Alzheimer disease(AD)is a common neurodegenerative disease with overall cognitive deterioration and mental and behavioral disorders,and due to unknown etiology and pathogenesis of AD,there is currently no effective medi-cation for AD.As a new noninvasive neuromodulation method,repetitive transcranial magnetic stimulation(rTMS)can improve cognitive impairment in patients with AD by regulating multiple pathways such as neural activity,synaptic plastic-ity,neurotransmitters,and neurotrophic factors.This article reviews the studies on the mechanism of action of rTMS in the treatment of AD in recent years,in order to clarify the mechanisms of rTMS such as anti-oxidation and regulation of synaptic plasticity.

Objective:To explore the value of a nomogram model based on the CT enterography (CTE) signs for prediction of intestinal penetrating lesions in patients with Crohn disease (CD).Methods:The clinical and CTE data of CD patients who underwent at least two CTE examinations from January 2010 to June 2020 in the First Affiliated Hospital of Sun Yat-sen University were retrospectively collected. A total of 112 patients were enrolled, and according to whether there was intestinal wall penetration in the last CTE observation were divided into non-penetration group (84 cases) and penetration group (28 cases). First, the clinical and CTE data for the first examination was analyzed by using univariate and multivariate Cox proportional hazards regression to screen out high-risk factors that could effectively predict intestinal wall penetrating lesions in CD patients and established a nomogram model. Then the change trend of CTE data (ΔCTE) between the first and last clinical and CTE signs was analyzed by using univariate and multivariate Cox proportional hazards regression, and built a nomogram model to sort out ΔCTE that may accompany the development of penetrating lesions in CD patients. The Harrell concordance index was used to evaluate the discriminative ability of the nomogram model.Results:In the first time clinical and CTE signs, multivariate Cox proportional hazards regression results showed that numbers of diseased bowel segments (HR=0.686, 95%CI 0.475-0.991, P=0.045) and the shortest diameter of the largest lymph node (HR=0.751, 95%CI 0.593-0.949, P=0.017) were independent protection factors for penetrating lesions, and rough bowel wall surface (HR=5.626, 95%CI 2.466-12.839, P<0.001) was an independent risk factor for penetrating lesions. The specificity and sensitivity of the nomogram model to predict non-penetration lesions were 82.1% and 59.5% respectively, and the Harrell concordance index was 0.810 (95%CI 0.732-0.888). In the ΔCTE signs, multivariate Cox proportional hazards regression showed that Δrough bowel wall surface (always rough bowel wall surface HR=12.344, 95%CI 2.042-74.625, P=0.006; slide bowel wall surface becomes rough bowel wall surface HR=28.720, 95%CI 4.580-180.112, P<0.001) and Δthe shortest diameter of the largest lymph node (HR=1.534, 95%CI 1.091-2.157, P=0.014) were independent risk factors for penetrating lesions. The specificity and sensitivity of the nomogram model were 89.3% and 79.2% respectively, and the Harrell concordance index was 0.876 (95%CI 0.818-0.934). Conclusion:The nomogram based on CTE signs of numbers of diseased bowel segments, the shortest diameter of the largest lymph node and rough bowel wall surface and ΔCTE can effectively predict the intestinal wall penetrating lesions of CD patients.

Early diagnosis of pulmonary diseases is of great significance for their prevention and treatment. Serum Krebs von den Lungen-6 (KL-6) assay can reflect the damage degree of alveolar epithelium and stromal tissue, and is simple, non-invasive and low-cost. Pervious study showed that the serum KL-6 level was higher in patients with various interstitial lung diseases (e.g. idiopathic pulmonary fibrosis and connective tissue disease, primary Sjögren's syndrome, rheumatoid arthritis, idiopathic inflammatory myopathy and systemic sclerosis combined with interstitial lung disease), non-small cell lung cancer, various pneumonias and chronic obstructive pulmonary disease compared to healthy controls. Therefore, serum KL-6 has good sensitivity and specificity for the early diagnosis of these diseases. Occupational pneumoconiosis is an interstitial lung disease with a well-established etiology. Pervious study has shown that serum KL-6 level was higher in patients with occupational silicosis, occupational asbestosis, and dust-exposed workers compared to healthy controls. However, due to the limited sample size and the inconsistent findings on different studies, further research is needed to study the role of serum KL-6 in the early diagnosis of pneumoconiosis. Future studies should increase the sample size, improve the detection methods for serum KL-6, explore its feasibility as an early diagnostic biomarker for occupational pulmonary diseases, and investigate the efficacy andvalue of its combined application with other biomarkers in the early diagnosis of various pulmonary diseases, including occupational lung diseases, to fully exploit its predictive role in pulmonary diseases.

Chronic hepatitis B is a public health issue worldwide. Nucleotide analogues and interferon therapy can effectively inhibit HBV replication, but they still have the shortcomings such as inability to achieve the clearance of HBV cccDNA and low HBsAg clearance rate. The academic viewpoint of "kidney-tonifying therapy for chronic hepatitis B" provides new ideas and methods for the treatment of hepatitis B. During long-term clinical practice, Department of Hepatology in Shuguang Hospital has identified that "deficiency of spleen and kidney with damp heat remaining" is the key pathogenesis of the continuous progression of chronic hepatitis B and has established the treatment regimen for chronic hepatitis B with the basic treatment method of tonifying the kidney, strengthening the spleen, and promoting diuresis. The clinical research of National Science and Technology Major Project from The 11th Five Year Plan to The 13th Five Year Plan has validated the clinical efficacy of this regimen and clarified that regulating the immune function of the body is the main mechanism of the kidney-tonifying, spleen-strengthening, and diuresis-promoting therapy in the treatment of chronic hepatitis B.

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies ΔG _FEP between ligands and their target, which were more consistent with the experimental binding potencies ΔG _EXP (the mean absolute deviations | Δ G FEP - Δ G EXP |  < 2 kcal/mol) than those ΔG _MM-PBSA or ΔG _MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC₅₀ of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery.

Objective To investigate the effect of naringenin on the killing rate of natural killer (NK) cells and related mechanism by amplification of human peripheral blood mononuclear cells into NK cells in vitro and co-culture with hepatocellular carcinoma (HCC) CLC5 cells at a ratio of 1∶ 1. Methods A lymphocyte separation medium was used to isolate human peripheral blood mononuclear cells, which were induced with recombinant human interleukin-2 in vitro to culture NK cells. CCK-8 assay was used to measure the proliferation of HCC cells after human HCC cells were treated with naringenin (0, 3.125, 6.25, 12.5, 25, and 50 μmol/L) for 0, 24, and 48 hours, and after human NK cells were treated with different concentrations of naringenin for 24 hours, CCK-8 assay was used to measure the proliferation of NK cells. CellTiter-LumiTM was used to measure the killing rate of NK cells after the NK-HCC cell co-culture system at the ratio of 1∶ 1 was treated with naringenin for 24 hours. Quantitative real-time PCR was used to measure the gene expression of the activating receptor NKG2D in NK cells and NKG2D ligands in HCC cells. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. Results After being induced and cultured by recombinant human interleukin-2, NK cells were amplified to 82.33%±0.70% of human peripheral blood mononuclear cells. After naringenin treatment for 24 hours, there was no significant difference in the proliferation rate of HCC CLC5 cells between all mass concentration groups (all P > 0.05), and in the 25 and 50 μmol/L mass concentration groups, naringenin significantly promoted the proliferation of NK cells (both P < 0.000 1). After the NK-HCC cell co-culture system at the ratio of 1∶ 1 was treated with naringenin for 24 hours, there was a significant increase in the killing rate of NK cells in the 25 and 50 μmol/L mass concentration groups (both P < 0.000 1). After the co-culture system was treated with naringenin for 24 hours, naringenin had no effect on the expression of NKG2D in NK cells in the 25 and 50 μmol/L mass concentration groups, and it also had no effect on the expression of MICB and ULBP2 in HCC cells (all P > 0.05); it significantly upregulated the expression of the NKG2D ligands such as ULBP1 and ULBP3 in HCC cells (all P < 0.001). Conclusion Naringenin may increase the killing activity of NK cells by upregulating the expression of NKG2D ligands in HCC cells.

Objective:To develop a mesenteric creeping fat index (MCFI) based on CT enterography (CTE) to characterize the degree of creeping fat wrapping around the inflamed gut in Crohn disease (CD), and to assess the relationship between MCFI and the inflammatory intestinal stricture.Methods:From December 2018 to July 2019, the patients with CD who underwent surgery in the First Affiliated Hospital of Sun Yat-Sen University were prospectively collected. The extent of perienteric mesenteric vessels wrapping around the gut was reconstructed to develop MCFI based on CTE images. The intestinal stricture index was obtained by calculating the ratio of the maximal upstream luminal diameter divided by the minimum luminal diameter apparent within the stricturing region. Using region-by-region correlation between CTE and surgical specimen, creeping fat score in intestinal specimen was obtained by assessing the extent of creeping fat wrapping around the resected bowel segment, and HE staining was performed on the bowel specimen corresponding to creeping fat to obtain the pathological inflammatory score. The Spearman correlation analysis was used to evaluate the correlation between MCFI, creeping fat score in intestinal specimen, and inflammatory score, intestinal stricture index. The ROC curve analysis was used to assess the accuracy of MCFI in distinguishing moderate-severe and mild inflammatory bowel walls.Results:Totally 30 CD patients were enrolled. The creeping fat score in intestinal specimen positively correlated with pathological inflammatory score ( r s=0.403, P=0.027) and with intestinal stricture index ( r s=0.642, P<0.001). MCFI positively correlated with creeping fat score in intestinal specimen ( r s=0.840, P<0.001), with pathological inflammatory score ( r s=0.497, P=0.005), and with intestinal stricture index ( r s=0.599, P<0.001). ROC analysis showed that the area under the curve of MCFI for differentiating moderate-severely from mildly inflammatory bowel walls was 0.718 (95%CI 0.522-0.913). Using MCFI≥4 as a cutoff value, the sensitivity and specificity were 81.8% and 47.4%, respectively. Conclusions:There was a correlation between creeping fat and inflammatory intestinal strictures in CD. MCFI can non-invasively depict the degree of creeping fat wrapping around the gut and assess the inflammatory intestinal stricture.

Objective:To construct the index system of the core competence of nursing emergency personnel in the case of infectious disease outbreak, and to provide reference basis for the assessment and training of the core competence of nursing emergency personnel.Methods:Based on the core competence indicators of nurses defined by the International Nurses' Association and the action framework of WHO's outbreak of infectious diseases as the theoretical framework, the item pool was summarized through semi-structured interviews and research group meetings, the Delphi expert letter consultation method was used to construct the indicator system, and the analytic hierarchy process and the average distribution method were used to determine the weight of indicators at all levels.Results:Two rounds of Delphi expert letter consultation, 36 questionnaires were issued in each round, and the effective recovery rate was 86% (31) and 92% (33), respectively.Finally, it was determined that the core competence index system of nursing emergency personnel for infectious disease emergencies included 5 first-level indicators, 13 second-level indicators and 53 third-level indicators. The coefficient of variation ranged from 0 to 0.173, the weight ranged from 0.074 to 0.525, and the balanced combination weight ranged from 0.165 to 0.266.Conclusion:The index system of the core competence of nursing emergency personnel in infectious disease emergencies is comprehensive and scientific, which can provide theoretical basis for evaluating and training the core competence of nursing emergency personnel in infectious disease emergencies.

ObjectiveTo investigate the effect of sustained virologic response on disease progression and the development of hepatocellular carcinoma (HCC) in patients with compensated hepatitis B cirrhosis receiving antiviral therapy with nucleos(t)ide analogues (NAs). MethodsA total of 542 patients with compensated hepatitis B cirrhosis who attended Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from January 1 to December 31, 2013, received antiviral therapy, and were followed up for more than 5 years were enrolled, and according to the status of virologic response during follow-up, they were divided into a sustained virologic response cohort with 496 cases and a non-sustained virologic response cohort with 46 cases. With disease progression as the outcome event, general information and examination data were collected during the 5-year follow-up period. The t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. A multivariate logistic regression analysis was performed; relative risk and 95% confidence interval (CI) were used to investigate the degree of correlation of factors measured with the progression of liver cirrhosis. The life-table method was used to calculate the 1-, 3-, and 5-year progression-free survival rates, and the Kaplan-Meier method was used to plot survival curves; the log-rank test was used for univariate analysis, and the Cox regression model was used for multivariate regression analysis. ResultsFor the 542 patients, the mean progression-free survival time was 62.50 months (95% CI: 61.01-63.92), and the 1-, 3-, and 5-year progression-free survival rates were 94%, 82%, and 71%, respectively. The sustained virologic response cohort had a significantly longer mean progression-free survival time than the non-sustained virologic response cohort ［63.10 months (95% CI: 61.65-64.55) vs 55.95 months (95% CI: 50.19-61.71), χ2=12.058, P=0.001］. Compared with the non-sustained virologic response cohort, the sustained virologic response cohort had significantly lower 5-year cumulative incidence rate of HCC than (20.6% vs 34.8%, χ2=5.759, P=0.016) and 5-year cumulative incidence rate of decompensated cirrhosis (5.0% vs 15.2%, χ2=8.239, P=0.004). Virologic response was an independent risk factor for disease progression (hazard ratio=232, 95% CI: 1.45-3.72). ConclusionSustained virologic response can reduce the incidence rates of complications and HCC, improve long-term prognosis, and prolong survival time in patients with compensated hepatitis B cirrhosis.

OBJECTIVE: To establish a novel standardized magnetization transfer ratio (MTR) parameter which considers the element of the normal bowel wall and to compare the efficacy of the MTR, normalized MTR, and standardized MTR in evaluating intestinal fibrosis in Crohn's disease (CD).MATERIALS AND METHODS: Abdominal magnetization transfer imaging from 20 consecutive CD patients were analyzed before performing elective operations. MTR parameters were calculated by delineating regions of interest in specified segments on MTR maps. Specimens with pathologically confirmed bowel fibrosis were classified into one of four severity grades. The correlation between MTR parameters and fibrosis score was tested by Spearman's rank correlation. Differences in MTR, normalized MTR, and standardized MTR across diverse histologic fibrosis scores were analyzed using the independent sample t test or the Mann-Whitney U test. The area under the receiver operating characteristic curve (AUC) was computed to test the efficacies of the MTR parameters in differentiating severe intestinal fibrosis from mild-to-moderate fibrosis.RESULTS: Normalized (r = 0.700; p < 0.001) and standardized MTR (r = 0.695; p < 0.001) showed a strong correlation with bowel fibrosis scores, followed by MTR (r = 0.590; p < 0.001). Significant differences in MTR (t = −4.470; p < 0.001), normalized MTR (Z = −5.003; p < 0.001), and standardized MTR (Z = −5.133; p < 0.001) were found between mild-to-moderate and severe bowel fibrosis. Standardized MTR (AUC = 0.895; p < 0.001) had the highest accuracy in differentiating severe bowel fibrosis from mild-to-moderate bowel wall fibrosis, followed by normalized MTR (AUC = 0.885; p < 0.001) and MTR (AUC = 0.798; p < 0.001).CONCLUSION: Standardized MTR is slightly superior to MTR and normalized MTR and therefore may be an optimal parameter for evaluating the severity of intestinal fibrosis in CD.
Crohn Disease ; Fibrosis ; Humans ; Magnetic Resonance Imaging ; ROC Curve