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Background: Depression and anxiety negatively affect asthma-related quality of life (QoL). Yet, little is known regarding mood and asthma-related factors that best uniquely explain asthma-related QoL in children., Objective: This cross-sectional study evaluated the unique variance explained by caregiver and child depressive and anxiety symptom severity in child asthma-related QoL, apart from that explained by demographics and asthma control., Methods: Children aged 7 to 17 years with asthma (n = 205) and their caregivers with major depressive disorder were included. A 3-stage hierarchical linear regression analysis was conducted with the Pediatric Asthma Quality of Life Questionnaire total scores considered as the outcome. Predictors included demographic characteristics (stage 1); asthma control assessed by the Asthma Control Test (stage 2); and caregiver depression and anxiety (Hamilton Rating Scale for Depression and the Spielberger State/Trait Anxiety Scale) and child depression and anxiety (Children's Depression Inventory and the Screen for Child Anxiety-Related Disorders) (stage 3)., Results: Demographic characteristics accounted for only 5.5% of the Pediatric Asthma Quality of Life Questionnaire scores. Asthma control significantly increased variance explained in QoL to 32.6%, whereas caregiver and child depression and anxiety symptoms significantly increased variance explained to 42.6%. Child anxiety was found to uniquely explain the largest proportion of variance in QoL (r s 2 = 0.584)., Conclusion: After adjusting variance in QoL for demographic characteristics and asthma control, caregiver and child depression and anxiety measures significantly increased the proportion of variance explained in a child's asthma-related QoL. In addition to better asthma control, child and caregiver depression and anxiety should be addressed to increase child asthma-related QoL., Trial Registration: ClinicalTrials.gov Identifier: NCT02809677., Competing Interests: Disclosures Dr Brown reports serving on an advisory board for Medscape/WebMD. The other authors have no conflicts of interest to report., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: This study updates the American Association for the Surgery of Trauma (AAST) Organ Injury Scale (OIS) for renal trauma using evidence-based criteria for bleeding control intervention., Methods: This was a secondary analysis of a multicenter retrospective study including patients with high-grade renal trauma from seven level 1 trauma centers from 2013 to 2018. All eligible patients were assigned new renal trauma grades based on revised criteria. The primary outcome used to measure injury severity was intervention for renal bleeding. Secondary outcomes included intervention for urinary extravasation, units of packed red blood cells transfused within 24 hours, and mortality. To test the revised grading system, we performed mixed-effect logistic regression adjusted for multiple baseline demographic and trauma covariates. We determined the area under the curve (AUC) to assess accuracy of predicting bleeding interventions from the revised grading system and compared this to 2018 AAST OIS., Results: Based on the 2018 OIS grading system, we included 549 patients with AAST grades III to V injuries and computed tomography scans (III, 52% [n = 284]; IV, 45% [n = 249]; and V, 3% [n = 16]). Among these patients, 89% experienced blunt injury (n = 491), and 12% (n = 64) underwent intervention for bleeding. After applying the revised grading criteria, 60% (n = 329) of patients were downgraded, and 4% (n = 23) were upgraded; 2.8% (n = 7) downgraded from grade V to IV, and 69.5% (n = 173) downgraded from grade IV to III. The revised renal trauma grading system demonstrated improved predictive ability for bleeding interventions (2018 AUC, 0.805; revised AUC, 0.883; p = 0.001) and number of units of packed red blood cells transfused. When we removed urinary injury from the revised system, there was no difference in its predictive ability for renal hemorrhage intervention., Conclusion: A revised renal trauma grading system better delineates the need for hemostatic interventions than the current AAST OIS renal trauma grading system., Level of Evidence: Diagnostic Test/Criteria; Level III., (Copyright © 2024 American Association for the Surgery of Trauma.)

Lys ubiquitination is catalysed by E3 ubiquitin ligases and is central to the regulation of protein stability and cell signalling in normal and disease states. There are gaps in our understanding of E3 mechanisms, and here we use protein semisynthesis, chemical rescue, microscale thermophoresis and other biochemical approaches to dissect the role of catalytic base/acid function and conformational interconversion in HECT-domain E3 catalysis. We demonstrate that there is plasticity in the use of the terminal side chain or backbone carboxylate for proton transfer in HECT E3 ubiquitin ligase reactions, with yeast Rsp5 orthologues appearing to be possible evolutionary intermediates. We also show that the HECT-domain ubiquitin covalent intermediate appears to eject the E2 conjugating enzyme, promoting catalytic turnover. These findings provide key mechanistic insights into how protein ubiquitination occurs and provide a framework for understanding E3 functions and regulation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one-third of the human genome through a 'copy and paste' mechanism catalysed by its multifunctional enzyme, open reading frame 2 protein (ORF2p) 1 . ORF2p reverse transcriptase (RT) and endonuclease activities have been implicated in the pathophysiology of cancer 2,3 , autoimmunity 4,5 and ageing 6,7 , making ORF2p a potential therapeutic target. However, a lack of structural and mechanistic knowledge has hampered efforts to rationally exploit it. We report structures of the human ORF2p 'core' (residues 238-1061, including the RT domain) by X-ray crystallography and cryo-electron microscopy in several conformational states. Our analyses identified two previously undescribed folded domains, extensive contacts to RNA templates and associated adaptations that contribute to unique aspects of the L1 replication cycle. Computed integrative structural models of full-length ORF2p show a dynamic closed-ring conformation that appears to open during retrotransposition. We characterize ORF2p RT inhibition and reveal its underlying structural basis. Imaging and biochemistry show that non-canonical cytosolic ORF2p RT activity can produce RNA:DNA hybrids, activating innate immune signalling through cGAS/STING and resulting in interferon production 6-8 . In contrast to retroviral RTs, L1 RT is efficiently primed by short RNAs and hairpins, which probably explains cytosolic priming. Other biochemical activities including processivity, DNA-directed polymerization, non-templated base addition and template switching together allow us to propose a revised L1 insertion model. Finally, our evolutionary analysis demonstrates structural conservation between ORF2p and other RNA- and DNA-dependent polymerases. We therefore provide key mechanistic insights into L1 polymerization and insertion, shed light on the evolutionary history of L1 and enable rational drug development targeting L1., (© 2023. The Author(s).)