Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.

Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study.

Development of a predictive model for loss of functional and cognitive abilities in long-term care home residents: a protocol.

Introduction: Long-term care (LTC) residents require extensive assistance with daily activities due to physical and cognitive impairments. Medical treatment for LTC residents, when not aligned with residents' wishes, can cause discomfort without providing substantial benefits. Predictive models can equip providers with tools to guide treatment recommendations that support person-centred medical decision-making.

Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation.

Objective: There is renewed interest in targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) for treatment of obesity and type 2 diabetes. G-protein coupled receptor desensitisation is suggested to reduce the long-term efficacy of glucagon-like-peptide 1 receptor (GLP-1R) agonists and may similarly affect the efficacy of GIPR agonists. We explored the extent of pancreatic GIPR functional desensitisation with sustained agonist exposure.

A National Survey of Caregiver Needs and Experiences When Attending the Emergency Department.

Objectives: Despite being a frequent entry point of care, it remains unknown if families' needs are being met across pediatric emergency departments (PEDs). Study objectives were to describe caregivers' perceived overall PED experience and needs and to what extent these needs were met.

Methods: This descriptive, cross-sectional survey with medical record review was conducted in 10 Canadian PEDs.

Biomarkers.

Background: Brain MRI segmentation is required for quantitative PET analysis, in order to derive regional uptake and calculate uptake ratio relative to reference regions. FreeSurfer has been a popular method but is being supplanted by faster and more robust AI-driven methods. The objective of this work is to confirm that the use of Clario's novel AI segmentation method, whose impact was assessed towards various MRI endpoints, is also valid in the context of PET quantification.

Biomarkers.

Background: Data-driven disease progression models of Alzheimer's disease (AD) have identified subtypes in regional patterns of Aβ deposition using amyloid PET. In addition to Aβ accumulation, early frame measures of tracer delivery from amyloid PET are strongly correlated with blood flow. This work explores whether combining tracer delivery with amyloid binding measures can improve the subtype and stage characterisation over amyloid binding alone.

Biomarkers.

Background: With an aging population, it is essential to identify subtle features of brain pathology - both neurodegenerative and vascular - at an early stage, which may predict risk of future decline. We used diffusion MRI (dMRI) to assess grey matter cortical microstructure and investigate associations with 1) Alzheimer's disease (AD) pathology and 2) mid/late-life vascular risk (as measured by blood pressure (BP)).

Method: 151 asymptomatic individuals from the British 1946 birth cohort underwent combined PET/MR with [18F]florbetapir Aβ-PET at ∼73yrs, and [18F]MK-6240 tau-PET at ∼76yrs.

Biomarkers.

Background: Retinal structure and microvasculature may be used as a surrogate for parallel processes in the brain. Previous studies have revealed differences in retinal structure and microvasculature in patients with Parkinson's disease (PD) compared to cognitively normal controls[1]. Previous work developed a convolutional neural network (CNN) trained on multimodal retinal images that was able to identify Alzheimer's dementia with an area under the curve (AUC) of 0.

Biomarkers.

Background: Understanding when Aβ positive cognitively normal individuals develop tau pathology has important implications for treatment with anti-Aβ therapies. We employed a changepoint regression approach to estimate time from Aβ-PET positivity to regionally elevated tau-PET in a population-based cohort of primarily cognitively unimpaired individuals.

Method: Participants from Insight 46 (1946 British birth cohort) underwent two [F]florbetapir Aβ-PET scans and a sub-sample enriched for Aβ were also scanned with [F]MK-6240 tau-PET, characteristics are presented in Table 1.

Public Health.

Background: Social media may be a useful method for research centers to deliver health messaging, increase their visibility in the local community, and recruit study participants. There are, however, few studies evaluating the outcomes of social media in this setting. The objective of this study was to describe one Alzheimer's Disease Research Center's social media activities for community education on topics related to aging, memory loss, and dementia, and evaluate their impact on recruitment into clinical research studies.

Public Health.

Background: Dementia incidence is projected to significantly increase, posing unique challenges to healthcare systems. Identifying non-modifiable and modifiable risk factors (RF) is crucial, including sex-specific factors, given the higher prevalence among females (60%). Here, we employed a network analysis to examine prominent RF in healthy controls compared to those with cognitive decline (CD), as well as the interrelationships and interactions of RF on CD.

Biomarkers.

Background: Plasma amyloid-beta (Aβ) 42/40 ratio and phosphorylated tau 181 (pTau181) are promising blood biomarkers for AD. Compared to heterogenous clinical phenotypes, they are more objective and proximal to the pathological hallmarks of Aβ plaques and tau tangles. Biomarker-guided clustering using Aβ42/40 and pTau181 can potentially establish subpopulations that share similar mechanisms of AD and treatment responses.

Biomarkers.

Background: Recent research suggests that soluble pathogenic tau accumulates in the brain microvasculature of patients with Alzheimer's Disease (AD) and primary tauopathies, driving cerebrovascular impairments and further tau accumulation. However, little is known about the interplay of these processes before dementia onset. In the present study, we investigated the association between free water (FW), an early biomarker of cerebral small vessel disease, and tau accumulation in the rhinal, entorhinal, and inferotemporal cortices derived from PET imaging in middle-aged adults.

Biomarkers.

Background: Cerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ-PET.

Nurses' Journey Towards Recovery: Describing Suffering During the COVID-19 Pandemic to Present Day.

The nursing profession has been significantly affected by the COVID-19 pandemic, and nurses continue to suffer emotionally and psychologically. The purpose of this study was to describe the experiences of chronic and ongoing occupational psychological trauma nurses have endured during the COVID-19 pandemic to present day. Eight nurses were interviewed between November 2022 and April 2023.

Vaccine hesitancy or hesitancies? A latent class analysis of pediatric patients' parents.

Vaccine hesitancy is an attitude of indecision toward vaccination that is related to but not determinative of vaccination behaviors. Although theories of vaccine hesitancy emphasize it is often vaccine-specific, we do not know the extent to which this is true across sociodemographic groups. In this study, we asked: What latent classes of vaccine hesitancy might exist when examining parents' attitudes toward vaccines in general and COVID-19 and human papillomavirus (HPV) vaccination specifically? Which sociodemographic, health access, and health-related variables are predictive of membership in those classes? To answer those questions, we analyze online survey data from parents of pediatric patients recruited through eight clinics within the University of Arkansas for Medical Sciences Rural Research Network.

Alzheimer's Imaging Consortium.

Background: Data-driven disease progression models of Alzheimer's disease (AD) have identified subtypes in regional patterns of Aß deposition using amyloid PET. In addition to Aß accumulation, early frame measures of tracer delivery from amyloid PET are strongly correlated with blood flow. This work explores whether combining tracer delivery with amyloid binding measures can improve the subtype and stage characterisation over amyloid binding alone.

Alzheimer's Imaging Consortium.

Background: Brain MRI segmentation is required for quantitative PET analysis, in order to derive regional uptake and calculate uptake ratio relative to reference regions. FreeSurfer has been a popular method but is being supplanted by faster and more robust AI-driven methods. The objective of this work is to confirm that the use of Clario's novel AI segmentation method, whose impact was assessed towards various MRI endpoints, is also valid in the context of PET quantification.

Alzheimer's Imaging Consortium.

Background: Understanding when Aß positive cognitively normal individuals develop tau pathology has important implications for treatment with anti-Aß therapies. We employed a changepoint regression approach to estimate time from Aß-PET positivity to regionally elevated tau-PET in a population-based cohort of primarily cognitively unimpaired individuals.

Method: Participants from Insight 46 (1946 British birth cohort) underwent two [18F]florbetapir Aß-PET scans and a sub-sample enriched for Aß were also scanned with [18F]MK-6240 tau-PET, characteristics are presented in Table 1.

Alzheimer's Imaging Consortium.

Background: Cerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ-PET.

Drug Development.

Background: Genetic variants in GRN, the gene encoding progranulin, are causal for or are associated with the risk of multiple neurodegenerative diseases. Modulating progranulin has been considered as a therapeutic strategy for neurodegenerative diseases including Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD). Here, we integrated genetics with proteomic data to determine the causal human evidence for the therapeutic benefit of modulating progranulin in AD.

Indirect Detection of the Protons in and around Biradicals and their Mechanistic Role in MAS-DNP.

The contribution of protons in or near biradical polarizing agents in Dynamic Nuclear Polarization (DNP) has recently been under scrutiny. Results from selective deuteration and simulations have previously suggested that the role of protons in the biradical molecule depends on the strength of the electron-electron coupling. Here we use the cross effect DNP mechanism to identify and acquire H solid-state NMR spectra of the protons that contribute to propagation of the hyperpolarization, via an experimental approach dubbed Nuclear-Nuclear Double Resonance (NUDOR).

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.

Emergency and postoperative access to critical and enhanced care: a multicentre prospective observational study.

Introduction: The ability to admit patients to enhanced or critical care may be limited by bed availability. In a network with low provision of critical and enhanced care beds, we aimed to assess the proportion of patients having surgery with moderate (1%-< 5%) or high (≥ 5%) predicted risk of 30-day postoperative mortality and their postoperative care location. We also aimed to study referral and admission outcomes to critical care.