Publications

Joint function is impaired by disuse, as well as overuse. However, the underlying mechanisms remain unclear. Here, we elucidate the mechanisms of synovial and cartilage changes using a minimized mechanical stress (MMS) mouse model by combining knee joint immobilization and unloading. In this model, synovitis appeared by day 3, followed by subsequent fibrosis leading to joint contracture within two weeks. In contrast, articular cartilage degeneration developed gradually after the synovial alterations. Notably, synovial changes were attenuated by discontinuation of joint immobilization, while cartilage changes improved after discontinuation of joint immobilization and loading. Bulk RNA sequencing (RNA-seq) analyses supported the transcriptomic alterations for synovitis, fibrosis, and cartilage degeneration, and identified ten cytokines associated with cartilage changes. Single-cell RNA-seq (scRNA-seq) further identified distinct subsets in the MMS synovium: Lrrc15+ myofibroblasts and Mmp9+ macrophages, expressing many of these cytokines. Histological examination showed that MMS initially induced macrophage proliferation, while macrophage depletion by intra-articular administration of clodronate liposomes inhibited MMS-induced synovitis, fibrosis and cartilage degeneration, accompanied by a marked reduction in the MMS-distinct subsets. Our findings identified MMS-induced alterations in synovial cells and their roles in joint phenotype, suggesting that joint motion and mechanical loading contribute to the regulation of joint homeostasis.

Diagnosing sleep disordered breathing requires manual annotation of events from sleep studies, such as nocturnal polysomnography, a process that is time-intensive, costly, and prone to inter-rater variability. Automatic approaches exist but lack generalizability due to signal variability across centers. We develop an automatic apneic breathing event detector to localize and classify obstructive apneas, central apneas, hypopneas, and isolated respiratory events without arousals or desaturations. The model is trained on 5456 polysomnographies and tested on 1099 polysomnographies from six cohorts uses an end-to-end deep learning architecture. The model's predictions show a strong correlation with expert annotations for apnea-hypopnea index (r² = 0.84) and achieve an F1 score of 0.78 across apnea event types, with specific F1 scores of 0.71, 0.51, and 0.65 for obstructive apnea, central apnea, and hypopnea events, respectively. In two independent, multi-scored datasets, The model performs comparably or better than individual expert raters. The model's probabilistic output, termed "apnotyping," provides insights into sleep disordered breathing etiology, with event probabilities correlating more strongly with key sleep apnea traits-such as loop gain and pharyngeal muscle compensation-than traditional apnea indexes. This probabilistic approach may enhance diagnostic accuracy and support personalized treatment strategies, leading to improved patient outcomes.

PURPOSE: Investigate the structure-function relationships between epiretinal membrane (ERM) stage, tractional abnormalities, and the gap area between the ERM and the retinal surface, in relation to visual acuity and quantitative contrast sensitivity function (qCSF) in patients with idiopathic epiretinal membrane.

METHODS: This was a retrospective, cross-sectional study involving 111 participants diagnosed with idiopathic epiretinal membrane (iERM). All patients underwent a comprehensive ophthalmological examination, optical coherence tomography imaging (SD-OCT) using the SPECTRALIS® Heidelberg system, and contrast sensitivity (CS) testing utilizing the qCSF method.

RESULTS: Progressive stages of ERM were associated with declines in both CS and visual acuity (β*=-0.45 to -0.19, p<0.02), with CS showing a more pronounced reduction than visual acuity, especially between controls and stage 1. Ectopic inner foveal layer (EIFL) thickness exhibited a similar pattern of decline in both visual acuity (β*=0.42, p<0.001) and CS (β*= -0.46 to -0.18, all p <0.02). In contrast, SUKIMA showed no significant association with any of the visual measurements assessed. Among the tractional abnormalities, the cotton ball sign correlated with diminished vision, particularly reflected by a notable drop in CS at the highest spatial frequencies tested with reduced CS at 12 cpd (β*=-0.44, p=0.02) and 18 cpd (β*=-0.46, p=0.02).

CONCLUSION: qCSF testing is particularly important for assessing visual function in ERM development, especially in the early stages.

Due to the limited size of viral genomes, most viral proteins are multifunctional; yet most direct-acting antivirals are designed as single-function inhibitors. The dengue virus (DENV) capsid protein serves as a building block for new virions while also interacting with multiple host factors to remodel the cellular environment. Using established capsid inhibitor ST148 as a targeting ligand, we develop a DENV capsid degrader, RPG-01-132, that exhibits a broadened spectrum of activity against the four DENV serotypes and an ST148-resistant mutant virus. Using multiple approaches, we show that RPG-01-132's sub-micromolar antiviral activity is due to CRL4CRBN-dependent degradation of capsid and that this mechanism disrupts capsid-related pathways required for productive infection, including infectious virus output and capsid-mediated antagonism of the interferon response. This pharmacology is well-differentiated from ST148, which interferes with assembly of new virions, but has no demonstrated effect on the capsid's nonstructural functions. These findings demonstrate that targeted protein degradation can thus enable antiviral pharmacology not observed with conventional antiviral inhibitors and that is resilient to point mutations that reduce inhibitor potency.

Thrombosis drives substantial global mortality across atrial fibrillation, venous thromboembolism, and atherosclerosis. However, clinical scores treat risk as a static variable and omit evolving comorbidities, functional biomarkers, anatomy, and treatment exposure, leading to misclassification and preventable events. This statement advances a unified scientific agenda for patient-specific digital twins that dynamically integrate multimodal longitudinal data with mechanistic insight to predict thrombogenesis risks. We position these digital twins as hybrid models anchored in physics and data-driven algorithms that can simulate disease progression and therapy. The goal of this approach is to refine stroke and bleeding estimation beyond current clinical rules. Continuous updating from imaging data, laboratory test results, wearables, and electronic health records supports dynamic risk trajectories and adaptive care pathways, facilitating continuous risk reassessment. This statement analyzes gaps in data quality, calibration, validation, and uncertainty quantification that presently limit the clinical translation of this technology. Research priorities are then proposed for multiscale thrombosis modelling, physics-informed learning, probabilistic forecasting, and regulatory-compliant data stewardship. Finally, we outline translation to in silico trials, regulatory alignment, and hospital workflows that link predictions to decisions. By articulating shared challenges across thrombosis-driven diseases and reframing risk as a time-varying measurable quantity, this statement lays a foundation for developing digital twin approaches that support a shift from population heuristics towards precise, timely thrombosis care. These advances are essential for translating digital twin technology from research to clinical practice, enabling dynamic risk prediction and personalized anticoagulation therapy.

Living donor kidney transplantation (LDKT) offers the most favorable outcomes for patients with end-stage kidney disease, yet Black patients have disproportionately low LDKT rates. This multicenter randomized controlled trial tested whether Transplant House Calls (THC), a home-based education program that engages patients and social networks, with or without Peer Mentorship (PM), could increase LDKT access among Black patients. Between 2018 and 2020, 319 patients were randomized to Usual Care (UC), THC, or THC+PM. The primary outcome was LDKT within 1 year; secondary outcomes included living donor inquiries, donor evaluations, and patient-reported outcomes (PROs) related to knowledge, attitudes, and readiness. Overall, 5% of patients received LDKT, with no statistically significant differences among groups (UC: 0%; THC: 5%; THC+PM: 6%, P=0.07). However, both THC and THC+PM participants were significantly more likely than UC patients to have at least one living donor inquiry (P=0.04 and P=0.01, respectively) and evaluation (P=0.04 and P=0.01, respectively). Intervention participants also showed greater improvements in LDKT knowledge, reduced concerns, increased readiness to act, and higher self-efficacy compared with UC. Although PM uptake was incomplete, satisfaction was high, and exploratory analyses suggested a potential incremental benefit. The COVID-19 pandemic curtailed intervention delivery, delayed donor evaluations and surgeries, and likely contributed to the modest transplant rates observed. In conclusion, culturally tailored, home-based education that directly engages patients' social networks improves intermediate outcomes and patient preparedness for LDKT. Further evaluation with larger samples, longer follow-up, and full THC and PM implementation is warranted to assess potential impact on reducing racial disparities in LDKT.

Background The management of incidental adnexal lesions encountered at CT depends on the diagnosis, but little evidence supports CT diagnosis of most adnexal lesion types. Purpose To evaluate the interreader agreement and CT diagnosis of incidentally discovered adnexal lesions. Materials and Methods This institutional review board-approved, multi-institutional, multireader retrospective study conducted from January 1, 2022, to June 30, 2023, included patients who had malignant ovarian lesions with metastases (n = 8) and without metastases (n = 8), simple cysts (n = 6), dermoids (n = 9), hydrosalpinx (n = 5), benign cystadenomas and/or cystadenofibromas (n = 10), hemorrhagic cysts (n = 8), endometriomas (n = 6), ovarian fibromas (n = 5), leiomyomas (n = 5), and peritoneal inclusion cysts (n = 5) detected at CT. Nine members of the Society of Abdominal Radiology Uterine and Ovarian Cancer Disease-Focused Panel, blinded to the final diagnosis, independently reviewed the CT images and used the American College of Radiology white paper to determine the most likely diagnosis. A 2 × 2 factorial random-effects model was used to calculate the mean adjusted accuracy and disparity among the readers. Interreader agreement was calculated using a Gwet AC1 test. Results In total, 75 patients (mean age, 50 years ± 16 [SD]) were included. The mean adjusted accuracy and interreader agreement were highest for dermoids (99% and 0.97, respectively), malignant ovarian lesions with metastases (94% and 0.90), and simple cysts (86% and 0.64). The mean adjusted accuracy for all other lesion types was less than 72%, with fair to moderate interreader agreement. Overall, readers more accurately diagnosed malignant lesions (82%) than benign lesions (52%) (P < .001). Readers recorded a benign diagnosis when a malignant lesion was present 28% of the time (20 of 72) (P < .001) when there were no metastases. Conclusion Readers' mean adjusted accuracy was greatest for dermoids, malignant ovarian lesions with metastases, and simple cysts at CT, with substantial to almost perfect interreader agreement; all other lesions were challenging, and a substantial number of malignant ovarian lesions were misdiagnosed as benign. © RSNA, 2026.

Newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD) enables early identification of boys at risk for adrenal insufficiency (AI) and cerebral ALD (CALD). However, NBS frequently identifies ABCD1 variants of uncertain significance (VUS), which are associated with only borderline-elevated C26:0-lysophosphatidylcholine (LPC(26:0)) levels. Traditional American College of Medical Genetics and Genomics (ACMG) pathogenicity classification does not account for age-dependent penetrance or the broader phenotypic spectrum, complicating risk assessment and clinical management. Through the Grey Zone Project, we developed a risk-stratification framework using a receiver operating characteristic (ROC)-based approach prioritizing 95% sensitivity. This framework incorporates biochemical and longitudinal clinical data from 1627 control subjects and 196 confirmed ALD patients. Three pediatric risk categories were defined: "no ALD" (<110 nmol/L LPC(26:0)), "lower-risk AI/CALD" (110-177 nmol/L), and "at-risk AI/CALD" (>177 nmol/L). When applied to 108 samples carrying 51 unique ABCD1 VUSs, 26 variants were reclassified as "no ALD," 15 as "lower-risk AI/CALD," and 10 as "at-risk AI/CALD." The framework reclassifies ABCD1 variants based on biochemical risk profiles, reducing false-positive referrals, avoiding unnecessary MRI surveillance, and alleviating parental anxiety by identifying children who are unlikely to develop childhood-onset disease. Integrating biochemical thresholds with genetic and longitudinal clinical data improves the specificity of NBS without compromising its sensitivity. Providing systematic feedback on false-positive cases to screening laboratories will further refine cut-offs. This framework provides a scalable, evidence-based model for interpreting variants and enabling personalized follow-up in ALD and other disorders with a variable age of onset.

INTRODUCTION: Bipolar disorder is a chronic, complex mental health condition. Chronic Care Models were developed to treat chronic medical conditions in primary care. Several clinical trials have assessed their effects in treating individuals with bipolar disorder.

METHODS: A systematic literature review identified randomized controlled trials that tested interventions utilizing at least three of the five Chronic Care Model clinical elements. Random effects meta-analysis assessed impact on six outcome domains: overall mental health, mania, depression, mental health-related quality of life, physical health-related quality of life, and treatment costs. Risk of bias for individual trials and confidence in the point estimate for outcome domains were determined following the Cochrane methodology.

RESULTS: Eight randomized controlled trials were identified, resulting in six meta-analyses of two to eight trials each. The single-blind methodology resulted in a high overall risk of bias for each trial. Statistically significant benefit was seen for overall mental health (standardized mean difference (SMD) = 0.28, 95% CI = 0.13-0.43, p < 0.01), mania (SMD = 0.16, 95% CI = 0.01-0.30, p = 0.03), and mental health-related quality of life (SMD = 0.24, 95% CI = 0.08-0.41, p < 0.01). No evidence of an effect was seen for depression, physical health-related quality of life, or costs. Confidence was moderate for overall mental health outcome, mania, depression, and mental health-related quality of life; low for physical health-related quality of life; and very low for costs.

CONCLUSIONS: Trials in diverse health care systems indicate that Chronic Care Model elements may improve mental health outcomes for bipolar disorder. This meta-analysis highlights the need for research to further explore the effectiveness and implementation of these models of care.