Citations

Background: Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by biliary fibroinflammation. TGFβ-activated cholangiocytes release signals that recruit immune cells and activate myofibroblasts, promoting inflammation and extracellular matrix (ECM) deposition. TGFβ also regulates stearoyl-CoA desaturase (SCD), an enzyme involved in lipid signaling. Yet, the role of SCD or its inhibitor, Aramchol, in biliary fibroinflammation had not been studied. Methods and Results: Mdr2 -/- with established biliary fibrosis and 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) diet-fed mice were treated with Aramchol meglumine (12.5 mg/kg/day). Hepatic fibrosis was assessed by qPCR, Picrosirius red staining, immunofluorescence, and hydroxyproline content. Human H69 or murine large cholangiocyte cell lines stimulated with TGFβ, as well as PSC-derived cholangiocytes (PSC-C), were treated with Aramchol or SCD siRNA. RNA-seq, fibroinflammatory marker expression, peroxisome proliferator-activated receptor (PPAR) activity, and targeted fatty acid profiling were performed. Aramchol treatment significantly reduced hepatic ECM gene expression, inflammatory cytokines ( Il6 , Tnfa ), collagen content, and myofibroblast activation (aSMA staining) in both mouse models. In TGFβ-stimulated H69 cells, Aramchol suppressed hepatic fibrosis pathways and enhanced PPAR signaling. Aramchol also reduced the expression of fibrotic markers, myofibroblast-activating mediators ( VEGFA and PDGFB ), and IL6, mirroring the effects of SCD knockdown. In PSC-C, Aramchol significantly downregulated SCD, VEGFA and IL6 . Conversely, PPARα and -γ activity and fatty acid agonist, linoleic acid levels were increased in cholangiocyte cell lines. Conclusions: Aramchol attenuates and prevents biliary fibrosis in mouse models of cholestatic liver disease by inhibiting TGFβ-induced fibroinflammatory mediators and activating PPARa/γ in cholangiocytes. These findings, combined with its favorable clinical safety profile, support the potential of Aramchol as a therapeutic candidate for PSC.

Comparative analysis of fibrin sealant and recombinant thrombin hydrogels reveals distinct microarchitectures and cellular responses, emphasizing recombinant thrombin’s potential to enhance cellular activity and enable vesicle delivery.

Background/Objectives: Traditional hearing aid noise reduction algorithms offer no additional benefit in noisy situations for bimodal cochlear implant (CI) users with a CI in one ear and a hearing aid (HA) in the other. Recent breakthroughs in deep neural network (DNN)-based noise reduction have improved speech understanding for hearing aid users in noisy environments. These advancements could also boost speech perception in noise for bimodal CI users. This study investigated the effectiveness of DNN-based noise reduction in the HAs used by bimodal CI patients. Methods: Eleven bimodal CI patients, aged 71–89 years old, were fit with a Phonak Audéo Sphere Infinio 90 HA in their non-implanted ear and were provided with a Calm Situation program and Spheric Speech in Loud Noise program that uses DNN-based noise reduction. Sentence recognition scores were measured using AzBio sentences in quiet and in noise with the CI alone, hearing aid alone, and bimodally with both the Calm Situation and DNN HA programs. Results: The DNN program in the hearing aid significantly improved bimodal performance in noise, with sentence recognition scores reaching 79% compared to 60% with Calm Situation (a 19% average benefit, p < 0.001). When compared to the CI-alone condition in multi-talker babble, the DNN HA program offered a 40% bimodal benefit, significantly higher than the 21% score seen with the Calm Situation program. Conclusions: DNN-based noise reduction in HA significantly improves speech understanding in noise for bimodal CI users. Utilization of this technology is a promising option to address patients’ common complaint of speech understanding in noise.

Abstract INTRODUCTION African American (AA) individuals are underrepresented in biomarker studies for Alzheimer's disease (AD). Biomarkers that reflect the heterogeneity of AD and achieve the greatest accuracy across populations are sorely needed. METHODS Untargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in AA participants with clinical diagnoses of AD dementia ( n = 181) and cognitively unimpaired (CU, n = 142). Machine learning was used to identify a set of plasma proteins that yielded the best classification accuracy. RESULTS A set of 36 proteins achieved an area under the curve (AUC) of 0.94 to classify AD dementia versus CU, a 16% improvement over age, sex, and apolipoprotein E ( APOE) . This finding was replicated in multiple plasma and brain datasets (AUCs 0.73–0.97). Our findings underscore the importance of matrisome and cerebrovascular dysfunction in AD pathophysiology. DISCUSSION This study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning. Highlights Conducted large‐scale plasma proteomics in Alzheimer's disease (AD) versus cognitively unimpaired controls. Machine learning biomarker discovery was replicated in an independent cohort. Novel set of proteins distinguishes AD versus controls with high accuracy (area under the curve [AUC] = 0.94). Achieved reproducibility across multiple replication cohorts (AUC = 0.73–0.97). Network analyses implicates matrisome biology and cerebrovascular dysfunction.

Objective How tumour-adherent microbiome can influence outcomes in patients with colorectal cancer (CRC). Methods and analysis CRC tissues (n=97) were analysed using RNAseq, whole exome sequencing (WES) and 16 r sRNA sequencing. Inflammatory/immune cells were quantified by immunohistochemistry in mice and human tissues. Patient outcomes were analysed according to virulent bacteria and gene RNA levels in tumour tissues. We performed faecal microbiota transfer (FMT) in germ-free mice using presurgery stool samples from nine patients with sporadic CRC. Changes in gene mutations and DNA methylation in the colonic mucosa were measured and compared with those in mice receiving FMT from nine healthy individuals. Immune cells in the tumour tissues of donor and mouse recipients were compared. Results FMT from CRC donors led to preferential DNA demethylation, but specific host genes, including pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), were hypermethylated compared with FMT from healthy donors. CRC faecal samples showed elevated levels of virulent bacteria, reduced levels of commensals and triggered colon inflammation in mice. Notably, PHLPP1 was downregulated in CRC tumours, and its expression varied in accordance with other CRC cardinal genes (n=137, as identified in the scientific literature to be involved in colon carcinogenesis), and was most pronounced in inflammatory bowel disease associated CRC. Tumours with reduced PHLPP1 expression are more inflammatory and correspond to patients with a higher relative abundance of adherent virulent bacteria and poorer outcomes. Conclusion The composition of CRC tumour-adherent bacteria predicts epigenetic modifications and altered expression of cardinal CRC genes such as PHLPP1. PHLPP1 downregulation characterises patients with CRC with inflammatory tumours and poor survival outcomes.

BACKGROUND/OBJECTIVE Patient- and family-centered rounds (PFCR) have become a pediatric standard of care. However, rounds experiences of families using languages other than English (LOE)—particularly languages other than English or Spanish (LOES; eg, Arabic)—receive less focus. We aimed to identify differences in PFCR communication and engagement by language. METHODS We analyzed postintervention data from a 21-center structured PFCR study, assessing communication practices, quality, and family and nurse engagement during PFCR. Logistic regression adjusted by site compared PFCR between families using (1) LOE vs English, (2) Spanish vs English, and (3) LOES vs English. RESULTS Among 3051 PFCR encounters, 348 (11.4%) involved LOE (Spanish = 260; LOES = 85). Interpretation was not used in 7.2%, 5.8%, and 9.4% of encounters using LOE, Spanish, and LOES, respectively. PFCR in the following groups had lower adjusted odds (adjusted odds ratio [95% CI]) for the following domains: (1) LOE vs English: including providing verbal patient summaries (0.66 [0.46–0.95]), explaining diagnoses and differentials (0.62 [0.44–0.88]), family engagement (0.34 [0.20–0.57]), nursing inclusion (0.75 [0.60–0.93]), and nursing engagement (0.69 [0.52–0.90]). (2) Spanish vs English: diagnoses/differentials being explained (0.56 [0.37–0.85]), family engagement (0.35 [0.18–0.67]), nursing inclusion (0.77 [0.59–1.00]), and nursing engagement (0.68 [0.52–0.89]). (3) LOES vs English: families sharing concerns (0.66 [0.47–0.93]), family engagement (0.30 [0.16–0.54]), and nursing inclusion (0.74 [0.55–0.99]). CONCLUSION Even after implementing a PFCR intervention, families using LOE—especially LOES—experienced significant disparities in communication and engagement. Future approaches to improving PFCR should emphasize language access and promote nurse and family engagement for families using LOE, particularly LOES.

Paget–Schroetter syndrome (PSS) is a form of effort thrombosis seen in young athletes and individuals with occupations involving repetitive upper limb movement. Arm swelling, distended veins, skin discoloration, and pain are characteristics of it. Diagnosis can be made with non-invasive investigations, such as Doppler ultrasound; however, a computed tomography venogram, magnetic resonance venogram, or traditional venogram may be required. Treatment involves anticoagulation, thrombolysis, and surgical decompression with removal of the first rib, and this is usually met with good outcomes. We present a young female diagnosed with PSS and requiring a staged multidisciplinary approach to treatment.

Abstract The initial method of detection (MOD) refers to the first imaging examination, physical symptom, or clinical sign that prompts further investigation and ultimately leads to a new breast cancer diagnosis. The MOD is assigned at the patient level and falls into 1 of 3 categories: screening in asymptomatic patients, detection by patients or health care providers, or neither of the above. The MOD should be assigned prospectively by the radiologist when interpreting an examination with a final BI-RADS category of 4 or 5, before image-guided biopsy and breast cancer diagnosis. The MOD is not assigned to examinations classified as BI-RADS category 0, 1, 2, 3, or 6, nor is it assigned in the setting of an active breast cancer diagnosis. This Clinical Practice article addresses frequently asked questions and challenging clinical scenarios compiled by the American College of Radiology’s Screening and Emerging Technology Committee to guide consistent MOD assignment. For example, if a patient presents with a lump but is ultimately found to have a suspicious finding requiring biopsy in the contralateral breast, the MOD should reflect the reason for presentation, the patient-detected symptom (Pat), even if the cancer itself is asymptomatic. By increasing awareness of MOD and standardizing MOD reporting practices, radiologists can contribute to improved data collection. While MOD is not currently tracked in U.S. cancer registries, its systematic collection may offer valuable insights into screening effectiveness, technology performance, and disparities in cancer detection. Standardized MOD reporting has the potential to strengthen early detection efforts and improve outcomes across diverse clinical settings.