BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

ObjectiveTo examine the protective mechanism of wogonin in SH-SY5Y cells cultured in the conditioned media with lipopolysaccharide （LPS）-induced BV-2 microglia. MethodBV-2 microglia were divided into the blank group， LPS group， low concentration group of wogonin （4 μmol∙L^-1）， medium concentration group of wogonin （8 μmol∙L^-1）， and high concentration group of wogonin （16 μmol∙L^-1）. The LPS group was given 1 mg·L^-1 LPS， and the other three groups were treated with the corresponding concentration of wogonin for 4 h and then given 1 mg·L^-1 LPS. The conditioned media from these groups were used to cultivate SH-SY5Y cells. Cell counting kit-8 （CCK-8） was used to assess the vitality of BV-2 cells in the above groups. The contents of interleukin-6 （IL-6） and tumor necrosis factor-alpha （TNF-α） in the supernatant of BV-2 cells were determined by enzyme-linked immunosorbent assay （ELISA）. The expression of tyrosine hydroxylase （TH） and α-Synuclein （α-Syn） in SH-SY5Y cells was detected by immunohistochemical staining （IHC）. The nuclear transfer and fluorescence expression intensity of nuclear transcription factor-κB p65 （NF-κB p65） protein in SH-SY5Y cells were detected by immunofluorescence staining （IF）. Western blot was used to detect the expression of Toll-like receptor 4 （TLR4）/myeloid differentiation factor 88 （MyD88）/NF-κB pathway-related proteins in SH-SY5Y cells. ResultThe levels of IL-6 and TNF-α in the supernatant of BV-2 cells in the LPS group were significantly higher than those in the blank group （P<0.01）. Compared with those in the LPS group， the IL-6 content of BV-2 cells in the low concentration group of wogonin was statistically significantly lower （P<0.05）， whereas the IL-6 and TNF-α contents of the medium and high concentration groups of wogonin were statistically lower （P<0.05，P<0.01）. The IL-6 and TNF-α contents in the high concentration group of wogonin decreased most significantly （P<0.01）， and the intervention effect was the best. Compared with that in the blank group， the expression of α-Syn protein in SH-SY5Y cells cultured with conditioned media in the LPS group was significantly increased， and the expression of TH protein was significantly decreased （P<0.05）. Compared with that in the LPS group， α-Syn protein expression in the medium and high concentration groups of wogonin showed a decreasing trend （P<0.05， P<0.01）. TH protein expression was increased in the low， medium， and high concentration groups of wogonin （P<0.05， P<0.01）. Compared with the blank group， NF-κB p65 protein gradually accumulated into the nucleus， and the fluorescence expression intensity was significantly enhanced （P<0.01）. Compared with the LPS group， the NF-κB p65 protein was gradually dispersed outside the nucleus， and the fluorescence expression intensity was gradually weakened in all concentration groups of wogonin. The fluorescence intensity in the high concentration group of wogonin was significantly reduced （P<0.01）. Compared with those in the blank group， the expression levels of TLR4 protein， phosphorylated（p）-NF-κB p65 protein， and MyD88 protein in the LPS group were significantly increased （P<0.05， P<0.01）. Compared with those in the LPS group， the expressions of TLR4 protein， p-NF-κB p65 protein， and MyD88 protein in the medium concentration group of wogonin were all significantly decreased （P<0.05， P<0.01）. The expressions of TLR4 protein， and MyD88 protein in the high concentration group of wogonin were significantly decreased （P<0.05， P<0.01）. ConclusionWogonin may regulate the TLR4/MyD88/NF-κB signaling pathway to inhibit the release of LPS-induced inflammatory factors in BV-2 microglia and protect SH-SY5Y cells， thereby reducing inflammation and achieving neuroprotective effects.

Background The substantial health damage attributed to heat waves, along with their increasing intensity and frequency in the context of global warming, highlights the importance of exploring the health effects of heat waves. Objective To calculate the excess heat stroke cases during heat waves in the summer of 2013—2023 in Shanghai, analyze the association between heat waves and heat stroke, and to further explore the modifying effects of heat wave characteristics on heat stroke. Methods Using a retrospective ecological study design, data on heat stroke cases were collected from the heat stroke case reporting system of the Chinese Center for Disease Control and Prevention, and concurrent meteorological data from Xujiahui Meteorological Station. A heat wave was defined as at least 3 consecutive days with daily maximum temperature meeting or exceeding 35 ℃ in this study, excess heat stroke cases related to heat waves were assessed as the difference between the numbers of heat stroke cases observed on a given day and the corresponding 31 d (15 d before and after that day) moving average, and statistical analyses using generalized linear model based on time series study were performed to assess the impact of heat waves on heat stroke. Results Overall 25 heat waves during the study period were observed, leading to a total of estimated 792.6 extra heat stroke cases. The risk of heat stroke significantly increased during heat waves (RR=2.60, 95%CI: 2.08, 3.26), but no statistically significant differences in heat wave effects were observed among different genders, ages, or regions. In terms of the timing of heat waves, the risk of heat stroke was highest during the first heat wave (RR=3.58, 95%CI: 2.82, 4.55), which was significantly higher than that during the second heat wave (RR=2.19, 95%CI: 1.66, 2.90), and no significant effect was observed during the third or subsequent heat waves. The impact of heat waves on heat stroke persisted for more than 4 d, with the risk higher on the fourth day and beyond (RR=2.95, 95%CI: 2.28, 3.83), significantly higher than on the first day of heat wave (RR=1.74, 95%CI: 1.18, 2.56). Conclusion Heat waves had a substantial effect on heat stroke in Shanghai from 2013 to 2023, and special attention need to be paid to heat waves with early onset and long duration.

Objective It conducted a grounded theory on the factors influencing the sense of job significance of hospital administrators to provide suggestions and references for the promotion of high-quality development of hospital management work.Methods From April to September 2023,it interviewed 23 administrators from various departments across Provinces/Cities,including Zhejiang,Heilongjiang,Guangdong,Shanghai,Henan,Jilin,Sichuan and others,using a theoretical sampling method.Employing Grounded Theory,it encoded over transcriptional information at three levels.Results Three-level coding process yielded 66 free nodes,19 initial concepts,7 main categories,and 3 dimensions,leading to the development of a theoretical model encompassing existence,relatedness,and growth.Conclusion The job meaning for hospital administrators is shaped by existence,relatedness,and growth.It recommend revising performance assessments,fostering an empowering culture,enhancing informal communication,providing professional growth pathways,and offering diverse career development options to deepen administrators'job meaning.

Objective It conducted a grounded theory on the factors influencing the sense of job significance of hospital administrators to provide suggestions and references for the promotion of high-quality development of hospital management work.Methods From April to September 2023,it interviewed 23 administrators from various departments across Provinces/Cities,including Zhejiang,Heilongjiang,Guangdong,Shanghai,Henan,Jilin,Sichuan and others,using a theoretical sampling method.Employing Grounded Theory,it encoded over transcriptional information at three levels.Results Three-level coding process yielded 66 free nodes,19 initial concepts,7 main categories,and 3 dimensions,leading to the development of a theoretical model encompassing existence,relatedness,and growth.Conclusion The job meaning for hospital administrators is shaped by existence,relatedness,and growth.It recommend revising performance assessments,fostering an empowering culture,enhancing informal communication,providing professional growth pathways,and offering diverse career development options to deepen administrators'job meaning.

Objective It conducted a grounded theory on the factors influencing the sense of job significance of hospital administrators to provide suggestions and references for the promotion of high-quality development of hospital management work.Methods From April to September 2023,it interviewed 23 administrators from various departments across Provinces/Cities,including Zhejiang,Heilongjiang,Guangdong,Shanghai,Henan,Jilin,Sichuan and others,using a theoretical sampling method.Employing Grounded Theory,it encoded over transcriptional information at three levels.Results Three-level coding process yielded 66 free nodes,19 initial concepts,7 main categories,and 3 dimensions,leading to the development of a theoretical model encompassing existence,relatedness,and growth.Conclusion The job meaning for hospital administrators is shaped by existence,relatedness,and growth.It recommend revising performance assessments,fostering an empowering culture,enhancing informal communication,providing professional growth pathways,and offering diverse career development options to deepen administrators'job meaning.

Objective It conducted a grounded theory on the factors influencing the sense of job significance of hospital administrators to provide suggestions and references for the promotion of high-quality development of hospital management work.Methods From April to September 2023,it interviewed 23 administrators from various departments across Provinces/Cities,including Zhejiang,Heilongjiang,Guangdong,Shanghai,Henan,Jilin,Sichuan and others,using a theoretical sampling method.Employing Grounded Theory,it encoded over transcriptional information at three levels.Results Three-level coding process yielded 66 free nodes,19 initial concepts,7 main categories,and 3 dimensions,leading to the development of a theoretical model encompassing existence,relatedness,and growth.Conclusion The job meaning for hospital administrators is shaped by existence,relatedness,and growth.It recommend revising performance assessments,fostering an empowering culture,enhancing informal communication,providing professional growth pathways,and offering diverse career development options to deepen administrators'job meaning.

Objective It conducted a grounded theory on the factors influencing the sense of job significance of hospital administrators to provide suggestions and references for the promotion of high-quality development of hospital management work.Methods From April to September 2023,it interviewed 23 administrators from various departments across Provinces/Cities,including Zhejiang,Heilongjiang,Guangdong,Shanghai,Henan,Jilin,Sichuan and others,using a theoretical sampling method.Employing Grounded Theory,it encoded over transcriptional information at three levels.Results Three-level coding process yielded 66 free nodes,19 initial concepts,7 main categories,and 3 dimensions,leading to the development of a theoretical model encompassing existence,relatedness,and growth.Conclusion The job meaning for hospital administrators is shaped by existence,relatedness,and growth.It recommend revising performance assessments,fostering an empowering culture,enhancing informal communication,providing professional growth pathways,and offering diverse career development options to deepen administrators'job meaning.

Objective It conducted a grounded theory on the factors influencing the sense of job significance of hospital administrators to provide suggestions and references for the promotion of high-quality development of hospital management work.Methods From April to September 2023,it interviewed 23 administrators from various departments across Provinces/Cities,including Zhejiang,Heilongjiang,Guangdong,Shanghai,Henan,Jilin,Sichuan and others,using a theoretical sampling method.Employing Grounded Theory,it encoded over transcriptional information at three levels.Results Three-level coding process yielded 66 free nodes,19 initial concepts,7 main categories,and 3 dimensions,leading to the development of a theoretical model encompassing existence,relatedness,and growth.Conclusion The job meaning for hospital administrators is shaped by existence,relatedness,and growth.It recommend revising performance assessments,fostering an empowering culture,enhancing informal communication,providing professional growth pathways,and offering diverse career development options to deepen administrators'job meaning.

Objective It conducted a grounded theory on the factors influencing the sense of job significance of hospital administrators to provide suggestions and references for the promotion of high-quality development of hospital management work.Methods From April to September 2023,it interviewed 23 administrators from various departments across Provinces/Cities,including Zhejiang,Heilongjiang,Guangdong,Shanghai,Henan,Jilin,Sichuan and others,using a theoretical sampling method.Employing Grounded Theory,it encoded over transcriptional information at three levels.Results Three-level coding process yielded 66 free nodes,19 initial concepts,7 main categories,and 3 dimensions,leading to the development of a theoretical model encompassing existence,relatedness,and growth.Conclusion The job meaning for hospital administrators is shaped by existence,relatedness,and growth.It recommend revising performance assessments,fostering an empowering culture,enhancing informal communication,providing professional growth pathways,and offering diverse career development options to deepen administrators'job meaning.