Effectiveness of a Quality Improvement Intervention on Reperfusion Treatment for Patients With Acute Ischemic Stroke: A Stepped-Wedge Cluster Randomized Clinical Trial.

Importance: Reperfusion therapy is the most effective treatment for acute ischemic stroke but remains underused in China. Objective: To evaluate the effect of a problem-oriented, culturally adapted, targeted quality improvement intervention on reperfusion therapy for patients with acute ischemic stroke in China. Design, Setting, and Participants: In this stepped-wedge cluster randomized clinical trial, patients from 16 secondary and 33 tertiary hospitals in China with acute ischemic stroke within 6 hours of symptom onset were consecutively recruited between July 1, 2018, and June 30, 2020. Interventions: Hospitals were randomly assigned to 1 of 3 sequences to receive the targeted quality improvement intervention (n = 5689), in which workflow reconstruction was promoted to reduce in-hospital reperfusion treatment delays, or usual care (n = 6443), in which conventional stroke care was left to the discretion of the stroke team. Main Outcomes and Measures: The primary outcome was the reperfusion therapy rate, a composite outcome of intravenous recombinant tissue plasminogen activator (IV rtPA) or endovascular thrombectomy (EVT) for eligible patients who arrived within 3.5 or 4.5 hours of symptom onset. Secondary outcomes were the IV rtPA administration rate among eligible patients who arrived within 3.5 hours of symptom onset, the EVT rate among eligible participants who arrived within 4.5 hours of symptom onset, the proportion of patients with door-to-needle time within 60 minutes, the proportion of patients with door-to-puncture time within 90 minutes, in-hospital mortality, and 3-month disability as measured by a modified Rankin Scale score greater than 2. Results: All 12 132 eligible patients (mean [SD] age, 66 [12.1] years; 7759 male [64.0%]) completed the trial. The reperfusion rate was 53.5% (3046 of 5689) for the eligible patients in the intervention period and 43.9% (2830 of 6443) in the control period. No significant improvement in primary outcomes was found for the intervention after adjusting for cluster, period, and imbalanced baseline covariates (adjusted risk difference [ARD], 5.5%; 95% CI, -8.0% to 19.0%; adjusted odds ratio [AOR], 1.26; 95% CI, 0.72-2.21) or for the secondary outcomes. However, significant improvements were found in secondary hospitals for reperfusion therapy (1081 of 1870 patients [57.8%] vs 945 of 2022 patients [42.9%]; ARD, 19.0%; 95% CI, 6.4%-31.6%; AOR, 2.24; 95% CI, 1.29-3.88), IV rtPA administration (1062 of 1826 patients [58.2%] vs 916 of 2170 patients [42.2%]; ARD, 20.3%; 95% CI, 7.4%-33.1%; AOR, 2.37; 95% CI, 1.34-4.19), and EVT (51 of 231 patients [22.1%] vs 37 of 259 patients [14.3%]; ARD, 13.6%; 95% CI, 1.0%-26.3%; AOR, 3.03; 95% CI, 1.11-8.25) in subgroup analyses. Conclusions and Relevance: In this stepped-wedge cluster randomized clinical trial of patients with acute ischemic stroke in China, the use of a targeted quality improvement intervention compared with usual care did not improve the reperfusion therapy rate. However, the intervention may be effective in secondary hospitals. Trial Registration: ClinicalTrials.gov Identifier: NCT03578107.

The association of white matter hyperintensities with stroke outcomes and antiplatelet therapy in minor stroke patients.

BACKGROUND: To characterize the severity and distribution of white matter hyperintensities (WMHs) and to assess the relationship of WMHs with initial stroke severity, 3-month functional outcome, stroke recurrence and response to antiplatelet therapies. METHODS: In Clopidogrel High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, 787 minor stroke patients with baseline magnetic resonance imaging (MRI) information were included in this analysis. Deep and periventricular WMHs (DWMHs and PVWMHs) were rated using the Fazekas scale and categorized into mild (grades 0-2), moderate (grades 3-4) and severe (grades 5-6). Multivariable logistic regression was used to examine the associations between WMHs severities and outcomes, including initial stroke severity by the National Institutes of Health Stroke Scale (NIHSS) scores, 3-month functional outcome by modified Rankin Scale (mRS), and stroke recurrence. Cox proportional hazards model was used to assess the treatment-by-subgroup interaction effect. RESULTS: Among the 787 patients in this analysis, 432 (54.9%) had moderate or severe WMHs (3-6). Compared with mild WMHs, the adjusted odds ratio (OR) of severe WMHs for risk of higher NIHSS was 2.10, 95% confidence interval (CI), 1.26-3.48 (P=0.004). Both severities of SDWMHs (OR 1.66; 95% CI, 1.15-2.40; P=0.007) and PVWMHs (OR 1.47; 95% CI, 1.02-2.10; P=0.04) were associated with higher NIHSS scores. There were no statistically significant associations of WMHs with 3-month functional outcome and stroke recurrence. There were no significant interactions between WMHs and antiplatelet therapy. CONCLUSIONS: In patients with minor stroke, both SDWMHs and PVWMHs might related with initial stroke severity. No interaction was detected between the severity of WMHs and antiplatelet treatment.Trial registration: ClinicalTrials.gov identifier: NCT00979589. Date of registration: Sep 18, 2009.

Intranasal inoculation with an adenovirus vaccine encoding ten repeats of Aß3-10 reduces AD-like pathology and cognitive impairment in Tg-APPswe/PSEN1dE9 mice.

To develop a safe and efficient vaccine for AD treatment, we constructed an adenovirus vector vaccine encoding ten repeats of Aß3-10 and CpG motif as a molecular adjuvant. We demonstrated that therapeutic immunization with Ad-10×Aß3-10-CpG elicits Aß3-10 specific Th2-polarized immune response with high titers of anti-Aß antibodies in APPswe/PSEN1dE9 mice, which in turn reduced Aß deposits in brains and cognitive impairment. In addition, Ad-10×Aß3-10-CpG reduced astrocytosis without increasing the incidence of microhemorrhage. Our findings of this study raise the possibility that the adenovirus vaccine Ad-10×Aß3-10-CpG would be a safe and effective alternative for AD immunotherapy.

In vivo electroporation of a new gene vaccine encoding ten repeats of Aß3-10 prevents brain Aß deposition and delays cognitive impairment in young Tg-APPswe/PSEN1dE9 mice.

Active immunization holds great promise for the treatment of Alzheimer's disease but the infiltration of T-lymphocytes and associated meningoencephalitis observed in clinical trials needs to be overcome. To avoid this toxicity, previous studies have used synthetic truncated derivatives of Aß to promote humoral immunity. In this study, we developed a novel vaccine [p(Aß3-10)10-MT] that expresses ten repeats of Aß3-10 with melatonin (MT) as an adjuvant, and administered it intramuscularly in three-month-old Tg-APPswe/PSEN1dE9 (Tg) mice by in vivo electroporation. The p(Aß3-10)10-MT vaccine induced high titers of anti-Aß antibodies, which in turn reduced Aß deposits in the mouse brains and decreased cognitive impairment. Immunoglobulin isotyping revealed a predominantly IgG1 response, indicating a Th2 anti-inflammatory response. Ex vivo cultured splenocytes exhibited a low IFN-γ and high IL-4 response. Immunohistochemical analysis revealed that glial cell activation was also attenuated. These results indicate that p(Aß3-10)10-MT may potentially be an effective vaccine to reduce accumulated Aß and attenuate cognitive deficits.

Intranasal inoculation with an adenovirus vaccine encoding ten repeats of Aß3-10 induces Th2 immune response against amyloid-ß in wild-type mouse.

To develop a safe and efficient vaccine for the treatment of Alzheimer's disease, we constructed a novel adenovirus vaccine encoding ten repeats of Aß3-10 and CpG motif as an adjuvant and investigated the immune response in BALB/c mouse after intranasal inoculation with this vaccine. The Ad-10×Aß3-10-CpG induces an IgG1 predominant humoral response and production of IL-4 and IL-10 in splenocytes in vitro, indicating a Th2-polarized immune response. Stimulation of splenocytes with Aß3-10 peptide induces robust proliferation but not with full-length Aß42 peptide, demonstrating that Ad-10×Aß3-10-CpG does not induces Aß42 specific T cell immune response. The findings raise the possibility that the adenovirus vaccine Ad-10×Aß3-10-CpG could be a safe and effective alternative for immunotherapy in Alzheimer's disease.

Improving memory and decreasing cognitive impairment in Tg-APPswe/PSEN1dE9 mice with Aß3-10 repeat fragment plasmid by reducing Aß deposition and inflammatory response.

The present study aimed to investigate the effects of Aß3-10 repeat fragment plasmid for the treatment of Tg-APPswe/PSEN1dE9 (Tg) mice. The plasmid pcDNA3.1-(Aß3-10)10-CpG was constructed and intramuscularly injected into 12-month-old Tg mice. Through the use of behavioral tests, anti-Aß antibody and Aß assays, cytokine assay, Aß deposition, and astrocytes analysis results demonstrated that Aß3-10 repeat fragment plasmid exhibited immunogenicity and reduced memory impairment in Tg mice via clearance of cerebral Aß deposition, without significant side effects. Aß3-10 repeat fragment plasmid immunization reduced Th1 cell-mediated immunity, secretion of interferon-γ, and stimulation to astrocytes. These data showed that the Aß3-10 repeat fragment plasmid improved memory and decreased cognitive impairment in Tg mice by reducing Aß deposition and inflammatory responses.