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Background: As people age the risk of dementia increases. Balance and strength deteriorate with ageing, but their associations with dementia are not clear. We aimed to determine relationships of balance and strength performance with incident dementia in the Health in Men Study (HIMS) cohort. Methods: We used wave 4 of the HIMS as baseline for analyses (2011–2013), following 1261 men until December 2017 via data linkage to determine incident dementia. Balance was measured using a modified Balance Outcome Measure for Elder Rehabilitation (mBOOMER) Score and strength with the knee extension test. Cox proportional hazards regression was used, adjusting for sociodemographic and health data. Strength and balance scores were analysed non-linearly using restricted cubic splines. Results: 13.7% of men were diagnosed with dementia over a mean period of 4.7 (SD 1.5) years. Higher baseline mBOOMER scores were associated with a reduced risk of incident dementia, with greater changes in risk at higher mBOOMER scores (9 vs 8: HR 0.80, 95% CI 0.73–0.88; 12 vs 11: 0.49, 95% HR 0.36–0.68). Higher baseline lower limb strength was associated with a reduced risk of incident dementia, with greater changes occurring at lower scores, plateauing at around 25 kg (5 vs 4: HR 0.93, 95% CI 0.89–0.98; 25 vs 24: HR 0.99, 95% CI 0.95–1.03). Conclusions: This study demonstrated a non-linear association of better performance in both strength and balance with reduced likelihood of incident dementia. These results raise the hypothesis that strategies to improve strength and balance could reduce the incidence of dementia in older men.

Abstract Background Past studies suggest that there are changes in peripheral blood cell gene expression in response to ischaemic stroke; however, the specific changes which occur during the acute phase are poorly characterised. The current study aimed to identify peripheral blood cell genes specifically associated with the early response to ischaemic stroke using whole blood samples collected from participants diagnosed with ischaemic stroke (n = 29) or stroke mimics (n = 27) following emergency presentation to hospital. Long non-coding RNA (lncRNA), mRNA and micro-RNA (miRNA) abundance was measured by RNA-seq, and the consensusDE package was used to identify genes which were differentially expressed between groups. A sensitivity analysis excluding two participants with metastatic disease was also conducted. Results The mean time from symptom onset to blood collection was 2.6 h. Most strokes were mild (median NIH stroke scale score 2.0). Ten mRNAs (all down-regulated in samples provided by patients experiencing ischaemic stroke) and 30 miRNAs (14 over-expressed and 16 under-expressed in participants with ischaemic stroke) were significantly different between groups in the whole cohort and sensitivity analyses. No significant over-representation of gene ontology categories by the differentially expressed genes was observed. Random forest analysis suggested a panel of differentially expressed genes (ADGRG7 and miRNAs 96, 532, 6766, 6798 and 6804) as potential ischaemic stroke biomarkers, although modelling analyses demonstrated that these genes had poor diagnostic performance. Conclusions This study provides evidence suggesting that the early response to minor ischaemic stroke is predominantly reflected by changes in the expression of miRNAs in peripheral blood cells. Further work in independent cohorts particularly in patients with more severe stroke is needed to validate these findings and investigate their clinical relevance.

Objective: We examined the associations between 25-hydroxy vitamin D (25(OH)D3) concentration and the diagnosis and growth of abdominal aortic aneurysm (AAA). Methods: AAA cases and healthy controls were recruited from vascular centers or the community. A subset of participants with AAA were monitored by repeat ultrasound examination to assess AAA growth. Serum 25(OH)D3 concentration was measured using a validated mass spectrometry method and categorized into guideline-recommended cut-points after deseasonalization. The associations between deseasonalized 25(OH)D3 concentration and AAA diagnosis and growth were examined using logistic regression and linear mixed effects modeling. Results: A total of 4673 participants consisting of 873 (455 controls and 418 cases) from Queensland and 3800 (3588 controls and 212 cases) from Western Australia were recruited. For every 1 standard deviation increase in 25(OH)D3 concentration, odds of AAA diagnosis was significantly reduced in both Queensland (adjusted odds ratio: 0.81; 95% confidence interval [CI]: 0.69-0.95; P = .009) and Western Australia (adjusted odds ratio: 0.80; 95% CI: 0.68-0.94; P = .005) cohorts. A subset of 310 eligible participants with small AAA from both regions were followed for a median of 4.2 (interquartile range: 2.0-5.8) years. Compared with vitamin D sufficient participants (50 to ˂75 nmol/L), annual mean AAA growth was significantly greater in those with higher vitamin D (≥75 nmol/L) (adjusted mean difference: 0.1 mm/y, 95% CI: 0.1-0.2; P < .001). Conclusions: High 25(OH)D3 concentration was paradoxically associated with a lower likelihood of AAA diagnosis and faster AAA growth. Further research is needed to resolve these conflicting findings. : Clinical Relevance: The findings of this study suggest that relative vitamin D deficiency increases the risk of abdominal aortic aneurysm diagnosis, but paradoxically high circulating markers of vitamin D are associated with faster aneurysm growth. These findings support the need for vitamin D sufficiency not excess, but need validation in other cohorts before incorporation into clinical management protocols.

IntroductionMinor amputation is commonly needed to treat diabetes-related foot disease (DFD). Remoteness of residence is known to limit access to healthcare and has previously been associated with poor outcomes. The primary aim of this study was to examine the associations between ethnicity and remoteness of residency with the risk of major amputation and death following initial treatment of DFD by minor amputation. A secondary aim was to identify risk factors for major amputation and death following minor amputation to treat DFD.Research design and methodsThis was a retrospective analysis of data from patients who required a minor amputation to treat DFD between 2000 and 2019 at a regional tertiary hospital in Queensland, Australia. Baseline characteristics were collected together with remoteness of residence and ethnicity. Remoteness was classified according to the 2019 Modified Monash Model (MMM) system. Ethnicity was based on self-identification as an Aboriginal and Torres Strait Islander or non-Indigenous person. The outcomes of major amputation, repeat minor amputation and death were examined using Cox-proportional hazard analyses.ResultsA total of 534 participants were included, with 306 (57.3%) residing in metropolitan or regional centres, 228 (42.7%) in rural and remote communities and 144 (27.0%) were Aboriginal or Torres Strait Islander people. During a median (inter quartile range) follow-up of 4.0 (2.1-7.6) years, 103 participants (19.3%) had major amputation, 230 (43.1%) had repeat minor amputation and 250 (46.8%) died. The risks (hazard ratio [95% CI]) of major amputation and death were not significantly higher in participants residing in rural and remote areas (0.97, 0.67-1.47; and 0.98, 0.76-1.26) or in Aboriginal or Torres Strait Islander people (HR 1.44, 95% CI 0.96, 2.16 and HR 0.89, 95% CI 0.67, 1.18). Ischemic heart disease (IHD), peripheral artery disease (PAD), osteomyelitis and foot ulceration (pConclusionMajor amputation and death are common following minor amputation to treat DFD and people with IHD, PAD and osteomyelitis have an increased risk of major amputation. Aboriginal and Torres Strait Islander People and residents of remote areas were not at excess risk of major amputation.

Implant-associated infections (IAI) cause significant health issues and healthcare costs. In this research, we deposited graphene (Gr) on a medical-grade cobalt-chromium (CoCr) alloy surface by radiofrequency plasma-enhanced chemical vapor deposition (RF-PECVD) using Origanum vulgare as a precursor material. The deposition of Gr on the CoCr was confirmed using Raman spectroscopy and X-Ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). The biocompatibility and antibacterial properties of CoCr-Gr were investigated. CoCr-Gr was biocompatible and promoted cell adhesion and spreading of RAW 267.4 macrophage cells. CoCr-Gr were antibacterial against Staphylococcus aureus and Pseudomonas aeruginosa and inhibited P. aeruginosa attachment. The results indicate that CoCr-Gr could be used as a potential antibacterial coating material for implantable devices.

Abstract We investigated the association of dietary intake of major types of fatty acids with heart disease mortality in a general adult cohort with or without a prior diagnosis of myocardial infarction (MI). This cohort study included US adults who attended the National Health and Nutrition Examination Surveys from 1988 to 2014. Heart disease mortality was ascertained by linkage to the National Death Index records through 31 December 2015. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of fatty acid intake for heart disease mortality. This cohort included 45,820 adults among which 1,541 had a prior diagnosis of MI. Participants were followed up for 532,722 person-years (mean follow-up, 11.6 years), with 2,313 deaths recorded from heart disease being recorded. Intake of saturated (SFAs) and monounsaturated fatty acids (MUFAs) was associated with heart disease mortality after adjustment for all the tested confounders. In contrast, a 5% higher calorie intake from polyunsaturated fatty acids (PUFAs) was associated with a 9% (HR, 0.91; 95% CI 0.83–1.00; P = 0.048) lower multivariate-adjusted risk of heart disease mortality. Sub-analyses showed that this inverse association was present in those without a prior diagnosis of MI (HR,0.89; 95% CI 0.80–0.99) but not in those with the condition (HR, 0.94; 95% CI 0.75–1.16). The lack of association in the MI group could be due to a small sample size or severity and procedural complications (e.g., stenting and medication adherence) of the disease. Higher PUFA intake was associated with a favourable lipid profile. However, further adjustment for plasma lipids did not materially change the inverse association between PUFAs and heart disease mortality. Higher intake of PUFAs, but not SFAs and MUFAs, was associated with a lower adjusted risk of heart disease mortality in a large population of US adults supporting the need to increase dietary PUFA intake in the general public.

Abstract Background A previous study found that circulating angiopoietin-1 (angpt-1) concentrations were significantly lower in patients who had a recent ischaemic stroke compared to healthy controls. The primary aim of this study was to assess whether serum angpt-1 could be used as a diagnostic test of ischemic stroke in patients presenting to hospital as an emergency. Exploratory analyses investigated the association of proteins functionally related to angpt-1 (angpt-2, Tie-2, matrix metalloproteinase-9 and vascular endothelial growth factors A, C and D) with ischaemic stroke diagnosis. Methods Patients presenting to Townsville University Hospital for emergency assessment of stroke-like symptoms were consecutively recruited and provided a blood sample. After assessment by a consultant neurologist, patients were grouped into those who did, or did not have ischaemic stroke. The potential for serum angpt-1 to diagnose ischaemic stroke was assessed using receiver operator characteristic (ROC) curves. Cross-sectional analyses appraised inter-group differences in the serum concentration of other proteins. Results One-hundred and twenty-six patients presenting to Townsville University Hospital for emergency assessment of stroke-like symptoms were recruited (median time from symptom onset to hospital presentation: 2.6 (inter-quartile range: 1.2–4.6) hours). Serum angpt-1 had poor ability to diagnose ischaemic stroke in analyses using the whole cohort, or in sensitivity analyses (area under the ROC curve 0.51 (95% CI: 0.41–0.62) and 0.52 (95% CI: 0.39–0.64), respectively). No associations of serum angpt-1 concentration with ischaemic stroke severity, symptom duration or aetiology were observed. Serum concentrations of the other assessed proteins did not differ between patient groups. Conclusions Serum angpt-1 concentration is unlikely to be useful for emergency diagnosis of ischaemic stroke.

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention. In addition to a potential unconscious bias faced by women with PAD in the health system, with underdiagnosis, and lower rates of guideline-based therapy, fundamental biological differences between men and women may be important. In this review, we highlight sexual dimorphisms in endothelial cell functions and how they may impact PAD pathophysiology in women. Understanding sex-specific mechanisms in PAD is essential for the development of new therapies and personalized care for patients with PAD.

The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in this field. Increased vascular inflammation and enhanced apoptosis of vascular smooth muscle cells (VSMCs) are implicated in AAA formation. Here, we investigated whether hydralazine, which has anti-inflammatory and anti-apoptotic properties, inhibited AAA formation and pathological hallmarks. In cultured VSMCs, hydralazine (100 μM) inhibited the increase in inflammatory gene expression and apoptosis induced by acrolein and hydrogen peroxide, two oxidants that may play a role in AAA pathogenesis. The anti-apoptotic effect of hydralazine was associated with a decrease in caspase 8 gene expression. In a mouse model of AAA induced by subcutaneous angiotensin II infusion (1 µg/kg body weight/min) for 28 days in apolipoprotein E-deficient mice, hydralazine treatment (24 mg/kg/day) significantly decreased AAA incidence from 80% to 20% and suprarenal aortic diameter by 32% from 2.26 mm to 1.53 mm. Hydralazine treatment also significantly increased the survival rate from 60% to 100%. In conclusion, hydralazine inhibited AAA formation and rupture in a mouse model, which was associated with its anti-inflammatory and anti-apoptotic properties.

Background: In the present study, we examined the association of immunosuppressant drug prescriptions with the growth of small abdominal aortic aneurysms (AAAs). Methods: Participants with an AAA measuring between 30 and 50 mm were recruited from four Australian centers. AAA growth was monitored by ultrasound. The immunosuppressant drugs included conventional disease-modifying antirheumatic drugs (eg, methotrexate, sulfasalazine, leflunomide), steroids, hydroxychloroquine, other immunosuppressant drugs (eg, cyclosporine, azacitidine), or a combination of these drugs. Linear mixed effects modeling was performed to examine the independent association of an immunosuppressant prescription with AAA growth. A subanalysis examined the association of steroids with AAA growth. Results: Of the 621 patients, 34 (5.3%) had been prescribed at least one (n = 26) or more (n = 8) immunosuppressant drug and had been followed up for a median period of 2.1 years (interquartile range, 1.1-3.5 years), with a median of three ultrasound scans (interquartile range, two to five ultrasound scans). No significant difference was found in AAA growth when stratified by a prescription of immunosuppressant drugs on either unadjusted (mean difference, 0.2 mm/y; 95% confidence interval [CI], −0.4 to 0.7; P = .589) or risk factor-adjusted (mean difference, 0.2 mm/y; 95% CI, −0.3 to 0.7; P = .369) analyses. The findings were similar for the unadjusted (mean difference, 0.0 mm/y; 95% CI, −0.7 to 0.7; P = .980) and risk factor-adjusted (mean difference, 0.1 mm/y; 95% CI, −0.6 to 0.7; P = .886) subanalyses focused on steroid use. Conclusions: The results from this study suggest that AAA growth is not affected by immunosuppressant drug prescription. Studies with larger sample sizes are needed before reliable conclusions can be drawn. : Clinical relevance: At present, it is unclear whether immunosuppression promotes or inhibits abdominal aortic aneurysm (AAA) progression. This has important implications for the management of AAA. With the increasing range of indications for which immunosuppressant medications are being prescribed, it is likely that more patients with AAAs will be prescribed these drugs for the treatment of comorbid diseases, such as rheumatoid arthritis, other autoimmune diseases, after organ transplantation, or coronary heart disease. The results from the present study suggest that patients prescribed a range of different immunosuppressant drugs for treating a variety of different inflammatory diseases did not experience a significantly different AAA growth compared with patients not receiving these medications. Our findings suggest that no strong case exists to either start or stop immunosuppressant drugs for AAA patients

Abstract Background Multiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms. Methods MAT is an international, multi-centre, prospective, parallel-group, randomised, placebo-controlled trial. Participants must have an asymptomatic AAA measuring at least 35 mm in maximum diameter, no diabetes, no contraindication to metformin and no current plans for surgical repair. The double-blind period is preceded by a 6-week, single-blind, active run-in phase in which all potential participants receive metformin. Only patients tolerating metformin by taking at least 80% of allocated medication will enter the trial and be randomised to 1500 mg of metformin XR or an identical placebo. The primary outcome is the proportion of AAA events defined as rupture-related mortality or need for surgical repair. Secondary outcomes include AAA growth, major adverse cardiovascular events and health-related quality of life. In order to test if metformin reduced the risk of AAA events by at least 25%, 616 primary outcome events will be required (power 90%, alpha 0.05). Discussion Currently, there is no drug therapy for AAA. Past trials have found no convincing evidence of the benefit of multiple blood pressure lowering, antibiotics, a mast cell inhibitor, an anti-platelet drug and a lipid-lowering medication on AAA growth. MAT is one of a number of trials now ongoing testing metformin for AAA. MAT, unlike these other trials, is designed to test the effect of metformin on AAA events. The international collaboration needed for MAT will be challenging to achieve given the current COVID-19 pandemic. If this challenge can be overcome, MAT will represent a trial unique within the AAA field in its large size and design. Trial registration Australian Clinical Trials ACTRN12618001707257 . Registered on 16 October 2018

Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy.

Abstract Background Conflicting findings and the analysis of unpublished and retracted data have led to controversy on the safety of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in people with COVID-19 infection. This meta-analysis examined the association of prescription of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) with the outcome from COVID-19. Methods A systematic search was conducted to find published studies that reported the outcome of COVID-19 in relation to prescription of ACEI or ARB. Two authors (MF and AD) independently screened and extracted data and assessed study quality and strength of association using standardised tools. The endpoints for the meta-analyses were severe or critical disease outcome and mortality based on standardised criteria. Results Twenty-six studies including 8389 people prescribed ACEI or ARB and 20,989 people not prescribed these medications were included. The quality of studies varied, and the overall strength of association was poor with a high risk of confounding bias. Patients prescribed ACEI or ARB had a greater prevalence of risk factors. Meta-analysis found an association between prescription of ACEI or ARB with severe or critical disease outcome (risk ratio, RR, 1.23, 95% confidence interval, CI, 1.06 to 1.42, p = 0.006, I 2 = 88%) but this association was lost in sensitivity analyses. There was no association between ACEI or ARB prescription and mortality (RR 1.18, 95% CI 0.92 to 1.50, p = 0.19, I 2 = 82%). Conclusions This meta-analysis suggests that people prescribed ACEI or ARB more commonly had severe or critical disease outcome, but not mortality, in published cohorts of patients diagnosed with COVID-19. This finding is most likely due to a greater prevalence of risk factors in these patients rather than due to exposure to angiotensin pathway inhibitors.

Abstract Inflammation, vascular smooth muscle cell apoptosis and oxidative stress are believed to play important roles in abdominal aortic aneurysm (AAA) pathogenesis. Human kallistatin (KAL; gene SERPINA4) is a serine proteinase inhibitor previously shown to inhibit inflammation, apoptosis and oxidative stress. The aim of this study was to investigate the role of KAL in AAA through studies in experimental mouse models and patients. Serum KAL concentration was negatively associated with the diagnosis and growth of human AAA. Transgenic overexpression of the human KAL gene (KS-Tg) or administration of recombinant human KAL (rhKAL) inhibited AAA in the calcium phosphate (CaPO4) and subcutaneous angiotensin II (AngII) infusion mouse models. Upregulation of KAL in both models resulted in reduction in the severity of aortic elastin degradation, reduced markers of oxidative stress and less vascular smooth muscle apoptosis within the aorta. Administration of rhKAL to vascular smooth muscle cells incubated in the presence of AngII or in human AAA thrombus-conditioned media reduced apoptosis and downregulated markers of oxidative stress. These effects of KAL were associated with upregulation of Sirtuin 1 activity within the aortas of both KS-Tg mice and rodents receiving rhKAL. These results suggest KAL-Sirtuin 1 signalling limits aortic wall remodelling and aneurysm development through reductions in oxidative stress and vascular smooth muscle cell apoptosis. Upregulating KAL may be a novel therapeutic strategy for AAA.

This systematic review pooled evidence from randomised controlled trials (RCTs) on the effectiveness of dietary upregulators of nitric oxide (NO) in improving the walking and quality of life of patients with peripheral artery disease (PAD). RCTs examining the effect of dietary upregulators of NO in patients with PAD were included. The primary outcome was the maximum walking distance. Secondary outcomes were the initial claudication distance, the six-minute walking distance, quality of life, the ankle-brachial pressure index (ABI), adverse events and risk of mortality, revascularisation or amputation. Meta-analyses were performed using random effects models. The risk of bias was assessed using Cochrane’s ROB-2 tool. Leave-one-out and subgroup analyses were conducted to assess the effect of individual studies, the risk of bias and intervention type on pooled estimates. Thirty-four RCTs involving 3472 participants were included. Seven trials tested NO donors, nineteen tested antioxidants, three tested NO synthase inducers and five tested enhancers of NO availability. Overall, the dietary supplements significantly improved the initial claudication (SMD 0.34; 95%CI 0.04, 0.64; p = 0.03) but not maximum walking (SMD 0.13; 95%CI −0.17, 0.43; p = 0.39) distances. Antioxidant supplements significantly increased both the maximum walking (SMD 0.36; 95%CI 0.14, 0.59; p = 0.001) and initial claudication (SMD 0.58; 95%CI 0.26, 0.90; p < 0.001) distances. The dietary interventions did not improve the physical function domain of the Short Form-36 (SMD −0.16; 95%CI −0.32, 0.00; p = 0.38), ABI or risk of adverse events, mortality, revascularisation or amputation. Dietary NO upregulators, especially antioxidants, appear to improve the initial claudication distance in patients with PAD. Larger high-quality RCTs are needed to fully examine the benefits and risks of these treatments. PROSPERO Registration: CRD42022256653.

Abstract Background This study estimated the incidence of major amputation for people in North Queensland, Australia, examined changes in amputation rates over time and investigated survival after major amputation. Methods This was a retrospective study of patients who underwent a major amputation above the ankle between 2000 and 2015. Major amputation rates and incidence rate ratios (IRR) were calculated using census data to define the at-risk population. Associations between risk factors and calendar year with major amputation were assessed using quasipoisson regression. Kaplan-Meier survival and Cox-proportional hazard analyses estimated the incidence of and risk factors for all-cause mortality. Results The annual incidence of major amputation was estimated to be greater in Aboriginal and Torres Strait Islanders than non-Indigenous people (IRR 2.75, 95 % CI 1.92 to 3.84). After adjusting for population growth, the annual incidence of major amputations did not change significantly over time for either groups. Aboriginal and Torres Strait Islander people were at greater risk of all-cause mortality after major amputation compared to non-Indigenous people, although this association was not significant after adjusting for other risk factors (hazard ratio 1.24, 95 % CI 0.82 to 1.90). Conclusions The incidence of major amputation in North Queensland has not reduced over time, indicating the need for better preventative treatments, particularly in Aboriginal and Torres Strait Islander people.

Background and AimThe benefit of controlling cardiovascular risk factors in slowing the progression of small abdominal aortic aneurysm (AAA) is controversial. This study investigated the association of optimal blood pressure control at entry with the growth of small AAA.Methods and ResultsA total of 1,293 patients with initial AAA diameter

Abstract 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.

Abstract 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.

Major adverse cardiovascular events (MACE), including myocardial infarction (MI), stroke and cardiovascular death, cause substantial morbidity and mortality. This review assessed the incidence rate of MACE and the association with modifiable risk factors (diabetes, hypertension) and medication use (aspirin, statins) in patients with unrepaired abdominal aortic aneurysm (AAA). Electronic databases were searched systematically for observational studies reporting the incidence of MI, stroke or cardiovascular death in patients with unrepaired AAAs. The primary outcome was cardiovascular death reported as an incidence rate (events per 100 person-years (PY)). Fourteen studies, including 69,579 participants with a mean follow-up time of 5.4 years, were included. Meta-analysis revealed the overall incidence of cardiovascular death, MI and stroke of 2.31 per 100 PY (95% CI, 1.63–3.26; I2 = 98%), 1.65 per 100 PY (95% CI, 1.01–2.69, I2 = 88%) and 0.89 per 100 PY (95% CI, 0.53–1.48, I2 = 87.0%), respectively. The mean rates of statin and aspirin prescriptions were 58.1% and 53.5%, respectively. In conclusion, there is a substantial incidence of MACE in patients with unrepaired AAA, but the prescription of preventative medication is suboptimal. Greater emphasis should be placed on secondary prevention in this population.

This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect of moxonidine on atherosclerosis was measured by examining aortic arch Sudan IV staining and quantifying the intima-to-media ratio of the left common carotid artery in apolipoprotein E-deficient (ApoE−/−) mice infused with angiotensin II. The levels of circulating lipid hydroperoxides in mouse plasma were measured by ferrous oxidation-xylenol orange assay. Moxonidine administration increased oxidised LDL uptake by VSMCs via activation of α2 adrenoceptors. Moxonidine increased the expression of LDL receptors and the lipid efflux transporter ABCG1. Moxonidine inhibited mRNA expression of inflammatory genes and increased VSMC migration. Moxonidine administration to ApoE−/− mice (18 mg/kg/day) decreased atherosclerosis formation in the aortic arch and left common carotid artery, associated with increased plasma lipid hydroperoxide levels. In conclusion, moxonidine inhibited atherosclerosis in ApoE−/− mice, which was accompanied by an increase in oxidised LDL uptake by VSMCs, VSMC migration, ABCG1 expression in VSMCs and lipid hydroperoxide levels in the plasma.

Abstract This study aimed to investigate the contribution of renal dysfunction to enhanced hyperuricemia prevalence in older people. A cohort of 13,288 Chinese people aged between 40 and 95 years were recruited from January to May 2019. Serum uric acid concentration and estimated glomerular filtration rate [eGFR] were measured. The associations between age or eGFR and serum uric acid or hyperuricemia were analyzed using linear or binary logistic regression adjusting for risk factors. Uric acid concentration and prevalence of hyperuricemia were greater in older participants. Adjustment for reduced renal function (eGFR

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.

Aims: This study aimed to investigate whether both high and low levels of low-density lipoprotein cholesterol (LDL-C), i.e., hypercholesterolemia and hypocholesterolemia, were associated with diabetes in Chinese adults. Methods: This cross-sectional study included 22,557 Chinese adults. The LDL-C reference interval was determined from a healthy sub-cohort. Associations between hypocholesterolemia or hypercholesterolemia with diabetes were analyzed using binary logistic regression. Results: The LDL-C reference interval was 1.48–3.77 mmol/L (57.23–145.78 mg/dL). Therefore, hypocholesterolemia, normocholesterolemia, and hypercholesterolemia were defined as an LDL-C concentration of 3.77 mmol/L, respectively. Prevalence of diabetes was higher in people with hypocholesterolemia or hypercholesterolemia than that in people with normocholesterolemia. Hypocholesterolemia was associated with an increased multivariable-adjusted risk for diabetes diagnosis (odds ratio, 1.57; 95% confidence interval, 1.18–2.08), and so was hypercholesterolemia (odds ratio, 1.29; 95% confidence interval, 1.10–1.51). The results remained significant after exclusion of those who took lipid-lowering drugs from the analysis. Conclusions: This study demonstrated that both low and high levels of LDL-C were associated with a higher risk of diabetes diagnosis. Patients with either high or low LDL-C may need to be closely monitored for the risk of diabetes .

Introduction Several risk factors for adverse events after endovascular aneurysm repair (EVAR) have been described, but there is no consensus on their comparative prognostic significance, use in risk stratification and application in determining postoperative surveillance.Methods and analysis A scoping review of the literature was conducted to identify risk factors for adverse events after EVAR. Main adverse events were considered post-EVAR abdominal aortic aneurysm rupture and reintervention. Risk factors were grouped into four domains: (1) preoperative anatomy, (2) aortic device, (3) procedure performance and (4) postoperative surveillance. The Delphi methodology will be used to steer a group of experts in the field towards consensus organised into three tiers. In tier 1, participants will be asked to independently rate risk factors for adverse events after EVAR. In tier 2, the panel will be asked to independently rate a range of combinations of risk factors across the four domains derived from tier 1. A risk-stratification tool will then be built, which will include algorithms that map responses to signalling questions onto a proposed risk judgement for each domain. Domain-level judgements will in turn provide the basis for an overall risk judgement for the individual patient. In tier 3, risk factor-informed surveillance strategies will be developed. Each tier will typically include three rounds and rating will be conducted using a 4-point Likert scale, with an option for free-text responses.Ethics and dissemination Research Ethics Committee and Health Research Authority approval has been waived, since this is a professional staff study and no duty of care lies with the National Health Service to any of the participants. The results will be presented at regional, national and international meetings and will be submitted for publication in peer-reviewed journals. The risk stratification tool and surveillance algorithms will be made publicly available for clinical use and validation.

BackgroundRemotely delivered interventions may be more efficient in controlling multiple risk factors in people with diabetes.PurposeTo pool evidence from randomized controlled trials testing remote management interventions to simultaneously control blood pressure, blood glucose and lipids.Data SourcesPubMed/Medline, EMBASE, CINAHL and the Cochrane library were systematically searched for randomized controlled trials (RCTs) until 20th June 2021.Study SelectionIncluded RCTs were those that reported participant data on blood pressure, blood glucose, and lipid outcomes in response to a remotely delivered intervention.Data ExtractionThree authors extracted data using a predefined template. Primary outcomes were glycated hemoglobin (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), systolic and diastolic blood pressure (SBP & DBP). Risk of bias was assessed using the Cochrane collaboration RoB-2 tool. Meta-analyses are reported as standardized mean difference (SMD) with 95% confidence intervals (95%CI).Data SynthesisTwenty-seven RCTs reporting on 9100 participants (4581 intervention and 4519 usual care) were included. Components of the remote management interventions tested were identified as patient education, risk factor monitoring, coaching on monitoring, consultations, and pharmacological management. Comparator groups were typically face-to-face usual patient care. Remote management significantly reduced HbA1c (SMD -0.25, 95%CI -0.33 to -0.17, p

Background and Aims. The nacht domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is upregulated in human abdominal aortic aneurysm (AAA), but its pathogenic role is unclear. The aims of this study were firstly to examine whether the inflammasome was upregulated in a mouse model of AAA and secondly to test whether the inflammasome inhibitor colchicine limited AAA growth. Methods. AAA was induced in eight-week-old male C57BL6/J mice with topical application of elastase to the infrarenal aorta and oral 3-aminopropionitrile (E-BAPN). For aim one, inflammasome activation, abdominal aortic diameter, and rupture were compared between mice with AAA and sham controls. For aim two, 3 weeks after AAA induction, mice were randomly allocated to receive colchicine (n=28, 0.2 mg/kg/d) or vehicle control (n=29). The primary outcome was the rate of maximum aortic diameter increase measured by ultrasound over 13 weeks. Results. There was upregulation of NLRP3 markers interleukin- (IL-) 1β (median, IQR; 15.67, 7.11-22.60 pg/mg protein versus 6.87, 4.54-11.60 pg/mg protein, p=.048) and caspase-1 (109, 83-155 relative luminosity units (RLU) versus 45, 38-65 RLU, p

Abstract 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.

Abstract Background There are no current Australian guidelines on the prevention of diabetes‐related foot ulceration (DFU). A national expert panel aimed to systematically identify and adapt suitable international guidelines to the Australian context to create new Australian evidence‐based guidelines on prevention of first‐ever and/or recurrent DFU. These guidelines will include for the first‐time considerations for rural and remote, and Aboriginal and Torres Strait Islander peoples. Methods The National Health and Medical Research Council procedures were followed to adapt suitable international guidelines on DFU prevention to the Australian health context. This included a search of public databases after which the International Working Group on the Diabetic Foot (IWGDF) prevention guideline was deemed the most appropriate for adaptation. The 16 IWGDF prevention recommendations were assessed using the ADAPTE and GRADE systems to decide if they should be adopted, adapted or excluded for the new Australian guideline. The quality of evidence and strength of recommendation ratings were re‐evaluated with reference to the Australian context. This guideline underwent public consultation, further revision, and approval by national peak bodies. Results Of the 16 original IWGDF prevention recommendations, nine were adopted, six were adapted and one was excluded. It is recommended that all people at increased risk of DFU are assessed at intervals corresponding to the IWGDF risk ratings. For those at increased risk, structured education about appropriate foot protection, inspection, footwear, weight‐bearing activities, and foot self‐care is recommended. Prescription of orthotic interventions and/or medical grade footwear, providing integrated foot care, and self‐monitoring of foot skin temperatures (contingent on validated, user‐friendly and affordable systems becoming available in Australia) may also assist in preventing DFU. If the above recommended non‐surgical treatment fails, the use of various surgical interventions for the prevention of DFU can be considered. Conclusions This new Australian evidence‐based guideline on prevention of DFU, endorsed by 10 national peak bodies, provides specific recommendations for relevant health professionals and consumers in the Australian context to prevent DFU. Following these recommendations should achieve better DFU prevention outcomes in Australia.

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.

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.

Background: This study aimed to investigate whether home exercise programs informed by wearable activity monitors improved walking ability of patients with peripheral artery disease (PAD). Methods: A systematic literature search was performed to identify randomised controlled trials (RCT) testing home exercise that were or were not informed by wearable activity monitors. The primary outcome was the change in walking distance measured by a six-minute walking test or treadmill test over the course of the trial. Network meta-analysis (NMA) was performed using the gemtc R statistical package. The risk of bias was assessed using Cochrane tool for assessing risk of bias in RCTs (RoB 2.0). Results: A total of 14 RCTs involving 1544 participants were included. Nine trials used wearable activity monitors to inform the home exercise program tested, while five trials did not use wearable activity monitors to inform the home exercise program tested. Overall quality assessment showed 12 trials to be at low risk of bias and two trials at high risk of bias. Home exercise programs informed by wearable activity monitors significantly improved walking distance compared to non-exercise controls (Mean difference, MD: 32.8 m [95% credible interval, CrI: 6.1, 71.0]) but not compared to home exercise programs not informed by wearable activity monitors (MD: 4.7 m [95% CrI: −38.5, 55.4]). Conclusions: Home exercise informed by wearable activity monitors improve walking ability of patients with PAD. It is, however, unclear if activity monitoring informed exercise programs are more effective than exercise programs not using activity monitors.

Inflammation is strongly implicated in the pathogenesis of abdominal aortic aneurysms (AAA). This review examined the potential role of biologic disease-modifying anti-rheumatic drugs (bDMARDs) as repurposed drugs for treating AAA. Published evidence from clinical and preclinical studies was examined. Findings from animal models suggested that a deficiency or inhibition of tumour necrosis factor-α (TNF-α) (standard mean difference (SMD): −8.37, 95% confidence interval (CI): −9.92, −6.82), interleukin (IL)-6 (SMD: −1.44, 95% CI: −2.85, −0.04) and IL-17 (SMD: −3.36, 95% CI: −4.21, −2.50) led to a significantly smaller AAA diameter compared to controls. Human AAA tissue samples had significantly increased TNF-α (SMD: 1.68, 95% CI: 0.87, 2.49), IL-1β (SMD: 1.93, 95% CI: 1.08, 2.79), IL-6 (SMD: 2.56, 95% CI: 1.79, 3.33) and IL-17 (SMD: 6.28, 95% CI: 3.57, 8.99) levels compared to non-AAA controls. In human serum, TNF-α (SMD: 1.11, 95% CI: 0.25, 1.97) and IL-6 (SMD: 1.42, 95% CI: 0.91, 1.92) levels were significantly elevated compared to non-AAA controls. These findings implicate TNF-α, IL-17 and IL-6 in AAA pathogenesis. Randomised controlled trials testing the value of bDMARDs in limiting AAA growth may be warranted.

Background: Most abdominal aortic aneurysms (AAA) have large volumes of intraluminal thrombus which has been implicated in promoting the risk of major adverse events. The aim of this study was to examine the association of therapeutic anticoagulation with AAA-related events and major adverse cardiovascular events (MACE) in patients with an unrepaired AAA. Methods: Patients with an asymptomatic unrepaired AAA were recruited from four sites in Australia. The primary outcome was the combined incidence of AAA repair or AAA rupture-related mortality (AAA-related events). The main secondary outcome was MACE (the combined incidence of myocardial infarction, stroke, or cardiovascular death). The associations of anticoagulation with these outcomes were assessed using Cox proportional hazard analyses (reporting hazard ratio, HR, and 95% confidence intervals, CI) to adjust for other risk factors. Results: A total of 1161 patients were followed for a mean (standard deviation) of 4.9 (4.0) years. Of them, 536 (46.2%) patients had a least one AAA-related event and 319 (27.5%) at least one MACE. In the sample, 98 (8.4%) patients were receiving long-term therapeutic anticoagulation using warfarin (84), apixaban (7), rivaroxaban (6), or dabigatran (1). Prescription of an anticoagulant was associated with a reduced risk of an AAA-related event (adjusted HR 0.61; 95% CI 0.42, 0.90, p = 0.013), but not MACE (HR 1.16; 95% CI 0.78, 1.72, p = 0.476). Conclusions: These findings suggest that AAA-related events but not MACE may be reduced in patients prescribed an anticoagulant medication. Due to the inherent biases of observational studies, a randomized controlled trial is needed to assess whether anticoagulation reduces the risk of AAA-related events.

Background No network meta‐analysis has considered the relative efficacy of cilostazol, home exercise therapy, supervised exercise therapy (SET), endovascular revascularization (ER), and ER plus SET (ER+SET) in improving maximum walking distance (MWD) over short‐ (

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.

Background/Aim: Natural outdoor environments may mitigate harmful environmental factors associated with city living. We studied the longitudinal relationship between natural (‘green and blue’) outdoor environments and mortality in a cohort of older men residing in Perth, Western Australia. Methods: We studied a cohort of 9218 men aged 65 years and older from the Health In Men Study. Participants were recruited in 1996–99 and followed until 2014, during which 5889 deaths were observed. Time-varying residential surrounding greenness based on the Normalized Difference Vegetation Index, and the number and size of parks, natural space and waterbodies were defined to characterize the natural outdoor environment. All-cause non-accidental and cause-specific mortality was ascertained with the Western Australian Data Linkage System. The association of the natural outdoor environment with mortality was examined using Cox regression analysis. Results: After adjusting for age, men living in the highest quartile of cumulative average surrounding greenness had a 9% lower rate of all-cause non-accidental mortality (95% confidence interval [CI] 0.84, 0.98; p = .013) compared with those in the lowest quartile. This association was no longer present after adjustment for other risk factors, especially level of education. Living within 500 m of one (vs. no) natural space was associated with decreased mortality risk (adjusted hazard ratio 0.93; 95% CI 0.86, 1.00; p = .046), but no association with mortality was found for two or more natural spaces compared to none and for parks. Associations between waterbodies and mortality were inconsistent, showing non-linear beneficial and harmful associations. Conclusions: In this longitudinal study of older men residing in Perth, we observed evidence suggestive of an association between access to natural spaces and decreased mortality. Associations between surrounding greenness and mortality seemed to be confounded by level of education, and associations with waterbodies were complex and need to be studied further.

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.

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.

Background Abdominal 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 E2 in human AAA explants. Methods and Results Neutralization 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 E2 and 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 E2 and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils. Conclusions These findings suggest that kallikrein‐1 neutralization could be a treatment target for AAA.

Abstract Impairments in skeletal muscle microvascular function are frequently reported in patients with various cardiometabolic conditions for which older age is a risk factor. Whether aging per se predisposes the skeletal muscle to microvascular dysfunction is unclear. We used contrast‐enhanced ultrasound (CEU) to compare skeletal muscle microvascular perfusion responses to cuff occlusion and leg exercise between healthy young (n = 12, 26 ± 3 years) and older (n = 12, 68 ± 7 years) adults. Test–retest reliability of CEU perfusion parameters was also assessed. Microvascular perfusion (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after: (a) 5‐min of thigh‐cuff occlusion, and (b) 5‐min of submaximal intermittent isometric plantar‐flexion exercise (400 N) using CEU. Whole‐leg blood flow was measured using strain‐gauge plethysmography. Repeated measures were obtained with a 15‐min interval, and averaged responses were used for comparisons between age groups. There were no differences in post‐occlusion whole‐leg blood flow and muscle microvascular perfusion between young and older participants (p > .05). Similarly, total whole‐leg blood flow during exercise and post‐exercise peak muscle microvascular perfusion did not differ between groups (p > .05). The overall level of agreement between the test–retest measures of calf muscle perfusion was excellent for measurements taken at rest (intraclass correlation coefficient [ICC] 0.85), and in response to cuff occlusion (ICC 0.89) and exercise (ICC 0.95). Our findings suggest that healthy aging does not affect muscle perfusion responses to cuff‐occlusion and submaximal leg exercise. CEU muscle perfusion parameters measured in response to these provocation tests are highly reproducible in both young and older adults.

Mouse models are frequently used to study diabetes-associated ulcers, however, whether these models accurately simulate impaired wound healing has not been thoroughly investigated. This systematic review aimed to determine whether wound healing is impaired in mouse models of diabetes and assess the quality of the past research. A systematic literature search was performed of publicly available databases to identify original articles examining wound healing in mouse models of diabetes. A meta-analysis was performed to examine the effect of diabetes on wound healing rate using random effect models. A meta-regression was performed to examine the effect of diabetes duration on wound healing impairment. The quality of the included studies was also assessed using two newly developed tools. 77 studies using eight different models of diabetes within 678 non-diabetic and 720 diabetic mice were included. Meta-analysis showed that wound healing was impaired in all eight models. Meta-regression suggested that longer duration of diabetes prior to wound induction was correlated with greater degree of wound healing impairment. Pairwise comparisons suggested that non-obese diabetic mice exhibited more severe wound healing impairment compared with db/db mice, streptozotocin-induced diabetic mice or high-fat fed mice at an intermediate stage of wound healing (p

Introduction Hyperbaric oxygen therapy (HBOT) has been suggested to improve healing of lower limb ulcers, though the quality of available evidence is weak to moderate. This study assessed the opinions and use of HBOT by specialists treating lower limb ulcers.Research design and methods Accredited vascular surgeons and podiatrists in Australia and New Zealand were sent an online survey via their professional organizations. The survey asked about their use and opinions of HBOT in treating lower limb ischemic, neuropathic and venous ulcers. Data were summarized with descriptive statistics. Non-parametric tests were used to compare survey results obtained from vascular surgeons and podiatrists.Results 61 vascular surgeons and 40 podiatrists completed the survey. Thirty-seven specialists used HBOT for treating lower limb ulcers, with the remainder indicating they did not feel there was a role for HBOT (n=25) or did not have access to HBOT (n=39). Less than 8% of specialists indicated that HBOT frequently or always had a role in treating ischemic, neuropathic or venous ulcers. Compared with podiatrists, vascular surgeons were significantly less likely to indicate HBOT had a treatment role for any ulcer type (p

The aims of this systematic review were to assess the clinical relevance and quality of previously published animal models of ischemic ulceration and examine the available evidence for interventions improving ulcer healing in these models. Publicly available databases were searched for original studies investigating the effect of limb ischemia on wound healing in animal models. The quality of studies was assessed using two tools based on the Animal research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the clinical relevance of the models. A total of 640 wounds (ischemic=314; non-ischemic=326) were assessed in 252 animals (92 mice, 140 rats, 20 rabbits) from 7 studies. Meta-analyses showed that wound healing was consistently delayed by ischemia at all time-points examined (day-7 standard median difference (SMD) 5.36, 95% CI 3.67 to 7.05; day-14 SMD 4.50, 95% CI 2.90 to 6.10 and day-21 SMD 2.53, 95% CI 1.25 to 3.80). No significant difference in wound healing was observed between 32 diabetic and 32 non-diabetic animals with ischemic wounds. Many studies lacked methods to reduce bias, such as outcome assessors blinded to group allocation and sample size calculations and clinically relevant model characteristics, such as use of older animals and a peripheral location of the wound. Five different interventions were reported to improve wound healing in these models. The impaired wound healing associated with limb ischemia can be modeled in a variety of different animals. Improvements in study design could increase clinical relevance, reduce bias and aid the discovery of translatable therapies.

Background The aim of this study was to assess the relationship between serum lipoprotein (a) (Lp[a]) concentration and the requirement for peripheral artery disease (PAD) operations or incidence of major adverse cardiovascular events. Methods and Results A total of 1472 people with PAD presenting with intermittent claudication (n=355), abdominal aortic aneurysm (n=989) or critical limb ischemia (n=128) were prospectively recruited from 4 outpatient clinics in Australia. Lp(a) was measured in serum samples collected at recruitment using an immunoassay. Participants were followed for a median (interquartile range) of 2.4 (0.1–6.1) years to record requirement for any PAD operation, defined to include any open or endovascular PAD intervention (lower limb peripheral revascularization, abdominal aortic aneurysm repair, other aneurysm repair, or carotid artery revascularization). Myocardial infarctions, strokes, and deaths were also recorded. The association of Lp(a) with events was assessed using Cox proportional hazard analysis adjusting for traditional risk factors. Participants with Lp(a) ≥30 mg/dL had a greater requirement for any PAD operation (hazard ratio, 1.20, 95% CI, 1.02–1.41) and lower limb peripheral revascularization alone (hazard ratio 1.33, 95% CI, 1.06–1.66) but no increased risk of major adverse cardiovascular events or all‐cause mortality. Lp(a) ≥50 mg/dL and a 40 mg/dL increase in Lp(a) were also associated with an increased risk of lower limb peripheral revascularization alone but not with other outcomes. Conclusions In participants with PAD referred for hospital management those with high Lp(a) had greater requirement for lower limb peripheral revascularization but Lp(a) was not consistently associated with other clinical events.

Ankle-brachial pressure index (ABPI) is commonly measured in people referred to vascular specialists. This study aimed to assess the association of high ABPI (≥ 1.4) with cardiovascular events in people with peripheral artery disease (PAD). 1533 participants with PAD diagnosed by a vascular specialist were prospectively recruited from four out-patient clinics in Australia. ABPI was measured at recruitment and the occurrence of myocardial infarction (MI), stroke or cardiovascular death (major cardiovascular events; MACE) and any amputation were recorded over a median (inter-quartile range) follow-up of 3.3 (1.0-7.1) years. The association of high, compared to normal, low (0.5-0.9) or very low (

ObjectiveTo assess whether survival and clinical events following elective abdominal aortic aneurysm (AAA) repair were associated with remoteness of residence in North Queensland, Australia.MethodsThis retrospective cohort study included participants undergoing elective AAA repair between February 2002 and April 2020 at two hospitals in Townsville, North Queensland, Australia. Outcomes were all-cause survival and AAA-related events, defined as requirement for repeat AAA repair or AAA-related mortality. Remoteness of participant's place of residence was assessed by the Modified Monash Model classifications and estimated distance from the participants' home to the tertiary vascular centre. Cox proportional hazard analysis examined the association of remoteness with outcome.ResultsThe study included 526 participants undergoing elective repair by open (n = 204) or endovascular (n = 322) surgery. Fifty-four (10.2%) participants had a place of residence at a remote or very remote location. Participants' were followed for a median of 5.2 (inter-quartile range 2.5-8.3) years, during which time there were 252 (47.9%) deaths. Survival was not associated with either measure of remoteness. Fifty (9.5%) participants had at least one AAA-related event, including 30 (5.7%) that underwent at least one repeat AAA surgery and 23 (4.4%) that had AAA-related mortality. AAA-related events were more common in participants resident in the most remote areas (adjusted hazard ratio 2.83, 95% confidence intervals 1.40, 5.70) but not associated with distance from the participants' residence to the tertiary vascular centre.ConclusionsThe current study found that participants living in more remote locations were more likely to have AAA-related events but had no increased mortality following AAA surgery. The findings emphasize the need for careful follow-up after AAA surgery. Further studies are needed to examine the generalisability of the findings.