ObjectiveTo investigate the effects of different fermentation methods and times on the fungal flora and chemical composition of Aurantii Fructus， in order to obtain the optimal fermentation conditions and flora structure， and to ensure the stability and controllability of the fermented varieties. MethodsScanning electron microscopy was used to observe and analyze the colony characteristics on the surface of Aurantii Fructus under different fermentation conditions. Internal transcribed spacer 2（ITS2） high-throughput sequencing， combined with fungal community diversity analysis and fungal community structure analysis， were used to obtain the fungal flora microbial categories of Aurantii Fructus under the conditions of traditional pressure-shelf fermentation and non-pressure-shelf natural fermentation for 7， 14， 21 d（numbered Y1-Y3 for the former， and numbered F1-F3 for the latter）， respectively. At the same time， the chemical components in the fermentation process were detected by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS/MS）， combined with principal component analysis（PCA）， partial least squares-discriminant analysis（PLS-DA） and compound retention time， parent ions， characteristic fragment ions and other information， the differential compounds between the different fermentation samples were screened and identified. ResultsThe analysis of fungal community diversity showed that the dominant flora did not change at different fermentation time points in the traditional pressure-shelf fermentation method， while in the non-pressure-shelf natural fermentation method， there was a significant difference with the fermentation process， and at the genus level， the dominant genus of samples Y1， Y2， Y3 and F2 was Aspergillus， while the dominant genera of samples F1 and F3 were both Rhizopus. This indicated that the microbial growth environment provided by the traditional fermentation method was more stable， and the microbial community structure was more stable， which was more conducive to the stable and controllable fermentation process and fermented products. A total of 155 compounds were identified by compositional analysis， including 70 flavonoids， 38 coumarins， 10 alkaloids， 34 organic acids and 3 other compounds. After fermentation， two new components of ribalinine and pranferin were produced. Different fermentation conditions also brought about differences in chemical composition， multivariate statistical analysis obtained 26 differential compounds under two different fermentation methods， mainly including flavonoids， organic acids and coumarins. Comprehensively， the microbial community structure of samples fermented by the traditional pressure-shelf method of Aurantii Fructus for 14 d was stable， the species richness was high and the overall content of differential compounds was high， which was the optimal processing condition. ConclusionCompared with non-pressure-shelf natural fermentation， the traditional method has obvious advantages in terms of the stability of the microbial community structure and the content of chemical compounds， and the optimal condition is 14 days of fermentation. This study is helpful to promote the quality stability and fermentation bioavailability of fermented products of Aurantii Fructus， as well as to provide an experimental basis for the further improvement of the quality control methods of this variety.

ObjectiveTo investigate the effects of different fermentation methods and times on the fungal flora and chemical composition of Aurantii Fructus， in order to obtain the optimal fermentation conditions and flora structure， and to ensure the stability and controllability of the fermented varieties. MethodsScanning electron microscopy was used to observe and analyze the colony characteristics on the surface of Aurantii Fructus under different fermentation conditions. Internal transcribed spacer 2（ITS2） high-throughput sequencing， combined with fungal community diversity analysis and fungal community structure analysis， were used to obtain the fungal flora microbial categories of Aurantii Fructus under the conditions of traditional pressure-shelf fermentation and non-pressure-shelf natural fermentation for 7， 14， 21 d（numbered Y1-Y3 for the former， and numbered F1-F3 for the latter）， respectively. At the same time， the chemical components in the fermentation process were detected by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS/MS）， combined with principal component analysis（PCA）， partial least squares-discriminant analysis（PLS-DA） and compound retention time， parent ions， characteristic fragment ions and other information， the differential compounds between the different fermentation samples were screened and identified. ResultsThe analysis of fungal community diversity showed that the dominant flora did not change at different fermentation time points in the traditional pressure-shelf fermentation method， while in the non-pressure-shelf natural fermentation method， there was a significant difference with the fermentation process， and at the genus level， the dominant genus of samples Y1， Y2， Y3 and F2 was Aspergillus， while the dominant genera of samples F1 and F3 were both Rhizopus. This indicated that the microbial growth environment provided by the traditional fermentation method was more stable， and the microbial community structure was more stable， which was more conducive to the stable and controllable fermentation process and fermented products. A total of 155 compounds were identified by compositional analysis， including 70 flavonoids， 38 coumarins， 10 alkaloids， 34 organic acids and 3 other compounds. After fermentation， two new components of ribalinine and pranferin were produced. Different fermentation conditions also brought about differences in chemical composition， multivariate statistical analysis obtained 26 differential compounds under two different fermentation methods， mainly including flavonoids， organic acids and coumarins. Comprehensively， the microbial community structure of samples fermented by the traditional pressure-shelf method of Aurantii Fructus for 14 d was stable， the species richness was high and the overall content of differential compounds was high， which was the optimal processing condition. ConclusionCompared with non-pressure-shelf natural fermentation， the traditional method has obvious advantages in terms of the stability of the microbial community structure and the content of chemical compounds， and the optimal condition is 14 days of fermentation. This study is helpful to promote the quality stability and fermentation bioavailability of fermented products of Aurantii Fructus， as well as to provide an experimental basis for the further improvement of the quality control methods of this variety.

Objective To investigate the quality and in vitro release behavior of the sirolimus self-microemulsion-mesoporous silicon sustained release tablets and provide a basis for further research and development of related preparations. Methods The hardness, brittleness and content uniformity of the sustained-release tablets were tested refer to Pharmacopoeia of the People’s Republic of China 2020. Different diameters （10, 11, 12 mm）, different hardness （50, 70, 90 N）, different speed （50, 75, 100 r/min）, different dissolution methods （pulp method, basket method） were investigated. The release conditions of the sustained-release tablets with different pH solution （distilled water solution and 0.4% SDS solution with pH of 1.2, 4.5 and 6.8, respectively） and the in vitro release conditions of the sustained-release tablets were observed. Results The hardness, brittleness and content uniformity of the self-made sustained-release tablets were qualified; different diameters and dissolution methods had no effect on the drug release behavior of the sustained-release tablets in vitro, while the different hardness, different rotational speed and the different pH release media had certain effects. Conclusion The sirolimus self-microemulsion-mesoporous silicon sustained release tablets had good sustained-release effect in vitro and was deserved to further study.

Objective:To characterize and analyze the genetic variation of hemagglutinin (HA) of influenza A (H1N1) pdm09 subtype virus in Shandong Province, and explore the genetic variation patterns for providing reference for influenza monitoring, epidemic prevention and control, and vaccine strain selection.Methods:HA gene sequences of the recommended strains of influenza vaccine from 2009 to 2024 and the representative strains of each branch were downloaded from the GISAID Influenza Data Platform, and were phylogenetically analyzed and characterized in terms of amino acid site variation with the HA gene sequences of 298 influenza A (H1N1) virus strains isolated from Shandong Province. A phylogenetic tree was constructed using the maximum likelihood (ML) method of the IQ-TREE online tool, and the amino acid site variants were viewed using MegAlign software. The potential glycosylation sites of the HA gene were predicted using the NetNGlyc 1.0 online software.Results:The HA gene homology of the 298 influenza A (H1N1) viruses isolated in Shandong Province ranged from 91.2% to 100.0%. The evolutionary branches were gradually distantly related over time, but the direction of evolution was roughly the same as that in other provinces. Amino acid mutations in the HA occurred every year and most were found in the antigenic determinants.Conclusions:The HA genes of influenza viruses isolated in Shandong Province from 2009 to 2024 are still in the process of continuous evolution, and continuous monitoring of the epidemiological trends and the evolutionary directions of influenza viruses is essential for early warning of influenza virus pandemics.

ObjectiveTo explore the association between short-term exposure to atmospheric fine particulate matter （PM_2.5） and ozone （O₃） and systemic inflammatory indicators in patients with pneumonia， and to identify the susceptible populations. MethodsFrom September 2018 to April 2020， data of 1 480 patients admitted for pneumonia was collected from a tertiary hospital in Taiyuan City. Generalized additive models （GAMs） were used to explore the associations between PM_2.5 and O₃ exposure and inflammatory indicators of patients with pneumonia； and to explore the susceptibility factors and susceptible populations to PM_2.5 and O₃ exposures through stratified analyses. ResultsThe short-term exposure to PM_2.5 was associated with changes in peripheral blood C-reation protein （CRP）， erythrocyte sedimentation （ESR）， easinophil （EOS）， neutrophil （NEU） and neutrophil-lymphocyte ratio （NLR） in patients with pneumonia， and there were different degrees of hysteresis effects， with the effect values reaching a maximum at lag03， lag03， lag0， lag03， lag03， respectively， which were 4.13% （95%CI： 0.43%‒7.84%）， 3.10% （95%CI： 0.24%‒5.97%）， 5.27% （95%CI： 3.12%‒7.42%）， 1.85% （95%CI： 0.36%‒3.34%）， and 2.53% （95%CI： 0.53%‒4.74%） for every 10 μg·m^-3 of PM_2.5. The changes in O₃ concentration were associated with the elevation of peripheral blood PCT and ESR in patients with pneumonia， and their effect values all reached the maximum at lag01 d， every 1 μg·m^-3 of O₃ elevation increased by 0.38% （95%CI： 0.04%‒0.73%） and 0.47% （95%CI： 0.19%‒0.76%）， respectively. Stratified analyses showed that the associations of PM_2.5 with peripheral blood CRP， ESR， NEU， and NLR in pneumonia patients were more significant in males， the elderly， and those with onset in the cold season； the associations of O₃ with peripheral blood PCT and ESR in pneumonia patients were more significant in the elderly and those with onset in the warm season， and the peripheral blood CRP and PCT in female patients with pneumonia were more susceptible to the changes of O₃. ConclusionShort-term exposure to atmospheric PM_2.5 and O₃ are positively associated with changes in inflammatory indicators in patients with pneumonia， and the effects of PM_2.5 on patients with pneumonia are more extensive than those of O₃， with a longer lag effect. In addition， elderly patients with pneumonia are more sensitive to air pollution， male patients with pneumonia are more sensitive to PM_2.5， and female patients with pneumonia are more sensitive to O₃. Cold and warm seasons can exacerbate the effects of PM_2.5 and O₃ on inflammatory indicators in patients with pneumonia， respectively， and the patients must be protected well.

Objective:By analyzing the relationship between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong,it explores the path of coordinated development between traditional Chinese medicine and western medicine in traditional Chinese medicine hospitals,providing references for the high-quality development of county-level traditional Chinese medicine hospitals.Methods:The efficiency of traditional Chinese medicine services and comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong Province from 2019 to 2022 was analyzed by Data Envelopment Analysis(DEA),and the correlation was analyzed by Spearman correlation coefficient.Results:The efficiency of traditional Chinese medicine services in county-level traditional Chinese medicine hospitals in Shandong Province is lower than that of comprehensive medical services,and the scale return coefficient of traditional Chinese medicine category indicators is better than that of comprehensive category indicators.There is a positive correlation between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services.Conclusion:Traditional Chinese medicine hospitals should appropriately expand their investment in traditional Chinese medicine resources.Adhere to the hospital management model of traditional Chinese medicine services as the main focus,and build a coordinated development path between traditional Chinese and western medicine from both the supply and demand sides.

Objective:By analyzing the relationship between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong,it explores the path of coordinated development between traditional Chinese medicine and western medicine in traditional Chinese medicine hospitals,providing references for the high-quality development of county-level traditional Chinese medicine hospitals.Methods:The efficiency of traditional Chinese medicine services and comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong Province from 2019 to 2022 was analyzed by Data Envelopment Analysis(DEA),and the correlation was analyzed by Spearman correlation coefficient.Results:The efficiency of traditional Chinese medicine services in county-level traditional Chinese medicine hospitals in Shandong Province is lower than that of comprehensive medical services,and the scale return coefficient of traditional Chinese medicine category indicators is better than that of comprehensive category indicators.There is a positive correlation between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services.Conclusion:Traditional Chinese medicine hospitals should appropriately expand their investment in traditional Chinese medicine resources.Adhere to the hospital management model of traditional Chinese medicine services as the main focus,and build a coordinated development path between traditional Chinese and western medicine from both the supply and demand sides.

Objective:By analyzing the relationship between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong,it explores the path of coordinated development between traditional Chinese medicine and western medicine in traditional Chinese medicine hospitals,providing references for the high-quality development of county-level traditional Chinese medicine hospitals.Methods:The efficiency of traditional Chinese medicine services and comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong Province from 2019 to 2022 was analyzed by Data Envelopment Analysis(DEA),and the correlation was analyzed by Spearman correlation coefficient.Results:The efficiency of traditional Chinese medicine services in county-level traditional Chinese medicine hospitals in Shandong Province is lower than that of comprehensive medical services,and the scale return coefficient of traditional Chinese medicine category indicators is better than that of comprehensive category indicators.There is a positive correlation between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services.Conclusion:Traditional Chinese medicine hospitals should appropriately expand their investment in traditional Chinese medicine resources.Adhere to the hospital management model of traditional Chinese medicine services as the main focus,and build a coordinated development path between traditional Chinese and western medicine from both the supply and demand sides.

Objective:By analyzing the relationship between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong,it explores the path of coordinated development between traditional Chinese medicine and western medicine in traditional Chinese medicine hospitals,providing references for the high-quality development of county-level traditional Chinese medicine hospitals.Methods:The efficiency of traditional Chinese medicine services and comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong Province from 2019 to 2022 was analyzed by Data Envelopment Analysis(DEA),and the correlation was analyzed by Spearman correlation coefficient.Results:The efficiency of traditional Chinese medicine services in county-level traditional Chinese medicine hospitals in Shandong Province is lower than that of comprehensive medical services,and the scale return coefficient of traditional Chinese medicine category indicators is better than that of comprehensive category indicators.There is a positive correlation between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services.Conclusion:Traditional Chinese medicine hospitals should appropriately expand their investment in traditional Chinese medicine resources.Adhere to the hospital management model of traditional Chinese medicine services as the main focus,and build a coordinated development path between traditional Chinese and western medicine from both the supply and demand sides.

Objective:By analyzing the relationship between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong,it explores the path of coordinated development between traditional Chinese medicine and western medicine in traditional Chinese medicine hospitals,providing references for the high-quality development of county-level traditional Chinese medicine hospitals.Methods:The efficiency of traditional Chinese medicine services and comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong Province from 2019 to 2022 was analyzed by Data Envelopment Analysis(DEA),and the correlation was analyzed by Spearman correlation coefficient.Results:The efficiency of traditional Chinese medicine services in county-level traditional Chinese medicine hospitals in Shandong Province is lower than that of comprehensive medical services,and the scale return coefficient of traditional Chinese medicine category indicators is better than that of comprehensive category indicators.There is a positive correlation between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services.Conclusion:Traditional Chinese medicine hospitals should appropriately expand their investment in traditional Chinese medicine resources.Adhere to the hospital management model of traditional Chinese medicine services as the main focus,and build a coordinated development path between traditional Chinese and western medicine from both the supply and demand sides.