Citations

Abstract Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multimodal analyses on isolated lung mesenchyme during the initiation, progression, and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrotic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme exhibits an enhanced fibrotic program upon reinjury. We identify RUNX1 as a critical driver of both fibrotic activation and fibrotic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that RUNX1 is spontaneously activated in standard culture conditions, previously masking these roles of RUNX1. Targeted knockdown of RUNX1 dampens fibrotic mesenchymal cell activation immediately after cell isolation, but with reduced efficacy after only days of culture, confirming its functional importance to both early activation and long-term memory. Collectively, our findings implicate RUNX1 in the initiation and memory of fibrotic mesenchymal cell activation that together prime enhanced mesenchymal cell responses upon repeated injury.

Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Abstract Background Many patients with atrial fibrillation (AF) suffer life-limiting symptoms and heart failure. Although enormous advances in rhythm control have been made, device-based therapies for treating recurrent episodes are limited. Using pulsed electric fields (PEF) to induce reversible electroporation of cardiac tissue may effectively terminate AF. Purpose To assess the feasibility of PEF delivery for converting atrial arrhythmias via reversible electroporation. Methods Four swine models were used in this acute study. Custom-made decapolar catheters for PEF delivery were deployed with the following configurations: 1. Endocardial right atrium (RA) and coronary sinus (CS), n=2; 2. Endocardial RA and epicardial left atrium (epiLA), n=2. AF and atrial flutter (AFL) were induced with programmed stimulation. PEF delivery was performed using the BTX 830 generator. For each attempt, a single monophasic pulse at 10 or 20µs pulse width was administered, with voltage varied across attempts (range 750-3000V). Successful (type 1 and 2 breaks) and unsuccessful conversion attempts were recorded. Post-PEF signal changes and arrhythmias were identified. Results A total of 58 AF/AFL (28 and 30 respectively) episodes were induced. Of the 37 successful conversion attempts, 33 (89.1%) were type 1 breaks. Conversion success probabilities generally increased with higher voltages for both configurations. >70% conversion success was seen with ≥1500V for the RA/CS configuration and ≥2000V for the RA/epiLA configuration. Arrhythmias including intra-atrial delay and high-grade atrioventricular block were seen, usually following successive PEF deliveries. Significant muscle stimulation was provoked with the current experimental setup. Conclusion Termination of atrial arrhythmias with PEF delivery is feasible, although further work is required to optimize its efficacy and safety.

Abstract Background Ventricular fibrillation (VF) is a leading cause of sudden cardiac death worldwide. Defibrillation via direct current shocks is effective but associated with significant pain and morbidity, prompting the need for alternative approaches. Reversible electroporation of cardiac tissue with pulsed electric fields (PEF) may be an effective means of terminating VF. Purpose To assess the feasibility of PEF delivery for terminating VF. Methods 5 acute swine models were used. Mechanical circulatory support with peripheral veno-arterial extracorporeal membrane oxygenation +/- percutaneous left ventricular assist device (Impella 5.5 L) was implemented and titrated to a mean arterial pressure ≥65 mmHg. Decapolar catheters were introduced into the endocardial right and/or left ventricle as well as epicardium. VF was induced with R on T shocks or rapid ventricular pacing. PEF was delivered with the endocardial catheter as the cathode and epicardial catheter as the anode; monophasic pulses (5-10) at 3000V, 100µs, and 200ms inter-pulse intervals were used. If VF persisted post-PEF, catheters were repositioned into regions of intact voltages for repeat delivery. Results 10 VF episodes were induced, 7 of which were successfully terminated with PEF delivery (70.0%). The median number of attempts to achieve VF termination was 2 (range 1-5). The post-VF rhythm was complete heart block with ventricular asystole in all successful defibrillation attempts, with no recovery after 30 minutes of observation. Significant muscle stimulation was seen with the utilized PEF parameters and catheter configurations. Conclusion Termination of VF using PEF – pulsed field defibrillation – is possible. However, further study is required to optimize delivery parameters/configurations to improve effectiveness and avoid muscle stimulation as well as conduction abnormalities.

Abstract Background Emerging evidence suggests that premature ventricular contractions (PVCs) may influence atrial electrophysiology and remodeling, potentially leading to higher rates of atrial fibrillation (AF) recurrence. However, existing data is limited to small-scale studies. Therefore, we conducted a retrospective study to evaluate the potential association between PVCs and AF ablation outcomes, which may suggest the need for more aggressive management of ventricular ectopy in this population. Objective This study aims to assess the 5-year outcomes of catheter ablation for AF in patients with and without a diagnosis of PVCs. Methods Using the TriNetX Analytics Research Network, we included patients aged ≥ 18 years who underwent AF catheter between January 1, 2014, and January 1, 2020. Patients were further categorized into two groups based on the presence of a diagnosis of PVCs. Propensity score matching (PSM) was performed using patient demographics, left ventricular ejection fraction (LVEF), cardiac comorbidities, and medications. Study outcomes included all-cause mortality & hospitalization, acute heart failure (HF), and rhythm control interventions during a 5-year follow-up. Results A total of 15,987 patients with PVCs and 40,605 patients without PVCs were identified. After PSM, 15,152 patients from each group were included for further analysis. Compared to control group, patients with PVCs had significantly higher odds of all-cause mortality (odds ratio [OR], 1.138; 95% confidence interval [CI], 1.034–1.253), all-cause hospitalization (OR, 1.300; 95% CI, 1.243–1.360), acute heart failure (HF) (OR, 1.223; 95% CI, 1.162–1.287), and cardiogenic shock (OR, 2.059; 95% CI, 1.751–2.420) following catheter ablation for AF at 5-year follow-up. Additionally, higher odds of AF requiring cardioversion (OR, 1.135; 95% CI, 1.074–1.199) or repeated ablation (OR, 1.164; 95% CI, 1.085–1.249) were observed in the PVCs group. Conclusion Premature ventricular contractions were associated with poorer clinical outcomes and a higher odds of requiring additional rhythm control intervention following catheter ablation for AF. These findings suggest that PVCs may be a marker for worse outcomes after AF ablation.

Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining chromatin topology while allowing dynamic changes to chromatin structure, thereby influencing gene expression. Growing evidence indicates that disruptions in HOCS contribute to a diverse array of human diseases, including cancer, aging-related disorders, and congenital abnormalities, primarily through aberrant gene regulation. We further discuss the concept of distinct genomic areas, in which specific chromatin regions orchestrate three-dimensional (3D) genome dynamics, positioning them as potential biomarkers and therapeutic targets. By emphasizing chromatin architecture on a global scale rather than at the level of individual genes, this review underscores its emerging relevance to precision medicine. Finally, we synthesize current technical advances, outline future directions for leveraging chromatin topology in disease diagnosis and treatment, and highlight key biological insights to reshape our understanding of genome function.

An understanding of regions of endemicity and the spectrum of organ system involvement can improve recognition of the imaging features of coccidioidomycosis, which can overlap with those of other diseases.

The iStent series constitutes a range of trabecular bypass minimally invasive glaucoma surgery (MIGS) devices, which offers intraocular pressure (IOP) reduction with favourable safety profiles, in patients with open-angle glaucoma (OAG). Having undergone significant evolution since its initial US FDA-approval in 2012, successive generations address previous limitations, while enhancing IOP-lowering efficacy through device and delivery system design iterations. Longer-term and real-world iStent data demonstrate the durability of IOP- and medication-lowering outcomes with minimal complications, while preliminary studies across a wider spectrum of glaucoma subtypes and severities provide limited evidence of successful outcomes beyond mild-to-moderate OAG, both with and without concomitant cataract surgery. Aqueous humour outflow assessment and novel intra-operative techniques may further facilitate more accurate and effective iStent positioning. Despite typically higher upfront costs, results from both cost-effectiveness and patient-reported outcome studies are encouraging. Combination MIGS with the iStent, leveraging on the multiple mechanisms of actions of various procedures, may provide greater IOP-lowering efficacy without compromising safety. With expanding clinical data and progressive enhancements, iStent technology is likely to remain a key component of the evolving MIGS landscape.

Abstract Background We aimed to describe the real-world durability of clinical and endoscopic outcomes of upadacitinib (UPA) in ulcerative colitis (UC). Methods We retrospectively analyzed an ongoing multi-center cohort of UC patients(pts) in the United States who were started on UPA for active disease. Primary outcome was clinical remission at 1yr assessed by partial Mayo score(pMS)(resolution of all UC related symptoms and physician global assessment). Secondary outcomes assessed at various timepoints, including after re-escalation, included clinical response(>50%reduction in symptoms utilizing the pMS), endoscopic response (Mayo endoscopic score≤1or absence of erosions/ulcerations) and histological remission(defined as normal or chronic inactive). Durable secondary outcomes achieved at both 6months and at 1yr and beyond were also assessed. Descriptive statistics were performed. Adverse events(AEs) investigated included cardiovascular events and herpes zoster (HZ). Results 416pts were included(Table 1) with median values for age at initiation of36.00yrs(range27-48), disease duration7.00yrs(range3-14)and follow-up 993days(IQR,672-1103), with206(49.52%)with follow-up at 1yr or beyond. Of these, 66.1%had extensive colitis. Induction duration was8wks in 86.5%and16wks in 4.8 %(20/416). Most received an induction dose of45mg(97.1%)and maintenance dose of30mg(85.8%). Among the evaluable population at1yr and beyond, 62.5%(45/80)were in clinical remission, 75.9%(22/29)in endoscopic response with58.6%(17/29) in remission and66.6%(20/30)in histological remission. At 6months, clinical remission was51.6%(42/93), endoscopic response was 75%(24/32) of which43.75%(14/32)were in remission and histologic remission was seen in 40.8%(20/49).Durable secondary outcomes of clinical remission were seen in 71.4%(30/42), endoscopic improvement in 45.8%(11/24), and histologic remission in35%(7/20). Re-escalation to 45mg occurred in 35pts, of which48.6%(17/35)were re-escalated due to incomplete induction clinical response with all achieving response(11 in remission). The rest(18/35)were re-escalated for clinical relapse after initial remission where72.2%(13/18)were able to recapture remission. After re-escalation,54.3%(19/35)continued on 45mg daily. AEs were reported in12.7%with HZ in 7pts(2.1%). One pt aged53yrs had an episode of TIA after 1yr on UPA at 15mg, without pre-existing cardiovascular risk factors and UPA use is ongoing at the same dose. There were no reported episodes of worsening of pre-existing cardiovascular disease or DVT/PE. Conclusion UPA is durably effective and safe in a real-world clinical setting with re-escalation to 45mg capturing response in a majority of the pts. Ongoing recruitment will provide further evidence on long term effectiveness and safety. Conflict of interest: Ms. Huang, Katherine: No conflict of interest Chandnani, Arun: No conflict of interest Samaan, Sami: None Tan, Tingyi: I have no conflict of interests to declare. Ramesh, Prajith Raj: None Conlon, Caroline: No conflict of interest Klein, Jeremy: None Reddy, Nikhil: No conflict of interest Ayoub, Malek: None Cervantes Limon, Gabriela: none Myers, Melissa: None Bucaram, Martha: No conflict of interest Lieto, Stephen: No conflict of interest Scalzo, Nicholas: No conflict of interest Cohen, Benjamin: Abbvie - consulting and speaking ALPCO - consulting J & J Innovative Medicine - consulting Takeda - consulting and speaking Emmes Biopharma Services LLC - DSMB Pfizer - consulting Mohamed, Islam: nothing to declare Ciorba, Matthew: Advisory Board: Janssen, AbbVie, Pfizer, Geneoscopy Consulting: Janssen, AbbVie, Pfizer, Geneoscopy Grant contracts: Janssen, Pfizer, Incyte Shukla, Richa: Speakers bureau - Abbvie and Lilly Wright, Michael: None Xu, An Tao: No conflict of interest Chowla, Navreet: No conflict of interest Ogholikhan, Sina: Abbvie Medical Director Kujawski, Michelle: Abbvie Scientific Director Dulaney, David: Speaker bureau - Regeneron Speaker bureau - Sanofi Speaker bureau - Takeda Speaker bureau - Eli Lilly Fenster, Marc: none Benson, Caroline: No conflict of interest Alhobayb, Tamara: No conflict of interest Berinstein, Jeffrey: No conflict of interest Shivashankar, Raina: Abbvie and BMS - speaker bureau Janssen and Celltrion - grant for IBD fellowship funding Pfizer - consultant Bishu, Shrinivas: None Patel, Anish: speaker: abbvie, J & J, Lilly, BMS, Pfizer, Phathom, Takeda consultant: abbvie Ungaro, Ryan: Personal Fees: AbbVie, Bristol Myers Squibb, Genentech, Lilly, Pfizer, Janssen, Takeda Johnson, Amanda: Research grant: Abbvie, Spyre Therapeutics Pekow, Joel R.: CVS Health - Consulting Abbvie, Eli Lilly, Pfizer, Johnson and Johnson - Stocks Yarur, Andres: Personal Fees: Consultant for Takeda, Pfizer, Roche, Merck, Abbvie, Eli Lilly. Bristol Myers Squibb, Celltrion, Johnson and Johnson. Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI.

Objective: To establish international benchmark values for relevant outcome parameters in robotic Whipple. Summary Background Data: For safe adoption of surgical innovation, robust quality control is essential. Benchmarking is a validated tool for assessing surgical performance. Recent international consensus identified establishing benchmark values for robotic Whipple as top priority. Methods: We analyzed consecutive patients undergoing robotic Whipple between 2020-2023 with a minimum one-year follow-up. Reference centers were required to perform ≥15 cases/year, be scientifically active in the field, and maintain a prospective database. Benchmark criteria included benign or resectable malignant disease without neoadjuvant therapy, arterial resection, major co-morbidities, or significant previous abdominal surgery. Benchmarks were established for 13 outcome parameters. Result: The benchmark cohort comprised 418 patients from 12 centers across four continents. Benchmark values were: conversion rate ≤4.3%, transfusion rate ≤2.1%, 6-month mortality ≤2.2%, major complications ≤23.2%, and CCI® ≤20.9. Clinically relevant pancreatic fistula (grade B/C) and hemorrhage (grade B/C) rates were ≤23.6% and ≤12.7%, respectively. For pancreatic ductal adenocarcinoma (n=123), the benchmark for lymph node yield was ≥20. Higher surgical difficulty was associated with increased overall postoperative morbidity (R 2 =0.38, P =0.019), higher center caseload with reduced pancreas-specific complications (R 2 =0.28, P =0.044). Independent POPF predictors included duct diameter ≤4 mm (OR 1.37, 95% CI: 1.03, 1.82), anticoagulation (OR 2.45, 95% CI: 1.47, 3.99), and indication other than PDAC (OR 2.33, 95% CI: 1.68, 3.27). Conclusions: This study establishes the first international benchmarks for robotic Whipple, demonstrating oncologic outcomes and morbidity comparable to open surgery with the benefits of minimally invasive surgery.