Citations

Abstract Endoscopic retrograde cholangiopancreatography (ERCP)-based tissue acquisition is the cornerstone for assessment of suspected malignant biliary strictures. Conventional techniques, including biliary brush cytology and transpapillary forceps biopsy, are highly specific but are limited by modest sensitivity for detection of malignancy, often leaving a substantial proportion of individuals without a definitive diagnosis. To improve diagnostic sensitivity for cancer, several adjunctive approaches have been integrated into ERCP-based sampling. Peroral cholangioscopy (POC)-guided biopsies have become a reliable ERCP-based adjunctive modality, allowing direct visualization and targeted sampling, particularly in individuals with prior nondiagnostic procedures. Fluorescence in situ hybridization (FISH) is a technique used to improve diagnostic yield with biliary brushings by detecting chromosomal abnormalities, but is limited to specialized centers due to the need for specialized processing and training. Next-generation sequencing provides high sensitivity and can enable identification of actionable genomic alterations, while methylated DNA markers represent a promising, scalable molecular approach with strong diagnostic performance. Additional techniques include artificial intelligence–augmented direct visualization by POC and bile-based liquid biopsy. Current guidelines recommend multimodal ERCP-based sampling, combining at least two modalities where feasible, to optimize diagnostic accuracy. This review highlights the clinical performance, strengths, and limitations of established and emerging ERCP-guided techniques, emphasizing their evolving role in improving the diagnosis and management of malignant biliary strictures.

Abstract Background Adipose tissue influences blood pressure regulation through depot-specific endocrine, inflammatory, and exosome-dependent mechanisms. While obesity is a well-established risk factor for hypertension, emerging evidence suggests that distinct fat depots may contribute to vascular dysfunction independent of total adiposity. Methods: This review synthesizes post-2020 literature on 6 anatomically defined depots: visceral, perivascular, epicardial, bone marrow, brown, and beige adipose tissue, with an emphasis on their mechanistic roles, imaging biomarkers, and translational relevance. Results Alterations in adipose depot function can impair nitric oxide signaling, promote oxidative stress, and modulate sympathetic tone, even in the absence of obesity. Exosomal microRNAs from dysfunctional adipose tissue further disrupt vascular homeostasis. Although clinical tools for assessing depot dysfunction are limited, advances in imaging and molecular profiling may enable targeted therapeutic strategies. Conclusions Reframing adipose tissue as a modular regulator of blood pressure, rather than a passive consequence of obesity, may unlock new venues for precision management of hypertension.

Background: Pediatric tibial fractures are common long-bone injuries, yet uncertainty remains in the optimal immobilization strategy. The comparative effectiveness and safety of short leg versus long leg casts in achieving stable healing and functional recovery have not been clearly established. Methods: A literature search was conducted across Medline, CINAHL, Embase, and Cochrane Library, from inception to August 2025, following PRISMA guidelines and registered with the International Prospective Register of Systematic Reviews (PROSPERO). Statistical analyses were performed using a random-effects model. Results: The initial search yielded 1236 studies; 6 studies with 413 pediatric patients met the inclusion criteria. A total of 163 underwent short leg casting (SLC) and 250 long leg casting (LLC). No differences were observed between SLC and LLC for coronal angulation (MD=0.12 degrees, 95% CI=−0.89 to 1.12, I 2 =58%) or sagittal angulation (MD=0.18 degrees, 95% CI=−0.71 to 1.07, I 2 =56%). Subgroup analyses showed no differences for tibial shaft fractures or Salter-Harris distal tibial fractures. Cast duration was similar between groups (MD=−0.74 wk, 95% CI=−1.49 to 0.01, I 2 =92%). Overall complication rates did not differ (OR=0.76, 95% CI=0.25 to 2.34, I 2 =0%), with no differences in Salter-Harris subgroup analysis (OR=0.67, 95% CI=0.05 to 9.91; I 2 =54%). SLC was associated with shorter time to weight-bearing (MD=−2.29, 95% CI=−4.49 to −0.08, I 2 =68%) and faster time to union (MD=−1.21, 95% CI=−2.16 to −0.25, I 2 =30%). Conclusion: SLCs may be considered as an alternative to LLCs in pediatric tibial shaft and distal tibial physeal fractures based on currently available retrospective comparative evidence. However, the evidence is limited by the retrospective design, clinical heterogeneity, and risk of confounding. Further prospective comparative studies are needed to define optimal indications for SLC use in this population. Level of Evidence: Level III, systematic review and meta-analysis of retrospective comparative studies.

This study investigates how word-initial /l/ and /n/ are phonetically realized in Mandarin Chinese as produced by speakers from three regions: Beijing (close to Standard Mandarin), Changsha (where Xiang, which contains /l/ but not /n/, is also spoken locally), and Meizhou (where Hakka, which contains both /l/ and /n/, is also spoken locally), focusing on acoustic cue use and phonological context effects. Using acoustic analysis and random forest classification, we analyzed five acoustic measures (F2–F1 spacing, F3 frequency, BW1, ΔA1, and A1–P0) and evaluated their contribution to distinguishing the two sounds. Results showed that speakers from different regions used distinct cue weighting strategies: Beijing Mandarin speakers relied more on spectral cues, Meizhou Mandarin speakers showed greater reliance on nasality-related cues, and Changsha Mandarin speakers combined both, with greater variability. Phonological context, including preceding nasals and following vowels, further modulated cue realization in region-specific ways. These findings demonstrate how native phonological background and phonological environment shape the phonetic implementation of a shared Mandarin contrast and illustrate the value of combining acoustic and classification-based approaches for modeling gradient phonetic variation.

Abstract Multiple myeloma (MM) is a heterogenous cancer that remains mostly incurable. A unifying feature of MM cells is a highly interconnected network of transcription factors and co-factors that coordinate the activity of super-enhancers to enforce myeloma cell identity. Targeting this network offers a promising avenue for therapeutic intervention across genetically diverse myeloma sub-types. Using integrated molecular and functional genomic approaches we identified Menin as a key driver of oncogenic gene expression in MM cells. Menin and its co-factor KMT2A bind at super-enhancers and maintain expression of essential myeloma genes, including IRF4. We demonstrate that Menin inhibitors, which have recently been approved for treatment of acute myeloid leukaemia, are highly active in myeloma cell lines and in vivo models. Combining Menin inhibitors with other super-enhancer targeting therapies such EP300/CREBBP inhibitors or immunomodulatory drugs (IMiDs) overcomes epigenetic plasticity in cells resistant to single agent treatment.

BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure—a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS: The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS: The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; P =0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)–age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS: The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

ABSTRACT Background Plasma cell mucositis (PCM) is a rare, chronic inflammatory condition of mucosal surfaces that is likely underdiagnosed and underreported, with limited data on its clinical characteristics, extracavitary involvement, and treatment outcomes. Objectives To characterize the clinical presentation, comorbidities, and treatment patterns of PCM in a cohort of patients from a tertiary care center. Methods We conducted a retrospective cohort study of histopathologically confirmed PCM cases diagnosed at a tertiary care center between 2004 and 2024. Cases were identified based on clinicopathologic correlation demonstrating a polyclonal plasma cell–rich infiltrate. Demographic data, clinical features, comorbidities, laboratory findings, and treatment outcomes were collected and analyzed descriptively. Results Ten patients were included, of whom 7 (70%) were aged ≥ 50 years and 6 (60%) were male. Genital involvement was observed in 6 patients (60%), whereas oral involvement occurred in 4 (40%). Symptom duration exceeded 2 years in 6 patients (60%). Concurrent malignancies were identified in 4 patients (40%), and autoimmune conditions in 2 (20%). Treatment responses were heterogeneous; topical corticosteroids were the most consistently effective therapy, while systemic immunosuppressive agents were required in 3 patients (30%) with variable outcomes. Patch testing identified contact allergens in 2 patients, with improvement following allergen avoidance. Conclusions PCM is a rare and often chronic condition with heterogeneous clinical manifestations and variable therapeutic responses. Genital involvement may be more common than previously recognized. Management remains challenging, highlighting the need for improved understanding of disease pathogenesis and development of more effective treatment strategies.