Pupil Abnormality Frequency in the First 72 Hours Improves IMPACT score in Traumatic Brain Injury.

Importance: In patients with traumatic brain injury (TBI), baseline pupillary assessment is common. However, the incidence and frequency of pupil abnormalities within the first several days remain poorly characterized.

Objectives: Our aim was to test the association between pupil abnormality frequency over the first 72 hours of admission and clinical outcomes.

Accounting for genetic effect heterogeneity in fine-mapping and improving power to detect gene-environment interactions with SharePro.

Classical gene-by-environment interaction (GxE) analysis can be used to characterize genetic effect heterogeneity but has a high multiple testing burden in the context of genome-wide association studies (GWAS). We adapt a colocalization method, SharePro, to account for effect heterogeneity in fine-mapping and identify candidates for GxE analysis with reduced multiple testing burden. SharePro demonstrates improved power for both fine-mapping and GxE analysis compared to existing methods as well as well-controlled false type I error in simulations.

The Upper Limit of Normal Rate of Lung Function Decline in Healthy Adults in the Framingham Heart Study.

Background: Lung function declines over the course of adulthood; however, a consensus on the normal range of decline in an individual's lung function is lacking.

Research Question: What is the normal range and the upper limit of normal (ULN) decline in lung function in adults without prior tobacco use, occupational dust exposure, or a known diagnosis or symptoms of cardiopulmonary disease?

Study Design And Methods: A retrospective analysis of healthy individuals who have never smoked (N = 1,305) from the Framingham Heart Study with repeated lung function meeting standards for acceptability and reproducibility was conducted. Longitudinal change was derived using a linear mixed effects model and estimated to a 6-year interval.

Association of Dynamic Trajectories of Time-Series Data and Life-Threatening Mass Effect in Large Middle Cerebral Artery Stroke.

Background: Life-threatening, space-occupying mass effect due to cerebral edema and/or hemorrhagic transformation is an early complication of patients with middle cerebral artery stroke. Little is known about longitudinal trajectories of laboratory and vital signs leading up to radiographic and clinical deterioration related to this mass effect.

Methods: We curated a retrospective data set of 635 patients with large middle cerebral artery stroke totaling 95,463 data points for 10 longitudinal covariates and 40 time-independent covariates.

Association of large core middle cerebral artery stroke and hemorrhagic transformation with hospitalization outcomes.

Historically, investigators have not differentiated between patients with and without hemorrhagic transformation (HT) in large core ischemic stroke at risk for life-threatening mass effect (LTME) from cerebral edema. Our objective was to determine whether LTME occurs faster in those with HT compared to those without. We conducted a two-center retrospective study of patients with ≥ 1/2 MCA territory infarct between 2006 and 2021.

SharePro: an accurate and efficient genetic colocalization method accounting for multiple causal signals.

Motivation: Colocalization analysis is commonly used to assess whether two or more traits share the same genetic signals identified in genome-wide association studies (GWAS), and is important for prioritizing targets for functional follow-up of GWAS results. Existing colocalization methods can have suboptimal performance when there are multiple causal variants in one genomic locus.

Results: We propose SharePro to extend the COLOC framework for colocalization analysis.

Exploiting meta-analysis of genome-wide interaction with serum 25-hydroxyvitamin D to identify novel genetic loci associated with pulmonary function.

Background: Higher 25-hydroxyvitamin D (25(OH)D) concentrations in serum has a positive association with pulmonary function. Investigating genome-wide interactions with 25(OH)D may reveal new biological insights into pulmonary function.

Objectives: We aimed to identify novel genetic variants associated with pulmonary function by accounting for 25(OH)D interactions.

Genetically Predicted Body Mass Index and Mortality in Chronic Obstructive Pulmonary Disease.

Body mass index (BMI) is associated with chronic obstructive pulmonary disease (COPD) mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate the causal mechanisms and predict risk. To examine the associations of genetically predicted BMI with all-cause and cause-specific mortality in COPD.

Follow-up ASPECTS improves prediction of potentially lethal malignant edema in patients with large middle cerebral artery stroke.

Background: Recent studies have shown that follow-up head CT is a strong predictor of functional outcomes in patients with middle cerebral artery stroke and mechanical thrombectomy. We sought to determine whether total and/or regional follow-up Alberta Stroke Program Early CT Score (ASPECTS) are associated with important clinical outcomes during hospitalization and improve the performance of clinical prediction models of potentially lethal malignant edema (PLME).

Methods: We conducted a retrospective study of patients at three medical centers in a major North American metropolitan area with baseline and follow-up head CTs after large middle cerebral artery stroke between 2006 and 2022.

Bik promotes proteasomal degradation to control low-grade inflammation.

Although chronic low-grade inflammation does not cause immediate clinical symptoms, over the longer term, it can enhance other insults or age-dependent damage to organ systems and thereby contribute to age-related disorders, such as respiratory disorders, heart disease, metabolic disorders, autoimmunity, and cancer. However, the molecular mechanisms governing low-level inflammation are largely unknown. We discovered that Bcl-2-interacting killer (Bik) deficiency causes low-level inflammation even at baseline and the development of spontaneous emphysema in female but not male mice.

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

Background: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV) <80% predicted and FEV/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities.

Dynamic trajectories of life-threatening mass effect in patients with large middle cerebral artery stroke.

Background: Life-threatening, space-occupying mass effect due to cerebral edema and/or hemorrhagic transformation is an early complication of patients with middle cerebral artery () stroke. Little is known about longitudinal trajectories of laboratory and vital signs leading up to radiographic and clinical deterioration related to this mass effect.

Methods: We curated a granular retrospective dataset of 635 patients with large middle cerebral artery () stroke totaling 108,547 data points for repeated measurements of 10 covariates, and 40 time-independent covariates.

Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP).

Background: Prior studies using the ADSP data examined variants within presenilin-2 (PSEN2), presenilin-1 (PSEN1), and amyloid precursor protein (APP) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer's Disease Sequencing Project (ADSP).

Objective: To characterize previously-reported clinically-relevant variants and DM variants in PSEN2, PSEN1, APP within the participants from the ADSP.

Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer's disease at CPT1A locus.

Background: Insulin resistance (IR) is a major risk factor for Alzheimer's disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD.