Discovery of (2,4)-4-(()-2-Amino-3-methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic Acid (AZD0011), an Actively Transported Prodrug of a Potent Arginase Inhibitor to Treat Cancer.

Arginase is a promising immuno-oncology target that can restore the innate immune response. However, it's highly polar active site often requires potent inhibitors to mimic amino acids, leading to poor passive permeability and low oral exposure. Using structure-based drug design, we discovered a novel proline-based arginase inhibitor () that was potent but had low oral bioavailability in rat.

Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors.

Arginase has long been a target of interest in immuno-oncology, but discovering an orally bioavailable inhibitor is severely constrained by the requisite boronic acid pharmacophore. We began our drug discovery campaign by building off the β-position of the literature inhibitor ABH (). A divergent synthesis with an Ireland-Claisen rearrangement as the key step allowed access to numerous compounds, some of which we crystallized in the active site of arginase 2.

Type-H endothelial cell protein Clec14a orchestrates osteoblast activity during trabecular bone formation and patterning.

Type-H capillary endothelial cells control bone formation during embryogenesis and postnatal growth but few signalling mechanisms underpinning this influence have been characterised. Here, we identify a highly expressed type-H endothelial cell protein, Clec14a, and explore its role in coordinating osteoblast activity. Expression of Clec14a and its ligand, Mmrn2 are high in murine type-H endothelial cells but absent from osteoblasts.

Tissue-resident memory T cells in epicardial adipose tissue comprise transcriptionally distinct subsets that are modulated in atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia and carries an increased risk of stroke and heart failure. Here we investigated how the immune infiltrate of human epicardial adipose tissue (EAT), which directly overlies the myocardium, contributes to AF. Flow cytometry analysis revealed an enrichment of tissue-resident memory T (T) cells in patients with AF.

Forever young: The end of history illusion in children.

The "end of history" illusion in adults (Quoidbach et al., 2013) is an asymmetrical pattern in which people accept that they've changed in the past but don't believe they will change in the future. We explore here whether the same psychological forces that cause the illusion in adults exist in the minds of children.

Mid-life sleep is associated with cognitive performance later in life in aging American Indians: data from the Strong Heart Study.

Background: Sleep-related disorders have been associated with cognitive decline and neurodegeneration. American Indians are at increased risk for dementia. Here, we aim to characterize, for the first time, the associations between sleep characteristics and subsequent cognitive performance in a sample of aging American Indians.

Learning to Trust Yourself: Decision-Making Skills Among Parents of Children With Medical Complexity.

Context: Children with medical complexity have substantial medical needs and their caregivers must make many challenging decisions about their care. Caregivers often become more involved in decisions over time, but it is unclear what skills they develop that facilitate this engagement.

Objectives: To describe the skills that caregivers developed as they gained experience making medical decisions.

Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss.

The existing suite of therapies for bone diseases largely act to prevent further bone loss but fail to stimulate healthy bone formation and repair. We describe an endogenous osteopeptide (PEPITEM) with anabolic osteogenic activity, regulating bone remodeling in health and disease. PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength.

Post-Activation Performance Enhancement of Punch Force and Neuromuscular Performance in Amateur Boxing: Toward a More Individualized and "Real-World" Approach.

Finlay, MJ, Greig, M, Bridge, CA, and Page, RM. Post-activation performance enhancement of punch force and neuromuscular performance in amateur boxing: Toward a more individualized and "real-world" approach. J Strength Cond Res 38(6): 1063-1071, 2024-Previous research on post-activation performance enhancement has been applied in several sporting settings, although this is lacking in a boxing setting.

The BLISTER Score: A Novel, Externally Validated Tool for Predicting Cardiac Implantable Electronic Device Infections, and Its Cost-Utility Implications for Antimicrobial Envelope Use.

Background: Antimicrobial envelopes reduce the incidence of cardiac implantable electronic device infections, but their cost restricts routine use in the United Kingdom. Risk scoring could help to identify which patients would most benefit from this technology.

Methods: A novel risk score (BLISTER [Blood results, Long procedure time, Immunosuppressed, Sixty years old (or younger), Type of procedure, Early re-intervention, Repeat procedure]) was derived from multivariate analysis of factors associated with cardiac implantable electronic device infection.

Feasibility of double-blinded, placebo-controlled interventional study for assessing catheter ablation efficacy in persistent atrial fibrillation: Insights from the ORBITA AF feasibility study.

Background: To date, there are no randomized, double-blinded clinical trials comparing catheter ablation to DC cardioversion (DCCV) with medical therapy in patients with persistent atrial fibrillation (PersAF). Conducting a large-scale trial to address this question presents considerable challenges, including recruitment, blinding, and implementation. We conducted a pilot study to evaluate the feasibility of conducting a definitive placebo-controlled trial.

ECGI targeted ablation for persistent AF not responding to pulmonary vein isolation: Results of a two-staged strategy (TARGET AF2).

Background: Mechanisms sustaining persistent atrial fibrillation (AF) remain unclear.

Objectives: The study sought to evaluate both the clinical outcomes and response to ablation of potential drivers in patients with recurrent persistent AF recurrence following pulmonary vein isolation (PVI).

Methods: A total of 100 patients with persistent AF of <2 years' duration underwent cryoballoon PVI (ECGI phenotyping of persistent AF based on driver burden and distribution to predict response to pulmonary vein isolation).

DOACs vs Vitamin K Antagonists During Cardiac Rhythm Device Surgery: A Multicenter Propensity-Matched Study.

Background: There is a paucity of data comparing vitamin K antagonists (VKAs) to direct oral anticoagulants (DOACs) at the time of cardiac implantable electronic device (CIED) surgery. Furthermore, the best management of DOACs (interruption vs continuation) is yet to be determined.

Objectives: This study aimed to compare the incidence of device-related bleeds and thrombotic events based on anticoagulant type (DOAC vs VKA) and regimen (interrupted vs uninterrupted).

Nighttime Sleep and Respiratory Disturbances in Individuals Receiving Methadone to Treat Opioid Use Disorder.

Opioids are a leading cause of drug overdose deaths in the United States. Methadone used as medication for opioid use disorder (MOUD) reduces drug cravings and promotes abstinence. However, individuals in methadone-based MOUD treatment commonly report subjective sleep complaints and are at risk for respiratory depression from opioids.

Atrial fibrillation cryoablation is an effective day case treatment: the UK PolarX vs. Arctic Front Advance experience.

Aims: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation for atrial fibrillation (AF). There are limited data on the PolarX Cryoballoon. The study aimed to establish the safety, efficacy, and feasibility of same day discharge for Cryoballoon PVI.

Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.

Background: Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (K) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of K pore-forming subunits.

Test-retest reliability and sensitivity of senior elite amateur boxers maximal punch force, as quantified by a vertically mounted force plate.

An ecologically valid, reliable and sensitive method of quantifying punch force variables would be useful for coaches and practitioners monitoring combat-specific performance. The present study utilised a vertically mounted force plate to quantify the peak punch force and rate of force development (RFD) of amateur boxers. Ten male senior elite amateur boxers performed maximal jab, cross, and hook punches across two separate days.

Catheter ablation of atrial fibrillation with a multi-electrode radiofrequency balloon; first and early two centre experience in Europe.

Introduction: The Heliostar™ ablation system is a novel RF balloon ablation technology with an integrated three-dimensional mapping system. Here, we describe our early experience and procedural outcomes using this technology for atrial fibrillation catheter ablation.

Methods: We sought to comprehensively assess the first 60 consecutive patients undergoing pulmonary vein isolation using the novel HELISOTAR™ RF balloon technology including procedural outcomes.