Active deprescribing attitudes and practices in a large regional tertiary health service: a mixed methods study.

In this pilot study, we explored current attitudes and deprescribing practices of clinicians in a large regional health service through a mixed methods approach. Respondents included doctors, pharmacists and nurse practitioners, who outlined three themes including professional and organisational contexts, disconnect between goals and practices and factors influencing deprescribing.

A better representation of VOC chemistry in WRF-Chem and its impact on ozone over Los Angeles.

The declining trend in vehicle emissions has underscored the growing significance of Volatile Organic Compound (VOC) emissions from Volatile Chemical Products (VCP). However, accurately representing VOC chemistry in simplified chemical mechanisms remains challenging due to its chemical complexity including speciation and reactivity. Previous studies have predominantly focused on VOCs from fossil fuel sources, leading to an underrepresentation of VOC chemistry from VCP sources. We developed an integrated chemical mechanism, RACM2B-VCP, that is compatible with WRF-Chem and is aimed to enhance the representation of VOC chemistry, particularly from VCP sources, within the present urban environment. Evaluation against the Air Quality System (AQS) network data demonstrates that our model configured with RACM2B-VCP reproduces both the magnitude and spatial variability of O3 as well as PM2.5 in Los Angeles. Furthermore, evaluation against comprehensive measurements of O3 and PM2.5 precursors from the Reevaluating the Chemistry of Air Pollutants in California (RECAP-CA) airborne campaign and the Southwest Urban NO x and VOC Experiment (SUNVEx) ground site and mobile laboratory campaign, confirm the model's accuracy in representing NOx and many VOCs and highlight remaining biases. Although there exists an underprediction in the total VOC reactivity of observed VOC species, our model with RACM2B-VCP exhibits good agreement for VOC markers emitted from different sectors, including biogenic, fossil fuel, and VCP sources. Through sensitivity analyses, we probe the contributions of VCP and fossil fuel emissions to total VOC reactivity and O3. Our results reveal that 52% of the VOC reactivity and 35% of the local enhancement of MDA8 O3 arise from anthropogenic VOC emissions in Los Angeles. Significantly, over 50% of this anthropogenic fraction of either VOC reactivity or O3 is attributed to VCP emissions. The RACM2B-VCP mechanism created, described, and evaluated in this work is ideally suited for accurately representing ozone for the right reasons in the present urban environment where mobile, biogenic, and VCP VOCs are all important contributors to ozone formation.

Changes in Human Meibum Lipid Composition Related to the Presence and Severity of Meibomian Gland Dysfunction.

Purpose: Changes in meibum composition and quantity in meibomian gland dysfunction (MGD) result in tear film instability and dry eye. This exploratory study aimed to identify changes in (O-acyl)-ω-hydroxy fatty acid (OAHFA) and hydrocarbon chain (HC) unsaturation levels in meibum related to the presence and severity of MGD. Methods: Meibum samples were collected from 3 cohorts of adults with no MGD, mild-to-moderate MGD, and severe MGD in a noninterventional clinical trial (NCT01979887). OAHFAs, cholesterol esters (CE), HC unsaturation, and HC length in the meibum samples were quantified with 1H-nuclear magnetic resonance spectroscopy using 2 methods of normalization. Results: Meibum samples from 62 subjects were analyzed: 21 non-MGD, 21 mild-to-moderate MGD, and 20 severe MGD. Meibum OAHFA and CE levels and HC unsaturation were reduced with increasing severity of MGD, with most pairwise comparisons significant (P < 0.05, t-tests), following the order non-MGD > mild-to-moderate MGD > severe MGD. Regardless of the resonances used for normalization, each pairwise comparison of OAHFA, CE, and HC unsaturation levels in MGD (combined severities) versus non-MGD samples was significant (P < 0.01, t-test). Analysis using various normalization equations showed reductions of 20%-22% for OAHFAs, 51%-57% for CE, and 36%-66% for HC unsaturation in MGD (combined severities) compared with non-MGD. HC length was not altered in MGD (combined severities) compared with non-MGD samples (t-test). Conclusions: Meibum OAHFA, CE, and HC unsaturation levels were reduced in MGD and were lowest in the severe MGD cohort. These findings may contribute to the understanding of the pathophysiology of MGD.

Patient perspectives on incretin-based weight loss medications and relationship with demographic factors.

Objective: Treatment of obesity has been transformed by the recent approval of incretin-based therapies for weight loss (e.g., glucagon-like peptide 1 agonist semaglutide), but little is known about patient perspectives on these medications. Methods: Between December 2023 and March 2024, healthcare patients from an academic medical center in the Southeast United States with Body Mass Index ≥30 kg/m2 completed a cross-sectional online survey on attitudes toward incretin-based medications. Results: Compared to patients with a bachelor's degree, those without a degree were less likely to be aware of incretin-based pharmacotherapies (96% vs. 78%) and to have discussed pharmacotherapies with a doctor (43% vs. 27%) but had greater interest in using these pharmacotherapies (4.3 vs. 4.7). These pharmacotherapy-related variables did not differ significantly according to gender, race, or financial security. Concerns about side effects, long-term health risks, and potential for weight regain were highly endorsed and were associated with lower interest in using incretin-based therapies and with some demographic factors. Patients reported high interest in lifestyle programs designed for individuals taking anti-obesity medications. Conclusion: Demographic considerations, notably education level, should be factored into the strategy to promote equitable utilization of incretin-based therapies, particularly as their accessibility expands.

Sarcoidosis with laryngeal and tracheal involvement.

A woman in her early 30s presented to her primary care physician's office with hoarseness, joint pain and facial swelling. The objective evaluation revealed elevated inflammatory markers and angiotensin-1-converting enzyme, a chest radiograph with bilateral hilar prominence and a maxillofacial CT scan with diffuse inflammation in the upper airway. Otolaryngology evaluation revealed exophytic lesions diffusely within the nasal cavity, base of tongue, supraglottis, glottis and trachea. A biopsy confirmed the diagnosis of sarcoidosis. She was treated with corticosteroids with improvement in upper and lower airway symptoms. She continued to experience other extrapulmonary manifestations of sarcoidosis requiring alternative immunosuppressant therapy. At 30 months from symptom onset, her disease was noted to be in remission.

Intraparenchymal Chordoma in the Brain Stem: A Review of Surgical Management and Case Highlight.

We present a rare case of an intraparenchymal chordoma in the brain stem of a 69-year-old male with a history of multiple chordoma recurrences. Chordomas are uncommon tumors that originate from notochordal remnants, with intraparenchymal presentations in the brain stem being particularly rare. A 69-year-old male with a history of clival chordoma three years after primary endoscopic resection and adjuvant proton-beam radiotherapy and a recurrence one year postoperatively for which he underwent a second surgery, presented with severe headaches, weakness, diaphoresis, and difficulty ambulating. Head CT in the ER revealed a 2.7 x 3.5 cm hyperdense lesion in the pons, indicating acute hemorrhage. Magnetic resonance imaging (MRI) suggested a hemorrhagic radiation-induced cavernoma. A right retrosigmoid craniotomy was performed, and the lesion was resected without major complications. Final pathology reported an intraparenchymal hemorrhagic chordoma. To our knowledge, this is the first case of intra-axial chordoma, particularly in the brain stem. It highlights the importance of considering intraparenchymal chordoma on the differential when evaluating for recurrence versus other treatment-induced pathologies and changes. This may prompt the neurosurgeon to reconsider treatment options and weigh the risks of watchful waiting versus biopsy or even aggressive surgical management.

A Transcriptomics Analysis of the Regulation of Lens Fiber Cell Differentiation in the Absence of FGFRs and PTEN.

Adding 50% vitreous humor to the media surrounding lens explants induces fiber cell differentiation and a significant immune/inflammatory response. While Fgfr loss blocks differentiation in lens epithelial explants, this blockage is partially reversed by deleting Pten. To investigate the functions of the Fgfrs and Pten during lens fiber cell differentiation, we utilized a lens epithelial explant system and conducted RNA sequencing on vitreous humor-exposed explants lacking Fgfrs, or Pten or both Fgfrs and Pten. We found that Fgfr loss impairs both vitreous-induced differentiation and inflammation while the additional loss of Pten restores these responses. Furthermore, transcriptomic analysis suggested that PDGFR-signaling in FGFR-deficient explants is required to mediate the rescue of vitreous-induced fiber differentiation in explants lacking both Fgfrs and Pten. The blockage of ß-crystallin induction in explants lacking both Fgfrs and Pten in the presence of a PDGFR inhibitor supports this hypothesis. Our findings demonstrate that a wide array of genes associated with fiber cell differentiation are downstream of FGFR-signaling and that the vitreous-induced immune responses also depend on FGFR-signaling. Our data also demonstrate that many of the vitreous-induced gene-expression changes in Fgfr-deficient explants are rescued in explants lacking both Fgfrs and Pten.

Attuned to the Flux of Life: Relations Between Ability Emotional Intelligence and Emotional Reactivity.

The field of ability-related emotional intelligence (ability EI) could benefit from new perspectives concerning dynamic operations. According to a recent perspective, variations in ability EI are likely to be linked to variations in skills related to evaluation. This perspective contends, perhaps counterintuitively, that higher levels of ability EI are likely to be linked to higher levels of emotional reactivity, defined in terms of stronger event-emotion relationships. Two studies (total N = 245) pursue such ideas in the context of multilevel models involving event valence and emotional experience. Variations in ability EI modulated event-emotion relationships in the context of laboratory inductions involving hypothetical events (Study 1), affective images varying in valence (Study 1), and with respect to naturally occurring variations in positive and negative daily events (Study 2), such that higher levels of ability EI were linked to stronger event-emotion relationships, regardless of whether events and emotions were positive or negative in valence. These results provide new evidence for recent theorizing concerning ability EI while speaking to functional versus dysfunctional perspectives on emotional reactivity.

AAV gene replacement therapy for treating MPS IIIC: Facilitating bystander effects via EV-mRNA cargo.

MPS IIIC is a lysosomal storage disease caused by mutations in heparan-α-glucosaminide N-acetyltransferase (HGSNAT), for which no treatment is available. Because HGSNAT is a trans-lysosomal-membrane protein, gene therapy for MPS IIIC needs to transduce as many cells as possible for maximal benefits. All cells continuously release extracellular vesicles (EVs) and communicate by exchanging biomolecules via EV trafficking. To address the unmet need, we developed a rAAV-hHGSNATEV vector with an EV-mRNA-packaging signal in the 3'UTR to facilitate bystander effects, and tested it in an in vitro MPS IIIC model. In human MPS IIIC cells, rAAV-hHGSNATEV enhanced HGSNAT mRNA and protein expression, EV-hHGSNAT-mRNA packaging, and cleared GAG storage. Importantly, incubation with EVs led to hHGSNAT protein expression and GAG contents clearance in recipient MPS IIIC cells. Further, rAAV-hHGSNATEV transduction led to the reduction of pathological EVs in MPS IIIC cells to normal levels, suggesting broader therapeutic benefits. These data demonstrate that incorporating the EV-mRNA-packaging signal into a rAAV-hHGSNAT vector enhances EV packaging of hHGSNAT-mRNA, which can be transported to non-transduced cells and translated into functional rHGSNAT protein, facilitating cross-correction of disease pathology. This study supports the therapeutic potential of rAAVEV for MPS IIIC, and broad diseases, without having to transduce every cell.

Astrocytic PAR1 and mGluR2/3 control synaptic glutamate time course at hippocampal CA1 synapses.

Astrocytes play an essential role in regulating synaptic transmission. This study describes a novel form of modulation of excitatory synaptic transmission in the mouse hippocampus by astrocytic G-protein-coupled receptors (GPCRs). We have previously described astrocytic glutamate release via protease-activated receptor-1 (PAR1) activation, although the regulatory mechanisms for this are complex. Through electrophysiological analysis and modeling, we discovered that PAR1 activation consistently increases the concentration and duration of glutamate in the synaptic cleft. This effect was not due to changes in the presynaptic glutamate release or alteration in glutamate transporter expression. However, blocking group II metabotropic glutamate receptors (mGluR2/3) abolished PAR1-mediated regulation of synaptic glutamate concentration, suggesting a role for this GPCR in mediating the effects of PAR1 activation on glutamate release. Furthermore, activation of mGluR2/3 causes glutamate release through the TREK-1 channel in hippocampal astrocytes. These data show that astrocytic GPCRs engage in a novel regulatory mechanism to shape the time course of synaptically-released glutamate in excitatory synapses of the hippocampus.

Feelings as a currency of care: A role for agreeableness in emotional reactivity.

OBJECTIVE AND BACKGROUND: The personality trait of agreeableness is linked to a number of core tendencies (e.g., empathy, warmth) that operate in a feeling-based manner. Following considerations of this type, it is proposed that the motivations and characteristics of agreeable individuals, relative to disagreeable individuals, should render them more receptive to emotional events and more responsive to them for this reason. METHOD: Potential links between agreeableness and emotional reactivity were assessed in two studies involving four samples (total N = 517) in which participants continuously rated their feeling states in response to a variety of affective images. RESULTS: Agreeableness did not predict the speed with which emotional reactions began, but agreeable individuals exhibited higher-magnitude peak intensities, regardless of whether stimuli were appetitive (pleasant) or aversive (unpleasant) in nature. CONCLUSIONS: The findings provide novel insights into the personality trait of agreeableness, emotional reactivity phenomena, and the dynamic processes that link agreeableness to emotion.

Ability-Related Emotional Intelligence: An Introduction.

Emotionally intelligent people are thought to be more skilled in recognizing, thinking about, using, and regulating emotions. This construct has garnered considerable interest, but initial enthusiasm has faded and it is time to take stock. There is consensus that ability-related measures of emotional intelligence (EI) can be favored to self-report tests, in part because the resulting scores cannot be equated with personality traits. However, there are questions surrounding measurement as well as predictive value. Experts in the field were encouraged to chart new directions, with the idea that these new directions could reinvigorate EI scholarship. Special Issue papers speak to theory, mechanism, measurement, and training. In addition, these papers seek to forge links with research traditions focused on interpersonal perception, emotional awareness, and emotion regulation. As a result of these efforts, new insights into what EI is and how it works can be anticipated in upcoming years.

Using a Novel, Subconjunctival, Sustained-Release Mitomycin C Formulation in a Rabbit Model of Filtration Surgery with Gel Stent Implantation.

Purpose: To investigate gel stent implantation with and without intraoperative sustained-release mitomycin C (MMC SR) in a rabbit model for gel stent implantation, and to examine aqueous humor outflow (AHO) postimplantation. Methods: Four groups of rabbits were included. Group 1 was untreated (control). Groups 2, 3, and 4 received the gel stent without MMC, with MMC solution (subconjunctival injection), and with MMC SR (subconjunctival injection), respectively. Intraocular pressure (IOP) and AHO were assessed via tonometry and indocyanine green-based angiography, respectively. The main efficacy measure was change in IOP from baseline. Results: Following gel stent implantation, Groups 2, 3, and 4 maintained ≥20% IOP reduction (response) for a median duration of 1 week, 6.5 weeks, and 30 weeks, respectively. Angiography showed normal aqueous humor drainage (Group 1) beginning at the perilimbal trabecular plexus and continuing posteriorly to episcleral outflow vessels. Following implantation, drainage occurred preferentially and directly into the subconjunctival bleb. Conclusions: Gel stent implantation with MMC SR was most effective in achieving sustained, long-term IOP reduction in the rabbit model, compared with implantation with or without MMC solution. Bleb presence and the postimplantation aqueous angiography results indicated redirection of the AHO to the subconjunctival vasculature and presumed lymphatics, suggesting efficient glaucoma filtration to lower IOP in this model. This rabbit model and aqueous angiography may help refine understanding of the mechanism of action of minimally invasive glaucoma surgeries and ultimately translate to improved surgical devices and procedures for patients with glaucoma.

Threat sensitivity in emotion dynamics: Negativity effects and sex differences.

Evolutionary theorizing has given rise to the idea that responding to any particular threat may be more mandatory than responding to any particular reward. The present three experiments (total N = 375) sought to provide support for this perspective in an emotion dynamics task in which participants continuously rated their affective state in response to appetitive (reward-related) versus aversive (threat-related) images. Even when equating images for arousal and extremity, several negativity effects (e.g., steeper reactivity slopes in response to aversive images) were found. These negativity effects can serve as an experimental model of threat sensitivity, which should predispose some individuals, more than others, to symptoms related to fear and anxiety. This point was made with respect to sex differences, given that women (relative to men) are diagnosed with anxiety disorders at higher rates. Sex differences were pronounced and extensions of this work, both basic and applied, are proposed.

miR-26 Deficiency Causes Alterations in Lens Transcriptome and Results in Adult-Onset Cataract.

Purpose: Despite strong evidence demonstrating that normal lens development requires regulation governed by microRNAs (miRNAs), the functional role of specific miRNAs in mammalian lens development remains largely unexplored. Methods: A comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance, was conducted by miRNA sequencing. Mouse lenses lacking each of three abundantly expressed lens miRNAs (miR-184, miR-26, and miR-1) were analyzed to explore the role of these miRNAs in lens development. Results: Mice lacking all three copies of miR-26 (miR-26TKO) developed postnatal cataracts as early as 4 to 6 weeks of age. RNA sequencing analysis of neonatal lenses from miR-26TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens enriched and linked to cataract (e.g., Foxe3, Hsf4, Mip, Tdrd7, and numerous crystallin genes) and abnormal elevated expression of genes related to neural development (Lhx3, Neurod4, Shisa7, Elavl3), inflammation (Ccr1, Tnfrsf12a, Csf2ra), the complement pathway, and epithelial to mesenchymal transition (Tnfrsf1a, Ccl7, Stat3, Cntfr). Conclusions: miR-1, miR-184, and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.

The length and spacing of river tributaries.

River networks are composed of a mainstem and tributaries. These tributaries dissect landscapes, regulate water and habitat availability, and transport sediment and nutrients. Despite the importance of tributaries, we currently lack theory and data describing whether and how tributary length and spacing varies within watersheds, thereby limiting our ability to accurately describe river network geometry. We address this knowledge gap by analyzing 4,696 tributaries across six landscapes with varying climate, tectonic setting, and lithology. Our results show that both tributary length and spacing systematically increase with downstream distance along the mainstem river, following a power-law scaling. This power-law scaling can be modulated by basin shape, with tributaries becoming shorter and, in some cases, more closely spaced as basin elongate. Furthermore, the power-law scaling may break down in cases where river networks have been disturbed by pervasive faulting, raising the possibility that the scaling we observe is not unique to all branching networks, and instead may be universal across undisturbed fluvial networks. These findings can be used to improve predictions of river network geometry and potentially to distinguish fluvial river networks from other branching networks.

Mr. Gilbert's World Tour: Rethinking Disabled Veterans Across British Imperial Spaces.

This article provides a comparative analysis of the treatment of disabled First World War veterans in 1920s Britain and the simultaneous care of Imperial Pensioners residing in Australia and South Africa via the detailed administrative reports of a British civil servant, G.F. Gilbert. Imperial Pensioners were disabled veteran migrants of the British Army residing overseas. A study of these veteran populations in Australia and South Africa provides two primary insights into the broader historiography of disabled veterans. Firstly, a comparative case study helps to show the way in which cultural notions of disability were part of broader ideas of nation-building overseas. Secondly, the specific disability diagnosis category chosen as a more in-depth case study can further complicate and contradict broader assessments of national responses. This article attempts to build upon recent transnational histories of veterans by transcending national boundaries and homogenous veteran profiles with an extension in methodological scope by providing an intra-national case study via the Imperial Pensioner.

Evaluation experts: Relations between ability emotional intelligence and attitude strength indicators.

New efforts to understand the processes involved in ability-related emotional intelligence (ability EI) could reinvigorate this area of scholarship and research. It is proposed that participants with higher levels of ability EI are evaluation experts, which should be evident in the attitude domain. Study 1 (n = 148) probed for affective, cognitive, and behavioral reactions to a diverse set of attitude objects. In addition, attitude certainty ratings were collected. Higher levels of ability EI, but not self-reports of EI, were linked to attitudes that were more extreme, certain, and structurally integrated. In Study 2 (n = 602), participant employees completed standard personality and job satisfaction assessments. Higher levels of ability EI were predictive of greater polarization (as assessed in extremity-related terms) in both domains. The individual differences assessed by ability EI, these results suggest, also tend to support attitudes and opinions with stronger features. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

miR-26 deficiency causes alterations in lens transcriptome and results in adult-onset cataract.

Purpose: Despite strong evidence demonstrating that normal lens development requires regulation governed by miRNAs, the functional role of specific miRNAs in mammalian lens development remains largely unexplored. Methods: A comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance was conducted by miRNA-seq. Mouse lenses lacking each of three abundantly expressed lens miRNAs: miR-184, miR-26 and miR-1 were analyzed to explore the role of these miRNAs in lens development. Results: Mice lacking all three copies of miR-26 (miR-26TKO) developed postnatal cataracts as early as 4-6 weeks of age. RNA-seq analysis of neonatal lenses from miR-26TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens-enriched and linked to cataract (e.g. Foxe3, Hsf4, Mip, Tdrd7, and numerous crystallin genes), and abnormal elevated expression of genes related to neural development (Lhx3, Neurod4, Shisa7, Elavl3 ), inflammation (Ccr1, Tnfrsf12a, Csf2ra), the complement pathway, and epithelial to mesenchymal transition (Tnfrsf1a, Ccl7, Stat3, Cntfr). Conclusion: miR-1, miR-184 and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.

Brain energy metabolism: A roadmap for future research.

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.