriptome analysis and hepatic amino acid detection were conducted using RNA-seq and targeted LC-MS, respectively. Results: HE staining and oil red O staining of the aortic root showed that AS models were successfully established in ApoE-/-mice fed on Western diet for 14 weeks. Canagliflozin alleviated the severity of atherosclerosis in pathology. Hepatic transcriptome analysis indicated that canagliflozin impacted on amino acid metabolism, especially arginine synthesis in ApoE-/-mice. Targeted metabolomics analysis of amino acids showed that canagliflozin reduced hepatic levels of L-serine, L-aspartic acid, tyrosine, L-hydroxyproline, and L-citrulline, but raised the hepatic level of L-arginine. Compared to the model group, the canagliflozin group exhibited higher serum arginine and nitric oxide levels as well as elevated nitric oxide mRNA expression in aortic tissues (P<0.05). Conclusion: Canagliflozin regulated the amino acid metabolism, reduced the levels of glucogenic amino acids,and promoted the synthesis of arginine in atherosclerotic mice.

[Exploration of the clinical pathway for etiological diagnostics of androgen excess in female].

Androgen excess is a common endocrine and metabolic problem in clinical practice, which affects the health of women throughout their life cycle. Usually, its diagnosis and treatment need multidisciplinary cooperation. The etiological diagnosis of female hyperandrogenism should be based on the etiological characteristics at different ages and should be comprehensively evaluated from medical history, physical examination, determination of androgen and other endocrine hormones, functional tests, imaging, and genetic testing, etc. The general principle of androgen excess cause diagnosis is first to determine whether the patient has clinical and/or biochemical androgen excess, then determine whether she conforms to the diagnostic criteria of polycystic ovary syndrome (PCOS), and then determine whether it is a specific disease or not. Finally, mass spectrometry should be adopted for verifying the androgen levels in those without clear causes found to exclude pseudo-elevation, thus it can be diagnosed as idiopathic androgen excess. Exploring the clinical pathway for the etiological diagnosis of female hyperandrogenism has important reference significance for guiding the standardized and accurate diagnosis and treatment of female hyperandrogenism.

[Effects of three medical nutrition therapies for weight loss on metabolic parameters and androgen level in overweight/obese patients with polycystic ovary syndrome].

Objective: To investigate the effects of calorie-restricted diet (CRD), high protein diet (HPD), high protein, and high dietary fiber diet (HPD+HDF) on metabolic parameters and androgen level in overweight/obese patients with polycystic ovary syndrome(PCOS). Methods: Ninety overweight/obese patients with PCOS from Peking University First Hospital from October 2018 to February 2020 were given medical nutrition weight loss therapy for 8 weeks and were randomly divided into CRD group, HPD group, and HPD+HDF group, with 30 patients in each group. Body composition, insulin resistance, and androgen level were detected before and after weight loss, and the efficacy of three weight loss therapies was compared through variance analysis and Kruskal-Wallis H test. Results: Eight patients in CRD group quit because they could not strictly complete the follow-up, therefore at the end of weight loss, 22, 30, and 30 patients in CRD group, HPD group and HPD+HDF group, respectively, were included in the final analysis. The baseline ages of the three groups were (31±2) years, (32±5) years and (31±5) years, respectively (P=0.952). After weight loss, the relevant indicators in HPD group and HPD+HDF group decreased more than those in CRD group. The body weight of CRD group, HPD group and HPD+HDF group decreased by 4.20 (11.92, 1.80), 5.00 (5.10, 3.32) and 6.10 (8.10, 3.07) kg, respectively (P=0.038); BMI of the three groups decreased by 0.80 (1.70, 0.40), 0.90 (1.23, 0.50) and 2.20 (3.30, 1.12) kg/m2, respectively (P=0.002); homeostatic model assessment-insulin resistance(HOMA-IR) index decreased by 0.48(1.93, 0.05), 1.21(2.91, 0.18) and 1.22(1.75, 0.89), respectively (P=0.196); and free androgen index(FAI) decreased by 0.23(0.67, -0.04), 0.41(0.64, 0.30) and 0.44(0.63, 0.24), respectively (P=0.357). Conclusions: The three medical nutrition therapies can effectively reduce the weight of overweight/obese patients with PCOS, and improve insulin resistance and hyperandrogenism. Compared with CRD group, HPD group, and HPD+HDF group have better fat-reducing effect, and can better preserve muscle and basal metabolic rate while losing weight.

Spatial epidemiological characteristics and exponential smoothing model application of tuberculosis in Qinghai Plateau, China.

The epidemic of tuberculosis has posed a serious burden in Qinghai province, it is necessary to clarify the epidemiological characteristics and spatial-temporal distribution of TB for future prevention and control measures. We used descriptive epidemiological methods and spatial statistical analysis including spatial correlation and spatial-temporal analysis in this study. Furthermore, we applied an exponential smoothing model for TB epidemiological trend forecasting. Of 43 859 TB cases, the sex ratio was 1.27:1 (M:F), and the average annual TB registered incidence was 70.00/100 000 of 2009-2019. More cases were reported in March and April, and the worst TB stricken regions were the prefectures of Golog and Yushu. High TB registered incidences were seen in males, farmers and herdsmen, Tibetans, or elderly people. 7132 cases were intractable, which were recurrent, drug resistant, or co-infected with other infections. Three likely cases clusters with significant high risk were found by spatial-temporal scan on data of 2009-2019. The exponential smoothing winters' additive model was selected as the best-fitting model to forecast monthly TB cases in the future. This research indicated that TB in Qinghai is still a serious threaten to the local residents' health. Multi-departmental collaboration and funds special for TB treatments and control are still needed, and the exponential smoothing model is promising which could be applied for forecasting of TB epidemic trend in this high-altitude province.

Pancreatic cystic lesions and the role of contrast enhanced endoscopic ultrasound.

An exponential rise in the use of cross-sectional imaging has led to an increase in the incidental identification of pancreatic cystic lesions (PCL); however, with many subtypes defined to date and heterogeneous morphology with often absent defining radiological features, PCLs present a diagnostic challenge. Computed tomography (CT) and/or magnetic resonance imaging (MRI) alone are frequently not sufficient to provide accurate characterisation. Endoscopic ultrasound (EUS) has an important role in the evaluation and classification of PCLs through its ability to define the internal architecture, which is further enhanced by the use of contrast medium. It is also used widely for the surveillance of larger cysts (>2 cm), which are associated with a greater malignant potential. The aim of this review is to demonstrate the role of contrast-enhanced (CE)-EUS in the diagnosis and risk stratification of PCLs. The features of the main non-neoplastic and neoplastic PCLs observed on CE-EUS are provided. When used in combination with other imaging techniques and patient characteristics, CE-EUS offers a more accurate assessment of PCLs and aids risk stratification. Additionally, CE-EUS enables assessment of parenchymal perfusion improving the precision of cyst characterisation and targeted biopsy of worrisome components. The International Consensus Guidelines recommend regular follow up for patients with mucinous or indeterminate PCLs that are fit enough for surgery. With the growing range of tools available to assess PCLs including CE-EUS, it is hoped that patients can be steered towards surgery, surveillance, or discharge with increasing accuracy.

[Establishment and effect evaluation of nomogram model for diagnosis and prediction of pulmonary hypertension in patients with chronic obstructive pulmonary disease].

Objective: To construct a diagnostic and predictive model for chronic obstructive pulmonary disease complicated with pulmonary hypertension (COPD-PH) and evaluate its effect. Methods: A total of 1 514 COPD patients treated in 5 hospitals from January 1, 2014 to December 31, 2019 were retrospectively collected and divided into training cohort (1 072 cases) and validation cohort (442 cases) according to the ratio of 7∶3 according to the inclusion time. Data including demographic data, smoking status, history of disease, and clinical examination were collected through patient medical records and electronic medical record systems. Multivariate logistic regression models were used to explore the related factors of COPD-PH, and the nomogram model was constructed using the "rms" program package. The calibration curve was used to evaluate the consistency between the prediction probability of the model and the actual results. The C index and the area under the receiver operating characteristic curve (ROC) were used to evaluate the discrimination of the model. The decision curve analysis (DCA) was used to evaluate the clinical practicability of the model. Results: In the training cohort, 3.7%, 15.2% and 81.1% were aged 50-59, 60-69 and ≥70 years, respectively, which were significantly different from the age composition of the validation cohort (7.9%, 27.8% and 64.3%, respectively) (P=0.041). There was no significant difference between the training cohort (79.4%) and the validation cohort (84.6%) (P=0.243). Multivariate logistic regression analysis of the training cohort showed that age ≥70 years [OR (95%CI): 3.32 (1.49-7.36)] and smoking status [former (current) smoking, OR (95%CI)] were 3.67 (2.51-5.37) and 2.04 (1.44-2.90), respectively], NT-probNP≥1 400 ng/L[OR (95%CI): 9.88 (6.23-15.66)], right atrial diameter [OR (95%CI): 1.11 (1.07-1.15)] was COPD-related factors of PH, based on the above factors-PH nomogram COPD model was set up and develop for online tools (https://ph-666.shinyapps.io/zhonghua-PH/). The calibrated C index (95%CI) of the training cohort and the validation cohort were 0.82 (0.77-0.87) and 0.77 (0.68-0.86), respectively. The calibration curve was close to the diagonal in both the training cohort and the validation cohort. The AUC (95%CI) of the nomogram model was 0.82 (0.80-0.85) in the training cohort and 0.77 (0.73-0.82) in the validation cohort. ROC curve showed that the optimal threshold in the training cohort was 0.60, and the sensitivity and specificity under this value were 0.74 and 0.78, respectively; the optimal threshold for the validation cohort was 0.70, and the sensitivity and specificity under this value were 0.76 and 0.65, respectively. DCA analysis showed that the nomogram model provided better net benefits than the all-variable selection and no-variable selection strategies with threshold probabilities greater than 15.0% and 13.0% in the training and validation cohorts, respectively. Conclusions: The nomogram model for the diagnosis and prediction of COPD-PH is simple and accurate, which has a good clinical application prospect.

[Analysis of clinical features and etiological diagnostic indices of reproductive age women with hyperandrogenism].

Objective: To investigate the clinical features and the value of different diagnostic indices for etiology in reproductive age women with hyperandrogenism. Methods: The medical records of 96 reproductive age women with hyperandrogenism in the multi-disciplinary team of Peking University First Hospital from January 2020 to April 2021 were collected. The patients were divided into four groups based on final diagnosis: congenital adrenal hyperplasia (CAH) (n=8), polycystic ovary syndrome (PCOS) (n=67), idiopathic hyperandrogenism (n=13) and other specific diseases (n=8), respectively. The indices related to androgens in different groups were compared, and then their efficiency for diagnosis of CAH and PCOS were analyzed with receiver operator characteristic curve (ROC curve). Results: A total of 96 patients with hyperandrogenism were recruited, with the age of 19-45 (29±6) years old. Overall, 4.2% (4/96) of the patients were with single clinical hyperandrogenism, 56.3% (54/96) were with single laboratory hyperandrogenaemia and 39.6% (38/96) were with both. The breakdown into laboratory hyperandrogenaemia subtypes was as follows: only T elevation 22.8% (21/92), only A2 elevation 7.6% (7/92), none DHEAS elevation, only FAI elevation 5.4% (5/92) and elevation of more than one of the androgen indices mentioned above accounted for 64.1% (59/92). In the reasons of consultation, simple irregular menstruation (36.0%, 32/89) or accompanied by clinical hyperandrogenism with or without infertility (36.0%, 32/89) were the most common. As for primary visiting departments, Obstetrics and Gynecology accounted for 53.2% (51/96), and then Endocrinology as 39.5% (38/96). The 17-OHP level of CAH, PCOS and idiopathic hyperandrogenism group was 20.0 (8.2, 33.1), 1.1 (0.8, 1.4), 0.9 (0.8, 1.3) ng/ml, respectively. The androstenedione level in these groups was 6.3 (4.6, 8.7), 3.8 (2.9, 4.8) and 3.2 (2.7, 3.7) ng/ml, respectively. The 17-OHP and androstenedione levels of CAH group were significantly higher than that in PCOS or idiopathic hyperandrogenism group (all P<0.05). The ratio of LH and FSH in these three groups was 0.8(0.5, 1.0), 1.3(0.6, 1.9) and 0.6(0.3, 0.7), respectively. The ratio of LH and FSH was significantly higher in PCOS than that in idiopathic hyperandrogenism group (P=0.024), but yet there was no significant difference compared with CAH group (P>0.05). The AUC of ROC curve of 17-OHP for CAH diagnosis was 0.94, followed by androstenedione 0.83, whereas LH/FSH for PCOS diagnosis was only 0.63. Conclusions: Among the reasons of consultation in reproductive age women who visited our multi-disciplinary team for female hyperandrogenism, simple irregular menstruation or accompanied by clinical hyperandrogenism with or without infertility are the most common. PCOS accounts for the majority of different androgen excess disorders. 17-OHP is the most valuable parameter for the diagnosis of CAH and secondly androstenedione.

[The diagnostic value of CCNB3 and BCOR expression in BCOR-CCNB3 sarcoma].

Objective: To investigate the diagnostic value of expression of CCNB3 and BCOR in BCOR-CCNB3 sarcoma (BCS). Methods: Fifteen cases of BCS confirmed by fluorescence in situ hybridization (FISH) and/or reverse transcription-polymerase chain reaction (RT-PCR) from January 2014 to October 2021 at Beijing Jishuitan Hospital were collected. Immunohistochemical EnVision method was used to detect the expression of CCNB3 and BCOR in 15 cases of BCS and in 65 non-BCS tumors (54 cases of Ewing's sarcoma, 5 cases of CIC rearranged sarcoma, 4 cases of synovial sarcoma, 1 case of mesenchymal chondrosarcoma and 1 case of soft tissue clear cell sarcoma). Results: Immunohistochemical staining for CCNB3 revealed strongly diffuse nuclear staining in 14 of 15 (14/15) BCS cases, whereas none of the 65 non-BCS tumors showed any staining. Immunohistochemical staining for BCOR showed strongly diffuse nuclear staining in 11 (11/14) BCS cases; seven of the 65 (7/65, 10.8%) non-BCS tumors showed variable staining (five cases of Ewing sarcoma, one cases of synovial sarcoma, and one case of mesenchymal chondrosarcoma). The sensitivity and specificity of CCNB3 in diagnosing BCS were 93.3% and 100% and these of BCOR were 78.6% and 89.2%, respectively. Conclusions: CCNB3 is a highly sensitive and specific marker for BCS.The antibody may help screening BCS.

[Progress on the pathogenesis of chronic thromboembolic pulmonary hypertension].

Chronic thrombotic pulmonary hypertension (CTEPH) is a rare progressive pulmonary vascular disease, which is classified as World Health Organization (WHO) functional class Ⅳ pulmonary arterial hypertension (PAH). The diagnosis was based on mean pulmonary arterial pressure ≥25 mmHg(1 mmHg=0.133 kPa) and pulmonary arterial wedge pressure ≤15 mmHg measured by right heart catheterization, with the under-utilization of radionuclide ventilation/perfusion scan and regular anticoagulation therapy for at least three months. The incidence of CTEPH is low, at 4 cases per million population per year. Despite the in-depth research on CTEPH in recent years, the strengthening of clinical diagnostic awareness, and the emergence of treatment methods such as pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA), the prognosis of CTEPH patients has been dramatically improved. However, the pathogenesis of CTEPH is unclear, and the lack of effective early diagnostic methods has become a bottleneck limiting the improvement of clinical diagnosis and treatment. In this paper, we reviewed the current research progress on the pathogenesis of CTEPH to increase the understanding of CTPTH disease.

[Reassessment of EWSR1 gene rearrangement-negative undifferentiated round cell sarcomas in bone and soft tissues by fluorescence in situ hybridization].

Objective: To unravel the CIC rearrangement sarcomas and BCOR-CCNB3 sarcomas from EWSR1 rearrangement-negative undifferentiated round cell sarcomas in the bone and soft tissues. Methods: Twenty-eight cases of EWSR1 rearrangement-negative undifferentiated round cell sarcomas of bone and soft tissues, tested for CIC rearrangement and BCOR rearrangement by fluorescence in situ hybridization and related immunostaining were analyzed, and some of the BCOR rearrangement cases were verified by reverse transcription-polymerase chain reaction. Results: Five of 28 (17.9%) tested cases were positive for CIC rearrangement and six (21.4%) for BCOR rearrangement. Histopathologically, CIC rearrangement sarcomas comprised nodular aggregates of round to polygonal cells, containing hyperchromatic nuclei, prominent nucleoli and moderate cytoplasm, with focal variable necrosis and myxoid stroma. BCOR-CCNB3 sarcomas mostly comprised diffusely arranged, round to oval to short spindly cells with angulated nuclei, vesicular chromatin, inconspicuous nucleoli and interspersed vessels. Immunohistochemically, five of six BCOR-CCNB3 sarcomas showed CCNB3 immunostaining, which could be helpful for diagnosis. Two patients with CIC rearrangement sarcoma died of the diseases in seven months and twenty-two months. One patient with BCOR-CCNB3 sarcoma died of the diseases in forty-six months. Conclusions: Overall, 39.3% of the EWSR1 rearrangement-negative undifferentiated round cell sarcomas are CIC rearrangement sarcomas and BCOR-CCNB3 sarcomas. Molecular testing is helpful for diagnosis.

[Efficacy and safety of Changsulin® compared with Lantus® in type 2 diabetes: a phase â ¢ multicenter, randomized, open-label, parallel, controlled clinical trial].

Objective: To compare the efficacy and safety of Changsulin® with Lantus® in treating patients with type 2 diabetes mellitus (T2DM). Methods: This was a phase Ⅲ, multicenter, randomized, open-label, parallel-group, active-controlled clinical trial. A total of 578 participants with T2DM inadequately controlled on oral hypoglycemic agents were randomized 3∶1 to Changsulin® or Lantus® treatment for 24 weeks. The efficacy measures included changes in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2h postprandial plasma glucose (2hPG), 8-point self-monitoring of blood glucose (SMBG) profiles from baseline, and proportions of subjects achieving targets of HbA1c and FPG. The safety outcomes included rates of hypoglycemia, adverse events (AEs) and anti-insulin glargine antibody. Results: After 24 weeks of treatment, mean HbAlc decreased 1.16% and 1.25%, FPG decreased 3.05 mmol/L and 2.90 mmol/L, 2hPG decreased 2.49 mmol/L and 2.38 mmol/L in Changsulin® and in Lantus®, respectively. No significant differences could be viewed in above parameters between the two groups (all P>0.05). There were also no significant differences between Changsulin® and Lantus® in 8-point SMBG profiles from baseline and proportions of subjects achieving the targets of HbA1c and FPG (all P>0.05). The rates of total hypoglycemia (38.00% and 39.01% for Changsulin® and Lantus®, respectively) and nocturnal hypoglycemia (17.25% and 16.31% for Changsulin® and Lantus®, respectively) were similar between the two groups (all P>0.05). Most of the hypoglycemia events were asymptomatic, and no severe hypoglycemia were found in both groups. No differences were observed in rates of AEs (61.77% vs.52.48%) and anti-insulin glargine antibody (after 24 weeks of treatment, 6.91% vs.3.65%) between the two groups (all P>0.05). Conclusions: Changsulin® shows similar efficacy and safety profiles compared with Lantus® and Changsulin® treatment was well tolerated in patients with T2DM.

[A 5-year follow-up study of pneumoconiosis patients with positive autoantibody].

Objective: To explore the progress of small shadow and the change of lung function in pneumoconiosis with positive autoantibody, so as to provide basis for clinical treatment of pneumoconiosis. Methods: A total of 756 patients were admitted to the pneumoconiosis department of the Guangzhou Occupational Disease Prevention Hospital from January 1, 2013 to June 1, 2019. The patients with combined infection were excluded. According to whether the autoantibody was positive, they were divided into positive group and negative group, 25 cases in each group. Follow-up observation of X-ray chest radiographs, chest CT, forced expiratory volume in one second (FEV(1)) and forced expired flow at 50% of FVC (MEF(50)) of pneumoconiosis patients for 5 years, to analyze the influence of positive autoantibody on the morphology of X-ray chest film, the pneumoconiosis promotion in 5 years and lung function. Results: There were 22 males and 3 females in the autoantibody positive group, aged 53.14±10.51 years. In the autoantibody negative group, there were 23 males and 2 females, aged 53.88±8.10 years. During the 5-year observation period, there was no significant difference of small shadow shape, pneumoconiosis stage, and the pneumoconiosis promotion in 5 years between the autoantibody positive group and the autoantibody negative group (P>0.05). However, the increment of small shadow area in the autoantibody positive group was higher than that in the autoantibody negative group (P<0.05). FEV(1) and MEF(50) of the autoantibody positive group were significantly lower than those of the autoantibody negative group in the fourth and third years, respectively (P<0.05). Positive autoantibody was negatively correlated with FEV(1) and MEF(50) (P<0.05). Conclusion: The positive autoantibody can't promote the progress of X-ray, but show more small shadows on chest CT; the positive autoantibody may aggravate the decline of lung function.

Phononic Helical Nodal Lines with PT Protection in MoB_{2}.

While condensed matter systems host both fermionic and bosonic quasiparticles, reliably predicting and empirically verifying topological states is only mature for Fermionic electronic structures, leaving topological Bosonic excitations sporadically explored. This is unfortunate, as Bosonic systems such as phonons offer the opportunity to assess spinless band structures where nodal lines can be realized without invoking special additional symetries to protect against spin-orbit coupling. Here we combine first-principles calculations and meV-resolution inelastic x-ray scattering to demonstrate the first realization of parity-time reversal symmetry protected helical nodal lines in the phonon spectrum of MoB_{2}. This structure is unique to phononic systems as the spin-orbit coupling present in electronic systems tends to lift the degeneracy away from high-symmetry locations. Our study establishes a protocol to accurately identify topological Bosonic excitations, opening a new route to explore exotic topological states in crystalline materials.

[Tear film stability after trabeculectomy and its relationship with bleb morphology].

Objective: To investigate the tear film stability after trabeculectomy and its relationship with bleb morphology using Optical Quality Analysis System Ⅱ (OQAS Ⅱ). Methods: A cross-sectional study. Glaucoma patients undergoing trabeculectomy in the Eye Hospital of Wenzhou Medical University from November 2011 to November 2016 were invited by telephone to perform optical quality, bleb photography, and break-up time examinations, and history of surgeries and medications was collected. Bleb morphology was graded according to the Indiana bleb appearance grading scale. The tear film stability was the average objective scatter index value measured using OQAS Ⅱ for 10 seconds after blinking minus the baseline objective scatter index. The higher the tear film stability value, the worse the stability. The difference in the tear film stability between the surgical eyes and non-surgical eyes was compared by the Mann-Whitney U test, and the relationships between the optical quality, bleb height, extent and vascularity were compared by the Kruskal-Wallis H test. Results: Sixty-three patients (76 eyes) were enrolled in the study, including 55 surgical eyes and 21 non-surgical eyes. The mean follow-up time was (39.6±26.2) months.In the surgical and non-surgical eyes, the M(Q(R)) of tear film stability was 0.46 (0.86) and 0.23 (0.41), respectively. The tear film stability in the surgical eyes was reduced compared to the non-surgical eyes (P=0.044). The trabeculectomy group was divided into three subgroups according to the height of the filtering bleb: H0 (17 eyes), H1 (24 eyes) and H2-3 (14 eyes). The M(Q(R)) of tear film stability in the three subgroups was 0.40(0.68), 0.70(1.02) and 0.40(1.24), respectively, with no statistically significant difference detected (P=0.481). According to the bleb extent, the surgical group was divided into two subgroups: E0-1 (36 eyes) and E2-3 (19 eyes). The M(Q(R)) of optical quality in the two subgroups was 0.63 (0.78) and 0.26(1.17), respectively, with no significant difference detected (P=0.261). According to the degree of bleb vascularity, the surgical group was divided into three subgroups: V0 (25 eyes), V1 (14 eyes), and V2-3 (16 eyes). The M(Q(R)) of optical quality in the three subgroups was 0.39 (0.69), 0.55 (1.18) and 0.63 (1.24), respectively, with no significant difference (P=0.401). Conclusion: Although tear film stability decrease after trabeculectomy, the decrease is not associated with the bleb morphology. (Chin J Ophthalmol, 2019, 55:214-219).

[Lung transplantation in patients with paraquat poisoning: a case report and literature review].

Objective: To analyze 8 cases of paraquat lung transplantation in the world, and to explore the timing of lung transplantation and the factors affecting prognosis. Methods: An analysis of the clinical data of a paraquat poisoning lung transplant patient completed by The 12th People's Hospital of Guangzhou Medical University and The First People's Hospital affiliated to Guangzhou Medical University in August 2017 and literature review. Results: A 26 years old female patient was admitted to the hospital ingested 20% paraquat solution 20ml. On the 58th day of poisoning, she underwent double lung transplantation under general anesthesia. The operation was successful. Excised lungs show extensive lung fibrosis in both lungs, which was consistent with paraquat poisoning. Used tacrolimus and corticosteroids and mycophenolate antirejection, the patient discharged 46 days after surgery. 7 articles were retrieved through the search tool, and a total of 8 articles included this case were reported. Five patients who underwent lung transplantation within 1 month after poisoning all died, And 3 patients conducted lung transplantation for more than 1 month after poisoning survived; Pathogenic bacteria were isolated from the sputum in 3 of the 8 cases, all containing Pseudomonas, 2 of which died, and our case survived. Conclusion: Appropriate transplantation time window is very important for the prognosis of paraquat poisoning after lung transplantation. Active treatment of the sputum pathogens, improving the donor receptor matching, and exhausting the various means to remove the paraquat from the storage pool which may improve success rate of lung transplantation.