Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.

Members of the KMT2C/D-KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation.

Cardiovascular magnetic resonance-estimated pulmonary capillary wedge pressure, congestion markers, and effect of empagliflozin in patients with heart failure with reduced ejection fraction and dysglycaemia (SUGAR-DM-HF).

Aims: A cardiovascular magnetic resonance (CMR) approach to non-invasively estimate left ventricular (LV) filling pressure was recently developed and shown to correlate with invasively measured pulmonary capillary wedge pressure (PCWP). We examined the association between CMR-estimated PCWP (CMR-PCWP) and other imaging and biomarker measures of congestion, and the effect of empagliflozin on these, in the SUGAR-DM-HF trial (NCT03485092).

Methods And Results: SUGAR-DM-HF enrolled 105 patients with heart failure with reduced ejection fraction (HFrEF) and pre-diabetes or type 2 diabetes who were randomly assigned to empagliflozin 10 mg or placebo once daily for 36 weeks.

Topographic changes in macula and its association with visual outcomes in idiopathic epiretinal membrane surgery.

Purpose: We investigated changes in macular topography and their association with visual acuity and metamorphopsia in the idiopathic epiretinal membrane (iERM).

Methods: Twenty-four eyes that underwent vitrectomy and ERM removal with internal limiting membrane peeling were included in this study. Best-corrected visual acuity (BCVA) and horizontal/vertical metamorphopsia scores (h and vM-scores in the M-chart) were assessed.

Neither Bone Marrow Aspirate Concentrate nor Platelet-Rich Plasma Improves Patient-Reported Outcomes After Surgical Management of Acetabular Labral Tears; However, Bone Marrow Aspirate Concentrate May Be Effective for Moderate Cartilage Damage: A Systematic Review.

Purpose: To (1) systematically assess which orthobiologic agents are being used in acetabular labral repairs and (2) report all available outcomes for patients undergoing operative management for labral repairs with orthobiologic agents.

Methods: The PubMed, Embase, and Cochrane databases were queried in August 2023. Articles were included if they used an orthobiologic agent during hip arthroscopy for acetabular labral repair and reported functional outcomes.

A Novel method for quantifying fluctuations in wearable derived daily cardiovascular parameters across the menstrual cycle.

Currently, knowledge of changes in cardiovascular function across the menstrual cycle and how these changes may inform upon underlying health is limited. Utilizing wrist-worn biometric data we developed a novel measure to quantify and investigate the cardiovascular fluctuation (i.e.

Design and Optimization of Isothermal Gene Amplification for Generation of High-Gain Oligonucleotide Products by MicroRNAs.

Thermal cycling-based quantitative polymerase chain reaction (qPCR) represents the gold standard method for accurate and sensitive nucleic acid quantification in laboratory settings. However, its reliance on costly thermal cyclers limits the implementation of this technique for rapid point-of-care (POC) diagnostics. To address this, isothermal amplification techniques such as rolling circle amplification (RCA) have been developed, offering a simpler alternative that can operate without the need for sophisticated instrumentation.

Reversal of chirality in solutions and aggregates of chiral tetrachlorinated diperylene diimides towards efficient circularly polarized light detection.

Helicenes exhibit promise as active layer materials for circularly polarized light (CPL) detectors due to their strong chiroptical activity. However, their practical application is limited by the complicated synthesis and loosely solid-state packing. This study introduces a chiral induction strategy towards the synthesis of helicene derivatives, chiral tetrachlorinated diperylene diimides (()-4CldiPDI or ()-4CldiPDI).

mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting.

We investigated mRNA vaccines encoding a membrane-anchored receptor-binding domain (RBD), each a fusion of a variant RBD, the transmembrane (TM) and cytoplasmic tail fragments of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In naive mice, RBD-TM mRNA vaccines against SARS-CoV-2 variants induced strong humoral responses against the target RBD. Multiplex surrogate viral neutralization (sVNT) assays revealed broad neutralizing activity against a range of variant RBDs.

Independent SAGE as an example of effective public dialogue on scientific research.

The World Health Organization declared COVID-19 to be a public health emergency of international concern on 30 January 2020 and then a pandemic on 11 March 2020. In early 2020, a group of UK scientists volunteered to provide the public with up-to-date and transparent scientific information. The group formed the Independent Scientific Advisory Group for Emergencies (Independent SAGE) and provided live weekly briefings to the public via YouTube.

scTrends: A living review of commercial single-cell and spatial 'omic technologies.

Understanding the rapidly evolving landscape of single-cell and spatial omic technologies is crucial for advancing biomedical research and drug development. We provide a living review of both mature and emerging commercial platforms, highlighting key methodologies and trends shaping the field. This review spans from foundational single-cell technologies such as microfluidics and plate-based methods to newer approaches like combinatorial indexing; on the spatial side, we consider next-generation sequencing and imaging-based spatial transcriptomics.

Elevated Donor-Derived Cell-Free DNA Levels Are Associated With Reduced Myocardial Blood Flow but Not Angiographic Cardiac Allograft Vasculopathy: The EVIDENT Study.

Background: Cardiac allograft vasculopathy (CAV) leads to impaired myocardial blood flow (MBF), increasing the risk of cardiovascular death or retransplant among heart transplantation (HT) recipients. Data on elevation in donor-derived cell-free DNA (dd-cfDNA) and CAV in the absence of rejection are mixed. We sought to test the hypothesis that CAV with reduced MBF (RMBF) is associated with elevated dd-cfDNA.

Quantum game strategy solution for R&D cartel: Reorganizing government R&D investment strategy in Korea.

This study reevaluates criticism of the Korean government's R&D investment strategy, which was considered an 'R&D cartel' and was cited as a reason for the Korean government's R&D cuts in 2023, through an advanced framework of quantum game theory. By modeling the interaction between the government and researchers as a quantum information strategy game, it redefines the dynamics of R&D investment as a quantum game involving two key players: the R&D manager (Alice) and the research performer (Bob). This quantum game, akin to the Prisoner's Dilemma but focused on responsibility and sincerity, allows for the exploration of strategic complexities and decision-making dynamics not possible in classical models.

BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis.

Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation in multiple sclerosis (MS) but has not been addressed therapeutically. Bruton's tyrosine kinase (BTK) is expressed in both B-lymphocytes and innate immune cells, including microglia, where its role is poorly understood. BTK inhibition may provide therapeutic benefit within the CNS by targeting adaptive and innate immunity-mediated disease progression in MS.

Nationwide, Couple-Based Genetic Carrier Screening.

Background: Genomic sequencing technology allows for identification of reproductive couples with an increased chance, as compared with that in the general population, of having a child with an autosomal recessive or X-linked genetic condition.

Methods: We investigated the feasibility, acceptability, and outcomes of a nationwide, couple-based genetic carrier screening program in Australia as part of the Mackenzie's Mission project. Health care providers offered screening to persons before pregnancy or early in pregnancy.

Routine Spironolactone in Acute Myocardial Infarction.

Background: Mineralocorticoid receptor antagonists have been shown to reduce mortality in patients after myocardial infarction with congestive heart failure. Whether routine use of spironolactone is beneficial after myocardial infarction is uncertain.

Methods: In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients with myocardial infarction who had undergone percutaneous coronary intervention to receive either spironolactone or placebo and either colchicine or placebo.

Circulating tumor DNA status and dynamics predict recurrence in patients with resected extrahepatic cholangiocarcinoma.

Background & Aims: Surgery is the only curative therapeutic option for resectable extrahepatic cholangiocarcinoma, but recurrence is common, and prognosis is poor. There is an unmet clinical need for improved decision-making regarding adjuvant chemotherapy (ACT). Herein, we evaluated the usefulness of monitoring longitudinal circulating tumor DNA (ctDNA) for molecular residual disease (MRD) in patients from the STAMP trial, which compares the efficacy of adjuvant capecitabine (CAP) vs.

Colorectal Cancer Screening Completion and Yield in Patients Aged 45 to 50 Years : An Observational Study.

Background: Guidelines now recommend initiating colorectal cancer (CRC) screening at age 45 years rather than 50 years, but little is known about screening completion and yield among people aged 45 to 49 years.

Objective: To evaluate fecal immunochemical test (FIT) completion and yield in patients aged 45 to 49 versus 50 years.

Design: Retrospective cohort study.

The relative data hungriness of unpenalized and penalized logistic regression and ensemble-based machine learning methods: the case of calibration.

Background: Machine learning methods are increasingly being used to predict clinical outcomes. Optimism is the difference in model performance between derivation and validation samples. The term "data hungriness" refers to the sample size needed for a modelling technique to generate a prediction model with minimal optimism.

A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease.

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences.

Optimizing Corticosteroid Sinonasal Irrigation Outcomes Through 3D Printing: A Randomized Pilot Clinical Trial.

Objective: Topical corticosteroid irrigation plays critical role in the management of chronic rhinosinusitis (CRS). Yet, its efficacy can be highly variable. We sought to determine if personalized, 3-dimensional (3D)-printed nasal models can optimize head positioning and irrigation parameters, therefore improving patient outcomes.