This paper discussed how to set the limit of impurities in the quality standard when the impurities in small-molecular innovative drugs were metabolites.Firstly,through the analysis and interpretation of each relevant guideline,in combination with the review cases of FDA and EMA,found out the conditions for qualification of im-purity,and then establ ish the acceptable limit of impurities based on the test results of multiple batches,the incre-ments of production process and storage process.

Objective:To summarize the current research status, assessment tools, and influencing factors of fatigue in patients receiving maintenance hemodialysis (MHD) and provide a reference for the management of fatigue in this patient population.Methods:A literature search was conducted in databases including PubMed, Web of Science, ProQuest, Cochrane Library, Science Direct, Embase, CINAHL, China National Knowledge Infrastructure, WanFang Data, VIP, and China Biology Medicine disc for studies related to fatigue in patients receiving MHD. The search timeframe was from establishing the databases to January 23, 2024.Results:A total of 46 studies were included. Various assessment tools for fatigue in patients receiving MHD were identified, though specific tools were limited. The Short Form 36 Vitality Subscale (SF-36 VS) was the most commonly used assessment tool. The main factors influencing fatigue in these patients included sociodemographic, dialysis-related, disease-related, physical, nutritional, and psychological factors.Conclusions:Fatigue is a significant symptom in patients receiving MHD. Healthcare professionals must develop specific tools for accurately assessing fatigue in this population and explore standardized management plans.

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the main pathogen that causes COVID-19,which is fast-mutating and highly transmissible.The infection has led to a global epidemic.As the main preventive and control measure,vaccination plays a critical role in fighting a-gainst COVID-19.Although a large number of epitope-based and mucosal vaccines have been stud-ied,few peptide epitope vaccines targeting the mucosa and their functional evaluation have been re-ported.In this study,we used SARS-CoV-2 structural protein M peptide epitope predicted by the IEDB database as an antigenic target to design the MS-3S gene containing 3 050 and 1 229 signal peptides and DCpep optimized for insertion into MS2 phage coat proteins.The expression plasmid pSIP:MS-3S was constructed by cloning the PCR fragments seamlessly and was transformed into Lactiplantibacillus plantarum 18 to obtain the recombinant bacterium LP18:MS-3S.Expression conditions such as induction time,inducer concentration,rotational speed and initial pH were opti-mized.The intranasal immunization experiments were performed to examine the vaccine efficacy.The results showed that the 916 bp-long target gene MS-3S modified and optimized was amplified and used to successfully construct the recombinant bacterial strain LP18:MS-3S.The optimal con-ditions for recombinant protein expression were obtained and verified by Western blot,flow cy-tometry,immunofluorescence and other detection methods.The optimal expression conditions were determined as follows:induction time was 4 h with 100 pg/L of SppIP as the optimal induction concentration.Antibody-specific for the epitope was verified by ELISA experiments in serum,alve-olar lavage fluid and fecal dilutions of mice.In summary,a recombinant bacterial strain expressing the epitope antigen of the SARS-CoV-2 M protein peptide was constructed.The obtained protein can induce the body to produce humoral and mucosal immunity,which lays the foundation for the development of a vaccine candidate for the mucosal immunity of COVID-19.

Objective:To explore the long-term efficacy of laparoscopic fundoplication for proton pump inhibitor dependent gastroesophageal reflux disease (GERD).Method:Clinical data of proton pump inhibitor dependent GERD patients who underwent fundoplication at the Rocket Force Characteristic Medical Center from Jan to Jun 2012 were analyzed, including GERD symptom score, subjective symptom relief rate, PPI discontinuation rate and surgical satisfaction, as well as recurrence and complications.Result:A total of 160 GERD patients were included in this study, with 64% of patients having respiratory symptoms. Nissen and Toupet fundoplication were performed in 43 and 117 cases, respectively, with a follow-up time of (127±3) months. The postoperative GERD symptom scores of the patients were significantly lower than before treatment (all P<0.001); The subjective relief of overall symptoms in the digestive tract and airway problem was 90% (80%, 100%) and 100%, respectively. The PPI discontinuation rate was 86%, and the overall satisfaction rate of the treatment was 92%, and the satisfaction rate of patients with respiratory symptoms was 89%. 7% of patients experienced varying degrees of symptomatic recurrence, 4% of patients re-underwent endoscopic treatment and/or laparoscopic fundoplication due to symptom recurrence. The incidence of long-term postoperative dysphagia, bloating, belching, increased exhaust, abdominal pain, diarrhea, and constipation were 11.3%, 16.9%, 0, 1.3%, 0, 2.5%, and 5.6%, respectively. Conclusions:Laparoscopic fundoplication has good long-term efficacy in the treatment of GERD. A small number of patients may experience postoperative recurrence, as well as complications such as dysphagia and gas-bloat syndrome. Most recurrent patients can achieve good therapeutic effect by redoing endoscopic treatment or redoing surgery.

Objective:To analyze the new value of gastroscopy in the diagnosis of esophageal hiatal hernia(EHH).Methods:From March 7 to September 24 in 2019, 194 patients with gastroesophageal reflux disease who received endoscopy and high resolution esophageal manometry (HREM) at the Department of Gastroesophageal Surgery, the PLA Rocket Force Medical Center were selected. The transverse diameter of esophageal hiatus and the upward length of esophagogastric junction (EGJ) were measured under endoscopy, and the relevant data of reflux esophagitis (RE) and length and pressure of lower esophageal sphincter (LES) were collected. The value of traditional method under endoscopy and esophageal hiatus transverse diameter (EHTD) method under endoscopy in the diagnosis of EHH was compared. Independent sample- t test, rank sum test and chi-square test were used for statistical analysis. Results:The detection rate of EHH by EHTD method under endescopy was higher than that by traditional method under endoscopy and HREM method (60.8%, 118/194 vs. 14.9%, 29/194 and 37.1%, 72/194), and the detection rate of EHH by HREM method was higher than that by traditional method under endoscopy, and the differences were statistically significant ( χ2=86.75, 21.82, and 24.75; all P<0.001). The proportion of RE, the upward length of EGJ and the transverse diameter of esophageal hiatus of EHH patients diagnosed by traditional method under endoscopy and EHTD method under endoscopy were all higher than those of non-EHH patients (79.3%, 23/29 vs. 28.5%, 47/165; 49.2%, 58/118 vs. 15.8%, 12/76; 2.0 (2.0, 3.0) cm vs. 0.4(0, 0.7) cm, 0.7(0, 1.6) cm vs. 0(0, 0.6) cm; (2.60±0.71) cm vs. (1.88±0.44) cm, (2.30±0.45) cm vs. (1.51±0.29) cm); the minimum resting pressure of LES and resting pressure of LES were both lower than those of non-EHH patients(3.7(0.3, 12.1) mmHg (1 mmHg=0.133 kPa) vs. 9.1(3.3, 14.2) mmHg, 6.4(2.2, 12.5) mmHg vs. 10.8 (4.7, 15.5) mmHg; (9.70±7.92) mmHg vs. (14.92±10.30) mmHg, (11.36±7.79) mmHg vs. (18.44±11.78) mmHg); the length of intraperitoneal LES were shorter than that of non-EHH patients (0(0, 1.4) cm vs. 1.1(0, 1.7) cm, 0.3(0, 1.5) cm vs. 1.3(0.4, 1.8) cm); the length of LES of EHH patients diagnosed by EHTD method under endoscopy was shorter than that of non-EHH patients ((2.83±0.63) cm vs. (3.10±0.66) cm), and the differences were statistically significant ( χ2=26.53 and 22.31, Z=-8.26 and-5.04, t=5.26 and 13.67, Z=-2.14 and-2.71, t=-2.59 and-4.63, Z=-2.58 and-3.60, t=-2.96; all P<0.05). There were no significant differences in gender, LES length, intraperitoneal LES length, minimum resting pressure of LES, resting pressure of LES and residual pressure of LES between EHH patients diagnosed by EHTD method and traditional method under endoscopy (all P>0.05). Conclusions:Endoscopy plays a significant role in the diagnosis of EHH. EHTD method under endoscopy is more accurate in the diagnosis of sliding EHH, which is worthy of clinical reference.

Objective:To analyze the monitoring data of Kashin-Beck disease (KBD) in Gansu Province and learn about the long-term trend of KBD incidence.Methods:The X-ray detection rate of children with KBD in Gansu Province from 1990 to 2021 was collected through Gansu Provincial Center for Disease Control and Prevention. Joinpoint regression model was used to analyze the trend of X-ray detection rate of KBD in children. The annual percent change (APC) and average annual percent change (AAPC) were used to analyze the trend of the observed indicators. In addition, a polynomial regression model was constructed to fit the change of X-ray detection rate of children with KBD over time.Results:From 1990 to 2021, a total of 126 726 children were examined for KBD by X-ray in Gansu Province, with 3 011 positive cases, X-ray detection rate of KBD in children was 0 in 2019 - 2021. Joinpoint regression model analysis showed that the X-ray detection rate of children with KBD in Gansu Province from 1990 to 2018 showed a decreasing trend (AAPC = - 14.40%, P = 0.001). The APC of 1990 - 1998, 2002 - 2008 and 2008 - 2012 was - 17.75%, - 21.89% and - 49.89%, respectively, showing a decreasing trend ( P < 0.05). The APC of 2012 - 2018 was 6.15%, but the trend change was not statistically significant ( P = 0.475). The curve fitting of X-ray detection rate of KBD in children in Gansu Province over time was carried out, and the quadric polynomial equation was y = 0.000 314 5 x4 - 0.021 37 x3 + 0.487 1 x2 - 4.635 x + 22.08. Conclusions:The condition of KBD in children of Gansu Province has been effectively controlled. The X-ray detection rate has remained at a relatively low level since 2012, and it has reached a state of elimination since 2019.

Objective:To explore the distribution characteristics of common clinical manifestations of elbow joint in patients with endemic fluorosis and their correlation with the influencing factors.Methods:A cross-sectional survey was conducted on all permanent adult residents in 13 endemic fluorosis villages in Gaotai and Gaolan counties of Gansu province. The survey included: ① Demographic information, family history, and current medical history. ② Physical examination specifically focued on the orthopedic clinical presentations. ③Taking DR films of the forearm (including elbow joint) and calf (including knee joint), and classify the elbow joint to grade K-L based on X-ray manifestations. ④ Measuring height and weight, and calculating BMI index. ⑤Applying the Mayo elbow joint rating scale to evaluate elbow joint function. Based on the survey results, the distribution characteristics of clinical symptoms and signs of elbow joint in patients with skeletal fluorosis, as well as the distribution characteristics and correlation of factors affecting elbow joint function such as age, gender, disease course, BMI, K-L grade, etc were described. The comparison of counting data and rates were analyzed with χ2 test or Fisher exact probability test. Pearson′s test was used for correlation analysis of continuous data that conforms to normal distribution, and Spearman test was used for non-normal distribution measurement and counting data. The correlation analysis of ordered hierarchical data was conducted using Kendall′s Tau- b test. Results:①Among 501 patients with skeletal fluorosis, a total of 465 cases (92.8%) were diagnosed with elbow joint pain. A total of 185 cases (36.9%) were with elbow joint tenderness, 300 cases (59.9%) were with elbow joint enlargement, 415 cases (82.8%) were with morning stiffness of the elbow joint, 102 cases (20.4%) were with cubital tunnel syndrome, 153 cases (30.5%) were with positive forearm extensor tendon traction test, and 97 cases (19.4%) were with positive forearm flexor tendon traction test. The detection rate of elbow joint rotation limitation was the highest among those with ROM ranging from 30 ° to 70 ° (261/501, 52.1%), and the detection rate of elbow joint extension and flexion limitation was the highest among those with ROM ranging from 50 ° to 90 °(274/501, 54.7%). ②Among 501 patients with skeletal fluorosis, a total of 465 cases were found to have symptoms and positive signs in the elbow joint, with the detection rate in males being lower than that in females, with a significant difference ( χ2=41.19, P<0.001). The majority of patients were between the ages of 50 and 65 (274/501, 58.9%), with a body mass index of <18 (217, 46.67%), K-L arthritis with a radiologic grade of Ⅲ (256/501, 55.0%), and a disease course of >30 years (217/501, 46.67%). ③The correlation between clinical characteristics, the Mayo score, and various influencing factors of skeletal fluorosis found a high correlation between pain and age ( r=0.79, P<0.001) and pain and disease course ( r=0.71, P<0.001). The ROM of extension and flexion was negatively correlated with age ( r=-0.43, P<0.001), K-L grade ( r=-0.67, P<0.001), and disease course ( r=-0.48, P<0.001); Elbow tunnel syndrome was positively correlated with age ( r=0.72, P<0.001). The Mayo functional score was negatively correlated with age ( r=-0.35, P<0.001). Conclusion:Early morning stiffness of the elbow joint (<30 min), limited rotation of the elbow joint, limited extension and flexion of the elbow joint, and cubital tunnel syndrome (degree Ⅰ) have a high detection rate in the population with skeletal fluorosis. Age, course of disease, and degree of joint degeneration have a significant impact on elbow joint function in patients with fluorosis.

Objective To understand the impact of system reform of salt industry on iodine nutrition of people in Gansu Province, and to provide a scientific basis for policy adjustment of relevant departments. Methods The investigation period (2014-2021) was divided into two sub-periods: before system reform of salt industry (2014-2016) and after system reform of salt industry (2017-2021). Thirty counties were selected according to the method of ^“population proportional probability sampling (PPS)^” in 2014. According to the iodine deficiency disease monitoring program of Gansu Province, from 2016 to 2021, children aged 8-10 years and pregnant women were taken as research objects to collect urine samples for urine iodine detection. Children in 2014 and 2018 were selected to measure thyroid volume. Results A total of 90 989 children urine iodine samples were investigated, and the median urinary iodine (MUI) of children was 194.70µg/L; 7 663 and 83,326 children's urinary iodine samples were investigated in the two periods, the MUI was 180.73 µg/L and 196.00 µg/L, respectively, and the difference was statistically significant (P<0.05). A total of 44 741 pregnant women's urinary iodine samples were investigated, and the MUI of pregnant women was 176.50 µg/L; 4 480 and 40 261 pregnant women's urinary iodine samples were investigated in the two periods, the MUI was 160.61 µg/L and 178.10 µg/L, respectively, and the difference was statistically significant (P<0.05). The thyroid volume of 1 555 children and 8 509 children was investigated in the two periods, the median thyroid volume was 2.70 mL and 2.55 mL , respectively, and the difference was statistically significant (P<0.05). The rates of goiter in children were 3.15% and 1.26%, respectively, and the difference was statistically significant (P<0.05). Conclusion The iodine nutrition of people in Gansu Province has not fluctuated significantly after the reform of salt industry system and has maintained an appropriate level. It is necessary to pay attention to the potential risk of insufficient iodine nutrition level and thyroid health of key populations such as children and pregnant women and strengthen health education of scientific iodine supplementation.

Presbycusis is a disease characterized by hidden and slowly progressive bilateral sensorineural hear-ing loss.Its occurrence and development is a multifactorial process.The expression of each factor varies greatly a-mong individuals.Currently,there have been some studies on the pathogenesis of presbycusis,which can be catego-rized into ion channel abnormalities,cochlear synaptopathy,reactive oxygen species,hormone effects,mitochondrial abnormalities,genetic factors and vari other factors.This review summarizes the pathogenesis of presbycusis in re-cent years.

Objective:To explore the clinical characteristics of children with septic shock and analyze the drug resistance of blood culture positive bacteria.Methods:The clinical data,positive blood culture strains and drug sensitivity results of 127 children with septic shock admitted to the Department of Intensive Care Medicine of Hunan Children's Hospital from September 2015 to August 2021 were retrospectively analyzed.Results:A total of 134 strains of bacteria or fungi were isolated from the blood culture samples of 127 children with septic shock,and gram-negative strains were the main ones,accounting for 67.16% (90/134).Haemophilus influenzae and Escherichia coli were the main gram-negative bacteria,accounting for 38.81% (52/134) and 20.15% (27/134)，respectively,while Streptococcus pneumoniae was the main gram-positive bacteria,accounting for 8.21% (11/134),and Candida albicans was the main fungus,accounting for 10.45% (14/134).The number of white blood cells,the levels of serum C-reactive protein,procalcitonin,venous blood sugar and arterial blood lactic acid in patients were all significantly higher than normal values,and the white blood cells count and neutrophil percentage in gram-positive bacterial infections were significantly higher than those with gram-negative bacterial infections and fungal infections( P<0.05).Procalcitonin increased most obviously when infected by gram-negative bacteria,and the difference was statistically significant ( P<0.05).Gram-positive strains were sensitive to vancomycin,teicoplanin,and linezolid,but only 50% of Streptococcus pneumoniae were sensitive to penicillin.Gram-negative strains had relatively high drug resistance,among which Klebsiella pneumoniae were only highly resistant to imipenem,cilastatin and levofloxacin,reaching 50%.Haemophilus influenzae was resistant to cephalosporins and β-amides enzyme antibiotic,and the drug sensitivity rate of lactamase antibiotics was high,with a resistance rate of 50% only to ampicillin,cefuroxime,amikacin,and compound sulfamethoxazole.There were not many fungal strains,and most antifungal drugs were effective against blood culture-positive fungi. Conclusion:The main pathogens of infection in children with septic shock are gram-negative bacteria,and have high resistance to general antibiotics.We should pay attention to their drug resistance when using antibiotics empirically.