Arg18 Substitutions Reveal the Capacity of the HIV-1 Capsid Protein for Non-Fullerene Assembly.

In the fullerene cone HIV-1 capsid, the central channels of the hexameric and pentameric capsomers each contain a ring of arginine (Arg18) residues that perform essential roles in capsid assembly and function. In both the hexamer and pentamer, the Arg18 rings coordinate inositol hexakisphosphate, an assembly and stability factor for the capsid. Previously, it was shown that amino-acid substitutions of Arg18 can promote pentamer incorporation into capsid-like particles (CLPs) that spontaneously assemble in vitro under high-salt conditions. Here, we show that these Arg18 mutant CLPs contain a non-canonical pentamer conformation and distinct lattice characteristics that do not follow the fullerene geometry of retroviral capsids. The Arg18 mutant pentamers resemble the hexamer in intra-oligomeric contacts and form a unique tetramer-of-pentamers that allows for incorporation of an octahedral vertex with a cross-shaped opening in the hexagonal capsid lattice. Our findings highlight an unexpected degree of structural plasticity in HIV-1 capsid assembly.

A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.

Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.

Psychopathy measurement practices moderate psychopathy's association with anxiety and depression: A comprehensive meta-analysis.

Theories of psychopathy development traditionally emphasize that individuals high in psychopathy experience diminished internalizing symptoms (e.g., anxiety and depression). However, many studies find null or even positive relationships between psychopathy and internalizing. The current meta-analysis therefore aimed to provide a comprehensive understanding of heterogeneity in psychopathy-anxiety/depression relationships by examining measurement and sample-related variables that may moderate these associations (e.g., psychopathy subdimensions assessed, different measures/operationalizations of psychopathy and anxiety/depression, and demographic characteristics). Results suggest that psychopathy demonstrates a small, positive overall association with anxiety/depression (r = 0.09), which may indicate that psychopathy is unrelated to subjective experiences of anxiety and sadness, but results could also reflect that varying psychopathy and anxiety/depression assessment practices contribute to heterogeneity in psychopathy-anxiety/depression associations. Most notably, results indicate that associations vary substantially across different measures/operationalizations of psychopathy, even when controlling for sample type and informant. Some psychopathy scales could therefore inadvertently capture anxiety/depression symptoms or broader psychopathology in addition to psychopathic traits. Findings from the current meta-analysis can inform future efforts to understand how measurement-related considerations influence relationships between psychopathy and anxiety/depression.

Choanephora infundibulifera Rhinosinusitis in Man with Acute Lymphoblastic Leukemia, Tennessee, USA.

Choanephora infundibulifera is a member of the Mucorales order of fungi. The species is associated with plants as a saprophyte or parasite and may be responsible for spoilage or disease but is an uncommon cause of human infection. We describe C. infundibulifera rhinosinusitis in a young man with leukemia in Tennessee, USA.

Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy.

Background: Anthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy and heart failure. Our laboratory previously reported that induction of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute Dox cardiotoxicity in zebrafish and in mice, and that potent Cyp1 inhibitors prevent cardiotoxicity. However, the role of Cyp1 enzymes in chronic Dox cardiomyopathy, as well as the mechanisms underlying cardioprotection associated with Cyp1 inhibition, have not been fully elucidated. Methods: The Cyp1 pathway was evaluated using a small molecule Cyp1 inhibitor in wild-type (WT) mice, or Cyp1-null mice ( Cyp1a1/1a2 -/- , Cyp1b1 -/- , and Cyp1a1/1a2/1b1 -/- ). Low-dose Dox was administered by serial intraperitoneal or intravenous injections, respectively. Expression of Cyp1 isoforms was measured by RT-qPCR, and myocardial tissue was isolated from the left ventricle for RNA sequencing. Cardiac function was evaluated by transthoracic echocardiography. Results: In WT mice, Dox treatment was associated with a decrease in Cyp1a2 and increase in Cyp1b1 expression in the heart and in the liver. Co-treatment of WT mice with Dox and the novel Cyp1 inhibitor YW-130 protected against cardiac dysfunction compared to Dox treatment alone. Cyp1a1/1a2 -/- and Cyp1a1/1a2/1b1 -/- mice were protected from Dox cardiomyopathy compared to WT mice. Male, but not female, Cyp1b1 -/- mice had increased cardiac dysfunction following Dox treatment compared to WT mice. RNA sequencing of myocardial tissue showed upregulation of Fundc1 and downregulation of Ccl21c in Cyp1a1/1a2 -/- mice treated with Dox, implicating changes in mitophagy and chemokine-mediated inflammation as possible mechanisms of Cyp1a-mediated cardioprotection. Conclusions: Taken together, this study highlights the potential therapeutic value of Cyp1a inhibition in mitigating anthracycline cardiomyopathy.

Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling.

Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues.

Age-specific Patterns of Intimate Partner Violence Related Injuries in US Emergency Departments.

PURPOSE: To identify intimate partner violence (IPV)-related injury patterns of U.S. patients of three age groups: <18 years (adolescents), 18-25 years (emerging adults), and >25 years (adults). METHODS: We performed a nationally representative retrospective review of all patients presenting to U.S. Emergency Department for IPV-related injuries from 2005 through 2020. Demographics and injury patterns were calculated using statistical methods accounting for the weighted stratified data. Main outcomes were injury morphology, mechanism, severity, location, and temporal associations of IPV-related injuries among the three age groups. RESULTS: There was a higher proportion of female victims, sexual assault cases, and lower trunk injuries among adolescents compared to emerging adults and adults. There was increasing injury severity, fractures, and hospital admissions with increasing age. Adolescents experienced a greater prevalence of fractures of the head, neck, hands, fingers, and distal lower extremity, while trunk fractures increased with age. The peak prevalence of violence-related Emergency Department visits among adolescents was in June and September, with the peak day as Tuesday. DISCUSSION: Injurious forms of IPV are prevalent across all age groups, with sexual assault cases demonstrably higher among adolescents and increasing severity of injuries as victims age. Identification of age-specific injury patterns will aid health-care professionals and policymakers in developing targeted interventions for adolescents who experience IPV.

Water Supply Planning in the Face of Drought and Ecosystem Flows: Examining the Impact of the Bay-Delta Plan on Bay Area Water Supply.

In California, recent Bay-Delta Plan legislation attempts to balance water supply and ecosystem protection by requiring 40% of the flow to remain in-stream in the Tuolumne River from February through June. Serious questions remain about what this means for the Bay Area water supply, especially during drought. Our work develops a new approach to analyze how in-stream flow policy coupled with climate change could impact regional water supply over the coming decades. Results show that the new in-stream flow demand would exceed urban water deliveries in a typical year. In wet years, water supply performance is minimally impacted, but in drought, the policy can lead to less water in storage, delayed reservoir recovery, and increased time at critically low storage. Storage impact exceeding 50 000 acre-feet (60 million m3) is anticipated with at least 18% frequency, demonstrating that, climate uncertainty notwithstanding, this impact must be planned for and managed to ensure a reliable future water supply.

Proposed Specifiers for Conduct Disorder (PSCD): Further validation of the parent-report version in a nationally representative U.S. sample of 10- to 17-year-olds.

The Proposed Specifiers for Conduct Disorder (PSCD; Salekin & Hare, 2016) is a new self-report and informant measure designed to assess psychopathic characteristic domains along with symptoms of conduct disorder in youth. Previous factor analytic studies on the PSCD have found that the items are accounted for by a four-factor model reflecting grandiose-manipulative, callous-unemotional, daring-impulsive, and conduct disorder (CD) symptoms. The present study examined the factor structure, psychometric properties, and criterion-related validity of the parent-report version of the PSCD (PSCD-P) in a nationally representative U.S. sample of children and adolescents (N = 1,091, Mage = 13.39, SD = 2.20, range age = 10-17; 50.0% boys, 76% White). Confirmatory factor analyses for the full (24-item) and a shortened (13-item) PSCD-P revealed good internal reliability estimates and support for the four-factor model (grandiose-manipulative, callous-unemotional, daring-impulsive, CD). Results also provided evidence for (a) measurement invariance of the PSCD-P items across sex, race/ethnicity, and age of the child; (b) convergent validity with CD/oppositional defiant disorder symptoms and discriminant validity with a measure of neuroticism; and (c) criterion-related validity with respect to prosociality, peer and family functioning, reactive and proactive aggression, delinquency, academic performance, and substance use. The prevalence for psychopathic personality propensity was found to be 2%. We discuss clinical and research implications regarding the use of the parent-report version of the PSCD for school-aged children. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A Healed Intertrochanteric Femur Fracture, Shoulder, and Rib Fractures in an Ancient Nubian Female: An Osteoarchaeological Perspective.

This report is a case of a healed proximal intertrochanteric femur fracture nonunion in an ancient Nubian adult female, approximately 58 years old at the time of death, from the Tombos archaeological site in present day northern Sudan. Tombos was founded as an Egyptian colonial town during the New Kingdom Period (14001070 BC). The individual was radiocarbon dated to 1114-910 BC and also exhibited healed fractures of the left proximal humerus and ribs. There was shortening and mild atrophy of the right femur compared to the left; radiographs demonstrated a varus deformity of the proximal femur with associated retroversion. Bone density analysis revealed that the tissue mineral density z-score for this individual was -0.798, with the z-score for Tombos females 15-24 years old being 0.396, or a total difference of 1.194. This indicates that the individual was osteopenic but not osteoporotic prior to demise. This is an important case as it occurred approximately 3000 years ago and is the oldest known reported case of a healed intertrochanteric hip fracture in the archaeological literature. Archaeological cases of intertrochanteric hip fractures are rare, with none previously reported from the BC era. The timing of these multiple fractures is unknown, but all healed before the demise of the individual. Thus, there must have been considerable care afforded to such an individual to minimize the morbidities associated with nonoperative care of such a fracture. If all these fractures occurred at the same time due to a traumatic, accidental injury, the Modified Injury Severity Score (MISS) would be 25. Modern day trauma resuscitation and orthopaedic care gives an estimated mortality for such a MISS score of 28% for those <50 years old. It is likely that this individual's high socioeconomic status allowed for intensive nursing care which likely decreased the morality risk.

Injury patterns and demographics in older adult abuse and falls: A comparative study in emergency department settings.

BACKGROUND: Falls and interpersonal violence pose significant threats to older adults, leading to injuries, hospitalizations, and emergency department (ED) visits. This study investigates the demographics and injury patterns in older adults (aged 60 and above) who sought ED care due to assaults, comparing them with those who experienced falls to gain a deeper understanding of older adult abuse patterns. METHOD: This study utilizes data from the National Electronic Injury Surveillance System (NEISS) All Injury Program (2005-2019) to examine injuries among older adults aged 60 years and above. Participants were categorized into two groups: older adult abuse and injuries due to falls. The differences between the groups by demographics, injury locations, patterns, and temporal trends were analyzed using statistical methods accounting for the weighted stratified nature of the data. Cosinor analysis and Joinpoint regression were used for temporal analysis. RESULTS: Over 15 years, there were an estimated 307,237 ED visits for older adult abuse and 39,477,217 for falls. Older adults experiencing abuse were younger and had lower hospital admission rates compared to fall patients. Injuries associated with abuse included contusions/abrasions, penetrating injuries, and fractures to the head/neck, fingers, toes, ribs, and lower extremities. In contrast, fall patients had higher admission rates, with more fractures, including cervical spine and hip fractures. Temporal patterns showed a higher rate of assaults during the summer, whereas abuse demonstrated bimodal peaks in the summer and fall. CONCLUSIONS: Injuries associated with abuse such as facial, upper trunk, and upper extremity fractures should raise suspicion even in the absence of severe symptoms. These findings emphasize the importance of early identification to connect older adults with support resources, as patients experiencing abuse often get discharged from the ED.

Glucagon-Like Peptide-1 Receptor Agonists During Electroconvulsive Therapy: Case Report With Evolving Concerns and Management Considerations.

ABSTRACT: Glucagon-like peptide-1 receptor agonists are an emerging class of medications transforming the management of diabetes mellitus and obesity, two highly prevalent and chronic medical conditions associated with significant morbidity and posing serious public health concerns. Although generally well tolerated and relatively safe to use, case reports of patients taking these medications while undergoing elective procedures with general anesthesia describe a potential heightened risk of regurgitation and pulmonary aspiration of gastric contents, deriving from the delayed gastric emptying effect of these agents. Based on increased recognition of this risk, the American Society of Anesthesiologists convened a task force to review available data, resulting in the promulgation of a new procedural management guideline for patients on these drugs and undergoing elective procedures with general anesthesia. However, this guideline pertains mostly to procedures and situations that are distinct from electroconvulsive therapy (ECT). This case report describes the experience of a patient on semaglutide, a glucagon-like peptide-1 receptor agonist for obesity, undergoing ECT, provides a general overview of this novel drug class, identifies issues specific to ECT management, and suggests potential adaptations to patient care over different phases of ECT practice.

Pain management in trauma: the need for trauma-informed opioid prescribing guidelines.

Background/objectives: Surgical populations and particularly injury survivors often present with complex trauma that elevates their risk for prolonged opioid use and misuse. Changes in opioid prescribing guidelines during the past several years have yielded mixed results for pain management after trauma, with a limiting factor being the heterogeneity of clinical populations and treatment needs in individuals receiving opioids. The present analysis illuminates this gap between clinical guidelines and clinical practice through qualitative feedback from hospital trauma providers and unit staff members regarding current opioid prescribing guidelines and practices in the setting of traumatic injury. Methods: The parent study aimed to implement a pilot screening tool for opioid misuse in four level I and II trauma hospitals throughout Wisconsin. As part of the parent study, focus groups were conducted at each study site to explore the facilitators and barriers of implementing a novel screening tool, as well as to examine the current opioid prescribing guidelines, trainings, and resources available for trauma and acute care providers. Focus group transcripts were independently coded and analyzed using a modified grounded theory approach to identify themes related to the facilitators and barriers of opioid prescribing guidelines in trauma and acute care. Results: Three major themes were identified as impactful to opioid-related prescribing and care provided in the setting of traumatic injury; these include (1) acute treatment strategies; (2) patient interactions surrounding pain management; and (3) the multifactorial nature of trauma on pain management approaches. Conclusion: Providers and staff at four Wisconsin trauma centers called for trauma-specific opioid prescribing guidelines in the setting of trauma and acute care. The ubiquitous prescription of opioids and challenges in long-term pain management in these settings necessitate additional community-integrated research to inform development of federal guidelines. Level of evidence: Therapeutic/care management, level V.

Mucormycosis in children with cancer and hematopoietic cell transplant-A single center cohort study.

Although mucormycosis is an important cause of morbidity and mortality in children with cancer, our understanding of the typical characteristics of these infections is incomplete. We reviewed all cases of mucormycosis diagnosed at a single pediatric cancer center over 5 decades to identify the clinical features of mucormycosis in pediatric oncology patients and to identify risk factors for mortality. There were 44 cases of mucormycosis diagnosed between 1970-2019. Most patients (89%) had hematological malignancies and a history of prolonged and severe neutropenia (91%). In this series, hyperglycemia and exposure to corticosteroids were common. Pulmonary (36%) and disseminated infections (32%) were most common; rhino-orbital-cerebral infections were relatively infrequent (11%). Rhizopus spp. was the most common etiological agent (40%) followed by Mucor spp. (31%), and Cunninghamella spp. (19%). Overall mortality was 44% and 51% and attributable mortality was 39% and 41% at the end of antifungal therapy and end of follow up, respectively. Attributable mortality fell to 18% in 2010-2019, from 58-60% in previous decades; adjunctive surgery was associated with decreased mortality. Mortality remains unacceptably high despite aggressive antifungal therapy and adjunctive surgery, suggesting novel therapeutic strategies are needed.

Structural brain plasticity and inflammation are independently related to changes in depressive symptoms six months after an index ECT course.

BACKGROUND: Electroconvulsive therapy (ECT) is effective for treatment-resistant depression and leads to short-term structural brain changes and decreases in the inflammatory response. However, little is known about how brain structure and inflammation relate to the heterogeneity of treatment response in the months following an index ECT course. METHODS: A naturalistic six-month study following an index ECT course included 20 subjects with treatment-resistant depression. Upon conclusion of the index ECT course and again after six months, structural magnetic resonance imaging scans and peripheral inflammation measures [interleukin-6 (IL-6), IL-8, tumor necrosis factor (TNF-α), and C-reactive protein] were obtained. Voxel-based morphometry processed with the CAT-12 Toolbox was used to estimate changes in gray matter volume. RESULTS: Between the end of the index ECT course and the end of follow-up, we found four clusters of significant decreases in gray matter volume (p < 0.01, FWE) and no regions of increased volume. Decreased HAM-D scores were significantly related only to reduced IL-8 level. Decreased volume in one cluster, which included the right insula and Brodmann's Area 22, was related to increased HAM-D scores over six months. IL-8 levels did not mediate or moderate the relationship between volumetric change and depression. CONCLUSIONS: Six months after an index ECT course, multiple regions of decreased gray matter volume were observed in a naturalistic setting. The independent relations between brain volume and inflammation to depressive symptoms suggest novel explanations of the heterogeneity of longer-term ECT treatment response.

Proposed Specifiers for Conduct Disorder (PSCD) scale: A Latent Profile Analysis with At-Risk Adolescents.

The Proposed Specifiers for Conduct Disorder (PSCD; Salekin in Pers Disord: Theory Res Treat 7:180-191, 2016) scale was designed to assess interrelated psychopathic trait domains in conjunction with symptoms of Conduct Disorder (CD) in children and adolescents (i.e., grandiose-manipulative, callous-unemotional, daring-impulsive). Variable-centered studies have provided support for a four-factor PSCD structure (Salekin et al. in Psychol Assess 34(10):985-992, 2022) in line with other adolescent and adult studies. The current person-centered study used latent profile analysis of the PSCD domains to examine whether theoretically meaningful and empirically robust PSCD subtypes emerged from a diverse sample (70.9% White, 20.1% Black, 3.6% Hispanic, and 5.4% other) of adolescents (modal age = 17) in a military style residential facility (N = 409; Males = 80.6%). As hypothesized, a four-class solution was best, consistent with adult psychopathy subtyping research (Hare et al. in Handbook of Psychopathy 39-79, 2018; Roy et al. in Pers Disord: Theory Res Treat, in press). The PSCD subtype profiles were uniform across sex and race/ethnicity. Adolescents evincing a psychopathic trait propensity profile (elevated on all four PSCD domains) displayed the greatest number of arrests and higher overall externalizing psychopathology, compared to the other three latent classes, as well as higher internalizing psychopathology compared to adolescents with general delinquency. The PSCD provides a sound measure of psychopathic trait propensities in youth and our results offer investigators and clinicians a means for understanding person-centered psychopathic traits versus antisocial profiles among at-risk adolescents. Taken together, the current results may offer a viable approach for examining specific treatment targets based on PSCD subtype profiles.