Background High-speed train engineers' lower extremities are constrained by compulsive vigilance pedal tasks and limited space beneath the control console during driving. Shifts in alertness triggered by running route observation may share the same mental resource required by moderate-to-low physical exertion. Current research on improving cab design and maintaining optimal on-duty attention allocation remains limited. Objective To examine variations in lower extremity muscle load, gaze-tracking behavior, and driving performance under various combinations of vigilance pedal positions and route scenarios during simulated high-speed train tasks. To identify optimal working condition combinations that promote level and variety of physical activity and facilitate rational attention allocation. Methods A 4×2 within-subjects design were employed (4 vigilance pedal position profiles: knee front, side, and any; 2 route scenarios: monotonous and complex). Nine male college volunteers were recruited as simulated drivers to perform designated interval driving tasks. Surface electromyography and eye tracking were used to assess leg muscle load and gaze behavior respectively. Task performance and subjective fatigue were recorded. Results In all simulation driving tasks, skeletal muscle loads were low with the percentage of maximum voluntary contraction (%MVC) at approximately 4%. No fatigue tendencies were observed within single trial blocks (7 min), and the subjective fatigue ratings remained relatively low. While the activation of the dominant-side tibialis anterior was higher for the knee pedal than for the front (%MVC: 3.7% ± 3.13% vs. 1.08% ± 0.72%) or the side pedals (%MVC: 3.7% ± 3.13% vs. 1.4% ± 0.77%). The activation level of the dominant-side gastrocnemius was higher for the knee pedal than for the other three pedal profiles. For the any pedal condition, the intercept of the instantaneous median frequency curve for the dominant-side rectus femoris was lower in the monotonous route than in the complex route [(111.18 ± 35.78) Hz vs. (153.33 ± 39.12) Hz]. Among eye-tracking metrics, total fixations were higher during knee-level pedaling than side pedaling, while more saccades were recorded in monotonous routes than in complex ones. Regarding task performance, the any pedal yielded fewer missed signals than the front pedal, with 2/3 and 1/3 of participants preferring the front and knee pedals, respectively. The activation levels of the dominant tibialis anterior and dominant gastrocnemius muscles during the knee pedal × complex route combination were higher than any combination involving the front pedal. No statistically significant effect of pedal position or route scenario was found on other indicators. Conclusion The combination of knee pedal and complex route provides an optimal working setting for maximizing leg muscle mobility without compromising attention allocation or driving performance. It is recommended that train engineers modulate attention during monotonous routes to avoid emotional tension and increased muscle strain caused by over-monitoring. Given the ergonomic characteristics of high cognitive load, low physical exertion levels, and highly restricted lower limb mobility among high-speed train engineers, future cab designs should consider incorporating knee-level vigilance pedal and adjust safety alertness rules to allow reset via either front or knee pedal.

Background High-speed train engineers' lower extremities are constrained by compulsive vigilance pedal tasks and limited space beneath the control console during driving. Shifts in alertness triggered by running route observation may share the same mental resource required by moderate-to-low physical exertion. Current research on improving cab design and maintaining optimal on-duty attention allocation remains limited. Objective To examine variations in lower extremity muscle load, gaze-tracking behavior, and driving performance under various combinations of vigilance pedal positions and route scenarios during simulated high-speed train tasks. To identify optimal working condition combinations that promote level and variety of physical activity and facilitate rational attention allocation. Methods A 4×2 within-subjects design were employed (4 vigilance pedal position profiles: knee front, side, and any; 2 route scenarios: monotonous and complex). Nine male college volunteers were recruited as simulated drivers to perform designated interval driving tasks. Surface electromyography and eye tracking were used to assess leg muscle load and gaze behavior respectively. Task performance and subjective fatigue were recorded. Results In all simulation driving tasks, skeletal muscle loads were low with the percentage of maximum voluntary contraction (%MVC) at approximately 4%. No fatigue tendencies were observed within single trial blocks (7 min), and the subjective fatigue ratings remained relatively low. While the activation of the dominant-side tibialis anterior was higher for the knee pedal than for the front (%MVC: 3.7% ± 3.13% vs. 1.08% ± 0.72%) or the side pedals (%MVC: 3.7% ± 3.13% vs. 1.4% ± 0.77%). The activation level of the dominant-side gastrocnemius was higher for the knee pedal than for the other three pedal profiles. For the any pedal condition, the intercept of the instantaneous median frequency curve for the dominant-side rectus femoris was lower in the monotonous route than in the complex route [(111.18 ± 35.78) Hz vs. (153.33 ± 39.12) Hz]. Among eye-tracking metrics, total fixations were higher during knee-level pedaling than side pedaling, while more saccades were recorded in monotonous routes than in complex ones. Regarding task performance, the any pedal yielded fewer missed signals than the front pedal, with 2/3 and 1/3 of participants preferring the front and knee pedals, respectively. The activation levels of the dominant tibialis anterior and dominant gastrocnemius muscles during the knee pedal × complex route combination were higher than any combination involving the front pedal. No statistically significant effect of pedal position or route scenario was found on other indicators. Conclusion The combination of knee pedal and complex route provides an optimal working setting for maximizing leg muscle mobility without compromising attention allocation or driving performance. It is recommended that train engineers modulate attention during monotonous routes to avoid emotional tension and increased muscle strain caused by over-monitoring. Given the ergonomic characteristics of high cognitive load, low physical exertion levels, and highly restricted lower limb mobility among high-speed train engineers, future cab designs should consider incorporating knee-level vigilance pedal and adjust safety alertness rules to allow reset via either front or knee pedal.

In the century-long evolution of insulin pharmaceuticals, each transformative advancement in this drug class has been closely tied to the ability to obtain new insulin isoforms for research. Despite this, the recently discovered naturally occurring isoforms of glycosylated human insulin have remained largely unattainable for proper characterization. Herein, we demonstrate for the first time that total chemical synthesis can be used to generate all isoforms. This achievement required maintaining the correct positions of the interchain disulfide bonds while effectively removing protecting groups on complex glycans. Notably, the availability of seven glycoforms reveals the important effects of natural sialylated glycans in suppressing insulin self-association and enhancing its solubility, surpassing the performance of currently employed rapid-acting insulin drugs. This work not only offers a readily adaptable platform for exploring natural O-glycosylation in other therapeutic proteins and peptides but also lays the groundwork for further research into harnessing natural glycosylation for therapeutic applications.

Objective To investigate the regulatory effects of liraglutide(Lira)on adipocyte brown-ing and its underlying molecular mechanisms.Methods Adipose-derived mesenchymal stem cells were induced to differentiate with palmitic acid(PA)simulating a high-fat environment and lenti-viral transfection to silence the expression of PGC1α.The cell groups included control,Lira(100 nmol/L),PA(200 nmol/L),PA+Lira,scrambled siRNA,scrambled siRNA+Lira,siRNA PGC1α,and siRNA PGC1α+Lira groups(n=3).After corresponding treatments were given,quantitative PCR and Western blotting were employed to detect the mRNA and protein expres-sion levels of UCP-1,Prdm16,Agt,and adiponectin,as well as AMPK and p-AMPK.Results Compared to the control group,the PA group had significantly increased expression of Agt and adiponectin but decreased UCP-1 and Prdm16 at protein and mRNA levels,and the Lira group showed obviously increased protein and mRNA levels of UCP-1 and Prdm16 but decreased Agt and adiponectin levels(P＜0.05).Addition of Lira treatment resulted in increments in UCP-1 and Prdm16 while declines Agt and adiponectin at both mRNA and protein levels when compared with the levels in the PA group(P＜0.05).In comparison to the scrambled siRNA group,the siRNA PGC1α group showed decreases in UCP-1 and Prdm16 expression,accompanied by increa-ses in Agt and adiponectin levels(P＜0.05),similar results were observed in the scrambled siRNA+Lira group(P＜0.05).The p-AMPK/AMPK ratio was significantly increased in the scrambled siRNA+Lira group(1.415±0.176 vs 0.837±0.049,P＜0.05),but decreased in the siRNA PGC1α group(0.534±0.035 vs 0.837±0.049,P＜0.01)when compared with the scram-bled siRNA group.Conclusion Lira promotes adipocyte browning and improves lipid metabolism disorders in a high-fat environment by activating the AMPK/PGC1α signaling pathway.

Objective Under the guidance of the Social Ecosystems Theory(SET)framework,this study explores the experience of social isolation among patients with chronic obstructive pulmonary disease(COPD),providing a basis for the development of targeted clinical interventions.Methods This study employed purposeful sampling methods.Semi-structured interviews were conducted from April to July 2024 with patients diagnosed with COPD at a tertiary hospital in Shanxi Province,China,who met the inclusion and exclusion criteria.Data were analyzed using Colaizzi's seven-step analysis method and NVivo 12.0 software.Results This study involved in-depth interviews with 15 patients suffering from COPD,totaling approximately 405 minutes of interview time and yielding over 40,000 words in transcribed text.Totally 3 main themes and 9 sub-themes were distilled,among which the microsystem level reflects the intricate interplay of individual experiences(physical functional limitations,severe negative emotions,heightened emotional imbalance,and weakened social roles);the mesosystem level pertains to the support and challenges from family and social networks(intense need for familial emotional support,widening social gaps in interactions with friends and relatives,and pronounced interpersonal communication barriers);the macrosystem level involves the integrated influence of societal and policy environments(restricted living conditions and urgent demands for policy support and service accessibility).Conclusion The social isolation experienced by patients with COPD manifests in multiple dimensions of experience.It is necessary to develop interdisciplinary and multi-level comprehensive intervention strategies for the future,to create more social opportunities and emotional connections for patients,thereby improving their quality of life.

Objective:To observe the morphological characteristics of dome-shaped macula (DSM) and macular hole (MH) in high myopia by optical coherence tomography (OCT), to further explore the correlation between DSM and MH.Methods:A retrospective case-control study. From April 2021 to December 2023, 963 eyes of 503 patients with high myopia (myopic diopter ≥6.00 D) in Department of Ophthalmology of the Fourth Hospital of Hebei Medical University were enrolled in the study. The age of patients ranged from 5 to 89 years old, with the mean age of (48.91±16.69) years. Diopter was -6.00 to -26.00 (-10.49±3.15) D. All eyes were examined by OCT. The width and height of DSM, subfoveal choroidal thickness (SFCT), inner port diameter and base diameter of MH were measured by software on OCT. According to the OCT image features, DSM was divided into horizontal and vertical oval-shaped DSM, and symmetrical round DSM. According to the presence or absence of DSM, the eyes were divided into DSM group and non-DSM group. Then, the affected eyes with MH were divided into DSM with MH group and non-DSM with MH group. The incidence of DSM, the incidence of MH in the DSM group and the non-DSM group, the inner port diameter of MH, the base diameter of MH, SFCT, and the location of retinoschisis (RS) in the DSM with MH group and the non-DSM with MH group were observed. Independent sample t test or non-parametric Mann-Whitney U test was used for comparison between groups. Pearson correlation analysis was used to analyze the related factors of MH inner port diameter, base diameter and DSM width, height, height/width ratio. Results:Among the 963 eyes, the DSM group and the non-DSM group were 266 (27.6%, 266/963) and 697 (72.4%, 697/963) eyes. Compared with the non-DSM group, patients in the DSM group were older ( Z=-11.302), had higher degree of myopia ( Z=-8.944), thinner SFCT ( Z=-16.244), and higher incidence of MH ( χ2=8.828), and the differences were statistically significant ( P<0.05). Compared with non-DSM with MH group, the patients in DSM with MH group were older ( t=2.610), higher myopia diopter ( t=3.593), and thinner SFCT ( t=3.505), the differences were statistically significant ( P<0.05). There was no significant difference in the number of eyes in the epiretinal membrane between the two groups ( χ2=0.119, P=0.730). In the DSM with MH group, RS mostly occurred in the outer retina with a large range, while in the non-DSM with MH group, RS mostly occurred in the outer and inner retina with a small range. There was a statistically significant difference in the number of eyes at different positions of RS between the two groups ( χ2=25.131, P<0.05). The results of correlation analysis showed that there was no correlation between the inner port and base diameter of MH and the width, height, height/width ratio of DSM ( P>0.05). Conclusions:Compared with high myopia patients without DSM, patients with DSM are older, have more severe myopia and thinner SFCT. In DSM patients with MH, RS often occurs in the outer retina and has a large range. There was no significant association between DSM morphology and MH size.

In current clinical practice, various dermal templates and skin substitutes are used to enhance wound healing. However, the role of wound commensal microbiome in regulating scaffold performance and the healing process remains unclear. In this study, we investigated the influence of both natural and synthetic scaffolds on the wound commensal microbiome and wound repair in three distinct models including diabetic wounds, burn injuries, and germ-free (GF) wounds. Remarkably, synthetic electrospun polycaprolactone (PCL) scaffolds were observed to positively promote microbiome diversity, leading to enhanced diabetic wound healing compared to the natural scaffolds Integra® (INT) and MatriDerm® (MAD). In contrast, both natural and synthetic scaffolds exhibited comparable effects on the diversity of the microbiome and the healing of burn injuries. In GF wounds with no detectable microorganisms, a reversed healing rate was noted showing natural scaffold (MAD) accelerated wound repair compared to the open or the synthetic scaffold (PCL) treatment. Furthermore, the response of the wound commensal microbiome to PCL scaffolds appears pivotal in promoting anti-inflammatory factors during diabetic wound healing. Our results emphasize that the wound commensal microbiome, mediated by different scaffolds plays an important role in the wound healing process.

Azvudine and nirmatrelvir/ritonavir (Paxlovid) are recommended for COVID-19 treatment in China, but their safety and efficacy in the elderly population are not fully known. In this multicenter, retrospective, cohort study, we identified 5131 elderly hospitalized COVID-19 patients from 32,864 COVID-19 patients admitted to nine hospitals in Henan Province, China, from December 5, 2022, to January 31, 2023. The primary outcome was all-cause death, and the secondary outcome was composite disease progression. Propensity score matching (PSM) was performed to control for confounding factors, including demographics, vaccination status, comorbidities, and laboratory tests. After 2:1 PSM, 1786 elderly patients receiving azvudine and 893 elderly patients receiving Paxlovid were included. Kaplan-Meier and Cox regression analyses revealed that compared with Paxlovid group, azvudine could significantly reduce the risk of all-cause death (log-rank P = 0.002; HR: 0.71, 95% CI: 0.573-0.883, P = 0.002), but there was no difference in composite disease progression (log-rank P = 0.52; HR: 1.05, 95% CI: 0.877-1.260, P = 0.588). Four sensitivity analyses verified the robustness of above results. Subgroup analysis suggested that a greater benefit of azvudine over Paxlovid was observed in elderly patients with primary malignant tumors (P for interaction = 0.005, HR: 0.32, 95% CI: 0.18-0.57) compared to patients without primary malignant tumors. Safety analysis revealed that azvudine treatment had a lower incidence of adverse events and higher lymphocyte levels than Paxlovid treatment. In conclusion, azvudine treatment is not inferior to Paxlovid treatment in terms of all-cause death, composite disease progression and adverse events in elderly hospitalized COVID-19 patients.

Objective : To explore whether chrysophanol(CHR) affects macrophage polarization by promoting mitochondrial biosynthesis through AMPK/PGC-1α pathway. Methods : The molecular docking and binding ability of CHR with AMPK and PGC-1α were predicted by Autodock vina software. Human monocytes(THP-1) were induced to M0 macrophages by phorbol myristate acetate(PMA), and to M1 macrophages by lipopolysaccharide(LPS) combined with interferon-γ(IFN-γ), which were set as Control group. M1 macrophages treated with CHR were set as CHR group. M1 macrophages treated with CHR combined with AMPK inhibitor(Compound C) were set as CHR+Compound C group. The mRNA expression levels of M1 macrophage markers(iNOS, CD86) and mitochondrial biosynthesis related genes(PGC-1α, NFR-1, TFAM) were detected by Quantitative real time polymerase chain reaction(qRT-PCR). The expression level of M1 macrophage marker iNOS was detected by immunofluorescence. The protein expression levels of AMPK, p-AMPK and PGC-1α were detected by Western blot. Results : The docking results showed that the binding energies of CHR with AMPK and PGC-1α were-8.4 kcal/mol and-7.4 kcal/mol, respectively. qRT-PCR results showed that the in vitro model of M1 macrophages was successfully established. Compared with the Control group, CHR treatment significantly increased the mRNA expression of mitochondrial biosynthesis-related genes PGC-1α, NFR-1, and TFAM(P<0.001). Compared with CHR treatment group, CHR combined with Compound C treatment significantly decreased the mRNA expression levels of mitochondrial biosynthesis-related genes PGC-1α, NFR-1, and TFAM(P<0.05). Immunofluorescence results showed that CHR treatment inhibited the protein expression of iNOS compared with the Control group(P<0.001). Compared with CHR treatment group,CHR combined with Compound C treatment reversed the inhibitory effect of CHR on i NOS protein expression(P<0.05). Western blot results showed that compared with the Control group,the CHR treatment group had significant increase in the protein expression levels of p-AMPK and PGC-1α(P<0.001).Compared with CHR treatment group,CHR combined with Compound C treatment significantly decreased the protein expression levels of p-AMPK and PGC-1α(P<0.05). Conclusion Chrysophanol may inhibit macrophage polarization to M1 by activating AMPK/PGC-1α signaling pathway to promote mitochondrial biosynthesis.

Objective:To retrieve and summarize the best evidence for cognitive function improvement in Alzheimer's disease patients, so as to provide reference for clinical practice.Methods:Following the "6S" evidence model, guidelines, expert consensus, clinical decision, and systematic reviews on cognitive function improvement in Alzheimer's disease patients were systematically retrieved from domestic and foreign databases and websites. The search keywords included "Alzheimer's disease, cognitive function, improvement". Evidence-based nursing methods were used to evaluate the quality of literature and extract evidence. The search period was from July 1, 2000 to July 31, 2024.Results:A total of 15 articles were included, including five guidelines, four expert consensus, two clinical decision, and four systematic reviews. Sixteen pieces of best evidence were summarized from four aspects of evaluation and identification, pharmacological intervention, non-pharmacological intervention, and caregiver support.Conclusions:Patients with Alzheimer's disease require timely identification of symptoms related to cognitive impairment and assessment using standardized scales. Multiple intervention methods, such as pharmacological intervention, non-pharmacological intervention, and caregiver support, should be used to enhance patients' quality of life. Evidence application should be tailored to each patient's specific circumstances through individualized selection and adjustment to ensure the effectiveness and scientific rigor of cognitive function improvement strategies, thereby facilitating the translation of optimal evidence into clinical practice.