Haloperidol dopamine receptor occupancy and antagonism correspond to delirium agitation scores and EPS risk: A PBPK-PD modeling analysis.

Background: Delirium is a severe neuropsychiatric disorder associated with increased morbidity and mortality. Numerous precipitating factors and etiologies merge into the pathophysiology of this condition which can be marked by agitation and psychosis. Judicious use of antipsychotic medications such as intravenous haloperidol reduces these symptoms and distress in critically ill individuals.

Early noninvasive ventilation in general wards for acute respiratory failure: an international, multicentre, open-label, randomised trial.

Background: The impact of noninvasive ventilation (NIV) managed outside the intensive care unit in patients with early acute respiratory failure remains unclear. We aimed to determine whether adding early NIV prevents the progression to severe respiratory failure.

Methods: In this multinational, randomised, open-label controlled trial, adults with mild acute respiratory failure (arterial oxygen partial pressure/fraction of inspiratory oxygen [Pao/FiO] ratio ≥200) were enrolled across 11 hospitals in Italy, Greece, and Kazakhstan.

Effect of providing at-home opioid disposal kits at discharge after an orthopaedic surgery.

Prescription opioids after surgery may pose a risk if left unused. However, prescribers rely on their best judgement in determining how much their patients need, often resulting in over-prescription of these medications. Opioid disposal is a strategy to reduce the risk of persistent use or misuse of opioids.

Basic Science and Pathogenesis.

Background: Several viruses have been linked to Alzheimer disease (AD) by independent lines of evidence.

Method: Whole genome and whole exome sequences (WGS/WES) derived from brain (3,404 AD cases, 894 controls) and blood (15,612 AD cases, 24,544 controls) obtained from European ancestry (EU), African American (AA), Mexican (HMX), South Asian Indian (IND), and Caribbean Hispanic (CH) participants of the Alzheimer's Disease Sequencing Project (ADSP) and 276 AD cases 3,584 controls (all EU) from the Framingham Heart Study (FHS) that did not align to the human reference genome were aligned to viral reference genomes. A genome-wide association study (GWAS) for viral DNA load was conducted using PLINK software and regression models with covariates for sex, age, ancestry principal components, and tissue source.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) in Alzheimer's disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.

Method: We conducted a meta-analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.

Basic Science and Pathogenesis.

Background: The Apolipoprotein E ε4 (APOE-ε4) allele is common in the population, but acts as the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Despite the strength of the association, there is notable heterogeneity in the population including a strong modifying effect of genetic ancestry, with the APOE-ε4 allele showing a stronger association among individuals of European ancestry (EUR) compared to individuals of African ancestry (AFR). Given this heterogeneity, we sought to identify genetic modifiers of APOE-ε4 related to cognitive decline leveraging APOE-ε4 stratified and interaction genome-wide association analyses (GWAS).

Basic Science and Pathogenesis.

Background: Recent studies suggest genome-wide-association-studies (GWAS) loci confer their effects on microglia in late-onset Alzheimer's disease (LOAD) brains. Relatively fewer studies have investigated the effects of other genome-wide significant loci (p<5e) using human neurons.

Method: GWAS itself cannot directly identify causal variant-(effector)gene-pairs as GWAS only reports the sentinel variant at a given locus.

Basic Science and Pathogenesis.

Background: Alcohol Use Disorder (AUD) affects over 15 million individuals in the United States, contributing to oxidative stress, neuroinflammation, and elevating the risk of neurodegeneration. Despite this, the connection between AUD and aging conditions, particularly Alzheimer's disease (AD), remains unclear. AD, with a heritability of 60-80%, is genetically linked, necessitating an exploration of the molecular implications of AUD and genetic susceptibility to AD.

Basic Science and Pathogenesis.

Background: In this introductory talk, we embark on a journey of through the genomic frontiers of Alzheimer's research via the revolutionary Alzheimer's Disease Sequencing Project (ADSP).

Method: ADSP integrates together various components that collectively unravel the intricate genetic landscape of Alzheimer's disease with the ultimate goal of advancing precision medicine for the millions affected globally by this devastating disease. With a goal of sequencing and analyzing up to 150,000 complete genomes and associated clinical and functional data in the next five years, ADSP has amassed an unprecedented wealth of genomic data from diverse populations, providing a comprehensive and holistic understanding of the genetic underpinnings of Alzheimer's disease.

Basic Science and Pathogenesis.

Background: The H1/H2 haplotype on 17q21.31 represent the foremost genetic factor contributing to the risk of progressive supranuclear palsy (PSP). Various structural forms of 17q21.

Basic Science and Pathogenesis.

Background: Age is the largest risk factor for late-onset Alzheimer's Disease (LOAD). Although >80 genetic loci have been associated with LOAD, little is known about the age dependencies of these associations except the APOE region.

Method: We performed cross-ancestry and ancestry-specific genome-wide gene-age interaction and age-stratified association study using TOPMed-imputed genome-wide association study (GWAS) data from Alzheimer's Disease Genetics Consortium (ADGC) including 34,833 non-Hispanic Whites (NHW), 7,264 African Americans (AA), 3,232 East Asians (EA), and 2,024 Caribbean Hispanics (CH) aged 60 years and older.

Basic Science and Pathogenesis.

Background: "SuperAgers" are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle-aged and older adults.

Basic Science and Pathogenesis.

Background: Recent advances in Alzheimer's Disease (AD) research have emphasized the importance of recruiting from diverse populations. Notably, African-descent individuals have an almost doubled risk of developing AD compared to European-descent individuals. Transcriptome-wide association studies (TWAS) have advanced the analysis of non-coding variants by integrating gene expression with GWAS data.

Basic Science and Pathogenesis.

Background: NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer's disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer's Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Alzheimer's Disease Sequencing Project (ADSP), and the Genome Center for Alzheimer's Disease (GCAD) allow NIAGADS to lead the effort in managing large AD datasets that can be easily accessed and fully utilized by the research community.

Method: NIAGADS is supported by the National Institute on Aging (NIA) under a cooperative agreement.

Basic Science and Pathogenesis.

Background: Recent genetic studies have implicated >70 genomic loci associated with the risk for Alzheimer's Disease. However, the underlying functional mechanisms remain unclear. Several functional genomics (FG) methods such as chromosome conformation (CC) capture technologies and expression quantitative trait loci (eQTLs) have been developed to study the genetic targets.

Basic Science and Pathogenesis.

Background: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify genetic variation contributing to the development or protection of Alzheimer's disease (AD) in diverse ancestral populations. The latest ADSP whole genome sequencing (WGS) data release includes over 36,000 individuals from 37 datasets (NIAGADS NG00067.v11 ADSP R4).

Basic Science and Pathogenesis.

Background: NIAGADS is a national data repository that offers qualified investigators access to genomic data for Alzheimer's disease (AD) and related dementia. In addition, NIAGADS has made substantial effort to curate, harmonize, standardize, and disseminate AD-relevant variant, gene, and sequence annotations from publications, functional genomics datasets, and summary statistics deposited at NIAGADS. These results are made available to the public in a collection of interactive knowledgebases (AD Variant Portal, FILER Functional Genomics Repository, VariXam, Alzheimer's GenomicsDB & Genome Browser), all of which are accessible programmatically via the NIAGADS API.

Basic Science and Pathogenesis.

Background: To gain a deeper understanding of underlying molecular mechanisms in genomic regions associated with Alzheimer's disease (AD), the National Institute on Aging (NIA) launched the Alzheimer's Disease Sequencing Project (ADSP) Functional Genomics Consortium (FunGen-AD) in 2021.

Method: The first effort of this collaboration, coordinated by the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), aggregated functional genomics (FG) data from 5 cohorts, including ∼3,000 samples of European (EA) and African ancestries (AA). We used this data to map Quantitative Trait Loci (xQTL) on AD-specific human tissues and cells, providing insights into how non-coding genetic variants contribute to AD risk.

Basic Science and Pathogenesis.

Background: The ADSP is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD). Initial phases (Discovery and Discovery Extension) were predominantly non-Hispanic Whites of European Ancestry (NHW-EA). The ADSP expanded the population diversity in the Follow Up Study (ADSP-FUS), and the current phase, ADSP-FUS 2.

Basic Science and Pathogenesis.

Background: Studies of the genetics of Alzheimer's disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, much of the disease heritability has yet to be uncovered, suggesting that other forms of genetic variation promote substantial portions of genetic risk. Uncovering the genetic basis of AD can lead to new disease biomarkers and delineate disease mechanisms.

Basic Science and Pathogenesis.

Background: The prevalence of dementia in India is approximately 7.4% among those aged 60 years and older, yet little is known about genetic risk factors for dementia in this population. Examining genetic variants at higher frequency in India than other ancestries (i.

Clinical Manifestations.

Background: Passively-obtained smartphone digital phenotypes may yield objective estimates of everyday cognition in older adults compared to traditional cognitive/self-report measures typically confounded by sociodemographics. However, it is currently unknown what covariates are relevant when interpreting smartphone sensor data. We aimed to clarify which intrinsic and extrinsic factors are associated with digital phenotyping versus traditional cognitive measures in a cohort of older adults.

Clinical Manifestations.

Background: Intraindividual variability (IIV) on neuropsychological task performance has demonstrated enhanced sensitivity to neuropathological decline compared to mean performance. It is currently unknown whether increased IIV in everyday behaviors may also lend added sensitivity to detect early subtle changes seen in pre-clinical ADRD.

Methods: In a pilot smartphone digital phenotyping study, 34 participants (M = 71.

ATLAS-seq: a microfluidic single-cell TCR screen for antigen-reactive TCRs.

Discovering antigen-reactive T cell receptors (TCRs) is central to developing effective engineered T cell immunotherapies. However, the conventional technologies for isolating antigen-reactive TCRs (i.e.