The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron.

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs.

Ischemia-induced cardiac dysfunction is exacerbated in adiponectin-knockout mice due to impaired autophagy flux.

Strategies to enhance autophagy flux have been suggested to improve outcomes in cardiac ischemic models. We explored the role of adiponectin in mediating cardiac autophagy under ischemic conditions induced by permanent coronary artery ligation. We studied the molecular mechanisms underlying adiponectin's cardio-protective effects in adiponectin knockout (Ad-KO) compared with wild-type (WT) mice subjected to ischemia by coronary artery ligation and H9c2 cardiomyocyte cell line exposed to hypoxia.

Hypotension During Vasopressor Infusion Occurs in Predictable Clusters: A Multicenter Analysis.

Published evidence indicates that mean arterial pressure (MAP) below a goal range (hypotension) is associated with worse outcomes, though MAP management failures are common. We sought to characterize hypotension occurrences in ICUs and consider the implications for MAP management. Retrospective analysis of 3 hospitals' cohorts of adult ICU patients during continuous vasopressor infusion.

Swimming Against the Current: Addressing Community Needs and Establishing Partnerships for the Prevention of Opioid and Methamphetamine use Among Parents.

The opioid and methamphetamine crises in Oregon have a consequential impact on young families, as an increasing number of parents experience substance use disorder (SUD). As parental substance use escalates, the child welfare system (CWS) becomes overwrought with families who have complex needs. The burden placed on families and on the CWS indicates a need for prevention and treatment interventions for parental SUDs.

NIOSH Hearing Loss Prevention Program for Mining.

Noise-induced hearing loss (NIHL) continues to be a pervasive problem for the nation's workforce, particularly the nation's mining personnel. As one of the leading health and safety organizations in the world, the National Institute for Occupational Health and Safety (NIOSH) in Pittsburgh maintains a Hearing Loss Prevention Program (HLPP) to conduct research to reduce NIHL loss among the nation's miners. This document provides a brief overview of this HLPP, describing some of the research techniques involved in the development of engineering noise controls, methods for the development of administrative noise controls, and some of the products available to the public to protect the nation's workers hearing.

Preventing Occupational Hearing Loss: 50 Years of Research and Recommendations from the National Institute for Occupational Safety and Health.

For more than 50 years, the National Institute for Occupational Safety and Health (NIOSH), part of the United States (U.S.) Centers for Disease Control and Prevention (CDC), has been actively working to reduce the effects of noise and ototoxic chemicals on worker hearing.

Detecting whether L1 or other lumbar levels would be excluded from DXA bone mineral density analysis during opportunistic CT screening for osteoporosis using machine learning.

Purpose: One or more vertebrae are sometimes excluded from dual-energy X-ray absorptiometry (DXA) analysis if the bone mineral density (BMD) T-score estimates are not consistent with the other lumbar vertebrae BMD T-score estimates. The goal of this study was to build a machine learning framework to identify which vertebrae would be excluded from DXA analysis based on the computed tomography (CT) attenuation of the vertebrae.

Methods: Retrospective review of 995 patients (69.

Radiologists should use the hip-knee-ankle angle rather than the mechanical axis deviation to describe knee alignment.

Objective: Preoperative and postoperative coronal knee alignment is an important predictor of total knee arthroplasty (TKA) failure. Radiologists often report the mechanical axis deviation (MAD) rather than hip-knee-ankle angle (HKAA) to describe coronal knee alignment. The aim of this study is to evaluate (i) how well the MAD predicts the HKAA; (ii) if patient height and sex affect the performance of the MAD; and (iii) if the MAD could be measured faster than the HKAA.

A first in man study to evaluate the safety, pharmacokinetics and pharmacodynamics of RP7214, a dihydroorotate dehydrogenase inhibitor in healthy subjects.

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that is essential for pyrimidine de novo synthesis. Rapidly growing cancer cells and replicating viruses are dependent on host cell nucleotides, the precursors of which are provided by DHODH. Hence, DHODH becomes an ideal target for pharmacological intervention.

Differential Latencies Sculpt the Time Course of Contextual Effects on Spatial Perception.

The ability to judge an object's orientation with respect to gravitational vertical relies on an egocentric reference frame that is maintained using not only vestibular cues but also contextual cues provided in the visual scene. Although much is known about how static contextual cues are incorporated into the egocentric reference frame, it is also important to understand how changes in these cues affect perception, since we move about in a world that is itself dynamic. To explore these temporal factors, we used a variant of the rod-and-frame illusion, in which participants indicated the perceived orientation of a briefly flashed rod (5-msec duration) presented before or after the onset of a tilted frame.

Shoulder Osteoarthritis.

Glenohumeral osteoarthritis has proven to be a major contributor to shoulder joint pain and dysfunction in the elderly. There are several conditions about the shoulder that contribute to the development of glenohumeral osteoarthritis, which includes traumatic injuries, rotator cuff pathology, glenohumeral instability, glenoid dysplasia, and osteonecrosis. When glenohumeral osteoarthritis pain is refractory to conservative treatment, intra-articular injections and surgery can be performed.

Cohort dominance rank and "robbing and bartering" among subadult male long-tailed macaques at Uluwatu, Bali.

Robbing and bartering is a habitual behavior among free-ranging long-tailed macaques (Macaca fascicularis) at a single site in Bali, Indonesia. The behavior consists of three main elements: (1) a macaque takes an item from a human; (2) the macaque maintains possession of the item; then (3) the macaque releases or hands off the item after accepting a food offer from a human. In this paper, we analyze data on individual variation in robbing and bartering among subadult males in relation to dominance rank.

The AMPK-related kinase NUAK2 suppresses glutathione peroxidase 4 expression and promotes ferroptotic cell death in breast cancer cells.

Ferroptosis is a caspase-independent form of regulated cell death strongly linked to the accumulation of reactive lipid hydroperoxides. Lipid hydroperoxides are neutralized in cells by glutathione peroxidase 4 (GPX4) and inhibitors of GPX4 are potent ferroptosis inducers with therapeutic potential in cancer. Here we report that siRNA-mediated silencing of the AMPK-related kinase NUAK2 suppresses cell death by small-molecule inducers of ferroptosis but not apoptosis.

Society of Skeletal Radiology- white paper. Guidelines for the diagnostic management of incidental solitary bone lesions on CT and MRI in adults: bone reporting and data system (Bone-RADS).

The purpose of this article is to present algorithms for the diagnostic management of solitary bone lesions incidentally encountered on computed tomography (CT) and magnetic resonance (MRI) in adults. Based on review of the current literature and expert opinion, the Practice Guidelines and Technical Standards Committee of the Society of Skeletal Radiology (SSR) proposes a bone reporting and data system (Bone-RADS) for incidentally encountered solitary bone lesions on CT and MRI with four possible diagnostic management recommendations (Bone-RADS1, leave alone; Bone-RADS2, perform different imaging modality; Bone-RADS3, perform follow-up imaging; Bone-RADS4, biopsy and/or oncologic referral). Two algorithms for CT based on lesion density (lucent or sclerotic/mixed) and two for MRI allow the user to arrive at a specific Bone-RADS management recommendation.

Effects of pharmacological inhibition of the sodium-dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models.

An excess phosphate burden in renal disease has pathological consequences for bone, kidney, and heart. Therapies to decrease intestinal phosphate absorption have been used to address the problem, but with limited success. Here, we describe the in vivo effects of a novel potent inhibitor of the intestinal sodium-dependent phosphate cotransporter NPT2b, LY3358966.

Differential visual and auditory effects in a crossmodal induced Roelofs illusion.

For vision and audition to accurately inform judgments about an object's location, the brain must reconcile the variable anatomical correspondence of the eyes and ears, and the different frames of reference in which stimuli are initially encoded. To do so, it has been suggested that multisensory cues are eventually represented within a common frame of reference. If this is the case, then they should be similarly susceptible to distortion of this reference frame.

IMPDH1 retinal variants control filament architecture to tune allosteric regulation.

Inosine-5'-monophosphate dehydrogenase (IMPDH), a key regulatory enzyme in purine nucleotide biosynthesis, dynamically assembles filaments in response to changes in metabolic demand. Humans have two isoforms: IMPDH2 filaments reduce sensitivity to feedback inhibition, while IMPDH1 assembly remains uncharacterized. IMPDH1 plays a unique role in retinal metabolism, and point mutants cause blindness.

Rose Bengal Photodynamic Antimicrobial Therapy: A Pilot Safety Study.

Purpose: To evaluate the in vivo corneal changes after Rose Bengal photodynamic antimicrobial therapy (RB-PDAT) treatment in New Zealand White rabbits.

Methods: Sixteen rabbits were divided into 5 groups. All groups underwent deepithelialization of an 8 mm diameter area in the central cornea.

Social media and public perception as core aspect of public health: The cautionary case of @realdonaldtrump and COVID-19.

The social media milieu in which we are enmeshed has substantive impacts on our beliefs and perceptions. Recent work has established that this can play a role in influencing understanding of, and reactions to, public health information. Twitter, in particular, appears to play a substantive role in the public health information ecosystem.

Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1.

Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown.

Detection of singlet oxygen luminescence for experimental corneal rose bengal photodynamic antimicrobial therapy.

Rose bengal photodynamic antimicrobial therapy (RB-PDAT) treats corneal infection by activating rose bengal (RB) with green light to produce singlet oxygen (O). Singlet oxygen dosimetry can help optimize treatment parameters. We present a O dosimeter for detection of O generated during experimental RB-PDAT.

Development and Validation of a Predictive Model for Hemodynamic Responses to Resuscitation during Uncontrolled Hemorrhage.

We investigated whether a statistical model could predict mean arterial pressure (MAP) during uncontrolled hemorrhage; such a model could be used for automated decision support, to help clinicians decide when to provide intravascular volume to achieve MAP goals. This was a secondary analysis of adult swine subjects during uncontrolled splenic bleeding. By protocol, after developing severe hypotension (MAP < 60 mmHg), subjects were resuscitated with either saline (NS) or fresh frozen plasma (FFP), determined randomly.

Radiology-pathology correlation for bone and soft tissue tumors or tumor-like masses: single institutional experience after implementation of a weekly conference.

Objectives: To determine the frequency of non-diagnostic and discordant results from bone and soft tissue biopsies performed at our institution over a 3-year period and to investigate whether implementation of a weekly musculoskeletal radiology-pathology correlation conference decreased the time to appropriate patient management in cases of discordance.

Methods: Consecutive image-guided core needle biopsy results obtained over a 12 month period of time were reviewed in a retrospective fashion. Following implementation of the correlation conference, subsequent consecutive image-guided core needle biopsy results obtained over a 26 month period of time were reviewed in a prospective fashion.

Freedom of assembly: metabolic enzymes come together.

Many different enzymes in intermediate metabolism dynamically assemble filamentous polymers in cells, often in response to changes in physiological conditions. Most of the enzyme filaments known to date have only been observed in cells, but in a handful of cases structural and biochemical studies have revealed the mechanisms and consequences of assembly. In general, enzyme polymerization functions as a mechanism to allosterically tune enzyme kinetics, and it may play a physiological role in integrating metabolic signaling.