Citations

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Abstract Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase–activating mutation in >95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor–based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.

Abstract Background Central precocious puberty (CPP), which is traditionally defined as the development of secondary sexual characteristics before age 8 years in girls and age 9 years in boys, results from the premature activation of the hypothalamic–pituitary–gonadal (HPG) axis. CPP can be associated with short adult stature, adverse psychosocial outcomes, and increased cardiometabolic and cancer risks in adulthood. Gonadotropin-releasing hormone (GnRH) agonists can effectively suppress premature activation of the HPG axis and have the potential to increase adult height as well as improve psychosocial and long-term health outcomes among patients with CPP. However, as secular trends have continued to shift toward earlier age of pubertal onset, some subpopulations of children with CPP, as it is currently defined, may not require the same extent of diagnostic evaluation and treatment. Objective Develop evidence-based recommendations related to the diagnosis and treatment of CPP. Methods A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to address 10 clinical questions related to the diagnosis and treatment of CPP. Systematic reviews of health-related benefits and harms were conducted for each clinical question. The guideline development panel (GDP) also used the GRADE evidence-to-decision (EtD) framework to address stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and potential impacts on health equity. Results In girls with thelarche (Tanner stage B2) between ages 7.0 and 8.0 years, the GDP suggests watchful waiting via periodic physical examinations (every 4-6 months) rather than immediately performing evaluation with laboratory testing or radiologic imaging. In addition, the GDP suggests that all girls with breast development (ie, Tanner stage B2) before age 7 years should first be observed for 4 to 6 months to differentiate unsustained or slowly progressive puberty vs rapidly progressive puberty. These recommendations are largely based on evidence that girls with slowly progressive puberty attain a normal adult height without treatment. When hormonal evaluation is performed to confirm central (GnRH-dependent) activation as the cause of precocious puberty, the GDP suggests starting the evaluation with ultrasensitive basal luteinizing hormone (LH) concentration rather than routine GnRH/GnRH agonist (GnRHa) stimulation testing for all patients. While brain magnetic resonance imaging has been a traditional part of CPP evaluation, the GDP suggests that it should not be routinely performed in girls ages 6.0 to 8.0 years and boys ages 8.0 to 9.0 years without central nervous system (eg, neuro-ophthalmologic) symptoms, largely based on a low prevalence of pathologic intracranial findings in these age groups. The GDP suggests against routine genetic testing for patients with CPP, although they judged that genetic testing (eg, MKRN3 sequencing) should be considered for patients with familial CPP through a shared decision-making process. The GDP suggests GnRHa treatment for many children with CPP, although available evidence suggests that some patient subgroups (eg, older girls with slowly progressive CPP) may be less likely to receive a net benefit with this treatment. Rather than always starting GnRHa treatment with a monthly injectable formulation, the GDP suggests that treatment should be initiated with the formulation (such as a longer-acting formulation) that is anticipated to be used long-term. The GDP suggests against routine addition of growth hormone therapy to increase adult height. They also suggest against the routine biochemical testing (eg, LH, sex steroids) to monitor pubertal suppression while receiving GnRHa, instead reserving biochemical testing to confirm clinically suspected treatment failure. Finally, the GDP suggests against routinely continuing GnRHa treatment beyond chronologic age 10.0 to 11.0 years (girls) or 11.0 to 12.0 years (boys) and/or bone age 11.0 to 12.0 years (girls) or 12.0 to 13.0 years (boys). Conclusion These clinical recommendations were developed to address important uncertainties in the diagnosis and treatment of children with CPP. They are based on the best available scientific evidence regarding clinical outcomes judged to be most important to patients and families. The GDP's overarching goal was to suggest diagnostic and therapeutic strategies that will most likely provide net clinical benefits while simultaneously considering important contextual factors such as cost and feasibility. The guideline-development process highlighted important knowledge gaps and the substantial need for additional research.

Cholangiocytes are specialized epithelial cells that line the intrahepatic and extrahepatic biliary tree and play a critical role in bile modification, liver homeostasis, and response to injury. Cholangiocytes exhibit notable heterogeneity and plasticity, and their dysfunction is central to a spectrum of diseases targeting the bile ducts, collectively called cholangiopathies. These disorders include genetic, infectious, immune-mediated, and malignant diseases, with primary sclerosing cholangitis (PSC) representing one of the most complex and enigmatic of these disorders. PSC is a progressive, fibro-inflammatory disease of the bile ducts that is closely linked to inflammatory bowel disease, carries a heightened risk of cancer, and lacks any approved therapies. This review explores the biology of cholangiocytes, including their development, functional plasticity, and roles in secretion, absorption, and cellular signaling. We provide a detailed examination of cholangiopathies, particularly PSC, a complex cholangiopathy characterized by a paradoxical state of cholangiocyte senescence and hyperproliferation. We describe how immune cell dysfunction, the gut microbiome, genetic predispositions, and environmental factors converge to mediate PSC pathogenesis. We revisit the foundational technologies that empowered early discoveries and shaped the field as we know it today. We also explore how newer techniques such as organoid cultures, single-cell transcriptomics, epigenomics, and spatialomics have transformed our modern understanding of biliary pathophysiology. Finally, we provide an overview of existing rodent models of cholangiopathies and discuss their relevance to human disease. PSC remains therapeutically unaddressed, and thus ongoing multidisciplinary efforts are essential to developing targeted interventions. This review serves as a comprehensive resource for researchers and clinicians navigating the rapidly evolving landscape of cholangiocyte-centered liver disease research.

Importance Transcatheter tricuspid valve replacement (TTVR) demonstrated superior outcomes over medical therapy in patients with severe tricuspid regurgitation (TR) in the Edwards EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy Using a Novel Device II (TRISCEND II) randomized clinical trial, and received regulatory approval in the US in 2024. Contemporary real-world data on its effectiveness and safety remain limited. Objective To evaluate 30-day clinical, echocardiographic, and health status outcomes of TTVR in real-world use. Design, Setting, and Population Retrospective cohort study of all consecutive patients who underwent TTVR in the US from February 2024 through March 2025 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Patients had symptomatic, severe TR despite optimal medical therapy and TTVR was deemed appropriate by a heart team. Statistical analysis was conducted from September 2025 to February 2026. Exposure Device-enabled TTVR. Main Outcomes and Measures Thirty-day event rates (all-cause death, stroke, bleeding, new cardiac implantable electronic device [CIED] implantation, heart failure hospitalizations), TR reduction, and changes in health status (New York Heart Association [NYHA] functional class and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS] score) are reported. Subgroup analyses examined the impact of baseline CIED status on outcomes. Results Among 1034 attempted procedures at 82 centers (mean [SD] age, 77.1 [10.6] years; 69.1% female; 73.2% NYHA functional class III/IV), a valve was successfully implanted in 1017 patients (98.4%). Mild or less TR was achieved in 98.4% of patients post procedure and in 97.7% at 30 days. At 30 days, all-cause mortality was 3.1%; stroke, 0.2%; bleeding, 7.9%; new CIED, 15.9% in CIED-naive patients; and heart failure hospitalization, 3.1%. There were significant improvements in NYHA functional class (class I/II, 82.7%; P < .001) and mean KCCQ-OS score (22.4 points; P < .001) from baseline to 30 days. There were no significant differences in 30-day mortality ( P = .47), heart failure hospitalization ( P > .99), and functional outcomes ( P = .55) when patients were stratified by baseline CIED status. Conclusions and Relevance Early US real-world experience with TTVR confirms safety and effectiveness in patients with severe TR. Thirty-day outcomes are consistent with the TRISCEND II pivotal trial, demonstrating acceptable safety, near-complete TR elimination, and significant health status improvements in an older, comorbid population. Rates of new CIED implantation and bleeding were lower than randomized clinical trial experience.

Abstract Background and Aims Acute myocarditis (AM) is a T cell-mediated myocardial disease with clinical manifestations ranging from mild chest pain to cardiogenic shock. Reliable biomarkers to stratify patients and guide therapy are currently lacking. In particular, the extent of the dysregulation of inflammatory pathways, and the impact on myocardial dysfunction, remain elusive. Methods Serum analyses were performed in prospectively recruited AM patients (n = 103) from two independent cohorts. Multimodal data integration combining profiling of cytokine and chemokine dysregulation with clinical biomarkers was used to define clinical phenotypes with distinct inflammatory signatures. Machine-learning and regression models were applied to determine biomarkers that indicate clinical severity. Results Immuno-proteomic profiling revealed conserved inflammatory patterns across AM cohorts, dominated by T cell-related cytokines and chemokines. In addition, AM patients showed dysregulation of fibroblast-derived cytokines, including hepatocyte growth factor (HGF), bone morphogenic protein 4 (BMP4) and the BMP4 inhibitors Gremlin-1 (GREM1) and Gremlin-2 (GREM2). Data integration and unsupervised clustering revealed two immuno-clinical phenotypes, linking T cell activation and fibroblast dysregulation to disease severity. Machine learning-based analysis identified CXCL10, GREM2 and LVEF as critical parameters for stratifying disease severity. Conclusions These findings highlight a systemic T cell activation signature as diagnostic hallmark of AM. In addition, dysregulation of fibroblast-derived tissue cytokines serves as an indicator for distinct immuno-clinical phenotypes in myocardial inflammatory disease. Thus, the clinically relevant link between T cell-driven immune activation, myocardial inflammation and fibroblast-driven remodelling provides a versatile set of parameters to identify severe manifestations of AM. Graphical Abstract Key Question: Are serological immune signatures linked to clinical severity in acute myocarditis and do they enable patient stratification? Key Findings: T cell- and fibroblast associated proteomic signatures indicate disease severity in acute myocarditis. Novel immuno-clinical phenotypes stratify patients according to distinct immune responses and clinical manifestations. CXCL10, GREM2 and LVEF are the most important parameters to identify immuno-clinical phenotypes. Take Home Message: CXCL10, GREM2 and LVEF emerge as key determinants for a severe immuno-clinical phenotype in acute myocarditis, highlighting the role of T cell-fibroblast interaction in the disease process and linking T cell activation, fibroblastic tissue remodelling and impaired cardiac function.

Abstract Most oncolytic viruses are delivered by intratumoural injection, and local administration can induce regression of both injected and distant tumours in mice and patients. However, the mechanisms by which local viral infection reprograms systemic immunity remain poorly understood. Here we show that intratumoural RP1, an oncolytic HSV-1 encoding GM-CSF and GALV-GP-R ⁻ , drives regression of injected and uninjected murine melanoma tumours and prolongs survival. RP1 elicits coordinated CD4 ⁺ and CD8 ⁺ T cell infiltration accompanied by local cytokine remodelling, reshaping the immune landscape at both tumour sites. Leveraging the Timer of Cell Kinetics and Activity (Tocky) system and Kaede photoconvertible protein technology, we resolve the temporal dynamics of CD8 ⁺ T cell responses following local virotherapy and identify two systemically induced, virus-driven CD8 ⁺ T cell populations distinguished by TCR engagement kinetics: antigen-engaged Timer-positive ‘viral-induced precursors’ (VIPs) and Timer-negative KLRG1 ⁺ ‘viral-induced terminal effectors’ (VITEs). Single-cell transcriptomic and pseudotime analyses reveal divergent differentiation trajectories; VIPs exhibit sustained antigen engagement within the tumour microenvironment (TME), a transcriptional programme associated with self-renewal, and preferential homing to draining lymph nodes. A VIP-associated gene signature correlates with clinical response to RP1 plus PD-1 blockade in the IGNYTE trial of RP1 and nivolumab in PD-1-refractory melanoma and is independently associated with response to immune checkpoint inhibitor (ICI) therapy in melanoma. These findings establish a mechanistic link between local oncolytic virotherapy, systemic CD8 ⁺ T cell reprogramming, and durable regression of distant lesions in patients.

BACKGROUND: Burnout remains prevalent among anesthesiology residents. Contributing workplace factors include limited control over scheduling, unpredictable hours, critical patient care needs, and other residency challenges. The Family Anesthesia Experience (FAX) is a program designed to educate residents and their support persons on wellness and residency demands. The focus of this multisite study was to evaluate the impact of FAX on first year clinical anesthesiology (CA1, ie, PGY2s) residents’ wellness. METHODS: This was a prospective evaluation study involving 15 US anesthesiology residency programs, 13 of which completed FAX. CA1 wellness was evaluated through surveys assessing perceived stress as the primary outcome, with exploratory outcomes including burnout, depression, psychological wellness, and social support. Additionally, changes in support persons’ understanding and knowledge of residency demands were tracked over time. The study included a historical control group of 302 CA1s (2019-2021) who did not participate in FAX, and an intervention group of 88 CA1s that participated in FAX (2021-2022). Statistical analyses compared changes in metrics between groups using linear mixed models and generalized linear models. RESULTS: Significant reductions in perceived stress were observed in the intervention group at 6 months post-FAX (mean change = –2.14, 95% CI, –3.95 to –0.34; P = .021, effect size = 0.58) relative to the control group, but there was no sustained difference at 12 months. Compared to the control support persons, intervention support persons reported increased understanding of residency demands, with significant improvements at 6 (mean change = 2.80, 95% CI, 1.12–4.48; P = .001, effect size = 0.77) and 12 (mean change = 2.59, 95% CI, 0.12–5.05; P = .039, effect size = 0.71) months. Improvement in support persons’ understanding did not predict changes in CA1 wellness outcomes. First generation physician residents reported lower family support at baseline but showed significant improvements in family support at 6 months (mean change = 3.05 points; 95% CI, 0.25–5.84; P = .033; effect size = 1.23) compared to their non first generation peers. CONCLUSIONS: FAX participation was associated with reduced perceived stress in residents up to 6 months post-intervention. First generation physicians experienced greater improvements in perceived family support compared to their non first generation peers. Our findings suggest that resident wellness may be enhanced by engaging both residents and their support persons in an educational wellness program that outlines the professional expectations and demands of anesthesiology residency training.

Abstract Spontaneous coronary artery dissection is an unusual, but increasingly recognized, cause of acute coronary syndrome. It is a potentially fatal disorder that predominantly (>90% of cases) affects women, who are about 20 years younger (age 45–52 years) than those presenting with an acute coronary syndrome due to atherosclerotic coronary artery disease, and is the commonest cause of myocardial infarction associated with pregnancy. With the advent of improved coronary artery imaging modalities, including invasive coronary angiography, intravascular ultrasonography (IVUS), and optical coherence tomography (OCT), spontaneous coronary artery dissection is being increasingly diagnosed. It is typically due to a spontaneous bleed in the tunica media of an epicardial coronary artery, with or without an intimal tear, that results in an intramural haematoma; the latter, in turn causing a separation or dissection of the lamellae formed by the layers of smooth muscle cells of the tunica media, which can propagate longitudinally. Although coronary artery dissection can be due to atherosclerotic disease that may, in fact, present spontaneously, or to trauma, or guidewire-induced intimal injury, the understanding that the entity now known as spontaneous coronary artery dissection is an idiopathic disorder that is not associated with atherosclerosis or trauma, and is not iatrogenic, is one that has emerged only relatively recently (last 10–15 years). This raises the question, what is the provenance of spontaneous coronary artery dissection as it is now defined and understood? Here, this issue is addressed by a detailed consideration of the medical literature from 1800.