Background Frailty serves as a significant precursor to falls, disability, and mortality. Epidemiological evidence examining the impact of working hours on frailty remains scarce. Objective To explore the prevalence of frailty and the relationship between frailty and working hours among full-time middle-aged and older workers in China. Methods Data were derived from the 2020 China Health and Retirement Longitudinal Study (CHARLS). The study included full-time workers aged 45 years and above with a weekly working duration exceeding 35 h. Frailty was assessed using the Frailty Index (FI). First, the dose-response relationship between working hours and FI was explored using a generalized additive model (GAM). Second, univariate analyses were performed using t-tests, χ² tests, and the Jonckheere–Terpstra trend test. Restricted cubic splines (RCS) were introduced for modeling. Based on ordinal logistic regression models, covariates were adjusted sequentially to examine whether differences in frailty prevalence existed across different weekly working hour categories. Finally, subgroup analyses were performed. Results Among the 5504 included participants, the mean age was (56.41±7.30) years, with 2304 being female (41.86%). A total of 807 participants (14.66%) were identified as frail, and 2 686 participants (48.80%) were pre-frail. After standardization for gender and age according to the seventh national census data, the standardized prevalence of frailty and prefrailty were 18.89% and 47.25%, respectively. Significant higher proportions of frail individuals were found among those in non-managerial (73.73%), agricultural (64.06%), and non-employed (65.68%) occupations. Long working hours were prevalent: 2596 (47.17%) workers worked 41–60 h per week, 1649 (29.96%) worked >60 h per week, and only 1259 (22.87%) worked 35–40 h per week. GAM analysis showed a non-linear relationship between weekly working hours and FI. Restricted cubic spline analysis showed a statistically significant association between weekly working hours and frailty status (P=0.022). Logistic regression analysis revealed that individuals working more than 60 h per week had a 23% higher odds of frailty compared to those working 41–60 h (OR=1.23, 95%CI: 1.09, 1.38, P<0.01), while those working 35–40 h per week showed a 15% higher odds of frailty (OR=1.15, 95%CI: 1.01, 1.31, P=0.034). The subgroup analysis revealed that the positive association between working more than 60 h per week and frailty remained generally consistent across sex, age, urban/rural residence, occupational attributes, industry, or employment type, although the association did not reach statistical significance among non-rural residents and individuals aged 60 years and older. Conclusion The prevalence of frailty among full-time middle-aged and older labor force in China is relatively high, and the odds of frailty increases significantly among those who work more than 60 h per week. It is recommended to implement frailty prevention and management strategies targeting long-working-hour workers and to prioritize the impact of working duration on frailty.

Distinct from the complementary inhibition mechanism through binding to the target with three-dimensional conformation of small molecule inhibitors, targeted protein degradation technology takes tremendous advantage of endogenous protein degradation pathway inside cells to degrade plenty of “undruggable” target proteins, which provides a novel route for the treatment of many serious diseases, mainly including proteolysis-targeting chimeras, lysosome-targeting chimeras, autophagy-targeting chimeras, antibody-based proteolysis-targeting chimeras, etc. Unlike proteolysis-targeting chimeras first found in 2001, which rely on ubiquitin-proteasome system to mainly degrade intracellular proteins of interest, lysosome-targeting chimeras identified in 2020, which was act as the fastly developing technology, utilize cellular lysosomal pathway through endocytosis mediated by lysosome-targeting receptor to degrade both extracellular and membrane proteins. As an emerging biomedical technology, nucleic acid-driven lysosome-targeting chimeras utilize nucleic acids as certain components of chimera molecule to replace with ligand to lysosome-targeting receptor or protein of interest, exhibiting broad application prospects and potential clinical value in disease treatment and drug development. This review mainly introduced present progress of nucleic acid-driven lysosome-targeting chimeras technology, including its basic composition, its advantages compared with antibody or glycopeptide-based lysosome-targeting chimeras, and focused on its chief application, in terms of the type of lysosome-targeting receptors. Most research about the development of nucleic acid-driven lysosome-targeting chimeras focused on those which utilized cation-independent mannose-6-phosphonate receptor as the lysosome-targeting receptor. Both mannose-6-phosphonate-modified glycopeptide and nucleic aptamer targeting cation-independent mannose-6-phosphonate receptor, even double-stranded DNA molecule moiety can be taken advantage as the ligand to lysosome-targeting receptor. The same as classical lysosome-targeting chimeras, asialoglycoprotein receptor can also be used for advance of nucleic acid-driven lysosome-targeting chimeras. Another new-found lysosome-targeting receptor, scavenger receptor, can bind dendritic DNA molecules to mediate cellular internalization of complex and lysosomal degradation of target protein, suggesting the successful application of scavenger receptor-mediated nucleic acid-driven lysosome-targeting chimeras. In addition, this review briefly overviewed the history of lysosome-targeting chimeras, including first-generation and second-generation lysosome-targeting chimeras through cation-independent mannose-6-phosphonate receptor-mediated and asialoglycoprotein receptor-mediated endocytosis respectively, so that a clear timeline can be presented for the advance of chimera technique. Meantime, current deficiency and challenge of lysosome-targeting chimeras was also mentioned to give some direction for deep progress of lysosome-targeting chimeras. Finally, according to faulty lysosomal degradation efficiency, more cellular mechanism where lysosome-targeting chimeras perform degradation of protein of interest need to be deeply explored. In view of current progress and direction of nucleic acid-driven lysosome-targeting chimeras, we discussed its current challenges and development direction in the future. Stability of natural nucleic acid molecule and optimized chimera construction have a great influence on the biological function of lysosome-targeting chimeras. Discovery of novel lysosome-targeting receptors and nucleic aptamer with higher affinity to the target will greatly facilitate profound advance of chimera technique. In summary, nucleic acid-driven lysosome-targeting chimeras have many superiorities, such as lower immunogenicity, expedient synthesis of chimera molecules and so on, in contrast to classical lysosome-targeting chimeras, making it more valuable. Also, the chimera technology provides new ideas and methods for biomedical research, drug development and clinical treatment, and can be used more widely through further research and optimization.

BACKGROUND:Transcranial magneto-acoustic-electrical stimulation is a novel non-invasive neural regulation technique that utilizes the induced electric field generated by the coupling effect of ultrasound and static magnetic field to regulate the discharge activity of the nervous system.However,the mechanism by which it affects synaptic plasticity in the brain is still not enough. OBJECTIVE:To explore the effect of transcranial magneto-acoustic-electrical stimulation intensity on synaptic plasticity of the prefrontal cortex neural network in mice. METHODS:(1)Animal experiment:Twenty-four C57 mice were equally and randomly divided into four groups:the control group receiving pseudo-stimulation,the 6.35 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,6.35 W/cm2,the 17.36 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,17.36 W/cm2,and the 56.25 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,56.25 W/cm2.The local field potential signals and behavioral correctness were recorded during the execution of T-maze in mice.(2)Modeling and simulation experiments:A neural network model of the prefrontal cortex in mice stimulated by transcranial magneto-acoustic-electrical stimulation was constructed to compare the structural connectivity characteristics of the neural network under different stimulation intensities. RESULTS AND CONCLUSION:Transcranial magneto-acoustic-electrical stimulation could effectively shorten the behavior learning time,improve the working memory ability of mice(P＜0.05),and continue to stimulate the frontal lobe of mice after learning behavior.There was no significant difference in the accuracy of the T-maze behavioral experiment among the experimental groups(P＞0.1).Analysis of local field potential signals in the frontal lobe of mice revealed that transcranial magneto-acoustic-electrical stimulation promoted energy enhancement of β and γ rhythms.As the stimulation intensity increased,there was an asynchronous decrease in β and γ rhythms.Through β-γ phase amplitude coupling,it was found that stimuli could enhance the neural network's ability to adapt to new information and task requirements.Modeling and simulation experiments found that stimulation could enhance the discharge level of the neural network,increase the long-term synaptic weight level,and decrease the short-term synaptic weight level only when the stimulation intensity was high.To conclude,there is a complex nonlinear relationship between different stimulus intensities and the functional structure of neural networks.This neural regulation technique may provide new possibilities for the treatment of related neurological diseases such as synaptic dysfunction and neural network abnormalities.

Operation management is an important tool to promote the high-quality development of public hospitals in China.Since the founding of New China,based on China's economic and social development and medical and health system reform,the evolution of operation management of public hospitals in China can be divided into four stages,the system building stage(1949-1978),the liberalization and revitalization stage(1979-1996),the operation mechanism reform stage(1997-2020),and the new stage of high-quality development(2021 present).The development trend of public hospital operation management in future should deepen the public welfare-oriented public hospital operation management,explore the value-oriented medical operation management model based on high-quality development and the refined operation and management model of public hospitals,so as to promote the high-quality development of public hospitals in China.

OBJECTIVE To investigate the biodistribution of lipid nanoparticles(LNPs)with different surface charges and different particle sizes in mice.METHODS LNPs were prepared using microfluidic technology by incorporating positively charged phospholipids,negatively charged phospholipids,ioniz-able phospholipids,and neutral phospholipids into the formulation to create LNPs with corresponding surface charges.The particle size of the LNPs was controlled by polyethylene glycol(PEG)modifica-tion and measured using dynamic light scattering(DLS)and transmission electron microscopy(TEM),while the surface charge was analyzed using a zeta potential analyzer.The LNPs were labeled with a fluorescent dye,and the mice were intravenously injected with 0.625 μmol·kg-1 of LNPs.At 1,4,12 and 24 h post-injection,the brain,heart,livers,spleen,lungs and kidneys were collected.The fluorescence distribution in different organs was detected using an in vivo imaging system to reflect the distribution of LNPs in various organs.RESULTS Particle size analysis showed that,except the ionizable lipid nanoparticles without PEG modification(LNP-MC3),which had a particle size>200 nm,the particle sizes of positively charged LNPs without PEG modification(LNP-Pos),PEG-modified positively charged LNPs(LNP-Pos-P),PEG-modified neutral LNPs(LNP-Neu-P),PEG-modified ionizable LNPs(LNP-MC3-P),and PEG-modified negatively charged LNPs(LNP-Neg-P)were all<200 nm.Zeta potential analysis revealed that the surface charges of the LNPs were the highest in LNP-Pos,followed by LNP-Pos-P,LNP-MC3-P,LNP-Neu-P,LNP-MC3 and LNP-Neg-P.In vivo imaging results indicated that LNP-Pos-P,LNP-Pos and LNP-MC3-P were primarily distributed in the livers,lungs and kidneys,respectively,while LNP-Neu-P and LNP-Neg-P in the livers,kidneys,and lungs,respectively.The distribution of LNP-MC3-P in the brain,heart,spleen and kidneys peaked at 12 h post-injection,but at 24 h in the livers.The distribution of LNP-Pos-P in the lungs peaked at 1 h post-injection.CONCLUSION LNPs are primarily distributed in the livers.Surface charges influence the second most highly-distributed organs.LNP-Pos-P and LNP-MC3-P are the second most highly-distributed in the lungs,and LNP-Neu-P and LNP-Neg-P in the kidneys.

Objective:To investigate the correlation between the hemodynamic pattern of non-culprit vessel stenosis and long-term vessel-oriented composite outcome(VOCO) in patients with acute ST-segment elevation myocardial infarction (STEMI).Methods:From January 2019 to December 2021, 233 consecutive patients with STEMI and non-culprit vessel stenosis were prospectively enrolled at Shanghai East Hospital. The median follow-up duration was 3.9 years. The 367 non-culprit vessels of the 233 patients were divided into the VOCO group (33 vessels, 9.0%) and the non-VOCO group (334 vessels, 91.0%). Parameters pertaining to the hemodynamic pattern of non-culprit vessel stenosis between the two groups were compared. Receiver operating characteristic (ROC) curves were used to assess the correlation between hemodynamic pattern and VOCO, and Cox multivariate regression and logistic multivariate regression analyses were applied to identify independent predictors of VOCO.Results:The 233 enrolled patients were aged (62.5±12.9) years, with 193 males (82.8%). In the VOCO group, the maximum quantitative flow ratio (QFR) decreased within 20 mm of the QFR-assessed segment, the difference in QFR across the entire vessel, the length of functionally significant vessel, and the maximum gradient of QFR decrease (dQFR/dsmax) were significantly greater than those in the non-VOCO group. ROC curve analysis showed that the optimal threshold for predicting VOCO using dQFR/dsmax was 0.009 6 (area under the curve: 0.691, 95% CI: 0.606-0.775, P<0.001). Multivariable Cox regression analysis revealed that dQFR/dsmax was an independent predictor of VOCO ( HR=1.199, 95% CI: 1.070-1.343, P=0.002). When anatomical and functional stenosis severities were included in the model, a high pullback pressure gradient (PPG) index ( HR=1.572, 95% CI: 1.052-2.351, P=0.027) emerged as an independent predictor of VOCO. Multivariable logistic regression analysis revealed that a low PPG index( OR=2.851, 95% CI: 1.945-4.178, P<0.001) was an independent predictor of QFR≤0.80 without long-term VOCO. Conclusion:In patients with STEMI, localized hemodynamic patterns of coronary artery stenosis, characterized by high dQFR/dsmax and high PPG index, are associated with long-term VOCO.

Objective To investigate the effects of a continuous-dose administration versus different dosage regimens of polyethylene glycol electrolyte solution(PEG)taken in two doses with a 12-hour interval on bowel cleansing efficacy,with the goal of optimizing bowel preparation protocols and improving patient tolerability.Methods 232 patients who underwent painless colonoscopy and used PEG as a bowel cleanser from June 2024 to September 2024 were selected as study subjects.Participants were divided into three groups:the control group(3.00 L PEG continuous dose),experimental group A(0.75 L+2.25 L PEG),and experimental group B(1.50 L+1.50 L PEG).All patients underwent painless colonoscopy within 4～6 h after completing PEG intake.The interval between the two doses of PEG in group A and group B was 12 h.The bowel cleansing efficacy was assessed by using the Boston bowel preparation scale(BBPS),and the rates of colon polyp detection,adverse reactions,sleep duration,and tolerability were recorded.Results There were no significant statistical differences in BBPS scores and colon polyp detection rates among the three groups(P>0.05).Experimental group B experienced the least adverse reactions,followed by experimental group A,while the control group reported the most significant adverse reactions(P<0.05).The timing of PEG administration did not have a significant impact on sleep duration among the three groups(P>0.05).Patients in experimental group B showed good tolerability to PEG and were willing to accept this bowel preparation regimen,followed by group A,while the control group exhibited the poorest tolerability,with significant statistical differences among the three groups(P<0.05).Conclusion The continuous administration and divided administration of PEG have no significant impact on the effectiveness of intestinal cleansing and the detection rate of colonic polyps.However,the divided PEG regimen with a 12 h interval results in fewer adverse reactions and better tolerance,especially the optimal regimen of taking 1.50 L PEG in two doses with a 12 h interval.

Objective To sort out the management system of clinical trial drugs in our hospital,and analyze the construction and practical experience of the information system in the whole process management of clinical trial drugs,and to further improve the efficiency and quality of clinical trials.Methods Based on the original management of clinical trial drugs,an information system in line with the situation of our hospital was applied to manage the whole process of clinical trial drugs.Results Compared with the traditional management,the information system can automatically record the data of inbound and outbound storage,distribution,retrieval and return of trial drugs in real time,pre-review the prescriptions and randomized documents of clinical trial drugs,and realise paperless office.Conclusions The information system can ensure the safety,accuracy and traceability of the data of drugs used in clinical trial.The system can also save resources,improve the efficiency and quality of clinical trial management.

Objective:To identify strain-specific features of Klebsiella pneumoniae by analyzing metagenomics next generation sequencing (mNGS) data, thereby expanding the downstream applications of mNGS. Methods:The sequences of K.pneumoniae strains were organized from both the self-built database of the long-term multi-center research cohort in China established by the Peking University People′s Hospital from 2009 to 2020 (with 2 345 sequences) and the public databases (with 19 648 sequences). The existing large-scale databases were compressed, and a set of strains representative of clonal groups were screened. A strain genome information library was constructed based on k-mer features, and the most matching representative sequences in the database were searched for the raw mNGS data. The search results of the self-built library and public library were merged and optimized to update the prediction of antimicrobial-resistance characteristics and avoid the impact of uneven data distribution on the results. A total of 314 clinical samples from patients with K.pneumoniae detected by mNGS in the Clinical Microbiology Laboratory of Peking University People′s Hospital from 2022 to 2024 were retrospectively collected, and 101 samples with positive clinical culture results were selected to validate the prediction results. The antimicrobial-resistance phenotypes were verified by clinical antimicrobial susceptibility test results. Whole-genome sequencing was performed on the culture strains of 14 samples randomly selected using random numbers to verify the genotypes. Single nucleotide polymorphism distance analysis was used to verify the occurrence of outbreak events. The χ2 test and Mann-Whitney U test were used for statistical analysis. Results:A representative strain sequence k-mer feature library containing self-built and public sub-libraries was constructed. The library construction required only about 1 hour with <3 GB storage, with a high compression ratio and low update cost. Using k-mer-based analysis, mNGS data achieved precise strain characterization within 4 minutes and and <5 GB memory occupation. There was a significant difference in the antimicrobial-resistance rates to more than half of the antibiotics between the self-built database (90.8%, 2 130/2 345) and the public database (22.7%, 4 457/19 648) ( χ2=4 634.1, P<0.001). After optimizing the search results, the mean category agreement, sensitivity, and specificity of the prediction for eight antibiotics reached 84.8% (323/381), 78.9% (131/166), and 91.2% (196/215), respectively. The target genotypes were successfully detected in 10 out of 12 samples, and two outbreak events (2 samples per event) were successfully identified. Conclusions:An independent analysis process adapted to the needs of identifying the features of K. pneumoniae strains in mNGS data was developed. This process requires minimal computational resources and processing time and can directly achieve the simultaneous analysis of the antimicrobial-resistance phenotypes of K. pneumoniae at the strain level and their corresponding genomic characteristic profiles based on the raw mNGS reads.

Objective To observe the value of multi-detector CT(MDCT)for evaluating changes of aortic root parameters caused by aortic stenosis(AS).Methods MDCT data of 20 cases with severe AS were retrospectively analyzed.The changes of the long diameter,short diameter,mean diameter,area,circumference,as well as diameter derived from area(DA)and diameter derived from circumference(DC)of aortic annulus(AA),left ventricular outflow tract(LVOT)and sinotubular junction(STJ)during early systole,late systole,early diastole and late diastole were measured and calculated,respectively.Results In early systole,the short diameter,mean diameter,area,circumference,DA and DC of A A were all significantly larger than that those in late systole,early diastole and late diastole(all P＜0.05).No significant difference of the long diameter of AA was found among different phases(all P＞0.05).Meanwhile,the short diameter,mean diameter,area,circumference,DA and DC of LVOT in early systole were all significantly larger than those in late systole,early diastole and late diastole(all P＜0.05).The long diameter of LVOT in early systole was larger than in late systole(P＜0.05),but not significantly different compared with that in early and late diastole(both P＞0.05).No significant difference of the above parameters of STJ was found among different phases(all P＞0.05).At early systole,DA and the mean diameter of AA were both significantly smaller than those of DC(both P＜0.05).Conclusion AA parameters obtained with MDCT in patients with severe AS were valuable for selecting prosthetic valves during transcatheter aortic valve replacement.