Mid-to-Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals.

IMPORTANCE: Genetic and lifestyle factors contribute to an individual's risk of developing Alzheimer's disease. However, it is unknown whether and how adherence to healthy lifestyles can mitigate the genetic risk of Alzheimer's. OBJECTIVE: The aim of this study is to investigate whether adherence to healthy lifestyles can modify the impact of genetic predisposition to Alzheimer's disease on later-life cognitive decline. DESIGN SETTING AND PARTICIPANTS: This prospective cohort study included 891 adults of European ancestry, aged 40 to 65, who were without dementia and had complete healthy-lifestyle and cognition data during the follow-up. Participants joined the Wisconsin Registry for Alzheimer's Prevention (WRAP) beginning in 2001. We conducted replication analyses using a subsample with similar baseline age range from the Health and Retirement Study (HRS). EXPOSURES: We assessed participants' exposures using a continuous non-APOE polygenic risk score for Alzheimer's, a binary indicator for APOE-ε4 carrier status, and a weighted healthy-lifestyle score, including factors such as no current smoking, regular physical activity, healthy diet, light to moderate alcohol consumption, and frequent cognitive activities. MAIN OUTCOMES AND MEASURES: We z-standardized cognitive scores for global (Preclinical Alzheimer's Cognitive Composite score 3 - PACC3) and domain-specific assessments (delayed recall and immediate learning). RESULTS: We followed 891 individuals for up to 10 years (mean [SD] baseline age, 58 [6] years, 31% male, 38% APOE-ε4 carriers). After false discovery rate (FDR) correction, we found statistically significant PRS × lifestyle × age interactions on preclinical cognitive decline but the evidence is stronger among APOE-ε4 carriers. Among APOE-ε4 carriers, PRS-related differences in overall and memory-related domains between people scoring 0-1 and 4-5 regarding healthy lifestyles became evident around age 67 after FDR correction. These findings were robust across several sensitivity analyses and were replicated in the population-based HRS. CONCLUSION: A favorable lifestyle can mitigate the genetic risk associated with current known non-APOE genetic variants for longitudinal cognitive decline, and these protective effects are particularly pronounced among APOE-ε4 carriers.

The Effect of Distance Education on Self-care in Patients With Heart Failure in the Chronic or Stable Phase: A Systematic Review and Meta-analysis.

BACKGROUND: Health education is important for self-care in patients with heart failure. However, the evidence for the effect of distance education as an intervention to deliver instruction for patients after discharge through digital devices on self-care is limited. OBJECTIVES: In this study, our aim was to explore the effect of distance education on self-care in patients with heart failure. METHODS: We searched 11 electronic databases and 3 trial registries for randomized controlled trials with low risk of bias and high-quality evidence to compare the effect of usual and distance education on self-care. Quality appraisal was performed using the Cochrane Risk of Bias Tool. Using the Review Manager 5.4 tool, a meta-analysis was conducted. Certainty of the evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). RESULTS: Fifteen articles were eligible for this study. Compared with usual education, distance education improved self-care maintenance (mean difference [MD], 6.62; 95% confidence interval [CI], 3.93-9.31; GRADE, moderate quality), self-care management (MD, 5.10; 95% CI, 3.25-6.95; GRADE, high quality), self-care confidence (MD, 6.66; 95% CI, 4.82-8.49; GRADE, high quality), heart failure knowledge (MD, 0.78; 95% CI, 0.01-1.56; GRADE, moderate quality), and quality of life (MD, -5.35; 95% CI, -8.73 to -1.97; GRADE, moderate quality). Subgroup analysis revealed distance education was more effective than usual education in self-care when the intervention was conducted for 1 to 6 months, more than 3 times per month, and a single intervention lasting more than 30 minutes. CONCLUSIONS: This review shows the benefits of distance education on self-care, heart failure knowledge, and quality of life of patients with heart failure. The intervention duration, frequency, and duration of a single intervention could have affected the intervention effect.

Apolipoprotein E moderates the association between non-APOE polygenic risk score for Alzheimer's disease and aging on preclinical cognitive function.

INTRODUCTION: Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer's disease (eg, a non-APOE polygenic risk score [PRS]) may interact with the APOE ε4 allele to influence cognitive decline. METHODS: We tested the PRS × APOE ε4 × age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer's Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1190 individuals. RESULTS: We found statistically significant PRS × APOE ε4 × age interactions on immediate learning (P = 0.038), delayed recall (P < 0.001), and Preclinical Alzheimer's Cognitive Composite 3 score (P = 0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE ε4 emerge around age 70, with a much stronger adverse PRS effect among APOE ε4 carriers. The findings were replicated in a population-based cohort. DISCUSSIONS: APOE ε4 can modify the association between PRS and cognition decline. HIGHLIGHTS: APOE ε4 can modify the association between polygenic risk scores (PRSs) and longitudinal cognition decline, with the modifying effects more pronounced when the PRS is constructed using a conservative P threshold (eg, P < 5e-8 ). The adverse genetic effect caused by the combined effect of the currently known genetic variants is more detrimental among APOE Îµ4 carriers around age 70. Individuals who are APOE Îµ4 carriers with high PRSs are the most vulnerable to the harmful effects caused by genetic burden.

Apolipoprotein E moderates the association between Non-APOE Polygenic Risk Score for Alzheimer's Disease and Aging on Preclinical Cognitive Function.

INTRODUCTION: Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer's disease (e.g., a non-APOE polygenic risk scores [PRS]) may interact with the APOE ε4 allele to influence cognitive decline. METHODS: We tested the PRS×APOE ε4×age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer's Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1,190 individuals. RESULTS: We found statistically significant PRS×APOE ε4×age interactions on immediate learning (P=0.038), delayed recall (P<0.001), and Preclinical Alzheimer's Cognitive Composite 3 score (P=0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE ε4 emerge around age 70, with a much stronger adverse PRS effect among APOE ε4 carriers. The findings were replicated in a population-based cohort. DISCUSSION: APOE ε4 can modify the association between PRS and cognition decline.

Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals.

BACKGROUND: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. OBJECTIVE: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. METHODS: PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. RESULTS: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-ß, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. CONCLUSION: In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-ß, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-ß and tau, long before the onset of clinical symptoms.

Effect of Pathway-specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-related Biomarkers among Asymptomatic Individuals.

Background: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. Objective: In this study, we leveraged 10 years of longitudinal data from initially cognitively unimpaired individuals in the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. Methods: PRS and p-PRSs with and without apolipoprotein E ( APOE ) were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and global/domain-specific cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers for beta-amyloid 42 (Aß42), Aß42/40 ratio, total tau, and phosphorylated tau in a subset. Replication analyses were performed in an independent sample. Results: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of p-PRSs/PRS on rate of change in cognition, beta-amyloid, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. Conclusion: In addition to APOE , the p-PRSs can predict age-dependent changes in beta-amyloid, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating beta-amyloid and tau, long before the onset of clinical symptoms.

Impedance Iterative Learning Backstepping Control for Output-Constrained Multisection Continuum Arms Based on PMA.

BACKGROUND: Pneumatic muscle actuator (PMA) actuated multisection continuum arms are widely applied in various fields with high flexibility and bionic properties. Nonetheless, their kinematic modeling and control strategy proves to be extremely challenging tasks. METHODS: The relationship expression between the deformation parameters and the length of PMA with the geometric method is obtained under the assumption of piecewise constant curvature. Then, the kinematic model is established based on the improved D-H method. Considering the limitation of PMA telescopic length, an impedance iterative learning backstepping control strategy is investigated. For one thing, the impedance control is utilized to ensure that the ideal static balance force is maintained constant in the Cartesian space. For another, the iterative learning backstepping control is applied to guarantee that the desired trajectory of each PMA can be accurately tracked with the output-constrained requirement. Moreover, iterative learning control (ILC) is implemented to dynamically estimate the unknown model parameters and the precondition of zero initial error in ILC is released by the trajectory reconstruction. To further ensure the constraint requirement of the PMA tracking error, a log-type barrier Lyapunov function is employed in the backstepping control, whose convergence is demonstrated by the composite energy function. RESULTS: The tracking error of PMA converges to 0.004 m and does not exceed the time-varying constraint function through cosimulation. CONCLUSION: From the cosimulation results, the superiority and validity of the proposed theory are verified.

Study on the Modeling and Compensation Method of Pose Error Analysis for the Fracture Reduction Robot.

BACKGROUND: In the process of fracture reduction, there are some errors between the actual trajectory and the ideal trajectory due to mechanism errors, which would affect the smooth operation of fracture reduction. To this end, based on self-developed parallel mechanism fracture reduction robot (FRR), a novel method to reduce the pose errors of FRR is proposed. METHODS: Firstly, this paper analyzed the pose errors, and built the model of the robot pose errors. Secondly, mechanism errors of FRR were converted into drive bar parameter's errors, and the influence of each drive bar parameter on the robot pose error were analyzed. Thirdly, combining with Cauchy opposition-based learning and differential evolution algorithm (DE), an improved whale optimization algorithm (CRLWOA-DE) is proposed to compensate the end-effector's pose errors, which could improve the speed and accuracy of fracture reduction, respectively. RESULTS: The iterative accuracy of CRLWOA-DE is improved by 50.74%, and the optimization speed is improved by 22.62% compared with the whale optimization algorithm (WOA). Meanwhile, compared with particle swarm optimization (PSO) and ant colony optimization (ACO), CRLWOA-DE is proved to be more accurate. Furthermore, SimMechanics in the software of MATLAB was used to reconstruct the fracture reduction robot, and it was verified that the actual motion trajectory of the CRLWOA-DE optimized kinematic stage showed a significant reduction in error in both the x-axis and z-axis directions compared to the desired motion trajectory. CONCLUSIONS: This study revealed that the error compensation in FRR reset process had been realized, and the CRLWOA-DE method could be used for reducing the pose error of the fracture reduction robot, which has some significance for the bone fracture and deformity correction.

N-Butylidenephthalide Inhibits the Phenotypic Switch of VSMCs through Activation of AMPK and Prevents Stenosis in an Arteriovenous Fistula Rat Model.

The phenotypic switch of vascular smooth muscle cells (VSMCs) plays a pivotal role in the development of vascular disorders, such as atherosclerosis, stenosis and restenosis, after vascular intervention. In our previous study, n-butylidenephthalide (BP) was reported to have anti-proliferating and apoptotic effects on VSMCs. The purpose of the current study is to further investigate its role in platelet-derived growth factor (PDGF)-induced VSMC phenotypic modulation in an arteriovenous fistula model. In vitro, we observed that BP inhibited the PDGF-induced cytoskeleton reorganization of the VSMCs. The enhanced expression of vimentin and collagen, as well as the migration ability induced by PDGF, were also inhibited by BP. By cell cycle analysis, we found that BP inhibited the PDGF-induced VSMCs proliferation and arrested the VSMCs in the G0/G1 phase. In an arteriovenous fistula rat model, the formation of stenosis, which was coupled with a thrombus, and the expression of vimentin and collagen in VSMCs, were also inhibited by administration of BP, indicating that BP inhibited the PDGF-induced phenotypic switch and the migration of VSMCs. Besides, the inhibitory effects of BP on the phenotypic switch were found to accompany the activated 5' AMP-activated protein kinase (AMPK) as well as the inhibited phosphorylation of mTOR. Knockdown of AMPK by gene silencing conflicted the effects of BP and further exacerbated the PDGF-induced VSMCs phenotypic switch, confirming the modulating effect that BP exerted on the VSMCs by this pathway. These findings suggest that BP may contribute to the vasculoprotective potential in vasculature.