Design and Characterization of a Novel Intravitreal Dual-Transgene Genetic Medicine for Neovascular Retinopathies.

Purpose: Intravitreal delivery of therapeutic transgenes to the retina via engineered viral vectors can provide sustained local concentrations of therapeutic proteins and thus potentially reduce the treatment burden and improve long-term vision outcomes for patients with neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy.

Methods: We performed directed evolution in nonhuman primates (NHP) to invent an adeno-associated viral (AAV) variant (R100) with the capacity to cross vitreoretinal barriers and transduce all regions and layers of the retina following intravitreal injection. We then engineered 4D-150, an R100-based genetic medicine carrying 2 therapeutic transgenes: a codon-optimized sequence encoding aflibercept, a recombinant protein that inhibits VEGF-A, VEGF-B, and PlGF, and a microRNA sequence that inhibits expression of VEGF-C.

Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated.

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies.

BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.

Safety and Efficacy of Outpatient Drainless Abdominoplasty: A Single-Surgeon Experience of 454 Consecutive Patients.

Background: The incidence of seroma after abdominoplasty is accepted as approximately 10% (with a range) in the literature. Progressive tension sutures (PTS) have arisen as a means of reducing seroma, however there are conflicting data regarding their efficacy.

Objectives: The primary aim of this study was to describe the incidence of postabdominoplasty seroma in the setting of drainless abdominoplasty with PTS.

Centralizing prescreening data collection to inform data-driven approaches to clinical trial recruitment.

Background: Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources.

Tau Mediates Synergistic Influence of Vascular Risk and Aβ on Cognitive Decline.

Objective: Elevated vascular risk and beta-amyloid (Aβ) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aβ interaction on cognitive decline.

Methods: We included 175 cognitively unimpaired older adults (age 70.

Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality.

Background: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline.

Objectives: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.

Physical activity is associated with increased resting-state functional connectivity in networks predictive of cognitive decline in clinically unimpaired older adults.

Introduction: Physical activity (PA) promotes resilience with respect to cognitive decline, although the underlying mechanisms are not well understood. We examined the associations between objectively measured PA and resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) across seven anatomically distributed neural networks.

Methods: rs-fcMRI, amyloid beta (Aβ) positron emission tomography (PET), PA (steps/day × 1 week), and longitudinal cognitive (Preclinical Alzheimer's Cognitive Composite) data from 167 cognitively unimpaired adults (ages 63 to 90) were used.

Functional improvements to 6 months of physical activity are not related to changes in size or density of multiple lower-extremity muscles in mobility-limited older individuals.

Older adults are encouraged to engage in multicomponent physical activity, which includes aerobic and muscle-strengthening activities. The current work is an extension of the Vitality, Independence, and Vigor in the Elderly 2 (VIVE2) study - a 6-month multicenter, randomized, placebo-controlled trial of physical activity and nutritional supplementation in community dwelling 70-year-old seniors. Here, we examined whether the magnitude of changes in muscle size and quality differed between major lower-extremity muscle groups and related these changes to functional outcomes.

Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults.

Introduction: Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aβ), remains unclear.

Methods: We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aβ.

Oncolytic Vaccinia Virus Gene Modification and Cytokine Expression Effects on Tumor Infection, Immune Response, and Killing.

Oncolytic vaccinia viruses have promising efficacy and safety profiles in cancer therapy. Although antitumor activity can be increased by manipulating viral genes, the relative efficacy of individual modifications has been difficult to assess without side-by-side comparisons. This study sought to compare the initial antitumor activity after intravenous administration of five vaccinia virus variants of the same Western Reserve backbone and thymidine kinase gene deletion in RIP-Tag2 transgenic mice with spontaneous pancreatic neuroendocrine tumors.

Quantification of RPE Changes in Choroideremia Using a Photoshop-Based Method.

Purpose: To develop a reliable and efficient method for quantifying the area of preserved retinal pigment epithelium (RPE), facilitating the evaluation of disease progression or response to therapy in choroideremia (CHM).

Methods: The fundus autofluorescence images of CHM patients were captured at baseline and 1 year. A Photoshop-based method was developed to allow the reliable measurement of the RPE area.

Amyloid-beta burden predicts prospective decline in body mass index in clinically normal adults.

In the present study, we tested the hypothesis that higher amyloid-beta (Aβ) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aβ positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years.

Associations of Widowhood and β-Amyloid With Cognitive Decline in Cognitively Unimpaired Older Adults.

Importance: To reduce the rising incidence of clinical impairment due to Alzheimer disease, it is essential to define older adults at highest risk. Widowhood may be an unrecognized factor contributing to accelerated clinical progression along the Alzheimer disease pathway among cognitively unimpaired older adults.

Objective: To determine whether widowhood status and level of brain β-amyloid (ie, the Alzheimer disease pathologic protein) are additively or interactively associated with cognitive decline among cognitively unimpaired older adults.

Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE).

Associations of Physical Activity and β-Amyloid With Longitudinal Cognition and Neurodegeneration in Clinically Normal Older Adults.

Importance: In the absence of disease-modifying therapies for Alzheimer disease, there is a critical need to identify modifiable risk factors that may delay the progression of Alzheimer disease.

Objective: To examine whether physical activity moderates the association of β-amyloid (Aβ) burden with longitudinal cognitive decline and neurodegeneration in clinically normal individuals and to examine whether these associations are independent of vascular risk.

Design, Setting, And Participants: This longitudinal observational study included clinically normal participants from the Harvard Aging Brain Study.

Social Engagement and Amyloid-β-Related Cognitive Decline in Cognitively Normal Older Adults.

Objective: Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-β, the Alzheimer's disease (AD) pathologic marker.

Methods: Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC).

Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults.

Importance: Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.

Vascular Risk and β-Amyloid Are Synergistically Associated with Cortical Tau.

Objective: Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co-occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well-validated measure of systemic vascular risk and β-amyloid (Aβ) burden have an interactive association with regional tau burden.

The impact of amyloid-beta and tau on prospective cognitive decline in older individuals.

Objectives: Amyloid-beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated.

Methods: One hundred thirty-seven older individuals (age = 76.

Effect of exercise and nutritional supplementation on health-related quality of life and mood in older adults: the VIVE2 randomized controlled trial.

Background: Health-related quality of life (HRQoL) and absence of depressive symptoms are of great importance for older people, which may be achieved through lifestyle interventions, e.g., exercise and nutrition interventions.

Translating the Lifestyle Interventions and Independence for Elders Clinical Trial to Older Adults in a Real-World Community-Based Setting.

Background: The Lifestyle Interventions and Independence for Elders (LIFE) clinical trial demonstrated that a structured program of physical activity (PA) reduced mobility-disability in older adults by up to 28%. It remains unknown whether the benefits of LIFE PA can be translated to older adults at risk for mobility-disability in real-world community-based settings. To address this knowledge gap, we conducted the ENhancing independence using Group-based community interventions for healthy AGing in Elders (ENGAGE) pilot study and examined the safety, feasibility, and preliminary effectiveness of translating LIFE PA to a community-based senior center.

Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts.

Introduction: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid β (Aβ) burden and apolipoprotein E genotype.

Methods: We analyzed sex-specific effects on Aβ-positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite-5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755; clinical dementia rating = 0; age (standard deviation) = 73.6 (6.