Nitazene opioids and the heart: Identification of a cardiac ion channel target for illicit nitazene opioids.

The growing use of nitazene synthetic opioids heralds a new phase of the opioid crisis. However, limited information exists on the toxic effects of these drugs, aside from a propensity for respiratory depression. With restricted research availability of nitazenes, we used machine-learning-based tools to evaluate five nitazene compounds' interaction potential with the hERG potassium channel, a key drug antitarget in the heart.

Preventive Human Genome Editing and Enhancement: Candidate Criteria for Governance.

While somatic cell editing to treat disease is widely accepted, the use of human genome editing for "enhancement" remains contested. Scientists and policy-makers routinely cite the prospect of enhancement as a salient ethical challenge for human genome editing research. If preventive genome editing projects are perceived as pursuing human enhancement, they could face heightened barriers to scientific, public, and regulatory approval.

Validation and clinical performance of a single test, DNA based endometrial cancer molecular classifier.

Objectives: We have previously shown that DNA based, single test molecular classification by next generation sequencing (NGS) (Proactive Molecular risk classifier for Endometrial cancer (ProMisE) NGS) is highly concordant with the original ProMisE classifier and maintains prognostic value in endometrial cancer. Our aim was to validate ProMisE NGS in an independent cohort and assess the performance of ProMisE NGS in real world clinical practice to address if there were any practical challenges or learning points for implementation.

Methods: We evaluated DNA extracted from an external research cohort of 211 endometrial cancer cases diagnosed in 2016 from Germany, Switzerland, and Austria, across seven European centers, comparing standard molecular classification (NGS for status, immunohistochemistry for mismatch repair and p53) with ProMisE NGS (NGS for and microsatellite instability assay) for concordance metrics and Kaplan-Meier survival statistics across molecular subtypes.

International expert guidance for defining and monitoring small bowel strictures in Crohn's disease on intestinal ultrasound: a consensus statement.

Background: Diagnostic imaging using CT enterography, magnetic resonance enterography, and intestinal ultrasound are important tools in evaluating stricturing Crohn's disease. Definitions of strictures have been developed for CT enterography and magnetic resonance enterography. However, expert recommendations for definitions and treatment response of strictures on intestinal ultrasound are not available.

Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the μ-opioid receptor.

Background And Purpose: Fentanyls and nitazenes are μ-opioid receptor agonists responsible for a large number of opioid overdose deaths. Here, we determined the potency, dissociation kinetics and antagonism by naloxone at the μ receptor of several fentanyl and nitazene analogues, compared to morphine and DAMGO.

Experimental Approach: In vitro assays of G protein activation and signalling and arrestin recruitment were performed.

Redefining Candidates for Deintensification in Locoregionally Advanced P16+ Oropharyngeal Cancer Based on Relative Risk.

Purpose: Randomized trials have found that patients with locoregionally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC) do not benefit from treatment deintensification, even among favorable risk groups. Although various methods have been used to identify candidates for treatment deintensification, the optimal approach is unknown.

Methods And Materials: We conducted a multi-institutional cohort study of 444 patients with previously untreated p16+ OPSCC undergoing definitive radiation therapy with or without systemic therapy between 2009 and 2022.

Metabolic responses to albumin deficiency differ distinctly between partial and full ablation of albumin expression in mice.

It had been observed that homozygous albumin knockout mice (Alb) exhibit low plasma free fatty acid (FFA) concentration and improved blood glucose regulation. However, it was not yet known to what extent heterozygous albumin knockout (Alb) mice would display a similar phenotype. Alb, Alb, and wild-type (WT) female mice were studied on a low-fat diet (LFD) or high-fat diet (HFD).

A global consensus on the definitions, diagnosis and management of fibrostenosing small bowel Crohn's disease in clinical practice.

Fibrostenosis of the small bowel is common in patients with Crohn's disease. No consensus recommendations on definition, diagnosis and management in clinical practice are currently available. In this Consensus Statement, we present a clinical practice RAND/UCLA appropriateness study on the definition, diagnosis and clinical management of fibrostenosing Crohn's disease.

Digital mental health and peer support: Building a Theory of Change informed by stakeholders' perspectives.

Digital Mental Health and Peer support has the potential to bridge gaps in support through its scalability and accessibility. Despite the increasing use of these platforms, there remains a lack of understanding of how they operate in real life, from initial engagement to longer-term impact. We aimed to explore the key inputs, processes, user interactions, assumptions, barriers, facilitators, outcomes, and impacts associated with the use of DMH and peer support platforms by developing a Theory of Change with stakeholders.

The public-private research ecosystem in the genome editing era.

Biomedical research in the US has long been conducted in a public-private (PP) "ecosystem." Today, especially with gene therapies and genome editing-based medicine, publicly funded researchers frequently hand off their research to the private sector for clinical development, often to small, venture capital-funded startups in which they have a financial interest. This trend raises ethical questions about conflicts of interest, effectiveness of regulatory oversight, and justice in therapy access, that we are addressing in a multi-year, multidisciplinary study of the evolving governance of genome editing.

Facilitators and Barriers to Adherence to Anti-Retroviral Treatment Among Pregnant or Breastfeeding Women Living with HIV and Perinatally Infected Infants: A Scoping Review.

In 2022, 54% of 1.5 million children (age 0-14) living with HIV had access to anti-retroviral medication (ART). Adherence to ART for pregnant or breastfeeding HIV + women is critical for maintaining their personal health and to prevent mother-to-child-transmission (MTCT).

Correction: Foss et al. The Rise of Population Genomic Screening: Characteristics of Current Programs and the Need for Evidence Regarding Optimal Implementation. 2022, , 692.

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Albumin is an important factor in the control of serum free fatty acid flux in both male and female mice.

Albumin knockout (Alb) mice exhibit a low plasma free fatty acid (FFA) concentration, but it was not known if the suppressed concentration reflects a lower rate of appearance (Ra) of FFA in the circulation (i.e., lower FFA flux) or if the absence of albumin alters the relationship between FFA flux and concentration.

Performance evaluation of different albumin assays for the detection of analbuminemia.

Analbuminemia is characterized by the near absence of albumin in the plasma. Different methods are available for measuring albumin levels, but they do not necessarily agree with one another. It is a concern that analbuminemic samples could be falsely characterized due to the incorrect estimation of albumin.

Complete genome sequence of sp. ISO3-F5, a rumen methylotrophic methanogen.

spp. are methylotrophic methanogenic archaea and members of the order Methanobacteriales with few cultured representatives. sp.

Why Climate Literacy Is Health Literacy.

Health problems of global warming are daunting in severity and magnitude and will only get worse. Yet literacy about these problems is poor and plans to alleviate them are too early in development to be responsive to current levels of global threat and individual need. Social and ecological determinants of health and illness are exacerbated by excessive heat and flooding; lack of food, safe water, and secure shelter; and loss of arable land for farming.

New synthetic cannabinoids and the potential for cardiac arrhythmia risk.

Synthetic cannabinoid receptor agonists (SCRAs) have been associated with QT interval prolongation. Limited preclinical information on SCRA effects on cardiac electrogenesis results from the rapid emergence of new compounds and restricted research availability. We used two machine-learning-based tools to evaluate seven novel SCRAs' interaction potential with the hERG potassium channel, an important drug antitarget.

Comparison of the effects of fentanyls and other opioid receptor agonists on the electrical activity of respiratory muscles in the rat.

Deaths due to overdose of fentanyls result primarily from depression of respiration. These potent opioids can also produce muscle rigidity in the diaphragm and the chest muscles, a phenomenon known as Wooden Chest Syndrome, which further limits ventilation. We have compared the depression of ventilation by fentanyl and morphine by directly measuring their ability to induce muscle rigidity using EMG recording from diaphragm and external and internal intercostal muscles, in the rat working heart-brainstem preparation.

SPLASH: A statistical, reference-free genomic algorithm unifies biological discovery.

Today's genomics workflows typically require alignment to a reference sequence, which limits discovery. We introduce a unifying paradigm, SPLASH (Statistically Primary aLignment Agnostic Sequence Homing), which directly analyzes raw sequencing data, using a statistical test to detect a signature of regulation: sample-specific sequence variation. SPLASH detects many types of variation and can be efficiently run at scale.

Genome sequence of bacteriophage DumpQuist isolated from soil in Clarksville, Tennessee.

Bacteriophage DumpQuist was isolated from soil collected in Clarksville, TN, using the bacterium . Electron microscopy revealed that DumpQuist has a podovirus morphology. DumpQuist has a 53,924-bp genome that contains 54 predicted protein-coding genes and is most similar to phages in actinobacteriophage cluster EK1.