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Background Depression is associated with an increased risk of cardiovascular events but its association with abdominal aortic aneurysm (AAA) progression is unknown. This study examined if a diagnosis of depression was association with more rapid AAA growth. Methods Patients with small AAA measuring between 30 and 50 mm were recruited from surveillance programs at 4 Australian centres. Maximum AAA diameter was measured by ultrasound imaging using a standardised and reproducible protocol to monitor AAA growth. Depression was defined from medical records of treatment for depression at recruitment. Linear mixed effects modelling was performed to examine the independent association of depression with AAA growth. A propensity matched sub-analysis was performed. Results A total of 574 participants were included of whom 73 (12.7%) were diagnosed with depression. Participants were followed with a median of 3 (Inter-quartile range (IQR): 2, 5) ultrasound scans for a median of 2.1 (IQR: 1.1, 3.5) years. The unadjusted model suggested that annual AAA growth was non-significantly reduced (mean difference: -0.3 mm/year; 95% confidence interval (CI): -0.7, 0.2; P = 0.26) in participants with a diagnosis of depression compared to other participants. After adjustment for covariates, depression was not significantly associated with AAA growth (mean difference: -0.3 mm/year; 95% CI: -0.8, 0.2; P = 0.27). Findings were similar in the propensity matched sub-analysis. Sensitivity analyses investigating the impact of initial AAA diameter and follow up on the association of depression with AAA growth found no interaction. Conclusions This study suggested that depression was not associated with faster AAA growth.

Objective The aim of this study was to examine whether there were independent associations between abdominal aortic diameter, size index, and height index and the risk of major adverse events in patients referred for treatment of various types of aortic and peripheral occlusive and aneurysmal disease (APOAD). Methods In total, 1 752 participants with a variety of APOADs were prospectively recruited between 2002 and 2020 and had a maximum abdominal aortic diameter, aortic size index (aortic diameter relative to body surface area), and aortic height index (aortic diameter relative to height) measured by ultrasound at recruitment. Participants were followed for a median of 4.6 years (interquartile range 2.0 – 8.0 years) to record outcome events, including major adverse cardiovascular events (MACE), peripheral artery surgery, abdominal aortic aneurysm (AAA) events (rupture or repair), and all cause mortality. The association between aortic size and events was assessed using Cox proportional hazard analysis. The ability of aortic size to improve risk of events classification was assessed using the net reclassification index (NRI). Results After adjusting for other risk factors, larger aortic diameter was associated with an increased risk of MACE (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.05 – 1.31), requirement for peripheral artery surgery (HR 2.05, 95% CI 1.90 – 2.22), AAA events (HR 3.01, 95% CI 2.77 – 3.26), and all cause mortality (HR 1.20, 95% CI 1.08 – 1.32). Findings were similar for aortic size and aortic height indices. According to the NRI, all three aortic size measures significantly improved classification of risk of peripheral artery surgery and AAA events but not MACE. Aortic size index, but not aortic diameter or aortic height index, significantly improved the classification of all cause mortality risk. Conclusion Larger abdominal aortic diameter, size index, and height index are all independently associated with an increased risk of major adverse events in patients with established vascular disease.

Objective A meta-analysis of the association between metformin prescription and abdominal aortic aneurysm (AAA) growth and events (rupture or surgical repair) was performed. Methods Open source databases were searched for observational studies reporting the association between metformin prescription and AAA growth or events. Meta-analyses were performed using random effects models. The risk of bias of included studies was assessed using a quality assessment tool developed in a previous systematic review. Sensitivity analyses restricted to people with diabetes, leave one out analyses, and an individual patient risk factor adjusted sub-analysis were performed. Funnel plots assessed reporting bias. Results Eight studies comprising 153 553 patients were included, of whom 35 240 were and 118 313 were not prescribed metformin. Pooled weighted mean (± standard deviation) AAA growth was significantly reduced in patients prescribed metformin (0.9 ± 0.4 mm/year) compared with those not receiving the medication (1.8 ± 0.4 mm/year; weighted mean difference [WMD] 0.8 mm/year, 95% confidence interval [CI] 0.5 – 1.1; p Conclusion Observational studies suggest that metformin prescription is associated with a clinically important significant reduction in both growth and clinically relevant events in people with AAA. These findings support the need for randomised trials to examine the benefit of metformin.

A simple objective test is required to identify people with impaired physical aspects of health-related quality of life (QOL) due to intermittent claudication. This study assessed the relationship of QOL, function and physical activity to the need to stop during a six-minute walking test (6MWT) amongst people with intermittent claudication.This was a prospective case-control study conducted at two centers in Australia. 173 participants with a history of intermittent claudication and peripheral artery disease diagnosed by ankle brachial pressure index0.9, completed two 6MWTs one week apart. QOL was assessed with the short form (SF)-36. Physical activity was assessed by an accelerometer to record step count, stepping time and energy expenditure over 7 days. Physical performance was assessed by the Short Physical Performance Battery (SPPB) test. The associations of the need to stop at least once during the 6MWT with QOL, function and activity were assessed using Mann Whitney U test and analysis of covariates.Participants that had to stop at least once during the two 6MWTs (46; 26.6%) had significantly lower scores for three of the domains (physical functioning, role-physical and bodily pain) and the physical component summary (PCS) measure of the SF-36 compared to those who did not need to stop (n = 127; 73.4%). After adjusting for the risk factor co-variates (diabetes, hypertension and ankle brachial pressure index) which were significantly unequally distributed, needing to stop during the 6MWTs was significantly associated with a lower PCS score (adjusted mean 36.5, standard error 0.8 vs. 30.5, standard error 1.3; F = 14.0; P0.001; partial eta squared 0.077). Participants that had to stop at least once during the two 6MWTs had significantly lower 7-day step count, time stepping and energy expenditure, but not total SPPB score, compared to those who did not need to stop.Needing to stop during a 6MWT identified participants with intermittent claudication with poorer QOL and less physical activity compared to those that do not need to stop.

Objective: To assess whether outcomes of peripheral artery disease (PAD) were related to remoteness from the treating tertiary vascular centre. Setting and Participants: Participants with a variety of types of occlusive and aneurysmal diseases were recruited from a tertiary hospital in North Queensland, Australia. Remoteness was assessed by residence outside Townsville and estimated distance to the vascular centre. Cox proportional hazard analyses were used to examine the association of remoteness with outcome. Design: Cohort study. Main outcome measures: The primary outcome was requirement for surgery to treat PAD. Secondary outcomes were major adverse cardiovascular events (MACE) and all-cause mortality. Results: Of 2487 patients recruited, 1274 (51.2%) had at least one PAD surgery, 720 (29.0%) at least one MACE, and 909 (36.6%) died during a median of 4.2 (inter-quartile range 1.3-7.7) years. Compared to Townsville residents (n = 1287), those resident outside Townsville (n = 1200) had higher rates of PAD surgery (hazard ratio, HR 1.55, 95% confidence intervals, CI, 1.39, 1.73) but no increased risk of MACE (HR 1.00, 95% CI 0.86, 1.16) or death (HR 1.03, 95% CI 0.90, 1.17). This association was attenuated when adjusting for distance from the vascular centre (HR 1.31, 95% CI 1.14, 1.51). Patients in the highest quartile of distance presented with lower ankle-brachial pressure index, more severe carotid artery disease and larger aortic diameter. Conclusions: People with PAD in North Queensland residing furthest from the tertiary hospital presented with more severe artery disease and had greater rates of PAD surgery.

BACKGROUND People with diabetes and peripheral artery disease (PAD) have a high risk of major adverse cardiovascular events (MACE). Prior research suggests that medical therapies aimed to control modifiable risk factors are poorly implemented in patients with PAD. AIM To examine the association between the control of modifiable risk factors, estimated by the novel PAD-medical score, and the incidence of MACE in people with PAD and diabetes. METHODS Participants were recruited from out-patient clinics if they had a diagnosis of both PAD and diabetes. Control of reversible risk factors was assessed by a new composite measure, the PAD-medical score. This score takes into account the control of low-density lipoprotein cholesterol, blood pressure, blood glucose, smoking and prescription of an anti-platelet. Participants were followed to record incidence of myocardial infarction, stroke and cardiovascular death (MACE). The association of PAD-medical score with MACE was assessed using Cox proportional hazard analyses adjusting for age, sex and prior history of ischemic heart disease and stroke. RESULTS Between 2002 and 2020, a total of 424 participants with carotid artery disease (n = 63), aortic or peripheral aneurysm (n = 121) or lower limb ischemia (n = 240) were prospectively recruited, and followed for a median duration (inter-quartile range) of 2.0 (0.2–4.4) years. Only 33 (7.8%) participants had the optimal PAD-medical score of five, with 318 (75%) scoring at least three out of five. There were 89 (21.0%) participants that had at least one MACE during the follow-up period. A one-unit higher PAD-medical score was associated with lower risk of MACE (HR = 0.79, 95%CI: 0.63-0.98) after adjusting for other risk factors. CONCLUSION The PAD-medical score provides a simple way to assess the control of modifiable risk factors targeted by medical management aimed to reduce the incidence of MACE.

Context The osteoblast-derived polypeptide, osteocalcin (OC), has been associated with lower risk of type 2 diabetes and metabolic syndrome (MetS) in several epidemiological studies. Animal studies have indicated the undercarboxylated form of OC (ucOC) drives its association with metabolic outcomes. Objective We compared associations of ucOC and carboxylated OC (cOC) with MetS and its components in older men. Methods A cross-sectional analysis of 2575 men aged ≥70 years and older resident in Perth, Western Australia. ucOC was assayed using a hydroxyapatite-binding method, and cOC calculated by subtracting ucOC from total OC. Main outcome measures were MetS and its components. Results Both lower serum ucOC and cOC levels, and the proportion of cOC (%cOC) were associated with less favorable metabolic parameters (higher waist circumference, triglyceride, glucose, blood pressure, and lower high-density lipoprotein cholesterol), whereas inverse associations were found with %ucOC. Men in the lowest quintile of ucOC had higher risk of MetS compared to men in the highest quintile (Q1 ≤ 7.7 vs Q5 > 13.8 ng/mL; OR = 2.4; 95% CI, 1.8-3.2). Men in the lowest quintile of cOC had higher risk of MetS compared to those in the highest quintile (≤ 5.8 vs > 13.0 ng/mL; OR = 2.4; 95% CI, 1.8-3.2). Conclusion Lower concentrations of serum ucOC or cOC were associated with less favorable metabolic parameters and a higher risk of MetS. In contrast, a lower proportion of ucOC was associated with better metabolic parameters and lower MetS risk. Further research is warranted to determine whether ucOC and cOC are suitable biomarkers for cardiometabolic risk in men.

Objective: There are no current effective abdominal aortic aneurysm (AAA) drug therapies. An important limitation of most preclinical studies is that they test the effect of drugs on AAA formation rather than AAA progression. The aim of this study was to systematically review AAA mouse model studies that have tested the effect of interventions in limiting the progression of preestablished AAA. Approach and Results: The literature search identified 35 studies meeting eligibility, and 30 (n=935 mice) contributed to the meta-analyses. AAAs were induced with angiotensin II (n=745 mice), calcium chloride (n=91 mice), or elastase (n=99 mice). Anti-inflammatory drugs (standardized mean difference [SMD], 1.62 [95% CI, 0.93–2.30]), protease inhibitors (SMD, 1.23 [95% CI, 0.52–1.95]), stem cells (SMD, 1.64 [95% CI, 1.05–2.24]), antiplatelet or anticoagulant drugs (SMD, 0.93 [95% CI, 0.63–1.22]), and renin-angiotensin system inhibitors (SMD, 1.45 [95% CI, 0.58–2.33]) reduced AAA diameter. Interventions initiated soon after model induction commenced were more likely to reduce AAA diameter (R 2 , 16%; P =0.007). Funnel plots suggested possible publication bias. Most studies did not report blinding or sample size calculations, and the risk of bias was considered medium or high in 20 (57%) of the 35 studies. Conclusions: There is low-quality evidence that a range of drugs are effective in limiting AAA progression when administered early after AAA induction in mouse models. Some of these drugs, such as antiplatelet and renin-angiotensin system inhibitors, have been reported to be ineffective in clinical trials.

Disease modifying anti-rheumatic drugs (DMARDs) were developed to treat joint inflammation. There is growing evidence that anti-inflammatory drugs prevent major cardiovascular events (MACE). The aim of this systematic review and meta-analysis was to examine whether DMARDs reduce the risk of MACE. A systematic literature search was performed to identify randomized controlled trials (RCTs) testing the effect of DMARDs on cardiovascular events. The primary outcome was MACE defined as the first occurrence of non-fatal myocardial infarction (MI), non-fatal stroke or cardiovascular death. Secondary outcomes were myocardial infarction or stroke alone and all-cause mortality. Safety was assessed by fatal or life threatening infection. Meta-analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Study quality and publication bias were assessed using the Cochrane Collaboration’s tool for assessing risk of bias and funnel plots. Twelve RCTs involving 18,056 participants testing three different DMARDs subclasses (Tumor Necrosis Factor inhibitors—4 trials; Janus Kinase inhibitors—5 trials; Interleukin inhibitors—3 trials) were included. Meta-analysis suggested that none of the DMARD subclasses had any effect on MACE, MI alone, stroke alone, risk of fatal or life threatening infection or death. Risk of bias was high, low and unclear in five, six and one studies respectively. Funnel plots suggested a low possibility of publication bias. This meta-analysis suggests that DMARDs do not affect the incidence of MACE. More trials are needed for firm conclusions.

Introduction Fractures are common and disabling health events, particularly later in life. The presence of clinically significant depressive symptoms has been associated with increased risk of fractures, and we designed the present study to clarify if this association is likely to be causal or due to the confounding effect of measures associated with both fractures and depression. Method Cohort study of a community-derived sample of 4224 men aged 70 to 88 years at the start of the follow-up period of up to 17 years. Clinically significant symptoms of depression were defined as a recorded diagnosis of depressive episode in the Western Australian Data Linkage System (WADLS) or by a total score of 7 or greater on the 15-item Geriatric Depression Scale. Health contacts associated with fractures were retrieved from WADLS. Other measures included age, past history of fractures, education, smoking, frailty, poor vision, falls, medications, and the concentration of vitamin D, homocysteine, hsCRP and testosterone. Death was considered a competing risk for fractures. Results 911 (21.6%) participants had a bone fracture during follow-up. After adjustment for multiple potential confounders, past and current depression were associated with an increase in the risk of novel fractures; respective odds ratios were 1.41 (95%CI = 1.03, 1.93) and 1.64 (95%CI = 1.20, 2.25). Parsimonious competing risk regression showed that both past and current depression were associated with an increase in the risk of novel fractures: sub-hazard ratio = 1.29 (95%CI = 1.03, 1.63) and 1.27 (95%CI = 1.05, 1.55) respectively. Estimation of confounding due to unmeasured factors showed that a small additional effect could potentially dilute the association between depression and fractures. Discussion History of clinically significant symptoms of depression is associated with an increased risk of future fractures. This association may be due to multiple other associated risk factors, both measured and unmeasured, but nevertheless the presence of depression should alert clinicians to the need to develop a management plan that includes the management not only of depression but also of fracture risk.

Background Accurate repeat assessment of the diameter of an abdominal aortic aneurysm (AAA) is important. This study investigated the reproducibility of different methods of measuring AAA diameter from ultrasound images. Methods Fifty AAA patients were assessed by ultrasound. Maximum AAA diameter was measured independently by three trained observers on two separate occasions using a standardised protocol. Five diameters were measured from each scan, three in the anterior–posterior (AP) and two in the transverse (TV) plane, including inner-to-inner (ITI), outer-to-outer (OTO) and leading edge-to-leading edge (LETLE). Intra- and inter-observer reproducibility were reported as reproducibility coefficients. Statistical comparison of methods was performed using linear mixed effects models. Results Intra-observer reproducibility coefficients (AP LETLE 2.2 mm; AP ITI 2.4 mm; AP OTO 2.6 mm) were smaller than inter-observer reproducibility coefficients (AP LETLE 4.6 mm: AP ITI 4.5; and AP OTO 4.8 mm). There was no statistically significant difference in intra-observer reproducibility of three types of measurements performed in the AP plane. Measurements obtained in the TV plane had statistically significant worse intra-observer reproducibility than those performed in the AP plane. Conclusions This study suggests that the comparison of maximum AAA diameter between repeat images is most reproducibly performed by a single trained observer measuring diameters in the AP plane.

Objective Two consensus histopathological classifications for thoracic aortic aneurysms (TAAs) and inflammatory aortic diseases have been issued to facilitate clinical decision-making and inter-study comparison. However, these consensus classifications do not specifically encompass abdominal aortic aneurysms (AAAs). Given its high prevalence and the existing profound pathophysiologic knowledge gaps, extension of the consensus classification scheme to AAAs would be highly instrumental. The aim of this study was to test the applicability of, and if necessary to adapt, the issued consensus classification schemes for AAAs. Methods Seventy-two AAA anterolateral wall samples were collected during elective and emergency open aneurysm repair performed between 2002 and 2013. Histologic analysis (hematoxylin and eosin and Movat Pentachrome) and (semi-quantitative and qualitative) grading were performed in order to map the histological aspects of AAA. Immunohistochemistry was performed for visualization of aspects of the adaptive and innate immune system, and for a more detailed analysis of atherosclerotic lesions in AAA. Results Because the existing consensus classification schemes do not adequately capture the aspects of AAA disease, an AAA-specific 11-point histopathological consensus classification was devised. Systematic application of this classification indicated several universal features for AAA (eg, [almost] complete elastolysis), but considerable variation for other aspects (eg, inflammation and atherosclerotic lesions). Conclusions This first multiparameter histopathological AAA consensus classification illustrates the sharp histological contrasts between thoracic and abdominal aneurysms. The value of the proposed scoring system for AAA disease is illustrated by its discriminatory capacity to identify samples from patients with a nonclassical (genetic) variant of AAA disease., Clinical Relevance The pathophysiology of abdominal aortic aneurysm (AAA) disease remains an enigma. Histological evaluation is critical for appreciation of the tissue remodeling and spatial aspects of AAA disease. Histopathological classification schemes have been devised for aortic pathology. Unfortunately, these schemes do not specifically address the most common aortic pathology, AAA disease. In order to facilitate interstudy comparisons and pathophysiologic understanding of AAA disease, we here present a multiparameter consensus histopathological AAA classification scheme. The scheme clearly discriminates AAA disease from thoracic aortic aneurysm disease. Systematic implementation of this AAA classification system indicates a substantial biological variation for AAA disease, and stresses the need for adequate group sizes in order to adequately cover the natural variability. Examples illustrating the diagnostic value of the classification system are provided.

ObjectiveThere is currently no medical treatment proven to limit abdominal aortic aneurysm (AAA) progression. The aim of this systematic review and meta-analysis was to pool data from previous randomised controlled trials assessing the efficacy of blood pressure-lowering and antibiotic medications in limiting AAA growth and AAA-related events, that is, rupture or repair.MethodsA systematic literature search was performed to identify randomised controlled trials that examined the efficacy of blood pressure-lowering medications or antibiotics in reducing AAA growth and AAA-related events. AAA growth (mm/year) was measured by ultrasound or computed tomography imaging. Meta-analyses were performed using random effects models. A subanalysis was conducted including trials that investigated tetracycline or macrolide antibiotics.ResultsTen randomised controlled trials including 2045 participants with an asymptomatic AAA were included. Follow-up was between 18 and 63 months. Neither blood pressure-lowering medications (mean growth±SD 2.0±2.4 vs 2.3±2.7 mm/year; standardised mean difference (SMD) −0.07, 95% CI −0.19 to 0.06; p=0.288) or antibiotics (mean growth±SD 2.6±2.1 vs 2.6±2.5 mm/year; SMD −0.11, 95% CI −0.38 to 0.16; p=0.418) reduced AAA growth or AAA-related events (blood pressure-lowering medications: 92 vs 95 events; risk ratio (RR) 0.86, 95% CI 0.66 to 1.11; p=0.244; and antibiotics: 69 vs 73 events; RR 0.93, 95% CI 0.69 to 1.25; p=0.614). The subanalysis of antibiotics showed similar results.ConclusionsThis meta-analysis suggests that neither blood pressure-lowering medications or antibiotics limit growth or clinically relevant events in people with AAAs.

Background and aims Prior epidemiological studies have suggested that individuals with gout are at greater risk of cardiovascular events, but there have been no studies in people with peripheral artery disease (PAD). The aim of this study was to investigate the relationship between gout and major adverse cardiovascular events (MACE) and all-cause mortality in people with PAD. Methods Participants with a range of PAD presentations, including carotid artery disease, aortic or peripheral aneurysm and lower limb PAD, were prospectively recruited from outpatient vascular departments within Australia. MACE (myocardial infarction, stroke or cardiovascular death) and all-cause mortality were identified through out-patient follow-up and linked medical records. Propensity-score matching was undertaken to generate a matched cohort of patients with and without a history of gout. Kaplan-Meier survival analysis and Cox-proportional hazard analysis were used to examine the association of gout with MACE and all-cause mortality. Results A total of 4308 people with PAD, of whom 334 had a history of gout, were included and followed for a median (inter-quartile range) of 2.1 (0.1–5.9) years. In the unadjusted analyses, participants with gout were at increased risk of MACE (hazard ratio, HR 1.37, 95% confidence intervals, CI 1.09–1.71, p = 0.006) and all-cause mortality (HR 1.38, 95% 1.13–1.68, p = 0.002), however, the associations were lost in the adjusted analyses. In the propensity-score matched cohort, gout was not significantly associated with an increased risk for MACE or all-cause mortality. Conclusions Gout was not independently associated with increased cardiovascular events in PAD patients.

The recommendations of international guidelines for the management of asymptomatic carotid stenosis (ACS) often vary considerably and extend from a conservative approach with risk factor modification and best medical treatment (BMT) alone, to a more aggressive approach with a carotid intervention plus BMT. The aim of the current multispecialty position statement was to reconcile the conflicting views on the topic. A literature review was performed with a focus on data from recent studies. Several clinical and imaging high-risk features have been identified that are associated with an increased long-term ipsilateral ischemic stroke risk in patients with ACS. Such high-risk clinical/imaging features include intraplaque hemorrhage, impaired cerebrovascular reserve, carotid plaque echolucency/ulceration/ neovascularization, a lipid-rich necrotic core, a thin or ruptured fibrous cap, silent brain infarction, a contralateral transient ischemic attack/stroke episode, male patients

Background There is a lack of high quality evidence to guide the optimal management of diabetes-related foot infection, particularly in cases of severe diabetes-related foot infection and diabetes-related foot osteomyelitis. This study examined the opinions of surgeons about the preferred management of severe diabetes-related foot infection. Methods Vascular and orthopaedic surgeons in Australia and New Zealand were invited to complete an online survey via email. The survey included multi-choice and open-ended questions on clinical management of diabetes-related foot infection. Responses of vascular surgeons and orthopaedic surgeons were compared using non-parametric statistical tests. Open-text responses were examined using inductive content analysis. Results 29 vascular and 20 orthopaedic surgeons completed the survey. One-third (28.6%) used best-practice guidelines to assist in decisions about foot infection management. Areas for guideline improvement identified included more specific advice regarding the indications for available treatments, more recommendations about non-surgical patient management and advice on how management can be varied in regions with limited health service resource. The probe-to-bone test and magnetic resonance imaging were the preferred methods of diagnosing osteomyelitis. Approximately half (51.2%) of respondents indicated piperacillin combined with tazobactam as the preferred antibiotic choice for empirical treatment of severe diabetes-related foot infection. Negative pressure wound therapy was the most common way of managing a wound following debridement. All vascular surgeons (100%) made revascularisation decisions based on the severity of ischemia while most orthopaedic surgeons (66.7%) were likely to refer to vascular surgeons to make revascularisation decisions. Vascular surgeons preferred using wound swabs while orthopaedic surgeons favoured tissue or bone biopsies to determine the choice of antibiotic. Respondents perceived a moderate variation in management decisions between specialists and supported the need for randomised controlled trials to test different management pathways. Conclusions Most vascular and orthopaedic surgeons do not use best-practice guidelines to assist in decisions about management of diabetes-related foot infection. Vascular and orthopaedic surgeons appear to have different preferences for wound sampling to determine choice of antibiotic. There is a need for higher quality evidence to clarify best practice for managing diabetes-related foot infection.

Objective Experimental studies suggest that fenofibrate prevents abdominal aortic aneurysm (AAA) development by lowering aortic osteopontin (OPN) concentration and reducing the number of macrophages infiltrating the aortic wall. The current study examined the effects of a short course of fenofibrate on AAA pathology in people with large AAAs awaiting aortic repair. Methods This randomised double blind parallel trial included male and female participants aged ≥ 60 years who had an asymptomatic AAA measuring ≥ 50 mm and were scheduled to undergo open AAA repair. Participants were allocated to fenofibrate (145 mg/day) or matching placebo for at least two weeks before elective AAA repair. Blood samples were collected at recruitment and immediately prior to surgery. AAA biopsies were obtained during aortic surgery. The primary outcomes were (1) AAA OPN concentration; (2) serum OPN concentration; and (3) number of AAA macrophages. Exploratory outcomes included circulating and aortic concentrations of other proteins previously associated with AAA. Outcomes assessed at a single time point were compared using logistic regression. Longitudinal outcomes were compared using linear mixed effects models. Results Forty-three participants were randomised. After three withdrawals, 40 were followed until the time of surgery (21 allocated fenofibrate and 19 allocated placebo). As expected, serum triglycerides reduced significantly from recruitment to the time of surgery in participants allocated fenofibrate. No differences in any of the primary and exploratory outcomes were observed between groups. Conclusion A short course of 145 mg of fenofibrate/day did not lower concentrations of OPN or aortic macrophage density in people with large AAAs.

Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P

Purpose Whether androgens, distinct from estrogen, maintain bone health during male aging has implications for understanding osteoporosis. We assessed associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. Participants and methods Analysis of 3307 community-dwelling men aged 76.8 ± 3.5 years, median follow-up period of 10.6 years. Plasma testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) assayed by mass spectrometry, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) using immunoassay. Incident fractures determined via data linkage. We analyzed probability of fracture and performed Cox regression adjusted for age, medical comorbidities, and frailty. Results Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested nonlinear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher plasma T, lower E2, higher SHBG, and higher LH. In fully adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Quartile 2 [Q2] versus Q1: fully adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] 0.51–0.94, P = .020; Q3: HR 0.59, 95% CI 0.42–0.83, P = .002) and hip fracture (Q2 versus Q1: HR 0.60, 95% CI 0.37–0.93, P = .043; Q3: HR 0.52, 95% CI 0.31–0.88, P = .015). DHT, E2, and LH were not associated with fracture. Higher SHBG was associated with hip fracture (Q4 versus Q1: HR 1.76, 95% CI 1.05–2.96, P = .033). Conclusions Midrange plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk.

Peripheral arterial disease (PAD) develops due to the narrowing or blockage of arteries supplying blood to the lower limbs. Surgical and endovascular interventions are the main treatments for advanced PAD but alternative and adjunctive medical therapies are needed. Currently the main preclinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) by a 1-stage procedure. Since there are concerns regarding the ability to translate findings from this animal model to patients, we aimed to develop a novel clinically relevant animal model of PAD. HLI was induced in male Apolipoprotein E (ApoE−/−) deficient mice by a 2-stage procedure of initial gradual femoral artery occlusion by ameroid constrictors for 14 days and subsequent excision of the femoral artery. This 2-stage HLI model was compared to the classical 1-stage HLI model and sham controls. Ischemia severity was assessed using Laser Doppler Perfusion Imaging (LDPI). Ambulatory ability was assessed using an open field test, a treadmill test and using established scoring scales. Molecular markers of angiogenesis and shear stress were assessed within gastrocnemius muscle tissue samples using quantitative polymerase chain reaction. HLI was more severe in mice receiving the 2-stage compared to the 1-stage ischemia induction procedure as assessed by LDPI (p = 0.014), and reflected in a higher ischemic score (p = 0.004) and lower average distance travelled on a treadmill test (p = 0.045). Mice undergoing the 2-stage HLI also had lower expression of angiogenesis markers (vascular endothelial growth factor, p = 0.004; vascular endothelial growth factor- receptor 2, p = 0.008) and shear stress response mechano-transducer transient receptor potential vanilloid 4 (p = 0.041) within gastrocnemius muscle samples, compared to animals having the 1-stage HLI procedure. Mice subjected to the 2-stage HLI receiving an exercise program showed significantly greater improvement in their ambulatory ability on a treadmill test than a sedentary control group. This study describes a novel model of HLI which leads to more severe and sustained ischemia than the conventionally used model. Exercise therapy, which has established efficacy in PAD patients, was also effective in this new model. This new model maybe useful in the evaluation of potential novel PAD therapies.

To summarize recent data on the role of dyslipidaemia and the benefit from managing this in people with disease of the abdominal aorta and its peripheral branches (peripheral artery disease, PAD).Findings from the Further Cardiovascular Outcomes Research with Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition in Subjects with Elevated Risk (FOURIER) trial demonstrate the benefit of intensely lowering low-density lipoprotein-cholesterol (LDL-c) in people with PAD to substantially reduce the incidence of major cardiovascular events (MACE; myocardial infarction, stroke or cardiovascular death) and major adverse limb events (MALE). Despite the evidence of substantial benefits from lowering LDL-c, the uptake of drug therapies to lower LDL-c remains sub-optimal in people with PAD.Effective methods to educate physicians and patients on best medical management are needed. Further research is needed to examine the benefit of LDL-c lowering and other lipid therapies for PAD-specific problems like abdominal aortic aneurysm progression and walking impairment. Other novel lipid therapies, such as those that lower lipoprotein (a), maybe particularly beneficial to people with PAD given the evidence indicating high concentrations in this population and the high incidence of MACE in these individuals.

Objective/background: Elevated arterial stiffness is a characteristic of abdominal aortic aneurysm (AAA), and is associated with AAA growth and cardiovascular mortality. A bout of exercise transiently reduces aortic and systemic arterial stiffness in healthy adults. Whether the same response occurs in patients with AAA is unknown. The effect of moderate- and higher intensity exercise on arterial stiffness was assessed in patients with AAA and healthy adults. Methods: Twenty-two men with small diameter AAAs (36 ± 5 mm; mean age 74 ± 6 years) and 22 healthy adults (mean age 72 ± 5 years) were included. Aortic stiffness was measured using carotid to femoral pulse wave velocity (PWV), and systemic arterial stiffness was estimated from the wave reflection magnitude (RM) and augmentation index (Alx75). Measurements were performed at rest and during 90 min of recovery following three separate test sessions in a randomised order: (i) moderate intensity continuous exercise; (ii) higher intensity interval exercise; or (iii) seated rest. Results: At rest, PWV was higher in patients with AAA than in healthy adults (p < .001), while AIx75 and RM were similar between groups. No differences were observed between AAA patients and healthy adults in post-exercise aortic and systemic arterial stiffness after either exercise protocol. When assessed as the change from baseline (delta, Δ), post-exercise ΔAIx75 was not different to the seated rest protocol. Conversely, post-exercise ΔPWV and ΔRM were both lower at all time points than seated rest (p < .001). ΔPWV was lower immediately after higher intensity than after moderate intensity exercise (p = .015). Conclusion: High resting aortic stiffness in patients with AAA is not exacerbated after exercise. There was a similar post-exercise attenuation in arterial stiffness between patients with AAA and healthy adults compared with seated rest. This effect was most pronounced following higher intensity interval exercise, suggesting that this form of exercise may be a safe and effective adjunctive therapy for patients with small AAAs.

IntroductionDiabetes-related foot disease is a large cause of the global disease burden yet receives very little research funding to address this large burden. To help address this gap, it is recommended to first identify the consensus priority research questions of relevant stakeholders, yet this has not been performed for diabetes-related foot disease. The aim of this study was to determine the national top 10 priority research questions for diabetes-related foot health and disease from relevant Australian stakeholders.Research design and methodsA modified three-round Delphi online survey design was used to seek opinions from relevant Australian stakeholders including those with diabetes or diabetes-related foot disease or their carers (consumers), health professionals, researchers and industry. Participants were recruited via multiple public invitations and invited to propose three research questions of most importance to them (Round 1), prioritize their 10 most important questions from all proposed questions (Round 2), and then rank questions in order of importance (Round 3).ResultsAfter Round 1, a total of 226 unique questions were proposed by 210 participants (including 121 health professionals and 72 consumers). Of those participants, 95 completed Round 2 and 69 completed Round 3. The top 10 priority research questions covered a range of topics, including health economics, peripheral neuropathy, education, infection, technology, exercise, and nutrition. Consumers prioritized peripheral neuropathy and prevention-related questions. Health professionals prioritized management-related questions including Australia’s First Peoples foot health, health economics and infection questions.ConclusionsThese priority research questions should guide future national research agendas, funding and projects to improve diabetes-related foot disease burdens in Australia and globally. Future research should focus on consumer priority research questions to improve the burden of diabetes-related foot disease on patients and nations. Further research should also investigate reasons for different priorities between consumers and health professionals.

Background: The aim of this systematic review was to pool evidence from studies testing if pentagalloyl glucose (PGG) limited aortic expansion in animal models of abdominal aortic aneurysm (AAA). Methods: The review was conducted according to the PRISMA guidelines and registered with PROSPERO. The primary outcome was aortic expansion assessed by direct measurement. Secondary outcomes included aortic expansion measured by ultrasound and aortic diameter at study completion. Sub analyses examined the effect of PGG delivery in specific forms (nanoparticles, periadventitial or intraluminal), and at different times (from the start of AAA induction or when AAA was established), and tested in different animals (pigs, rats and mice) and AAA models (calcium chloride, periadventitial, intraluminal elastase or angiotensin II). Meta-analyses were performed using Mantel-Haenszel’s methods with random effect models and reported as mean difference (MD) and 95% confidence intervals (CIs). Risk of bias was assessed with a customized tool. Results: Eleven studies reported in eight publications involving 214 animals were included. PGG significantly reduced aortic expansion measured by direct observation (MD: −66.35%, 95% CI: −108.44, −24.27, p = 0.002) but not ultrasound (MD: −32.91%, 95% CI: −75.16, 9.33, p = 0.127). PGG delivered intravenously within nanoparticles significantly reduced aortic expansion, measured by both direct observation (MD: −116.41%, 95% CI: −132.20, −100.62, p &lt, 0.001) and ultrasound (MD: −98.40%, 95% CI: −113.99, −82.81, 0.001). In studies measuring aortic expansion by direct observation, PGG administered topically to the adventitia of the aorta (MD: −28.41%, 95% CI −46.57, −10.25, p = 0.002), studied in rats (MD: −56.61%, 95% CI: −101.76, −11.46, p = 0.014), within the calcium chloride model (MD: −56.61%, p = 0.014) and tested in established AAAs (MD: −90.36, 95% CI: −135.82, −44.89, 0.001), significantly reduced aortic expansion. The findings of other analyses were not significant. The risk of bias of all studies was high. Conclusion: There is inconsistent low-quality evidence that PGG inhibits aortic expansion in animal models.

Background While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin‐II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease. Methods and Results This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1‐(4‐pyridinyl)‐3‐(2‐quinolinyl)‐2‐propen‐1‐one (PFK15)‐mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self‐limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation. Conclusions Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.

IntroductionThere is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the β3-adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating β3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication.Methods and analysisThe STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care.Ethics and disseminationThe STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes.Trial registration numberACTRN12619000423112; Results.

Introduction Mendelian randomisation (MR) has been suggested to be able to overcome biases of observational studies, but no meta-analysis is available on MR studies on abdominal aortic aneurysm (AAA). This systematic review and Meta-analysis examined the evidence of causal risk factors for AAA identified in MR studies. Methods Publicly available databases were systematically searched for MR studies that reported any causal risk factors for AAA diagnosis. Meta-analyses were performed using random effect models and reported as odds ratio (OR) and 95% confidence intervals (CI). Study quality was assessed using a modified version of Strengthening the Reporting of Mendelian Randomisation Studies (STROBE-MR) guidelines. Results Sixteen MR studies involving 34,050 patients with AAA and 2,205,894 controls were included. Meta-analyses suggested that one standard deviation increase in high density lipoprotein (HDL) significantly reduced (OR: 0.66, 95% CI: 0.61, 0.72) and one standard deviation increase in low density lipoprotein (LDL) significantly increased the risk (OR: 1.68, 95%, CI: 1.55, 1.82) of AAA. One standard deviation increase in triglycerides did not significantly increase the risk of AAA (OR: 1.21, 95% CI: 0.86, 1.71). Quality assessment suggested that ten and five studies were of low and moderate risk of bias respectively, with one study considered as high risk of bias. Conclusion This meta-analysis suggests LDL and HDL are positive and negative casual risk factors for AAA.

IntroductionGout is a systemic inflammatory disease which has been associated with an increased risk of cardiovascular events but its association with abdominal aortic aneurysm (AAA) progression is unknown. The aim of this study was to investigate the association of gout with growth of small AAA. MethodsPatients with initial AAA diameter measuring 30-54mm were recruited from surveillance programs at four Australian centres. Maximum AAA diameter was measured with a standardised and reproducible protocol to monitor AAA growth. Presence of gout was defined by clinical diagnosis by clinician or prescription of medications used to treat gout. Linear mixed effects modelling was performed to examine the independent association of gout with AAA growth. ResultsA total of 637 participants, including 66 (10.3%) diagnosed with gout, received a median of 4 (Inter-quartile range (IQR): 3, 6) scans over a median follow-up of 1.8 (IQR: 1.0, 3.0) years. In unadjusted analyses, participants with diagnosis of gout had a slower mean annual AAA growth of -0.3 mm/year (95% CI: -0.7, 0.2; p=0.25) than those without gout. After adjusting for potential confounders including initial AAA diameter, body mass index, prior stroke and anti-hypertensive medication prescription, gout was not significantly associated with AAA growth (-0.3 mm/year; 95% CI: -0.7, 0.2; p=0.24). Sensitivity analyses investigating the impact of initial AAA diameter on the association of gout with AAA growth found no interaction. ConclusionThis study suggests diagnosis of gout is not associated with growth of small AAA.

Objective The aim of the present study was to examine whether severe chronic venous disease (CVD) is associated with a greater risk of major adverse cardiovascular events (MACE) compared with mild CVD. Methods Participants with CVD were prospectively recruited from outpatient vascular departments at two hospitals in North Queensland, Australia. CVD severity was ascertained by vascular specialists using the CEAP (clinical, etiologic, anatomic, pathophysiologic) classification. MACE, defined as myocardial infarction, stroke, or cardiovascular death, were identified from the outpatient follow-up and linked medical records. Kaplan-Meier and Cox proportional hazard analyses were used to examine the association of CVD severity with the occurrence of MACE. A subanalysis was performed in which participants with CEAP C5 and C6 (severe CVD) were compared with those with CEAP C2 to C4 (mild CVD). Results A total of 774 participants were included and followed up for a median of 3.09 years (interquartile range, 1.09-8.14 years). The participants with C6 CVD (n = 69) had a threefold greater risk of MACE (hazard ratio, 3.03; 95% confidence interval, 1.02-9.03; P = .046) compared with those with C2 CVD (n = 326) after adjusting for other risk factors. Participants with severe CVD had an increased risk of MACE compared with those with mild CVD (adjusted hazard ratio, 2.37; 95% confidence interval, 1.12-5.04; P = .024). Conclusions Individuals with severe CVD have an increased risk of MACE compared with those with mild CVD, independently of traditional risk factors. Further research is required to clarify the cause of the excess risk.

Aim Immune activation is strongly implicated in atherosclerotic plaque instability, however, the effect of immunosuppressant drugs on cardiovascular events in patients with peripheral artery disease (PAD) is not known. The aim of this study was to assess whether prescription of one or more immune suppressant drugs was associated with a lower risk of major adverse cardiovascular (MACE; i.e. myocardial infarction, stroke or cardiovascular events) or limb events (MALE; i.e. major amputation or requirement for peripheral revascularization) in patients with PAD. Methods A total of 1506 participants with intermittent claudication (n = 872) or chronic limb threatening ischemia (CLTI; n = 634) of whom 53 (3.5%) were prescribed one or more immunosuppressant drugs (prednisolone 41; methotrexate 17; leflunomide 5; hydroxychloroquine 3; azathioprine 2; tocilizumab 2; mycophenolate 1; sulfasalazine 1; adalimumab 1) were recruited from 3 Australian hospitals. Participants were followed for a median of 3.9 (inter-quartile range 1.2, 7.3) years. The association of immunosuppressant drug prescription with MACE or MALE was examined using Cox proportional hazard analyses. Results After adjusting for other risk factors, prescription of an immunosuppressant drug was associated with a significantly greater risk of MACE (Hazard ratio, HR, 1.83, 95% confidence intervals, CI, 1.11, 3.01; P = 0.017) but not MALE (HR 1.32, 95% CI 0.90, 1.92; P = 0.153). In a sub-analysis restricted to participants with CLTI findings were similar: MACE (HR 2.44, 95% CI 1.32, 4.51; P = 0.005); MALE (HR 1.38, 95% CI 0.87, 2.19; P = 0.175); major amputation (HR 1.37, 95% CI 0.49, 3.86; P = 0.547). Conclusions This cohort study suggested that immunosuppressant drug therapy is associated with a greater risk of MACE amongst patients with PAD.

Background Abnormalities in gait have been associated with high plantar pressures and diabetes-related plantar foot ulcers. Whether these are a transient response to the ulcer or are representative of long-term lower limb biomechanical abnormalities is currently unknown. Objective The aim of this study was to examine whether 12 gait parameters identified as being associated with nonhealing diabetes-related plantar foot ulcers at baseline remained associated during a 6-month follow-up period. Design This was a longitudinal observational case-control study. Methods Gait assessments were performed at entry and twice during follow-up over a 6-month period in 12 participants with nonhealing diabetes-related plantar foot ulcers (case participants) and 62 people with diabetes and no history of foot ulcers (control participants) using a standardized protocol. Linear mixed-effects random-intercept models were used to identify gait parameters that consistently differed between case participants and control participants at all assessments after adjustment for age, sex, body mass index, presence of peripheral neuropathy, and follow-up time. Standardized mean differences (SMD) were used to measure effect sizes. Results Five of the 12 gait parameters were significantly different between case participants and control participants at all 3 time points. Case participants had a more abducted foot progression angle (SMD = 0.37), a higher pelvic obliquity at toe-off (SMD = −0.46), a greater minimum pelvic obliquity (SMD = −0.52), a lower walking speed (SMD = −0.46), and a smaller step length (SMD = −0.46) than control participants. Limitations The limitations included a small sample size, the observational nature of the study, and the inability to evaluate the impact of gait on wound healing. Conclusions This study identified abnormal gait parameters consistently associated with nonhealing diabetes-related plantar foot ulcers. Further research is needed to test the clinical importance of these gait characteristics.

Abdominal aortic aneurysm (AAA) rupture is a common cause of death in adults. Current AAA treatment is by open surgical or endovascular aneurysm repair. Rodent model and human epidemiology, and genetic and observational studies over the last few decades have highlighted the potential of a number of drug therapies, including medications that lower blood pressure, correct dyslipidaemia, or inhibit thrombosis, inflammation or matrix remodelling, as approaches to managing small AAA. This review summarizes prior AAA pathogenesis data from animal and human studies aimed at identifying targets for the development of drug therapies. The review also systematically assesses past randomized placebo-controlled drug trials in patients with small AAAs. Eleven previously published randomized-controlled clinical trials testing different drug therapies aimed at slowing AAA progression were identified. Five of the trials tested antibiotics and three trials assessed medications that lower blood pressure. Meta-analyses of these trials suggested that neither of these approaches limit AAA growth. Allocation to blood pressure-lowering medication was associated with a small reduction in AAA rupture or repair, compared to placebo (relative risk 0.94, 95% confidence intervals 0.89, 1.00,P = 0.047). Three further trials assessed the effect of a mast cell inhibitor, fibrate or platelet aggregation inhibition and reported no effect on AAA growth or clinical events. Past trials were noted to have a number of design issues, particularly small sample sizes and limited follow-up. Much larger trials are needed to properly test potential therapeutic approaches if a convincingly effective medical therapy for AAA is to be identified.

Background: Skin autofluorescence has been used to assess longer term glycemic control and risk of complications. There is however no agreed site at which autofluorescence should be measured. This study evaluated the within- and between-site agreement in measurement of skin autofluorescence using a noninvasive advanced glycation end product (AGE) reader. Methods: Overall, 132 participants were included: 16 with diabetes-related foot ulcers (DFU), 63 with diabetes but without foot ulcers (DMC), 53 without diabetes or foot ulcers (HC). Skin autofluorescence was measured using the AGE Reader (DiagnOptics technologies BV, the Netherlands). Three consecutive skin autofluorescence measurements were each performed at six different body sites: the volar surfaces of both forearms (arms), dorsal surfaces of both calves (legs), and plantar surfaces of both feet (feet). Within- and between-site agreements were analyzed with concordance correlation coefficients (CCC) and 95% confidence intervals (95% CI), absolute mean differences (±standard deviation), and Bland-Altman limits of agreement. Results: The agreement between repeat assessments at the same site was almost perfect (CCC [95% CI] ranging from 0.94 [0.91-0.96] for assessments in the right foot to 0.99 [0.99-0.99] for assessments in the left arm). The limits of agreement were narrow within ±0.5 arbitrary units for all sites. The between-site agreement in measurements was poor (CCC < 0.65) with large maximum absolute mean differences (±SD) in arbitrary units (DFU = 3.40 [±2.04]; DMC = 3.15 [±2.45]; HC = 2.72 [±1.83]) and wide limits of agreement. Conclusions: Skin autofluorescence measurements can be repeated at the same site with adequate repeatability but measurements at different sites in the same patient have marked differences. The reason for this variation across sites and whether this has any role in diabetes-related complications needs further investigation.

Abdominal aortic aneurysm (AAA) is an important cause of death in older adults, which has no current drug therapy. Inflammation and abnormal redox status are believed to be key pathogenic mechanisms for AAA. In light of evidence correlating inflammation with aberrant fatty acid profiles, this study compared erythrocyte fatty acid content in 43 AAA patients (diameter 3.0–4.5 cm) and 52 healthy controls. In addition, the effect of omega-3 PUFA (n-3 PUFA) supplementation on erythrocyte fatty acid content was examined in a cohort of 30 AAA patients as part of a 12 week randomized placebo-controlled clinical trial. Blood analyses identified associations between AAA and decreased linoleic acid (LA), and AAA and increased Δ6-desaturase activity and biosynthesis of arachidonic acid (AA) from LA. Omega-3 PUFA supplementation (1.5 g DHA + 0.3 g EPA/day) decreased red blood cell distribution width (14.8 ± 0.4% to 13.8 ± 0.2%; P = 0.003) and levels of pro-inflammatory n-6 PUFAs (AA, 12.46 ± 0.23% to 10.14 ± 0.3%, P < 0.001; adrenic acid, 2.12 ± 0.13% to 1.23 ± 0.09%; P < 0.001). In addition, Δ-4 desaturase activity increased (DHA/docosapentaenoic acid ratio, 1.85 ± 0.14 to 3.93 ± 0.17; P < 0.001) and elongase 2/5 activity decreased (adrenic acid/AA ratio, 0.17 ± 0.01 to 0.12 ± 0.01; P < 0.01) following supplementation. The findings suggest that n-3 PUFAs improve fatty acid profiles and ameliorate factors associated with inflammation in AAA patients.

Objectives: Currently there is no drug therapy for abdominal aortic aneurysm (AAA) and most previous investigations have focused on imaging rather than clinical outcomes. The aim of this study was to assess whether AAA related clinical events were lower in patients prescribed metformin. Methods: This was a prospective cohort observational study performed in three cities in Australia, which was designed to study risk factors for clinical events not simply to focus on metformin. Patients with an asymptomatic unrepaired AAA of any diameter ≥30 mm were recruited from hospital outpatient clinics and surveillance programs run at four centres. The main outcome was the requirement for AAA repair or AAA related mortality (AAA events). The association between metformin prescription and AAA events was assessed using Kaplan-Meier analysis and Cox proportional hazard analysis. Results: Patients (1,080) with a mean (SD) initial AAA diameter of 46.1 (11.3) mm were followed for a mean (SD) of 2.5 (3.1) years until an AAA event (n ¼ 454), death (n ¼ 176), loss to follow up (n ¼ 128), or completion of current follow up (n ¼ 322). Patients with diabetes who were prescribed metformin (adjusted HR 0.63, 95% CI 0.44e0.93), but not patients with diabetes who were not prescribed metformin (adjusted HR 1.15, 95% CI 0.83e 1.59), had a lower incidence of AAA events compared with those without diabetes. Findings were similar in sensitivity analyses restricted to patients with an initial AAA diameter ≤ 50 mm and patients with a minimum follow up of six months before an AAA event. Conclusions: These findings suggest that clinically important AAA events may be reduced in patients with diabetes who are prescribed metformin, but not those with diabetes receiving other treatments. A randomised controlled trial is needed to definitively test whether metformin reduces AAA related clinical events in patients with small AAAs who do not have diabetes.

Background Bipolar disorder (BD) has been associated with greater health morbidity burden, but it is unclear if this association is affected by age at the time of diagnosis and how this might impact on the use of general hospital services. Methods Cross-sectional study investigating the prevalence of common medical morbidities among participants with early (EOBD) and late onset diagnosis of BD (LOBD – age at diagnosis ≥ 60 years) derived from a community-representative sample of 37,183 men aged 65–85 years. Cohort study over a follow up period of up to 17.7 years investigating the hazard of general hospital use among older men associated with EOBD and LOBD taking into account age and prevalent medical morbidities. Results 250 older men had a recorded diagnosis of BD, 75 of whom had LOBD. Diabetes, stroke and diseases of the respiratory and digestive systems were more frequent in men with than without BD. There were no differences in the distribution of medical morbidities between men with EOBD and LOBD. The adjusted hazard ratio (HR) of contact with general hospital services was significantly higher among men with EOBD (HR = 1.33; 95%CI = 1.14, 1.54) and LOBD (HR = 1.27, 95%CI = 1.06, 1.51) compared with older men without BD. Older men with EOBD had the highest number of contacts with general hospital services during follow up, although men with EOBD and LOBD did not differ in the number of contacts due to episodes of mania or depression. The medical reasons for contact with general hospital services of men with EOBD and LOBD overlapped but were not identical. Conclusions Older men with BD experience greater health morbidity than men without BD. Older men with BD access hospital services for the management of physical morbidities earlier and more frequently than men without BD. Age at the time of diagnosis of BD has limited impact on the risk of contact with general medical services, although subtle differences in the physical morbidity of men with EOBD and LOBD warrant further investigation.

Introduction: Topical oxygen therapy (TOT) has been suggested as a treatment for diabetes-related foot ulcer (DFU) but no prior meta-analyses of randomised clinical trials (RCT) have been reported. This systematic review and meta-analysis examined the randomised evidence for the benefit of TOT in healing DFU. Methods: Publicly available databases were searched for RCTs investigating the effect of TOT on wound healing in participants with a DFU. The primary outcome was ulcer healing defined as full epithelialisation. Meta-analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Study quality and publication bias were assessed using a modified version of the Cochrane Collaboration's tool and funnel plots, respectively. Results: Six RCTs involving 530 participants with a DFU testing TOT were included. Meta-analysis suggested that TOT significantly increased the likelihood of ulcer healing compared to controls (Risk ratio [RR] 1.94; 95% CI 1.19, 3.17; I2 = 57%; NNT = 5.33) and findings were robust in sensitivity analyses. Risk of bias was high, moderate and low in two, one and three studies, respectively. Analysis of the three trials judged to be at low risk of bias suggested that TOT increased the likelihood of ulcer healing compared to controls (RR 2.37; 95% CI 1.52, 3.68; I2 = 0%). Funnel plots suggested the possibility of publication bias. Data on amputation were too limited for meta-analysis. Conclusion: This meta-analysis suggests that TOT improves the likelihood of DFU healing; however, its effect on amputation and cost-effectiveness are unclear.

Background Prior studies have suggested aortic peak wall stress (PWS) and peak wall rupture index (PWRI) can estimate the rupture risk of an abdominal aortic aneurysm (AAA), but whether these measurements have independent predictive ability over assessing AAA diameter alone is unclear. The aim of this systematic review was to compare PWS and PWRI in participants with ruptured and asymptomatic intact AAAs of similar diameter. Methods and Results Web of Science, Scopus, Medline, and The Cochrane Library were systematically searched to identify studies assessing PWS and PWRI in ruptured and asymptomatic intact AAAs of similar diameter. Random‐effects meta‐analyses were performed using inverse variance‐weighted methods. Leave‐one‐out sensitivity analyses were conducted to assess the robustness of findings. Risk of bias was assessed using a modification of the Newcastle‐Ottawa scale and standard quality assessment criteria for evaluating primary research papers. Seven case‐control studies involving 309 participants were included. Meta‐analyses suggested that PWRI (standardized mean difference, 0.42; 95% CI, 0.14–0.70; P =0.004) but not PWS (standardized mean difference, 0.13; 95% CI, −0.18 to 0.44; P =0.418) was greater in ruptured than intact AAAs. Sensitivity analyses suggested that the findings were not dependent on the inclusion of any single study. The included studies were assessed to have a medium to high risk of bias. Conclusions Based on limited evidence, this study suggested that PWRI, but not PWS, is greater in ruptured than asymptomatic intact AAAs of similar maximum aortic diameter.

Patients with lower limb artery stenosis or occlusion (peripheral artery disease; PAD) have been determined to be at very high risk of both major adverse cardiovascular events, such as myocardial infarction and stroke, and major adverse limb events, such as amputation and requirement for artery surgery. Effective medical management has been identified as key in reducing this risk; however, this is often poorly implemented in clinical practice. Thus, the aim of this narrative review was to summarize the current evidence on the medical management of PAD in order to inform clinicians and highlight recommendations for clinical practice. International guidelines, randomized controlled trials, and relevant systematic reviews and meta-analyses have been included in this study. The focus was the management of the key modifiable risk factors to mitigate possible adverse events through prescription of anti-platelet and anticoagulation drugs and medications to control low-density lipoprotein cholesterol, blood pressure, and diabetes and aid smoking cessation. The available evidence from randomized clinical trials provide a strong rationale for the need for holistic medical management programs that are effective in achieving uptake of these medical therapies in patients with PAD. In conclusion, people with PAD have some of the highest adverse event rates among those with cardiovascular diseases. Secondary preventive measures have been proven effective in reducing these adverse events; however, they remain to be adequately implemented. Thus, the need for an effective implementation program has emerged to reduce adverse events in this patient group.

Improved understanding of abdominal aortic aneurysms (AAA) pathogenesis is required to identify treatment targets. This systematic review summarized evidence from animal studies and clinical research examining the role of adipokines and perivascular adipose tissue (PVAT) in AAA pathogenesis. Meta-analyses suggested that leptin (Standardized mean difference [SMD]: 0.50 [95% confidence interval (CI): −1.62, 2.61]) and adiponectin (SMD: −3.16 [95% CI: −7.59, 1.28]) upregulation did not significantly affect AAA severity within animal models. There were inconsistent findings and limited studies investigating the effect of resistin-like molecule-beta (RELMβ) and PVAT in animal models of AAA. Clinical studies suggested that circulating leptin (SMD: 0.32 [95% CI: 0.19, 0.45]) and resistin (SMD: 0.63 [95% CI 0.50, 0.76]) concentrations and PVAT to abdominal adipose tissue ratio (SMD: 0.56 [95% CI 0.33, 0.79]) were significantly greater in people diagnosed with AAA compared to controls. Serum adiponectin levels were not associated with AAA diagnosis (SMD: −0.62 [95% CI −1.76, 0.52]). One, eight, and one animal studies and two, two, and four human studies had low, moderate, and high risk-of-bias respectively. These findings suggest that AAA is associated with higher circulating concentrations of leptin and resistin and greater amounts of PVAT than controls but whether this plays a role in aneurysm pathogenesis is unclear.

BackgroundAbdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. The kinin B2 receptor agonist, bradykinin, has been implicated in AAA pathogenesis through promoting inflammation. Bradykinin is generated from high‐ and low‐molecular‐weight kininogen by the serine protease kallikrein‐1. The aims of this study were first to examine the effect of neutralizing kallikrein‐1 on AAA development in a mouse model and second to test how blocking kallikrein‐1 affected cyclooxygenase‐2 and prostaglandin E2in human AAA explants.Methods and ResultsNeutralization of kallikrein‐1 in apolipoprotein E‐deficient (ApoE−/−) mice via administration of a blocking antibody inhibited suprarenal aorta expansion in response to angiotensin (Ang) II infusion. Kallikrein‐1 neutralization decreased suprarenal aorta concentrations of bradykinin and prostaglandin E2and reduced cyclooxygenase‐2 activity. Kallikrein‐1 neutralization also decreased protein kinase B and extracellular signal‐regulated kinase 1/2 phosphorylation and reduced levels of active matrix metalloproteinase 2 and matrix metalloproteinase 9. Kallikrein‐1 blocking antibody reduced levels of cyclooxygenase‐2 and secretion of prostaglandin E2and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils.ConclusionsThese findings suggest that kallikrein‐1 neutralization could be a treatment target for AAA.

The aims of this study were to assess the incidence of major vascular events (MVE) and peripheral vascular events (PVE) in people with a small asymptomatic abdominal aortic aneurysm (AAA) and model the theoretical benefits and costs of an intensified low density lipoprotein cholesterol (LDL-C) lowering programme.A total of 583 participants with AAAs measuring 30 - 54 mm were included in this study. The control of LDL-C and prescription of lipid lowering drugs were assessed by dividing participants into approximately equal tertiles depending on their year of recruitment into the study. The occurrence of MVE (myocardial infarction, stroke, cardiovascular death, and coronary or non-coronary revascularisation) and PVE (non-coronary revascularisation, AAA repair, and major amputation) were recorded prospectively, and the incidence of these events was calculated using Kaplan-Meier analysis. The relative risk reduction reported for these events in a previous randomised control trial (RCT) was then applied to these figures to model the absolute risk reduction and numbers needed to treat (NTT) that could theoretically be achieved with a mean LDL-C lowering of 1 mmol/L. The maximum allowable expense for a cost effective intensive LDL-C lowering programme was estimated using a cost utility analysis.At entry, only 28.5% of participants had an LDL-C of1.8 mmol/L and only 18.5% were prescribed a high potency statin (atorvastatin 80 mg or rosuvastatin 40 mg). The five year incidences of MVE and PVE were 38.1% and 44.7%, respectively. It was estimated that if the mean LDL-C of the cohort had been reduced by 1 mmol/L, this could have reduced the absolute risk of MVE and PVE by 6.5% (95% CI 4.4 - 8.7; NNT 15) and 5.3% (95% CI 1.4 - 7.5; NNT 19), respectively. It was estimated that the maximum allowable expense for a cost effective LDL-C lowering programme would be between $1 239 AUD (€768) and $1 582 AUD (€981) per person per annum over a five year period.People with a small asymptomatic AAA are at high risk of MVE and PVE. This study provides evidence of the possible benefits and allowable expense for a cost effective intensive LDL-C lowering programme in this population.

Background There are currently few effective drugs to treat the leg symptoms of peripheral arterial disease (PAD). Previous studies have suggested that the nutraceutical, quercetin, can improve exercise performance and reduce pain sensitivity in healthy mice and improve blood supply in a rodent model of acute hind-limb ischaemia. These models may not be relevant to people with PAD. The aim of this study was to examine the effect of quercetin on exercise performance, physical activity and blood supply in a novel mouse model of sustained hind-limb ischaemia. Methods Hind-limb ischaemia was induced in 6-month-old male apolipoprotein E-deficient mice using a novel two-stage surgical procedure. Five days after induction of ischaemia, mice were allocated to commence dietary quercetin or a control diet for 4 weeks. The primary outcome was exercise performance evaluated using a treadmill test. Other outcomes included physical activity, estimated by an open field test, and hind-limb blood supply, assessed by laser Doppler monitoring. Results A sustained reduction in relative limb blood supply (P, The dietary flavonoid quercetin has been reported to improve exercise performance in healthy mice and people, and increase limb perfusion in models of acute hind limb ischemia. Acute hind limb ischemia models may not be representative of human peripheral artery disease.We report that quercetin does not improve exercise performance or limb perfusion in a newly developed two stage mouse model of sustained hind limb ischemia. Our findings suggest that quercetin may not be beneficial for patients with sustained limb ischemia due to peripheral artery disease. little evidence of efficacy

Background: Abdominal aortic aneurysms (AAAs) are a leading cause of death in older adults due to aortic rupture. There are currently no effective medical therapies for AAA, with surgery being the only acceptable treatment. There is frequently an extended period between AAA diagnosis and treatment by corrective surgery, during which an effective drug therapy could prevent or delay the need for AAA repair. Objective: This review aimed to critically summarize prior research investigating the potential benefits of phytochemicals in preventing or treating AAA. Methods: In vitro, in vivo, and human studies examining the effect of phytochemicals in AAA models and patients were critically summarised. Results: Some preliminary data support the further investigation of curcumin, radix astragali, grape seed polyphenols, resveratrol, Ginkgo biloba extract (EGb 761), Ginsenoide Rb1, Dan Hong, Epigallocatechin-3-gallate, Baicalein, Fucoidan, Quercetin, and Salvianolic acid as potential treatments for AAA. Conclusion: Experimental in vivo and in vitro studies suggest the potential benefits of a number of medicinal herbs and phytochemicals in preventing or reducing the progression of AAA. In order to assess whether these findings can be translated into proven treatments, adequately designed double-blind randomized clinical trials will be required.

Background The management of abdominal aortic aneurysm (AAA) is fully dictated by AAA size, but there are no uniform measurement guidelines, and systematic differences exist between ultrasound- and CT-based size estimation. The aim of this study was to devise a uniform ultrasound acquisition and measurement protocol, and to test whether harmonization of ultrasound and CT readings is feasible. Methods A literature review was undertaken to evaluate evidence for ultrasound-based measurement of AAA. A protocol for measuring AAA was then developed, and intraobserver and interobserver reproducibility was tested. Finally, agreement between ultrasound readings and CT-based AAA diameters was evaluated. This was an observational study of patients with a small AAA who participated in two pharmaceutical intervention trials. Results Based on a literature review, an ultrasound acquisition and reading protocol was devised. Evaluation of the protocol showed an intraobserver repeatability of 1.6 mm (2s.d.) and an interobserver intraclass correlation coefficient (ICC) of 0.97. Comparison of protocolled ultrasound readings and local CT readings indicated a good correlation (r = 0.81), but a systematic +4.1-mm difference for CT. Harmonized size readings for ultrasound imaging and CT increased the correlation (r = 0.91) and reduced the systematic difference to +1.8 mm by CT. Interobserver reproducibility of protocolized CT measurements showed an ICC of 0.94 for the inner-to-inner method and 0.96 for the outer-to-outer method. Conclusion The absence of harmonized size acquisition and reading guidelines results in overtreatment and undertreatment of patients with AAA. This can be avoided by the implementation of standardized ultrasound acquisition and a harmonized reading protocol for ultrasound- and CT-based readings., Absence of harmonized size acquisition and reading guidelines result in overtreatment and undertreatment of patients with an abdominal aortic aneurysm. This can be avoided by the implementation of standardized ultrasound acquisition and the proposed harmonized reading protocol for ultrasound- and CT-based readings. Reducing measurement errors

Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults. In clinical practice, the most established predictor of AAA rupture is maximum AAA diameter. Aortic diameter is commonly used to assess AAA severity in mouse models studies. AAA rupture occurs when the stress (force per unit area) on the aneurysm wall exceeds wall strength. Previous research suggests that aortic wall structure and strength, biomechanical forces on the aorta and cellular and proteolytic composition of the AAA wall influence the risk of AAA rupture. Mouse models offer an opportunity to study the association of these factors with AAA rupture in a way not currently possible in patients. Such studies could provide data to support the use of novel surrogate markers of AAA rupture in patients. In this review, the currently available mouse models of AAA and their relevance to the study of AAA rupture are discussed. The review highlights the limitations of mouse models and suggests novel approaches that could be incorporated in future experimental AAA studies to generate clinically relevant results.

Key PointsQuestionDoes telmisartan reduce the growth of small abdominal aortic aneurysms? FindingsIn this placebo-controlled randomized trial of 210 participants, a significant effect of telmisartan on abdominal aortic aneurysm growth rates was not shown. Telmisartan had no effect on requirement for abdominal aortic aneurysm repair or aneurysm rupture. MeaningFurther adequately powered trials are needed to assess the efficacy of medical therapies to slow abdominal aortic aneurysm growth.ImportanceCurrently there is no drug therapy for abdominal aortic aneurysm (AAA). ObjectiveTo test the efficacy of the angiotensin receptor blocker telmisartan in slowing AAA growth in the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. Design, Setting, and ParticipantsA randomized, double-blind, placebo-controlled trial recruited participants between September 6, 2011, and October 5, 2016, to evaluate the efficacy of telmisartan treatment in patients with AAA. Participants with 35- to 49-mm AAAs recruited from Australia, the Netherlands, and the US were randomized 1:1 to receive telmisartan, 40 mg, or identical placebo. Analyses were conducted according to intention-to-treat principles. Final follow-up was conducted on October 11, 2018, and data analysis was performed between June and November 2019. InterventionTelmisartan, 40 mg, or identical placebo. Main Outcomes and MeasuresThe primary outcome of the difference in AAA growth, assessed on core imaging laboratory-read ultrasonographic scanning, was tested with linear mixed-effects models. Other outcomes included effects on blood pressure, computed tomographic (CT)-measured AAA diameter and volume, time to AAA-related events (AAA repair or mortality due to AAA rupture), and health-related quality of life. ResultsOf 300 intended participants, 210 were enrolled and randomized to receive telmisartan (n=107) or placebo (n=103). Of patients included in the intention-to-treat analysis (telmisartan: n=106, placebo: n=101), 183 were men (88%); mean (SD) age was 73.5 (7.9) years. At 1 year, participants receiving telmisartan had mean lower systolic (8.9; 95% CI, 4.1-13.8 mm Hg; P

Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only indicated for large asymptomatic, symptomatic or ruptured aneurysms, is not always durable, and is associated with a risk of serious perioperative complications. As a result, patients with small asymptomatic aneurysms or who are otherwise unfit for surgery are treated conservatively, but up to 70% of small aneurysms continue to grow, increasing the risk of rupture. There is thus an urgent need to develop drug therapies effective at slowing AAA growth. This review describes the commonly used mouse models for AAA. Recent research in these models highlights key roles for pathways involved in inflammation and cell turnover in AAA pathogenesis. There is also evidence for long non-coding RNAs and thrombosis in aneurysm pathology. Further well-designed research in clinically relevant models is expected to be translated into effective AAA drugs. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Hyperuricemia has been associated with hypertension, however, whether this association exists across all decades of adult life is unknown. This study aimed to assess the association between hyperuricemia and hypertension in relation to age. This retrospective cross-sectional study included a total of 22,556 adult Chinese people who attended Health Physical Examination in a Chinese hospital. Participants were aged between 18 and 95 years (mean [standard deviation], 45.4 [14.0]). Serum uric acid levels and blood pressure were measured. Associations between serum uric acid and blood pressure, and between hyperuricemia and hypertension diagnosis were analyzed using linear or logistic regression, adjusting for confounding risk factors including age, sex, total cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose. Sub-analysis was stratified by age and sex. Before adjustment, high serum uric acid was associated with higher systolic blood pressure (β = 0.214, P < 0.001) and higher diastolic blood pressure (β = 0.271, P < 0.001). Hyperuricemia was associated with hypertension diagnosis (OR, 1.763; 95% CI, 1.635-1.901; P < 0.001) in an unadjusted analysis. These findings remained significant after adjusting for confounding factors. Sub-analysis suggested that the association between uric acid and blood pressure was weaker in older age groups and the association between hyperuricemia and hypertension was limited to people under 60 years. Hyperuricemia was independently associated with hypertension diagnosis in men but not in women, and the independent association between hyperuricemia and hypertension only presented in men under 60 years. This study suggests that hyperuricemia is independently associated with hypertension in Chinese men under 60 years.

Diabetes-related foot disease (DFD), which includes foot ulcers, infection and gangrene, is a leading cause of the global disability burden. About half of people who develop DFD experience a recurrence within one year. Long-term medical management to reduce the risk of recurrence is therefore important to reduce the global DFD burden. This review describes research assessing the value of sensors, wearables and telehealth in preventing DFD. Sensors and wearables have been developed to monitor foot temperature, plantar pressures, glucose, blood pressure and lipids. The monitoring of these risk factors along with telehealth consultations has promise as a method for remotely managing people who are at risk of DFD. This approach can potentially avoid or reduce the need for face-to-face consultations. Home foot temperature monitoring, continuous glucose monitoring and telehealth consultations are the approaches for which the most highly developed and user-friendly technology has been developed. A number of clinical studies in people at risk of DFD have demonstrated benefits when using one of these remote monitoring methods. Further development and evidence are needed for some of the other approaches, such as home plantar pressure and footwear adherence monitoring. As yet, no composite remote management program incorporating remote monitoring and the management of all the key risk factors for DFD has been developed and implemented. Further research assessing the feasibility and value of combining these remote monitoring approaches as a holistic way of preventing DFD is needed.