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Force-induced changes in protein structure and function mediate cellular responses to mechanical stresses. Existing methods to study protein conformation under mechanical force are incompatible with biochemical and structural analysis. Taking advantage of DNA nanotechnology, including the well-defined geometry of DNA origami and programmable mechanics of DNA hairpins, we built a DNA nanodevice to apply controlled forces to proteins. This device was used to study the R1-R2 segment of the talin1 rod domain as a model protein, which comprises two alpha-helical bundles that reversibly unfold under tension to expose binding sites for the cytoskeletal protein vinculin. Electron microscopy confirmed tension dependent protein extension while biochemical analysis demonstrated enhanced vinculin binding under tension. The device could also be used in pull down assays with cell lysates, which identified filamins as novel tension-dependent talin binders. The DNA nanodevice is thus a valuable addition to the molecular toolbox for studying mechanosensitive proteins., Competing Interests: Competing Interests The authors declare no competing interests.

Cellular mechanotransduction, a process central to cell biology, embryogenesis, adult physiology, and multiple diseases, is thought to be mediated by force-driven changes in protein conformation that control protein function. However, methods to study proteins under defined mechanical loads on a biochemical scale are lacking. We report the development of a DNA-based device in which the transition between single- and double-stranded DNA applies tension to an attached protein. Using a fragment of the talin rod domain as a test case, negative-stain electron microscopy reveals programmable extension, while pull down assays show tension-induced binding to two ligands, ARPC5L and vinculin, known to bind to cryptic sites inside the talin structure. These results demonstrate the utility of the DNA clamp for biochemical studies and potential structural analysis.

Background and Aims: A longer time to alive hospital discharge following infrarenal abdominal aortic aneurysm (AAA) repair is associated with reduced patient-satisfaction and increased length of stay, hospital-acquired deconditioning, infection and costs. This study investigated sex-specific differences in, and drivers of, the rate of alive hospital discharge., Methods: Examination of UK National Vascular Registry (UK NVR), 2014-2019 and Swedish National Patient Registry (SE NPR) elective AAA patients, 2010-2018, for endovascular (EVAR) or open (OAR) aneurysm repair. Cox models assessed sex-specific difference in rate of alive hospital discharge, adjusting for co-morbidity, anatomy, standard-of-care, post-operative complications, and year, with in-hospital death as the competing risk., Results: 29,751 AAA repairs (UK NVR -EVAR 12518:1532; OAR 6803:837; SE NPR - EVAR 4234:792; OAR 2638:497, men:women) were assessed. For EVAR, the unadjusted rate of alive hospital discharge was ∼25% lower for women (UK NVR HR 0.75 [0.71-0.80], p<.001; SE NPR HR 0.75 [0.69-0.81], p<.001). Following adjustment the sex-specific hazard ratio narrowed but remained significant (UK NVR: HR 0.83 [0.79-0.88], p<.001; SE NPR HR 0.83 [0.76-0.89], p<.001). For OAR, the rate of alive hospital discharge was 23-27% lower for women (UK NVR HR 0.73 [0.67-0.78], p<.001; SE NPR HR 0.77 [0.70-0.85], p<.001). Following adjustment the sex-specific hazard ratio narrowed (UK NVR HR 0.82 [0.76-0.88], p<.001; SE NPR HR 0.79 [0.72-0.88], p<.001) but remained significant., Conclusions: Women have a 25% lower rate of alive discharge after aortic surgery, despite adjustment for pre/peri- and postoperative parameters. Efforts to increase rate of alive hospital discharge for women should be sought., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: Technology and advances in clinical care have changed the management of abdominal aortic aneurysms (AAAs) but the clinical effectiveness of continuing advances needs to be assessed. To facilitate rapid synthesis of new evidence and improve stakeholder representation, including patients, the concept of core outcome sets (COS) has been developed. COS, reflecting the needs of all stakeholders, have been established across several surgical specialties. This study aimed to develop an international core outcome set for intact AAA repair., Methods: Following COMET methodology, potential outcomes were identified from a systematic review of published outcomes and focus groups involving patients, carers, and nurses. A 38 question Delphi consensus survey in lay language was developed (with translation to local languages); this included 35 themes identified from the findings of the systematic review and three themes from the focus groups. All three of the themes identified by the focus groups (cognitive, physical, and social functioning) can be evaluated from quality of life instruments, with overall quality of life being identified from the systematic review. The survey was completed by patients, carers or family members, vascular nurses, vascular surgeons, trainees, interventional radiologists, anaesthetists, and industry partners from six European countries. After two rounds of the survey, the top outcomes were discussed at a face to face multistakeholder consensus meeting., Results: The 38 item questionnaire was amended after piloting among all stakeholder groups. After the first round of the Delphi survey (98 respondents) 15 questions were eliminated, and 11 further questions were eliminated after round 2 (90 respondents). This left two outcome questions for discussion at the consensus meeting, where the top six outcomes were unanimously endorsed: death at 30 days (or in hospital if longer), secondary AAA rupture, overall quality of life and retention of cognitive functioning after recovery, five year survival, and continued sac growth., Conclusion: Six core outcomes are recommended for use as a minimum framework in all future studies and registries of intact open and endovascular AAA repair. Further work to select instruments for quality of life and to define instruments for cognitive functioning is needed., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Disclosures None.

Biocrusts dominate the soil surface in deserts and are composed of diverse microbial communities that provide important ecosystem services. Cyanobacteria in biocrusts produce many secondary metabolites, including the neurotoxins BMAA, AEG, DAB, anatoxin-a( S ) (guanitoxin), and the microcystin hepatotoxins, all known or suspected to cause disease or illness in humans and other animals. We examined cyanobacterial growth and prevalence of these toxins in biocrusts at millimeter-scales, under a desert-relevant illumination gradient. In contrast to previous work, we showed that hydration had an overall positive effect on growth and toxin accumulation, that nitrogen was not correlated with growth or toxin production, and that phosphorus enrichment negatively affected AEG and BMAA concentrations. Excess illumination positively correlated with AEG, and negatively correlated with all other toxins and growth. Basic pH negatively affected only the accumulation of BMAA. Anatoxin-a( S ) (guanitoxin) was not correlated with any tested variables, while microcystins were not detected in any of the samples. Concerning toxin pools, AEG and BMAA were good predictors of the presence of one another. In a newly conceptualized scheme, we integrate aspects of biocrust growth and toxin pool accumulations with arid-relevant desertification drivers., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: The European Society for Vascular Surgery (ESVS) has developed clinical practice guidelines for the care of patients with aneurysms of the abdominal aorta and iliac arteries in succession to the 2011 and 2019 versions, with the aim of assisting physicians and patients in selecting the best management strategy., Methods: The guideline is based on scientific evidence completed with expert opinion on the matter. By summarising and evaluating the best available evidence, recommendations for the evaluation and treatment of patients have been formulated. The recommendations are graded according to a modified European Society of Cardiology grading system, where the strength (class) of each recommendation is graded from I to III and the letters A to C mark the level of evidence., Results: A total of 160 recommendations have been issued on the following topics: Service standards, including surgical volume and training; Epidemiology, diagnosis, and screening; Management of patients with small abdominal aortic aneurysm (AAA), including surveillance, cardiovascular risk reduction, and indication for repair; Elective AAA repair, including operative risk assessment, open and endovascular repair, and early complications; Ruptured and symptomatic AAA, including peri-operative management, such as permissive hypotension and use of aortic occlusion balloon, open and endovascular repair, and early complications, such as abdominal compartment syndrome and colonic ischaemia; Long term outcome and follow up after AAA repair, including graft infection, endoleaks and follow up routines; Management of complex AAA, including open and endovascular repair; Management of iliac artery aneurysm, including indication for repair and open and endovascular repair; and Miscellaneous aortic problems, including mycotic, inflammatory, and saccular aortic aneurysm. In addition, Shared decision making is being addressed, with supporting information for patients, and Unresolved issues are discussed., Conclusion: The ESVS Clinical Practice Guidelines provide the most comprehensive, up to date, and unbiased advice to clinicians and patients on the management of abdominal aorto-iliac artery aneurysms., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: One strategy to reduce the burden of cardiovascular disease is the early detection and treatment of atherosclerosis. This has led to significant interest in studies of subclinical atherosclerosis, using different phenotypes, not all of which are accurate reflections of the presence of asymptomatic atherosclerotic plaques. The aim of part 2 of this series is to provide a review of the existing literature on purported measures of subclinical disease and recommendations concerning which tests may be appropriate in the prevention of incident cardiovascular disease., Methods: We conducted a critical review of measurements used to infer the presence of subclinical atherosclerosis in the major conduit arteries and focused on the predictive value of these tests for future cardiovascular events, independent of conventional cardiovascular risk factors, in asymptomatic people. The emphasis was on studies with >10 000 person-years of follow-up, with meta-analysis of results reporting adjusted hazard ratios (HRs) with 95% CIs. The arterial territories were limited to carotid, coronary, aorta, and lower limb arteries., Results: In the carotid arteries, the presence of plaque (8 studies) was independently associated with future stroke (pooled HR, 1.89 [1.04-3.44]) and cardiac events (7 studies), with a pooled HR, 1.77 (1.19-2.62). Increased coronary artery calcium (5 studies) was associated with the risk of coronary heart disease events, pooled HR, 1.54 (1.07-2.07) and increasing severity of calcification (by Agaston score) was associated with escalation of risk (13 studies). An ankle/brachial index (ABI) of <0.9, the pooled HR for cardiovascular death from 7 studies was 2.01 (1.43-2.81). There were insufficient studies of either, thoracic or aortic calcium, aortic diameter, or femoral plaque to synthesize the data based on consistent reporting of these measures., Conclusions: The presence of carotid plaque, coronary artery calcium, or abnormal ankle pressures seems to be a valid indicator of the presence of subclinical atherosclerosis and may be considered for use in biomarker, Mendelian randomization and similar studies., Competing Interests: Disclosures None.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are key determinants of drug-drug interactions (DDIs). Various drugs including the calcineurin inhibitor (CNI) cyclosporine A (CsA) exert preincubation-induced trans -inhibitory effects upon OATP1B1 and/or OATP1B3 (abbreviated as OATP1B1/3) by unknown mechanism(s). OATP1B1/3 are phosphoproteins; calcineurin, which dephosphorylates and regulates numerous phosphoproteins, has not previously been investigated in the context of preincubation-induced trans -inhibition of OATP1B1/3. Herein, we compare the trans -inhibitory effects exerted on OATP1B1 and OATP1B3 by CsA, the non-analogous CNI tacrolimus, and the non-CNI CsA analogue SCY-635 in transporter-overexpressing human embryonic kidney (HEK) 293 stable cell lines. Preincubation (10-60 min) with tacrolimus (1-10 µM) rapidly and significantly reduces OATP1B1- and OATP1B3-mediated transport up to 0.18 ± 0.03- and 0.20 ± 0.02-fold compared to the control, respectively. Both CsA and SCY-635 can trans -inhibit OATP1B1, with the inhibitory effects progressively increasing over a 60 min preincubation time. At each equivalent preincubation time, CsA has greater trans -inhibitory effects toward OATP1B1 than SCY-635. Preincubation with SCY-635 for 60 min yielded IC 50 of 2.2 ± 1.4 µM against OATP1B1, which is ~18 fold greater than that of CsA (0.12 ± 0.04 µM). Furthermore, a proteomics-based screening for protein interactors was used to examine possible proteins and processes contributing to OATP1B1/3 regulation and preincubation-induced inhibition by CNIs and other drugs. A total of 861 and 357 proteins were identified as specifically associated with OATP1B1 and OATP1B3, respectively, including various protein kinases, ubiquitin-related enzymes, the tacrolimus (FK506)-binding proteins FKBP5 and FKBP8, and several known regulatory targets of calcineurin. The current study reports several novel findings that expand our understanding of impaired OATP1B1/3 function; these include preincubation-induced trans -inhibition of OATP1B1/3 by the CNI tacrolimus, greater preincubation-induced inhibition by CsA compared to its non-CNI analogue SCY-635, and association of OATP1B1/3 with various proteins relevant to established and candidate OATP1B1/3 regulatory processes.

Abdominal aortic aneurysm (AAA) causes ∼170 000 deaths annually worldwide. Most guidelines recommend asymptomatic small AAAs (30 to <50 mm in women; 30 to <55 mm in men) are monitored by imaging and large asymptomatic, symptomatic, and ruptured AAAs are considered for surgical repair. Advances in AAA repair techniques have occurred, but a remaining priority is therapies to limit AAA growth and rupture. This review outlines research on AAA pathogenesis and therapies to limit AAA growth. Genome-wide association studies have identified novel drug targets, e.g. interleukin-6 blockade. Mendelian randomization analyses suggest that treatments to reduce low-density lipoprotein cholesterol such as proprotein convertase subtilisin/kexin type 9 inhibitors and smoking reduction or cessation are also treatment targets. Thirteen placebo-controlled randomized trials have tested whether a range of antibiotics, blood pressure-lowering drugs, a mast cell stabilizer, an anti-platelet drug, or fenofibrate slow AAA growth. None of these trials have shown convincing evidence of drug efficacy and have been limited by small sample sizes, limited drug adherence, poor participant retention, and over-optimistic AAA growth reduction targets. Data from some large observational cohorts suggest that blood pressure reduction, particularly by angiotensin-converting enzyme inhibitors, could limit aneurysm rupture, but this has not been evaluated in randomized trials. Some observational studies suggest metformin may limit AAA growth, and this is currently being tested in randomized trials. In conclusion, no drug therapy has been shown to convincingly limit AAA growth in randomized controlled trials. Further large prospective studies on other targets are needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: The aim of this study was to summarise the current knowledge of shared decision making (SDM) in patients facing a treatment decision about an intact abdominal aortic aneurysm (AAA), and to identify where further evidence is needed., Data Sources: MEDLINE, Embase, and the Cochrane Library were searched on 18 July 2021. An updated search was run on 31 May 2022 for relevant studies published from 1 January 2000 to 31 May 2022., Review Methods: This scoping review was undertaken in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines following a pre-defined protocol, retrieving studies reporting on aspects of SDM in those with intact AAAs. Qualitative synthesis of the articles was performed, and the results grouped according to theme., Results: Fifteen articles reporting on a total of 1 344 participants (age range 62-74 years) from hospital vascular surgery clinics with intact AAAs were included. Studies were observational (n = 9), non-randomised studies of an intervention (n = 3), and randomised clinical trials (n = 3). The first theme was the preferences and practice of SDM. The proportion of patients preferring SDM ranged from 58% to 95% (three studies), although objective rating of SDM practice was consistently < 50% (three studies). Clinician training improved SDM practice. The second theme was poor provision of information. Fewer than half of patients (0 - 46%) surveyed were informed about all available treatment options (three studies). Publicly available information sources were rated as poor. The third theme concerned the utility of decision making support tools (DSTs). Two randomised trials demonstrated that the provision of DSTs improves patient knowledge and agreement between patient preference and repair type received but not objective measures of SDM for patients with AAAs., Conclusion: SDM for patients with an intact AAA appears to be in its infancy. Most patients with an AAA want SDM, but this is not commonly applied. Most patients with an AAA do not receive adequate information for SDM, although the use of bespoke DSTs leaves patients better informed to facilitate SDM., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: This study investigated whether sex-specific differences in preoperative/perioperative standard of care (SOC) account for disparity in outcomes after elective infrarenal abdominal aortic aneurysm repair., Methods: This was a retrospective cohort study of elective infrarenal abdominal aortic aneurysm repairs (2013-2020) using depersonalized patient-level National Vascular Registry data. SOC was defined for waiting times, preoperative assessment (multidisciplinary/anaesthetic review), cardiovascular risk prevention, and perioperative medication. The primary outcome was major cardiovascular event and/or death (MACED)., Results: Some 21 810 patients with an infrarenal abdominal aortic aneurysm were included, 2380 women and 19 430 men. Women less often underwent aneurysm repair within SOC waiting times (51.5 versus 59.3 per cent; P < 0.001), but were equally likely to receive preoperative assessment (72.1 versus 72.5 per cent; P = 0.742). Women were less likely to receive secondary prevention for known cardiac disease (34.9 versus 39.6 per cent; P = 0.015), but more often met overall cardiovascular risk prevention standards (52.1 versus 47.3 per cent; P < 0.001). Women were at greater risk of MACED (open: 12.0 versus 8.9 per cent, P < 0.001; endovascular: 4.9 versus 2.9 per cent, P < 0.001; risk-adjusted OR 1.33, 95 per cent c.i. 1.12 to 1.59). A significant reduction in the odds of MACED was associated with preoperative assessment (OR 0.86, 0.75 to 0.98) and SOC waiting times (OR 0.78, 0.69 to 0.87). There was insufficient evidence to confirm a significant sex-specific difference in the effect of SOC preoperative assessment (women: OR 0.69, 0.50 to 0.97; men: OR 0.89, 0.77 to 1.03; interaction P = 0.170) or SOC waiting times (women: OR 0.84, 0.62 to 1.16; men: OR 0.76, 0.67 to 0.87; interaction P = 0.570) on the risk of MACED., Conclusion: SOC waiting times and preoperative assessment were not met for both sexes, which was associated with an increased risk of MACED. Sex-specific differences in SOC attenuated but did not fully account for the increased risk of MACED in women., (© Crown copyright 2023.)

Introduction: Most of the outcomes reported in the literature have been chosen by doctors, constituting "traditional" outcome measures such as mortality and re-intervention. Some of the key outcome measures important to patients, families, health providers and other stakeholders may have been overlooked. Core outcome sets, consisting of 6-15 outcomes, can improve representation of all key stakeholders, standardise outcome reporting, and improve future ability to pool results. The aim of this study was to outline the methods and challenges of conducting European core outcome sets., Report: As an overview, development of core outcome sets follows a multistep iterative process: (1) Systematic review of the literature summarising existing outcome measures, (2) Focus Group meeting with patients and other stakeholders to establish missing outcome measures, (3) Development and piloting of Delphi survey, (4) Delphi consensus study for prioritisation of outcomes and establishing consensus, and (5) European consensus meeting to produce a core outcome set. The challenges include the varying ethical requirements for survey work across Europe and translation for surveys and consensus meetings., Discussion: There is an increasing need for core outcome sets to complement clinical practice guidelines. As a European vascular community we need to produce these through collaborative efforts. Unfortunately, there are considerable barriers to doing so - the time and energy required to set up a core outcome study is not dissimilar to that of a multicentre randomised trial. Currently only one core outcome set exists for vascular surgery, for critical limb ischaemia, but this was developed in a single country., (© 2022 The Authors.)

Background: Low shear stress has been implicated in abdominal aortic aneurysm (AAA) expansion and clinical events. We tested the hypothesis that low shear stress in AAA at baseline is a marker of expansion rate and future aneurysm-related events., Methods: Patients were imaged with computed tomography angiography at baseline and followed up every 6 months >24 months with ultrasound measurements of maximum diameter. From baseline computed tomography angiography, we reconstructed 3-dimensional models for automated computational fluid dynamics simulations and computed luminal shear stress. The primary composite end point was aneurysm repair and/or rupture, and the secondary end point was aneurysm expansion rate., Results: We included 295 patients with median AAA diameter of 49 mm (interquartile range, 43-54 mm) and median follow-up of 914 (interquartile range, 670-1112) days. There were 114 (39%) aneurysm-related events, with 13 AAA ruptures and 98 repairs (one rupture was repaired). Patients with low shear stress (<0.4 Pa) experienced a higher number of aneurysm-related events (44%) compared with medium (0.4-0.6 Pa; 27%) and high (>0.6 Pa; 29%) shear stress groups ( P =0.010). This association was independent of known risk factors (adjusted hazard ratio, 1.72 [95% CI, 1.08-2.73]; P =0.023). Low shear stress was also independently associated with AAA expansion rate (β=+0.28 mm/y [95% CI, 0.02-0.53]; P =0.037)., Conclusions: We show for the first time that low shear stress (<0.4 Pa) at baseline is associated with both AAA expansion and future aneurysm-related events. Aneurysms within the lowest tertile of shear stress, versus those with higher shear stress, were more likely to rupture or reach thresholds for elective repair. Larger prospective validation trials are needed to confirm these findings and translate them into clinical management.