Citations

Abstract Background Keratoconus (KC) is a multifactorial disorder with unclear etiology, characterized by localized thinning and a cone-like protrusion of the cornea. The complex etiology of KC exacerbates the lack of an animal model. Previous studies by Tachibana et al. (2002) described an inbred mouse strain (SKC) with a spontaneous, androgen-dependent, cone-like corneal morphology. This study aimed to investigate the corneal phenotypes of SKC mice through an in-depth ophthalmic examination. Methods Mice (n=53) were examined via slit lamp biomicroscopy with fluorescein staining. Spectral-domain optical coherence tomography (SD-OCT) enabled central corneal thickness (CCT) measurement in selected mice (n=26 eyes), and OCT-based pachymetry mapping (n=16 eyes). In vivo corneal confocal microscopy was conducted on eyes to assess cellular morphology (n= 9 eyes). Eyes were collected for histology analysis (n=22). Results Lesions and epithelial breaks were present in ∼95% of eyes (n=101). Neovascularization, perforation, scarring, and hydrops were seen primarily in males. An opaque, unilateral cone-like morphology was exclusive to males (n=11). Male and female corneas showed no significant difference in CCT, though pachymetry mapping revealed regional thinning patterns in both sexes. Loosened epithelial tight junctions, stromal fibrosis, vascularization, and inflammation of variable severity were identified in both sexes. Conclusion This study identified previously unreported corneal phenotypes in SKC mice through ophthalmic examination. Unlike previous studies, gross and histological abnormalities were observed in female SKC mice. Our findings suggest a lower penetrance of the cone-like phenotype (∼20%) than previously reported (∼33%) and support that the conical phenotype in male mice may be secondary to keratitis.

Background and Aims: Unresolved inflammation and fibrosis are defining features of metabolic dysfunction–associated steatohepatitis (MASH), a progressive form of steatotic liver disease that can advance to cirrhosis and hepatocellular carcinoma. While innate immune mechanisms in MASH have been extensively characterized, the role of CD4 + T cells remains poorly understood despite their central function in orchestrating immune responses through effector and regulatory mechanisms. Approach and Results: Integrated single-cell proteomic, transcriptomic, and functional analyses were used to investigate the CD4 + T-cell landscape in murine and human MASH. We delineated a profound shift in the differentiation of intrahepatic and peripheral CD4 + T cells toward Th1, regulatory, and cytotoxic phenotypes in murine and human MASH. Notably, hepatic CD4 + T cells exhibited heightened effector activity and elevated secretion of proinflammatory cytokines, thus amplifying inflammatory signaling cascades. The CD4 + T-cell reprogramming in MASH also included the induction of the co-stimulatory receptor OX40. In parallel, OX40 ligand (OX40L)-expressing monocyte-derived macrophages and dendritic cells accumulated in MASH livers, establishing a feed-forward CD4 + T cell-myeloid activation loop. Therapeutic blockade of the OX40–OX40L axis, in turn, reversed liver pathology in mice with established MASH and reduced disease markers in an ex vivo human liver model. Furthermore, genetic depletion or functional inhibition of CD4 + T cells attenuated fibrosis, accompanied by decreased infiltration of monocyte-derived macrophages. Conclusions: These studies provide a comprehensive single-cell proteogenomic atlas of CD4 + T cells in MASH and identify an OX40-dependent CD4 + T cell-macrophage axis as a promising therapeutic target for the treatment of MASH and liver fibrosis.

Abstract Background/Aims Sleep disturbance is a defining feature of fibromyalgia (FM), contributing to pain, fatigue, cognitive dysfunction, and reduced quality of life. Effective management options remain limited. Cognitive behavioural therapy for insomnia (CBT-I) is effective in primary insomnia, but evidence in FM is sparse and access to face-to-face therapy is limited. Digital CBT-I (dCBT-I) offers a scalable, self-directed solution that may overcome these barriers. We conducted the first randomised controlled trial of dCBT-I in FM to evaluate its impact on quality of life and associated symptoms. Methods This single-blind randomised controlled trial evaluated Sleepio, a validated dCBT-I programme of six self-directed 20-minute sessions delivered over 12 weeks. Participants with a clinical diagnosis of FM, self-reported sleep disturbance, and cognitive complaints were recruited in Oxford, UK. After baseline assessment, participants were randomized to dCBT-I or a control group. All participants also received standardised sleep hygiene advice. The primary outcome was disease-specific quality of life measured by the revised Fibromyalgia Impact Questionnaire (FIQR). Secondary outcomes included insomnia severity (Insomnia Severity Index), actigraphy-derived sleep parameters, pain (SF36 Bodily Pain Scale), cognitive complaints (British Columbia Cognitive Complaints Inventory), sustained attention, and fear of movement (Tampa Scale of Kinesiophobia). Outcomes were collected online at baseline, 3 months, and 6 months. Analyses followed the intention-to-treat principle using constrained longitudinal data analysis. Ethical approval was obtained from South Central - Oxford B Research Ethics Committee (19/SC/0168). The study was pre-registered with clinicaltrials.gov (NCT05962138). Results Of 514 individuals contacted, 241 were screened, 132 were eligible, and 80 were randomised (42 dCBT-I, 38 control). The mean age was 46.6 (SD 14.5) years; 93.8% were female. Retention was high: 97.5% of participants provided outcomes at 3 months, and 83.8% at 6 months. In the dCBT-I group, 90.5% initiated the programme, and 54.8% reached the core session on sleep restriction therapy. At 3 months, there was no significant difference between groups in FIQR (mean difference −2.79; p = 0.3). At 6 months, however, dCBT-I participants demonstrated greater improvement in FIQR compared with controls (mean difference −5.45; 95% CI − 10.5 to − 0.4; p = 0.035), corresponding to a small-to-moderate effect size (Cohen’s d = −0.31). No significant between-group differences were observed for secondary outcomes. Conclusion In adults with FM, dCBT-I produced a sustained, clinically meaningful improvement in disease-related quality of life at 6 months compared with a sleep hygiene control. Although benefits were not observed across secondary outcomes, this trial provides the first controlled evidence that dCBT-I can address an important unmet need in FM. Digital behavioural therapies represent scalable, accessible, non-pharmacological interventions with potential for rapid integration into clinical care. Disclosure E. Kelleher: Grants/research support; National Institute for Health Research (NIHR) Pfizer Doctoral Fellowship (NIHR301808). A.J. Wall: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA. V. Wanigasekera: None. R. Sharman: None. S. Kyle: None. I. Tracey: None. B. Seymour: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA. A. Irani: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA.

Abstract Parkinson’s disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.

Background: Understanding drivers of supply and labor cost variation in orthopaedic surgery is crucial to provide value-based care. Time-driven activity-based costing (TDABC) is a more accurate methodology for capturing costs of care than traditional methods. Anterior cruciate ligament reconstruction (ACLR) is one of the most performed outpatient procedures within orthopaedic surgery. The purpose of this study was to characterize the cost composition of ACLR and identify factors that drive cost variation. Methods: Cost data for supplies and time-based personnel usage were extracted from electronic health records and were used to calculate costs using TDABC. TDABC methodology was applied to calculate the cost of personnel usage by multiplying the duration and associated cost per minute. Descriptive statistics and mixed-effects modeling were used to determine cost drivers. Results: This study included 861 patients who underwent ACLR at 8 hospitals. The mean patient age (and standard deviation) was 31.1 ± 11.6 years. Of the 861 patients, 350 were male and 511 were female; 85.6% of patients were White, 8.1% were Asian, and 3.4% were Black. There was 3.2-fold variation in supply costs ($2,950) and 1.6-fold variation in labor costs ($940) between the 10th and 90th percentiles. Overall, supply costs accounted for 58.2% of total costs, whereas labor costs comprised the remaining 41.8%. The intraoperative phase was the greatest generator of total cost (89.7%). After adjusting for surgeon and hospital variability, variation in total cost was most effectively explained by graft type, primary surgery status, and meniscal repair (conditional R 2 = 0.84; marginal R 2 = 0.27). On subanalysis, patients undergoing allograft ACLR had significantly higher total costs, implant costs, and age compared with those undergoing ACLR with any autograft type (all p < 0.01). Conclusions: The most notable drivers of labor and supply cost variation were graft type, surgeon, surgery center, primary surgery status, and concomitant meniscal repair. Understanding modifiable cost drivers may aid health systems in designing value-based pathways, implant formularies, and surgeon education programs. Future studies may integrate cost with outcome measures for a more holistic view of value. Level of Evidence: Economic and Decision Analysis Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P&lt; .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P&lt; .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

Purpose: Significant variation is observed in diagnostic assessments for individuals with acquired apraxia of speech (AOS). The lack of consistency across research related to AOS impacts the comparison of intervention outcomes. This extends to diagnostic criteria, assessment, and the inclusion of patient demographics. This viewpoint examines outcomes related to the consistency in diagnostic tool use and collection of demographic information and introduces a template to support researchers and clinicians conducting diagnostic evaluations. Materials include guidelines for a thorough case history, current diagnostic characteristics, and diagnostic assessment tools available for describing AOS. The template illustrates how such materials can be structured and applied in research and clinical practice. Method: The recommendations provided in this viewpoint are part of a recent systematic review about AOS treatment outcomes. Trained raters extracted data from a comprehensive literature search from 1951 to April 2024 using a consensus protocol. Results: Of the 92 studies included in data extraction, demographic information such as age, gender, etiology, and months post-onset was commonly reported, and information about race and ethnicity (described in 15% of studies), socioeconomic status (0%), current/previous occupation (8%), language history (10%), and education (59%) was described less frequently. Reported diagnostic characteristics varied across studies, reflecting differences in using discriminatory versus nondiscriminatory features. Concomitant diagnoses, such as aphasia severity (37%) and presence of dysarthria (32%), were not consistently reported or described. Conclusion: A template with specific criteria and assessments can support research replication, raise awareness of diagnostic strategies, and offer a structured framework for investigators and clinicians. Supplemental Material: https://doi.org/10.23641/asha.32012346

ABSTRACT The HLA‐DQB1*03:506:01:01 allele is characterised by a single nucleotide substitution in codon 130 in exon 3.

Importance Brain imaging biomarkers may (1) identify underlying mechanisms of intervention effects and (2) define brain characteristics of those most likely to benefit cognitively from the intervention. Objective To test whether (1) a lifestyle intervention is related to brain changes, (2) brain changes are correlated with intervention-specific cognition changes, and (3) brain imaging biomarkers provide information about who is likely to benefit from a lifestyle intervention. Design, Setting, and Participants In this randomized clinical trial, the POINTER Imaging study was an ancillary study of the 2-year, single-blind multicenter US POINTER clinical trial in which neuroimaging data were collected on eligible enrolled participants. The study was conducted from May 2019 to March 2023 (final follow-up, May 14, 2025). Participants were enrolled into the POINTER Imaging study following a standard procedure at 5 clinical sites in the US. Participant eligibility criteria included an age of 60 to 79 years, sedentary lifestyle, and suboptimal diet, plus at least 2 additional risk criteria for cognitive decline and no contraindications for neuroimaging. Interventions Participants were randomly assigned to receive the structured or self-guided intervention. Both interventions emphasized increased physical and cognitive activity, healthy nutrition, social engagement, and cardiovascular health monitoring, but they differed in intensity and accountability. Main Outcomes and Measures There were 4 primary imaging outcomes: global β-amyloid (Aβ) burden, tau burden in the entorhinal cortex (ERC), hippocampal (HC) volume, and white matter hyperintensity volume. The primary cognitive measure was a global cognitive composite. Results Among 1943 parent trial participants who were assessed for eligibility, 983 underwent at least 1 magnetic resonance imaging or positron emission tomography scanning session. The mean (SD) age was 68.4 (5.2) years; 605 participants (61.5%) were female and 378 male (38.5%). Five hundred sixteen participants received the structured intervention and 467 the self-guided intervention. There were no intervention group differences in longitudinal cognitive or imaging outcomes. Intervention group differences were not associated with or moderated by Aβ status or accumulation. There was a negative association between change in ERC tau and change in global cognition in the self-guided group that was attenuated in the structured group (difference in association: 0.289; 95% CI, 0.029 to 0.550; interaction P = .03). Lower baseline HC volume was associated with greater cognitive benefit for participants in the structured group vs the self-guided group (lower HC: 0.077 SD; 95% CI, 0.022 to 0.132; higher HC: 0.002 SD; 95% CI, −0.037 to 0.041; interaction P = .03). Conclusion and Relevance This study found that a high-intensity multidomain lifestyle intervention did not affect brain biomarker trajectories and was not associated with Aβ pathology, but older adults with specific at-risk brain characteristics, including lower baseline HC volume, showed a greater cognitive benefit of the structured intervention. Trial Registration ClinicalTrials.gov Identifier: NCT03688126