The aim of this study was to clarify the nature of psychological conflict among men aged 80 years or older who were living alone in eight depopulated municipalities designated by Japan's Ministry of Internal Affairs and Communications. Semi-structured interviews were conducted with 34 elderly men who were living alone. Text-mining analysis revealed that elderly men living alone in depopulated villages were feeling lonely because they [did not have anyone to talk to] but did not want to leave their homes. They were aware of [progressive decline in physical functions] after the age of 80 and thought that [it would be the end if no longer being able to walk]. Because they needed to drive a car in order to continue living their lives, they were [conflicted about continuing to drive] and [anxious that they would not be able to go shopping] if they were to stop driving. The elderly men living in depopulated villages had developed human relationships and attachments to their hometowns, and they wanted to continue living in the homes they were born and raised in until the end of their lives. At the same time, they were struggling with conflicts related to loneliness caused by the weakening of human relationships, feelings of self-deficiency due to physical decline, and a sense of crisis stemming from the decline of the community. On the other hand, one factor supporting them was their motivation to protect the community. These findings suggest the need for a community care system that helps older people feel a sense of solidarity with, and a sense of contribution to, the community.

Objective To observe the therapeutic effects of urolithin A(UA)on respiratory syncytial virus(RSV)-induced lung infection in neonatal mice and explore the underlying mechanisms.Methods Babl/c mice(5-7 days old)were subjected to nasal instillation of RSV and received intraperitoneal injection of saline or 2.5,5 and 10 mg/kg UA 2 h after the infection and then once daily for 2 weeks.Bronchoalveolar lavage fluid(BALF)was then collected for detection of inflammatory cells and mediators,and lung pathology was evaluated with HE staining.RSV-infected BEAS-2B cells were treated with 2.5,5 or 10 μmol/L UA.Inflammatory factors,cell viability,apoptosis and autophagy were analyzed using ELISA,CCK-8 assay,TUNEL staining,flow cytometry,Western blotting and immunofluorescence staining.The cellular expressions of miR-136 and Sirt1 mRNAs were detected using qRT-PCR.A dual-luciferase reporter system was used to verify the binding between miR-136 and Sirt1.Results In neonatal Babl/c mice,RSV infection caused obvious lung pathologies,promoted pulmonary cell apoptosis and LC3-Ⅱ/Ⅰ,Beclin-1 and miR-136 expressions,and increased the total cell number,inflammatory cells and factors in the BALF and decreased p62 and Sirt1 expressions.All these changes were alleviated dose-dependently by UA.In BEAS-2B cells,RSV infection significantly increased cell apoptosis,LC3B-positive cells and miR-136 expression and reduced Sirt1 expression(P<0.01),which were dose-dependently attenuated by UA.Dual-luciferase reporter assay confirmed the binding between miR-136 and Sirt1.In RSV-infected BEAS-2B cells with UA treatment,overexpression of miR-136 and Ex527 treatment both significantly increased the inflammatory factors and cell apoptosis but decreased LC3B expression,and these changes were further enhanced by their combined treatment.Conclusion UA ameliorates RSV-induced lung infection in neonatal mice by activating miR-136-mediated Sirt1 signaling pathway.

OBJECTIVE To predict the possible impact of pembrolizumab（PEM） as a first-line drug after being included in the national medical insurance system in the treatment of advanced or metastatic non-small cell lung cancer based on real-world data from the perspective of the national medical insurance payer， to provide a basis for the decision-making of the medical insurance department. METHODS A budget impact analysis model was constructed to compare the impact of pembrolizumab not included in medical insurance and included in medical insurance on medical insurance fund expenditure in the next five years（ 2024- 2028） with 2023 as the baseline year. The target population was the patients with EGFR gene mutation-negative and anaplastic lymphoma kinase （ALK）-negative locally advanced or metastatic non-small cell lung cancer； estimated cost mainly included the cost of drugs， the cost of adverse reaction treatment， the cost of examination， the cost of admission and monitoring， etc； equipment ratio of PEM in 183 hospitals of Guangdong province from 2020 to 2022 was used as the market share. Univariate sensitivity analysis was used to test the robustness of the basic analysis results. RESULTS When PEM was not included in the medical insurance， the medical insurance reimbursement amount of the target population from 2024 to 2028 was 4 933 623.5 thousand yuan-5 151 198.3 thousand yuan， respectively. If PEM was included in the medical insurance， the above data were 11 871 972.2 thousand yuan-14 540 571.0 thousand yuan， respectively； the increase in medical insurance reimbursement under the two scenarios was 6 720 773.9 thousand yuan-9 606 947.5 thousand yuan， respectively. The proportion of medical insurance reimbursement to the medical insurance expenditure of the year after PEM was included in medical insurance was 0.298 0%， 0.262 1%， 0.228 8%， 0.208 2%， and 0.185 7%， respectively. The increase in medical insurance reimbursement accounted for 1.084 0%， 0.995 7%， 0.888 6%， 0.886 3%， and 0.861 6% of the increase in the expenditure of the medical insurance fund in the current year， all of which showed a decreasing trend year by year. CONCLUSIONS If PEM is included in medical insurance， due to its high unit price， the medical expenditure will increase accordingly， which will have a great impact on the medical insurance fund expenditure. However， when the drug is used in patients with EGFR mutation-negative and ALK-negative locally advanced or metastatic non-small cell lung cancer， the proportion of the medical insurance reimbursement amount in the current year’s medical insurance fund expenditure and the proportion of the increase in medical insurance reimbursement in the current year’s increase in medical insurance fund expenditure are decreasing year by year.

Objective To observe the therapeutic effects of urolithin A(UA)on respiratory syncytial virus(RSV)-induced lung infection in neonatal mice and explore the underlying mechanisms.Methods Babl/c mice(5-7 days old)were subjected to nasal instillation of RSV and received intraperitoneal injection of saline or 2.5,5 and 10 mg/kg UA 2 h after the infection and then once daily for 2 weeks.Bronchoalveolar lavage fluid(BALF)was then collected for detection of inflammatory cells and mediators,and lung pathology was evaluated with HE staining.RSV-infected BEAS-2B cells were treated with 2.5,5 or 10 μmol/L UA.Inflammatory factors,cell viability,apoptosis and autophagy were analyzed using ELISA,CCK-8 assay,TUNEL staining,flow cytometry,Western blotting and immunofluorescence staining.The cellular expressions of miR-136 and Sirt1 mRNAs were detected using qRT-PCR.A dual-luciferase reporter system was used to verify the binding between miR-136 and Sirt1.Results In neonatal Babl/c mice,RSV infection caused obvious lung pathologies,promoted pulmonary cell apoptosis and LC3-Ⅱ/Ⅰ,Beclin-1 and miR-136 expressions,and increased the total cell number,inflammatory cells and factors in the BALF and decreased p62 and Sirt1 expressions.All these changes were alleviated dose-dependently by UA.In BEAS-2B cells,RSV infection significantly increased cell apoptosis,LC3B-positive cells and miR-136 expression and reduced Sirt1 expression(P<0.01),which were dose-dependently attenuated by UA.Dual-luciferase reporter assay confirmed the binding between miR-136 and Sirt1.In RSV-infected BEAS-2B cells with UA treatment,overexpression of miR-136 and Ex527 treatment both significantly increased the inflammatory factors and cell apoptosis but decreased LC3B expression,and these changes were further enhanced by their combined treatment.Conclusion UA ameliorates RSV-induced lung infection in neonatal mice by activating miR-136-mediated Sirt1 signaling pathway.

Model informed precision dosing for warfarin is to provide individualized dosing by integrating information related to patient characteristics, disease status and pharmacokinetics /pharmacodynamics of warfarin, through mathematical modeling and simulation techniques based on the quantitative pharmacology. Compared with empirical dosing, it can improve the safety, effectiveness, economy, and adherence of pharmacotherapy of warfarin. This consensus report describes the commonly used modeling and simulation techniques for warfarin, their application in developing and adjusting dosing regimens, medication adherence and economy. Moreover, this consensus also elaborates the detailed procedures for the implementation in the warfarin pharmacy service pathway to facilitate the development and application of model informed precision dosing for warfarin.

Development of thoracolumbar vertebra (TLV) and rib primordium (RP) is a common evolutionary feature across vertebrates, although whole-organism analysis of the expression dynamics of TLV- and RP-related genes has been lacking. Here, we investigated the single-cell transcriptome landscape of thoracic vertebra (TV), lumbar vertebra (LV), and RP cells from a pig embryo at 27 days post-fertilization (dpf) and identified six cell types with distinct gene expression signatures. In-depth dissection of the gene expression dynamics and RNA velocity revealed a coupled process of osteogenesis and angiogenesis during TLV and RP development. Further analysis of cell type-specific and strand-specific expression uncovered the extremely high level of HOXA10 3'-UTR sequence specific to osteoblasts of LV cells, which may function as anti-HOXA10-antisense by counteracting the HOXA10-antisense effect to determine TLV transition. Thus, this work provides a valuable resource for understanding embryonic osteogenesis and angiogenesis underlying vertebrate TLV and RP development at the cell type-specific resolution, which serves as a comprehensive view on the transcriptional profile of animal embryo development.

Model informed precision dosing (MIPD) is a new concept to guide precision dosing for individual patient by modeling and simulation based on the available information about the individual patient, medications and the disease. Compared to the empirical dosing, MIPD could improve the efficacy, safety, economics and adherence of the pharmacotherapy according to the individual's pathophysiology, genotyping and disease progression. This consensus report provides a brief account of the concept, methodology and implementation of MIPD as well as clinical decision supporting systems for MIPD. The status and future advancing of MIPD was also discussed to facilitate the appropriate application and development of MIPD in China.

AIM: To study chronopharmacokinetics of helicid and its metabolites. METHODS: An HPLC-MS method for simultaneous determination of helicid and its three phase I metabolites were established and validated. At 8:00, 14:00 and 0:00, the rats were given helicid 50 mg/kg by gavage, respectively. Blood samples were collected from ophthalmic venous plexus. Then plasma concentration was measured. Pharmacokinetic behaviors of the original drug and its metabolites after administration at different time points were calculated and compared. RESULTS: This established HPLC-MS/MS method was successfully applied to simultaneous determination of helicid and its three metabolites in rat plasma after intragastric administration. Using AUC

AIM: To investigate the absorption of helicid in different segments of intestine based on rat everted intestine sac model. METHODS: To establish a high-performance liquid chromatography method for simultaneous determination of helicid and its metabolite. Krebs-ringer solution containing helicid was added to everted intestine sacs of different segments (duodenum, Jejunum, ileum and colon). Drug concentration in sacs was determined at different time points (5, 10, 15, 30, 45, 60, 75, 90 min). Adsorptions of helicid in four intestinal segments were compared. RESULTS: This high-performance liquid chromatography was successfully applied to the simultaneous determination of helicid and its metabolite. Absorption of helicid was rapid and time-dependent. The absorption and metabolism of helicid in duodenum segment were higher than these in other segments. CONCLUSION: The duodenum segment is the main site of segmental absorption and metabolism of helicid. This is the first report on intestinal segment metabolism of helicid.

With the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice.