Citations

ABSTRACT Background and Aims Cellular senescence is a hallmark of several liver diseases, including primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Senescent cholangiocytes exhibit a senescence‐associated secretory phenotype (SASP), characterized by profibroinflammatory mediator release. Current cost‐effective biomarkers predicting disease progression, particularly for PSC, are limited and often lack mechanistic relevance. We sought to define a plasma biomarker signature for PSC and PBC. Methods Plasma from early‐ and late‐stage PSC and PBC, alcoholic liver disease (ALD), inflammatory bowel disease (IBD) patients, and healthy controls was analyzed. Seventy‐one analytes were quantified using Luminex Multiplex Immunoassay or enzyme‐linked immunosorbent assay (ELISA). Principal component analysis (PCA) identified key patterns. Findings from the PSC cohort were then applied to additional cohorts. Results Second principal component (PC2) (17 analytes, 17.1% variability) best separated PSC from controls. ANOVA showed significant differences in PC2 between early PSC vs. controls ( p = 0.0001), late PSC vs. controls ( p < 0.0001), and early vs. late PSC ( p < 0.0001). PC2 analytes also distinguished early PBC vs. controls ( p < 0.0332), late PBC ( p < 0.0001), and ALD ( p < 0.0001), and early vs. late PBC ( p < 0.0001), but not IBD vs. controls ( p = 0.119). Logistic regression using PC2 demonstrated strong discrimination of early‐ and late‐stage PSC (AUC = 0.86) and control vs. early‐stage PSC (AUC = 0.83). Conclusion This is the first study to define a plasma SASP biomarker signature associated with cholestatic liver disease. These analytes track disease stage and represent both mechanistic indicators and potential clinical trial endpoints.

Peroxisome-proliferator–activated receptor delta (PPARδ) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPARδ agonists, KD3010 and T3D-959, in two established ALS/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43Q331K transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9–10 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43Q331K mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement—particularly for T3D-959—neither PPARδ agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPARδ activation without therapeutic benefit. Together, these findings demonstrate that PPARδ agonism is insufficient to modify disease progression in these ALS/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.

The glomerular filtration rate (GFR) is a key indicator of kidney function, yet no ideal method exists for its direct measurement. This two-part review examines the development of GFR measurement techniques, focusing on their physiologic basis, performance characteristics, and clinical applications. Part 1 reviews endogenous markers used to estimate GFR (eGFR), including creatinine- and cystatin C-based equations, with emphasis on their derivation, limitations, and clinical use. Part 2 addresses exogenous filtration markers and measured GFR (mGFR) methodologies, highlighting comparative performance and specific uses. Emphasis is placed on innovation in marker development, highlighting the need for continued development and standardization to enhance accuracy and clinical utility.

Measured glomerular filtration rate (mGFR) remains the reference standard for precise assessment of kidney function when estimated approaches are insufficient. This second part of a two-part series reviews exogenous filtration markers used to obtain mGFR, including inulin, iothalamate, iohexol, and radionuclide-based tracers, with emphasis on their physiologic handling, analytic methods, accuracy, and clinical applicability. The review further examines emerging fluorescent and near-infrared tracers coupled with transcutaneous monitoring technologies that enable rapid or continuous assessment of GFR. Together, these approaches illustrate the evolution of mGFR measurement toward methods that are more practical, scalable, and responsive to dynamic changes in kidney function, while maintaining analytical accuracy.

OBJECTIVE: To evaluate the effect of joint preparation and patient factors on outcomes and complications in patients treated acutely with hindfoot fusion nails for ankle and pilon fractures. METHODS: Design: Retrospective chart review. Setting: Thirteen US trauma centers and 2 UK trauma centers. Patient Selection Criteria: Ankle and pilon fractures (AO-OTA types A-C) from 2010 to 2020 acutely treated definitively with hindfoot fusion nail were reviewed. Patients at least 18 years old and with minimum 6 months follow-up or earlier diagnosis of complication were included. Exclusion criteria included nonambulatory at baseline, prior internal fixation that failed and underwent revision, and prior tibiotalar or subtalar arthrodesis. Outcome Measurements and Comparisons: The primary outcome was final postoperative ambulatory status. Secondary outcomes were infectious and fracture-related complications. RESULTS: One hundred forty-nine patients (75 men; 74 women; age 20–99; median 63 years) were treated for ankle (104) or pilon (45; 8A, 13B, 24C) fractures. Eighty-five patients (44%) had open fractures and 55 (37%) had diabetes. Thirty-six patients (24%) had joint preparation at the time of surgery. Forty-five (30%) were made weight bearing as tolerated postoperatively; the median time to mobilize was 1.5 days (0–210) and to full weight bearing was 35 days (0–1462). Fifty-seven patients (85%) returned to their preinjury ambulatory status, which was not affected by joint preparation (50% vs. 59%, P = 0.327). Joint preparation led to higher articular fusion rates (94% vs. 24%; P = 0.001) and fewer hardware removals (19% vs. 42%, P = 0.013), but trended toward a higher fracture nonunion rate (19% vs. 8%, P = 0.053). Forty-five patients (30%) had infectious complications, 60 (40%) had a fracture-related complication, and 67 (45%) had additional procedures. Open fractures did not lead to any differences in superficial or deep infection. Insulin-dependent diabetes was associated with higher rates of infectious complications (31% vs. 15%, P = 0.028) and amputation (17% vs. 4%, P = 0.029). CONCLUSIONS: Hindfoot fusion nails for acute ankle and pilon injuries had high complication rates. More complications occurred in patients with insulin-dependent diabetes. While 95% regained ambulation, only 57% returned to preoperative status. Joint preparation led to higher rates of articular fusion (94% vs. 24%, P < 0.001) but not fracture union (81% vs. 66%, P = 0.106). LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

ABSTRACT Objectives Laryngeal chondrosarcoma (LC) is a rare tumor accounting for less than 1% of all laryngeal cancers. While surgery is the primary treatment, national trends in management and outcomes remain poorly defined. This study aimed to analyze incidence, survival, and treatment strategies for LC using the Surveillance, Epidemiology, and End Results (SEER) database. Methods Patients with LC diagnosed between 2000 and 2021 were identified from SEER. Demographic, treatment, and survival data were analyzed. Kaplan–Meier analysis and multivariate Cox regression were used to analyze survival outcomes. Results In total, 351 patients with LC were identified, representing 0.3% of all laryngeal malignancies. Among patients with treatment data, 53.3% underwent local excision or partial laryngectomy, 27.5% underwent total laryngectomy (TL), and 19.2% received no surgery. Ten‐year disease‐specific survival was 84.8%. Patients undergoing partial resection demonstrated significantly improved survival compared with TL ( p < 0.05), although this finding is likely confounded by tumor size and stage. On multivariate analysis, advanced stage (HR 2.59, 95% CI 1.68–3.97), older age (HR 1.66, 95% CI 1.36–1.99), and TL (HR 2.95, 95% CI 1.88–4.62) were associated with worse survival. Conclusion LC remains rare but carries favorable long‐term survival. National trends demonstrate a shift toward organ‐preserving surgery, with partial resections increasingly favored over TL. Prognosis is most strongly influenced by age and stage, while radiation therapy appears to play a little role. These findings support organ preservation in appropriately selected patients and highlight the need for prospective studies integrating oncologic and functional outcomes. Level of Evidence 4

Abstract Introduction: Recruitment for rare disease studies is challenging due to small eligible populations. Traditional clinical research management systems often lack tools to track recruitment contacts prior to enrollment. The NET-PRO study, focused on neuroendocrine tumors (NETs), implemented a participation monitoring system to enhance recruitment efficiency and representativeness. Methods: NET-PRO is a multicenter cohort study of 2538 adults diagnosed with gastroenteropancreatic (GEP) or lung NETs between January 2018 and September 2024. Recruitment occurred from January 2022 to February 2025 across 14 U.S. medical centers. Sites used flexible recruitment methods (email, mail, phone, in-clinic) and tracked contacts using REDCap-based tools. Participant characteristics were analyzed by enrollment mode (online or mail) and recruitment difficulty (number of contacts required prior to enrollment) using standardized mean differences, chi-square tests, and ANOVA. Results: Of 9279 contacted patients, 2675 consented (28.8%) and 2538 enrolled (27.4%). Most enrolled online (83.2%), while 16.8% enrolled by mail. Mail respondents were older, had lower education and income, and more comorbidities. Among those enrolled, recruitment difficulty was associated with older age, lower education and income, but not comorbidity. Over half of the most difficult-to-recruit participants enrolled online. Contact methods varied by attempt, with email dominating early contacts and phone/mail used more in later attempts. Conclusions: A participation monitoring tool supported flexible, multimodal recruitment and improved sample representativeness in a rare cancer study. Tracking recruitment contacts enabled adaptive strategies and may reduce bias in observational research by enabling better outreach to harder-to-reach populations.

Abstract Background Colonic strictures in Crohn’s disease (CD) are an important, but understudied clinical problem. Cross-sectional imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and intestinal ultrasound (IUS) effectively assess the small bowel in CD allowing for the diagnosis of strictures. However, radiologic definitions of colonic strictures and their diagnostic accuracy have not been developed. Endoscopic definitions of colonic strictures are the most well-described. Aims We aimed to systematically review available data to summarize definitions, diagnosis and differentiation between inflammation and fibrosis of colonic strictures on endoscopy, CT, MR, and IUS Methods We conducted a systematic review following PRISMA guidelines using MEDLINE, Scopus, CINAHL, and CENTRAL databases from inception to Oct 6, 2024 to identify literature with diagnostic imaging that included patients with colonic CD strictures. To distinguish fibrosis from inflammation, only studies comparing endoscopy or imaging to a full thickness histologic gold standard were included. Two stage screening was completed in duplicate, and risk of bias was assessed using QUADAS-2 Results 46 studies were eligible for inclusion. Definitions for colonic strictures on CT, MR, and IUS are heterogeneous with combinations of bowel wall thickness, luminal narrowing, and pre-stenotic dilation with no clear cut offs. Endoscopic definitions commonly included lack of colonoscope passage through a narrowed lumen. The diagnostic accuracy of colonic strictures on imaging to detect inflammation and fibrosis against a gold standard of endoscopy or surgical resection is unclear as direct comparisons are few. Meta-analyses were not conducted due to methodological heterogeneity of grading fibrosis and statistical heterogeneity of sensitivity, specificity, and accuracy of colonic stricture diagnoses limited by pooling with small bowel strictures in the studies Conclusions This systematic review describes a lack of definitions for the diagnosis of CD colonic strictures particularly on diagnostic imaging, and the limitations with the current available data to differentiate inflammation from fibrosis. Although bowel wall thickening, luminal narrowing, and pre-stenotic dilation are recognized as hallmark features of small bowel strictures, their adaptation to the colon requires further assessment. Definitions for colonic strictures should likely include imaging combined with endoscopy. Future endeavors are required to develop a consensus to define and diagnose colonic strictures on these modalities Funding Agencies None