Immediate- or Delayed-Intensive Statin in Acute Cerebral Ischemia: The INSPIRES Randomized Clinical Trial.

Importance: Comparisons are limited for immediate-intensive and delayed-intensive statin for secondary stroke prevention and neuroprotection in patients with acute mild ischemic stroke or transient ischemic attack (TIA) from atherosclerosis. Objective: To estimate whether immediate-intensive statin therapy is safe and can lower the risk of recurrent stroke compared with delayed-intensive statin in patients with acute mild ischemic stroke or high-risk TIA from atherosclerosis. Design, Setting, and Participants: The Intensive Statin and Antiplatelet Therapy for High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, a double-blind, placebo-controlled, 2 × 2 factorial, randomized clinical trial enrolled patients from September 2018 to October 2022. The trial was conducted at 222 hospitals in China. Patients aged 35 to 80 years with mild ischemic stroke or high-risk TIA of presumed atherosclerosis within 72 hours of symptom onset were assessed. Interventions: Patients were randomly assigned to receive immediate-intensive atorvastatin (80 mg daily on days 1-21; 40 mg daily on days 22-90) or 3-day delayed treatment (placebo for days 1-3, followed by placebo and atorvastatin, 40 mg daily on days 4-21, and then atorvastatin, 40 mg daily on days 22-90). Main Outcomes and Measures: The primary efficacy outcome was new stroke within 90 days, and a secondary efficacy outcome was poor functional outcome. Moderate to severe bleeding was the primary safety outcome. Results: A total of 11 431 patients were assessed for eligibility, and 6100 patients (median [IQR] age, 65 [57-71] years; 3915 men [64.2%]) were enrolled, with 3050 assigned to each treatment group. Within 90 days, new stroke occurred in 245 patients (8.1%) in the immediate-intensive statin group and 256 patients (8.4%) in the delayed group (hazard ratio, 0.95; 95% CI, 0.80-1.13). Poor functional outcome occurred in 299 patients (9.8%) and 348 patients (11.4%) in the immediate-intensive and delayed-intensive statin groups, respectively (odds ratio, 0.83; 95% CI, 0.71-0.98). Moderate to severe bleeding occurred in 23 of 3050 patients (0.8%) and 17 of 3050 patients (0.6%), in the immediate-intensive and delayed-intensive statin groups, respectively. Conclusions and Relevance: Immediate-intensive statin initiated within 72 hours did not reduce the risk of stroke within 90 days and may be associated with improved functional outcomes without significant difference in moderate to severe bleeding, compared with 3-day delayed-intensive statin in Chinese patients with acute mild ischemic stroke or TIA from atherosclerosis. Trial Registration: ClinicalTrials.gov Identifier: NCT03635749.

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke.

BACKGROUND: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied. METHODS: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days. RESULTS: A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).

Negative Parenting Styles and Psychological Crisis in Adolescents: Testing a Moderated Mediating Model of School Connectedness and Self-Esteem.

Little is known about how rejecting and controlling parenting styles may influence adolescent psychological crisis and what conditions may buffer the detrimental effects of psychological crisis. By integrating multiple theories, this study investigated self-esteem as an underlying mediator and school connectedness as a potential moderator to explain the link between negative parenting and the two psychological crises among Chinese adolescents. In this study, the questionnaire method is adopted to examine the combined mechanism of rejecting parenting style and controlling parenting style on the psychological crisis of adolescents. In total, 1863 adolescents were involved in this study, ranging from 13 to 17 years old. The results showed that both the rejecting parenting style and the controlling parenting style can significantly and positively predict the level of psychological crisis of adolescents, but the predictive power of the rejecting parenting style was stronger. Self-esteem partially mediates the relationship between rejecting parenting style, controlling parenting style, and psychological crisis. School connectedness moderates both the effects of rejecting parenting styles on self-esteem and the effects of self-esteem on the psychological crisis. This study identifies the internal mechanisms by which negative parenting styles affect adolescents' psychological crisis, and reveals the mediating and moderating roles of self-esteem and school connectedness, providing additional explanatory paths for the mechanisms of adolescents' psychological crisis.

Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.

OBJECTIVES: To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death. DESIGN: Multicentre, randomised, open label trial. SETTING: 106 hospitals in China between 13 June 2018 and 10 July 2022. PARTICIPANTS: 4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg. INTERVENTIONS: Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted. RESULTS: 2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups. CONCLUSIONS: Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03479554.

Indobufen versus aspirin in patients with acute ischaemic stroke in China (INSURE): a randomised, double-blind, double-dummy, active control, non-inferiority trial.

BACKGROUND: Aspirin is recommended for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke but can lead to gastrointestinal intolerance and bleeding. Indobufen is used as an alternative antiplatelet agent in some countries, despite an absence of large-scale clinical trials for this indication. We tested the hypothesis that indobufen is non-inferior to aspirin in reducing the risk of new stroke at 90 days in patients with moderate-to-severe ischaemic stroke. METHODS: We conducted a randomised, double-blind, double-dummy, active control, non-inferiority trial at 163 tertiary and district general hospitals in China. Eligible participants were aged 18-80 years with acute moderate-to-severe ischaemic stroke (National Institutes of Health Stroke Scale score 4-18). We randomly assigned (1:1) participants within 72 h of the onset of symptoms to receive either indobufen (100 mg tablet twice per day) or aspirin (100 mg tablet once per day) for 90 days. The randomisation sequence was computer generated centrally and stratified by local participating centres. Masked local investigators assigned the random code to patients in ascending order and provided a treatment kit corresponding to the random code. The primary efficacy outcome was new stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. This primary efficacy outcome was assessed in all randomly assigned and consenting patients and in a per-protocol group (ie, all patients finishing the treatment without major violation of the trial protocol). Safety analyses were done in the safety-analysis population (ie, all patients who received at least one dose of the study drug and had a safety assessment available). We assessed the non-inferiority of indobufen versus aspirin using the one-sided upper limit of the 95% CI of the hazard ratio (HR) with a prespecified non-inferiority margin of 1·25. This trial is registered with ClinicalTrials.gov (NCT03871517). FINDINGS: This trial took place between June 2, 2019, and Nov 28, 2021. Of 84 093 patients screened, 5438 patients were randomly assigned to receive either indobufen (n=2715) or aspirin (n=2723), all of whom were included in the primary analyses. Median age was 64·2 years (IQR 56·1-70·6); 1921 (35·3%) were women and 3517 (64·7%) were men. Stroke occurred within 90 days in 213 (7·9%) patients in the indobufen group versus 175 (6·4%) in the aspirin group (HR 1·23, 95% CI 1·01-1·50; pnon-inferiority=0·44). Moderate or severe bleeding occurred in 18 (0·7%) patients in the indobufen group and in 28 (1·0%) in the aspirin group (0·63, 95% CI 0·35 to 1·15; p=0·13). Adverse events within 90 days occurred in 666 (24·5%) patients in the indobufen group and 679 (24·9%) patients in the aspirin group (p=0·73). INTERPRETATION: In patients with acute moderate-to-severe ischaemic stroke, indobufen was not non-inferior to aspirin because the upper limit of the 95% CI was greater than 1·25. Furthermore, indobufen seemed to be inferior to aspirin in reducing the risk of recurrent stroke at 90 days because the lower limit of the 95% CI was greater than 1·00. Although moderate or severe bleeding did not differ between groups, these findings do not support the use of indobufen for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke. FUNDING: Hangzhou Zhongmei Huadong Pharmaceutical and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

What Makes Employees Green Advocates? Exploring the Effects of Green Human Resource Management.

Green advocacy has been the focus of both practitioners and theorists for decades. However, little attention has been paid to employee green advocacy despite its significance to employee green behaviors and the environmental sustainability of organizations. In an effort to contribute to this nascent field, this study investigates what promotes employee green advocacy and its psychological mechanisms. Based on cognitive consistency theory, we propose that green human resource management (GHRM) can influence employees' organization-based self-esteem, which motivates them to engage in employee green advocacy to sustain their positive self-image and avoid possible cognitive disorders. Perceived organizational support moderates the relationship between GHRM and employee organization-based self-esteem. Data from a sample of 135 employees and their chief human resource officer (CHO) supported our hypotheses. We discussed the theoretical and practical implications of our findings.

Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA.

BACKGROUND: Comparisons between ticagrelor and clopidogrel for the secondary prevention of stroke in CYP2C19 loss-of-function carriers have not been extensively performed. METHODS: We conducted a randomized, double-blind, placebo-controlled trial at 202 centers in China involving patients with a minor ischemic stroke or transient ischemic attack (TIA) who carried CYP2C19 loss-of-function alleles. Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel or to receive clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 through 90) and placebo ticagrelor; both groups received aspirin for 21 days. The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days. RESULTS: A total of 11,255 patients were screened and 6412 patients were enrolled, with 3205 assigned to the ticagrelor group and 3207 to the clopidogrel group. The median age of the patients was 64.8 years, and 33.8% were women; 98.0% belonged to the Han Chinese ethnic group. Stroke occurred within 90 days in 191 patients (6.0%) in the ticagrelor group and 243 patients (7.6%) in the clopidogrel group (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P = 0.008). Secondary outcomes were generally in the same direction as the primary outcome. Severe or moderate bleeding occurred in 9 patients (0.3%) in the ticagrelor group and in 11 patients (0.3%) in the clopidogrel group; any bleeding occurred in 170 patients (5.3%) and 80 patients (2.5%), respectively. CONCLUSIONS: Among Chinese patients with minor ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel. The risk of severe or moderate bleeding did not differ between the two treatment groups, but ticagrelor was associated with more total bleeding events than clopidogrel. (Funded by the Ministry of Science and Technology of the People's Republic of China and others; CHANCE-2 ClinicalTrials.gov number, NCT04078737.).

How CEO Ethical Leadership Influences Top Management Team Creativity: Evidence From China.

The creative thinking and ability of top management team (TMT) members is important in coping with rapid changes in the external environment and improving the competitive advantage of an organization. This research focuses on the CEO-TMT interface to explain how CEOs influence TMT characteristics, which in turn affects TMT outcomes. Based on social learning theory, this study examines the associations among CEO ethical leadership, TMT cohesion, and TMT creativity in a Chinese context using a total of 91 TMTs. To verify the reliability and validity of the constructs, a series of confirmatory factor analyses (CFAs) were run. The results showed that the hypothetical model captured distinct constructs and fits the data well. A multistep regression method was used to test hypotheses. The results indicated that: (a) CEO ethical leadership has a positive effect on TMT creativity; (b) TMT cohesion plays a mediating role in the relationship between CEO ethical leadership and TMT creativity; and (c) power distance plays a moderating role in the relationship between CEO ethical leadership and TMT creativity. The greater the power distance, the weaker the positive relationship between CEO ethical leadership and TMT creativity. This study demonstrates the value of CEO ethical leadership and advocates the importance of establishing team cohesion and building a psychologically safe environment to motivate top managers within an organization to share information and knowledge to improve creativity.

Total flavonoids of Epimedium ameliorates testicular damage in streptozotocin-induced diabetic rats by suppressing inflammation and oxidative stress.

Testicular damage is the anomaly that will often accompany diabetes mellitus. Thus, this study aimed to investigate the role that total flavonoids of Epimedium (TFE) played against streptozotocin (STZ)-induced diabetic testicular dysfunction and to elucidate the mechanism of action. The diabetic rat model was induced by vein injection of STZ in healthy rats. Thirty male healthy Spraque-Dawley rats were randomly divided into following groups: the control group, the diabetic group, and the diabetic + TFE group. Gastrointestinal administration begins at fifth week of TFE for 6 weeks. After TFE administration, all animals were euthanized. Testicular tissue samples and blood samples of rats were collected for histopathological examination and for determination of levels of various biomarkers including blood glucose, testosterone, testicular enzymes, and oxidative stress indicators. All testes were weighted to calculate the testicular organ index. Hematoxylin-eosin staining was used for observing the testis and epididymis pathological changes. Protein expression (monocyte chemoattractant protein-1, transforming growth factor-beta-1, interleukin-6, and 3-beta-hydroxysteroid dehydrogenase) was detected by immunohistochemistry and western blot techniques. There was a significant difference in the changes between the diabetes group and the control group. As a result of treat with TFE, the blood glucose decreased but there was no significant difference, and other indicators showed significant improvement. TFE may protect against STZ-induced testicular injury by suppressing inflammation and oxidative stress.

Ursolic acid improves diabetic nephropathy via suppression of oxidative stress and inflammation in streptozotocin-induced rats.

Inflammation plays a pivotal role in the pathogenesis of diabetic nephropathy (DN). Overexpression of inflammatory chemokine and cytokines is involved in the development of DN. Ursolic acid (UA), a common pentacyclic triterpenoid compound, has been reported to have myriad benefits and medicinal properties. However, its protective effects against renal injury in streptozotocin (STZ)-induced diabetic rats have not been firmly established. In the current report, we investigated whether UA inhibits oxidative stress and inflammation in the kidneys of STZ-induced diabetic rats. Diabetes mellitus (DM) was induced by STZ (40 mg/ kg, i.v.). Animals were randomly divided into control group (normal saline, i.g.), DN group (normal saline, i.g.), DN + UA group (35 mg/kg UA + normal saline, i.g.) and DN + telmisartan group (12 mg/kg telmisartan + normal saline, i.g.). Fasting blood glucose (FBG) levels were monitored at regular intervals. The administration of compounds started at 5th week and lasted for 8 weeks. At the beginning of 13th week, rats were humanely euthanized, KW/BW, BUN, SCr, SOD and MDA were measured. Histopathological changes in renal tissue were observed after hematoxylin-eosin (HE) staining. Furthermore, the expressions of TNF-α, MCP-1 and IL-1ß in kidney were determined by immunohistochemistry and western blot. Our results showed that UA significantly lowered the levels of FBG, KW/BW, BUN, SCr and MDA in diabetic rats. Additionally, the SOD activity in UA treated group was higher than that in DN group. Furthermore, renal structural abnormalities and the elevation of TNF-α, MCP-1 and IL-1ß expression level were blocked by the administration of UA. In conclusion, our data demonstrate that UA could be well used as a protective agent to counter renal dysfunction - through antioxidant and anti-inflammatory effects.

[Effect of ursolic acid on cardiomyopathy of mice with diabetes and its mechanism].

OBJECTIVE: To study the effect of ursolic acid on cardiomyopathy in mice with diabetes induced by high-fat diet combined with low dose streptozotocin, and to explore its possible mechanism. METHODS: Thirty male ICR mice were randomly divided into control group (n=10) and moulding group (n=20), the mice in the two groups were fed with regular diet and high-fat diet respectively for 6 weeks, and then the mice in the moulding group were injected with streptozotocin (30 mg/kg) for 5 successive days to induce diabetes mellitus (DM). Fasting blood glucose (FBG) was measured after 9 days. Mice with FBG over 11.1 mmol/L were regarded as DM. Twenty DM mice were randomly divided into model group and ursolic acid group (n=10). Mice in each group were continuously administrated ursolic acid (100 mg/kg) or corresponding solvent intragastrically for 8 weeks. After that, FBG was measured, body weight (BW), heart weight and left ventricular weight were weighed in order to calculate the heart mass index (HMI) and left ventricular mass index (LVMI). Levels of creatine kinase (CK), lactate dehydrogenase (LDH) in serum and the level of superoxide dismutase (SOD), malondialdehyde (MDA) in myocardial tissue were detected. HE staining was used to observe pathological changes of myocardial tissue. Immunohistochemistry was employed to determine the expression of NOD-like receptor protein 3 (NLRP3) and interleukin 1ß (IL-1ß). RESULTS: Compared with the control group, HMI, LVMI were apparently enlarged, levels of FBG, CK, LDH in serum and MDA in myocardial tissue were extremely increased, while the activity of SOD in myocardial tissue were extraordinary decreased in diabetic group. HE staining of myocardium showed that arrangement disorder of myocardial fibers, edema and hypertrophy in myocardial cell, as well as inflammatory cell infiltration in model group. Immunohistochemistry showed that the expression of NLRP3 and IL-1ß in myocardial tissue increased obviously in model group, the above changes inursolic acid group were significantly ameliorated. CONCLUSIONS: Ursolic acid has a obvious protective effect on myocardial injury in mice with diabetes induced by high-fat diet combined with low dose streptozotocin, and its mechanism may be associated with inhibiting NLRP3 inflammasome activation, reducing IL-1ß generation and alleviating myocardial inflammatory injury.

Ursolic acid ameliorates oxidative stress, inflammation and fibrosis in diabetic cardiomyopathy rats.

Diabetic cardiomyopathy is a major and severe cardiovascular complication of diabetes mellitus. Ursolic acid, a pentacyclic triterpene compound widespread in fruits and plants, performs a variety of pharmacological activities including lowering blood glucose, anti-oxidation, anti-inflammation and anti-fibrosis. Our present study aimed to investigate the cardioprotective effects of ursolic acid on diabetic cardiomyopathy rats and uncover its underlying mechanism. Diabetes mellitus was induced by a single injection of STZ-only (40 mg/ kg, i.v.) in male SD rats. Animals were divided into three groups (n=10): control group (normal saline, i.g.), diabetic group (normal saline, i.g.) and diabetic+ursolic acid group (35 mg/kg UA + normal saline, i.g.). Rats were administered for 8 weeks from 5th to 12th week. After the last administration, cardiac function was evaluated; HWI was calculated; FBG, CK, LDH in serum and SOD, MDA in cardiac tissue were detected. HE staining and Masson trichrome staining were employed to observe pathological alterations. Immunohistochemistry and western blotting were taken to determine the expression levels of TNF-α, MCP-1, TGF-ß1 and MMP-2 in the heart. The results dramatically showed increased levels of FBG, CK, LDH, MDA and a decreased activity of SOD in diabetic group, in which left ventricular dysfunction, cardiac myocytes hypertrophy, inflammatory cell infiltration and myocardial interstitial fibrosis had also been found. What's more, the expressions of TNF-α, MCP-1 and TGF-ß1 were significantly up-regulated and the expression of MMP-2 was markedly down-regulated in myocardium. Interestingly, treatment with ursolic acid remarkably ameliorated these changes. Collectively, our study strongly showed that ursolic acid is capable of improving the cardiac structure and function in STZ-induced diabetic cardiomyopathy rats by attenuating oxidative stress, inflammation and fibrosis.