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. Systemic infusion of a cathepsin-B activatable near-infrared probe as a biomarker for autophagy and detection via noninvasive three-dimensional fluorescence molecular tomography combined with computerized tomography to quantitate temporal changes, indicated increased activity in the myocardium of WT mice after myocardial infarction which was attenuated in Ad-KO. Seven days of ischemia increased myocardial adiponectin accumulation and elevated ULK1/AMPK phosphorylation and autophagy assessed by Western blotting for LC3 and p62, an outcome not observed in Ad-KO mice. Cell death, assessed by TUNEL analysis and the ratio of Bcl-2:Bax, plus cardiac dysfunction, measured using echocardiography with strain analysis, were exacerbated in Ad-KO mice. Using cellular models, we observed that adiponectin stimulated autophagy flux in isolated primary adult cardiomyocytes and increased basal and hypoxia-induced autophagy in H9c2 cells. Real-time temporal analysis of caspase-3/7 activation and caspase-3 Western blot indicated that adiponectin suppressed activation by hypoxia. Hypoxia-induced mitochondrial reactive oxygen species production and cell death were also attenuated by adiponectin. Importantly, the ability of adiponectin to reduce caspase-3/7 activation and cell death was not observed in autophagy-deficient cells generated by CRISPR-mediated deletion of Atg7. Collectively, our data indicate that adiponectin acts in an autophagy-dependent manner to attenuate cardiomyocyte caspase-3/7 activation and cell death in response to hypoxia in vitro and ischemia in mice.

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

Background: 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. Methods: Retrospective analysis of 3 hospitals' cohorts of adult ICU patients during continuous vasopressor infusion. Two cohorts were general, mixed ICU patients and one was exclusively acute spinal cord injury patients. "Hypotension-clusters" were defined where there were ≥10 min of cumulative hypotension over a 60-min period and "constant hypotension" was ≥10 continuous minutes. Trend analysis was performed (predicting future MAP using 14 min of preceding MAP data) to understand which hypotension-clusters could likely have been predicted by clinician awareness of MAP trends. Results: In cohorts of 155, 66, and 16 ICU stays, respectively, the majority of hypotension occurred within the hypotension-clusters. Failures to keep MAP above the hypotension threshold were notable in the bottom quartiles of each cohort, with hypotension durations of 436, 167, and 468 min, respectively, occurring within hypotension-clusters per day. Mean arterial pressure trend analysis identified most hypotension-clusters before any constant hypotension occurred (81.2%-93.6% sensitivity, range). The positive predictive value of hypotension predictions ranged from 51.4% to 72.9%. Conclusions: Across 3 cohorts, most hypotension occurred in temporal clusters of hypotension that were usually predictable from extrapolation of MAP trends.

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. In response to the worst statewide opioid and methamphetamine epidemics in the USA, a Hybrid Type 2 trial of PRE-FAIR-a prevention intervention for parents-is being implemented in five Oregon counties. Establishing strong partnerships within the communities helped identify the need to implement the evidence-based FAIR treatment model alongside PRE-FAIR. A strong focus on implementation includes meeting the needs of communities and establishing the infrastructure necessary for sustainment of the FAIR programs at the provider agencies. Despite implementation efforts to direct toward PRE-FAIR referrals, parents in need of treatment are being referred at a disproportionate rate, as are older parents who fall outside of study-eligibility. Both challenges have delayed the ability to enroll a sufficient number of participants for the prevention trial. This commentary describes the impact of the opioid and methamphetamine epidemics in Oregon as the crises relate to implementing prevention versus treatment interventions-highlighting the importance of addressing community needs and establishing strong partnerships, which has allowed creative strategies to increase PRE-FAIR recruitment.

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. NIOSH has pioneered basic and applied research on occupational hearing risks and preventive measures. The Institute has issued recommendations and promoted effective interventions through mechanisms ranging from formal criteria documents to blogs and social media. NIOSH has conducted surveillance and published statistics to guide policy and target prevention efforts. Over the past five decades, substantial progress has been made in raising awareness of noise as a hazard, reducing the risk of occupational hearing loss, improving the use of hearing protection, and advancing measurement and control technologies. Nevertheless, noise remains a prevalent workplace hazard and occupational hearing loss is still one of the most common work-related conditions. NIOSH continues to work toward preventing the effects of noise and ototoxicants at work and has many resources to assist audiologists in their hearing loss prevention efforts.

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.

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 (69.0% female) aged 50 years or greater with CT scans of the abdomen/pelvis and DXA within 1 year of each other. Volumetric semi-automated segmentation of each vertebral body was performed using 3D-Slicer to obtain the CT attenuation of each vertebra. Radiomic features based on the CT attenuation of the lumbar vertebrae were created. The data were randomly split into training/validation (90%) and test datasets (10%). We used two multivariate machine learning models: a support vector machine (SVM) and a neural net (NN) to predict which vertebra(e) were excluded from DXA analysis. RESULTS: L1, L2, L3, and L4 were excluded from DXA in 8.7% (87/995), 9.9% (99/995), 32.3% (321/995), and 42.6% (424/995) patients, respectively. The SVM had a higher area under the curve (AUC = 0.803) than the NN (AUC = 0.589) for predicting whether L1 would be excluded from DXA analysis (P = 0.015) in the test dataset. The SVM was better than the NN for predicting whether L2 (AUC = 0.757 compared to AUC = 0.478), L3 (AUC = 0.699 compared to AUC = 0.555), or L4 (AUC = 0.751 compared to AUC = 0.639) were excluded from DXA analysis. CONCLUSIONS: Machine learning algorithms could be used to identify which lumbar vertebrae would be excluded from DXA analysis and should not be used for opportunistic CT screening analysis. The SVM was better than the NN for identifying which lumbar vertebra should not be used for opportunistic CT screening analysis.

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. RP7214 is a potent and selective inhibitor of human DHODH and has shown antiviral and antileukaemic activity in preclinical studies. This paper describes the phase I study that evaluated the safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy volunteers (HVs). The study was a randomized, double-blind, placebo-controlled trial of single dose (100, 200 and 400 mg QD), multiple doses (200 and 400 mg BID for 7 days) and a food effect study at a single dose of 200 mg. A total of 18, 12 and 12 HVs were enrolled in the SAD, MAD and food effect parts of the study, respectively. RP7214 was well tolerated at all dose levels. There were 20 treatment-emergent adverse events (TEAEs) reported, out of which most were mild to moderate in severity while three TEAEs were grade ≥3. RP7214 showed accumulation on multiple dosing. Steady-state concentrations were reached within about 3-6 days. The mean plasma half-life at steady-state was 12.8 hours (9.9-15.3). Food did not impact the absorption of RP7214. Inhibition of DHODH, as evidenced by increased dihydroorotate levels, was observed, confirming target engagement. The high systemic exposure with a favourable safety profile shows potential for the development of RP7214 in SARS-CoV-2 and acute myeloid leukaemia (NCT04680429).

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. MATERIALS AND METHODS: Two hundred patients undergoing hip-to-ankle radiographs for TKA planning were retrospectively reviewed. The MAD and HKAA were measured using previously published methods by the Visage picture archiving and communication systems (PACS) tools. Receiver operator characteristic (ROC) curves were used to evaluate the performance of the MAD to predict HKAA by gender and height. The performance of a linear model was used to predict HKAA from MAD in a prospectively collected cohort of 40 patients. Paired t tests were used for the comparison of time measurement in MAD and HKAA in this cohort. RESULTS: MAD strongly correlated with HKAA (r = 0.99, p < 0.001); however, the performance of MAD differed by height (p = 0.005) and sex (p < 0.001). There was no significant difference in the time taken to measure HKAA versus MAD (p > 0.05). CONCLUSION: HKAA should be used instead of the MAD because it is more clinically relevant and takes the same amount of time to be measured.

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. The frame was found to bias the perceived orientation of rods presented as much as 185 msec before frame onset. To explain this postdictive effect, we propose a differential latency model, where the latency of the orientation judgment is greater than the latency of the contextual cues' initial impact on the egocentric reference frame. In a subsequent test of this model, we decreased the luminance of the rod, which is known to increase visual afferent delays and slow decision processes. This further slowing of the orientation judgment caused the frame-induced bias to affect the perceived orientation of rods presented even further in advance of the frame. These findings indicate that the brain fails to compensate for a mismatch between the timing of orientation judgments and the incorporation of visual cues into the egocentric reference 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. The radiologist should be aware of the varying types of shoulder arthroplasties, what preoperative findings influence that decision and the expected postoperative appearance of the differing components.

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. Mechanistically we find that NUAK2 suppresses the expression of GPX4 at the RNA level and enhances ferroptosis triggered by GPX4 inhibitors in a manner independent of its kinase activity. NUAK2 is amplified along with MDM4 in a subset of breast cancers, particularly the claudin-low subset, suggesting that this may predict vulnerability to GPX4 inhibitors. These findings identify a novel pathway regulating GPX4 expression as well as ferroptotic sensitivity with potential as a biomarker of breast cancer patients that might respond to GPX4 inhibition as a therapeutic strategy.

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. Using focal animal sampling we collected 197 observation hours of data on 13 subadult males from two groups (6 from Celagi; 7 from Riting) at the Uluwatu temple site from May 2017 to March 2018, recording 44 exchanges of items for food from 92 total robberies following 176 total attempts. We also measured dominance rank using interaction data from our focal animals. Dominance rank was strongly positively correlated with robbery efficiency in Riting, but not Celagi, meaning that more dominant Riting subadult males exhibited fewer overall robbery attempts per successful robbery. We suggest the observed variation in robbing and bartering practices indicates there are crucial, yet still unexplored, social factors at play for individual robbing and bartering decisions.

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. Representative cases are provided to illustrate the usability of the algorithms.

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. Following treatment with LY3358966, phosphate uptake into plasma 15 min following an oral dose of radiolabeled phosphate was decreased 74% and 22% in mice and rats, respectively, indicating NPT2b plays a much more dominant role in mice than rats. Following the treatment with LY3358966 and radiolabeled phosphate, mouse feces were collected for 48 h to determine the ability of LY3358966 to inhibit phosphate absorption. Compared to vehicle-treated animals, there was a significant increase in radiolabeled phosphate recovered in feces (8.6% of the dose, p < .0001). Similar studies performed in rats also increased phosphate recovered in feces (5.3% of the dose, p < .05). When used in combination with the phosphate binder sevelamer in rats, there was a further small, but not significant, increase in fecal phosphate. In conclusion, LY3358966 revealed a more prominent role for NPT2b on acute intestinal phosphate uptake into plasma in mice than rats. However, the modest effects on total intestinal phosphate absorption observed in mice and rats with LY3359866 when used alone or in combination with sevelamer highlights the challenge to identify new more effective therapeutic targets and/or drug combinations to treat the phosphate burden in patients with renal disease.

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. Following this reasoning, we asked participants to locate visual and auditory probes in a crossmodal variant of the induced Roelofs effect, a visual illusion in which a large, off-center visual frame biases the observer's perceived straight-ahead. Auditory probes were mislocalized in the same direction and with a similar magnitude as visual probes due to the off-center visual frame. However, an off-center auditory frame did not elicit a significant mislocalization of visual probes, indicating that auditory context does not elicit an induced Roelofs effect. These results suggest that the locations of auditory and visual stimuli are represented within a common frame of reference, but that the brain does not rely on stationary auditory context, as it does visual, to maintain this reference frame. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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. Here, in a series of cryogenic-electron microscopy structures we show that human IMPDH1 assembles polymorphic filaments with different assembly interfaces in extended and compressed states. Retina-specific splice variants introduce structural elements that reduce sensitivity to GTP inhibition, including stabilization of the extended filament form. Finally, we show that IMPDH1 disease mutations fall into two classes: one disrupts GTP regulation and the other has no effect on GTP regulation or filament assembly. These findings provide a foundation for understanding the role of IMPDH1 in retinal function and disease and demonstrate the diverse mechanisms by which metabolic enzyme filaments are allosterically regulated.

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. Group 1: balanced salt solution drops only, group 2: 0.2% RB only, group 3: green light exposure (525 nm, 5.4 J/cm2) only, group 4: 0.1% RB-PDAT, and group 5: 0.1% RB-PDAT. All rabbits were followed clinically. Group 5 rabbits were followed using anterior segment optical coherence tomography (AS-OCT) and clinically. On day 35 after initial treatment, 1 rabbit from group 5 was re-exposed to green light (5.4 J/cm2) to evaluate reactivation of the remaining RB dye, and terminal deoxynucleotyl transferase-mediated UTP-biotin-nick-end labeling assay was performed on corneal cryosections. RESULTS: Complete reepithelization was observed, and corneas remained clear after treatment in all groups. In group 5, AS-OCT revealed a cross-linking demarcation line. AS-OCT showed RB fluorescence and collagen cross-linking in all treated eyes of group 5 animals after 5 weeks of treatment. Photobleached RB retention in the corneal stroma was corroborated by fluorescence confocal microscopy on frozen sections. There was no evidence of a sustained cytotoxic effect through terminal deoxynucleotyl transferase-mediated UTP-biotin-nick-end labeling at 5 weeks. CONCLUSIONS: RB-PDAT with 0.1% RB is a safe procedure. There was no difference clinically and on histopathology compared with control groups. In eyes where RB dye is retained in the corneal stroma after 1 month of treatment, oxidative stress is not evidenced at long term.

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. From July 25th, 2020 to November 15th, 2020, we collected weekly tweets related to COVID19 keywords and assessed their networks, patterns and properties. Our analyses revealed the dominance of a handful of individual accounts as central structuring agents in the networks of tens of thousands of tweets and retweets, and thus millions of views, related to specific COVID19 keywords. These few individual accounts and the content of their tweets, mentions, and retweets are substantially overrepresented in terms of public exposure to, and thus interaction with, critical elements of public health information in the pandemic. Here we report on one particularly striking aspect of our dataset: the prominent position of @realdonaldtrump in Twitter networks related to four key terms of the COVID19 pandemic in 2020.

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. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition.

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 (1O2). Singlet oxygen dosimetry can help optimize treatment parameters. We present a 1O2 dosimeter for detection of 1O2 generated during experimental RB-PDAT. The system uses a 520 nm laser and an InGaAs photoreceiver with bandpass filters to detect 1O2 luminescence during irradiation. The system was validated in RB solutions and ex vivo in human donor eyes. The results demonstrate the feasibility of 1O2 dosimetry in an experimental model of RB-PDAT in the cornea.