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

This paper aims to evaluate the pharmacodynamic effect and mechanism of Zhifuxin in the prevention and treatment of vascular dementia(VD), providing a theoretical basis for later development. Bilateral common carotid artery ligation in male Wistar rats was conducted to replicate the long-term hypoperfused VD model, and the drug was given to groups after one month. The rats were fed daily with nimodipine of 20 mg·kg~(-1), Zhifuxin of 50, 100, and 200 mg·kg~(-1), or the same volume of solvent for four weeks. 24 hours after the last dose, Morris water maze experiments were performed to detect the learning and memory abilities of rats. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the brain tissue of rats; the immunohistochemical method was used to detect the expression of muscarinic acetylcholine receptors M1 and M4 in rats and determine the content of acetyl choline(Ach), acetylcholin esterase(AchE), malondialdehyde(MDA), choline acetyl transferase(ChAT), and dimethyl arginine hydrolase 1(DDAH1) in the cerebral cortex of rats. Western blot was employed to detect protein expression of endothelial nitric oxide synthase(eNOS), caveolin-1, monoamine oxidase A(MAO-A), and monoamine oxidase B(MAO-B). RT-qPCR was utilized to detect mRNA expression of eNOS, caveolin-1, MAO-A, and MAO-B. The results showed that compared with the model group, the different doses of Zhifuxin were able to shorten the latency of VD rats in the water maze positioning navigation test, increase the number of crossing platforms in the space exploration test, and alleviate cone cell contracture in the hippocampus of VD rats. The expression of biochemical indicators related to the cholinergic system in the cerebral cortex: M1 and M4 receptors increased, as well as ChAT activity, and AchE activity significantly decreased. The protein and mRNA expression of indicators related to the eNOS/NO pathway: DDAH1 content, eNOS, and caveolin-1 increased, and that of indicators related to monoamine oxidase(MAO): MAO-A and MAO-B significantly decreased. The results show that Zhifuxin can improve cognition ability in long-term hypoperfused VD rats, and its mechanism of action may be related to its ability to modulate the cholinergic system and the eNOS/NO pathway and inhibit MAO expression.
Animals ; Dementia, Vascular/metabolism* ; Male ; Rats, Wistar ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Maze Learning/drug effects* ; Nitric Oxide Synthase Type III/genetics* ; Acetylcholinesterase/metabolism* ; Humans ; Choline O-Acetyltransferase/genetics* ; Disease Models, Animal

Objective:To analyze the disease burden of colorectal cancer (CRC) among young and middle-aged people in China from 1990 to 2021, and to explore the influence of age, period and cohort on the incidence and mortality of CRC in young and middle-aged people of China.Methods:Data on CRC in patients aged 40-59 years in China from 1990 to 2021 were extracted from the Global Burden of Disease Study 2021 (GBD 2021) database. Statistics such as incidence rate, mortality rate, disability-adjusted life years (DALY), and their corresponding age-standardized rates were calculated to analyze the CRC incidence and mortality in different age and sex groups of young and middle-aged Chinese young people from 1990 to 2021. The Joinpoint regression model was used to analyze the CRC incidence, the mortality and the DALY rate, as well as to calculate the annual percentage change (APC) and the average annual percentage change (AAPC). The effects of three independent factors, namely age, period and cohort, on the incidence and mortality of CRC in young and middle-aged people of China were analyzed and evaluated through the age-period-cohort model.Results:From 1990 to 2021, there was a remarkable upward trend in the incidence, mortality, and DALY of CRC among Chinese young and middle-aged adults. In 2021, the number of incidence cases of CRC among young and middle-aged people in China reached 181 000, and the number of deaths reached 57 900, which were 236.80% and 75.48% higher than those in 1990 (53 800 and 33 000, respectively). During the same period, DALY increased by 62.59%, with the 55-59 age group having the largest increase at 83.35%. From 1990 to 2021, the age-standardized incidence rate (ASIR) increased by 49.04%, rising from 25.51/100 000 to 38.02/100 000, and the age-standardized mortality rate (ASMR) declined by 28.75%, decreasing from 17.01/100 000 to 12.12/100 000, respectively. The increase in ASIR was the greatest among the 40-44 age group, reaching 57.31%, while the decline in ASMR was the most significant among the 50-54 age group, amounting to 30.18%. However, the DALY rate declined by 26.66%, from 673.52/100 000 to 493.94/100 000. The decline in DALY was the greatest among the 50-54 age group, reaching 28.26%. Joinpoint regression model analysis showed that, from 1990 to 2021, the incidence of CRC in Chinese young and middle-aged adults rose on average by 1.32% annually, and the increase was higher in men (1.87%) than that in women (0.36%). The mortality rate showed a downward trend, with an average annual decline of 1.10%, with a higher decline in women than in men (-2.14% vs. -0.50%). The DALY rate showed a downward trend, with an average annual decline of 1.00%, and more decline in women than in men (-2.06% vs. -0.41%). All of these trends were statistically significant (all P<0.001). The age-period-cohort model analysis showed that, the net drift of CRC incidence was 1.21% (1.02%-1.41%) per year among Chinese young and middle-aged adults between 1990 and 2021, while the net drift in mortality was -1.40% (-1.59%--1.21%) per year. The impact of age on CRC incidence and mortality intensified with advancing age. Incidence attributable to age rose from 12.66% (11.90%- 13.46%) in the 40-44 age group to 56.68% (54.37%-59.08%) in the 55-59 age group. Similarly, mortality attributable to age increased from 6.47% (6.12%-6.85%) in the 40-44 age group to 25.74% (24.58%-26.96%) in the 55-59 age group. In all age groups, the role of CRC incidence and mortality attributable to age was higher in men than in women. Period effects on the RR value of CRC incidence showed a declining trend followed by an upward trend, with the highest risk during 2015-2019 ( RR=1.36, 95% CI: 1.28-1.43), using 2000-2004 as the reference. For mortality, period effects exhibited a declining trend, with the highest risk during 1990-1994 ( RR=1.23, 95% CI: 1.15-1.32), using 2000-2004 as the reference. Cohort effects indicated that later birth cohorts had higher incidence risks, with the highest incidence observed in the 1973-1977 birth cohort ( RR=1.30, 95% CI: 1.16-1.45), using the 1953-1957 birth cohort as the reference. Conversely, later birth cohorts had lower mortality risks, with the lowest mortality in the 1973-1977 birth cohort ( RR=0.78, 95% CI: 0.69-0.88), using the 1953-1957 birth cohort as the reference. Conclusions:From 1990 to 2021, the changes in the disease burden of CRC among young and middle-aged people in China are manifested as an increase in standardized incidence rate and a decrease in standardized mortality rate. Meanwhile, there are gender differences in the trend of temporal changes. Age, period and cohort all have a significant impact on the incidence and mortality trends of colorectal cancer in young and middle-aged people. Research on the etiology of CRC should be strengthened, and targeted prevention and control strategies should be formulated.

Objective This study aimed to clarify the intervention effect of salidroside(SAL)on lung injury caused by PM2.5 in mice and illuminate the function of SIRT1-PGC-1ɑ axis. Methods Specific pathogen-free(SPF)grade male C57BL/6 mice were randomly assigned to the following groups:control group,SAL group,PM2.5 group,SAL+PM2.5 group.On the first day,SAL was given by gavage,and on the second day,PM2.5 suspension was given by intratracheal instillation.The whole experiment consist of a total of 10 cycles,lasting 20 days.At the end of treatment,blood samples and lung tissues were collected and analyzed.Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy.The expression of inflammatory,antioxidants,apoptosis,and SIRT1-PGC-1ɑ proteins were detected by Western blotting. Results Exposure to PM2.5 leads to obvious morphological and pathologica changes in the lung of mice.PM2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1,Nrf2,SOD2,SIRT1 and PGC-1ɑ,and an increase in the protein expressions of IL-6,IL-1β,Bax,caspase-9 and cleaved caspase-3.However,SAL reversed the aforementioned changes caused by PM2.5 by activating the SIRT1-PGC-1α pathway. Conclusion SAL can activate SIRT1-PGC-1ɑ to ameliorate PM2.5-induced lung injury.

Objective: To explore the clinical characteristics of various types of infected pancreatic necrosis(IPN) and the prognosis of different treatment methods in the imaging classification of IPN proposed. Methods: The clinical data of 126 patients with IPN admitted to the Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University from December 2018 to December 2021 were analyzed retrospectively. There were 70 males(55.6%) and 56 females(44.4%), with age(M(IQR)) of 44(17)years (range: 12 to 87 years). There were 67 cases(53.2%) of severe acute pancreatitis and 59 cases (46.8%) of moderately severe acute pancreatitis. All cases were based on the diagnostic criteria of IPN. All cases were divided into Type Ⅰ(central IPN)(n=21), Type Ⅱ(peripheral IPN)(n=23), Type Ⅲ(mixed IPN)(n=74) and Type Ⅳ(isolated IPN)(n=8) according to the different sites of infection and necrosis on CT.According to different treatment strategies,they were divided into Step-up group(n=109) and Step-jump group(n=17). The clinical indicators and prognosis of each group were observed and analyzed by ANOVA,t-test,χ² test or Fisher exact test,respectively. Results: There was no significant difference in mortality, complication rate and complication grade in each type of IPN(all P>0.05). Compared with other types of patients, the length of stay (69(40)days vs. 19(19)days) and hospitalization expenses(323 000(419 000)yuan vs. 60 000(78 000)yuan) were significantly increased in Type Ⅳ IPN(Z=-4.041, -3.972; both P<0.01). The incidence of postoperative residual infection of Type Ⅳ IPN was significantly higher than that of other types (χ²=16.350,P<0.01). There was no significant difference in the mortality of patients with different types of IPN between different treatment groups. The length of stay and hospitalization expenses of patients in the Step-up group were significantly less than those in the Step-jump group(19(20)days vs. 33(35)days, Z=-2.052, P=0.040;59 000(80 000)yuan vs. 122 000(109 000)yuan,Z=-2.317,P=0.020). Among the patients in Type Ⅳ IPN, the hospitalization expenses of Step-up group was significantly higher than that of Step-jump group(330 000(578 000)yuan vs. 141 000 yuan,Z=-2.000,P=0.046). The incidence of postoperative residual infection of Step-up group(17.4%(19/109)) was significantly lower than that of Step-jump group(10/17)(χ²=11.980, P=0.001). Conclusions: Type Ⅳ IPN is more serious than the other three types. It causes longer length of stay and more hospitalization expenses. The step-up approach is safe and effective in the treatment of IPN. However, for infected lesions which are deep in place,difficult to reach by conventional drainage methods, or mainly exhibit "dry necrosis", choosing the step-jump approach is a more positive choice.
Male ; Female ; Humans ; Retrospective Studies ; Pancreatitis, Acute Necrotizing/complications* ; Acute Disease ; Intraabdominal Infections/complications* ; Necrosis/complications* ; Treatment Outcome

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

BACKGROUND: Butylphthalide (NBP) and edaravone (EDV) injection are common acute ischemic stroke medications in China, but there is a lack of large real-world safety studies on them. This study aimed to determine the incidence of adverse events, detect relevant safety signals, and assess the risk factors associated with these medications in real-world populations. METHODS: In this study, data of acute ischemic stroke patients were extracted from the electronic medical record database of six tertiary hospitals between January 2019 and August 2021. Baseline confounders were eliminated using propensity score matching. The drugs' safety was estimated by comparing the results of 24 laboratory tests standards on liver function, kidney function, lipid level, and coagulation function. The drugs' relative risk was estimated by logistic regression. A third group with patients who did not receive NBP or EDV was constructed as a reference. Prescription sequence symmetry analysis was used to evaluate the associations between adverse events and NBP and EDV, respectively. RESULTS: 81,292 patients were included in this study. After propensity score matching, the NBP, EDV, and third groups with 727 patients in each group. Among the 15 test items, the incidence of adverse events was lower in the NBP group than in the EDV group, and the differences were statistically significant. The multivariate logistic regression equation revealed that NBP injection was not a promoting factor for abnormal laboratory test results, whereas EDV had statistically significant effects on aspartate transaminase, low-density lipoprotein cholesterol and total cholesterol. Prescription sequence symmetry analysis showed that NBP had a weak correlation with abnormal platelet count. EDV had a positive signal associated with abnormal results in gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, prothrombin time, and platelet count. CONCLUSIONS In a large real-world population, NBP has a lower incidence of adverse events and a better safety profile than EDV or other usual medications.

OBJECTIVE: To derive the Chinese medicine (CM) syndrome classification and subgroup syndrome characteristics of ischemic stroke patients. METHODS: By extracting the CM clinical electronic medical records (EMRs) of 7,170 hospitalized patients with ischemic stroke from 2016 to 2018 at Weifang Hospital of Traditional Chinese Medicine, Shandong Province, China, a patient similarity network (PSN) was constructed based on the symptomatic phenotype of the patients. Thereafter the efficient community detection method BGLL was used to identify subgroups of patients. Finally, subgroups with a large number of cases were selected to analyze the specific manifestations of clinical symptoms and CM syndromes in each subgroup. RESULTS: Seven main subgroups of patients with specific symptom characteristics were identified, including M3, M2, M1, M5, M0, M29 and M4. M3 and M0 subgroups had prominent posterior circulatory symptoms, while M3 was associated with autonomic disorders, and M4 manifested as anxiety; M2 and M4 had motor and motor coordination disorders; M1 had sensory disorders; M5 had more obvious lung infections; M29 had a disorder of consciousness. The specificity of CM syndromes of each subgroup was as follows. M3, M2, M1, M0, M29 and M4 all had the same syndrome as wind phlegm pattern; M3 and M0 both showed hyperactivity of Gan (Liver) yang pattern; M2 and M29 had similar syndromes, which corresponded to intertwined phlegm and blood stasis pattern and phlegm-stasis obstructing meridians pattern, respectively. The manifestations of CM syndromes often appeared in a combination of 2 or more syndrome elements. The most common combination of these 7 subgroups was wind-phlegm. The 7 subgroups of CM syndrome elements were specifically manifested as pathogenic wind, pathogenic phlegm, and deficiency pathogens. CONCLUSIONS There were 7 main symptom similarity-based subgroups in ischemic stroke patients, and their specific characteristics were obvious. The main syndromes were wind phlegm pattern and hyperactivity of Gan yang pattern.
Humans ; Syndrome ; Ischemic Stroke ; Medicine, Chinese Traditional ; Liver ; Phenotype

Objective:To investigate the effect of tumor deposits on the prognosis and lymph node staging in patients with gastric cancer.Methods:The clinicopathological data of 907 patients with gastric cancer admitted to the Fourth Hospital of Hebei Medical University from Jan to Dec 2016 were retrospectively analyzed. According to the pathological diagnosis, the patients were divided into tumor deposits positive group (121 cases) and tumor deposits negative group (786 cases), and the relationship between tumor deposits and clinicopathological features and prognosis was analyzed.Results:Tumor deposits were found in 121 patients among 907 cases. Univariate analysis showed that tumor deposits were correlated with pT stage, pN stage, pTNM stage, tumor diameter, nerve invasion and vascular invasion (all P<0.05). Multivariate analysis showed that pT stage ( P<0.001), pN stage ( P=0.002), pTNM stage ( P=0.001), tumor diameter ( P=0.033),nerve invasion ( P=0.017), vascular invasion ( P=0.011) were the independent influencing factors of positive tumor deposits. The prognosis of patients with tumor deposits was worse than those without ( χ2=77.869, P<0.001). By univariate analysis, age, tumor location, size, pT stage, pN stage, pTNM stage, tumor thrombus, nerve invasion, tumor deposits and number affected prognosis (all P<0.05). Multivariate analysis showed that age, pT stage, pN stage, pTNM stage, nerve invasion, vascular invasion and the number of tumor deposits were independent prognostic factors (all P<0.05). By stratified analysis tumor deposits were found to have statistical difference in N0~N3a stage (all P<0.05). Conclusion:Tumor deposits is an independent risk factor affecting the prognosis of gastric cancer patients.

The quality control and evaluation methods of Schizonepeta tenuifolia were established by HPLC fingerprint, multi index component content determination and chemical pattern recognition to provide basis for the quality control of medicinal materials. The chemical components of 25 batches of Schizonepeta tenuifolia panicle medicinal materials and decoction pieces collected were analyzed by high performance liquid chromatography, and the common pattern of fingerprint was established. A total of 22 common chromatographic peaks were calibrated, and their similarity was more than 0.9. The samples were divided into three categories according to different producing areas by cluster analysis. The results of principal component analysis and cluster analysis were consistent. Finally, five differential markers of different batches of Schizonepeta tenuifolia were selected by orthogonal partial least squares discriminant analysis. Through the identification of the reference substance, it was determined that peak 9 was hesperidin, peak 10 was rosmarinic acid, peak 13 was tilianin, peak 14 was quercetin, and peak 20 was pulegone. The quality evaluation method established in this study is stable and reliable, and is suitable for the quality control of Schizonepeta tenuifolia.