Genetic and Cellular Architecture of Breast Cancer Risk in Multi-Ancestry Studies of 159,297 Cases and 212,102 Controls.

Breast cancer genome-wide association studies (GWAS) have identified over 200 independent genome-wide significant susceptibility markers. However, most studies have focused on one or two ancestral groups. We examined breast cancer genetic architecture using GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR) and Hispanic/Latina (H/L) samples, totaling 159,297 cases and 212,102 controls, comprising the largest multi-ancestry study of breast cancer to date.

Unraveling the Genetic Link Between Endocrine Hormones and Psychiatric Disorders: An Atlas of Genetic Correlations.

Background/objectives: Endocrine hormones play critical roles in regulating physiological processes, and previous studies have reported their associations with psychiatric disorders. Levels of endocrine hormones and the risk of developing psychiatric disorders are influenced by both genetic and non-genetic factors. However, the shared genetic basis underlying these associations remains largely unexplored.

Genetic and Nongenetic Risk Factors for Breast Cancer Risk Estimation.

Importance: Most breast cancers in Africa are diagnosed at advanced stages. Improved risk prediction tools to optimize screening and earlier diagnosis are urgently needed.

Objective: To build a comprehensive breast cancer risk estimation model by integrating a polygenic risk score (PRS), pathogenic variants (PVs) in high- or moderate-penetrance genes, and a questionnaire-based risk calculator.

Prehospital Cricothyrotomy: A Narrative Review of Technical, Educational, and Operational Considerations for Procedure Optimization.

Background: Definitive airway management is a requisite skill in the prehospital setting, most often accomplished with either an endotracheal tube or supraglottic airway. When clinicians encounter a cannot oxygenate and cannot ventilate scenario, a patient's airway still must be secured. Prehospital cricothyrotomy is a high acuity, low frequency procedure used to secure the airway through the anterior neck.

Characterization of DNA methylation clock algorithms applied to diverse tissue types.

Background: DNA methylation (DNAm) data from human samples has been leveraged to develop "epigenetic clock" algorithms that predict age and other aging-related phenotypes. Some DNAm clocks were trained using DNAm obtained from blood cells, while other clocks were trained using data from diverse tissue/cell types. To assess how DNAm clocks perform across non-blood tissue types, we applied DNAm algorithms to DNAm data generated from 9 different human tissue types.

The Causal Role of Thyroid Hormones in Bipolar Disorders: A Two-Sample Mendelian Randomization Study.

Introduction: Bipolar disorder is a complex psychiatric condition with distinctions between clinical subtypes including Type 1 and 2 disorders. Several studies have proposed that thyroid hormones may be involved in the aetiology of bipolar disorders.

Methods: This study employed a two-sample Mendelian randomization (MR) approach to investigate the causal relationships between six thyroid hormone metrics (TSH, FT4, FT3, TT3, FT3/FT4 and TT3/FT4) and bipolar disorder and Type 1 and 2 disorders, separately.

DNA methylation correlates of chronological age in diverse human tissue types.

Background: While the association of chronological age with DNA methylation (DNAm) in whole blood has been extensively studied, the tissue-specificity of age-related DNAm changes remains an active area of research. Studies investigating the association of age with DNAm in tissues such as brain, skin, immune cells, fat, and liver have identified tissue-specific and non-specific effects, thus, motivating additional studies of diverse human tissue and cell types.

Results: Here, we performed an epigenome-wide association study, leveraging DNAm data (Illumina EPIC array) from 961 tissue samples representing 9 tissue types (breast, lung, colon, ovary, prostate, skeletal muscle, testis, whole blood, and kidney) from the Genotype-Tissue Expression (GTEx) project.

Declination of Treatment, Racial and Ethnic Disparity, and Overall Survival in US Patients With Breast Cancer.

Importance: Declining treatment negatively affects health outcomes among patients with cancer. Limited research has investigated national trends of and factors associated with treatment declination or its association with overall survival (OS) among patients with breast cancer.

Objectives: To examine trends and racial and ethnic disparities in treatment declination and racial and ethnic OS differences stratified by treatment decision in US patients with breast cancer.

Increase in Hypofractionated Radiation Therapy Among Patients with Invasive Breast Cancer or Ductal Carcinoma In Situ: Who is Left Behind?

Purpose: We aimed to update the trend of hypofractionated whole-breast irradiation (HF-WBI) use over time in the US and examine factors associated with lack of HF-WBI adoption for patients with early-stage invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) undergoing a lumpectomy.

Methods And Materials: Among patients who underwent a lumpectomy, we identified 928,034 patients with early-stage IBC and 330,964 patients with DCIS in the 2004 to 2020 National Cancer Database. We defined HF-WBI as 2.

Expression- and splicing-based multi-tissue transcriptome-wide association studies identified multiple genes for breast cancer by estrogen-receptor status.

Background: Although several transcriptome-wide association studies (TWASs) have been performed to identify genes associated with overall breast cancer (BC) risk, only a few TWAS have explored the differences in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer. Additionally, these studies were based on gene expression prediction models trained primarily in breast tissue, and they did not account for alternative splicing of genes.

Methods: In this study, we utilized two approaches to perform multi-tissue TWASs of breast cancer by ER subtype: (1) an expression-based TWAS that combined TWAS signals for each gene across multiple tissues and (2) a splicing-based TWAS that combined TWAS signals of all excised introns for each gene across tissues.

The association of cigarette smoking with DNA methylation and gene expression in human tissue samples.

Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g.

Lateral Canthotomy Task Trainer in an Educational Small Group for Flight Providers.

Objective: Lateral canthotomy is a rare, emergent, vision-preserving procedure to treat orbital compartment syndrome. Using Ericsson's deliberate practice model, we aimed to develop a multimodal small group intervention including a modified low-fidelity task trainer to improve flight physician knowledge and technical competency for lateral canthotomy in the prehospital context.

Methods: Two cohorts of resident (postgraduate year 1) flight physicians received small group training during an all-day competency-based flight physician orientation.

Synonymous variants that disrupt messenger RNA structure are significantly constrained in the human population.

Background: The role of synonymous single-nucleotide variants in human health and disease is poorly understood, yet evidence suggests that this class of "silent" genetic variation plays multiple regulatory roles in both transcription and translation. One mechanism by which synonymous codons direct and modulate the translational process is through alteration of the elaborate structure formed by single-stranded mRNA molecules. While tools to computationally predict the effect of non-synonymous variants on protein structure are plentiful, analogous tools to systematically assess how synonymous variants might disrupt mRNA structure are lacking.