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

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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 To evaluate predictive factors affecting the short-term efficacy of PD-1 inhibitors in non-small cell lung cancer (NSCLC) and to construct a prediction model. Methods From October 2019 to November 2021, 221 patients with advanced NSCLC who met the inclusion criteria and were treated with PD-1 inhibitors were prospectively enrolled. Patients who were enrolled before May 1st, 2021 were included inthe modeling group (n=149), whereas those who enrolled thereafter were included in the validation group (n=72). The general clinical data of patients, information of the four TCM diagnoses were collected, and TCM syndrome elements were identified. R software version 4.0.4 was used in constructing a nomogram clinical prediction model of objective response rate. The predictive ability and discrimination of the model were evaluated and externally validated by using a validation group. Results After two to four cycles of PD-1 inhibitor therapy in 221 patients, the overall objective response rate was 44.80%. Multivariate logistic regression analysis of the modeling group showed that the TPS score (OR=0.261, P=0.001), number of treatment lines (OR=3.749, P=0.002), treatment mode (OR=2.796, P=0.019), qi deficiency disease syndrome elements (OR=2.296, P=0.043), and syndrome elements of yin deficiency disease (OR=3.228, P=0.005) were the independent predictors of the short-term efficacy of PD-1 inhibitors. Based on the above five independent predictors, a nomogram prediction model for the short-term efficacy of PD-1 inhibitors was constructed. The AUC values of the modeling and validation groups were 0.8317 and 0.7535, respectively. The calibration curves of the two groups showed good agreement between the predicted and true values. The mean absolute errors were 0.053 and 0.039, indicating that the model has good predictive performance. Conclusion The nomogram model constructed on the basis of the syndrome elements of Qi-deficiency disease and Yin-deficiency syndrome of TCM, as well as TPS score, number of treatment lines and treatment mode, is a stable and effective tool for predicting the short-term efficacy of PD-1 inhibitors in advanced non-small cell lung cancer.

Objective To construct a nomogram prediction model for the treatment effect of anlotinib with the participation of traditional Chinese medicine syndrome elements on the patients with extensive-stage small cell lung cancer (ES-SCLC) who previously received multiple lines of chemotherapy. Methods The clinical data of 127 patients with ES-SCLC who received at least two cycles of anlotinib treatment were retrospectively studied. Kaplan-Meier method was used to analyze the relationship between each factor and the overall survival time. Cox regression analysis was applied to screen the independent influencing factors of the prognosis of patients with ES-SCLC. R language was employed to build a nomogram prediction model, C-index was used to evaluate the model, and calibration curve was adopted to verify the accuracy of the model. Results Age, PS score, brain metastases, qi deficiency syndrome, yin deficiency syndrome, and blood stasis syndrome were related risk factors for ES-SCLC treated with anlotinib. PS score, brain metastasis, and blood stasis syndrome were independent prognostic factors. On the basis of these three independent influencing factors, a nomogram model was established to predict the prognosis of patients with ES-SCLC treated with anlotinib. The predicted risk was close to the actual risk, showing a high degree of coincidence. Conclusion The nomogram model established with PS score, blood stasis syndrome elements, and brain metastasis as independent factors can predict the prognosis of patients with ES-SCLC receiving second- and third-line treatment of anlotinib.

Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors. Brain metastasis, such as breast cancer and lung cancer, also leads to high mortality. The available medicines are limited due to blood-brain barrier. Abnormal activation of phosphatidylinositol 3-kinases (PI3K) signaling pathway is prevalent in glioblastoma and metastatic tumors. Here, we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3K inhibitor with excellent anti-tumor activity against human glioblastoma. XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3K signaling pathway, induced cell cycle arrest in G1 phase as well. Additionally, XH30 inhibited the migration of glioma cells and blocked the activation of PI3K pathway by interleukin-17A (IL-17A), which increased the migration of U87MG. Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models. XH30 also repressed tumor growth in brain metastasis models of lung cancers. Moreover, XH30 reduced IL-17A and its receptor IL-17RA in vivo. These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.

Background Air quality health index (AQHI) has been widely used to quantify the health effects of multiple pollutants observed in population-based epidemiological studies, and can better reflect the widespread linear non-threshold between air pollution and health effects. Objective To explore an AQHI for pediatric respiratory diseases (AQHI_r) in Shanghai and evaluate its feasibility. Methods The daily numbers of hospital outpatient visits for pediatric respiratory diseases from 2015 to 2019 were obtained from five general hospitals in Xuhui, Baoshan, Hongkou, Jinshan, and Chongming Districts of Shanghai. Monitoring data on air pollutants (PM_2.5, PM₁₀, SO₂, NO₂, and O₃), air quality index (AQI), and meteorological variables (temperature, relative humidity, air pressure, and wind speed) were collected from five air quality monitoring sites nearest to selected hospitals. Time-series analysis using generalized additive model (GAM) was conducted to estimate the associations between respiratory-related pediatric outpatient visits and the concentrations of air pollutants. The sum of excess risk (ER) of hospital outpatient visits was used to construct AQHI_r. To assess the predictive power of AQHI_r, the associations of AQHI_r and AQI with the number of pediatric respiratory outpatient visits in three hospitals in Xuhui, Hongkou, and Chongming districts were compared. Results Air pollutants had various effects on respiratory diseases outpatient visits. PM_2.5, NO₂, and O₃ had most significant impacts on lag0 day and the associated ERs of hospital outpatient visits for each 10 μg·m⁻³ increase in pollutant concentration were 1.27% (95%CI: 0.88%-1.66%), 0.75% (95%CI: 0.40%-1.11%), and 0.36% (95%CI: 0.10%-0.62%), respectively. PM₁₀ and SO₂ had most significant impacts on lag3 day and the associated ERs of hospital outpatient visits for each 10 μg·m⁻³ increase in pollutant concentration were 0.81% (95%CI: 0.51%-1.12%) and 5.64% (95%CI: 3.37%-7.96%), respectively. There were significant effects of combinations of two pollutants among PM_2.5, PM₁₀, NO₂, SO₂, and O₃ except for PM₁₀+NO₂, SO₂+PM_2.5, and SO₂+NO₂ (P<0.05). According to the results of single-pollutant and two-pollutant models, PM_2.5, NO₂, SO₂, and O₃ were selected to construct AQHI_r. The comparison showed that for every interquartile range increase in AQHI_r, the ER for pediatric outpatient visits was higher than that for the value corresponding to AQI. Conclusion Air pollutants in Shanghai have an impact on the number of pediatric respiratory outpatient visits. The AQHI_r based on and outpatient visits for pediatric respiratory diseases can be a sensitive index to predict the effects of air pollution on children's respiratory health.

Background Non-occupational carbon monoxide (CO) poisoning is a public health problem that seriously affect people’s health and lives. Objective To describe the prevalence of non-occupational CO poisoning during 2007—2018 in Shanghai, analyze its epidemiological characteristics and potential influencing factors, and explore effective prevention and control measures. Methods Daily reported non-occupational CO poisoning cases and meteorological factors from 2007 to 2018 were collected in Shanghai, epidemiological characteristics were analyzed by descriptive epidemiology methods, and a distributed lag nonlinear model was used to assess the association between temperature and non-occupational CO poisoning. Results A total of 2264 non-occupational CO poisoning events and 3866 cases from 2007 to 2018 were reported in Shanghai, including 59 death cases. More than half of the poisoning cases were female (56.3%), and young adults accounted for more cases than any other age group (54.8%). The poisoning events mainly occurred in winter (from December to next February); however, cases reported in summer increased in recent years. The peak period of the events was from 20:00 to 24:00. Households (85.2%) and restaurants (8.0%) were the common places of non-occupational CO poisoning events, and the main cause was improper use of gas water heater (36.9%). A nonlinear curve was found between daily average temperature of current day and the occurrence of non-occupational CO poisoning. Temperature was negatively associated with the risk of non-occupational CO poisoning when the temperature was lower than 9.6 ℃, while a positive association was found during 9.7-26.0 ℃. Conclusion Winter is a high season for non-occupational CO poisoning in Shanghai, rising cases reported in summer is also worthy of attention. Supervision should be strengthened to ban sales of unqualified gas water heaters, and health education on CO poisoning prevention and control should be conducted through multiple channels, in order to reduce the incidence of CO poisoning.

Objective:To analyze and summarize the application and significance of the computer-assisted surgery system in precision surgery of mediastinal tumors in children.Methods:The clinical data of 54 children that underwent mediastinal tumor resection surgery in the Affiliated Hospital of Qingdao University from August 2008 to November 2021 were collected.According to whether the Hisense CAS computer-assisted surgery system was used before the operation, the patients were divided into three-dimensional (3D) reconstruction group (29 cases, 53.70%) and two-dimensional (2D) CT group (25 cases, 46.30%). The surgical indicators, postoperative hospital stay, and the incidence of surgical complications were compared between the two groups.The t-test, Mann- Whitney U test, χ2 test or Fisher′ s exact test were carried out for statistical analysis.Simulated surgery and actual surgery were compared for both 3D reconstruction and 2D CT groups. Results:There were no significant differences in gender, age, height, weight, maximum tumor diameter and tumor location between the 3D reconstruction group and 2D CT group (all P>0.05). The operation time of the 3D reconstruction group was [(125.14±41.37) min] was shorter than that of the 2D CT group [(149.24±44.53) min] ( P=0.044). The intraoperative blood loss in the 3D reconstruction group [15.00(13.50, 25.00) mL] was less than that in the 2D CT group [36.00(30.00, 75.00) mL] ( P<0.001). In addition, the indwelling time the closed thoracic drainage tube [4.00 (3.00, 5.50) d] and postoperative hospitalization days [(8.83±3.39) d] in the 3D reconstruction group were shorter than those in the 2D CT group [7.00(5.00, 11.50) d, (11.00±4.10) d] ( P=0.001, 0.038). No significant difference in postoperative complication rates was found between the 3D reconstruction group and 2D CT group ( P>0.05). The simulated operation was consistent with the actual operation in the 3D reconstruction group. Conclusions:3D reconstruction by the computer-assisted surgery system can truly reveal the anatomical relationship between tumors and surrounding organs and blood vessels, and improve the accuracy and safety of surgical resection of mediastinal tumors in children.

Objective: To explore the related factors of death from severe heat stroke in Shanghai from 2013 to 2017. Methods: The data of 1 152 patients with severe heat stroke who were divided into survival (n=1 037) and death (n=115) groups including gender, age and heat stroke type (heat cramp, heat exhaustion, heat apoplexy and the mixed type) were collected from meteorological bureau and case report system for high temperature heat stroke in Shanghai from 2013 to 2017. Meanwhile, the meteorological data of the onset date of severe heat stroke cases were collected, including maximum temperature, minimum temperature, daily temperature, relative humidity, air pressure, precipitation and wind speed. The differences of individual and meteorological factors between the two groups were compared, and multivariate logistic regression model was used to analyze the related factors of death from severe heat stroke. Results: Among 1 152 cases, the mean±SD of age was (56.29±18.95) years old, 843 (73.18%)were male, 962 (83.51%) were in the heat wave period; 322 cases (27.95%) were heat cramp, 170 cases (14.76%) were heat exhaustion, 533 cases (46.27%) were heat apoplexy and 114 cases (9.90%) were the mixed type. Daily average temperature ((32.81±1.99) ℃), daily maximum and minimum temperatures ((38.20±2.24) ℃ and (29.22±1.94) ℃) in survival group were lower than those in death group (all P values<0.001), which were (33.76±1.17) ℃, (39.19±1.31) ℃ and (29.72±1.66) ℃. Daily average relative humidity ((60.36±9.75)%) and daily minimum relative humidity ((41.26±9.71)%) in survival group were higher than those in death group(allP values <0.05), which were (54.59±6.89)% and (35.60±7.24)%. The results of logistic regression analysis suggested that compared with the cases with daily average humidity <60% and a mixed type heat stroke, the death OR (95%CI) values of cases with daily average humidity >60%, heat cramp, heat exhaustion and heat apoplexy were 0.31 (0.18,0.54), 0.13 (0.05,0.34), 0.68 (0.58,2.30) and 0.87 (0.48,1.58). Conclusion The temperature, relative humidity and the type of heat stroke were the main related factors affecting the prognosis of severe heat stroke.