B cell activation gene signature in blood and liver of HBeAg+ immune active chronic hepatitis B patients.

BACKGROUND: Immunological studies on chronic hepatitis B virus (HBV) infection have convincingly shown immune dysfunction involving multiple cell types. The focus of the majority of studies has been on the role of T cells and showed an impaired functional T cell response to HBV. B cells have been evaluated more recently, but in contrast to T cells, more pronounced activation of circulating B cells has been reported. To gain more insight into the activation status of B cells, we investigated the activation gene profile of B cells in the blood and liver of chronic HBV patients. METHODS: RNA-seq and flow cytometric analysis was performed on peripheral blood B cells of immune active chronic HBV patients, comparing them with samples from healthy controls. In addition, gene expression profiles of B cells in the liver were analyzed by bulk and single-cell RNA-seq. RESULTS AND CONCLUSIONS: Our data show a distinctive B cell activation gene signature in the blood of immune active chronic HBV patients, characterized by a significant upregulation of immune-related genes, including IRF1, STAT1, STAT3, TAP1, and TAPBP. This peripheral activation profile was also observed in B cells from the liver by single cell RNA-seq showing upregulation of IRF1, CD83 and significantly higher CD69 expression, with naive and memory B cell subsets being the primary carriers of the signature. Our findings suggest that B cell gene profiles reflect responsiveness to HBV infection, these findings are relevant for clinical studies evaluating immunomodulatory treatment strategies for HBV.

A Comparative Analysis of Two Commonly Used FDA-Approved Immunoassays for Fentanyl Detection.

BACKGROUND: Given the opioid epidemic, fentanyl screening in urine has become increasingly important. Immunoassays remain the most common screening methodology due to the high throughput and ease of integration into automated chemistry systems. The fentanyl ARK II from Ark Diagnostics is a widely used immunoassay, while a novel fentanyl assay called FEN2 by Lin-Zhi has become available on the Roche platform. Here, we evaluate and compare their performance. METHODS: Four hundred and thirty-four urine samples were analyzed for fentanyl across the Lin-Zhi FEN2 and ARK II assays on the Cobas c502 platform. Samples were analyzed immediately upon request for drug of abuse screening or frozen for subsequent analysis. For confirmation testing, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a limit of detection of 1 ng/mL for fentanyl/norfentanyl was used. Any sample with either fentanyl or norfentanyl above the LC-MS/MS cutoff was deemed positive. RESULTS: The ARK II had 11 false negatives and 7 false positives, while the Lin-Zhi FEN2 had 12 false negatives and 2 false positives. This resulted in ARK II having a sensitivity and specificity of 90.4% and 97.8% respectively, while Lin-Zhi FEN2 had a sensitivity and specificity of 89.5% and 99.4%. CONCLUSIONS: Both the ARK II and Lin-Zhi FEN2 immunoassays detected fentanyl well. Overall, the Lin-Zhi assay had slightly better specificity than ARK II, in our data set. While some discrepant results were observed between the 2 immunoassay systems, most occurred near the immunoassay detection cutoffs.

Intrahepatic plasma cells, but not atypical memory B cells, associate with clinical phases of chronic hepatitis B.

Studies have traditionally focused on the role of T cells in chronic hepatitis B (CHB), but recent evidence supports a role for B cells. The enrichment of so-called atypical memory (AtM) B cells, which show reduced signaling and impaired differentiation, is believed to be a characteristic feature of CHB, potentially contributing to the observed dysfunctional anti-HBsAg B-cell responses. Our study, involving 62 CHB patients across clinical phases, identified AtM B cells expressing IFNLR1 and interferon-stimulated genes. Contrary to previous reports, we found relatively low frequencies of AtM B cells in the liver, comparable to peripheral blood. However, liver plasma cell frequencies were significantly higher, particularly during phases with elevated viral loads and liver enzyme levels. Liver plasma cells exhibited signs of active proliferation, especially in the immune active phase. Our findings suggest a potential role for plasma cells, alongside potential implications and consequences of local proliferation, within the livers of CHB patients. While the significance of AtM B cells remains uncertain, further investigation is warranted to determine their responsiveness to interferons and their role in CHB.

Molecular mechanism of choline and ethanolamine transport in humans.

Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome2-7. Earlier studies concluded that FLVCR1 may function as a haem exporter8-12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14-16. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation-π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.

Complications, Visual Acuity, and Refractive Error Three Years After Secondary Intraocular Lens implantation for Pediatric Aphakia.

OBJECTIVE: To report the cumulative incidence of complications and describe refractive error and visual acuity (VA) outcomes in children undergoing secondary intraocular lens (IOL) implantation following previous surgery for non-traumatic cataract. DESIGN: Pediatric cataract registry. PARTICIPANTS: 80 children (108 eyes: 60 bilateral, 48 unilateral) undergoing lensectomy at <13 years of age, followed by secondary IOL implantation at median age (range) of 2.7 (0.6 to 5.0) years for bilateral and 2.1 (0.5 to 6.4) for unilateral cases. METHODS: Annual data collection from medical record review through 5 years following lensectomy. MAIN OUTCOME MEASURES: Cumulative incidence of newly emergent complications following secondary IOL implantation; refractive error and VA by 5 years after lensectomy. RESULTS: Median (interquartile range [IQR]) follow-up following secondary IOL implantation was 2.5 years (0.8 to 3.3 years). A common complication following secondary IOL implantation was a glaucoma-related adverse event (GRAE: glaucoma or glaucoma suspect); the cumulative incidence was 17% (95% CI: 3%-29%) in bilateral and 12% (95% CI: 0%-23%) in unilateral cases. The cumulative incidence of surgery for visual axis opacification was 2% (95% CI: 0%-7%) for bilateral and 4% (95% CI: 0%-10%) for unilateral cases. Median prediction error (IQR) within 90 days of implantation was 0.88 D (-0.50 D to +3.00 D) less hyperopic than intended among 21 eyes for bilateral cases and 1.50 D (-0.25 D to +2.38 D) less among 19 unilateral cases. Median (IQR) spherical equivalent refractive error at 5 years (median 5.1 years of age) in eyes receiving a secondary IOL was +0.50 D (-2.38 D to +2.94 D) for 48 bilateral and +0.06 D (-2.25 D to +0.75 D) for 22 unilateral cases. Median (IQR) monocular VA at 5 years was 20/63 (20/50-20/100) for bilateral (n=42) and 20/400 (20/160-20/800) for unilateral (n=33) cases. CONCLUSIONS: Eyes with secondary IOL implantation have an ongoing risk of new glaucoma-related adverse events. Five years after lensectomy (approximately 2.5 years after secondary IOL implantation), average refractive error was less hyperopic than desired given the anticipated further myopic shift before refraction stabilizes.

Pragmatic strategies to address health disparities along the continuum of care in chronic liver disease.

Racial, ethnic, and socioeconomic disparities exist in the prevalence and natural history of chronic liver disease, access to care, and clinical outcomes. Solutions to improve health equity range widely, from digital health tools to policy changes. The current review outlines the disparities along the chronic liver disease health care continuum from screening and diagnosis to the management of cirrhosis and considerations of pre-liver and post-liver transplantation. Using a health equity research and implementation science framework, we offer pragmatic strategies to address barriers to implementing high-quality equitable care for patients with chronic liver disease.

Diagnostic performance of rapid antigen tests (RAT) for COVID-19 and factors associated with RAT-negative results among RT-PCR-positive individuals during Omicron BA.2, BA.5 and XBB.1 predominance.

BACKGROUND: While numerous studies have evaluated the real-world performance of rapid antigen tests (RATs), data on the effect of Omicron sublineages such as XBB and reinfections on RAT performance is limited. We assessed the performance of RATs and factors associated with RAT-negative results among individuals who tested SARS-CoV-2-positive by reverse transcription-polymerase chain reaction (RT-PCR). METHODS: We conducted a retrospective study among Singapore residents who underwent testing for SARS-CoV-2 with RAT (Acon Flowflex or SD Biosensor) and RT-PCR in the same clinical encounter between 9 May 2022 and 21 November 2022. RT-PCR served as a reference standard for RAT performance. Logistic regression was used to estimate the odds ratios (OR) of factors associated with negative RAT results among RT-PCR-positive cases. RESULTS: Of 8,620 clinical encounters analysed, 3,519 (40.8%) were SARS-CoV-2-positive on RT-PCR. Overall sensitivity and specificity of RAT was 84.6% (95% CI 83.3-85.7%) and 99.4% (95% CI 99.1-99.6%) respectively. Acon Flowflex consistently achieved higher sensitivity and specificity than SD Biosensor test kit. Among RT-PCR-positive cases, individuals who had a previous documented SARS-CoV-2 infection, coinfection with another respiratory pathogen or tested ≥ 6 days from symptom onset had higher odds of testing RAT-negative, but the associations were attenuated after adjustment for cycle threshold values (proxy for viral load). There was no significant difference in RAT performance between Omicron sublineages BA.2, BA.5 and XBB.1. CONCLUSION: Diagnostic performance of RAT was not affected by changes in predominant circulating Omicron sublineages. However, reinfection cases may be under ascertained by RAT. In individuals with a previous SARS-CoV-2 infection episode or symptom onset ≥ 6 days prior to testing, a confirmatory RT-PCR may be considered if there is high clinical suspicion.

GAGE-seq concurrently profiles multiscale 3D genome organization and gene expression in single cells.

The organization of mammalian genomes features a complex, multiscale three-dimensional (3D) architecture, whose functional significance remains elusive because of limited single-cell technologies that can concurrently profile genome organization and transcriptional activities. Here, we introduce genome architecture and gene expression by sequencing (GAGE-seq), a scalable, robust single-cell co-assay measuring 3D genome structure and transcriptome simultaneously within the same cell. Applied to mouse brain cortex and human bone marrow CD34+ cells, GAGE-seq characterized the intricate relationships between 3D genome and gene expression, showing that multiscale 3D genome features inform cell-type-specific gene expression and link regulatory elements to target genes. Integration with spatial transcriptomic data revealed in situ 3D genome variations in mouse cortex. Observations in human hematopoiesis unveiled discordant changes between 3D genome organization and gene expression, underscoring a complex, temporal interplay at the single-cell level. GAGE-seq provides a powerful, cost-effective approach for exploring genome structure and gene expression relationships at the single-cell level across diverse biological contexts.

Doses of medial rectus muscle recessions for divergence insufficiency-type esotropia.

We evaluated whether doses of bilateral medial rectus recessions greater than Parks's tables yielded superior outcomes for adult-onset divergence insufficiency. Forty-two patients underwent bilateral medial rectus recessions. Dose was analyzed as the average total per muscle (surgery + suture adjustment if performed) and compared with the standard dose tables (based on preoperative distance esodeviation), as difference between dose performed and dose indicated by Parks's tables. Each participant was classified as having received either Parks's dose (within 0.5 mm) or a dose greater than Parks's dose. Success was defined as "rarely" or "never" diplopia in distance straight-ahead gaze and reading. For patients classified as success, the mean difference between actual surgical dose performed and Parks's dose was calculated. Success was 91% (29/32) in those receiving greater than Parks's dose versus 67% (6/9) with Parks's dose (difference = 24%; 95% CI, -5% to 60%). The mean surgical dose was 1.0 mm greater than Parks's tables for the 35 successes (at 10 weeks) versus 0.7 mm greater for the 6 failures (difference = 0.4 mm; 95% CI, -0.2 to 0.9). For medial rectus recessions in adult-onset divergence insufficiency-type esotropia, a surgical dose 1 mm greater than Parks's tables, for each muscle, is a reasonable strategy.

Neutralizing antibodies to interferon alfa arising during peginterferon therapy of chronic hepatitis B in children and adults: Results from the HBRN Trials.

BACKGROUND AIMS: Pegylated interferon-α (PegIFNα) is of limited utility during immunotolerant or immune active phases of chronic hepatitis B infection but is being explored as part of new cure regimens. Low/absent levels of IFNα found in some patients receiving treatment are associated with limited/no virological responses. The study aimed to determine if sera from participants inhibit IFNα activity and/or contain therapy-induced anti-IFNα antibodies. APPROACH RESULTS: Pre-treatment, on-treatment, and post-treatment sera from 61 immunotolerant trial participants on PegIFNα/entecavir therapy and 88 immune active trial participants on PegIFNα/tenofovir therapy were screened for anti-IFNα antibodies by indirect ELISA. The neutralization capacity of antibodies was measured by preincubation of sera±recombinant human IFNα added to Huh7 cells with the measurement of interferon-stimulated gene (ISG)-induction by qPCR. Correlations between serum-induced ISG inhibition, presence, and titer of anti-IFNα antibodies and virological responses were evaluated. Preincubation of on-treatment serum from 26 immunotolerant (43%) and 13 immune active (15%) participants with recombinant-human IFNα markedly blunted ISG-induction in Huh7 cells. The degree of ISG inhibition correlated with IFNα antibody titer ( p < 0.0001; r = 0.87). On-treatment development of anti-IFNα neutralizing antibodies (nAbs) was associated with reduced quantitative HBsAg and qHBeAg declines ( p < 0.05) and inhibited IFNα bioactivity to 240 weeks after PegIFNα cessation. Children developed anti-IFNα nAbs more frequently than adults ( p = 0.004) but nAbs in children had less impact on virological responses. CONCLUSIONS: The development of anti-IFNα nAbs during PegIFNα treatment diminishes responses to antiviral therapy. Understanding how and why anti-IFNα antibodies develop may allow for the optimization of IFN-based therapy, which is critical given its renewed use in HBV-cure strategies.

Personality assessment in nursing home residents with mental and physical multimorbidity: two informant perspectives.

OBJECTIVES: In older patients with mental and physical multimorbidity (MPM), personality assessment is highly complex. Our aim was to examine personality traits in this population using the Hetero-Anamnestic Personality questionnaire (HAP), and to compare the premorbid perspective of patients' relatives (HAP) with the present-time perspective of nursing staff (HAP-t). DESIGN: Cross-sectional. SETTING: Dutch gerontopsychiatric nursing home (GP-NH) units. PARTICIPANTS: Totally, 142 GP-NH residents with MPM (excluding dementia). MEASUREMENTS: NH norm data of the HAP were used to identify clinically relevant premorbid traits. Linear mixed models estimated the differences between HAP and HAP-t trait scores (0-10). Agreement was quantified by intraclass correlation coefficients (ICCs). All HAP-HAP-t analyses were corrected for response tendency (RT) scores (-10-10). RESULTS: 78.4% of the patients had at least one premorbid maladaptive trait, and 62.2% had two or more. Most prevalent were: "disorderly" (30.3%), "unpredictable/impulsive" (29.1%) and "vulnerable" (27.3%) behavior. The RT of relatives appeared significantly more positive than that of nursing staff (+1.8, 95% CI 0.6-2.9, p = 0.002). After RT correction, the traits "vulnerable", "perfectionist" and "unpredictable/impulsive" behavior scored higher on the HAP than HAP-t (respectively +1.2, 95% CI 0.6-1.7, p < 0.001; +2.1, 95% CI 1.3-2.8, p < 0.001; +0.6, 95% CI 0.1-1.1, p = 0.013), while "rigid" behavior scored lower (-0.7, 95% CI -1.3 to -0.03, p = 0.042). Adjusted ICCs ranged from 0.15 to 0.58. CONCLUSIONS: Our study shows high percentages of premorbid maladaptive personality traits, which calls for attention on personality assessment in MPM NH residents. Results also indicate that the HAP and HAP-t questionnaires should not be used interchangeably for this patient group in clinical practice.

Predicting which patients with cancer will see a psychiatrist or counsellor from their initial oncology consultation document using natural language processing.

BACKGROUND: Patients with cancer often have unmet psychosocial needs. Early detection of who requires referral to a counsellor or psychiatrist may improve their care. This work used natural language processing to predict which patients will see a counsellor or psychiatrist from a patient's initial oncology consultation document. We believe this is the first use of artificial intelligence to predict psychiatric outcomes from non-psychiatric medical documents. METHODS: This retrospective prognostic study used data from 47,625 patients at BC Cancer. We analyzed initial oncology consultation documents using traditional and neural language models to predict whether patients would see a counsellor or psychiatrist in the 12 months following their initial oncology consultation. RESULTS: Here, we show our best models achieved a balanced accuracy (receiver-operating-characteristic area-under-curve) of 73.1% (0.824) for predicting seeing a psychiatrist, and 71.0% (0.784) for seeing a counsellor. Different words and phrases are important for predicting each outcome. CONCLUSION: These results suggest natural language processing can be used to predict psychosocial needs of patients with cancer from their initial oncology consultation document. Future research could extend this work to predict the psychosocial needs of medical patients in other settings.

Patients with cancer often need support for their mental health. Early detection of who requires referral to a counsellor or psychiatrist may improve their care. This study trained a type of artificial intelligence (AI) called natural language processing to read the consultation report an oncologist writes after they first see a patient to predict which patients will see a counsellor or psychiatrist. The AI predicted this with performance similar to other uses of AI in mental health, and used different words and phrases to predict who would see a psychiatrist compared to seeing a counsellor. We believe this is the first use of AI to predict mental health outcomes from medical documents written by clinicians outside of mental health. This study suggests this type of AI can predict the mental health needs of patients with cancer from this widely-available document.

Language outcomes of preschool children who are HIV-exposed uninfected: An analysis of a South African cohort.

INTRODUCTION: There are approximately 16 million children who are HIV-exposed and uninfected (CHEU) worldwide. Studies suggest that CHEU are at risk for developmental impairment in infancy, particularly in language domains. However, there is limited research examining neurocognitive function in CHEU older than 2 years, including important pre-school years. This study aimed to investigate associations between HIV exposure without infection and neurocognitive outcomes and to determine risk factors for neurodevelopment in CHEU at age 3-4 years. METHODS: The Drakenstein Child Health Study is a South African population-based birth cohort which enrolled women in pregnancy with ongoing follow up. Neurocognitive outcomes were assessed in children at 3.5 years by trained assessors blinded to HIV status including general cognitive function, language, and memory, measured using the Kaufmann Assessment Battery for Children, Second Edition (KABC-II). Data were compared between CHEU and children who were HIV-unexposed uninfected (CHUU) using multivariable logistic and linear regression, including testing for effect modification; sex-stratified risk factor analyses were performed. RESULTS: A total of 497 children were included (97 [20%] CHEU; 400 [80%] CHUU; 50% male), with a mean age of 3.5 years (range 3.4-3.6). Groups had similar birth and household characteristics, although mothers of CHEU were older, on average. Overall, CHEU had lower expressive language scores compared to CHUU on unadjusted and adjusted analyses (effect size: -0.23 [95% CI -0.45, -0.01]). There were no group differences in general cognitive or memory function (p>0.05). On sex-stratified analyses, male CHEU were found to have higher odds of suboptimal cognitive development compared to male CHUU (aOR 2.28 [95% CI 1.06, 4.87], p = 0.034). Several other factors including birthweight, maternal education, maternal ART duration and HIV viral load during pregnancy were associated with cognition, memory, or expressive language outcomes in CHEU, dependent on child sex. INTERPRETATION: The findings suggest that perinatal HIV exposure continues to be associated with impaired language development across the preschool years, highlighting the importance of targeting early interventions to optimise language outcomes. Further, the results suggest the importance of demographic, biological and HIV-related variables influencing developmental outcomes in CHEU. The greater risk of suboptimal cognitive development in male CHEU requires investigation around sex-specific mechanisms.

Refractive Error Change and Overminus Lens Therapy for Childhood Intermittent Exotropia.

Importance: Increased myopic shift was found to be associated with 1 year of overminus spectacle treatment for children with intermittent exotropia (IXT). Persistence of myopic shift after discontinuing overminus spectacles is unknown. Objective: To compare refractive error change over 3 years in children with IXT originally treated with overminus vs nonoverminus spectacles. Design, Setting, and Participants: This study was an 18-month extension of the Trial of Overminus Spectacle Therapy for Intermittent Exotropia cohort, which previously randomized children aged 3 to 10 years with IXT and baseline spherical equivalent refractive error (SER) between -6.00 diopters (D) and 1.00 D to overminus spectacles (-2.50 D for 12 months, -1.25 D for 3 months, and nonoverminus for 3 months) or nonoverminus spectacles. Children were recruited from 56 sites from July 2010 to February 2022. Data were analyzed from February 2022 to January 2024. Interventions: After trial completion at 18 months, participants were followed up at 24 and 36 months. Treatment was at investigator discretion from 18 to 36 months. Main Outcomes and Measures: Change in SER (cycloplegic retinoscopy) from baseline to 36 months. Results: Of 386 children in the Trial of Overminus Spectacle Therapy for Intermittent Exotropia, 223 (57.8%) consented to 18 months of additional follow-up, including 124 of 196 (63.3%) in the overminus treatment group and 99 of 190 (52.1%) in the nonoverminus treatment group. Of 205 children who completed 36-month follow-up, 116 (56.6%) were female, and the mean (SD) age at randomization was 6.2 (2.1) years. Mean (SD) SER change from baseline to 36 months was greater in the overminus group (-0.74 [1.00] D) compared with the nonoverminus group (-0.44 [0.85] D; adjusted difference, -0.36 D; 95% CI, -0.59 to -0.12; P = .003), with 30 of 112 (26.8%) in the overminus group having more than 1 D of myopic shift compared with 14 of 91 (15%) in the nonoverminus group (risk ratio, 1.8; 95% CI, 1.0-3.0). From 12 to 36 months, mean (SD) myopic shift was -0.34 (0.67) D and -0.36 (0.66) D in the overminus and nonoverminus groups, respectively (adjusted difference, -0.001 D; 95% CI, -0.18 to 0.18; P = .99). Conclusions and Relevance: The greater myopic shift observed after 1 year of -2.50-D overminus lens treatment remained at 3 years. Both groups had similar myopic shift during the 2-year period after treatment weaning and cessation. The risk of myopic shift should be discussed with parents when considering overminus lens treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02807350.

Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial.

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown. Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD. Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023. Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months. Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified. Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn. Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

Pharmacokinetics, Fecal Output, and Grimace Scores in Rabbits Given Long-acting Buprenorphine or Fentanyl for Postsurgical Analgesia.

The New Zealand white rabbit (Oryctolagus cuniculus) is a frequently used surgical model. Pain management after surgery is a critical aspect of animal welfare. Recently, a long-acting buprenorphine formulation (Ethiqa XR; EXR) was approved for use in rats and mice but has not yet been investigated in rabbits. The current study aimed to determine whether a single subcutaneous dose of 0.15 mg/kg of EXR could achieve and maintain therapeutic buprenorphine plasma concentrations (0.1 ng/mL) for 72 h in male and female rabbits. We also evaluated the safety profiles of EXR and the fentanyl patch (FP) by assessing fecal output after surgery, because opioids are known to decrease intestinal motility. Behavior and pain scores were compared for rabbits that received either EXR or the FP after undergoing an annulus puncture procedure to induce osteoarthritis. EXR at 0.15 mg/kg SC provided a shorter time to onset and sustained analgesia for 72 h in male and female rabbits, whereas the FP provided suboptimal analgesia after 48 h. Both EXR and FP reduced fecal output after surgery. Output returned to baseline levels within 72 h for the EXR group and remained slightly below baseline at 96 h after surgery for the fentanyl group. Grimace pain scores revealed no significant difference between treatment groups. These results suggest that EXR is a safe and effective option for postoperative pain management in rabbits.

Phosphate-binding pocket on cyclin B governs CDK substrate phosphorylation and mitotic timing.

Cell cycle progression is governed by complexes of the cyclin-dependent kinases (CDKs) and their regulatory subunits cyclin and Cks1. CDKs phosphorylate hundreds of substrates, often at multiple sites. Multisite phosphorylation depends on Cks1, which binds initial priming phosphorylation sites to promote secondary phosphorylation at other sites. Here, we describe a similar role for a recently discovered phosphate-binding pocket (PP) on B-type cyclins. Mutation of the PP in Clb2, the major mitotic cyclin of budding yeast, alters bud morphology and delays the onset of anaphase. Using phosphoproteomics in vivo and kinase reactions in vitro, we find that mutation of the PP reduces phosphorylation of several CDK substrates, including the Bud6 subunit of the polarisome and the Cdc16 and Cdc27 subunits of the anaphase-promoting complex/cyclosome. We conclude that the cyclin PP, like Cks1, controls the timing of multisite phosphorylation on CDK substrates, thereby helping to establish the robust timing of cell-cycle events.

The Edmonton Symptom Assessment System is a valid, reliable, and responsive tool to assess symptom burden in decompensated cirrhosis.

BACKGROUND: While there is a growing need for interventions addressing symptom burden in patients with decompensated cirrhosis (DC), the lack of validated symptom assessment tools is a critical barrier. We investigated the psychometric properties of the revised Edmonton Symptom Assessment System (ESAS-r) in a longitudinal cohort of patients with DC. METHODS: Adult outpatients with DC were prospectively recruited from a liver transplant center and completed ESAS-r at baseline and week 12. We examined reliability, floor/ceiling effects, structural validity, and known-groups validity. We examined the convergent and predictive validity of ESAS-r with health-related quality of life using the Short Form Liver Disease Quality of Life (SF-LDQOL) and responsiveness to changes in anxiety and depression using the Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9 from baseline to week 12. RESULTS: From August 2018 to September 2022, 218 patients (9% Child-Pugh A, 59% Child-Pugh B, and 32% Child-Pugh C) were prospectively recruited and completed the ESAS-r, SF-LDQOL, Patient Health Questionnaire-9, and Hospital Anxiety and Depression Scale at baseline and week 12 (n = 135). ESAS-r had strong reliability (Cronbach's alpha 0.86), structural validity (comparative fit index 0.95), known-groups validity (Child-Pugh A: 25.1 vs. B: 37.5 vs. C: 41.4, p = 0.006), and convergent validity (r = -0.67 with SF-LDQOL). Floor effects were 9% and ceiling effects were 0.5%. Changes in ESAS-r scores from baseline to week 12 significantly predicted changes in SF-LDQOL (ß = -0.36, p < 0.001), accounting for 30% of the variation. ESAS-r was strongly responsive to clinically meaningful changes in SF-LDQOL, Patient Health Questionnaire-9, and Hospital Anxiety and Depression Scale. CONCLUSIONS: ESAS-r is a reliable, valid, and responsive tool for assessing symptom burden in patients with DC and can predict changes in health-related quality of life. Future directions include its implementation as a key outcome measure in cirrhosis care and clinical trials.

Factors Affecting Gonadal Shielding Use Among Technologists in California.

PURPOSE: To assess the patient gonadal shielding practices of radiologic technologists in the state of California. METHODS: A survey invitation was sent via email to registered radiologic technologists in California to collect data to determine whether there were significant associations between gonadal shielding practices and various categorical variables, including patient sex, patient age, body part, availability of gonadal shielding protocols, availability of gonadal shields, and supervisor encouragement. RESULTS: There was a significant association between gonadal shielding protocol availability and supervisor encouragement of using gonadal shielding (P = .005) and between gonadal shielding availability and supervisor encouragement of using gonadal shielding (P < .001). Contrary to other studies in the literature, there was a significant difference between patient sex and the likelihood of gonadal shielding use, with participants indicating that they shield girls and women more often than they shield boys and men (P < .001). DISCUSSION: There was a sex-based difference in the frequency of gonadal shielding usage among the sample in this study. Also, supervisors providing accessible protocols and encouraging gonadal shielding can increase technologists' use of gonadal shielding. CONCLUSION: Gonadal shielding is the current Code of Federal Regulations standard, although most professional and scientific organizations support discontinuing shielding during abdominal and pelvic radiography examinations. Shielding of these areas is more likely to occur with the availability of gonadal shielding, supervisory encouragement, protocols mandating shielding, and state regulations.