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

BACKGROUND:Defective outgrowth of chondrocyte mitophagy causes degenerative chondrocyte pathological changes such as apoptosis and matrix loss.OBJECTIVE:To investigate the effects and possible mechanism of Juanbi Decoction-containing serum on interleukin-1β-induced inflammatory response and apoptosis of rat knee joint chondrocytes.METHODS:Fifty male Sprague-Dawley rats were randomly given saline,Juanbi Decoction in low,medium and high doses(1.24,2.48 and 4.96 g/kg),and celecoxib(positive drug)group.Drug-containing serum was obtained by continuous gavage for 2 weeks.(1)Chondrocytes were isolated and randomly divided into control group,interleukin-1β group,Juanbi Decoction low,medium and high dose containing serum groups and positive drug serum group.Cell counting kit-8 assay was used to detect cell viability;immunofluorescence double staining was used to detect mitophagy level;immunofluorescence was used to detect the phosphorylated AMP-activated protein kinase level;western blot was used to detect the expression of PTEN induced putative kinase 1/Parkin pathway-related protein and cleaved caspase-3;and ELISA was used to detect inflammatory factor level.(2)PTEN induced putative kinase 1 siRNA and Compound C were used for intervention to explore the role of AMP-activated protein kinase/PTEN induced putative kinase 1/Parkin pathway in the regulation of mitophagy by Juanbi Decoction-containing serum.RESULTS AND CONCLUSION:(1)Compared with the control group,chondrocyte survival,type II collagen,phosphorylated AMP-activated protein kinase,PTEN induced putative kinase 1,Parkin,and microtubule-associated proteins 1 light chain 3 protein levels,and mitophagy levels were significantly lower in the interleukin-1β group(P<0.05),while cleaved caspase-3 protein levels,interleukin-6,interleukin-8 and tumor necrosis factor-α levels were significantly higher(P<0.05).Compared with the interleukin-1β group,opposite changes in all the above indexes were observed in Juanbi Decoction low,medium and high dose containing serum groups and positive drug serum group(P<0.05).(2)PTEN induced putative kinase 1 siRNA significantly inhibited the effect of Juanbi Decoction-containing serum on mitophagy in interleukin-1β-treated chondrocytes and reduced the protective effect of Juanbi Decoction-containing serum on interleukin-1β-induced inflammation and apoptosis in chondrocytes;Compound C reversed the effect of Juanbi Decoction-containing serum on the PTEN induced putative kinase 1/Parkin signaling pathway in interleukin-1β-treated chondrocytes.To conclude,Juanbi Decoction-containing serum inhibits chondrocyte inflammation and apoptosis by affecting the level of mitochondrial autophagy,thereby attenuating interleukin-1β-induced chondrocyte degradation by a mechanism that may be related to the regulation of the AMP-activated protein kinase/PTEN induced putative kinase 1/Parkin pathway.

BACKGROUND:Defective outgrowth of chondrocyte mitophagy causes degenerative chondrocyte pathological changes such as apoptosis and matrix loss.OBJECTIVE:To investigate the effects and possible mechanism of Juanbi Decoction-containing serum on interleukin-1β-induced inflammatory response and apoptosis of rat knee joint chondrocytes.METHODS:Fifty male Sprague-Dawley rats were randomly given saline,Juanbi Decoction in low,medium and high doses(1.24,2.48 and 4.96 g/kg),and celecoxib(positive drug)group.Drug-containing serum was obtained by continuous gavage for 2 weeks.(1)Chondrocytes were isolated and randomly divided into control group,interleukin-1β group,Juanbi Decoction low,medium and high dose containing serum groups and positive drug serum group.Cell counting kit-8 assay was used to detect cell viability;immunofluorescence double staining was used to detect mitophagy level;immunofluorescence was used to detect the phosphorylated AMP-activated protein kinase level;western blot was used to detect the expression of PTEN induced putative kinase 1/Parkin pathway-related protein and cleaved caspase-3;and ELISA was used to detect inflammatory factor level.(2)PTEN induced putative kinase 1 siRNA and Compound C were used for intervention to explore the role of AMP-activated protein kinase/PTEN induced putative kinase 1/Parkin pathway in the regulation of mitophagy by Juanbi Decoction-containing serum.RESULTS AND CONCLUSION:(1)Compared with the control group,chondrocyte survival,type II collagen,phosphorylated AMP-activated protein kinase,PTEN induced putative kinase 1,Parkin,and microtubule-associated proteins 1 light chain 3 protein levels,and mitophagy levels were significantly lower in the interleukin-1β group(P<0.05),while cleaved caspase-3 protein levels,interleukin-6,interleukin-8 and tumor necrosis factor-α levels were significantly higher(P<0.05).Compared with the interleukin-1β group,opposite changes in all the above indexes were observed in Juanbi Decoction low,medium and high dose containing serum groups and positive drug serum group(P<0.05).(2)PTEN induced putative kinase 1 siRNA significantly inhibited the effect of Juanbi Decoction-containing serum on mitophagy in interleukin-1β-treated chondrocytes and reduced the protective effect of Juanbi Decoction-containing serum on interleukin-1β-induced inflammation and apoptosis in chondrocytes;Compound C reversed the effect of Juanbi Decoction-containing serum on the PTEN induced putative kinase 1/Parkin signaling pathway in interleukin-1β-treated chondrocytes.To conclude,Juanbi Decoction-containing serum inhibits chondrocyte inflammation and apoptosis by affecting the level of mitochondrial autophagy,thereby attenuating interleukin-1β-induced chondrocyte degradation by a mechanism that may be related to the regulation of the AMP-activated protein kinase/PTEN induced putative kinase 1/Parkin pathway.

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.

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.