Citations

ABSTRACT Objective(s) Fetal pleural effusion is a rare condition that may significantly impact fetal and neonatal outcomes. Currently, no universal standardized approach exists for diagnosing and managing primary fetal pleural effusions. This study aimed to develop structured, expert‐based clinical guidelines for the diagnosis, monitoring, management, and follow‐up care of primary fetal pleural effusion. Methods A Delphi method was employed to achieve consensus among an international panel of experts in fetal medicine. Experts were selected based on their clinical expertise, affiliations, and relevant publications. A three‐round anonymous electronic survey was sent to the full panel. In the initial two rounds, participants rated each statement on a Likert scale (1–5) and provided suggestions for modifications. Statements with a median score of five and no suggested changes were accepted as consensus. Statements with a median score below four were rejected. Statements scoring a median of four were revised according to suggestions and reconsidered in the subsequent round. In the final round, participants indicated their agreement or disagreement with the remaining statements. Consensus was defined as agreement from more than 70% of participants with no suggestions for further changes. Results A total of 101 expert clinicians accepted the invitation and completed the first round with 73 (72%) completing all three rounds. Consensus statements were achieved on aspects of diagnosis, monitoring, intervention, post‐intervention management, and delivery. Key recommendations concerning the diagnosis of primary fetal pleural effusion include the use of ultrasound as the primary modality for identifying fetal pleural effusion and excluding secondary causes through detailed genetic, infectious, and metabolic evaluations. Management strategies emphasized thoracoamniotic shunting as the preferred intervention in hydropic fetuses with primary pleural effusion. Experts reached consensus that shunt placement could be offered as early as 16 weeks. No consensus was reached for isolated effusion without hydrops, as management was considered case‐dependent. The importance of ultrasonographic monitoring of fetal status at least weekly post‐intervention was strongly endorsed. Conclusion(s) The Delphi method facilitated the development of a consensus‐based protocol for diagnosing and managing primary fetal pleural effusion. These standardized guidelines are intended to enhance clinical practice across various settings, improve perinatal outcomes, and serve as a foundation for future research for this high‐risk fetal condition.

Objective: To evaluate the institutional learning curve of robotic liver resection (RLR), its association with surgical complexity and outcomes in an international multicenter cohort. Summary of Background Data: RLR is increasingly adopted worldwide, but the dynamics of the learning process and its impact on surgical outcomes remain poorly defined. Methods: This international, multicenter, retrospective cohort study included consecutive patients who underwent RLR between 06/2013 and 12/2024 across 22 expert centers. Based on the first 150 cases at each center, three phases were used to define the learning curve: operative time for competency, major complications for proficiency, and textbook outcome for mastery. Risk-adjusted generalized additive models were used to assess the learning process. Benchmark performance was compared to international reference values. Results: Among 2,331 patients, the most common indications were hepatocellular carcinoma (36%), benign lesions (23%) and colorectal liver metastases (21%). Operative time decreased after achieving competency (case #62), from 240 to 220 minutes ( P <0.001). Major morbidity reached a plateau during the proficiency phase (cases #63–138; 9% vs. 11%, P =0.144), while progression to mastery (cases #139–150) was associated with a higher rate of textbook outcome (76% vs. 87%, P =0.021). In contrast, conversion (5.1% vs. 4.9% vs. 2%), bile leak (4.0% vs. 5.3% vs. 3.8%), and 90-day mortality (0.7% vs. 0.9% vs. 0.9%) remained low and stable across all learning phases. Importantly, benchmark criteria for operative time, hospital stay, and textbook outcome were met across all complexity groups, including during the early learning phase. Conclusions: Robotic liver surgery shows progressive outcome improvement with early achievement of benchmark-level results and stable performance across increasing complexity. These findings indicate that, in experienced centers, RLR can be safely implemented and integrated into clinical practice, supporting its key role in modern hepatobiliary surgery.

Abstract Rationale Pulmonary Fibrosis is characterized by excessive accumulation of extracellular matrix (ECM), primarily collagen I, leading to progressive lung scarring and loss of function. Many anti-fibrotic compounds have been found to attenuate collagen deposition. However, identifying compounds that stimulate collagen I degradation, a necessary step in fibrosis clearance, is less common. To identify such compounds, we developed in vitro and ex vivo assays to quantify extracellular collagen I and collagen I degradation products. Methods Primary lung fibroblasts (passage 1-3, N = 5) from patients with idiopathic pulmonary fibrosis (IPF) were cultured in DMEM/F12 with 2% FBS, 2 ng/mL TGF-β, and 50 µg/mL ascorbic acid for 72 hours to generate collagen-rich cell-derived ECM. Cells were then treated with test compounds for 24 hours in the same media. Nuclear labeling with Hoechst 33342 was used to quantify cell numbers by automated microscopy. Decellularization was then performed with a solution containing 20 mM ammonium hydroxide and 0.5% Triton X-100. Cell-derived ECM was then fixed, stained with anti-Collagen I antibody, and quantified by automated microscopy. Collagen I degradation was further assessed by measuring type I collagen C-telopeptide (ICTP) via ELISA in cell culture media. To investigate the role of matrix metalloproteinase-13 (MMP-13) in collagen degradation, we used T26-C, a selective MMP-13 inhibitor, or transfected cells with MMP-13 siRNA. Ex vivo validation of collagen-degrading activity was conducted by measuring type I collagen N-terminal telopeptide (NTX-I) in the culture media of human precision-cut lung slices (PCLS, N = 3) generated from upper and lower lobes of IPF tissue and stimulated with select compounds. Results Thirty-four candidate compounds (metabolic, epigenetic, and cAMP modulators) were tested for their ability to reduce collagen I levels in cell-derived ECM. Six hits and two positive controls were then validated using ICTP ELISAs. In total five compounds were found to stimulate collagen degradation: EGCG (1 μM), Nintedanib (0.25 μM), SB431542 (1 μM), and two dopamine receptor agonists, A68930 (10 μM) and Dihydrexidine (10 µM). MMP-13 inhibition or knockdown prevented collagen degradation by all five compounds. In human IPF PCLS, collagen degradation was confirmed in response to EGCG, Nintedanib and SB431542 but not Dihydrexidine, with much greater responses seen in PCLS from upper lobes than lower lobes. Conclusion Collagen degradation can be stimulated in cultured fibroblasts and IPF PCLS. These systems will assist in uncovering mechanisms and regulators of collagen degradation and may pave the way to better fibrosis-resolving therapies. This abstract is funded by: NIH U01 HL152967

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 Geroscience research benefits from interdisciplinary approaches, team science, and collaborations, which collectively facilitate the discovery of aging mechanisms and their translation into tangible, clinical interventions. Since its inception in 2019, the Midwest Aging Consortium (MAC) has provided an engaging platform for aging researchers in the United States’ Midwest to connect, collaborate, and exchange ideas. The Sixth Annual Research Symposium of the MAC held at the Mayo Clinic in Rochester, Minnesota, in April 2025 highlighted the continued impact of the MAC in bringing together aging researchers, including many trainees and early career investigators, into a collaborative environment. This record-setting event featured interdisciplinary research on key aging mechanisms, including lipid metabolism, mitochondrial dysfunction, stress response, cellular senescence, and immune adaptations across organ systems. New therapeutic concepts and clinical trial approaches were presented. Cutting-edge methodologies including single-cell and spatial transcriptomics, metabolomics, and organoid cultures, to dissect aging process in tissue-specific and systemic contexts also were presented. Overall, the MAC symposium underscored the translational potential of geroscience and reinforced the MAC’s mission to accelerate aging research through regional collaborations and innovation.

Background: The cumulative effect of repetitive subconcussive head impacts on neurocognitive function during youth contact sports remains largely unknown. There is a paucity of literature evaluating cumulative helmet forces over a season and their correlation with preseason and postseason cognitive performance tasks such as the King-Devick test (KDT). Hypothesis: Higher helmet forces recorded throughout a 10-week, 10-game youth football season would correlate with slower performance on postseason KDT. Study Design: Prospective cohort study. Level of Evidence: Level 3. Methods: A cohort of 58 youth football players (ages 9-13 years) underwent pre- and postseason KDT. Players wore SpeedFlex helmets (Riddell) fitted with InSite Impact Response System helmet accelerometers (Riddell) which recorded impacts of ≥15 g . Head impacts were tallied over a season and assigned a score of 1, 2, or 3 based on magnitude of g forces. Suspected concussions were correlated with KDT times and recorded instances of head impact. Pre- and postseason KDT scores were compared. Results: During the season, 2013 head impacts were recorded. Median (range) total cumulative force score was 24 (5-476); 6 players sustained head impacts concerning for concussion, and 4 were clinically diagnosed with concussions. Overall, postseason KDT times improved compared with preseason, with a median (range) change of −4.8 seconds (−7.6, −1.1). Analysis showed no correlation between changes in KDT time and total cumulative force score over the season. Conclusion: KDT times in youth football players did not change significantly based on head impact exposure over a single youth football season; most players’ KDT times improved from preseason to postseason. Clinical Relevance: Although our study did not show significant cognitive impact as measured by KDT over a single youth football season, the long-term effects of concussion on the immature brain and how it can impact cognitive development remains largely unknown and should be an area of ongoing study.

Purpose: To evaluate the potency and efficacy of a library of dopamine receptor D2 (D2R) antagonists in the mitigation of fibrotic activation in retinal pigment epithelial (RPE) cells. Methods: ARPE-19 cells were cultured and treated with methotrexate or 27 district D2R antagonists using a fibronectin deposition assay. The most potent compounds were then further assessed in assays measuring cellular proliferation, cellular migration, and profibrotic gene expression. Results: The previously established antifibrotic D2R antagonist loxapine exerted a robust and dose-dependent inhibition of fibronectin deposition, whereas methotrexate exerted minimal inhibition. The most potent D2R antagonist identified, fluphenazine, effectively blocked in vitro models of fibrosis at 300–1,000 nM concentrations. Conclusions: Here we found multiple FDA-approved D2R antagonists that potently block RPE cell fibrogenesis. These findings further support the potential of D2R antagonism as a potential therapeutic for retinal fibrotic disease.

AbstractPulmonary arterial hypertension (PAH) causes pulmonary vascular remodeling, increasing pulmonary vascular resistance (PVR) and leading to right heart failure and death. Matrix stiffening early in the disease promotes remodeling in pulmonary artery smooth muscle cells (PASMCs), contributing to PAH pathogenesis. Our research identified YAP and TAZ as key drivers of the mechanobiological feedback loop in PASMCs, suggesting targeting them could mitigate remodeling. However, YAP/TAZ are ubiquitously expressed and carry out diverse functions, necessitating a cell‐specific approach. Our previous work demonstrated that targeting non‐canonical IKB kinase TBK1 reduced YAP/TAZ activation in human lung fibroblasts. Here, we investigate non‐canonical IKB kinases TBK1 and IKKε in pulmonary hypertension (PH) and their potential to modulate PASMC pathogenic remodeling by regulating YAP/TAZ. We show that TBK1 and IKKε are activated in PASMCs in a rat PH model. Inflammatory cytokines, elevated in PAH, activate these kinases in human PASMCs. Inhibiting TBK1/IKKε expression/activity significantly reduces PAH‐associated PASMC remodeling, with longer‐lasting effects on YAP/TAZ than treprostinil, an approved PAH therapy. These results show that non‐canonical IKB kinases regulate YAP/TAZ in PASMCs and may offer a novel approach for reducing vascular remodeling in PAH.