BACKGROUND:Increasing evidence supports the association between different exercise intensities and the risk of osteoarthritis,but this may be affected by confounding and reverse causality,and the conclusions have not been unified. OBJECTIVE:To explore the causal association between different exercise intensities and osteoarthritis using Mendelian randomization method. METHODS:Data from genome-wide association studies associated with different exercise intensities were selected,and instrumental variables were screened with a threshold of P＜5×10-8.Causal associations between exposure and risk of outcome were assessed using five analysis methods of Mendelian randomization with inverse variance weighting as the primary analysis method.Selected instrumental variables were used to assess causal associations between different exercise intensities and osteoarthritis,and sensitivity analyses with inverse Mendelian randomization were performed. RESULTS AND CONCLUSION:In the analysis results of the inverse variance weighting method,low-intensity exercise showed a significant protective effect on knee osteoarthritis[odds ratio(OR)=0.14,95%confidence interval(CI):0.06-0.32,P＜0.001],while sedentary behavior without exercise intensity,such as watching TV,was confirmed to be a risk factor for knee osteoarthritis and hip osteoarthritis(OR=2.24,95%CI:1.74-2.88,P＜0.001;OR=1.34,95%CI:1.01-1.78,P=0.04).Through the reverse Mendelian randomization analysis of osteoarthritis to different exercise intensities,it was found that osteoarthritis was negatively correlated with low-intensity exercise and positively correlated with watching TV.The analysis results show that there is a two-way causal relationship between different exercise intensity and osteoarthritis risk.

Objective To explore the value of machine learning(ML)models based on non-contrast CT(NCCT)radiomics features for predicting the severity of acute phase traumatic brain injury(TBI).Methods Totally 600 TBI patients were retrospectively collected as observation group,other 65 TBI patients were taken as external validation set,while 50 TBI patients were prospectively enrolled as prospective validation set.Patients in observation group were divided into high-risk subgroup(n=240)and low-risk subgroup(n=360)according to Glasgow outcome scale(GOS)at discharge.The severity of acute phase TBI in observation group was assessed by doctor A and B with the same criteria,then an artificial model was established based on clinical and NCCT data at the time of first diagnosis using logistic regression(LR)method for predicting the severity of acute phase TBI.Patients in observation group were divided into training set(n=420,including 168 in high-risk subgroup and 252 in low-risk subgroup)and test set(n=180,including 72 in high-risk subgroup and 108 in low-risk subgroup)at the ratio of 7∶3.Based on NCCT of training set,radiomics features were extracted and selected,and LR,support vector machine(SVM),random forest(RF)and K-nearest neighbor(KNN)were used to establish 4 ML models.The efficacies of the above models were validated in test set,external validation set(including 34 cases of high-risk and 31 cases of low-risk TBI)and prospective validation set(including 21 cases of high-risk and 29 cases of low-risk TBI),respectively.Results The area under the curve(AUC)of doctor A and B for evaluating the severity of acute phase TBI in observation group was 0.606 and 0.771,respectively,of artificial model was 0.824.Based on NCCT in training set,6 optimal radiomics features were selected to construct LR,SVM,RF and KNN ML models,with AUC of 0.983,0.971,0.970 and 0.984 in test set,respectively,while the AUC of artificial model was 0.708.The AUC of LR,SVM,RF,KNN ML models and artificial model in external validation set was 0.879,0.881,0.984,0.863 and 0.733,while in prospective validation set was 0.984,0.873,0.982,0.897 and 0.704,respectively.Conclusion ML models based on CT radiomics could effectively predict the severity of acute phase TBI.

Objective:To explore the correlation of serum albumin level at admission with clinical prognoses in patients with acute traumatic brain injury (TBI).Methods:One hundred and fifty-four patients with acute moderate-extreme severe TBI (Glasgow Coma Scale [GCS] scores of 3-12 at admission) in Department of Neurosurgery, General Hospital of Western Theater Command from January 1, 2019 to December 31, 2020 were chosen. The comprehensive clinical data of these patients were collected, including age, gender, GCS scores, serum albumin level (hypoalbuminemia defined as<35 g/L), hemoglobin level, comorbidities, treatment measures, and prognoses 6 months after discharge (poor prognosis defined as Glasgow outcome Scale [GOS] scores of 1-2, and good prognosis defined as GOS scores of 3-5). Univariate and multivariate Logistic regressions were used to identify the independent factors for clinical prognoses of these patients, and differences in poor prognosis rate, length of ICU stay, and total hospital cost were compared between different groups.Results:Among the 154 patients, 43 had poor prognosis and 111 had good prognosis. Serum albumin level at admission ( OR=0.916, 95% CI: 0.843-0.996, P=0.001) and GCS scores at admission ( OR=0.701, 95% CI: 0.594-0.828, P<0.001) were independent factors for prognosis. Patients with hypoalbuminemia ( n=70) displayed significantly higher poor prognosis rate, longer ICU stays, and increased total hospitalization cost compared with those without hypoalbuminemia ( n=84, P<0.05); specifically, in patients with GCS scores of 9-12 at admission ( n=58), those with hypoalbuminemia ( n=27) exhibited significantly higher poor prognosis rate, longer ICU stays, and higher total hospitalization cost than their non-hypoalbuminemia counterparts ( n=31, P<0.05); similarly, in patients with GCS scores of 3-8 at admission ( n=96), those with hypoalbuminemia ( n=74) had significantly higher poor prognosis rate than their non-hypoalbuminemia counterparts ( n=22, P<0.05). In patients with good prognosis, those with hypoalbuminemia ( n=56) showed significantly longer total hospital stays, prolonged ICU stays, and increased total hospitalization cost compared with those without hypoalbuminemia ( n=55, P<0.05). Conclusion:Low serum albumin level at admission is likely to lead to poor prognosis, prolonged ICU stays and increased total hospitalization cost in patients with acute TBI.

In recent years, the incidence of digestive disorders has risen steadily. Among which, biliary dyskinesia, particularly biliary hyperkinesia, has become a growing concern. The basic concept, epidemiology, pathogenesis, pathology, clinical and imaging manifestations, diagnosis, and treatment of biliary hyperkinesia are systematically reviewed in this paper based on the current status of research in this field worldwide. On this basis, prospective future research directions are also provided.

OBJECTIVE: To assess the practical and health economical values of non-invasive prenatal test (NIPT) in Changsha Municipal Public Welfare Program. METHODS: A retrospective analysis was carried out on 149 165 women undergoing NIPT test from April 9, 2018 to December 31, 2019. For pregnant women with high risks, invasive prenatal diagnosis and follow-up of pregnancy outcome were conducted. The cost-benefit of NIPT for Down syndrome was analyzed. RESULTS: NIPT was carried out for 149 165 pregnant women and succeeded in 148 749 cases (99.72%), for which outcome were available in 148 538 (99.86%). 90% of pregnant women from the region accepted the screening with NIPT. 415 (0.27%) were diagnosed as high risk. Among these, 381 (91.81%) accepted amniocentesis, which led to the diagnosis of 212 cases of trisomy 21 (PPV=85.14%), 41 cases with trisomy 18 (PPV=48.81%) and 10 cases with trisomy 13 (PPV=20.83%). The sensitivity and specificity of NIPT for trisomy 21, trisomy 18 and trisomy 13 were (97.70%, 99.98%), (97.62%, 9.97%) and (100%, 99.97%), respectively. In addition, 213 and 30 cases were diagnosed with sex chromosomal aneuploidies (PPV=46.2%) and other autosomal anomalies (PPV=16.57%), respectively. For Down syndrome screening, the cost and benefit of the project was 120.79 million yuan and 1,056.95 million yuan, respectively. The cost-benefit ratio was 1: 8.75, and safety index was 0.0035. CONCLUSION NIPT is a highly accurate screening test for trisomy 21, which was followed by trisomy 18 and sex chromosomal aneuploidies, while it was less accurate for other autosomal aneuploidies. The application of NIPT screening has a high health economical value.
Aneuploidy ; Cost-Benefit Analysis ; Female ; Humans ; Noninvasive Prenatal Testing ; Pregnancy ; Retrospective Studies ; Trisomy 18 Syndrome/genetics*

Bacitracin is a broad-spectrum antibiotics mainly produced by Bacillus, and is used as veterinary medicine in the fields of livestock and poultry breeding. Insufficient supply of precursor amino acids might be an important factor that hinders high-level microbial production of bacitracin. We investigated the effect of strengthening L-cysteine supply on bacitracin production by an industrial bacitracin producer, Bacillus licheniformis DW2. Overexpression of cysK encoding L-cysteine synthase led to a 9.17% increase of the bacitracin titer. Moreover, overexpression of cysE encoding L-serine acetyltransferase and cysP encoding thiosulfate/sulfate intracellular transporter increased the bacitracin titers by 7.23% and 8.52%, respectively. Moreover, overexpression of a putative cystine importer TcyP led to a 29.19% increase of intracellular L-cysteine, and bacitracin titer was increased by 7.79%. Subsequently, the strong promoter PbacA was used to replace the promoters of genes cysP, cysE and tcyP in strain DW2::ysK, respectively. The resulted strain CYS4 (DW2::cysK-PbacA-(cysP)-PbacA(cysE)- PbacA(tcyP) produced 910.02 U/mL bacitracin, which was 21.10% higher than that of the original strain DW2 (747.71 U/mL). Together with the experiments in 3 L fermenters, this research demonstrated that enhancing intracellular L-cysteine supply is an effective strategy to increase bacitracin production of B. licheniformis.
Amino Acids ; Bacillus licheniformis/genetics* ; Bacitracin ; Cysteine ; Metabolic Engineering

Objective:To explore the clinical value of mean platelet volume/platelet count ratio(MPV/PLT)in predicting short-term prognosis of elderly patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD).Methods:A total of 226 elderly patients with AECOPD admitted to our hospital from January 2017 to January 2019 were retrospectively enrolled as research subjects.All cases were divided into the survival group(n=175)and the death group(n=51), based on prognosis 28-day after admission.General data and laboratory test results were compared between the two groups.The relevant factors for death were analyzed by the Logistic regression equation.The receiver operating characteristic(ROC)curve was used to evaluate the prognostic value of MPV/PLT, and the Kaplan-Meier survival curve was drawn according to the cut-off.Methods:Compared with the survival group, Acute Physiology and Chronic Health Status Evaluation(APACHEⅡ)score, levels of procalcitonin(PCT), high-sensitivity C-reactive protein(hs-CRP), creatinine, neutrophil count(NEU), lymphocyte count(LYM)and MPV were elevated, and levels of albumin and PLT decreased in the death group( P<0.05). Hospital stay lengths and costs were higher in the death group than in the survival group( P<0.05). The level of MPV/PLT was higher in the death group than in the survival group(0.065±0.016 vs.0.054±0.013, t=5.036, P<0.01). Multivariate Logistic regression showed that MPV/PLT was an independent risk factor for recent death( OR=2.331, 95% CI: 1.772-8.224, P<0.01). ROC curve analysis showed that the area under the curve(AUC)of MPV/PLT was 0.829, the sensitivity was 83.41%, the specificity was 82.80%, and the cut-off was 0.061.Optimal cut-off value analysis showed that APACHEⅡ score, PCT and hs-CRP levels and mortality were higher in patients with MPV/PLT≥0.061 than in patients with MPV/PLT<0.061( P<0.05). The Kaplan Meier survival curve showed that the cumulative survival rate was lower in those with MPV/PLT≥0.061 than in those with MPV/PLT<0.061( Log- rank=6.323, P<0.05). Conclusions:The increase of MPV/PLT may be an independent risk factor for recent death in elderly patients with AECOPD and has good clinical value in predicting poor prognosis.

Bacitracin is a broad-spectrum cyclic peptide antibiotic, and mainly produced by Bacillus. Energy metabolism plays as a critical role in high-level production of target metabolites. In this study, Bacillus licheniformis DW2, an industrial strain for bacitracin production, was served as the original strain. First, our results confirmed that elimination of cytochrome bd oxidase branch via deleting gene cydB benefited bacitracin synthesis. Bacitracin titer and ATP content were increased by 10.97% and 22.96%, compared with those of original strain, respectively. Then, strengthening cytochrome aa3 oxidase branch via overexpressing gene qoxA was conducive to bacitracin production. Bacitracin titer and ATP content were increased by 18.97% and 34.00%, respectively. In addition, strengthening ADP synthesis supply is also proven as an effective strategy to promote intracellular ATP accumulation, overexpression of adenosine kinase DcK and adenylate kinase AdK could all improve bacitracin titers, among which, dck overexpression strain showed the better performance, and bacitracin titer was increased by 16.78%. Based on the above individual methods, a method of combining the deletion of gene cydB and overexpression of genes qoxA, dck were used to enhance ATP content of cells to 39.54 nmol/L, increased by 49.32% compared to original strain, and bacitracin titer produced by the final strain DW2-CQD (DW2ΔcydB::qoxA::dck) was 954.25 U/mL, increased by 21.66%. The bacitracin titer produced per cell was 2.11 U/CFU, increased by 11.05%. Collectively, this study demonstrates that improving ATP content was an efficient strategy to improve bacitracin production, and a promising strain B. licheniformis DW2-CQD was attained for industrial production of bacitracin.
Bacillus licheniformis ; metabolism ; Bacitracin ; biosynthesis ; Energy Metabolism ; genetics ; Industrial Microbiology ; methods

Bacitracin is a broad-spectrum polypeptide antibiotic, which is formed by 11 amino acids residues. Precursor amino acids supply might be the limit factor during bacitracin fermentation. First, our results demonstrated that increasing Ile and Leu supplies were regarded as the efficient strategies for the enhanced titer of bacitracin. Then, the amino acid permease YhdG, which was identified as the BCAA permease, was deleted and overexpressed in DW2, respectively. Our results showed that knocking out of permease YhdG could improve bacitracin production remarkablely. The bacitracin titer of the yhdG deficient strain DW2ΔyhdG reached 917.35 U/mL by flask fermentation, increased by 11% compared with that of DW2. In addition, the bacitracin titer was decreased by 25% in the YhdG overexpressed strain. Meanwhile, the intracellular concentrations of BCAA were higher than DW2 during the biosynthesis of bacitracin. The above results suggested that the permease YhdG might act as an exporter for branched chain amino acids in B. licheniformis DW2. Taken together, the increasing intracellular concentrations of branched chain amino acids by deleting amino acid permease YhdG could improve bacitracin titer. This study provided a new strategy for high-level production of bacitracin.

Objective To analyze the clinical features and risk factors of invasive fungal infections (IFI) in children with acute leukemia.Methods Ninety-six acute leukemia children complicated with IFI admitted in Guangzhou Women and Children's Medical Center during January 2005 and February 2017 were retrospectively reviewed, and 96 cases of acute leukemia without IFI admitted at the same period were randomly selected as control group.The clinical manifestations of IFI were analyzed, multivariate Logistic regression was used to study risk factors of the complication of IFI in pediatric acute leukemia.Results Among 96 children complicated with IFI, fungus were detected in samples from sputum, bronchoalveolar lavage fluid, or blood in 78 cases, in which 42 cases (43.75％) were oral infection, 36 cases (37.50％) were pulmonary infection.Candida albicans (33.33％, 26/78) was the most commonly isolated pathogen, followed by Candida parapsilosis (20.51％, 16/78) and Candida tropicalis (20.51％, 16/78).Univariate analysis revealed hormone-containing chemotherapy, neutropenia (＜ 0.5 × 109/L), time duration of neutropenia ≥ 10 days, usage of carbapenem antibiotics and combined drug administration ≥2 types were associated with fungal infection (P ＜ 0.05 or ＜0.01).Multivariate Logistic regression showed that the time duration of neutropenia ≥ 10 days (OR =11.390, 95％ CI 4.145-55.263, P ＜ 0.01),usage of carbapenem antibiotics (OR =4.825, 95％ CI 1.681-13.842, P ＜ 0.01) and hormone-containing chemotherapy (OR =2.220, 95％ CI 1.542-8.246, P ＜ 0.05) were the independent risk factors of IFI.Conclusion Rational usage of antibiotics and effective measures taken to restore the granulocytes can help to reduce the incidence of IFI in children with acute leukemia.