Maternal n-3 enriched diet reprograms neurovascular transcriptome and blunts inflammation in neonate.

Infection during perinatal period can adversely affect brain development, predispose infants to ischemic stroke and have lifelong consequences. We previously demonstrated that diet enriched in n-3 polyunsaturated fatty acids (PUFA) transforms brain lipid composition and protects from neonatal stroke. Vasculature is a critical interface between blood and brain providing a barrier to systemic infection. Here we examined whether maternal PUFA-enriched diets exert reprograming of endothelial cell signalling in 9-day old mice after endotoxin (LPS)-induced infection. Transcriptome analysis was performed on brain microvessels from pups born to dams maintained on 3 diets: standard, n-3 or n-6 enriched. N-3 diet enabled higher immune reactivity in brain vasculature, while preventing imbalance of cell cycle regulation and extracellular matrix cascades that accompanied inflammatory response in standard diet. LPS response in blood and brain was blunted in n-3 offspring. Cerebral angioarchitecture analysis revealed modified vessel complexity after LPS. Thus, n-3-enriched maternal diet partially prevents imbalance in homeostatic processes and alters inflammation rather than affects brain vascularization during early life. Importantly, maternal diet may presage offspring neurovascular outcomes later in life.

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease.

Introduction: The 5xFAD mouse is a popular model of familial Alzheimer's disease (AD) that is characterized by early beta-amyloid (Aß) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan. Methods: Male and female 5xFAD and wild type (WT) littermates underwent in vivo 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals, and vessel diameter. Results: With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan. Discussion: While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aß deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of motor and visual cortex and increased vessel length alongside decreased collaterals which coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aß deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

Construction of a lipid metabolism-related risk model for hepatocellular carcinoma by single cell and machine learning analysis.

One of the most common cancers is hepatocellular carcinoma (HCC). Numerous studies have shown the relationship between abnormal lipid metabolism-related genes (LMRGs) and malignancies. In most studies, the single LMRG was studied and has limited clinical application value. This study aims to develop a novel LMRG prognostic model for HCC patients and to study its utility for predictive, preventive, and personalized medicine. We used the single-cell RNA sequencing (scRNA-seq) dataset and TCGA dataset of HCC samples and discovered differentially expressed LMRGs between primary and metastatic HCC patients. By using the least absolute selection and shrinkage operator (LASSO) regression machine learning algorithm, we constructed a risk prognosis model with six LMRGs (AKR1C1, CYP27A1, CYP2C9, GLB1, HMGCS2, and PLPP1). The risk prognosis model was further validated in an external cohort of ICGC. We also constructed a nomogram that could accurately predict overall survival in HCC patients based on cancer status and LMRGs. Further investigation of the association between the LMRG model and somatic tumor mutational burden (TMB), tumor immune infiltration, and biological function was performed. We found that the most frequent somatic mutations in the LMRG high-risk group were CTNNB1, TTN, TP53, ALB, MUC16, and PCLO. Moreover, naïve CD8+ T cells, common myeloid progenitors, endothelial cells, granulocyte-monocyte progenitors, hematopoietic stem cells, M2 macrophages, and plasmacytoid dendritic cells were significantly correlated with the LMRG high-risk group. Finally, gene set enrichment analysis showed that RNA degradation, spliceosome, and lysosome pathways were associated with the LMRG high-risk group. For the first time, we used scRNA-seq and bulk RNA-seq to construct an LMRG-related risk score model, which may provide insights into more effective treatment strategies for predictive, preventive, and personalized medicine of HCC patients.

Progressive Vascular Abnormalities in the Aging 3xTg-AD Mouse Model of Alzheimer's Disease.

Vascular dysfunction and structural abnormalities in Alzheimer's disease (AD) are known to contribute to the progression of the pathology, and studies have tended to ignore the role of the vasculature in AD progression. We utilized the 3xTg-AD mouse model of AD to examine individual cerebral vessels and the cortical vascular network across the lifespan. Our vessel painting approach was used to label the entire cortical vasculature, followed by epifluorescence microscopy. The middle cerebral artery (MCA) tree was assessed with confocal microscopy, and a new method was developed to assess branching patterns as a measure of aging-related changes. We found that vascular remodeling was profoundly altered at 4-6 months of age, when the 3xTg-AD mouse is known to transition to cognitive impairment and Aß deposition in both sexes. Analysis of vascular features (density, junctions, length) of the MCA territory highlighted sex-dependent differences across the 3xTg-AD mouse lifespan, with no alterations in branching patterns. Our current cerebrovascular angioarchitectural analyses demonstrate progressive alterations in individual cortical vessels, as well as in the vascular network of the cortex. These new findings advance our understanding of brain anatomy and physiology in the 3xTg-AD mouse, while potentially identifying unique diagnostic signatures of AD progression.

Pilot Results of a Digital Hypertension Self-management Program Among Adults With Excess Body Weight: Single-Arm Nonrandomized Trial.

BACKGROUND: Home-measured blood pressure (HMBP) in combination with comprehensive medication support and lifestyle change are the mainstays of evidence-based hypertension (HTN) management. To date, the precise components needed for effective HTN self-management programs have yet to be defined, and access to multicomponent targeted support for HTN management that include telemonitoring remain inaccessible and costly. OBJECTIVE: The aim of this pilot study was to evaluate the impact of a digital HTN self-management program on blood pressure (BP) control among adults with excess body weight. METHODS: A single-arm, nonrandomized trial was performed to evaluate a digital HTN self-management program that combines comprehensive lifestyle counseling with HTN education, guided HMBP, support for taking medications, and led by either a registered nurse or certified diabetes care and education specialist. A sample of 151 participants were recruited using a web-based research platform (Achievement Studies, Evidation Health Inc). The primary outcome was change in systolic BP from baseline to 3 months, and secondary outcomes included change in diastolic BP and medication adherence. RESULTS: Participants' mean age was 44.0 (SD 9.3) years and mean BP was 139/85 mm Hg. At follow-up, systolic and diastolic BP decreased by 7 mm Hg (P<.001, 95% CI -9.3 to -4.7) and 4.7 mm Hg (P<.001, 95% CI -6.3 to -3.2), respectively. Participants who started with baseline BP at goal remained at goal. For participants with stage 1 HTN, systolic and diastolic BP decreased by 3.6 mm Hg (P=.09, 95% CI -7.8 to 0.6) and 2.5 mm Hg (P=.03, 95% CI -4.9 to -0.3). Systolic and diastolic BP decreased by 10.3 mm Hg (P<.001, 95% CI -13.4 to -7.1) and 6.5 mm Hg (P<.001, 95% CI -8.6 to -4.4), respectively, for participants with stage 2 HTN. Medication adherence significantly improved (P=.02). CONCLUSIONS: This pilot study provides initial evidence that a digital HTN self-management program improves BP and medication adherence.

Early Insights From a Digitally Enhanced Diabetes Self-Management Education and Support Program: Single-Arm Nonrandomized Trial.

BACKGROUND: Translation of diabetes self-management education and support (DSMES) into a digital format can improve access, but few digital programs have demonstrated outcomes using rigorous evaluation metrics. OBJECTIVE: The aim of this study was to evaluate the impact of a digital DSMES program on hemoglobin A1c (HbA1c) for people with type 2 diabetes. METHODS: A single-arm, nonrandomized trial was performed to evaluate a digital DSMES program that includes remote monitoring and lifestyle change, in addition to comprehensive diabetes education staffed by a diabetes specialist. A sample of 195 participants were recruited using an online research platform (Achievement Studies, Evidation Health Inc). The primary outcome was change in laboratory-tested HbA1c from baseline to 4 months, and secondary outcomes included change in lipids, diabetes distress, and medication adherence. RESULTS: At baseline, participants had a mean HbA1c of 8.9% (SD 1.9) and mean BMI of 37.5 kg/m2 (SD 8.3). The average age was 45.1 years (SD 8.9), 70% were women, and 67% were White. At 4-month follow up, the HbA1c decreased by 0.8% (P<.001, 95% CI -1.1 to -0.5) for the total population and decreased by 1.4% (P<.001, 95% CI -1.8 to -0.9) for those with an HbA1c of >9.0% at baseline. Diabetes distress and medication adherence were also significantly improved between baseline and follow up. CONCLUSIONS: This study provides early evidence that a digitally enhanced DSMES program improves HbA1c and disease self-management outcomes.

Considering whether Medicaid is worth the cost: revisiting the Oregon Health Study.

The Oregon Health Study was a groundbreaking experiment in which uninsured participants were randomized to either apply for Medicaid or stay with their current care. The study showed that Medicaid produced numerous important socioeconomic and health benefits but had no statistically significant impact on hypertension, hypercholesterolemia, or diabetes. Medicaid opponents interpreted the findings to mean that Medicaid is not a worthwhile investment. Medicaid proponents viewed the experiment as statistically underpowered and, irrespective of the laboratory values, suggestive that Medicaid is a good investment. We tested these competing claims and, using a sensitive joint test and statistical power analysis, confirmed that the Oregon Health Study did not improve laboratory values. However, we also found that Medicaid is a good value, with a cost of just $62 000 per quality-adjusted life-years gained.

Longitudinal Youth-At-Risk Study (LYRIKS): outreach strategies based on a community-engaged framework.

UNLABELLED: Schizophrenia and psychoses are debilitating disorders often leading to serious functional impairments. Early detection efforts have shifted focus to the prodromal phase and the emphasis is now on individuals at risk of developing psychosis. AIM: The Longitudinal Youth-At-Risk Study (LYRIKS) seeks to elucidate the biological markers of psychosis. This paper describes the application of a community-engaged framework to the outreach strategies of LYRIKS. It describes the outreach goals, strategies used and their impact, as well as the various challenges faced by the research team and community partners. METHODS: The target population was defined. Community organizations having close ties with the target population were identified and approached for collaboration. These included educational and healthcare institutions, and government and welfare organizations. Strategies were categorized as active or passive. Active strategies included clinical screening and recruitment, workshops, roadshows and student internships. Passive strategies included utilizing print and social media. RESULTS: Three thousand three hundred twenty-one youth were approached and 401 called the hotline to find out more about the study. Three thousand five hundred one were pre-screened; 864 were further screened using the Comprehensive Assessment of At Risk Mental State. One hundred seventy-eight and 346 were eventually recruited as subjects and controls, respectively. CONCLUSIONS: Challenges encountered included differing priorities, maintaining collaborative relationships, stigmatization and inadequate understanding of the profile of at risk youth. Future community-engaged research should be conducted more comprehensively to generate maximum benefits.