Citations

Objectives Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are linked to disease activity, severity and cardiovascular risk in rheumatoid arthritis (RA). Since RA-related inflammation associates with cardiovascular disease, we investigated whether RF and ACPA status influence the relationship between RA activity and event risk. Methods We assessed 3952 cardiovascular disease-free patients with prevalent RA registered in an international observational consortium between 1985 and 2012. Main outcome was a first major adverse cardiovascular event (MACE) including myocardial infarction, stroke and cardiovascular death. Follow-up accrued from enrolment until first MACE or censoring. Multivariable Cox models stratified by centre risk evaluated disease activity, RF, ACPA and their interactions. Results We recorded 184 first MACE events over 22 981 patient-years. Disease activity associated with MACE (HR 1.18 (95% CI 1.03 to 1.35)), whereas RF (HR 1.26 (0.82 to 1.94)) and ACPA (HR 1.25 (0.85 to 1.83)) did not reach statistical significance, though CIs were wide and a clinically meaningful association cannot be excluded. A three-way interaction between disease activity, RF and ACPA on MACE (p for interaction=0.044) was observed. RA activity associated with MACE in seronegative and double seropositive (p≤0.047), but not single RF-positive or ACPA-positive patients. Among RF-negative participants, RA activity was linked to MACE in ACPA-negative but not positive ones (p for interaction=0.003). Among ACPA-positive patients, disease activity was linked to MACE in RF-positive but not RF-negative ones (p for interaction=0.040). Conclusions Disease activity may better discriminate inflammation-driven cardiovascular risk in seronegative and double seropositive than single RF-positive or ACPA-positive patients. Risk protection through lowering disease activity may be serostatus dependent.

The creation of an arteriovenous fistula in a uremic pig induces cardiac remodeling, which resembles contemporary clinical findings in patients with end-stage kidney disease (ESKD) and includes increased end-diastolic volumes and cardiomyocyte hypertrophy, potentially driven by fibrosis and senescence. This novel large animal model may now enable mechanistic and therapeutic studies aiming to ease the unacceptably high burden of cardiovascular disease on patients with ESKD.

Poststenotic dilatation in renal artery stenosis, evaluated at abdominal CT, might be related to stenotic kidney damage and inflammation, particularly to monocyte chemoattractant protein-1 release.

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 Untethered mobile milli/microrobots hold transformative potential for interventional medicine by enabling more precise and entirely non‐invasive diagnosis and therapy. Realizing this promise requires bridging the gap between groundbreaking laboratory demonstrations and successful clinical integration. Despite remarkable technical progress over the past two decades, most millirobots and microrobots remain confined to laboratory proof‐of‐concept demonstrations, with limited real‐world feasibility. Here, we identify key factors that slow translation from bench to bedside, focusing on the disconnect between technical innovation and meaningful patient outcomes. We argue that the long‐term impact and sustainability of the field depend on aligning development with unmet clinical needs, demonstrating feasibility, value and integration potential into existing clinical workflows. To foster translational research of milli/microrobots, we introduce a strategic milli/microrobot Technology Readiness Level framework (mTRL), which maps system development from initial conceptualization to clinical adoption through clearly defined milestones and their associated stepwise activities. The mTRL model provides a structured gauge of technological maturity, a common language for multi‐disciplinary collaboration and actionable guidance to accelerate translational development toward new, safer and more efficient interventions.

Objectives Female sex and anticitrullinated protein antibodies (ACPA) are associated with higher disease activity in rheumatoid arthritis (RA). Since disease-related inflammation is linked to cardiovascular risk, we explored whether sex and ACPA influenced the association between disease activity at study entry and cardiovascular risk in established RA. Methods We evaluated 4008 patients with prevalent RA from an international observational cohort enrolled between 1985 and 2012. Outcomes included major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction and stroke) and ischaemic cardiovascular events (iCVE: MACE, angina, revascularisation, transient ischaemic attack and peripheral arterial disease). Follow-up accrued from enrolment until the first event or censoring. Multivariable Cox models stratified by centre risk evaluated disease activity, sex, ACPA and their interactions. Results We documented 193 MACE and 299 iCVE. Disease activity and sex were associated with MACE (all p≤0.017) and iCVE (p≤0.005) but ACPA was only associated with MACE (p=0.043). A three-way interaction on MACE (p=0.034) but not iCVE was noted. Among ACPA-negative patients, disease activity was associated with MACE in males (HR 1.57 (95% CI 1.14 to 2.16)) but not females (p-for-interaction=0.022). Among ACPA-positive patients, neither the disease activity x sex interaction (p=0.929), nor main effect of disease activity on MACE (p=0.124) was significant, but male sex was (HR 1.61 (95% CI 1.15 to 2.27)). Among females, neither disease activity x ACPA interaction (p=0.523) nor disease activity (p=0.319) was significant for MACE, but ACPA was (HR 1.57 (95% CI 1.02 to 2.42)). Conclusions The effect of disease activity at enrolment on cardiovascular risk in prevalent RA varies across patient groups with different sex and ACPA characteristics.

Key Points This study reveals the temporal development and progression of senescence in an arteriovenous fistula of uremic mice. Senescent genes including p21 increased 7 days after arteriovenous fistula placement, and p16 and phosphorylated p53 cells accumulate between days 14 and 28. Transcriptomic analyses confirm established genes in arteriovenous fistula failure and suggest a collection of novel genes of interest. Background Hemodialysis therapy for ESKD requires suitable vascular access, most commonly the arteriovenous fistula (AVF). Forty percent of AVFs fail within 1 year, leading to morbidity and care costs. Failure mechanisms remain unclear, and current therapies are inadequate. Cellular senescence may be critical in AVF failure, and ESKD itself may accelerate senescence and subsequent vascular dysfunction. Senescence follows AVF placement in rodents with normal kidney function, but the temporal and spatial features in uremic conditions are unknown. This study aimed to characterize AVF changes in uremic mice over time and versus control vessels. Methods Six- to eight-week-old male C57BL6/J mice underwent five/six nephrectomy. Twenty-eight days later, an AVF was created by cuff anastomosis (right carotid artery to the right jugular vein). Transcriptomic analysis was performed 7 days post-AVF, and further samples were collected at 14 and 28 days post-AVF creation for histologic assessment. Results AVF outflow vein morphometry showed reduced neointimal cell density. Whole transcriptomic analysis of outflow versus control veins at 7 days post-AVF placement revealed 1187 upregulated and 3256 downregulated genes. Differentially expressed genes were significantly enriched in two established senescence-related gene sets, SenMayo (a curated panel of approximately 125 genes validated across species to capture senescence and associated proteins) and SenSig (a broader panel assessed to represent fibrotic and stress-induced cell response). Histologically, senescence markers p16, p21, and phospho53 increased between days 14 and 28. Genes common to our dataset, SenMayo, and SenSig were validated with quantitative reverse transcription PCR. Conclusions These data support established markers of AVF failure, such as matrix-metalloproteinases and monocyte chemokines, and identify potential novel modulators of AVF survival that may inform senolytic strategies to improve patency. In summary, this study reveals for the first time the chronologic progression of vascular senescence in the AVF of uremic mice.

Abstract Atraumatic and localized drug delivery to the vascular endothelium remains a critical unmet need in interventional medicine, with major implications for the management of arterial and venous diseases. Current approaches, such as drug-eluting stents and drug-coated balloons, combine mechanical revascularization with local drug release but frequently denude the endothelium and injure vessel walls, leading to restenosis, thrombosis, and chronic inflammatory repair cycles that severely limit long-term outcomes. Here, we present EndoBot, a soft, untethered millirobot designed for atraumatic navigation and targeted endovascular drug delivery during physiologic blood flow. EndoBot employs magnetically actuated corkscrew propulsion and mechanically adaptive surface crawling to maintain low radial pressure (<1 kPa) and preserve endothelial integrity. Its feasibility is established in arterial and venous phantom models, ex vivo human umbilical veins under normothermic perfusion, and in vivo rat inferior vena cava, all under clinical fluoroscopic guidance using a human-scale magnetic manipulation system. Despite periodic vessel motion, compression, and geometric irregularities, EndoBot maintains stable, mechanically adaptive navigation without endothelial injury. Under real-time fluoroscopic imaging, we identify key challenges and showcase clinically feasible strategies for 3D localization and tracking, overcoming intrinsic depth limitations of 2D clinical imaging. The device can be deployed and retrieved through standard vascular sheaths and remains stable under supraphysiologic arterial and venous flow conditions (flow rate >100 mL min-1; flow velocity >155 cm s-1, shear stress >10 Pa). Blood-compatibility testing demonstrates no increase in coagulation tendency and minimal hemolysis (<0.01%) during magnetic actuation. For drug delivery, EndoBot employs a novel endoluminal painting-based technique that transfers a hydrophobic and flow-resistant coating directly onto the inner vessel surface. This method ensures uniform deposition of a biodegradable drug depot without generating fragments larger than typical capillary diameters (>10 mm). By enabling local, atraumatic drug delivery without compromising vessel wall integrity, EndoBot first time demonstrates a translationally viable platform for exploring effectiveness in preventive interventions in early-stage vascular disease and for adjunctive therapies in advanced disease stages.