OBJECTIVE: To evaluate the efficacy and safety of dupilumab in the treatment of atopic dermatitis in the elderly. METHODS: In this study, elderly patients with atopic dermatitis treated with dupilumab for at least 16 weeks in the Department of Dermatology and Venereology of Beijing Anzhen Hospital from January 2021 to October 2023 were retrospectively collected. Clinical indicators were compared before, during and after treatment, including pruritus numerical rating score (PNRS), eczema area and severity index (EASI), dermatology life quality index (DLQI) score, and the incidence of adverse events was recorded. The expression of interferon γ (IFN-γ), interleukin-4 (IL-4) and interleukin-6 (IL-6) in peripheral blood were compared before treatment and after 16 weeks of treatment. RESULTS: A total of 90 elder patients with atopic dermatitis were included, EASI, PNRS and DLQI scores all showed a gradual downward trend during the treatment period, which was manifested as a rapid decline in the first 4 weeks after starting treatment, and then the decline gradually leveled off. The results of point-to-point comparison showed that EASI, PNRS and DLQI scores in 4 weeks after treatment were significantly lower than those before treatment (P < 0.001); In the 16th week after treatment, the scores of the above therapeutic indicators were further reduced, and the difference was statistically significant compared with the 4th week (P < 0.01); The EASI score was significantly lower at each time point than the previous time point, indicating that the patients' skin lesions continued to improve significantly. The overall efficacy of dupliumab was evaluated. After 4 weeks of treatment, 62.89% of patients achieved EASI-50 (EASI score decreased by ≥50%), and 74.4% of patients' DLQI score decreased by ≥4 points. After 16 weeks of treatment, 57.8% of the patients achieved EASI-75, 32.2% achieved EASI-90, and the PNRS and DLQI scores of all the patients decreased by ≥4 points. After 16 weeks of treatment, the expression levels of IL-4 and IL-6 were (31.62±6.23) ng/L and (14.36±2.25) ng/L, respectively, which were significantly lower than those before treatment (P < 0.001), and the expression level of IFN-γ was (15.37±3.14) ng/L, which was higher than before treatment (P < 0.001).The main adverse reactions were conjunctivitis (2 cases), injection site reaction (3 cases) and multiple bacterial folliculitis of the back (2 cases), which could be alleviated by symptomatic treatment, and no serious adverse reactions occurred. CONCLUSION Dupilumab has shown good efficacy in the treatment of elderly atopic dermatitis, which can effectively improve clinical symptoms such as itching and skin lesions, improve the quality of life of patients, and no serious adverse reactions occurred during treatment, so it is safe and worthy of clinical promotion.
Humans ; Dermatitis, Atopic/blood* ; Antibodies, Monoclonal, Humanized/adverse effects* ; Aged ; Male ; Female ; Interleukin-4/blood* ; Retrospective Studies ; Quality of Life ; Interleukin-6/blood* ; Interferon-gamma/blood* ; Middle Aged ; Treatment Outcome ; Severity of Illness Index

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

AIM:To explore the effects of CD38 on lysosome reformation and cholesterol efflux in macro-phages.METHODS:Bone marrow-derived macrophages from low-density lipoprotein(LDL)receptor knockout(LDLr-/-)mice were cultured as cell model.Live cell imaging system was applied to evaluate the effect of nicotinic acid adenine di-nucleotide phosphate(NAADP)on lysosome number.ELISA was conducted to measure NAADP level in macrophages.After the cells were treated with nicotinic acid(NA),RT-qPCR was conducted to detect CD38 mRNA expression,and Western blot was conducted to observe CD38 protein expression and phosphorylated transcription factor EB(TFEB)level.Laser scanning confocal microscopy was applied to evaluate the influence of CD38/NAADP signaling on lysosome number and cholesterol egression.RESULTS:NAADP remarkably increased lysosome number(P<0.05),and this effect was significantly inhibited by NAADP antagonist NED-19,Ca2+ chelator BAPTA,and calcineurin inhibitor CsA(P<0.05).CD38 markedly enhanced NAADP synthesis in macrophages(P<0.05).NAADP synthetic substrate NA prominently ele-vated the expression of CD38 mRNA and protein(P<0.05).NA significantly decreased the phosphorylated TFEB level;this effect was also attenuated by NED-19,BAPTA and CsA(P<0.05).Disrupting CD38/NAADP signaling pathway markedly inhibited NA-induced enhancement of lysosome number,lysosomal free cholesterol and cytosol cholesterol ester efflux in macrophages(P<0.05).NA-induced enhancement of lysosome number,lysosomal free cholesterol and cytosol cholesterol ester efflux abolished in LDLr/CD38 DKO macrophages(P<0.05),whereas these effects induced by NA were recovered after CD38 gene rescue.CONCLUSION:CD38 triggers lysosome reformation via TFEB and consequently pro-motes the efflux of lysosomal free cholesterol and cytosol cholesterol ester.

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2(ALDH2)alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.Methods Thirty 8-week-old C57 BL/6 mice were randomized into control,hypoxia,and hypoxia+Alda-1(an ALDH2 activator)group(n=10),and the mice in the latter two groups,along with 10 ALDH2 knockout(ALDH2-/-)mice,were exposed to hypoxia(10%O2,90%N2)with or without daily intraperitoneal injection of Alda-1 for 4 weeks.The changes in right ventricular function and pressure(RVSP)of the mice were evaluated by echocardiography and right ventricular catheter test,and pulmonary artery pressure was estimated based on RVSP.Pulmonary vascular remodeling,right ventricular injury,myocardial α-SMA expression,distal pulmonary arteriole muscle normalization,right ventricular cross-sectional area,myocardial cell hypertrophy,and right cardiac hypertrophy index were assessed with HE staining,immunofluorescence staining and WGA staining,and the expressions of ALDH2,SIRT1,PGC-1α,P16INK4A and P21CIP1 were detected.In pulmonary artery smooth muscle cells with hypoxic exposure,the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.Results The wild-type mice with hypoxic exposure showed significantly increased RVSP,right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1,which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/-mice.In cultured pulmonary artery smooth muscle cells,hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1,which were all lowered by treatment with Alda-1,but its effect was obviously attenuated by EX527 treatment.Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2(ALDH2)alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.Methods Thirty 8-week-old C57 BL/6 mice were randomized into control,hypoxia,and hypoxia+Alda-1(an ALDH2 activator)group(n=10),and the mice in the latter two groups,along with 10 ALDH2 knockout(ALDH2-/-)mice,were exposed to hypoxia(10%O2,90%N2)with or without daily intraperitoneal injection of Alda-1 for 4 weeks.The changes in right ventricular function and pressure(RVSP)of the mice were evaluated by echocardiography and right ventricular catheter test,and pulmonary artery pressure was estimated based on RVSP.Pulmonary vascular remodeling,right ventricular injury,myocardial α-SMA expression,distal pulmonary arteriole muscle normalization,right ventricular cross-sectional area,myocardial cell hypertrophy,and right cardiac hypertrophy index were assessed with HE staining,immunofluorescence staining and WGA staining,and the expressions of ALDH2,SIRT1,PGC-1α,P16INK4A and P21CIP1 were detected.In pulmonary artery smooth muscle cells with hypoxic exposure,the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.Results The wild-type mice with hypoxic exposure showed significantly increased RVSP,right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1,which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/-mice.In cultured pulmonary artery smooth muscle cells,hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1,which were all lowered by treatment with Alda-1,but its effect was obviously attenuated by EX527 treatment.Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Purpose/Significance To analyze the risks of near-source cyber-attacks faced by hospitals,and to propose counter-measures.Method/Process Combined with practical work experience,the risk analysis of hospital network architecture,on-site physi-cal environment,personnel behavior and other aspects is carried out from the perspective of near-source cyber-attacker.Then,from the perspective of defender and in combination with regulatory requirements and technical practices,countermeasures and suggestions are proposed.Result/Conclusion 5 main risks are identified,including wireless LAN cracking,exposed wired network sockets,improper configuration of self-service machines,poisoning & phishing,and sensitive information leakage.5 preventive suggestions are put for-ward,including strengthening Wi-Fi management,full coverage of network terminal access,multi-department collaboration in self-service device management,disabling mobile storage media on Intranet terminals,and updating cyber-security education.

Objective: To compare the efficiency of four methods that remove calcium hydroxide in root canals and to guide clinical practice. Methods : Sixty-five isolated mandibular single root canal premolars were collected. After crown cutting and root canal preparation, a tooth was randomly selected as the blank control group, and the remaining 64 teeth were equally divided into Groups A and B (n = 32). Group A was injected with water-soluble calcium hydroxide, and Group B was injected with oil-soluble calcium hydroxide. After 2 weeks of drug sealing, Groups A and B were randomly divided into 4 groups (n = 8), including the lateral opening syringe group, sonic vibration group, ultrasonic group, and Er: YAG laser group. Before and after calcium hydroxide removal, the samples were scanned by cone-beam CT, and the data were imported into Mimics for 3D reconstruction. The root canal was divided into the following segments: superior root segment, middle and apical, and the calcium hydroxide volume of each segment of the root canal was calculated. The volumes of calcium hydroxide before and after removal were V1 and V2, respectively, with a clearance rate = (V1-V2)/V1×100%. Three-factor ANOVA was used for statistical analysis. After Groups A and B were reconstructed, the apical region with residual calcium hydroxide was selected, and the blank control was observed by scanning electron microscopy (SEM). Results : Two types of calcium hydroxide could not be completely removed by the four flushing methods. The clearance rate of water-soluble calcium hydroxide was higher than that of oil-soluble calcium hydroxide (P<0.001). Among the three segments of the root canal, the clearance rate of the apical segment was lower (P<0.05). The Er: YAG laser treatment group showed the highest removal efficiency of two kinds of calcium hydroxide, which was higher than that of the other groups, especially in apical of the root. Compared with the sonic wave washing group and the syringe washing group, the ultrasonic wave washing group exhibited significant advantages (P<0.05). The clearance rate of the sonic wave washing group was higher in the oily calcium hydroxide root middle group than in the syringe washing group (P<0.05). SEM showed that the two kinds of calcium hydroxide could not be completely removed, but the residual rate of oil-soluble calcium hydroxide was large. Conclusion Both types of calcium hydroxide could not be completely removed, and compared to water-soluble calcium hydroxide, oil-soluble calcium hydroxide was more difficult to remove. Among the four cleaning methods, Er:YAG laser swing washing showed the higher cleaning efficiency.

Humans ; Asthma/drug therapy* ; Biological Therapy

METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.
Animals ; Mice ; Methylation ; Chromatin ; Histones/metabolism* ; RNA, Messenger/genetics* ; Methyltransferases/metabolism* ; RNA/metabolism*

This study aimed to explore key quality control factors that affected the prognosis of intensive care unit (ICU) patients in Chinese mainland over six years (2015-2020). The data for this study were from 31 provincial and municipal hospitals (3425 hospital ICUs) and included 2 110 685 ICU patients, for a total of 27 607 376 ICU hospitalization days. We found that 15 initially established quality control indicators were good predictors of patient prognosis, including percentage of ICU patients out of all inpatients (%), percentage of ICU bed occupancy of total inpatient bed occupancy (%), percentage of all ICU inpatients with an APACHE II score ⩾15 (%), three-hour (surviving sepsis campaign) SSC bundle compliance (%), six-hour SSC bundle compliance (%), rate of microbe detection before antibiotics (%), percentage of drug deep venous thrombosis (DVT) prophylaxis (%), percentage of unplanned endotracheal extubations (%), percentage of patients reintubated within 48 hours (%), unplanned transfers to the ICU (%), 48-h ICU readmission rate (%), ventilator associated pneumonia (VAP) (per 1000 ventilator days), catheter related blood stream infection (CRBSI) (per 1000 catheter days), catheter-associated urinary tract infections (CAUTI) (per 1000 catheter days), in-hospital mortality (%). When exploratory factor analysis was applied, the 15 indicators were divided into 6 core elements that varied in weight regarding quality evaluation: nosocomial infection management (21.35%), compliance with the Surviving Sepsis Campaign guidelines (17.97%), ICU resources (17.46%), airway management (15.53%), prevention of deep-vein thrombosis (14.07%), and severity of patient condition (13.61%). Based on the different weights of the core elements associated with the 15 indicators, we developed an integrated quality scoring system defined as F score=21.35%xnosocomial infection management + 17.97%xcompliance with SSC guidelines + 17.46%×ICU resources + 15.53%×airway management + 14.07%×DVT prevention + 13.61%×severity of patient condition. This evidence-based quality scoring system will help in assessing the key elements of quality management and establish a foundation for further optimization of the quality control indicator system.
Humans ; China/epidemiology* ; Cross Infection/epidemiology* ; Intensive Care Units/statistics & numerical data* ; Quality Control ; Quality Indicators, Health Care/statistics & numerical data* ; Sepsis/therapy* ; East Asian People/statistics & numerical data*