Mercury, legacy and emerging POPs, and endocrine-behavioural linkages: Implications of Arctic change in a diving seabird.

Arctic species encounter multiple stressors including climate change and environmental contaminants. Some contaminants may disrupt hormones that govern the behavioural responses of wildlife to climatic variation, and thus the capacity of species to respond to climate change. We investigated correlative interactions between legacy and emerging persistent organic pollutants (POPs), mercury (Hg), hormones and behaviours, in thick-billed murres (Uria lomvia) (N = 163) breeding in northern Hudson Bay (2016-2018).

Performance of the Universal Vital Assessment (UVA) mortality risk score in hospitalized adults with infection in Rwanda: A retrospective external validation study.

Background: We previously derived a Universal Vital Assessment (UVA) score to better risk-stratify hospitalized patients in sub-Saharan Africa, including those with infection. Here, we aimed to externally validate the performance of the UVA score using previously collected data from patients hospitalized with acute infection in Rwanda.

Methods: We performed a secondary analysis of data collected from adults ≥18 years with acute infection admitted to Gitwe District Hospital in Rwanda from 2016 until 2017.

Upregulation of SIRT1 Contributes to dmPGE2-dependent Radioprotection of Hematopoietic Stem Cells.

Exposure to potentially lethal high-dose ionizing radiation results in bone marrow suppression, known as the hematopoietic acute radiation syndrome (H-ARS), which can lead to pancytopenia and possible death from hemorrhage or infection. Medical countermeasures to protect from or mitigate the effects of radiation exposure are an ongoing medical need. We recently reported that 16,16 dimethyl prostaglandin E (dmPGE) given prior to lethal irradiation protects hematopoietic stem (HSCs) and progenitor (HPCs) cells and accelerates hematopoietic recovery by attenuating mitochondrial compromise, DNA damage, apoptosis, and senescence.

Trends in college student mental health and help-seeking by race/ethnicity: Findings from the national healthy minds study, 2013-2021.

Background: A considerable gap in knowledge exists around mental health trends in diverse racial and ethnic adolescent and young adult populations. The purpose of this study is to examine annual trends for mental health and help-seeking by race/ethnicity in a national sample of college students.

Methods: Survey data come from >350,000 students at 373 campuses that participated in the Healthy Minds Study between 2013 and 2021.

Multi-Omics Strategies for Investigating the Microbiome in Toxicology Research.

Microbial communities on and within the host contact environmental pollutants, toxic compounds, and other xenobiotic compounds. These communities of bacteria, fungi, viruses, and archaea possess diverse metabolic potential to catabolize compounds and produce new metabolites. Microbes alter chemical disposition thus making the microbiome a natural subject of interest for toxicology.

Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.

Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4.

Sleep and Economic Status Are Linked to Daily Life Stress in African-Born Blacks Living in America.

To identify determinants of daily life stress in Africans in America, 156 African-born Blacks (Age: 40 ± 10 years (mean ± SD), range 22-65 years) who came to the United States as adults (age ≥ 18 years) were asked about stress, sleep, behavior and socioeconomic status. Daily life stress and sleep quality were assessed with the Perceived Stress Scale (PSS) and Pittsburgh Sleep Quality Index (PSQI), respectively. High-stress was defined by the threshold of the upper quartile of population distribution of PSS (≥16) and low-stress as PSS < 16.

Predicting Clinical Events Based on Raw Text: From Bag-of-Words to Attention-Based Transformers.

Identifying which patients are at higher risks of dying or being re-admitted often happens to be resource- and life- saving, thus is a very important and challenging task for healthcare text analytics. While many successful approaches exist to predict such clinical events based on categorical and numerical variables, a large amount of health records exists in the format of raw text such as clinical notes or discharge summaries. However, the text-analytics models applied to free-form natural language found in those notes are lagging behind the break-throughs happening in the other domains and remain to be primarily based on older bag-of-words technologies.

Chirality-directed hydrogel assembly and interactions with enantiomers of an active pharmaceutical ingredient.

Enantiomers of the low-molecular-weight gelator (LMWG) DBS-CONHNH, based on D- or L- 1,3 : 2,4-dibenzylidenesorbitol (DBS), were synthesised. Enantiomeric gels are equivalent, but when mixtures of enantiomers are used, although gels still form, they are weaker than homochiral gels. Nanoscale chirality is lost on adding even a small proportion of the opposite enantiomer - homochiral assembly underpins effective gelation.

Thiocyanate toxicity: a teaching case.

Thiocyanate can cause gastrointestinal, neurologic, and cardiovascular toxicity. Additionally, it interferes with multiple laboratory assays. We present a case of acute thiocyanate toxicity.

Interrogation of the Structure-Activity Relationship of a Lipophilic Nitroaromatic Prodrug Series Designed for Cancer Gene Therapy Applications.

PR-104A is a dual hypoxia/nitroreductase gene therapy prodrug by virtue of its ability to undergo either one- or two-electron reduction to its cytotoxic species. It has been evaluated extensively in pre-clinical GDEPT studies, yet off-target human aldo-keto reductase AKR1C3-mediated activation has limited its use. Re-evaluation of this chemical scaffold has previously identified SN29176 as an improved hypoxia-activated prodrug analogue of PR-104A that is free from AKR1C3 activation.

Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling.

Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under pathological hypoxia to generate active metabolites with the potential to diffuse throughout the tumour microenvironment and potentiate cell killing by means of a "bystander effect". In the present study, we investigate the pharmacological properties of the nitrogen mustard prodrug CP-506 in tumour tissues using spatially-resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) modelling.

Bridged Piperidine Analogues of a High Affinity Naphthalene-Based P2YR Antagonist.

High affinity phenyl-piperidine P2YR antagonist (PPTN) was modified with piperidine bridging moieties to probe receptor affinity and hydrophobicity. Various 2-azanorbornane, nortropane, isonortropane, isoquinuclidine, and ring-opened cyclopentylamino derivatives preserved human P2YR affinity (fluorescence binding assay), and their pharmacophoric overlay was compared. Enantiomeric 2-azabicyclo[2.

Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease lacking effective treatments. This is due, in part, to a complex and incompletely understood pathophysiology. To shed light, we conducted untargeted metabolomics on plasma from two independent cross-sectional ALS cohorts versus control participants to identify recurrent dysregulated metabolic pathways.

Defective humoral immunity disrupts bile acid homeostasis which promotes inflammatory disease of the small bowel.

Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes. Whether and how mucosal antibody responses influence gut health through modulation of microbiota composition is unclear. Here, we use a CD19 mouse model of antibody-deficiency to demonstrate that a relationship exists between dysbiosis, defects in bile acid homeostasis, and gluten-sensitive enteropathy of the small intestine.

Case Series: Tattoo-associated Uveitis.

Significance: Tattoo-associated uveitis describes simultaneous tattoo inflammation and uveitis. Multiple cases exist in the literature related to systemic sarcoidosis or a delayed hypersensitivity reaction; however, there is no consensus on etiology. Clinicians should consider new tattoos as an associated factor for patients presenting with a new uveitis.

Fit for purpose. Co-production of complex behavioural interventions. A practical guide and exemplar of co-producing a telehealth-delivered exercise intervention for people with stroke.

Background: Careful development of interventions using principles of co-production is now recognized as an important step for clinical trial development, but practical guidance on how to do this in practice is lacking. This paper aims (1) provide practical guidance for researchers to co-produce interventions ready for clinical trial by describing the 4-stage process we followed, the challenges experienced and practical tips for researchers wanting to co-produce an intervention for a clinical trial; (2) describe, as an exemplar, the development of our intervention package.

Method: We used an Integrated Knowledge Translation (IKT) approach to co-produce a telehealth-delivered exercise program for people with stroke.

Discovery of Cysteine-targeting Covalent Protein Kinase Inhibitors.

Small molecule covalent kinase inhibitors (CKIs) have entered a new era in drug discovery, which have the advantage for sustained target inhibition and high selectivity. An increased understanding of binding kinetics of CKIs and discovery of additional irreversible and reversible-covalent cysteine-targeted warheads has inspired the development of this area. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative CKIs, which are categorized by the location of the target cysteine within seven main regions of the kinase: the front region, the glycine rich loop (P-loop), the hinge region, the DFG region, the activation loop (A-loop), the catalytic loop (C-loop), and the remote loop.

Infant Formula with Added Bovine Milk Fat Globule Membrane and Modified Iron Supports Growth and Normal Iron Status at One Year of Age: A Randomized Controlled Trial.

Inclusion of bovine-derived milk fat globule membrane (bMFGM) or bMFGM components in infant formulas (IFs) may support healthy brain development. This double-blind, prospective trial evaluated growth, tolerance, and iron status in infants receiving added bMFGM and modified protein, iron, and arachidonic acid (ARA) concentrations in IF. Healthy term infants were randomized to: control (marketed, routine cow's milk-based IF/100 kcal: 2.

Restoring Tumour Selectivity of the Bioreductive Prodrug PR-104 by Developing an Analogue Resistant to Aerobic Metabolism by Human Aldo-Keto Reductase 1C3.

PR-104 is a phosphate ester pre-prodrug that is converted in vivo to its cognate alcohol, PR-104A, a latent alkylator which forms potent cytotoxins upon bioreduction. Hypoxia selectivity results from one-electron nitro reduction of PR-104A, in which cytochrome P450 oxidoreductase (POR) plays an important role. However, PR-104A also undergoes 'off-target' two-electron reduction by human aldo-keto reductase 1C3 (AKR1C3), resulting in activation in oxygenated tissues.

Epidemiology and Outcome of Sepsis in Adults and Children in a Rural, Sub-Sahara African Setting.

Objectives: To identify the epidemiology and outcome of adults and children with and without sepsis in a rural sub-Sahara African setting.

Design: A priori planned substudy of a prospective, before-and-after trial.

Setting: Rural, sub-Sahara African hospital.

Self-rated physical health, health-risk behaviors, and disparities: A cross-sectional study of youth in the slums of Kampala, Uganda.

Self-rated physical health (SRPH) has been extensively used to assess health status. In this study, we examine how youth living in the slums of Kampala perceive their physical health and the psychosocial correlates of poor health. Cross-sectional data from the 2014 Kampala Youth Survey (N = 1,134) of youth ages 12-18 years was used to conduct the analyses.

Pitfalls in the diagnosis of yolk sac tumor: Lessons from a clinical trial.

Though outcomes for patients with recurrent/refractory malignant germ cell tumors (mGCTs) are poor, therapies targeting mTOR and EGFR inhibition have shown promise in vitro. We hypothesized that the combination of sirolimus and erlotinib will show activity in patients with recurrent/refractory mGCTs. Patients were enrolled in a prospective phase II clinical trial; central review of existing pathology specimens was performed.

The role of mouse and human peroxisome proliferator-activated receptor-α in modulating the hepatic effects of perfluorooctane sulfonate in mice.

Perfluorooctane sulfonate (PFOS) is a stable environmental contaminant that can activate peroxisome proliferator-activated receptor alpha (PPARα). In the present work, the specific role of mouse and human PPARα in mediating the hepatic effects of PFOS was examined in short-term studies using wild type, Ppara-null and PPARA-humanized mice. Mice fed 0.

Altered Oxidative Status as a Cost of Reproduction in a Seabird with High Reproductive Costs.

AbstractLife history theory posits that reproduction is constrained by a cost of reproduction such that any increase in breeding effort should reduce subsequent survival. Oxidative stress refers to an imbalance between the prooxidant reactive oxygen species (ROS) and antioxidant defense. If not thwarted, ROS can cause damage to DNA, lipids, and proteins, potentially increasing the rate of senescence and decreasing cellular function.