Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors.

Background: Microsatellite instability-high (MSI-high) tumors comprise ~15% of sporadic colorectal cancers (CRC) and are associated with elevated T cell infiltration. However, the universality of this response across T cell subtypes with distinct functions is unknown.

Methods: Including 1,236 CRC tumors from three observational studies, we conducted T cell profiling using a customized 9-plex (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT, MKI67, and DAPI) multispectral immunofluorescence assay.

Co-occurring Psychopathology in Children With and Without Autism Spectrum Disorder (ASD): Differences by Sex in the ECHO Cohorts.

Purpose: Our goals were to: 1) examine the occurrence of behavioral and emotional symptoms in children on the autism spectrum in a large national sample, stratifying by sex, and 2) evaluate whether children with increased autism-related social communication deficits also experience more behavioral and emotional problems.

Methods:  Participants (n = 7,998) were from 37 cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program. Cross-sectional information on demographic factors, parent-report of an ASD diagnosis by clinician, Social Responsiveness Scale (SRS) scores, and Child Behavior Checklist (CBCL) scores were obtained for children aged 2.

Assessing the Risk for Falls in Older Adults After Initiating Gabapentin Versus Duloxetine.

Background: The evidence informing the harms of gabapentin use are at risk of bias from comparing users with nonusers.

Objective: To describe the risk for fall-related outcomes in older adults starting treatment with gabapentin versus duloxetine.

Design: New user, active comparator study using a target trial emulation framework.

Prescribing Trends of Antidiabetes Medications Near End-of-Life Among Adults With Type 2 Diabetes: A Cohort Study.

Objective: To assess prescribing trends of antidiabetes medications in the last year of life among older adults with type 2 diabetes (T2D) and explore whether frailty is associated with differential prescribing.

Research Design And Methods: In this observational cohort study of Medicare beneficiaries aged ≥67 years (2015-2019) with T2D, we assessed temporal trends in prescribing an antidiabetes medication, stratified by frailty. The main outcome included antidiabetes medication fills within 1 year of death.

Rare germline structural variants increase risk for pediatric solid tumors.

Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and increased risk of solid tumors in male children.

Parkinson disease-associated toxic exposures selectively upregulate vesicular glutamate transporter vGlut2 in a model of human cortical neurons.

Parkinson disease (PD) is the second most common neurodegenerative disease, characterized by both motor and cognitive features. Motor symptoms primarily involve midbrain dopaminergic neurons, while cognitive dysfunction involves cortical neurons. Environmental factors are important contributors to PD risk.

Prospective pooled analyses of ambient ultraviolet radiation levels and risk of non-Hodgkin lymphoma and multiple myeloma.

Case-control studies of sun exposure and ultraviolet radiation (UVR) have consistently reported inverse associations with non-Hodgkin lymphoma (NHL) risk, but prospective studies have yielded mixed results. Few studies have explored these exposures in relation to multiple myeloma (MM) risk. To further evaluate these associations with NHL and MM risk and identify etiologically relevant exposure timing, we pooled data on 566,693 individuals from 6 United States (U.

Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.

Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions. Lissencephaly ('smooth brain') spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability.

miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthma.

Background: There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma.

Methods: We performed miRNAome-metabolome-wide association studies ('miR-metabo-WAS') in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (N = 312 and N = 454).

Automated chest CT three-dimensional quantification of body composition: adipose tissue and paravertebral muscle.

This retrospective study developed an automated algorithm for 3D segmentation of adipose tissue and paravertebral muscle on chest CT using artificial intelligence (AI) and assessed its feasibility. The study included patients from the Boston Lung Cancer Study (2000-2011). For adipose tissue quantification, 77 patients were included, while 245 were used for muscle quantification.

The Role of Endobronchial Ultrasound for Mediastinal Staging in Mesothelioma.

Background: Invasive mediastinal staging is a crucial component of the preoperative evaluation for potential surgical candidates with pleural mesothelioma (PM). Endobronchial ultrasound (EBUS) is less invasive than mediastinoscopy for staging; however, its accuracy in patients with PM remains undefined. We present our institutional experience with EBUS staging in patients with PM.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

Brain phosphoproteomic analysis identifies diabetes-related substrates in Alzheimer's disease pathology in older adults.

Introduction: Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD-related phosphoprotein in the human brain remains underexplored.

Introduction to the DETeCD-ADRD special issue.

This special issue contains multiple articles related to the DETeCD-ADRD guideline.

The T cell receptor sequence influences the likelihood of T cell memory formation.

The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells.

Causes of Death Following Coronary Revascularization in Patients with Diabetes.

Background: In patients with diabetes and multivessel coronary artery disease, percutaneous coronary intervention (PCI) has been associated with higher long-term cardiovascular mortality compared to coronary artery bypass grafting (CABG), but the specific causes of death are not well known. We aimed to determine the causes of death among patients with diabetes and multivessel disease undergoing coronary revascularization with PCI versus CABG.

Methods: We analyzed the centrally adjudicated causes of death of 1,900 participants in the FREEDOM trial.

Spotlight on YAP: Unlocking New Insights to Overcome the Barriers to Heart Regeneration.

This editorial refers to “Microtubules Sequester Acetylated YAP in the Cytoplasm and Inhibit Heart Regeneration” by Liu . and “YAP Overcomes Mechanical Barriers to Induce Mitotic Rounding and Adult Cardiomyocyte Division” by Morikawa

Urothelial carcinoma in situ with "early papillary formation" vs "lateral spread/shoulder lesion" of prior high-grade noninvasive papillary urothelial carcinoma: A survey of pathologist and urologist interpretations.

Objectives: Urothelial carcinoma in situ (CIS) with early papillary formation is terminology sometimes used to suggest incipient high-grade papillary urothelial carcinoma (PUC) but may lead to confusion between true CIS and lateral flat spread of PUC.

Methods: It remains unclear how pathologists and urologists interpret this scenario, so a survey was circulated to 68 pathologists (group 1 = 28 academic genitourinary pathologists; group 2 = 17 pathologists with a self-reported genitourinary focus; group 3 = 23 pathologists self-reported as not genitourinary specialists) and 32 urologists.

Results: Regarding atypical urothelial lesions that appear mainly flat but contain possible papillae, group 3 was more likely to label this as CIS compared with groups 1 and 2 (35% for group 3 vs 13% for groups 1 and 2), while groups 1 and 2 more often adopted another descriptive diagnosis, such as "CIS with early papillary features" (38% for groups 1 and 2 vs 13% for group 3).

FBG-driven simulation for virtual augmentation of fluoroscopic images during endovascular interventions.

Endovascular interventions are procedures designed to diagnose and treat vascular diseases, using catheters to navigate inside arteries and veins. Thanks to their minimal invasiveness, they offer many benefits, such as reduced pain and hospital stays, but also present many challenges for clinicians, as they require specialized training and heavy use of X-rays. This is particularly relevant when accessing (i.

Long-Term Cognitive Safety of Achieving Very Low LDL Cholesterol with Evolocumab.

Background: Concerns persist regarding the cognitive safety of achieving very low levels of low-density lipoprotein (LDL) cholesterol. Although short-term studies are reassuring, the long-term cognitive effects of sustained exposure to very low LDL cholesterol levels through combined proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition and statin therapy remain unknown.

Methods: This prospective study enrolled a subset of adults with atherosclerotic cardiovascular disease who had completed a neurocognitive substudy (EBBINGHAUS) of a placebo-controlled randomized trial of evolocumab (FOURIER) and were eligible for a long-term open-label extension.

Fine particulate matter and nonaccidental and cause-specific mortality: Do associations vary by exposure assessment method?

Background: There is considerable heterogeneity in fine particulate matter (PM)-mortality associations between studies, potentially due to differences in exposure assessment methods. Our aim was to evaluate associations of PM predicted from different models with nonaccidental and cause-specific mortality.

Methods: We followed 107,906 participants of the Nurses' Health Study cohort from 2001 to 2016.