Impact of population screening for Lynch syndrome insights from the All of Us data.

Lynch Syndrome (LS) is a common genetic cancer condition that allows for personalized cancer prevention and early cancer detection in identified gene carriers. We used data from the All of Us (AOU) Research Initiative to assess the prevalence of LS in the general U.S.

Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.

The 3-methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of inborn errors of metabolism defined biochemically by detectable elevation of 3-methylglutaconic acid (3-MGA) in the urine. In type 1 (or primary) 3-MGA-uria, distal defects in the leucine catabolism pathway directly cause this elevation. Secondary 3-MGA-uria syndromes, however, are unrelated to leucine metabolism-specific defects but share a common biochemical phenotype of elevated 3-MGA.

Itaconate drives pro-inflammatory responses through proteasomal degradation of GLO1.

Itaconate is a small-molecule metabolite generated by the enzyme aconitate decarboxylase 1 (ACOD1), which is upregulated during inflammation. Traditionally, itaconate has been recognized for its anti-inflammatory properties; however, this study reveals a pro-inflammatory mechanism of itaconate in macrophages. We demonstrate that itaconate promotes the proteasomal degradation of glyoxalase 1 (GLO1) via Cys139.

Hepatic Arterial Infusion Pump Complication With Multimodal Radiologic and Anatomic Review.

Hepatic arterial infusion therapy involves surgically implanting a subcutaneous hepatic arterial infusion pump with the catheter tip at the hepatic artery. This pump directly delivers chemotherapy to the liver, which may reduce systemic toxicity, improve resectability, and treat unresectable hepatic lesions. This therapy is used in primary or metastatic hepatic malignancies.

Biophysical and biochemical evidence for the role of acetate kinases (AckAs) in an acetogenic pathway in pathogenic spirochetes.

Unraveling the metabolism of Treponema pallidum is a key component to understanding the pathogenesis of the human disease that it causes, syphilis. For decades, it was assumed that glucose was the sole carbon/energy source for this parasitic spirochete. But the lack of citric-acid-cycle enzymes suggested that alternative sources could be utilized, especially in microaerophilic host environments where glycolysis should not be robust.

Atrial Fibrillation and Retinal Stroke.

Importance: Atrial fibrillation (AF) is the most common, chronic, cardiac arrythmia in older US adults. It is not known whether AF is independently associated with increased risk of retinal stroke (central retinal artery occlusion), a subtype of ischemic stroke that causes severely disabling visual loss in most cases and is a harbinger of further vascular events.

Objective: To determine whether there is an association between AF and retinal stroke.

Registry versus claims-based index dates for studies of cancer diagnosis in administrative data.

Purpose: Studies of healthcare encounters leading to cancer diagnosis have increased over recent years. While some studies examine healthcare utilization before the cancer registry date of diagnosis, relevant pre-diagnosis interactions are not always immediately prior to this date due to date abstraction guidelines. We evaluated agreement of a registry date with a claims-based index and examined Emergency Department (ED) involvement in cancer diagnosis as an example of possible pre-diagnostic healthcare misclassification that could arise from improper date choice.

Randomized Controlled Trial to Compare AmnioExcel Human Amniotic Allograft in Weekly Versus Biweekly Treatment of Diabetic Foot Ulcers.

Our objective was to compare clinical outcomes in diabetic foot ulcers (DFU) treated with AmnioExcel applied weekly (AMX1) or biweekly (AMX2) over a 12-week evaluation period. This randomized clinical trial evaluated 40 people with UT 1A and 1D DFUs >30 days but less than 6 months duration and age >21 years. We excluded patients with untreated osteomyelitis, gangrene, widespread malignancy, or active substance abuse.

Comparison of Associations of Food Security Instruments and Mediators With Premature All-Cause and Cardiovascular Disease Death in US Adults.

Background: Food insecurity is associated with high morbidity and mortality and is typically measured with the 10-item US Adult Food Security Survey Module. Shorter instruments may capture similar information, but this has not been validated against mortality in general populations.

Methods: A nationally representative sample of individuals aged 20 to 74 years from the US National Health Interview Survey 2011 to 2018 was included, with deaths linked to the National Death Index through 2019.

Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II.

The Rpd3S histone deacetylase complex has a crucial role in genomic integrity by deacetylating transcribed nucleosomes following RNA polymerase (Pol) II passage. Cryo-EM studies highlight the importance of asymmetrical Rco1-Eaf3 dimers in nucleosome binding, yet the interaction dynamics with nucleosomal substrates alongside elongating Pol II are poorly understood. Here we demonstrate the essential function of the Rco1 N-terminal intrinsically disordered region (IDR) in modulating Pol II association, in which K/R mutations within the Rco1 IDR impair interaction of Rpd3S with the C-terminal domain (CTD) of Rpb1, without affecting nucleosome recognition or complex integrity.

Mortality of gastrointestinal cancers attributable to smoking, alcohol, and metabolic risk factors, and its association with socioeconomic development status 2000-2021: GI Cancer Mortality and Risk Factors.

Objective: Gastrointestinal (GI) cancers account for one-third of global cancer mortality, with nearly half being preventable. This study updates the global burden of GI cancers attributed to major risk factors: smoking, alcohol, and metabolic disturbances.

Methods: We utilized data from the Global Burden of Disease Study 2021 to examine trends in death and age-standardized death rates related to GI cancers caused by smoking, alcohol, high body mass index (BMI), and high fasting blood glucose (FBG) from 2000 to 2021.

Recommended Elements of a Musculoskeletal Course for Fourth-Year Medical Students: A Modified Delphi Consensus.

Background And Objectives: A recognized gap exists between primary care physicians' training in musculoskeletal (MSK) medicine and the burden of MSK complaints in primary care. Family medicine interns often lack adequate baseline MSK physical exam skills, which prompted a proposal to introduce a fourth-year preceptorship to reinforce MSK education. The aim of this study was to prioritize the most important elements to include in this new clinical rotation.

Evaluating the Exposome Score for Schizophrenia in a Transdiagnostic Psychosis Cohort: Associations With Psychosis Risk, Symptom Severity, and Personality Traits.

Background: Investigations of causal pathways for psychosis can be guided by the identification of environmental risk factors. A recently developed composite risk tool, the exposome score for schizophrenia (ES-SCZ), which controls for intercorrelations between risk factors, has shown fair to good performance. We tested the transdiagnostic psychosis classifier performance of the ES-SCZ with the Bipolar-Schizophrenia Network for Intermedial Phenotypes data and examined its relationship with clinical-level outcomes.

Midface Degloving Approach for Total Maxillectomy Without Orbital Exenteration: A Case Series.

Objective: Evaluate the feasibility of the midface degloving approach (MDA) in total maxillectomy without orbital exenteration (TMWOE) and reconstruction for sino-nasal neoplasms.

Study Design: Retrospective case series.

Setting: Tertiary referral center.

Local and systemic biodistribution of a small-molecule radiopharmaceutical probe after transcatheter embolization and intra-arterial delivery in a porcine orthotopic renal tumor model.

Background: Small-molecule biomacromolecules target tumor-specific antigens. They are employed as theranostic agents for imaging and treatment. Intravenous small-molecule radioligands exhibit rapid tumor uptake and excretion.

Circulating immune biomarkers correlating with response in patients with metastatic renal cell carcinoma on immunotherapy.

As multiple front-line immune checkpoint inhibitor (ICI)-based combinations are approved for metastatic renal cell carcinoma, biomarkers predicting for ICI responses are needed past clinical prognostication scores and transcriptome gene expression profiling. Circulating markers represent opportunities to assess baseline and dynamic changes in immune cell frequency and cytokine levels while on treatment. We conducted an exploratory prospective correlative study of 33 patients with metastatic clear cell renal cell carcinoma undergoing treatment with ICIs and correlated changes in circulating immune cell subsets and cytokines with clinical responses to treatment.

Learning from Hindsight: Examining Autonomic, Inflammatory, and Endocrine Stress Biomarkers and Mental Health in Healthy Terrorism Survivors Many Years Later.

Introduction: Terrorism and trauma survivors often experience changes in biomarkers of autonomic, inflammatory and hypothalamic-pituitary-adrenal (HPA) axis assessed at various times. Research suggests interactions of these systems in chronic stress.

Study Objective: This unprecedented retrospective study explores long-term stress biomarkers in three systems in terrorism survivors.

VCP regulates early tau seed amplification via specific cofactors.

Background: Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. Seeding into the complex cytoplasmic milieu happens within hours, implying the existence of unknown factors that regulate this process.

Methods: We used proximity labeling to identify proteins that control seed amplification within 5 h of seed exposure.

A Phosphatidyl Conjugated Telomerase-Dependent Telomere-Targeting Nucleoside Demonstrates Colorectal Cancer Direct Killing and Immune Signaling.

Telomerase and telomeres are crucial in cancer cell immortalization, making them key targets for anticancer therapies. Currently, 6-thio-dG (THIO) combined with the anti-PD-1 inhibitor Cemiplimab is under phase II clinical investigation (NCT05208944) in NSCLC patients resistant to prior immunotherapies. This study presents the design, synthesis, and evaluation of novel bimodular conjugate molecules combining telomere-targeting nucleoside analogs and phosphatidyl diglyceride groups.

The Proteomics of T-Cell and Early T-Cell Precursor (ETP) Acute Lymphocytic Leukemia: Prognostic Patterns in Adult and Pediatric-ETP ALL.

Background: The 5-year overall survival (OS) rates of T-cell lymphocytic leukemia (T-ALL) are better for children (>90%) compared to adults (~57%). The early T-cell precursor (ETP) T-ALL subtype is prognostically unfavorable in adults, but less significant in pediatric T-ALL, and the diagnosis and prognosis of "near"-ETP is controversial. We compared protein and RNA expression patterns in pediatric and adult T-ALL to identify prognostic subgroups, and to further characterize ETP and near-ETP T-ALL in both age groups.

Increasing the acquisition speed in oblique plane microscopy via Aliasing.

Oblique plane microcopy (OPM), a variant of light-sheet fluorescence microscopy (LSFM), enables rapid volumetric imaging without mechanically scanning the sample or an objective. In an OPM, the sample space is mapped to a distortion free image space via remote focusing, and the oblique light-sheet plane is mapped via a tilted tertiary imaging system onto a camera. As a result, the 3D point-spread function and optical transfer function are tilted to the optical axis of the tertiary imaging system.

Genetically Labeled Premyelinating Oligodendrocytes: Bridging Oligodendrogenesis and Neuronal Activity.

To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs). PreOLs are thought to survey and begin ensheathing nearby axons, and their maturation is often stalled at human demyelinating lesions. Lack of genetic tools to visualize and manipulate preOLs has left this critical differentiation stage woefully understudied.

Tacrolimus to belatacept conversion in proteinuric kidney transplant recipients.

Background: Proteinuria is associated with worse allograft outcomes in kidney transplant recipients (KTRs) and treatment strategies are limited. We examined the outcomes of calcineurin inhibitor (CNI) to belatacept conversion in proteinuric KTRs.

Methods: In a pilot phase II single-arm multicenter prospective trial, we recruited adult KTRs >6 months post-kidney transplantation with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.