A Persistent Boron Tetraradical with Tetraphenylethene-Linked Boraphenanthrene-Type Units.

We report the first paramagnetic boron tetraradical, comprising four boraphenanthrene-type units with boryl radical centers bridged by a central tetraphenylethene (TPE) linker. With strongly π-accepting and sterically demanding cyclic(alkyl)(amino) carbene ligands (), spin densities localize on the boron-carbene fragments (92%), consistent with a true boron-centered tetraradical. Magnetic measurements of reveal minimal spin-spin coupling, consistent with four noninteracting = 1/2 centers.

Effective imaging and treatment of Acute Myeloid Leukemia with radiotheranostics targeting the activated conformation of integrin-βeta2.

Unlabelled: There remains an unmet clinical need for improved treatment strategies in Acute Myeloid Leukemia (AML). Although radiopharmaceutical therapies targeting non-cancer-selective antigens have shown promise in AML, their clinical utility is often limited by prolonged bone marrow suppression. Using a unique proteomics-based strategy, we recently identified the active conformation of integrin-β2 (aITGB2) as a novel, tumor-selective target for AML.

Discovery of AZD8421: A Potent CDK2 Inhibitor with Selectivity Against Other CDK Family Members and the Human Kinome.

Targeting CDK2 with first generation CDK2 inhibitors suffered from a reduced therapeutic index likely due to toxicity stemming from lack of selectivity against the CDK family and other kinases. Recently, CDK2 has been identified as a mediator of resistance to CDK4/6 inhibitors in the context of high levels of cyclin E expression. Discovery of highly selective CDK2 inhibitors may minimize off-target effects, reduce toxicity observed with first generation CDK2 inhibitors, and allow precise targeting of aberrant cell cycle progression and resistance mechanisms mediated by high cyclin E/CDK2 activity.

Severe Hemolytic Phenotype in Children With Sickle Cell Anemia and Co-Inherited Red Blood Cell Variants.

Remarkable phenotypic variability exists among individuals with sickle cell anemia (SCA), which may be explained by co-inheritance of traits affecting red blood cell (RBC) biology, such as genes affecting globin expression or glucose-6-phosphate dehydrogenase enzyme activity. Here, we describe three children with severe SCA who have co-inherited variants in genes for membrane proteins (SPTA1 and EPB1) and PIEZO1. These cases suggest that variants in RBC membrane proteins may contribute to SCA severity and phenotypic variation.

Strength and Balance in Recreational Golfers Aged Over 80 Years.

Muscle strength and balance decrease with age, particularly in those over 80. Playing golf is associated with greater strength and balance in 65-79-year-olds, but it is not known if this occurs in the over 80s. Strength and balance of golfers aged over 80 years were assessed and compared with data obtained by the same research group on golfers and nongolfers aged 65-79 years.

In Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties.

Myeloid Cell Leukemia 1, or MCL-1, is an anti-apoptotic protein belonging to the BCL-2 family of proteins, which regulate the mitochondrial pathway of cellular apoptosis via binding of pro- and anti-apoptotic family members. Genetic amplification and overexpression of MCL-1 is one mechanism cancer cells utilize to avoid death and thus MCL-1 has emerged as an attractive target for cancer treatment. Herein, we describe our strategy and medicinal chemistry efforts to identify best-in-class MCL-1 inhibitors with high cytotoxic potency and improved biorelevant solubility while aiming to maximize therapeutic index versus on-target toxicity via IV dosing.

Biologically Active Implants Prevent Mortality in a Mouse Sepsis Model.

Implant-associated infections remain a significant complication in medicine. often leading to chronic infection, tissue damage, or implant failure. To address this, this work develops a modular, triple-action titanium implant that integrates bacterial repellency, bactericidal activity, and enhanced tissue integration.

REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate.

Cell fate and identity require timely activation of lineage-specific and concomitant repression of alternate-lineage genes. How this process is epigenetically encoded remains largely unknown. In skeletal muscle stem cells, the myogenic regulatory factors are well-established drivers of muscle gene activation but less is known about how non-muscle gene repression is achieved.

Effectiveness and safety of oral vancomycin in non-primary sclerosing cholangitis paediatric inflammatory bowel disease.

Objectives: Oral vancomycin (OV) has limited usage in paediatric inflammatory bowel disease (PIBD) with reported efficacy in primary sclerosing cholangitis (PSC-PIBD), acute severe colitis as part of quadruple-antibiotic regimen, and very early-onset IBD. This study evaluates OV effectiveness and safety as a single-agent in non-PSC PIBD.

Methods: This single-centre retrospective study included patients on OV for active disease or steroid/topical therapy dependency.

Telomere interactions and structural variants in ALT cells revealed with TelSPRITE.

Acquisition of a telomere maintenance mechanism is essential for cancer cells. In a minority of tumors, telomeres are lengthened via Alternative Maintenance of Telomeres (ALT), a telomerase-independent pathway based on homologous recombination. ALT tumors have heavily rearranged genomes with many structural variants containing telomere repeats.

The daily auditory environments of people with tinnitus.

This study characterized typical noise exposure patterns in people with tinnitus relative to a control group. For a week, participants wore a personal noise dosimeter, with instructions to wear during all waking activities. The sample (n = 108) included both Tinnitus and Control groups.

Analytical and clinical validation of a high accuracy fully automated digital immunoassay for plasma phospho-Tau 217 for clinical use in detecting amyloid pathology.

Background: With the emergence of disease-modifying therapies for Alzheimer's disease (AD), there is an urgent need for scalable, accurate, and well-validated blood test alternatives to positron emission topography (PET) and lumbar punctures for identifying amyloid pathology to facilitate identification of candidates for therapy. Plasma p-Tau 217 has emerged as a plasma-based biomarker with sufficient sensitivity and specificity to both rule out and rule in amyloid pathology with high confidence, potentially serving as a readily scalable non-invasive test to aid AD diagnosis. In this report, we describe robust analytical and clinical validation of a lab developed test for plasma p-Tau 217 suitable for clinical diagnostic use.

Management of paediatric ulcerative colitis, part 1: Ambulatory care-An updated evidence-based consensus guideline from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organisation.

Objectives: Despite advances in the management of ambulatory paediatric ulcerative colitis (UC), challenges remain as many patients are refractory to therapy and some require colectomy. The aim of these guidelines is to provide an update on optimal care for UC through detailed recommendations and practice points.

Methods: These guidelines are an update to those published in 2018 and are a joint effort of the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organisation.

Generative AI enables medical image segmentation in ultra low-data regimes.

Semantic segmentation of medical images is pivotal in applications like disease diagnosis and treatment planning. While deep learning automates this task effectively, it struggles in ultra low-data regimes for the scarcity of annotated segmentation masks. To address this, we propose a generative deep learning framework that produces high-quality image-mask pairs as auxiliary training data.

Parental Adverse Childhood Experiences and Health Care Use Among Children With Sickle Cell Disease.

Importance: Adverse childhood experiences (ACEs) are associated with poor health care use. In African American communities, where ACEs are more prevalent, it is critical to understand the association of ACEs with chronic illnesses, such as sickle cell disease (SCD), in children to expand trauma-informed care and improve outcomes.

Objective: To examine the association between parental ACEs and health care use in pediatric patients with SCD, accounting for factors that may influence this association.

Management of pediatric inflammatory bowel diseases in limited-resource settings: A position paper from the Paediatric IBD Porto Group of ESPGHAN.

Objective: Pediatric inflammatory bowel diseases (PIBDs), despite being more prevalent in westernized nations, show an increasing incidence worldwide. Accurate evaluation, diagnosis, therapy, and monitoring are mandatory for the adequate management of patients, as is a sensible use of expensive resources, which may be limited in some parts of the world. This limitation often poses challenges to diagnose and treat patients.

Non-specific diagnostic labels for musculoskeletal conditions foster positive views about prognosis and non-invasive management but require clear explanation: a systematic review.

Questions: What are patient and public perceptions of diagnostic labels for musculoskeletal pain? How do these labels influence beliefs, emotions and treatment preferences?

Design: Systematic review and qualitative meta-synthesis.

Participants: People with musculoskeletal pain or people presented with hypothetical vignettes of musculoskeletal pain.

Intervention: Diagnostic labels for musculoskeletal pain.

Variations in Methodological Approaches to Measuring Health Inequalities and Inequities: A Scoping Review of Acute Stroke Pathways.

Background: There are a lot of advances that may affect the way treatment is delivered prehospital, including mobile stroke units and point-of-care diagnostics. These have the potential to affect populations differently and therefore affect the distribution of health outcomes.

Objectives: We aimed to address the following research questions: (1) Which geographic and socioeconomic inequalities have been included when evaluating access to acute stroke treatment (including reperfusion therapies)? (2) How have the identified measures been considered/assessed/calculated? (3) We also report any methodological approaches that have been proposed that might further improve the way in which acute stroke care interventions are analysed, specified relating to inequalities.

Digital education and exercise therapy versus minimal intervention for young people at high risk of early onset knee osteoarthritis after ACL reconstruction: a study protocol for the Stop OsteoARthritis (SOAR) randomized controlled trial.

Background: People who tear their anterior cruciate ligament and have reconstruction surgery (ACLR) are at elevated risk of inactivity, obesity, and early-onset knee osteoarthritis. Consensus recommendations to prevent post-traumatic knee osteoarthritis include person-centered education and exercise-based treatments. The effectiveness of these recommendations is unknown.

Management of paediatric ulcerative colitis, part 2: Acute severe colitis-An updated evidence-based consensus guideline from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organization.

Acute severe colitis (ASC) is a relatively frequent manifestation in children with ulcerative colitis and one of the few emergencies in paediatric gastroenterology. A standardized proactive approach based on tight monitoring and timely medical and surgical interventions may improve patients' outcomes. We aimed to update the previous ASC guidelines using detailed recommendations and practice points, based on a systematic review of the literature and consensus of experts.

Twenty-Year Trends in Colectomy Rates and Advanced Therapy Prescribing in Lothian, Scotland.

Background: The impact of advanced therapy prescribing on colectomy rates in ulcerative colitis (UC) is unknown with conflicting published evidence.

Aim: To describe advanced therapy prescribing trends and colectomy rates for patients with UC in Lothian, UK between January 1st, 2004 and December 31st, 2023.

Methods: We obtained incidence and prevalence data from the Lothian IBD Registry, a rigorously validated population cohort.

Evaluation of Ce/La-PSMA-617 for PET Imaging and Auger Electron Therapy of Prostate Cancer.

The Ce/La radionuclide pair has been proposed as a PET imaging surrogate for targeted α-radiotherapeutics. Ce decays to La via electron capture, emitting Auger electrons (AEs), which could be used for targeted radionuclide therapy. Additionally, the positron emission during this transition enables PET imaging, making Ce/La a promising theranostic pair for prostate cancer.

Opportunistic automated aortic valve calcification assessment in low-cost, screening CT calcium score exams.

Aortic valve stenosis (AS) is the most common valvular disease, with a growing impact in the aging population. AS can culminate in heart failure if left untreated. Early treatment with minimally-invasive transcatheter aortic valve replacement (TAVR) is being evaluated in clinical trials.

Topological isomers of a potent wound healing peptide: Structural insights and implications for bioactivity.

There are numerous examples of topological isomers in organic chemistry, but such isomers are rare in disulfide-rich peptides. Here, we characterize two structurally well-defined topological isomers in a peptide (GRN-P4A) containing the mini-granulin fold. The mini-granulin fold is emerging as an important disulfide-rich structural motif with promising implications for the enhancement of wound-healing strategies.

Beyond nodules: body composition as a biomarker for future lung cancer.

Objectives: To investigate if body composition can serve as a biomarker for assessing the risk of developing lung cancer.

Materials And Methods: We conducted a retrospective study using low-dose computed tomography (LDCT) scans from the Pittsburgh lung screening study (PLuSS) (n = 3635, 22 follow-up years) and the NLST-ACRIN (n = 16,360, 8 follow-up years) cohort. Five types of body tissues, including subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), intramuscular adipose tissue (IMAT), skeletal muscle (SM), and bone, were automatically segmented by our previously developed algorithms.