Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Objective:To investigate mRNA and N6-methyladenosine (m6A) changes in retinal pigment epithelium (RPE) cells treated with recombinant human methyl-CpG binding protein 2 (MeCP2) and the mechanisms.Methods:The passaged ARPE-19 cells were divided into normal control and MeCP2 groups after adhesion culture.Cells in the normal control group were continuously cultured in normal culture medium, and the cells in the MeCP2 group were cultured in culture medium containing a final concentration of 20 ng/ml of recombinant human MeCP2 protein for 72 hours.Transcriptomic sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq) were used to extract and analyze total RNA.Differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were screened using the edgeR software package based on P<0.05.The biological function of differential genes was determined by gene ontology (GO) enrichment analysis, and the pathway enrichment analysis was performed by Kyoto Encyclopedia of Genes and Genomes (KEGG).Intersection of genes between DEGs and DMGs were screened, and real-time fluorescence quantitative PCR was used to determine the mRNA expression levels of differential genes. Results:A total of 100 DEGs and 7 441 DMGs genes were screened.According to enrichment analysis, the DEGs were enriched to extracellular matrix (ECM)-receptor interaction, cell division, phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway and so on.The DMGs were associated with microtubule cytoskeleton, angiogenesis, epidermal growth factor receptor (ErbB) signaling pathway, advanced glycation end-products (AGEs) -glycation end-products receptor (RAGE) signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway, Notch signaling pathway and transforming growth factors-β (TGF-β) signaling pathway and so on.There were 24 up-regulated and 76 down-regulated DEGs.Five DMGs had hypermethylation peaks, and 7 439 DMGs had hypomethylation peaks.After annotation of peaks, 7 626 genes in the normal control group and 8 006 genes in the MeCP2 group had m6A methylation, with 7 360 intersecting genes between the two groups.The m6A methylation in the normal control group and MeCP2 group was concentrated in the CDS, intron and 3'-untranslated region (3'UTR) regions of the transcript, with the methylation ratio of 23.62%/22.27%, 48.53%/48.35% and 23.66%/25.28%, respectively.Joint analysis showed that CSPG5 and RBP1 genes related to the epithelial-mesenchymal transition (EMT) had lower amount of mRNA and m6A.Fluorescence quantitative PCR results showed that the relative mRNA expression levels of GSPG5, RBP1 and ZNF484 in MeCP2 group were significantly lower than those in normal control group ( t=7.885, 7.613, 7.345; all at P<0.01). Conclusions:The regulatory mechanism of MeCP2 on EMT in RPE cells is related to m6A methylation modification. CSPG5 and RBP1 genes may be the target genes of m6A methylation and participate in the EMT regulated by MeCP2.

Objective To evaluate the economic value of fluticasone furoate/umeclidinium/vilanterol(FF/UMEC/VI)powder for inhalation in the treatment of symptomatic chronic obstructive pulmonary disease patients with acute exacerbation risk from the perspective of the Chinese health system.Methods Based on subgroup analysis of the China cohort in the IMPACT trial,a four-state lifetime Markov model was established with a 3-month cycle.The model simulation period was 11 years.Clinical efficacy,health benefits,and cost data were obtained through published literature.The health outcomes included quality adjusted life year(QALY).Using 3 times Chinas per capita gross domestic product(GDP)in 2023 as the willingness-to-pay threshold,the cost-utility analysis method was used for analysis the economic viability of FF/UMEC/VI.The scenario analysis,one-way sensitivity analysis and probability sensitivity analysis were used to verify the robustness of the results.Results Compared with fluticasone furoate/vilanterol(FF/VI),FF/UMEC/VI in the treatment of symptomatic chronic obstructive pulmonary disease patients with acute exacerbation risk saved costs 8 118.66 yuan and obtained an additional 0.000 06 QALYs,giving it an economic advantage.Compared with umeclidinium/vilanterol(UMEC/VI),FF/UMEC/VI treatment paid 2 784.41 yuan more and received 0.000 45 QALYs less,making UMEC/VI more cost-utility.The scenario analysis results further confirmed the robustness of the model.The sensitivity analysis results showed that when the drug cost of FF/UMEC/VI per cycle decreases to 637.29 yuan,FF/UMEC/VI had economic benefits under a willingness-to-pay threshold of 3 times China's per capita GDP in 2023.Conclusion For patients with symptomatic chronic obstructive pulmonary disease at risk of acute exacerbation,FF/UMEC/VI is more cost-utility than FF/VI.Compared with UMEC/VI,FF/UMEC/VI has economic viability after price reducing.

OBJECTIVE To analyze the compatible stability of commonly used intravenous drugs in the intensive care units （ICU）， and to provide a reference for improving medication safety in clinic. METHODS The commonly used intravenous drugs in the ICU of Hebei General Hospital were investigated and confirmed in April 1-30， 2022， and used as keywords to retrieve the relevant literature about compatible stability from PubMed， CNKI， Wanfang Data and other databases， and manually filtered with Micromedex database at the same time. Then， the compatible stability results of the included literature were analyzed descriptively. RESULTS Totally 32 commonly used intravenous drugs and 39 mixed infusion combinations were collected from ICU of this hospital. A total of 40 studies were included， only 2 studies followed all quality requirements； 18 studies validated their methods to guarantee correct reproducibility； 33 studies evaluated physical stability， including precipitate formation and pH changes； 32 studies evaluated chemical compatibility， mainly content/concentration changes. A total of 666 possible two-drug combinations were obtained from the included literature， of which 254 combinations of stability data were available， including 176 were stable， 68 were unstable， and 10 were contradictory. Totally 412 combinations had no stability results. Among two-drug combinations in ICU of this hospital， 42 combinations were stable， 14 combinations were unstable， and 2 combinations were contradictory. CONCLUSIONS The pH， solvent， excipients and preparation concentration are the factors that affect the stability. There are drug combinations with unstable compatibility of commonly used intravenous drugs in ICU of this hospital. The stability study methods are limited， and the stability data cannot meet the actual clinical needs.

Liver fibrosis is a key step in the progression of chronic liver diseases to liver cirrhosis and even liver cancer. In recent years， a large number of studies have shown the necessity of intervening in the process of liver fibrosis， and various anti-liver fibrosis drugs and active ingredients have been discovered. Non-coding RNAs also play an important role in the process of liver fibrosis， and searching for upstream non-coding RNAs that can regulate signaling pathways can provide new insights for anti-liver fibrosis treatment. This article introduces the process of liver fibrosis mediated by the TGF-β， Wnt/β-catenin， PI3K/Akt/mTOR， NF-κβ， Hippo， and MAPK signaling pathways， lists the latest anti-liver fibrosis drugs or active components in each signaling pathway， and summarizes the research advances in anti-liver fibrosis targets and drugs mediated by related non-coding RNAs， so as to provide new research ideas and treatment methods for anti-liver fibrosis treatment.

AIM: To explore the pharmacokinetic interactions between sorafenib and dapagliflozin in rats and to provide some theoretical basis for the rational clinical use of the two drugs. METHODS: An ultra -performance liquid chromatography-tandem mass spectrometry (UPLC / MS / MS) method was developed for the simultaneous determination of sorafenib and dapagliflozin. Male SD rats were randomly divided into 5 groups (6 rats in each group), including 100 mg / kg sorafenib group, 0.5 mg / kg dapagliflozin group, 1 mg / kg dapagliflozin group, and 100 mg/kg sorafenib combined with 0.5 mg/kg dapagliflozin group and 100 mg/kg sorafenib combined with 1 mg / kg dapagliflozin group, for sorafenib and dapagliflozin drug interaction study. All samples were analyzed using a validated UPLC/ MS/MS method, and the main pharmacokinetic parameters were calculated by compartment model. RESULTS: 1 mg/kg dapagliflozin increased the C

Palbocicril, the first cyclin-dependent kinases 4 and 6 inhibitors, is a crucial milestone in the development history of antineoplastic drugs. It combined with aromatase inhibitor or fulvestrant as first-line, second-line or post-line therapy has good efficacy and safety for hormone receptor-positive, human epidermal growth factor receptor-2 negative locally advanced or metastatic breast cancer, which has a good application prospect. This article summarizes the clinical trials and safety studies related to palbociclib.

Objective To investigate the risk factors of cognitive dysfunction in patients with traumatic brain injury. Methods From March to September, 2021, 556 hospitalized patients with traumatic brain injury were selected from a multicenter study. A 1∶1 sex-matched case-control study design was used. After assessment by Montreal Cognitive Assessment (MoCA), those with cognitive impairment were as case group and those without cognitive impairment were as control group. They were collected general data and assessed with Social Support Rating Scale (SSRS) and Hospital Anxiety and Depression Scale (HADS). Results Logistic regression analysis showed that college education or above (OR = 0.040) and high level of social support (OR = 0.118) were protective factors for cognitive impairment (P < 0.05). Aged 60 to 88 years (OR = 9.996), severe brain injury (OR = 7.345), headache after injury (OR = 2.159), frequent waking at night or multiple dreams ≥ three times per week (OR = 3.705), severe upper limb dysfunction caused by brain injury (OR = 6.072), depression (OR = 5.202) were risk factors for cognitive impairment (P < 0.05). Conclusion The related factors for cognitive impairment in patients with traumatic brain injury include general factors, disease factors, sleep, psychological and social support and other factors. It is suggested that in addition to the treatment of disease, it is necessary to improve sleep, psychology and social support, to reduce the incidence of cognitive impairment and promote the recovery of disease.

ObjectiveTo analyze the typical performance of initiating and responding behaviors of turn-taking in operational games for autistic children with low language function in special education schools and to provide a reference for intervention of turn-taking behaviors in operational games. MethodsFrom November, 2021 to January, 2022, a total of 23 autistic children with low language function (language ability ≤ three years old) in Shanghai Putuo District Qixing School were selected. Their linguistic ability was evaluated. A behavioral assessment approach was used to evaluate the behavior of initiating and responding behaviors of turn-taking in three operational games. The typical errors in initiating behaviors were summarized as difficult to initiate, untimely initiation, no response and abnormal initiation. The typical errors in responding behaviors of turn-taking in operational games were summarized as difficult to respond, untimely response, no response and abnormal response. ResultsThere was no significant differences in the performance of initiating behaviors among three types of operational games (χ² = 11.106, P = 0.196), and there were significant differences in the performance of responding behaviors among operational games (χ² = 26.256, P = 0.001). The initiating behaviors were postively correlated with word comprehension (r = 0.420, P < 0.05), word naming (r = 0.510, P < 0.05), and sentence imitation (r = 0.505, P < 0.05). The responding behaviors were postively correlated with word comprehension (r = 0.546, P < 0.01), word naming (r = 0.728, P < 0.01), sentence comprehension (r = 0.668, P < 0.01) and sentence imitation (r = 0.656, P < 0.01). ConclusionAutistic children with low language function showed different typical behaviors of initiating and responding behaviors of turn-taking in operational games. It is suggested that when designing training programs for turn-taking skills, targeted interventions should be made to address the typical types of errors in response and initiation turns, and individualized intervention programs should be designed to enhance children's communicative efficacy in play game and promote their language development and social participation.

Presepsin(sCD14-ST), is an soluble leukocyte differentiation antigen 14 subtype. It is a glycoprotein fragment and a marker of acute phase reaction. For diagnosis of adult sepsis, bacteremia and bacterial DNAaemia, the area under of ROC is 0.88,0.78 and 0.79, respectively. The levels of Presepsin increase earlier than procalcitonin, and have better clinical value for early diagnosis of sepsis. It is significantly correlated with disease severity and can be used to predict prognosis. One study mentioned that in the absence of organ dysfunction, the value was 235.0 (172.0-340.3) pg/ml, and for one, two, three or more organ dysfunction, were 403.5 (275.8-587.3) pg / ml, 844.5 (559.8-1259.5) pg / ml, 1412.5 (893.0-2675.8) pg/ml (P<0.01), respectively. Another study mentioned that Presepsin is an independent risk factor for 30-day death of sepsis, and it is effective to evaluate poor prognosis with a threshold of >927.5 pg/ml. Presepsin also has clinical value for neonatal and child sepsis. The Greece meta-analysis showed that the AUC for neonatal sepsis diagnosis was 0.9751, which was higher and more sensitive than that of CRP and procalcitonin. Turkish study on children showed a significant increase in sCD14-ST in sepsis patients compared with healthy controls. Its AUC was 0.98, the best threshold was 990 pg/ml. The reference range of this value was been studied, showing that 75％ and 95％ percentiles of full-term infants are 791 and 1178 pg/ml. Adults do not exceed 200 pg/ml of all age groups. It is affected by renal function. Prospective trials are expected to further clarify its diagnostic value, more therapeutic research to elaborate its therapeutic value, and corresponding clinical practice guideline.