Evidence-based medicine (EBM) is a science that uses the best available research data to make decisions, and the core is that clinical decision-making is supported by the best research evidence. Incorporating EBM into traditional standardized residency training in hematology can foster residents' professional theoretical knowledge and clinical skills, improve the quality of standardized training, and provide ideas and methods for standardized training of hematology residents, which is worthy of further research and exploration.

Mitochondrial and peroxisome fission deficiency-related encephalopathy caused by DNM1L gene mutation is a rare and fatal epileptic encephalopathy, with clinical phenotype and genetic heterogeneity. The acute stage is drug-resistant epilepsy with poor prognosis and serious neurological sequelae. A case of genetically confirmed encephalopathy related to mitochondrial and peroxisome fission defects is reported, the clinical data, treatment process are summarized, and the previous literature is reviewed to improve the understanding of the rare disease.

Objective:To identify the genetic variation in a mucopolysaccharidosis type Ⅱ(MPS Ⅱ)family, and conduct a functional study of iduronate-2-sulfatase(IDS): c.323A>C.Methods:A five-generation MPS Ⅱ family of 83 individuals including 4 patients from northern China was collected. Urine mucopolysaccharide and Alder-Reilly body were tested to assist the clinical diagnosis of MPS Ⅱ. IDS enzyme activity was detected on core family members. By the whole exome sequencing of a MPS Ⅱ patient in this family and bioinformatics analysis, the variant was screened and further identified by PCR-Sanger sequencing. Finally, to validate the function of the variant in vitro, the wild-type IDS overexpression plasmid(pCMV-hIDS-WT)and the IDS overexpression plasmid carrying the mutation site(pCMV-hIDS-c.323A>C)were transfected into COS-7 cells and the IDS activity was detected. Results:The proband(Ⅳ3)and Ⅳ4 were diagnosed as MPS Ⅱ by urine mucopolysaccharide, Alder-Reilly body, and IDS enzyme activity tests. Ⅳ3, Ⅳ4, Ⅲ19, and Ⅲ32 were determined to carry IDS: c.323A>C missense variant through the whole-exome sequencing, and diagnosed as MPS Ⅱ. Meanwhile, Ⅱ2, Ⅱ4, Ⅱ8, Ⅱ12, Ⅱ14, Ⅲ5, Ⅲ7, Ⅳ14 in the MPS Ⅱ family carried IDS: c.323A>C missense variant, and were excluded as MPS Ⅱ. The in vitro experiment in COS-7 cells showed that the missense mutation led to a significant decrease in IDS enzyme activity. Conclusion:The variant IDS: c.323A>C: p.Y108S significantly decreases the activity of IDS enzyme in vivo and in vitro, and it is identified as a pathogenic variant for MPS Ⅱ.

Objective:To investigate the clinical characteristics and risk factors of multiple tophi among gout patients.Methods:Gout patients treated at Affiliated Hospital of Qingdao University from September 2017 to September 2021 were included retrospectively. According to the number of tophi, the patients were divided into the multiple tophi group, the single tophi group and the non-tophi group. Clinical data were collected, biochemical indices and urine pH value were determined. One- way ANOVA or Chi-square test was used to compare groups, and multivariate logistic regression was used to analyze the risk factors. Results:The age, disease course, blood pressure, serum uric acid, urea nitrogen, and the rate of family history, smoking, drinking, gout attacks≥2 twice per year, hypertension, cardio-cerebrovascular diseases, kidney stones in the multiple tophi group were significantly higher than those in the single tophi group and the non-tophi group. The glomerular filtration rate, urine pH value and the rate of regular exercise were significantly lower than those of single tophi group and non-tophi group. In the multiple tophi group, 245 cases(44.46%) were involved in the interphalangeal joint or metacarpophalangeal joint, 212 cases(38.47%) were involved in other joints of the upper limb, which was second only to the first metatarsophalangeal joint(349 cases, 63.33%). Logistic regression analysis showed that the course of disease, urea nitrogen, serum uric acid, positive family history, drinking, gout attacks ≥twice per year and hypertension were the risk factors for multiple tophi in gout patients. Conclusion:Patients with a long disease course, elevated uric acid, high urea nitrogen, positive family history, alcohol consumption, frequent gout flare and hypertension are more likely to develop multiple tophi.

Objective:To investigate the effect of digoxin on bleomycin-induced pulmonary fibrosis in mice, and investigate its possible mechanism through in vitro and in vivo experiments. Methods:① In vivo experiment: 60 C57/BL6J mice were randomly divided into control group, pulmonary fibrosis model group (model group), pirfenidone (300 mg/kg) group, digoxin 1.0 mg/kg and 0.2 mg/kg groups, with 12 mice in each group. The pulmonary fibrosis model of mice was reproduced by single intratracheal infusion of bleomycin (5 mg/kg). The control group was given the same amount of sterile normal saline. From the next day after modeling, each group was received corresponding drugs by intragastric administration once a day for 28 days. Control group and model group were given the same amount of normal saline. The mice were sacrificed and the lung tissue was collected to detect the lung coefficient. After hematoxylin-eosin (HE) and Masson staining, the lung tissue morphology and collagen changes were observed under light microscope. Immunohistochemistry was used to detect the positive expressions of α-smooth muscle actin (α-SMA) and extracellular matrix (ECM) collagen (COL-Ⅰ and COL-Ⅲ) in lung tissue. The protein expressions of ECM fibronectin (FN), transforming growth factor-β (TGF-β) and phosphorylation of Smad3 (p-Smad3) in lung tissue were detected by Western blotting. ② In vitro experiment: human embryonic lung fibroblast-1 (HFL-1) cells were cultured and divided into blank control group, fibroblast activation model group (model group), pirfenidone (2.5 mmol/L) group and digoxin 100 nmol/L and 50 nmol/L groups when cell density reached 70%-90%. After 3-hour treatment with corresponding drugs, except blank control group, the other groups were treated with TGF-β for 48 hours to establish fibroblast activation model. The expressions of α-SMA, FN and p-Smad3 proteins and the phosphorylations of phosphatidylinositol-3-kinase (PI3K)/Akt pathway proteins PI3K and Akt (p-PI3K, p-Akt) were detected by Western blotting. Results:① In vivo, compared with the control group, the alveolar structure of mice in the model group was significantly damaged, a large number of inflammatory cells infiltrated, collagen deposition in the lung interstitium was increased, the deposition of ECM in the lung tissue was also increased, and the expressions of α-SMA, FN, TGF-β and p-Smad3 protein were increased, indicating that the model of bleomycin-induced pulmonary fibrosis in mice was successfully prepared. Compared with the model group, digoxin significantly inhibited airway inflammation and collagen fiber deposition, reduced ECM deposition, and decreased the protein expressions of α-SMA, FN, TGF-β and p-Smad3, while the effect was better than that of the pirfenidone group, and the digoxin 1.0 mg/kg group had a better effect except FN [α-SMA ( A value): 5.37±1.10 vs. 9.51±1.66, TGF-β protein (TGF-β/GAPDH): 0.09±0.04 vs. 0.33±0.23, p-Smad3 protein (p-Smad3/GAPDH): 0.05±0.01 vs. 0.20±0.07, all P < 0.01]. ② In vitro, compared with the blank control group, the expressions of FN, α-SMA, p-Smad3 and PI3K/Akt signaling proteins in the model group were increased, indicating that the fibroblast activation model induced by TGF-β was successfully reproduced. Compared with the model group, digoxin significantly inhibited fibroblast activation, and decreased the expressions of FN, α-SMA, p-Smad3, and PI3K/Akt pathway proteins, moreover, the effect was better than that of the pirfenidone group, and decreased FN, SMA and p-Akt protein expressions were more obvious in digoxin 100 nmol/L group [FN protein (FN/GAPDH): 0.21±0.15 vs. 0.88±0.22, α-SMA protein (α-SMA/GAPDH): 0.20±0.01 vs. 0.50±0.08, p-Akt protein (p-Akt/GAPDH): 0.30±0.01 vs. 0.65±0.10, all P < 0.01]. Conclusion:Digoxin could suppress the pulmonary fibrosis in mice induced by bleomycin, which might be associated with the regulation of fibroblast activation via suppressing PI3K/Akt signaling pathway in a dose-dependent manner.

Objective:To analyze the clinical characteristics and risk factors associated with the formation of subcutaneous tophi among young gout patients.Methods:Gout patients treated at the Affiliated Hospital of Qingdao University from September 2016 to June 2020 were included. The clinical information was collected and relevant biochemical indices were detected. Fasting urine was collected to test urine pH value, urine uric acid and urine creatinine. Patients were divided into young tophi group and non-tophi group according to age. The measurement data of normal distribution was expressed as Mean±Standard deviation, and independent sample t test and one-way analysis of variance were used. The counting data was tested by Chi-square test. The risk factors were analyzed by logistic regression. Results:A total of 4 798 primary gout patients were collected. There were 915 patients with subcutaneous tophi, 2 308 young gout patients, 252 young gouty tophi patients among them. The average BMI, waist circumference, hip circumference, triglyceride level, serum uric acid level, glomerular filtration rate, alanineamino -transferase (ALT) and aspartate amino -transferase (AST) in the young tophi group were significantly higher than those in the middle-age tophi group ( F=46.074, 2.551, 9.203, 10.370, 15.118, 68.741, 35.023, 5.175, all P<0.05). Average age of disease onset, systolic blood pressure, fasting blood glucose, urine FEUA, Uua/Ucr and urea nitrogen level in young tophi group were significantly lower than those in middle-age tophi group ( F=474.876, 7.629, 6.441, 34.877, 3.633, 50.867, all P<0.05]. The age [(35±7) years old vs (33±7) years old], disease course [(7±4) years vs (4±3) years], blood pressure [(139±17) mmHg vs (135±16) mmHg], [(90±13) mmHg vs (86±12) mmHg], serum triglyceride [(2.6±2.1) mmol/L vs (2.4±2.0) mmol/L], total cholesterol [(4.9±1.4) mmol/L vs (4.6±1.4) mmol/L], serum uric acid [(547±171) μmol/L vs (490±160) μmol/L], urea nitrogen [(5.0±2.0) mmol/L vs (4.4±1.7) mmol/L], family history (27.0% vs 19.6%) and smoking rate(56.0% vs 48.9%) of tophi patients were significantly higher than those of non-tophi patients in young patients ( t=4.717, P<0.05; t=12.838, P<0.05; t=3.414, P<0.05; t=4.676, P<0.05; t=2.085, P<0.05; t=2.451, P<0.05; t=5.308, P<0.05; t=4.090, P<0.05; χ2=7.423, P<0.05; χ2=4.235, P<0.05) . The age of disease onset [(28±6) years vs (29±7) years] and glomerular filtration rate [(96±21) ml·min -1·1.73 m -2vs (103±21) ml·min -1·1.73 m -2] were statistically significantly lower than those of non-tophi patients ( t=-2.711, P<0.01; t=-4.907, P<0.01). Logistics regression analysis showed that age, course of disease, blood pressure, blood lipids level, serum uric acid level, family history of gout and smoking were risk factors for the formation of tophi in young people. After further adjusted for age, course of disease and family history of gout, it was found that serum uric acid, systolic blood pressure, diastolic blood pressure and urea nitrogen remined risk factors for tophi, while glomerular filtration rate remained a protective factor in young patients. Conclusion:Young tophi patients are always obese and have lipid metabolism disorder. Young patients with high level of serum uric acid and blood pressure, decreased renal function are prone to complicate with subcutaneous tophi. More attention should be paid in clinical practice to prevent or delay the formation of tophi.

Objective: To investigate the risk factors for susceptibility of abnormal liver function in patients with gout. Methods: A total of 5 044 cases of male gout patients in remission were selected and divided into normal liver function group with 3 693 patients and abnormal liver function group with 1 351 patients. The clinical information was collected and relevant biochemical indices were detected. Serum uric acid(SUA) was divided into quartiles, and its associations with elevated ALT were evaluated. Results: There were significant differences in the history of drinking, family history, combining with hyperlipidemia, fatty liver, and coronary heart disease between the abnormal liver function group and normal function group(P<0.05 or P<0.01). There were significant statistical differences in age, disease duration, body mass index, waist circumference, diastolic blood pressure, serum cholesterol and triglyceride, uric acid, and creatinine clearance rate between 2 groups(P<0.01), while without significant difference in history of smoking, regular exercise, combining hypertension and diabetes, the means of systolic blood pressure, and fasting blood glucose(all P>0.05). Further logistic regression analysis indicated that body mass, waist circumference, combining fatty liver, higher SUA level, higher cholesterol and triglyceride were risk factors of the early onset of abnormal liver function. ALT and the proportion of abnormal liver function were increased with the increase of UA. After adjustment for BMI, TG, TC and fatty liver, the ALT level and the proportion of abnormal liver function decreased significantly while still showed an upward trend. Conclusion Patients with obesity, high level of uric acid, high blood lipids and fatty liver were more likely to develop abnormal liver function, SUA was independently associated with elevated ALT.

Objective: To screen gene mutation information of gout pedigree through whole genome sequencing and to carry out preliminary analysis. Methods: One typical gout pedigree was selected as the study subjects. The clinical data and the peripheral blood samples were collected and constructed charts of the pedigree. DNAs were extracted from peripheral blood and analyzed by the whole genome sequencing, and by the software analysis and comparison, screening out the pathogenic genes and related mutations. Then the verifications were conducted in the family members and the controls. Bioinformatics software was applied to predict the effect of mutation on gene expression. Results: Based on the sequencing results, advanced informational analysis was performed to screen out the mutations 1040-8 A> G near the 5 ′end near the exon 8 of the PLAA gene. The results showed that all the gout patients in the family had 1040 -8 A> G sites, and none of the mutants were found in the non-gout group and 200 controls; bioinformatics analysis suggested that the mutation could affect PLAA gene expression, but not affecting PLAA mRNA structure. Conclusion PLAA gene 1040-8 A> G mutation is separated from patients in the gout pedigree, and the newly discovered PLAA gene may act as a gout pathogenic gene.

Objective:To investigate the efficacy of salbutamol combined with budesonide aerosol inhalation in the treatment of patients with acute attack of bronchial asthma and its influence on serum inflammatory factors.Methods:From January 2017 to December 2018, 78 patients with acute attack of bronchial asthma in Zhejiang Xin'an International Hospital were selected, and they were divided into combined group and control group according to the random number table method, with 39 cases in each group.The control group was treated with routine western medicine, and the combined group was treated with salbutamol and budesonide aerosol inhalation on the basis of the control group.The two groups were treated for 2 weeks.The changes of vital capacity(VC), forced expiratory volume in one second(FEV 1) and peak expiratory flow(PEF) were compared before and after treatment.The changes of serum high mobility group protein 1(HMGB1), C-reactive protein(CRP) and tumor necrosis factor-alpha(TNF-α) were measured before and after treatment. Results:The total effective rate of the combined group was 87.18%(34/39), which was higher than 68.57%(24/39) of the control group, the difference was statistically significant(χ 2=5.791, P<0.05). The values of VC, FEV 1 and PEF between the two groups before treatment had no statistically significant differences( t=0.588, 0.892, 0.371, all P>0.05), which in the two groups after treatment were all increased(the combined group: t=16.045, 7.193, 6.667; the control group: t=7.834, 8.354, 4.262, all P<0.05). The values of VC, FEV 1 and PEF in the combined group after treatment were higher than those in the control group ( t=6.591, 9.615, 11.383, all P<0.05). The levels of HMGB1, CRP and TNF-α in the two groups before treatment had no statistically significant differences( t=0.306, 0.669, 0.371, all P>0.05), which in the two groups after treatment were all decreased (the combined group: t=10.235, 16.992, 12.371; the control group: t=4.763, 15.663, 13.115, all P<0.05). The levels of HMGB1, CRP and TNF-α in the combined group were lower than those in the control group after treatment( t=6.591, 3.559, 8.307, all P<0.05). Conclusion:Salbutamol combined with budesonide aerosol inhalation in the treatment of acute attack of bronchial asthma has better effect, which can effectively improve the lung function of patients, inhibit the release of inflammatory factors, and with high safety.

Objective:To explore the mediating effects of self-control and rumination between neuroticism and insomnia in college students.Methods:A cross-sectional survey was conducted among 767 college students from a university in Sichuan province with Chinese big five personality inventory-15, insomnia severity index, ruminative responses scale, and self-control scale.Results:The prevalence of insomnia was 36.6% among college students.The scores of neuroticism (9.63±3.41), rumination (22.27±5.44) and ISI (6.61±4.28) were positively correlated with each other ( r=0.281-0.389, P<0.01), while each of them was negatively correlated ( r=-0.453--0.194, all P<0.01) with self-control (60.71±9.41). Analysis of mediating effects revealed that neuroticism not only directly affected insomnia, but also indirectly affected insomnia through the mediating effects of rumination and self-control respectively. Conclusion:Self-control and rumination have mediating effects between neuroticism and insomnia in college students.