Drug Development.

Background: Availability of amyloid modifying therapies will dramatically increase the need for disclosure of Alzheimer's disease (AD) related genetic and/or biomarker test results. The 21st Century Cares Act requires the immediate return of most medical test results, including AD biomarkers. A shortage of genetic counselors and dementia specialists already exists, thus driving the need for scalable methods to responsibly communicate test results.

Drug Development.

Background: To help improve the Alzheimer's disease (AD) therapeutics research and development process, the Critical Path for Alzheimer's Disease (CPAD) Consortium at the Critical Path Institute (C-Path) provides a neutral framework for the drug development industry, regulatory agencies, academia, and patient advocacy organizations to collaborate. CPAD's extensive track record of developing regulatory-grade quantitative drug development tools motivates sponsors to share patient-level data and neuroimages from clinical trials. CPAD leverages these data and uses C-Path's core competencies in data management and standardization, quantitative modeling, and regulatory science to develop tools that help de-risk decision making in AD drug development.

Drug Development.

Background: Randomized placebo-controlled trials (RCTs) are the gold standard to evaluate efficacy of new drug treatments for Alzheimer's disease. For example, the United States FDA approved the brain amyloid-targeting drug lecanemab following CLARITY AD, Biogen and Eisai's Phase 3 RCT. However, recruiting enough participants for a high-powered and demographically representative trial is difficult and expensive.

Drug Development.

Background: There are no approved oral disease-modifying treatments for Alzheimer disease (AD). This study was intended to assess efficacy and safety of blarcamesine (ANAVEX2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) designed to exert neuroprotection through restoration of cellular homeostasis including autophagy enhancement.

Method: ANAVEX2-73-AD-004 is a multicenter (52 medical research centers/hospitals in 5 countries), randomized, double-blind, placebo-controlled, 48-week phase 2b/3 trial that enrolled 508 participants with early AD (mild cognitive impairment/mild dementia) from July 2018 to June 2021 (last patient visit in June 2022).

Dementia Care Research and Psychosocial Factors.

Background: Prior research shows that caregiving for people living with dementia (PLWD) varies with cultural, institutional, and social structural context, but less is known about the role of context in dementias of different etiologies. We compared experiences of caregiving in frontal-temporal dementia (FTD) versus non-FTD dementias using community-based comparative ethnography. We expected to find differences in caring for people living with FTD (PLWFTD) versus people living with other dementias (PLWOD).

Dementia Care Research and Psychosocial Factors.

Background: A potential mechanism underpinning the cognitive benefits from physical activity and aerobic exercise is cardiorespiratory fitness (CRF). Greater cardiorespiratory fitness (CRF) was associated with better executive function, short-term memory, and global cognition in older adults without cognitive impairment. Sex differences in CRF has been established in adults.

Dementia Care Research and Psychosocial Factors.

Background: Subjective cognitive decline (SCD) represents an important therapeutic target to prevent future cognitive decline associated with aging as well as neurodegenerative diseases such as Alzheimer's disease. One such therapy is the "dual-task" exergaming with concurrent aerobic exercise (AEx) and cognitive training. The primary aim of this Stage IB randomized controlled trial (RCT) was to test the preliminary effects of a dual-task exergaming telerehabilitation intervention on cognition and aerobic fitness, in comparison to AEx only and attention control (stretching) in older adults with SCD METHOD: This RCT randomized 39 participants on a 2:1:1 allocation ratio to supervised exergame (Figure 1) (n = 20), AEx (n = 11), and stretching (n = 8), 3 times a week for 12 weeks.

Dementia Care Research and Psychosocial Factors.

Background: With the advent of FDA approved anti-amyloid therapy and recognition of increased side effects in APOE e4 carriers, APOE testing is now recommended for patients considering anti-amyloid therapies such as lecanemab. Given the therapeutic implications and anticipated volume of eligible patients, the traditional model of in-person, pre- and post-test genetic counseling is not feasible to incorporate in clinical pathways. Alternative delivery models, including digital tools and telehealth, will be key in providing APOE genetic counseling support.

Dementia Care Research and Psychosocial Factors.

Background: A large body of research supports the benefits of older adults engaging in physical activity outdoors. However, a paucity of research explores factors associated with the frequency of older adults going outdoors. The aim of this study was to explore how factors including cognition, neighborhood characteristics, and physical ability were associated with community-dwelling older adults' outdoor frequency.

Dementia Care Practice.

Background: In the United States, Latino older adults are 1.5x more likely to develop Alzheimer's disease than non-Latino White older adults. Latino Family Caregivers (LFC) maintain home care for longer periods of time but use formal care less.

Dementia Care Practice.

Introduction: Patient-reported outcomes are increasingly being utilized in clinical settings to identify psychological symptoms and track fluctuations over time. Some clinicians and researchers have expressed concerns about the validity of symptom questionnaires cognitively impaired populations. We sought to determine if differential item functioning (DIF) is present based on cognitive impairment using the patient reported outcomes measurement information system (PROMIS) inventories of anxiety and depression.

COMT and MTHFR Genetic Variants Combined Effects on Adolescent Idiopathic Scoliosis Progression.

Genetic variants encoding both low COMT and MTHFR activity are associated with idiopathic scoliosis. The combined impact of and on progression of adolescent idiopathic scoliosis (AIS) is unknown. This study investigated if and low activity variants are associated with AIS progression.

Is endometriosis typology a potentially better classification system for assessing risk of female infertility?

Objective: To determine whether endometriosis typology, namely ovarian endometriomas (OE), deep infiltrating endometriosis (DIE), or superficial endometriosis (SE), correlates with fertility history.

Design: Prospective cohort.

Setting: One of fourteen surgical centers in Salt Lake City, Utah (n = 5) or San Francisco, California (n = 9).

Moderators of interdependent psychological distress in cancer survivor-caregiver dyads.

Background: The purpose of this study was to test dyadic interdependence in psychological distress (anxiety and depressive symptoms) and explore moderators of interdependence among cancer survivors in treatment and their informal caregivers.

Methods: Cancer survivors and their caregivers completed measures of anxiety and depressive symptoms, social support, social isolation, and burden of other symptoms, at three points in time over the course of 17 weeks.

Results: In 315 dyads, depressive symptoms and anxiety were transmitted from caregivers to survivors.

Measuring trends in extinction risk: a review of two decades of development and application of the Red List Index.

The Red List Index (RLI) is an indicator of the average extinction risk of groups of species and reflects trends in this through time. It is calculated from the number of species in each category on the IUCN Red List of Threatened Species, with trends influenced by the number moving between categories when reassessed owing to genuine improvement or deterioration in status. The global RLI is aggregated across multiple taxonomic groups and can be disaggregated to show trends for subsets of species (e.

Integrating genetic algorithms and language models for enhanced enzyme design.

Enzymes are molecular machines optimized by nature to allow otherwise impossible chemical processes to occur. Their design is a challenging task due to the complexity of the protein space and the intricate relationships between sequence, structure, and function. Recently, large language models (LLMs) have emerged as powerful tools for modeling and analyzing biological sequences, but their application to protein design is limited by the high cardinality of the protein space.

Associations Between Walking Pace, APOE-ε4 Genotype, and Brain Health in Middle-Aged to Older Adults.

Poor physical function and possession of the e4 allele of the apolipoprotein E (APOE) gene are each associated with increased dementia risk, but it is unclear how these exposures interact to influence brain health. Purpose: To investigate whether self-reported walking pace (a marker of physical function) and the presence of APOE-ε4 allele interact to modify brain health outcomes. Methods: We used data from a prospective cohort study of middle-aged to older adults from the UK Biobank who self-reported walking pace (slow or steady-to-brisk), and who were initially free of dementia (n = 415,110).

Identifying clusters of raters with a common notion of diagnosing erosive tooth wear: a step towards improving the accuracy of diagnostic procedures.

Background: Heterogeneous results are to be expected when multiple raters diagnose whether the dentine of a tooth with erosive tooth wear (ETW) is exposed or not. Identification of notions (fundamental concepts and understanding) about the diagnostic problem shared by groups of raters can be helpful to develop guidelines and to optimize teaching and calibration procedures. We aim to illustrate how clusters of raters with a common notion can be identified and how first insights about the notions can be obtained.

evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease.

Background: Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes.

Carboplatin in combination with etoposide for advanced small cell lung cancer complicated with idiopathic interstitial pneumonia: a single-arm phase II study.

Background: Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP).

One-quarter of freshwater fauna threatened with extinction.

Freshwater ecosystems are highly biodiverse and important for livelihoods and economic development, but are under substantial stress. To date, comprehensive global assessments of extinction risk have not included any speciose groups primarily living in freshwaters. Consequently, data from predominantly terrestrial tetrapods are used to guide environmental policy and conservation prioritization, whereas recent proposals for target setting in freshwaters use abiotic factors.

The sequence-structure-function relationship of intrinsic ERα disorder.

The oestrogen receptor (ER or ERα), a nuclear hormone receptor that drives most breast cancer, is commonly activated by phosphorylation at serine 118 within its intrinsically disordered N-terminal transactivation domain. Although this modification enables oestrogen-independent ER function, its mechanism has remained unclear despite ongoing clinical trials of kinase inhibitors targeting this region. By integration of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy with functional studies, we show that serine 118 phosphorylation triggers an unexpected expansion of the disordered domain and disrupts specific hydrophobic clustering between two aromatic-rich regions.

Small variant benchmark from a complete assembly of X and Y chromosomes.

The sex chromosomes contain complex, important genes impacting medical phenotypes, but differ from the autosomes in their ploidy and large repetitive regions. To enable technology developers along with research and clinical laboratories to evaluate variant detection on male sex chromosomes X and Y, we create a small variant benchmark set with 111,725 variants for the Genome in a Bottle HG002 reference material. We develop an active evaluation approach to demonstrate the benchmark set reliably identifies errors in challenging genomic regions and across short and long read callsets.

Pilot Testing Digital Stories to Influence College Men's Intentions to Vaccinate Against HPV.

College men are among those least likely to be vaccinated against the human papillomavirus (HPV). Viewing digital stories from other college men who were vaccinated against HPV as young adults may help influence them to seek the vaccine. Guided by the Theory of Planned Behavior, this research reports on the creation and pilot testing of digital stories to increase college men's intentions to vaccinate against HPV.