A Population Pharmacokinetic Study to Evaluate Doxorubicin Exposure Across All Age Groups.

Background: The effect of age on doxorubicin pharmacokinetics remains inconclusive, especially in patients at the extremes of the age spectrum. We developed a population pharmacokinetic model to further investigate the impact of age on the pharmacokinetics of doxorubicin.

Methods: A three-compartment model, incorporating allometric scaling was developed to describe doxorubicin pharmacokinetics across all ages.

Does targeted temperature management at 33 °C improve outcome after cardiac arrest?

Purpose Of Review: Following successful resuscitation from cardiac arrest, a complex set of pathophysiologic processes are acutely triggered, leading to substantial morbidity and mortality. Postarrest management remains a major challenge to critical care providers, with few proven therapeutic strategies to improve outcomes. One therapy that has received substantial focus is the intentional lowering of core body temperature for a discrete period of time following resuscitation.

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology.

Personality is influenced by both genetic and environmental factors and is associated with other psychiatric traits such as anxiety and depression. The 'big five' personality traits, which include neuroticism, extraversion, agreeableness, conscientiousness and openness, are a widely accepted and influential framework for understanding and describing human personality. Of the big five personality traits, neuroticism has most often been the focus of genetic studies and is linked to various mental illnesses, including depression, anxiety and schizophrenia.

Estimating error rates for single molecule protein sequencing experiments.

The practical application of new single molecule protein sequencing (SMPS) technologies requires accurate estimates of their associated sequencing error rates. Here, we describe the development and application of two distinct parameter estimation methods for analyzing SMPS reads produced by fluorosequencing. A Hidden Markov Model (HMM) based approach, extends whatprot, where we previously used HMMs for SMPS peptide-read matching.

Multisite Validation of a Functional Assay to Adjudicate Brugada Syndrome-Associated Variants.

Background: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in . Interpreting the pathogenicity of missense variants is challenging, and ≈79% of missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.

Innovative Biomarkers for Obesity and Type 1 Diabetes Based on and Metabolomic Profiling.

The role of species and microbial metabolites such as short-chain fatty acids (SCFAs) and human milk oligosaccharides in controlling intestinal inflammation and the pathogenesis of obesity and type 1 diabetes (T1D) has been largely studied in recent years. This paper discusses the discovery of signature biomarkers for obesity and T1D based on data from a novel test for profiling several species, combined with metabolomic analysis. Through the NUTRISHIELD clinical study, a total of 98 children were recruited: 40 healthy controls, 40 type 1 diabetics, and 18 obese children.

Use of Tirzepatide in Adults with Type 2 Diabetes Mellitus: Scientific Evidence and Practical Aspects.

Tirzepatide is a novel antidiabetic medication a single-molecule, agonist to the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors. It is approved in the USA and EU for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Due to the potential novelty represented by incorporating tirzepatide to clinical practice, we aim to review practical aspects of tirzepatide use in T2DM and the supporting scientific evidence.

Quality of Life in Patients With Chronic Limb-Threatening Ischemia Treated With Revascularization.

Background: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL).

Methods: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein.

Angiotensinogen as a Therapeutic Target for Cardiovascular and Metabolic Diseases.

AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus.

In severe eosinophilic asthma controlled with benralizumab, tapering high-dose ICS reduced dose while maintaining control.

Jackson DJ, Heaney LG, Humbert M, et al; SHAMAL Investigators. Lancet. 2024;403:271-281.

COVID-19 Immunologic Antiviral Therapy With Omalizumab (CIAO)-a Randomized Controlled Clinical Trial.

Background: Omalizumab is an anti-immunoglobulin E monoclonal antibody used to treat moderate to severe chronic idiopathic urticaria, asthma, and nasal polyps. Recent research suggested that omalizumab may enhance the innate antiviral response and have anti-inflammatory properties.

Objective: We aimed to investigate the efficacy and safety of omalizumab in adults hospitalized for coronavirus disease 2019 (COVID-19) pneumonia.

Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression.

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on depression remains poorly understood. Here, we present whole-exome sequencing analyses of depression with seven different definitions based on survey, questionnaire, and electronic health records in 320,356 UK Biobank participants.

Multimodality Cardiac Imaging and the Imaging Workforce in the United States: Diversity, Disparities, and Future Directions.

Innovations in cardiac imaging have fundamentally advanced the understanding and treatment of cardiovascular disease. These advances in noninvasive cardiac imaging have also expanded the role of the cardiac imager and dramatically increased the demand for imagers who are cross-trained in multiple modalities. However, we hypothesize that there is significant variation in the availability of cardiac imaging expertise and a disparity in the adoption of advanced imaging technologies across the United States.

Genetic architecture distinguishes tinnitus from hearing loss.

Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries.

Association Between Draft Order and Stress Sonography of the Ulnar Collateral Ligament of the Elbow in Professional Baseball Pitchers: An 18-Year Study.

Background: The Major League Baseball (MLB) draft is a common route for players to enter professional baseball in the United States. Players taken in earlier rounds are typically higher-performing players. When looking at pitchers specifically, higher performance at the amateur level may be associated with an increased frequency of adaptive change in the throwing elbow.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses.

Copy Number Variant Analysis of Spinocerebellar Ataxia Genes in a Cohort of Dutch Patients With Cerebellar Ataxia.

Background And Objectives: The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders generally caused by single nucleotide variants (SNVs) or indels in coding regions or by repeat expansions in coding and noncoding regions of SCA genes. Copy number variants (CNVs) have now also been reported for 3 genes-, , and -but not all SCA genes have been screened for CNVs as the underlying cause of the disease in patients. In this study, we aim to assess the prevalence of CNVs encompassing 36 known SCA genes.