Objective:To investigate differences in bacterial and fungal microbiome between infected nails and healthy nails among patients with onychomycosis.Methods:Nail scraping samples were collected from infected nails and healthy nails of 31 patients with onychomycosis, who visited Dalian Dermatosis Hospital from August 2020 to July 2021. The total DNA of nail microbiota was extracted, and the V3-V4 regions of the bacterial 16S rDNA gene and the fungal internal transcribed spacer (ITS) region were amplified and sequenced using Illumina technology. The USEARCH and mothur softwares were used for data cluster analysis to obtain the operational taxonomic units (OTUs) , Wilcoxon rank sum test was used to analyze α diversity, analysis of similarities (ANOSIM) was performed to analyze β diversity, linear discriminant analysis of effect size (LEfSe) was performed to evaluate the species difference.Results:Among the 31 patients with onychomycosis, 16 were males and 15 were females. According to the age, they were divided into young group (18 - 35 years old, 10 cases) , middle-aged group (36 - 60 years old, 11 cases) , and elderly group (over 60 years old, 10 cases) . As the α-diversity analysis revealed, the infected nail group showed significantly decreased Shannon index ( W = 290, P = 0.007) , but significantly increased Simpson index ( W = 663, P = 0.010) compared with the healthy nail group, suggesting that the diversity and evenness of bacterial communities were lower in the infected nail group than in the healthy nail group; however, there was no significant difference in the diversity of fungal communities between the infected nail group and healthy nail group. The β-diversity analysis based on the unweighted-UniFrac distance matrix showed no significant difference in the fungal or bacterial community composition between the infected nail group and healthy nail group (bacterial communities: R = 0.0052, P = 0.331; fungal communities: R = 0.0036, P = 0.337) ; the β-diversity analysis based on the weighted-UniFrac distance matrix showed significant differences in the abundance of bacterial and fungal communities between the two groups (both P = 0.001) . In terms of the species composition, the bacterial flora with significantly decreased abundance in the infected nail group compared with the healthy nail group included Bacteroidetes, Proteobacteria, Betaproteobacteria, Burkholderiales, Ralstonia, Sphingomonas and Streptococcus, while the abundance of Bacilli, Bacillales and Staphylococcus was significantly higher in the infected nail group than in the healthy nail group. Compared with the healthy nail group, the fungal flora with significantly increased abundance in the infected nail group included Eurotiomycetes, Onygenales, Leotiomycetes-ord-incertae-sedis, Arthrodermataceae, Periconia, Erysiphe, Tilletiopsis, Trichophyton, Erysiphe cruciferarum, Trichophyton rubrum, Malassezia sympodialis, while the abundance of Saccharomycetes, Saccharomycetales, Saccharomycetaceae, Dothioraceae, Candida and Alternaria was significantly lower in the infected nail group than in the healthy nail group. Conclusion:The diversity and abundance of bacterial communities significantly differed between infected nails and healthy nails among patients with onychomycosis, while only the abundance of fungal communities differed between the two groups, and perhaps there was correlations between some bacterial and fungal communities.

Objective:To evaluate the effect of Empagliflozin on the incidence of major adverse cardiovascular events(MACE)in elderly patients with heart failure and reduced ejection fraction(HFrEF)over a period of 1 year.Additionally, the study will analyze the influence of frailty on MACE.Methods:This study is a retrospective analysis of 577 elderly patients with type 2 diabetes and heart failure with reduced ejection fraction(HFrEF)who were consecutively admitted to Beijing Anzhen Hospital from January 2018 to December 2020.The patients were divided into three groups according to frailty index(FI): non-frailty(FI ≤ 0.210, 301 cases), moderate frailty(FI 0.211-0.310, 184 cases), and severe frailty(FI>0.311, 92 cases).Additionally, a control group of 300 elderly HFrEF patients with T2DM who did not receive Sodium glucose co-transporter type 2(SGLT-2)inhibitors was included.The MACE outcomes of different patient groups who were followed up for a year after discharge were compared.The composite outcomes of cardiac death, worsening heart failure readmission, non-fatal myocardial infarction, and non-fatal stroke were recorded and analyzed.The study also includes Cox regression analysis of relevant factors that may affect MACE outcomes.Results:A total of 877 patients were monitored for a period of 7-14 months, with a median follow-up duration of(11.4±2.3)months.Out of these patients, 47(5.4%)were lost to follow-up.During the follow-up period, 108 patients(18.7%)in the Empagliflozin group experienced major adverse cardiovascular events(MACE), which included 43 patients(7.5%)with heart failure readmission, 29 patients(5.0%)with non-fatal myocardial infarction, 23 patients(4.0%)with non-fatal stroke, and 13 patients(2.3%)with cardiovascular death.The control group had 73 cases of major adverse cardiac events(MACE), which included 33 cases(11.0%)of readmission due to heart failure, 18 cases(6.0%)of non-fatal myocardial infarction, 14 cases(4.7%)of non-fatal stroke, and 8 cases(2.7%)of cardiovascular death.The Kaplan-Meier survival analysis revealed significant differences in the risk of readmission for heart failure exacerbation and MACE among the groups.The study found that the Empagliflozin group had a significantly lower risk of MACE(18.7% vs.24.3%, HR=0.792, 95% CI: 0.639-0.982, P=0.033)compared to the control group.Additionally, as frailty level increased, the risk of MACE in each empagliflozin subgroup also increased significantly(14.6% vs.19.6% vs.30.4%, P<0.001).The moderate and severe frailty groups had a 1.342 times( HR=1.342, 95% CI: 1.116-1.768, P=0.022)and 1.933 times( HR=1.933, 95% CI: 1.207-3.854, P=0.019)higher risk of MACE compared to the non-frailty group.The study conducted a multivariate Cox regression analysis and found that several factors were independently associated with the risk of MACE, including age( HR=1.164), duration of heart failure( HR=1.225), B-type natriuretic peptide level( HR=1.221), albumin/creatinine ratio( HR=1.158), renin-angiotensin-aldosterone system blocker( HR=0.891), frailty index( HR=1.764), and empagliflozin( HR=0.792)( P<0.05 for all). Conclusions:Empagliflozin has been shown to reduce the risk of major adverse cardiovascular events(MACE)in patients with heart failure with reduced ejection fraction(HFrEF).However, it is important to note that the cardiovascular benefits of SGLT-2 inhibitors may be affected by frailty in elderly patients with heart failure.As frailty worsens, the risk of readmission and MACE may increase significantly.

Influenza is an acute respiratory infection caused by influenza viruses (IFV), According to the World Health Organization (WHO), seasonal IFV epidemics result in approximately 3-5 million cases of severe illness, leading to about half a million deaths worldwide, along with severe economic losses and social burdens. Unfortunately, frequent mutations in IFV lead to a certain lag in vaccine development as well as resistance to existing antiviral drugs. Therefore, it is of great importance to develop anti-IFV drugs with high efficiency against wild-type and resistant strains, needed in the fight against current and future outbreaks caused by different IFV strains. In this review, we summarize general strategies used for the discovery and development of antiviral agents targeting multiple IFV strains (including those resistant to available drugs). Structure-based drug design, mechanism-based drug design, multivalent interaction-based drug design and drug repurposing are amongst the most relevant strategies that provide a framework for the development of antiviral drugs targeting IFV.

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.

Objective:To investigate the predictive value of Graeb score for the outcome of high-grade aneurysmal subarachnoid hemorrhage (aSAH) patients with intraventricular hemorrhage (IVH).Methods:Consecutive high-grade aSAH patients with IVH admitted to the No. 1 People's Hospital of Jiujiang from January 2012 to March 2020 were enrolled retrospectively. High-grade aSAH was defined as grade Ⅳ to Ⅴ according to the World Federation of Neurological Surgeons (WFNS) scale. The outcome of patients was evaluated by the modified Rankin Scale (mRS) at 3 months after discharge. A score of ≤2 was defined as a good outcome and a score of >2 were defined as a poor outcome. Multivariate logistic regression model was used to evaluate the correlation between Graeb score and clinical outcome, and the receiver operating characteristic (ROC) curve was used to determine the predictive value of Graeb score for clinical outcome. Results:A total of 86 high-grade aSAH patients with IVH were enrolled. Aneurysm treatment: craniotomy clipping in 42 patients (48.8%), intravascular embolization in 21 (24.4%), and conservative treatment in 23 (26.7%). Twenty-nine patients (33.7%) had a good outcome and 57 (66.3%) had a poor outcome. Multivariate logistic regression analysis showed that the Graeb score >6 (odds ratio [ OR] 26.360, 95% confidence interval [ CI] 4.106-169.235; P<0.001), the modified Fisher grade 3-4 ( OR 11.674, 95% CI 1.540-88.512; P=0.017) and complicated with chronic hydrocephalus ( OR 21.236, 95% CI 2.883-156.431; P=0.003) were the independent risk factors for the poor outcome. ROC curve analysis showed that the area under the curve of the Graeb score predicting for poor outcome was 0.843 (95% CI 0.760-0.926; P<0.001), the best cut-off value was 6.5, and the corresponding sensitivity and specificity were 71.9% and 86.2%, respectively. Conclusion:The Graeb score is an independent influencing factor affecting the clinical outcome of high-grade aSAH patients with IVH. Graeb score >6.5 had higher predictive value for the poor outcome in such patients.

Objective:To evaluate the safety and efficacy of endoscopic resection in the treatment of patients with primary non-ampullary duodenal early cancer.Methods:A total of 20 cases with primary non-ampullary duodenal early cancer receiving endoscopic resection were collected from Jan 2015 to Dec 2019 at the Department of Endoscopy, the First Affiliated Hospital of Shandong First Medical University.Results:The size of lesions ranged from 0.3-2.5 cm (0.9±0.5)cm.The size of removed membrane samples ranged from 1.5-3.5 cm (2.5±0.7)cm. The edges were all negatiue pathologically. Duodenal perforation occurred in 2 cases, and all were successfully clipped by endoscopy. The follow-up time was from 4-42 months (20.4±11.4)m and no recurrence was found.Conclusion:Endoscopic resection is a safe and effective method for primary non-ampullary duodenal early cancer.

BACKGROUND: Targeted therapy for patients with driver genes positive and immunotherapy for patients with driver gene-negative but high programmed death ligand 1 (PD-L1) expression are the standards of first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). The treatment options for patients with driver gene positive and high PD-L1 expression are still worth exploring. METHODS: The characteristics of 315 patients with NSCLC were identified to analyze the clinicopathological characteristics of patients with driver gene positive and high PD-L1 expression, and the efficacy of targeted therapy. RESULTS: Among the 315 patients, the total positive rate of driver genes was 62.2%, and the high PD-L1 expression rate (≥50.0%) was 11.2%. The proportion of patients with driver gene positive and high PD-L1 expression was 10.7%. PD-L1 was highly expressed in patients with epidermal growth factor receptor (EGFR) mutation, KRAS mutation, ALK fusion, BRAF mutation, and MET 14 exon skip mutation, the proportions were 7.8% (11/141), 18.2% (4/22), and 23.1%, (3/13), 50.0% (2/4) and 100.0% (1/1) respectively. EGFR mutation positive with PD-L1 high expression was mainly in patients with stage IV lung adenocarcinoma. KRAS mutation positive with PD-L1 high expression was mainly in patients with a history of smoking. Among them, two patients were followed in detail for targeted therapy, who with ALK fusion-positive and PD-L1 high expression (90.0%), EGFR L858R mutation and PD-L1 high expression (70.0%) respectively. The total OS of the patients was 5 months, 2 months. CONCLUSIONS The high PD-L1 expression rate in NSCLC patients with different driver gene mutations was variable, which maybe correlated with distinct clinicopathological characteristics. Patients with sensitive mutations and high PD-L1 expression may be less benefit from targeted therapy and have poor prognosis.

BACKGROUND: Immunotherapy represented by immune checkpoint inhibitors (ICIs) has been widely used in the treatment of lung cancer. There are controversies in clinical practice for patients with advanced non-small cell lung cancer (NSCLC) and high programmed cell death-ligand 1 (PD-L1) expression receiving ICIs monotherapy or combination chemotherapy. METHODS: This study retrospectively analyzed the clinical data of 49 patients with advanced NSCLC and high PD-L1 expression. Immunohistochemistry was performed with 22C3 antibody, and the expression level of PD-L1 was evaluated according to tumor proportion score (TPS). Objective response rate (ORR) and progression free survival (PFS) were compared by groups of different clinical characteristics. RESULTS: ORR of monotherapy and combination therapy group was 47.1% (8/17) and 43.8% (14/32), respectively, without statistical difference (P=0.825). The median PFS of monotherapy and combination therapy group was 8.0 months and 6.8 months, respectively, without statistical difference (P=0.502). Statistical analysis of predictors of immunotherapy for the patients showed first-line immunotherapy had better ORR than subsequent immunotherapy (12/19, 63.2% vs 10/30, 33.3%, P=0.041), however no difference in PFS. And there were no differences in ORR or PFS among groups of age, gender, smoking status, performance status (PS), pathological type, tumor size and tumor-node-metastasis (TNM) stage. CONCLUSIONS The therapeutic effect is similar between ICIs monotherapy and combination chemotherapy for patients with advanced NSCLC and high PD-L1 expression. ORR of first-line immunotherapy was better in patients with advanced NSCLC and high PD-L1 expression. The optimal treatment for this population remains further prospective clinical studies.

BACKGROUND: Immune checkpoint inhibitor monotherapy is reported to have little effect in advanced non-small cell lung cancer (NSCLC) patients with driver oncogenes. However, recent studies have shown that some patients with driver genes are still benefit from combination immunotherapy after tyrosine kinase inhibitors (TKIs) drug resistance. The purpose of this study was to analyze the efficacy of posterior line immunotherapy in NSCLC patients with epidermal growth factor (EGFR) sensitive mutation, and to evaluate the value of immunotherapy in posterior line therapy in patients with advanced EGFR mutation. METHODS: A total of 27 patients with EGFR mutation diagnosed in Beijing Chest Hospital, Capital Medical University from June 2018 to November 2020 were collected. After the progress of targeted therapy, they had received programmed cell death protein 1 (PD-1) checkpoint inhibitor combined with chemotherapy and anti-angiogenic drug therapy. RESULTS: Of the 27 advanced NSCLC patients, 19 cases (70.4%) did not have T790M mutation. There were 8 cases (29.6%) with T790M point mutation. The total objective response rate (ORR) was 40.7%. Kaplan-Meier survival analysis showed that there was no statistically significant difference among different EGFR mutations (χ²=4.15, P=0.230). But progression-free survival (PFS) was significantly longer in patients without T790M mutation than in patients with T790M mutation (9.2 mon vs 3.3 mon, χ²=2.808, P=0.041), and the same trend was observed in patients with overall survival treated with the PD-1 inhibitor (12.2 mon vs 7.3 mon, χ²=3.22, P=0.062). ORR of patients without T790M was significantly better than that with T790M (52.63% vs 12.5%, P=0.045). CONCLUSIONS Patients with EGFR mutation can benefit from later-line combined immunotherapy. The patients with T790M mutation in the population of EGFR mutation had the worst effect of immunotherapy in the later line. Therefore, the follow-up treatment and whole-course management of these patients need to explore better treatment strategies to improve the benefit.

Objective:To evaluate the clinical efficacy and safety of SpyGlass-guided laser lithotripsy for large common bile duct (CBD) stones with diameter>2 cm.Methods:From August 2015 to August 2018, a total of 157 patients with large CBD stones at the First Affiliated Hospital of Shandong First Medical University who met the inclusion criteria were randomly divided into SpyGlass group ( n=78, underwent SpyGlass-guided laser lithotripsy) and laparoscopic common bile duct exploration (LCBDE) group ( n=79, underwent LCBDE) by using random numbers. Non-inferiority test was used for rates of one-time stone removal and total stone removal, and the non-inferiority margin was set to 10%. The transform rate, incidence of short-term complications, hospital stay, and quality of life (assessed by the gastrointestinal quality of life index) were compared between the two groups. Results:The total success rates of stone clearance were 92.3% (72/78) and 96.2% (76/79) in the SpyGlass group and LCBDE group, respectively ( P=0.023), with valid non-inferiority hypothesis. The one-time stone removal rates were 83.3% (65/78) and 96.2% (76/79), respectively ( P=0.124), with invalid non-inferiority hypothesis. There were no significant differences in the incidence of transform [7.7% (6/78) VS 3.8% (3/79), P=0.294] or short-term complications [5.1% (4/78) VS 10.1% (8/79), P=0.246] between the two groups. Compared with the LCBDE group, the SpyGlass group had a shorter hospital stay (5.65±0.94 d VS 8.84±1.54 d, P=0.001) and higher scores of gastrointestinal quality of life index (1 month after operation: 99.85±4.36 VS 91.51±5.47, P=0.001; 3 months after operation: 131.24±3.32 VS 112.32±7.77, P=0.001). Conclusion:For large CBD stones, the efficacy of SpyGlass-guided laser lithotripsy is not inferior to LCBDE, and it is less invasive. In the future, SpyGlass-guided laser lithotripsy could be an important option for the treatment of large CBD stones.