Citations

Objective Despite the reported clinical significance of anti-C1q immunoglobulin G autoantibodies (anti-C1q) for SLE and the development of anti-C1q commercial kits, their performance characteristics in routine patient evaluation remain poorly defined. Methods In this cross-sectional study, an unselected cohort of 107 patients with suspicion of a systemic autoimmune disease and 102 controls were included and evaluated for anti-C1q autoantibodies with three kits (Bühlmann, Orgentec and Werfen). Patients in the unselected cohort were classified as having SLE or a mimicker condition. Disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K and SLE patients were subclassified based on the presence of lupus nephritis (LN) (history/active). Each kit was assessed for diagnostic performance. The degree of association between anti-C1q and SLEDAI/complement levels was assessed using the Spearman correlation coefficient (rho). Between-kit agreement was evaluated using Fleiss Ƙ. Results Werfen had the best performance in discriminating patients with SLE from non-SLE (area under the curve (AUC)=0.76), whereas for the SLE versus mimicker comparison Bühlmann (AUC=0.71) and Werfen (AUC=0.71) exhibited adequate discrimination. Among patients with SLE, all kits exhibited poor discrimination of patients with history of LN versus non-renal SLE, but Orgentec displayed good discrimination for patients with active LN from non-active LN (AUC=0.74). A positive correlation was observed between anti-C1q and SLEDAI scores, whereas a negative correlation was found between anti-C1q and complement C3 and C4 across all kits. Agreement for SLE between the three kits was moderate (Ƙ=0.42). Conclusion Anti-C1q can identify patients with SLE and correlate with global and renal disease activity, highlighting their potential to function as follow-up markers in SLE. Agreement with commercial anti-C1q kits is variable. Further studies are required to harmonise anti-C1q kits for optimal routine patient evaluation.

INTRODUCTION: Long-term data are needed for offspring exposed in utero to medications for inflammatory bowel disease (IBD). METHODS: We used a prospective cohort of pregnant women with IBD and their offspring (Pregnancy in IBD and Neonatal Outcomes) to compare rates of serious infection, congenital malformations, and developmental delay by medication exposures. RESULTS: We included 438 offspring with at least 4 years of follow-up. No differences in adverse outcomes were observed by medication. Preterm birth, but not specific drug exposure, was associated with infection risk. Breastfeeding was not associated with serious infection differences. DISCUSSION: These findings support the use of effective IBD therapies throughout pregnancy.

Abstract Introduction Left atrial-to-coronary sinus (LA-to-CS) shunting through the APTURE transcatheter shunt system aims to unload the LA while preserving the interatrial septum. This article aims to examine the 3-year health status, functional capacity, and clinical outcomes of the ALT-FLOW Early Feasibility Study (EFS). Methods Device safety, patency, and echocardiographic parameters, but also symptoms, health status, and exercise capacity were assessed in patients with left ventricular ejection fraction (LVEF) > 40% (n & 95). Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score predicted 3-year all-cause mortality was compared with observed mortality assessed by Kaplan–Meier analysis using adjudicated events. Predicted and observed HF hospitalization (HFH)-free survival rates were also compared. Results At 3 years, the safety profile remained stable with no new safety signals, and all implanted shunts remained patent. 76.3% of patients improved by at least one NYHA class, and mean KCCQ Overall Summary Scores increased by 25 points from baseline (P < .0001). The 6-min walk distance improved by an average of 39 m (P & .002). These benefits were consistent regardless of baseline pulmonary vascular resistance (PVR). Right heart echocardiographic parameters after 3 years were stable, though a reduction in TAPSE was observed, primarily in the high PVR subgroup. The observed 3-year survival was significantly higher than the MAGGIC-predicted survival (84.4% vs 70.2, respectively; P & .009), as well as the HFH-free survival (68.0% vs 24.0%, respectively; P < 0001). Conclusion In patients with HF and LVEF >40%, the APTURE LA-to-CS shunting confirmed an acceptable safety profile with stable right heart parameters and sustained improvements in symptoms, quality of life, and functional capacity at 3 years. Observed survival and HFH were superior to MAGGIC predictions.

Oversight of Artificial Intelligence in Human Subjects Research (AI HSR) presents unique challenges. These challenges arise from both the non-linear and iterative nature of AI development, as well as from the way AI shifts risk from individual research subjects to larger populations affected by AI-driven decisions and data handling. Traditional Institutional Review Boards (IRBs) often struggle to keep pace with these changes, which can lead to gaps in risk assessment and delays in the review process. There is a growing need for transparent, repeatable methods to manage AI risk in healthcare. This paper introduces the Three-Stage Framework, a risk-based oversight model designed to align ethical and regulatory review with an AI project’s stage of maturity and potential human impact. By aligning the level and timing of IRB review with the types of risks present at each stage of AI system development, the framework supports appropriate regulatory pathways and documents expectations while maintaining effective protection of human subjects. Through gradual, stage-appropriate documentation, the approach supports responsible and adaptive innovation while preparing AI systems for safe and ethical use across biomedical, social, behavioral, and educational domains. This approach prepares AI systems for safe and ethical use, accelerates compliant research, and helps IRBs and institutions maintain trustworthiness while protecting human subjects.

Abstract Background: Hemorrhagic necrotizing pancreatitis (HNP) is a highly lethal form of pancreatitis that lacks mechanism-based therapy. Intra-acinar enzyme activation is fundamental to pancreatitis initiation, yet it does not explain why only a subset of episodes progress to catastrophic hemorrhagic necrosis. Objective: To identify determinants of progression to lethal HNP and test a mechanism-based preventive intervention. Design: Using humanized trypsinogen mouse models and secretagogue regimens, we compared high-dose cerulein with low/moderate-dose cerulein and bombesin. We quantified pancreatic protease activity, performed blinded histopathologic scoring, assessed hemorrhage/vascular disruption, and evaluated enzyme localization and ductal injury by PRSS1 immunostaining. De-identified human pancreatic histology from HNP were examined. We tested a repurposed strategy using clinically approved agents for other indications: secretin to stimulate ductal fluid secretion and isosorbide mononitrate (ISMN) to promote ductal outflow via sphincter of Oddi relaxation. Results: High-dose cerulein induced robust intrapancreatic protease activation but predominantly caused edematous pancreatitis. Paradoxically, bombesin and low/moderate-dose cerulein elicited lower total pancreatic protease activity yet produced severe, frequently lethal HNP with vascular disruption and lobular ischemic necrosis. HNP was associated with intraductal enzyme accumulation and ductal injury. Secretin or ISMN alone showed limited protection, whereas combined secretin+ISMN prevented hemorrhagic necrotizing injury. Conclusion: Pancreatitis severity is determined not only by the magnitude of enzyme activation but also by where enzyme activity is exerted, implicating intraductal enzyme accumulation as a mechanistic determinant and therapeutic target in HNP. Coordinated enhancement of ductal secretion and outflow with clinically approved agents prevents HNP in vivo, supporting a translatable prevention strategy.

Since the early 21st century, team science has significantly influenced emerging perspectives, processes, and expectations across various industries, human development, and scholarly activities. Research over the past 25 years—drawing on psychology, management, social psychology, anthropology, organizational sciences, and sociology—has shaped best practices and redefined how academics and practitioners approach collaborative work. Despite substantial progress in understanding team dynamics, a critical gap remains: the absence of a clearly defined professional pathway for team scientists and science workers. Specifically, there is a lack of a secure, structured pipeline that supports training, recognition, and career advancement in team science roles. This paper addresses the limited presence of systematic organizational strategies that help science workers from the early stages of their careers through long-term professional growth. As higher education confronts a shifting paradigm, institutions must now prepare students not only as disciplinary experts but also as collaborators equipped to thrive in a cross-disciplinary, problem-solving environment that embraces the workforce competencies employers seek. We examine the organizational requirements and challenges necessary to ensure success in science careers, emphasizing developmental training, robust mentorship, the professionalization and institutionalization of team structures, and sustaining collaboration. These elements are essential for preparing a workforce that is capable, resilient, and ready for the demands of future collaborative scientific endeavors.

Abstract Multidrug efflux pumps transport antibiotics across the cellular membrane resulting in resistance conferred to the host organism. Efflux pump inhibitors (EPIs) potentiate the efficacy of antibiotics by blocking drug efflux and hold promise as adjuvant therapeutics in the fight against multidrug resistant pathogenic bacteria. A hurdle in the field has been the lack of selectivity of small molecule EPIs which often display off-target toxicity due to non-specific binding. To tackle this specificity challenge, we aimed to maximize an inhibitor’s binding surface area to efflux pumps by designing miniprotein EPIs using computational protein design and an E. coli co-expression assay to screen inhibition in cells. We used S. aureus NorA as a model efflux transporter since it confers drug resistance to fluoroquinolones, puromycin, and other cytotoxic compounds. Starting from a focused miniprotein library of only 86 members, we identified inhibitors in the screen that blocked NorA transport under active efflux conditions in vitro . Our most promising inhibitor I-23 was validated by solving a cryo-EM structure of the miniprotein in complex with NorA, which stabilized the transporter in the outward-open conformation. I-23 has a ferredoxin-like fold with one of its β-hairpins inserted into the substrate binding pocket of NorA and other parts of the globular fold occupying the shallow pocket and making extensive intermolecular contacts with NorA. An arginine residue on the tip of the hairpin loop was positioned near an anionic patch required for NorA antibiotic efflux. The identified structural motifs in this work could be employed to explore the molecular properties of peptidoglycan penetration; full realization of the therapeutic potential of the designed miniprotein inhibitors will require determining the principles for facilitating passage of ∼7 to 8 kDa miniproteins across the peptidoglycan bacterial cell wall.