Background: Genetic defects in the human thyroid-stimulating hormone (TSH) receptor (TSHR) gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype–phenotype relationships for most TSHR variants associated with CH remain unexplored. We aimed to identify TSHR variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships between TSHR genotypes and clinical phenotypes. Methods: In total, 367 patients with CH were recruited for TSHR variant screening using whole-exome sequencing. The effects of the variants were evaluated by in-silico programs such as SIFT and polyphen2. Furthermore, these variants were transfected into 293T cells to detect their Gs/cyclic AMP and Gq/11 signaling activity. Results: Among the 367 patients with CH, 17 TSHR variants, including three novel variants, were identified in 45 patients, and 18 patients carried biallelic TSHR variants. In vitro experiments showed that 10 variants were associated with Gs/cyclic AMP and Gq/11 signaling pathway impairment to varying degrees. Patients with TSHR biallelic variants had lower serum TSH levels and higher free triiodothyronine and thyroxine levels at diagnosis than those with DUOX2 biallelic variants. Conclusions We found a high frequency of TSHR variants in Chinese patients with CH (12.3%), and 4.9% of cases were caused by TSHR biallelic variants. Ten variants were identified as loss-of-function variants. The data suggest that the clinical phenotype of CH patients caused by TSHR biallelic variants is relatively mild. Our study expands the TSHR variant spectrum and provides further evidence for the elucidation of the genetic etiology of CH.

italic>Platycodon grandiflorum (Jacq.) A. DC is one of the most commonly used bulk medicinal herbs. It has important value in the fields of medicine, food and cosmetics, and its market demand is increasing year by year, and it has a good development prospect. In this study, based on 403 distribution records and 8 environmental variables, we used Maxent model to predict the potential distribution of P. grandiflorum under climate change. The results showed that the model simulation effect was the best when the Maxent parameter was FC (feature combination) = LQPH (L: linear features; Q: quadratic features; P: product features; H: hinge features) and RM (regularization multiplier) = 2.1, AUC (area under curve) = 0.901, and the model prediction showed that P. grandiflorum was widely distributed in 28 provinces of China under the current climate conditions, with a suitable area of 2 337 419.98 km². Under the influence of climate change in the future, the area of suitable habitat of P. grandiflorum showed a decreasing trend, and the distribution center as a whole showed a trend of northward and eastward shift. The distribution area of P. grandiflorum in the three main producing areas is affected by climate change, and the overall trend is that the future suitable distribution area of Chifeng in Inner Mongolia increases, while the future suitable distribution area of Zibo in Shandong and Taihe, Bozhou in Anhui decreases or even disappears under the SSP5-8.5 scenario (shared socioeconomic pathways). It is suggested to maintain and protect the ecological environment and germplasm resources of the reserved area suitable for the growth of P. grandiflorum, and increase the cultivation research in the expansion area of P. grandiflorum, so as to lay a foundation for the subsequent expansion of P. grandiflorum planting and to promote the protection and sustainable development of P. grandiflorum resources.

Objective To investigate the clinical phenotypes and genotypes of children with congenital fibrinogen disorder(CFD).Methods A retrospective analysis was conducted on the clinical data of 16 children with CFD.Polymerase chain reaction was used to amplify all exons and flanking sequences of the FGA,FGB,and FGG genes,and sequencing was performed to analyze mutation characteristics.Results Among the 16 children,there were 9 boys(56%)and 7 girls(44%),with a median age of 4 years at the time of attending the hospital.Among these children,9(56%)attended the hospital due to bleeding events,and 7(44%)were diagnosed based on preoperative examination.The children with bleeding events had a significantly lower fibrinogen activity than those without bleeding events(P<0.05).Genetic testing was conducted on 12 children and revealed a total of 12 mutations,among which there were 4 novel mutations,i.e.,c.80T>C and c.1368delC in the FGA gene and c.1007T>A and C.1053C>A in the FGG gene.There were 2 cases of congenital afibrinogenemia caused by null mutations of the FGA gene,with relatively severe bleeding symptoms.There were 7 cases of congenital dysfibrinogenemia mainly caused by heterozygous missense mutations of the FGG and FGA genes,and their clinical phenotypes ranged from asymptomatic phenotype to varying degrees of bleeding.Conclusions The clinical phenotypes of children with CFD are heterogeneous,and the severity of bleeding is associated with the level of fibrinogen activity,but there is a weak association between clinical phenotype and genotype.

OBJECTIVE: To observe the clinical characteristics and impact on mortality of carbapenem-resistant Pseudomonas aeruginosa (CRPA) colonized or infected patients with hematological disorders in order to provide evidence for the prevention and treatment of CRPA. METHODS: The patients who were colonized or infected with CRPA in the Department of Hematology of The First Affiliated Hospital of Zhejiang Chinese Medical University from January 2020 to March 2021 were selected as the research subjects, the clinical data such as hospitalization time, primary disease treatment regimen, granulocyte count, previous infection and antibiotic regimen of these patients were analyzed, meanwhile, antibiotic regimen and efficacy during CRPA infection, 30-day and long-term survival were also analyzed. RESULTS: A total of 59 patients were included in this study, and divided into CRPA infection group (43 cases) and CRPA colonization group (16 cases). Univariate logistic regression analysis showed that ECOG score (P =0.003), agranulocytosis (P <0.001), and exposure to upper than 3^rd generations of cephalosporins and tigecycline within 30 days (P =0.035, P =0.017) were the high-risk factors for CRPA infection. Multivariate logistic regression analysis showed that ECOG score of 3/4 ( OR=10.815, 95%CI: 1.260-92.820, P =0.030) and agranulocytosis ( OR=13.82, 95%CI: 2.243-85.176, P =0.005) were independent risk factors for CRPA infection. There was a statistically significant difference in cumulative survival rate between CRPA colonization group and CRPA infection group ( χ²=14.134, P < 0.001). Kaplan-Meier survival analysis showed that the influencing factors of 30-day survival in patients with CRPA infection were agranulocytosis (P =0.022), soft tissue infection (P =0.03), and time of hospitalization before CRPA infection (P =0.041). Cox regression analysis showed that agranulocytosis was an independent risk factor affecting 30-day survival of patients with CRPA infection (HR=3.229, 95%CI :1.093-3.548, P =0.034). CONCLUSIONS Patients with hematological disorders have high mortality and poor prognosis after CRPA infection. Bloodstream infection and soft tissue infection are the main causes of death. Patients with high suspicion of CRPA infection and high-risk should be treated as soon as possible.
Humans ; Carbapenems/therapeutic use* ; Pseudomonas aeruginosa ; Soft Tissue Infections/drug therapy* ; Anti-Bacterial Agents/therapeutic use* ; Hematologic Diseases ; Survival Analysis

Objective: To investigate the antimicrobial resistance of food-borne diarrheagenic Escherichia coli (DEC) and the prevalence of mcr genes that mediates mobile colistin resistance in parts of China, 2020. Methods: For 91 DEC isolates recovered from food sources collected from Fujian province, Hebei province, Inner Mongolia Autonomous Region and Shanghai city in 2020, Vitek2 Compact biochemical identification and antimicrobial susceptibility testing platform was used for the detection of antimicrobial susceptibility testing (AST) against to 18 kinds of antimicrobial compounds belonging to 9 categories, and multi-polymerase chain reaction (mPCR) was used to detect the mcr-1-mcr-9 genes, then a further AST, whole genome sequencing (WGS) and bioinformatics analysis were platformed for these DEC isolates which were PCR positive for mcr genes. Results: Seventy in 91 isolates showed different antimicrobial resistance levels to the drugs tested with a resistance rate of 76.92%. The isolates showed the highest antimicrobial resistance rates to ampicillin (69.23%, 63/91) and trimethoprim-sulfamethoxazole (59.34%, 54/91), respectively. The multiple drug-resistant rate was 47.25% (43/91). Two mcr-1 gene and ESBL (extended-spectrum beta-lactamase) positive EAEC (enteroaggregative Escherichia coli) strains were detected. One of them was identified as serotype of O11:H6, which showed a resistance profile to 25 tested drugs referring to 10 classes, and 38 drug resistance genes were predicted by genome analysis. The other one was O16:H48 serotype, which was resistant to 21 tested drugs belonging to 7 classes and carried a new variant of mcr-1 gene (mcr-1.35). Conclusion: An overall high-level antimicrobial resistance was found among foodborne DEC isolates recovered from parts of China in 2020, and so was the MDR (multi-drug resistance) condition. MDR strains carrying multiple resistance genes such as mcr-1 gene were detected, and a new variant of mcr-1 gene was also found. It is necessary to continue with a dynamic monitoring on DEC contamination and an ongoing research into antimicrobial resistance mechanisms.
Humans ; Colistin/pharmacology* ; Anti-Bacterial Agents/pharmacology* ; Escherichia coli Infections/epidemiology* ; Escherichia coli Proteins/genetics* ; Drug Resistance, Bacterial/genetics* ; China/epidemiology* ; Escherichia coli ; Plasmids/genetics* ; Microbial Sensitivity Tests

Aim To study the protective effect of eplerenone on the contralateral kidney in pregnant rats with chronic kidney disease (CKD) and its mechanism. Methods Female Wistar rats were randomly divided into sham-operation group, sham-operation pregnancy group, model group and eplerenone group. The rats in the model group and eplenone group had ligation unilateral ureter, and the rats in the eplenone group were treated with 100 mg • kg

COVID-19 has been prevalent for three years. The virulence of SARS-CoV-2 is weaken as it mutates continuously. However, elderly patients, especially those with underlying diseases, are still at high risk of developing severe infections. With the continuous study of the molecular structure and pathogenic mechanism of SARS-CoV-2, antiviral drugs for COVID-19 have been successively marketed, and these anti-SARS-CoV-2 drugs can effectively reduce the severe rate and mortality of elderly patients. This article reviews the mechanism, clinical medication regimens, drug interactions and adverse reactions of five small molecule antiviral drugs currently approved for marketing in China, so as to provide advice for the clinical rational use of anti-SARS-CoV-2 in the elderly.

To investigate the clinical efficacy and safety of dupilumab in the treatment of moderate to severe atopic dermatitis (AD) in China. A small sample self-controlled study before and after treatment was conducted to retrospective analysis patients with moderate to severe AD treated with dupilumab in the department of dermatology of the First Affiliated Hospital of Chongqing Medical University from July 2020 to March 2022. Dupilumab 600 mg was injected subcutaneously at week 0, and then 300 mg was injected subcutaneously every 2 weeks. The condition was evaluated by SCORAD(severity scoring of atopic dermatitis), NRS(numerical rating scale), DLQI(dermatology life quality index) and POEM(patient-oriented eczema measure). The improvement of SCORAD, NRS, DLQI and POEM was analyzed by paired t test and non-parametric paired Wilcoxon. The results showed that a total of 67 patients with moderate to severe AD received dupilumab treatment, of which 41 patients (the course of treatment was more than 6 weeks) had reduced the severity of skin lesions, improved quality of life and reduced pruritus. A total of 23 patients completed 16 weeks of treatment. At 4, 8, 12 and 16 weeks, SCORAD, NRS, DLQI and POEM decreased compared with the baseline, and the differences were statistically significant. SCORAD (50.13±15.19) at baseline, SCORAD (36.08±11.96)(t=6.049,P<0.001) at week 4,SCORAD (28.04±11.10)(t=10.471,P<0.001) at week 8, SCORAD (22.93±9.72)(t=12.428,P<0.001) at week 12, SCORAD (16.84±7.82)(t=14.609,P<0.001) at week 16, NRS 7(6,8) at baseline, NRS 4(3,5)(Z=-3.861,P<0.001) at week 4, NRS 2(1,4)(Z=-4.088,P<0.001) at week 8, NRS 1(0,2)(Z=-4.206,P<0.001) at week 12, NRS 2(0,2)(Z=-4.222,P<0.001) at week 16, DLQI (13.83±5.71) at baseline, DLQI (8.00±4.02)(t=6.325,P<0.001) at week 4, DLQI (5.61±3.50)(t=8.060,P<0.001) at week 8, DLQI (3.96±1.99)(t=8.717,P<0.001) at week 12, DLQI (2.70±1.89)(t=10.355,P<0.001) at week 16, POEM (18.04±6.41) at baseline, POEM (9.70±4.70)(t=7.031,P<0.001) at week 4, POEM (7.74±3.48)(t=8.806,P<0.001) at week 8, POEM (6.35±3.33)(t=10.474,P<0.001) at week 12, POEM (4.26±2.51)(t=11.996,P<0.001) at week 16. In the 16th week, 100%(23 patients), 91.3%(21 patients), 34.8%(8 patients) and 8.7%(2 patients) of 23 patients reached SCORAD30, SCORAD50, SCORAD70, and SCORAD90 statuses, respectively. There were 82.6%(19 patients), 95.7%(22 patients) and 95.7%(22 patients) of 23 patients with NRS, DLQI and POEM improved by≥4 points compared with baseline. Twelve patients with AD who continued to receive dupilumab after 16 weeks showed further improvement in skin lesions. The adverse events were conjunctivitis and injection site reaction. In conclusion, dupilumab is an effective and safe treatment for moderate and severe AD. However, the longer-term efficacy and safety require further studies involving larger sample sizes and a longer follow-up time.
Humans ; Dermatitis, Atopic/drug therapy* ; Quality of Life ; Retrospective Studies ; Severity of Illness Index ; Treatment Outcome

To investigate the clinical efficacy and safety of dupilumab in the treatment of moderate to severe atopic dermatitis (AD) in China. A small sample self-controlled study before and after treatment was conducted to retrospective analysis patients with moderate to severe AD treated with dupilumab in the department of dermatology of the First Affiliated Hospital of Chongqing Medical University from July 2020 to March 2022. Dupilumab 600 mg was injected subcutaneously at week 0, and then 300 mg was injected subcutaneously every 2 weeks. The condition was evaluated by SCORAD(severity scoring of atopic dermatitis), NRS(numerical rating scale), DLQI(dermatology life quality index) and POEM(patient-oriented eczema measure). The improvement of SCORAD, NRS, DLQI and POEM was analyzed by paired t test and non-parametric paired Wilcoxon. The results showed that a total of 67 patients with moderate to severe AD received dupilumab treatment, of which 41 patients (the course of treatment was more than 6 weeks) had reduced the severity of skin lesions, improved quality of life and reduced pruritus. A total of 23 patients completed 16 weeks of treatment. At 4, 8, 12 and 16 weeks, SCORAD, NRS, DLQI and POEM decreased compared with the baseline, and the differences were statistically significant. SCORAD (50.13±15.19) at baseline, SCORAD (36.08±11.96)(t=6.049,P<0.001) at week 4,SCORAD (28.04±11.10)(t=10.471,P<0.001) at week 8, SCORAD (22.93±9.72)(t=12.428,P<0.001) at week 12, SCORAD (16.84±7.82)(t=14.609,P<0.001) at week 16, NRS 7(6,8) at baseline, NRS 4(3,5)(Z=-3.861,P<0.001) at week 4, NRS 2(1,4)(Z=-4.088,P<0.001) at week 8, NRS 1(0,2)(Z=-4.206,P<0.001) at week 12, NRS 2(0,2)(Z=-4.222,P<0.001) at week 16, DLQI (13.83±5.71) at baseline, DLQI (8.00±4.02)(t=6.325,P<0.001) at week 4, DLQI (5.61±3.50)(t=8.060,P<0.001) at week 8, DLQI (3.96±1.99)(t=8.717,P<0.001) at week 12, DLQI (2.70±1.89)(t=10.355,P<0.001) at week 16, POEM (18.04±6.41) at baseline, POEM (9.70±4.70)(t=7.031,P<0.001) at week 4, POEM (7.74±3.48)(t=8.806,P<0.001) at week 8, POEM (6.35±3.33)(t=10.474,P<0.001) at week 12, POEM (4.26±2.51)(t=11.996,P<0.001) at week 16. In the 16th week, 100%(23 patients), 91.3%(21 patients), 34.8%(8 patients) and 8.7%(2 patients) of 23 patients reached SCORAD30, SCORAD50, SCORAD70, and SCORAD90 statuses, respectively. There were 82.6%(19 patients), 95.7%(22 patients) and 95.7%(22 patients) of 23 patients with NRS, DLQI and POEM improved by≥4 points compared with baseline. Twelve patients with AD who continued to receive dupilumab after 16 weeks showed further improvement in skin lesions. The adverse events were conjunctivitis and injection site reaction. In conclusion, dupilumab is an effective and safe treatment for moderate and severe AD. However, the longer-term efficacy and safety require further studies involving larger sample sizes and a longer follow-up time.
Humans ; Dermatitis, Atopic/drug therapy* ; Quality of Life ; Retrospective Studies ; Severity of Illness Index ; Treatment Outcome

OBJECTIVE: Preliminary assessment of rabies virus neutralizing activity, safety and immunogenicity of a recombinant human rabies antibody (NM57) compared with human rabies immunoglobulin (HRIG) in Chinese healthy adults. METHODS: Subjects were randomly (1:1:1) allocated to Groups A (20 IU/kg NM57), B (40 IU/kg NM57), or C (20 IU/kg HRIG). One injection was given on the day of enrollment. Blood samples were collected on days -7 to 0 (pre-injection), 3, 7, 14, 28, and 42. Adverse events (AEs) and serious AEs (SAEs) were recorded over a period of 42 days after injection. RESULTS: All 60 subjects developed detectable rabies virus neutralizing antibodies (RVNAs) (> 0.05 IU/mL) on days 3, 7, 14, 28, and 42. The RVNA levels peaked on day 3 in all three groups, with a geometric mean concentration (GMC) of 0.2139 IU/mL in Group A, 0.3660 IU/mL in Group B, and 0.1994 IU/mL in Group C. At each follow-up point, the GMC in Group B was significantly higher than that in Groups A and C. The areas under the antibody concentration curve over 0-14 days and 0-42 days in Group B were significantly larger than those in Groups A and C. Fifteen AEs were reported. Except for one grade 2 myalgia in Group C, the other 14 were all grade 1. No SAEs were observed. CONCLUSION The rabies virus neutralizing activity of 40 IU/kg NM57 was superior to that of 20 IU/kg NM57 and 20 IU/kg HRIG, and the rabies virus neutralizing activity of 20 IU/kg NM57 and 20 IU/kg HRIG were similar. Safety was comparable between NM57 and HRIG.
Adult ; Antibodies, Neutralizing ; Antibodies, Viral ; Data Collection ; Humans ; Rabies/prevention & control* ; Rabies Vaccines/adverse effects* ; Rabies virus/genetics*