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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.

Abstract Recent advances in long-read transcriptome sequencing enable high-throughput profiling of full-length RNA isoforms in bulk, single-cell, and single-nucleus samples. However, long-read datasets typically contain a mixture of complete and partial transcripts, leading to pervasive ambiguity in read-to-isoform assignment and complicating accurate isoform identification and quantification, particularly in the absence of reliable reference annotations. These challenges are further amplified in single-cell and single-nucleus samples, where coverage is sparse and transcriptional heterogeneity is high. Here, we present the Long Read Alignment Assembler (LRAA), a unified and versatile computational framework for isoform identification and quantification from long-read RNA sequencing data across bulk, single-cell, and single-nucleus transcriptomic samples. LRAA combines splice-graph based structural modeling with expectation maximization based optimization to probabilistically resolve ambiguous read assignments and improve isoform abundance estimation. The framework supports quantification-only, reference-guided, and fully reference-free (de novo) modes of analysis within a single methodological paradigm. We benchmarked LRAA using both simulated and genuine long-read datasets spanning sequencing standards and whole transcriptomes. Central to this evaluation is a novel benchmarking strategy based on Multiplexed Overexpression of Regulatory Factors (MORFs), which provides biologically expressed, barcoded isoforms with unambiguous read-level ground truth. Across all benchmarks, including MORFs, synthetic spike-ins, and whole-transcriptome datasets, LRAA consistently outperformed state-of-the-art methods in isoform identification accuracy, sensitivity, and expression quantification. Finally, we demonstrate the biological utility of LRAA by resolving cell-type-specific isoform usage across peripheral blood immune cell populations and by detecting a pathogenic cryptic isoform of STMN2 with associated transcriptional changes in single-nucleus RNA-seq data from frontal cortex tissue of an individual with frontotemporal dementia (FTD). Together, these results establish LRAA as a robust and general solution for resolving transcript diversity in complex biological systems, from development to disease.

BACKGROUND: Obstructed defecation syndrome and posterior compartment (rectal) prolapse significantly impact patients’ quality of life. Pelvic floor physical therapy is a critical part of multidisciplinary management for these conditions, yet there is little guidance or standardization to guide providers’ referral practices, diagnostic approaches, or treatment. OBJECTIVE: To develop multidisciplinary consensus-based recommendations for incorporating pelvic floor physical therapy into the treatment of obstructed defecation syndrome and posterior compartment prolapse. DATA SOURCES: MEDLINE, PubMed, Embase, and the Cochrane Database of Systematic Reviews were searched for English-language studies on pelvic floor physical therapy, obstructed defecation, diagnostic criteria, imaging, and pelvic organ prolapse. STUDY SELECTION: Studies identified in the literature search were reviewed by multidisciplinary expert subgroups, who formulated draft statements based on the available evidence. INTERVENTION: Consensus meetings were conducted and included experts from colorectal surgery, urogynecology, physical therapy, gastroenterology, radiology, and urology. Statements were evaluated via structured discussions and voting processes. Those reaching more than 70% consensus were adopted for inclusion. Statements underwent final review and editing by the leadership of the American Society of Colon and Rectal Surgeons and the International Urogynecological Association. MAIN OUTCOME MEASURES: Consensus statements addressed referral criteria, diagnostic evaluations, therapy protocols, timing, coordination with surgery, and management of anatomical abnormalities. RESULTS: Fifteen statements reached consensus. Key recommendations included prompt referral to pelvic floor physical therapy for patients without contraindications, individualized therapy based on appropriate diagnostic evaluation and patient goals, timing of pelvic floor physical therapy relative to surgery, and trauma-informed patient care. LIMITATIONS: Recommendations primarily reflect expert consensus due to limited high-quality evidence. Variability in practitioner expertise and geographic access to trained therapists are barriers to consistent implementation. CONCLUSIONS: These recommendations provide structured guidance for integrating pelvic floor physical therapy into the management of obstructed defecation syndrome and rectal prolapse. Additional research and standardized training are essential to optimize patient outcomes.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; help guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current guidelines focus primarily on assessment of pathogenic and likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants associated with increased risk of these cancers. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding screening for prostate cancer and pancreas cancer, as well as testing criteria for nonepithelial ovarian cancer.

Abstract Background Recurrent pericarditis (RP) predominantly shows features consistent with IL-1-mediated chronic autoinflammatory disease (1-4). A recent analysis suggested that supplementing anakinra with colchicine incrementally reduced pericarditis recurrence vs. anakinra alone (5). Rilonacept (a weekly IL-1α and IL-1β cytokine trap with 6-week washout) prevents engagement with IL-1 receptor, inhibiting both IL-1α and IL-1β activity (6). The Phase 3 trial RHAPSODY demonstrated rilonacept efficacy in two independent analyses: Randomized Withdrawal (RW) and Long-Term Extension (LTE) periods (7,8). Purpose Assess long-term recurrence-free persistence with rilonacept as monotherapy in pts with RP during the combined RW and LTE periods of RHAPSODY. Methods Post-hoc analysis. Freedom from recurrence on rilonacept monotherapy was quantified using the Kaplan-Meier (KM) method from RW start (if randomized to rilonacept) or from initiation of bailout rilonacept (if randomized to placebo) until the end of treatment. Prespecified recurrence adjudication criteria were pericarditis pain (numerical rating scale [NRS]) ≥4 plus C-reactive protein (CRP) ≥1 mg/dL. Per RHAPSODY protocol, background therapies were discontinued during the Run-In Period before randomization. In pts treated with rilonacept, concomitant colchicine was not added during the RW period. In the LTE, 6.8% (5/74) of pts added colchicine: one for 2 days of chest pain without CRP elevation, 4 in the absence of chest pain, CRP elevation, or recurrence; these 5 pts were censored in the KM curve at 6 days after last rilonacept dose or at colchicine initiation (whichever was first). One additional pt added colchicine prophylactically before an intentional rilonacept treatment interruption for elective cardiac surgery and experienced a recurrence after this interruption; this pt was not censored from the recurrence-free persistence analysis at colchicine initiation in order to capture this event. Results 74 pts (mean [SD] age 43.9 [15.7] years, 83.8% idiopathic pericarditis, mean [SD] disease duration 2.5 [3.2] years) were analyzed over three years. Rilonacept was well tolerated. Recurrence-free persistence was 95.9% (n=71/74) while receiving rilonacept as monotherapy (Figure 1). The three observed adjudicated recurrences were each associated with temporary interruptions of 1-3 doses of rilonacept. Conclusions Rilonacept as monotherapy provided recurrence-free persistence over the three-year trial duration when used continuously without interruption; pericarditis recurrences occurred only after interruptions. These findings support evidence-based use of rilonacept as monotherapy, minimizing the need for adjunctive treatments and reducing polypharmacy in long-term RP management. Further investigations are warranted to address how to assess pts as candidates for long-term treatment with rilonacept and when to cease rilonacept treatment.

Abstract Background Recurrent pericarditis (RP) is an IL-1-mediated chronic autoinflammatory disease (1,2). The phase 3 trial RHAPSODY demonstrated that rilonacept (IL-1α and IL-1β cytokine trap), the first and only FDA-approved treatment for RP, was effective in treating RP not only as a third-line agent (3L; after corticosteroids) but also as a second-line agent (2L; instead of corticosteroids) and reduced recurrence risk as monotherapy (3). The REgiStry Of the NAtural history of recurreNt periCarditis in pEdiatric and adult patients (RESONANCE) has been collecting long-term combined prospective and retrospective data from US-based pericardial-disease-dedicated programs since 2020 (4). Purpose To assess the efficacy of rilonacept in RP in a real-world setting, extending the clinical trial findings of RHAPSODY. Methods Database cut-off (DCO) was 05 February 2025. Data on RP management were collected and analyzed from pts with ≥2 years of observation in RESONANCE. Disease duration at DCO was defined as time from RP diagnosis to either disease resolution (no disease flares while off all RP treatments for ≥6 months before DCO) or last follow-up (for pts with ongoing treatment at DCO). Pericarditis recurrences (investigator-assessed) were confirmed based on RP symptom data and/or objective findings. Annualized recurrence rates were calculated per RP treatment regimen as total pericarditis recurrences divided by total patient-years (PY) while receiving that treatment. Wilcoxon signed-rank test was utilized to analyze the significance in change of annualized recurrence rates before and after rilonacept initiation. Results At DCO, 81 pts had ≥2 years of follow-up data in RESONANCE; mean (SD) age was 51.0 (16.8) years; most (66.7%) were female; 84% had idiopathic etiology; median (Q1-Q3) disease duration was 3.1 (2.6-3.7) years; and median observation was 2.93 (2.54-3.38) years. Patient-year treatment exposures per treatment were: NSAIDS ± colchicine (n=79; 187.8 PY), corticosteroids (n=30; 61.1 PY), anakinra (n=1; 1.2 PY) and rilonacept (n=35; 72.8 PY). Of the 35 pts treated with rilonacept for any duration (median observation: 3.2 years; median time on rilonacept: 2.08 years), the most common reason for rilonacept initiation was chest pain/recurrence on prior treatment (n=28). The annualized recurrence rate while receiving rilonacept was significantly lower versus all combined prior lines of treatment (4.00 vs. 0.02 events per PY; p=0.002); this outcome was consistent across line of treatment for rilonacept use (2L: 3.73 vs. 0.06 events per PY, p=0.02; 3L: 4.14 vs. 0 events per PY, p&lt;0.001; Table 1). Conclusions This first report of real-world outcomes from RESONANCE shows that rilonacept-containing regimens for RP as 1st, 2nd, or 3rd line therapy reduced recurrence risk over long- term (&gt;2 year) treatment, supporting prolonged management during RP natural history.

Abstract Background Inability to reach age-predicted peak heart rate (APPHR) of &gt;85%, or submaximal heart rates, on treadmill exercise stress testing (TMET) is associated with increased mortality risk [1]. Evidence is limited on mortality outcomes with heart rates greater than APPHR, or ‘supramaximal’ heart rates, especially when using heart rate metrics alone. Purpose Use of a comprehensive, compositive assessment of heart rate, termed ‘vigor’, to determine mortality outcomes has yet to be explored, especially for those with supramaximal heart rates. We sought to investigate this relationship. Methods We queried our stress database from 1993-2010 for patients &gt;30 years old without cardiovascular disease and not on antichronotropic therapy. Clinical and mortality outcomes were retrieved from patient records. Patients were stratified into groups based on APPHR as achieved on TMET: &lt;75%, 75-84%, 85-94%, 95-104%, ≥105% of APPHR. For our study, heart rate ‘vigor’ served as a composite assessment of cardiovascular fitness based solely on heart rate. This was derived from resting heart rate, heart rate recovery, and achieved percentage of APPHR. A higher Heart Rate Vigor Score (HRViS) for this study was, by definition, indicative of better cardiac responsiveness and recovery following exertion. Patients were stratified based on their achieved HRViS. Scores were determined as follows: All patients were initially assigned 3 points. 1 point was subtracted for each of the following parameters met: resting heart rate &gt;90 beats per minute (BPM), heart rate recovery &lt;13 BPM, or submaximal heart rates of APPHR &lt;85%. Patients that remained at HRViS 3 and achieved supramaximal heart rates (≥105% APPHR) were assigned an additional point, amounting to HRViS 4. HRViS stratifications are detailed in Table 1. Mortality rates were calculated for all HRViS stratifications, with adjustment for FAC and known confounders. HRViS 3 was used as the referent. Results 18,961 total patients were included. 88 patients were classified with HRViS of 0; 1,763 as HRViS 1; 5,409 as HRViS 2; 9,902 as HRViS 3; and 1,799 as HRViS 4. Those with lower HRViS scores had more comorbid conditions (Table 1). 2,144 patients achieved submaximal APPHR (&lt;85%) on TMET, and 2,917 achieved supramaximal APPHR (≥105%). HRViS 0, 1, and 2 had higher mortality risks compared to referent HRViS 3: 0 [3.76 (2.34-6.04), p&lt;0.0001]; 1 [1.80 (1.53-2.12), p&lt;0.0001]; 2 [1.29 (1.12-1.48), p=0.0004]. HRViS 4 had a non-statistically significant trends towards lower mortality risk compared to 3: 0.85 (0.66-1.08), p=0.1768. Conclusions HRViS 4 had a non-statistical trend towards lower mortality risk. Our findings do not support concern for adverse outcomes with excessive heart rates during exercise, and rather, may indicate a trend towards mortality benefit.HRViS Table 1

ABSTRACT Atraumatic and localized drug delivery to the vascular endothelium remains a critical unmet need in interventional medicine, with major implications for arterial and venous disease management. Here, we present EndoBot, an untethered elastic millirobot designed to enable endothelial‐safe, soft‐contact operation, under physiologic blood flow. EndoBot is magnetically actuated and navigates along the vessel lumen through curved, non‐uniform geometries while maintaining ultra‐low radial contact pressures (<1 kPa), far below endothelial injury thresholds. We demonstrate stable locomotion, with intrinsically compliant mechanics within a defined safety envelope under arterial and venous hemodynamics in phantom vessels, ex vivo human umbilical veins, and an in vivo rat inferior vena cava, without detectable vessel damage. EndoBot is compatible with standard vascular sheaths for wireless deployment and retrieval and is controlled under clinical fluoroscopic guidance using a human‐scale magnetic manipulation platform. Blood compatibility testing confirms safety, with minimal hemolysis and no increased coagulation tendency during navigation. For localized therapy, EndoBot employs a gentle endoluminal painting strategy, transferring a washout‐resistant drug depot directly onto the vessel lumen. By combining atraumatic mobility, clinical deployability, and localized drug deposition, EndoBot establishes a translationally viable platform for developingmaintenance‐oriented endovascular therapies, supporting prevention of restonosis, thrombosis and inflammatory remodeling following intervention.

Abstract The Association for Diagnostics & Laboratory Medicine (ADLM) aims to improve health by providing education to laboratory scientists worldwide. Different regions of the world face unique challenges shaped by their national and regional contexts. However, the needs of clinical laboratories worldwide remain largely understudied. To address this gap, we conducted a comprehensive needs assessment survey among laboratory professionals in the Latin American region. The survey was distributed to over 2708 individuals across Latin American countries and yielded 148 responses. Most respondents were from urban areas (74%) and worked in private hospital laboratories (45%), with microbiology (25%) and chemistry (23%) identified as the most common specialties. Key findings include continuing education as the top challenge, identified by 59% of respondents, with a predominant preference for virtual learning formats (83%), though not exclusively; 50% also identified a preference for in-person learning. Other challenges, such as staff shortages, lack of equipment and funding, were selected by 30% to 36% of respondents, whereas regulatory oversight and quality management were less frequently identified as priorities. To contextualize the survey findings, we conducted interviews with laboratory professionals in the region. Common themes included resource and technology constraints, uneven implementation of quality standards, and the need for collaboration between government and professional organizations to bridge gaps in practice. This assessment highlights the need for targeted educational interventions to address the distinct challenges faced by Latin American laboratories. Addressing these gaps in continued education, fostering collaboration, and engaging stakeholders in the region offer a roadmap to strengthening laboratory services and health outcomes.