Cancer stem cells (CSCs) are proposed to account for the progression, metastasis, and recurrence of diverse malignancies. However, the disorganized vasculars in tumors hinder the accumulation and penetration of nanomedicines, posing a challenge in eliminating CSCs located distantly from blood vessels. Herein, a pair of twin-like small-sized nanoparticles, sunitinib (St)-loaded ROS responsive micelles (RM@St) and salinomycin (SAL)-loaded GSH responsive micelles (GM@SAL), are developed to normalize disordered tumor vessels and eradicate CSCs. RM@St releases sunitinib in response to the abundant ROS in the tumor extracellular microenvironment for tumor vessel normalization, which improved intratumor accumulation and homogeneous distribution of small-sized GM@SAL. Sequentially, GM@SAL effectively accesses CSCs and achieves reduction-responsive drug release at high GSH concentrations within CSCs. More importantly, RM@St significantly extends the window of vessel normalization and enhances vessel integrity compared to free sunitinib, thus further amplifying the anti-tumor effect of GM@SAL. The combination therapy of RM@St plus GM@SAL produces considerable depression of tumor growth, drastically reducing CSCs fractions to 5.6% and resulting in 78.4% inhibition of lung metastasis. This study offers novel insights into rational nanomedicines designed for superior therapeutic effects by vascular normalization and anti-CSCs therapy.

Objective:To explore the adaptive index of pulmonary rehabilitation self-efficacy and its influencing factors in elderly patients with chronic obstructive pulmonary disease (COPD), and to provide reference for formulating and implementing effective intervention strategies.Methods:This was a cross-sectional study. The convenience sampling method was used to select 279 elderly COPD patients hospitalized in the Department of Respiratory and Critical Care Medicine of Xinjiang Uygur Autonomous Region People′s Hospital from March 2023 to June 2023. They were investigated by the general information questionnaire, Chinese version of Pulmonary Rehabilitation Adapted Index of Self-Efficacy, Social Support Scale and Frailty Phenotype. Multiple linear stepwise regression analysis was used to explore the influencing factors of pulmonary rehabilitation self-efficacy in elderly patients with COPD.Results:The age distribution of 279 elderly COPD patients was 117 cases aged 60-69, 102 cases aged 70-79, and 60 cases aged ≥ 80, including 134 males and 145 females. The total score of Chinese version of Pulmonary Rehabilitation Adapted Index of Self-Efficacy in elderly COPD patients was (24.95 ± 5.20) points, and the highest dimension of item mean score was exercise self-efficacy (1.99 ± 0.62) points, while the lowest mean score was strain capacity (1.88 ± 0.44) points. Multiple linear regression analysis showed that educational level, pulmonary function grade, COPD assessment test (CAT) score, social support level and frailty were influencing factors of pulmonary rehabilitation self-efficacy in elderly COPD patients ( t values were - 9.01-3.36, all P<0.05), accounting for 43.4% of the total variation. Conclusions:The self-efficacy adaptation index of pulmonary rehabilitation in the elderly patients with COPD is at the middle-lower level. Health care providers should fully understand the relevant influencing factors, and establish targeted and individualized pulmonary rehabilitation intervention strategies on these basis to maximize the subjective initiative of patients.

OBJECTIVES: Shelter hospital was an alternative way to provide large-scale medical isolation and treatment for people with mild coronavirus disease 2019 (COVID-19). Due to various reasons, patients admitted to the large shelter hospital was reported high level of psychological distress, so did the healthcare workers. This study aims to introduce a comprehensive and multifaceted psychosocial crisis intervention model. METHODS: The psychosocial crisis intervention model was provided to 200 patients and 240 healthcare workers in Wuhan Wuchang shelter hospital. Patient volunteers and organized peer support, client-centered culturally sensitive supportive care, timely delivery of scientific information about COVID-19 and its complications, mental health knowledge acquisition of non-psychiatric healthcare workers, group activities, counseling and education, virtualization of psychological intervention, consultation and liaison were exhibited respectively in the model. Pre-service survey was done in 38 patients and 49 healthcare workers using the Generalized Anxiety Disorder 7-item (GAD-7) scale, the Patient Health Questionnaire 2-item (PHQ-2) scale, and the Primary Care PTSD screen for the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (PC-PTSD-5). Forty-eight healthcare workers gave feedback after the intervention. RESULTS: The psychosocial crisis intervention model was successfully implemented by 10 mental health professionals and was well-accepted by both patients and healthcare workers in the shelter hospital. In pre-service survey, 15.8% of 38 patients were with anxiety, 55.3% were with stress, and 15.8% were with depression; 16.3% of 49 healthcare workers were with anxiety, 26.5% were with stress, and 22.4% were with depression. In post-service survey, 62.5% of 48 healthcare workers thought it was very practical, 37.5% thought more practical; 37.5% of them thought it was very helpful to relief anxiety and insomnia, and 27.1% thought much helpful; 37.5% of them thought it was very helpful to recognize patients with anxiety and insomnia, and 29.2% thought much helpful; 35.4% of them thought it was very helpful to deal with patients' anxiety and insomnia, and 37.5% thought much helpful. CONCLUSIONS Psychological crisis intervention is feasible, acceptable, and associated with positive outcomes. Future tastings of this model in larger population and different settings are warranted.
Humans ; COVID-19 ; Sleep Initiation and Maintenance Disorders ; Crisis Intervention ; Psychosocial Intervention ; SARS-CoV-2 ; Mental Health ; Depression/epidemiology* ; Health Personnel/psychology* ; Anxiety/etiology*

ObjectiveTo investigate the effect of anodal transcranial direct current stimulation (atDCS) combined with contralaterally controlled functional electrical stimulation (CCFES) on upper limb motor function of stroke patients. MethodsFrom January to December, 2022, 60 stroke patients from Zhejiang Provincial People's Hospital were randomly divided into atDCS group (n = 20), CCFES group (n = 20) and combined group (n = 20). All the groups accepted routine rehabilitation, while atDCS group accepted atDCS on the primary motor (M1) area of the damaged hemisphere, CCFES group accepted CCFES on the triceps brachii and extensors carpi muscles, and the combined group accepted atDCS on the M1 area of damaged hemisphere and CCFES on triceps brachii and extensors carpi muscles, for six weeks. They were assessed with Fugl-Meyer Assessment-Upper Extremities (FMA-UE), Wolf Motor Function Test (WMFT), and the electromyography root mean square (RMS) ratio of bilateral triceps brachii muscles and extensor carpi muscles, before and after treatment. ResultsThe FMA-UE score, WMFT score, and the RMS ratio of the triceps brachii muscles and extensor carpi muscles improved in all the groups after treatment (|t| > 5.007, P < 0.001), and improved the most in the combined group (F > 14.492, P < 0.001). ConclusionatDCS combined with CCFES can effectively improve upper limb motor function of stroke patients.

Epilepsy is a common chronic neurological disease, and its comorbidity has attracted more attention.The proportion of epileptic children with mental disorders is also increasing year by year.Among them, children with epilepsy have more depression and anxiety disorders.Repeated seizures can easily cause depression and anxiety, and depression and anxiety can also induce epilepsy, thus the two affect each other.The assessment, screening, diagnosis and intervention of comorbid depression and anxiety in children with epilepsy have become an important part of clinical practice.This review summarized the relationship between epilepsy and depression and anxiety disorders in children, and its research progress on pathogenesis, clinical diagnosis, evaluation and treatment.

Abstract OBJECTIVE To establish an efficient and simple HPLC-MS/MS method for determination of flucloxacillin in newborn plasma, and to investigate the interaction between ambroxol and flucloxacillin in newborns. METHODS The samples were analyzed by API4000 HPLC-MS/MS. Ultimate XB-C18 column(2.1 mm×100 mm, 5 μm) were carried out. The mobile phase was composed of water-0.1% formic acid(A) and acetonitrile-0.1% formic acid(B). The quantitative analysis of the ion transitions were monitored at m/z 452.6→284.2 for flucloxacillin and m/z 821.4→397.3 for rifampicin(internal standard). RESULTS The linear range of flucloxacillin under this analysis method was 0.20-80 ng·mL-1, and the lower limit of quantification was 0.20 ng·mL-1; The intra-day and inter-day precision of flucloxacillin were both less than 8.23%; The extraction recovery was in the range of 85.3%-89.2%, and the matrix effect was between 89.3%-92.3%; The stability of plasma samples was good under conditions of 12 h at room temperature, 4 h at room temperature after treatment, repeated freeze-thaw for 3 times, and -20 ℃ freezing for 30 d. The results of clinical samples indicated that the combination of ambroxol could significantly increase the blood concentration of flucloxacillin. CONCLUSION The established HPLC-MS/MS method is accurate, sensitive and can be used for the determination of flucloxacillin concentration in neonatal plasma. The results of clinical samples indicate that ambroxol can significantly increase the blood concentration of flucloxacillin. There are drug interactions between ambroxol and flucloxacillin.

Antrodia cinnamomea is extensively used as a traditional medicine to prevention and treatment of liver cancer. However, its comprehensive chemical fingerprint is uncertain, and the mechanisms, especially the potential therapeutic target for anti-hepatocellular carcinoma (HCC) are still unclear. Using UPLC‒Q-TOF/MS, 139 chemical components were identified in A. cinnamomea dropping pills (ACDPs). Based on these chemical components, network pharmacology demonstrated that the targets of active components were significantly enriched in the pathways in cancer, which were closely related with cell proliferation regulation. Next, HCC data was downloaded from Gene Expression Omnibus database (GEO). The Cancer Genome Atlas (TCGA) and DisGeNET were analyzed by bioinformatics, and 79 biomarkers were obtained. Furtherly, nine targets of ACDP active components were revealed, and they were significantly enriched in PI3K/AKT and cell cycle signaling pathways. The affinity between these targets and their corresponding active ingredients was predicted by molecular docking. Finally, in vivo and in vitro experiments showed that ACDPs could reduce the activity of PI3K/AKT signaling pathway and downregulate the expression of cell cycle-related proteins, contributing to the decreased growth of liver cancer. Altogether, PI3K/AKT-cell cycle appears as the significant central node in anti-liver cancer of A. Cinnamomea.

  Objective  To study the demographic and clinical characteristics, correlation of genotype and phenotype and treatment of Blau syndrome to facilitate early diagnosis and timely treatment of Blau syndrome.  Methods  Seventy-two patients with Blau syndrome from 11 centers from May 2006 to April 2022 were retrospectively analyzed, and their general information, clinical data, laboratory examination and treatment medication were collected.  Results  The distribution of patients with Blau syndrome was uniform in geographical north and south of China, and there was no obvious gender bias. The mean age of onset was (14.30±12.81) months, and the age of diagnosis was (55.18±36.22) months. 35% of patients with Blau syndrome happened before 1 year old, and all patients developed before 5 years old. 87.50% (63/72) had granulomatous arthritis, 65.28% (47/72) had rash, 36.11% (26/72) had ocular involvement, 27.78% (20/72) had fever, and 15.28% (11/72) had pulmonary involvement. Arthritic manifestations of Blau syndrome were most at risk, followed by rash, ocular involvement, and fever.The first 25 months of the disease, the risk of developing a rash was the greatest. The risk of developing arthritis was the greatest between 25 months and 84 months. The main mutations were p.R334Q and p.R334W, and patients with p.R334Q mutation had relatively high incidence of fever (35.71%[5/14] vs. 14.29%[1/7], P=0.43) and ocular involvement (42.86%[6/14]vs. 28.57%[2/7], P=0.51). There was a relatively high incidence of rash (85.71%[6/7] vs. 64.29%[9/14], P=0.59) in patients with the p.R334W mutation. Forty-five patients(62.50%)were treated with a combina-tion of glucocorticoid and methotrexate. Twenty-two patients were treated with tumor necrosis factor antagonist in addition to glucocorticoid and methotrexate.  Conclusions  The risk of different clinical manifestations of Blau syndrome from high to low was arthritis, followed by rash, ocular involvement and fever. The main treatment was glucocorticoid combined with methotrexate, to which biological agents could be added.

Alfalfa(Medicago sativa L.)is the most important legume forage crop worldwide with high nutritional value and yield.For a long time,the breeding of alfalfa was hampered by lacking reliable information on the autotetraploid genome and molecular markers linked to important agro-nomic traits.We herein reported the de novo assembly of the allele-aware chromosome-level genome of Zhongmu-4,a cultivar widely cultivated in China,and a comprehensive database of genomic variations based on resequencing of 220 germplasms.Approximate 2.74 Gb contigs(N50 of 2.06 Mb),accounting for 88.39％of the estimated genome,were assembled,and 2.56 Gb contigs were anchored to 32 pseudo-chromosomes.A total of 34,922 allelic genes were identified from the allele-aware genome.We observed the expansion of gene families,especially those related to the nitrogen metabolism,and the increase of repetitive elements including transposable elements,which probably resulted in the increase of Zhongmu-4 genome compared with Medicago truncatula.Population structure analysis revealed that the accessions from Asia and South America had rela-tively lower genetic diversity than those from Europe,suggesting that geography may influence alfalfa genetic divergence during local adaption.Genome-wide association studies identified 101 sin-gle nucleotide polymorphisms(SNPs)associated with 27 agronomic traits.Two candidate genes were predicted to be correlated with fall dormancy and salt response.We believe that the allele-aware chromosome-level genome sequence of Zhongmu-4 combined with the resequencing data of the diverse alfalfa germplasms will facilitate genetic research and genomics-assisted breeding in variety improvement of alfalfa.

Immunotherapy is a new anti-tumor method. The application of immune checkpoint inhibitor greatly improves the survival benefit for patients, but the drug resistance of immunotherapy affects the efficacy. Therefore, it is very important to explore the mechanism of drug resistance and solve the problem of drug resis-tance in tumor immunotherapy. Hypoxia in tumor microenvironment is the key factor of immune drug resistance. Hypoxia can inhibit the immune cells function and lead to immune escape through various mechanisms. It can be the breakthrough for overcoming the immunotherapy drug resistance that blocking pathway of hypoxia to promote immune resistance. By reviewing the mechanism of immunotherapy drug resistance induced by hypoxia, it is helpful to explore the development prospect of hypoxia-inducible factor-1α (HIF-1α) related targeted drugs in clinical application for immunotherapy.