Small AAAs: Recommendations for Rodent Model Research for the Identification of Novel Therapeutics.

CLINICAL PROBLEM: Most abdominal aortic aneurysms (AAAs) are small with low rupture risk (<1%/y) when diagnosed but slowly expand to ≥55 mm and undergo surgical repair. Patients and clinicians require medications to limit AAA growth and rupture, but drugs effective in animal models have not translated to patients. RECOMMENDATIONS FOR INCREASING TRANSLATION FROM MOUSE MODELS: Use models that simulate human AAA tissue pathology, growth patterns, and rupture; focus on the clinically relevant outcomes of growth and rupture; design studies with the rigor required of human clinical trials; monitor AAA growth using reproducible ultrasound; and perform studies in both males and females. SUMMARY OF STRENGTHS AND WEAKNESSES OF MOUSE MODELS: The aortic adventitial elastase oral ß-aminopropionitrile model has many strengths including simulating human AAA pathology and modeling prolonged aneurysm growth. The Ang II (angiotensin II) model performed less well as it better simulates acute aortic syndrome than AAA. The elastase plus TGFß (transforming growth factor-ß) blocking antibody model displays a high rupture rate, making prolonged monitoring of AAA growth not feasible. The elastase perfusion and calcium chloride models both display limited AAA growth.

Assessment of Subclinical Atherosclerosis in Asymptomatic People In Vivo: Measurements Suitable for Biomarker and Mendelian Randomization Studies.

BACKGROUND: One strategy to reduce the burden of cardiovascular disease is the early detection and treatment of atherosclerosis. This has led to significant interest in studies of subclinical atherosclerosis, using different phenotypes, not all of which are accurate reflections of the presence of asymptomatic atherosclerotic plaques. The aim of part 2 of this series is to provide a review of the existing literature on purported measures of subclinical disease and recommendations concerning which tests may be appropriate in the prevention of incident cardiovascular disease. METHODS: We conducted a critical review of measurements used to infer the presence of subclinical atherosclerosis in the major conduit arteries and focused on the predictive value of these tests for future cardiovascular events, independent of conventional cardiovascular risk factors, in asymptomatic people. The emphasis was on studies with >10 000 person-years of follow-up, with meta-analysis of results reporting adjusted hazard ratios (HRs) with 95% CIs. The arterial territories were limited to carotid, coronary, aorta, and lower limb arteries. RESULTS: In the carotid arteries, the presence of plaque (8 studies) was independently associated with future stroke (pooled HR, 1.89 [1.04-3.44]) and cardiac events (7 studies), with a pooled HR, 1.77 (1.19-2.62). Increased coronary artery calcium (5 studies) was associated with the risk of coronary heart disease events, pooled HR, 1.54 (1.07-2.07) and increasing severity of calcification (by Agaston score) was associated with escalation of risk (13 studies). An ankle/brachial index (ABI) of <0.9, the pooled HR for cardiovascular death from 7 studies was 2.01 (1.43-2.81). There were insufficient studies of either, thoracic or aortic calcium, aortic diameter, or femoral plaque to synthesize the data based on consistent reporting of these measures. CONCLUSIONS: The presence of carotid plaque, coronary artery calcium, or abnormal ankle pressures seems to be a valid indicator of the presence of subclinical atherosclerosis and may be considered for use in biomarker, Mendelian randomization and similar studies.

Changes in thyroid function and evolution of subclinical thyroid disease in older men.

OBJECTIVE: Prevalence of subclinical thyroid disease increases with age, but optimal detection and surveillance strategies remain unclear particularly for older men. We aimed to assess thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations and their longitudinal changes, to determine the prevalence and incidence of subclinical thyroid dysfunction in older men. DESIGN, PARTICIPANTS AND MEASUREMENTS: Longitudinal study of 994 community-dwelling men aged ≥70 years without known or current thyroid disease, with TSH and FT4 concentrations assessed at baseline and follow-up (after 8.7 ± 0.9 years). Factors associated with incident subclinical thyroid dysfunction were examined by logistic regression and receiver operating characteristic analyses. RESULTS: At baseline, 85 men (8.6%) had subclinical hypothyroidism and 10 (1.0%) subclinical hyperthyroidism. Among 899 men euthyroid at baseline (mean age 75.0 ± 3.0 years), 713 (79.3%) remained euthyroid, 180 (20.0%) developed subclinical/overt hypothyroidism, and 6 (0.7%) subclinical/overt hyperthyroidism. Change in TSH correlated with baseline TSH (r = .16, p < .05). Change in FT4 correlated inversely with baseline FT4 (r = -0.35, p < .05). Only higher age and baseline TSH predicted progression from euthyroid to subclinical/overt hypothyroidism (fully-adjusted odds ratio [OR] per year=1.09, 95% confidence interval [CI] = 1.02-1.17, p = .006; per 2.7-fold increase in TSH OR = 65.4, CI = 31.9-134, p < .001). Baseline TSH concentration ≥2.34 mIU/L had 76% sensitivity and 77% specificity for predicting development of subclinical/overt hypothyroidism. CONCLUSIONS: In older men TSH concentration increased over time, while FT4 concentration showed little change. Subclinical or overt hypothyroidism evolved in one fifth of initially euthyroid men, age and higher baseline TSH predicted this outcome. Increased surveillance for thyroid dysfunction may be justified in older men, especially those with high-normal TSH.

Effectiveness of educational interventions for diabetes-related foot disease: A systematic review and meta-analysis.

This systematic review and meta-analysis pooled evidence from randomised controlled trials (RCTs) on the effectiveness of educational programs for people with or at risk of diabetes-related foot disease (DFD). A systematic search identified RCTs evaluating the effectiveness of educational programs in preventing or managing DFD. The primary outcome was risk of developing a foot ulcer. Secondary outcomes included any amputation, mortality, changes in cardiovascular risk factors, foot-care knowledge and self-care behaviours. Meta-analyses were performed using random effects models. Risk of bias was assessed using Cochrane's ROB-2 tool. Education programs were tested in 29 RCTs (n = 3891) and reduced risk of a foot ulcer by approximately half although the upper 95% confidence interval (CI) reached 1.00 (odds ratio [OR], OR 0.54; 95% CI 0.29, 1.00, I2  = 65%). Education programs reduced risk of any amputation (OR 0.34; 95% CI 0.13, 0.88, I2  = 38%) and HbA1c levels (standardized mean difference -0.73; 95% CI -1.26, -0.20, I2  = 93%) without affecting all-cause mortality (OR 1.09; 95% CI 0.57, 2.07, I2  = 0%). Education programs mostly significantly improved DFD knowledge (13 of 16 trials) and self-care behaviour scores (19 of 20 trials). Only one trial was deemed at low risk of bias. Previously tested education programs have mostly effectively improved participants' knowledge and self-care behaviours and reduced risk of foot ulceration and amputation. Larger high quality trials with longer follow-up are needed.

Recent developments in targets for ischemic foot disease.

Diabetes is a key risk factor for ischaemic foot disease, which causes pain, tissue loss, hospital admission, and major amputation. Currently, treatment focuses on revascularisation, but many patients are unsuitable for surgery and revascularisation is frequently unsuccessful. The authors describe recent research in animal models and clinical trials investigating novel medical targets for ischaemia, including theories about impaired wound healing, animal models for limb ischaemia and recent randomised controlled trials testing novel medical therapies. Novel targets identified in animal models included stimulating mobilisation of CD34+ progenitor cells through upregulating oncostatin M or microRNA-181, downregulating tumour necrosis factor superfamily member 14, or activating the Wingless pathway. Within the ischaemic limb vasculature, upregulation of apolipoprotein L domain containing 1, microRNA-130b or long noncoding RNA that enhances endothelial nitric oxide synthase expression promoted limb blood supply recovery, angiogenesis, and arteriogenesis. Similarly, administration of soluble guanylate cyclase stimulators riociguat or praliciguat or 3-ketoacyl-CoA thiolase inhibitor trimetazidine promoted blood flow recovery. Translating pre-clinical findings to patients has been challenging, mainly due to limitations in clinically translatable animal models of human disease. Promising results have been reported for administering plasmids encoding hepatocyte growth factor or intra-arterial injection of bone marrow derived cells in small clinical trials. It remains to be seen whether these high resource therapies can be developed to be widely applicable. In conclusion, an ever-expanding list of potential targets for medical revascularisation is being identified. It is hoped that through ongoing research and further larger clinical trials, these will translate into new broadly applicable therapies to improve outcomes.

A case-control comparison of acute-phase peripheral blood gene expression in participants diagnosed with minor ischaemic stroke or stroke mimics.

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.

Systematic Review Examining the Association Between Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Prescription and Abdominal Aortic Aneurysm Growth and Events.

OBJECTIVE: Whether angiotensin II blockade is an effective medical treatment for abdominal aortic aneurysms (AAAs) has not been established. This systematic review and meta-analysis aimed to determine the association between angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) prescription and AAA growth and events. DATA SOURCES: MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library databases were searched from their inception to 4 January 2024, with no language restrictions. REVIEW METHODS: The five databases were searched for randomised controlled trials (RCTs) and observational studies reporting the association between ACEi or ARB prescription and AAA growth, repair, or rupture. The primary outcome was AAA growth, with secondary outcomes of AAA rupture, AAA repair, and AAA related events (rupture and repair combined). Risk of bias was assessed using the Risk of Bias 2 tool for RCTs and with a modified Newcastle-Ottawa scale for observational studies. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Random effects models were used for meta-analyses. RESULTS: Eleven studies (two RCTs, eight observational studies, and one meta-analysis of individual patient data from seven populations) involving 58 022 patients were included. ACEi prescription was not associated with a statistically significant reduction in AAA growth (standard mean difference 0.01 mm/year, 95% confidence interval [CI] -0.26 - 0.28; p = .93; I2 = 98%) or AAA repair (odds ratio [OR] 0.73, 95% CI 0.50 - 1.09; p = .65; I2 = 61%), but was associated with a statistically significantly lower risk of AAA rupture (OR 0.87, 95% CI 0.81 - 0.93; p < .001; I2 = 26%) and AAA related events (OR 0.82, 95% CI 0.72 - 0.95; p = .006; I2 = 80%). ARB prescription was not associated with significantly reduced AAA growth or a lower risk of AAA related events. The two RCTs had a low risk of bias, with one observational study having low, seven moderate, and one high risk of bias. All of the findings had a very low certainty of evidence based on the GRADE analysis. CONCLUSION: There was no association between ACEi or ARB prescription and AAA growth, but ACEi prescription was associated with a reduced risk of AAA rupture and AAA related events with very low certainty of evidence.

Network Meta-analysis of Randomised Controlled Trials Comparing the Outcomes of Different Endovascular Revascularisation Treatments for Infra-inguinal Peripheral Arterial Disease Causing Chronic Limb Threatening Ischaemia.

OBJECTIVE: The aim of this study was to compare the efficacy of different endovascular revascularisation procedures for treating chronic limb threatening ischaemia (CLTI) using network meta-analysis (NMA). DATA SOURCES: The databases PubMed and Cochrane Central Register for Controlled Trials were searched on 14 March 2023. REVIEW METHODS: A NMA of randomised controlled trials (RCTs) reporting the efficacy of different endovascular revascularisation techniques for treating CLTI was performed according to PRISMA guidelines. The primary and secondary outcomes were major amputation and death, respectively. Random effects models were developed and the results were presented using surface under the cumulative ranking curve plots and forest plots. A p value of ≤ .050 was considered statistically significant. The Cochrane collaborative tool was used to assess risk of bias. RESULTS: A total of 2 655 participants of whom 94.8% had CLTI were included. Eleven trials compared plain balloon angioplasty (PBA) vs. drug coated balloon (DCB) angioplasty (n = 1 771), five trials compared bare metal stent (BMS) vs. drug coated stent (DCS) (n = 466), three trials compared atherectomy vs. DCB (n = 194), two trials compared PBA vs. BMS (n = 70), one trial compared PBA vs. atherectomy (n = 50), and one trial compared BMS vs. DCB (n = 104). None of the revascularisation strategies significantly reduced the risk of major amputation or death compared with PBA. Using the network estimates, GRADE certainty of evidence for improvement in major amputation outcomes for DCB was moderate, for atherectomy and BMS was low, and for DCS was very low compared with PBA. Risk of bias was low in 16 trials, of some concerns in six trials, and high in one trial, respectively. CONCLUSION: There is no current evidence from RCTs to reliably conclude that BMS, DCB, DCS, or atherectomy are superior to PBA in preventing major amputation and death in patients with CLTI. Larger comparative RCTs are needed to identify the best endovascular revascularisation strategy.

Editor's Choice -- European Society for Vascular Surgery (ESVS) 2024 Clinical Practice Guidelines on the Management of Abdominal Aorto-Iliac Artery Aneurysms.

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

Pathogenesis and management of abdominal aortic aneurysm.

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

Global trends in the incidence of hospital admissions for diabetes-related foot disease and amputations: a review of national rates in the 21st century.

AIMS/HYPOTHESIS: Diabetic foot disease (DFD) is a leading cause of hospital admissions and amputations. Global trends in diabetes-related amputations have been previously reviewed, but trends in hospital admissions for multiple other DFD conditions have not. This review analysed the published incidence of hospital admissions for DFD conditions (ulceration, infection, peripheral artery disease [PAD], neuropathy) and diabetes-related amputations (minor and major) in nationally representative populations. METHODS: PubMed and Embase were searched for peer-reviewed publications between 1 January 2001 and 5 May 2022 using the terms 'diabetes', 'DFD', 'amputation', 'incidence' and 'nation'. Search results were screened and publications reporting the incidence of hospital admissions for a DFD condition or a diabetes-related amputation among a population representative of a country were included. Key data were extracted from included publications and initial rates, end rates and relative trends over time summarised using medians (ranges). RESULTS: Of 2527 publications identified, 71 met the eligibility criteria, reporting admission rates for 27 countries (93% high-income countries). Of the included publications, 14 reported on DFD and 66 reported on amputation (nine reported both). The median (range) incidence of admissions per 1000 person-years with diabetes was 16.3 (8.4-36.6) for DFD conditions (5.1 [1.3-7.6] for ulceration; 5.6 [3.8-9.0] for infection; 2.5 [0.9-3.1] for PAD) and 3.1 (1.4-10.3) for amputations (1.2 [0.2-4.2] for major; 1.6 [0.3-4.3] for minor). The proportions of the reported populations with decreasing, stable and increasing admission trends were 80%, 20% and 0% for DFD conditions (50%, 0% and 50% for ulceration; 50%, 17% and 33% for infection; 67%, 0% and 33% for PAD) and 80%, 7% and 13% for amputations (80%, 17% and 3% for major; 52%, 15% and 33% for minor), respectively. CONCLUSIONS/INTERPRETATION: These findings suggest that hospital admission rates for all DFD conditions are considerably higher than those for amputations alone and, thus, the more common practice of reporting admission rates only for amputations may substantially underestimate the burden of DFD. While major amputation rates appear to be largely decreasing, this is not the case for hospital admissions for DFD conditions or minor amputation in many populations. However, true global conclusions are limited because of a lack of consistent definitions used to identify admission rates for DFD conditions and amputations, alongside a lack of data from low- and middle-income countries. We recommend that these areas are addressed in future studies. REGISTRATION: This review was registered in the Open Science Framework database ( https://doi.org/10.17605/OSF.IO/4TZFJ ).

Exposure to low-level ambient air pollution and the relationship with lung and bladder cancer in older men, in Perth, Western Australia.

BACKGROUND: Air pollution is a cause of lung cancer and is associated with bladder cancer. However, the relationship between air pollution and these cancers in regions of low pollution is unclear. We investigated associations between fine particulate matter (PM2.5), nitrogen dioxide, and black carbon (BC), and both these cancers in a low-pollution city. METHODS: A cohort of 11,679 men ≥65 years old in Perth (Western Australia) were followed from 1996-1999 until 2018. Pollutant concentrations, as a time-varying variable, were estimated at participants' residential addresses using land use regression models. Incident lung and bladder cancer were identified through the Western Australian Cancer Registry. Risks were estimated using Cox proportional-hazard models (age as the timescale), adjusting for smoking, socioeconomic status, and co-pollutants. RESULTS: Lung cancer was associated with PM2.5 and BC in the adjusted single-pollutant models. A weak positive association was observed between ambient air pollution and squamous cell lung carcinoma but not lung adenocarcinoma. Positive associations were observed with bladder cancer, although these were not statistically significant. Associations were attenuated in two-pollutant models. CONCLUSION: Low-level ambient air pollution is associated with lung, and possibly bladder, cancer among older men, suggesting there is no known safe level for air pollution as a carcinogen.

Healthy lifestyles are associated with better vitamin D status in community-dwelling older men: The Health In Men Study (HIMS).

OBJECTIVE: Older people are more prone to vitamin D deficiency than younger populations. Individual lifestyle factors have been associated with vitamin D status. We examined the influence of a combination of lifestyle factors on vitamin D status in older men. PARTICIPANTS AND MEASUREMENTS: In a population-based cohort study of older men (age ≥65 years), a lifestyle score was calculated from eight prudent health-related behaviours (smoking, exercise, alcohol, fish and meat consumption, adding salt, milk choices and obesity) collected via questionnaire at baseline. Blood samples were collected 5 years afterwards to measure plasma 25-hydroxyvitamin D (25OHD) levels. Associations between lifestyles and the likelihood of having plasma 25OHD levels of ≥75 versus <75 nmol/L and ≥50 versus <50 nmol/L were tested using logistic regression models. RESULTS: Of the 2717 men analysed, mean plasma 25OHD was 69.0 ± 23.5 nmol/L, with 20.7% having plasma 25OHD <50 nmol/L. Men engaging in ≥4 healthy lifestyle behaviours had 20% higher odds of plasma 25OHD ≥75 nmol/L (adjusted OR = 1.20, 95% CI: 1.01-1.45) compared to those with <4 healthy behaviours. No association was found for 25OHD ≥50 nmol/L. Higher physical activity was the only individual component significantly associated with vitamin D sufficiency (highest vs. lowest quintiles of physical activity, adjusted OR = 2.01, 95% CI: 1.47-2.74 for 25OHD ≥50 nmol/L, adjusted OR = 2.35, 95% CI: 1.81-3.06 for 25OHD ≥75 nmol/L). CONCLUSION: Multiple healthy lifestyle behaviours are associated with better vitamin D status in older men. Further work is needed to determine the effects of promoting healthy lifestyle behaviours, including physical activity, on vitamin D sufficiency.

The predictive value of four serum biomarkers for major adverse events in patients with small abdominal aortic aneurysm.

BACKGROUND: The primary aim of this study was to test which of a group of four inflammation and thrombosis biomarkers were independently predictive of major adverse cardiovascular events (MACE) in patients with small abdominal aortic aneurysm (AAA). METHODS: A total of 471 participants with a 30- to 54-mm AAA had serum C-reactive protein (CRP), fibrinogen, neutrophil-lymphocyte ratio (NLR), and homocysteine measured. The primary outcome was MACE, which was defined as the first occurrence of myocardial infarction, stroke, or cardiovascular death. The association of biomarkers with events was assessed using Kaplan-Meier and Cox proportional hazard analyses. The net improvement in risk of event categorization with addition of a biomarker to clinical risk factors alone was assessed using net reclassification index. RESULTS: Participants were followed for a median of 2.4 years (interquartile range, 0.8-5.4 years), and 102 (21.7%) had a MACE. The incidence of MACE was 13.2% in participants with CRP >3.0 mg/L, compared with 10.1% in those with CRP ≤3.0 mg/L at 2.5 years (P = .047). After adjusting for other risk factors, higher CRP was associated with a significantly higher risk of MACE (hazard ratio, 1.19; 95% confidence interval, 1.05-1.35). None of the other biomarkers were associated with the risk of MACE. According to the net reclassification index, CRP significantly improved the risk classification of MACE compared with clinical risk factors alone. CONCLUSIONS: CRP can assist in classification of risk of MACE for patients with small AAA.

Comparative efficacy of growth factor therapy in healing diabetes-related foot ulcers: A network meta-analysis of randomized controlled trials.

INTRODUCTION: This study examined the relative efficacy of growth factor therapies in healing diabetes-related foot ulcers (DFU). METHODS: PubMed and Cochrane databases were searched for randomized controlled trials testing growth factor therapies for treating DFU. The primary outcome was complete wound closure. Results were reported as relative risk (RR) ± 95% credible intervals (CrI). The risk of bias was assessed using Cochrane's RoB-2 tool. RESULTS: A total of 31 RCTs involving 2174 participants were included. Only 13 of the trials (n = 924) reported on the aetiology of the ulcers (85.4% neuropathic and 14.6% ischaemic). Epidermal growth factor (RR 3.83; 95% CrI 1.81, 9.10), plasma-rich protein (PRP) (RR 3.36; 95% CrI 1.66, 8.03) and platelet-derived growth factor (PDGF) (RR 2.47; 95% CrI 1.23, 5.17) significantly improved the likelihood of complete ulcer healing compared to control. Sub-analyses suggested that PRP (3 trials - RR 9.69; 95% CrI 1.37, 103.37) and PDGF (6 trials - RR 2.22; 95% CrI 1.12, 5.19) significantly improved the likelihood of wound closure amongst trial mainly recruiting participants with neuropathic ulcers. Eleven trials had a low risk of bias, 9 had some concerns and 11 had a high risk of bias. Sub-analysis of trials with a low risk of bias suggested that none of the growth factors significantly improved ulcer healing compared with control. DISCUSSION: This network meta-analysis found low-quality evidence that Epidermal growth factor, PRP and PDGF therapy improved DFU healing likelihood compared with control. Larger well-designed trials are needed.

Association between aortic peak wall stress and rupture index with abdominal aortic aneurysm-related events.

OBJECTIVE: The aim of this study was to assess whether aortic peak wall stress (PWS) and peak wall rupture index (PWRI) were associated with the risk of abdominal aortic aneurysm (AAA) rupture or repair (defined as AAA events) among participants with small AAAs. METHODS: PWS and PWRI were estimated from computed tomography angiography (CTA) scans of 210 participants with small AAAs (≥ 30 and ≤ 50 mm) prospectively recruited between 2002 and 2016 from two existing databases. Participants were followed for a median of 2.0 (inter-quartile range 1.9, 2.8) years to record the incidence of AAA events. The associations between PWS and PWRI with AAA events were assessed using Cox proportional hazard analyses. The ability of PWS and PWRI to reclassify the risk of AAA events compared to the initial AAA diameter was examined using net reclassification index (NRI) and classification and regression tree (CART) analysis. RESULTS: After adjusting for other risk factors, one standard deviation increase in PWS (hazard ratio, HR, 1.56, 95% confidence intervals, CI 1.19, 2.06; p = 0.001) and PWRI (HR 1.74, 95% CI 1.29, 2.34; p < 0.001) were associated with significantly higher risks of AAA events. In the CART analysis, PWRI was identified as the best single predictor of AAA events at a cut-off value of > 0.562. PWRI, but not PWS, significantly improved the classification of risk of AAA events compared to the initial AAA diameter alone. CONCLUSION: PWS and PWRI predicted the risk of AAA events but only PWRI significantly improved the risk stratification compared to aortic diameter alone. KEY POINTS: • Aortic diameter is an imperfect measure of abdominal aortic aneurysm (AAA) rupture risk. • This observational study of 210 participants found that peak wall stress (PWS) and peak wall rupture index (PWRI) predicted the risk of aortic rupture or AAA repair. • PWRI, but not PWS, significantly improved the risk stratification for AAA events compared to aortic diameter alone.

Role of Sclerostin in Cardiovascular Disease.

Sclerostin is most recognized for its role in controlling bone formation but is also expressed in the heart, aorta, coronary, and peripheral arteries. This review summarizes research on sclerostin's role in cardiovascular disease. Rodent studies have found sclerostin to be expressed at sites of arterial calcification. In contrast, aortic sclerostin was reported to be downregulated in a mouse model of abdominal aortic aneurysm, and transgenic upregulation or administration of sclerostin was found to prevent abdominal aortic aneurysm and atherosclerosis formation. Sclerostin deficiency was reported to stimulate cardiac rupture in one rodent model. In humans, 7 of 11 studies reported a significant association between high serum sclerostin and high carotid intima media thickness. Ten of 15 studies reported a significant association between high serum sclerostin and severe arterial calcification. Twelve of 14 studies reported a significant association between high serum sclerostin and high arterial stiffness or atherosclerosis severity. Four of 9 studies reported a significant association between high serum sclerostin and high risk of cardiovascular events. A meta-analysis of randomized controlled trials suggested that administration of the sclerostin blocking antibody romosozumab did not significantly increase the risk of major adverse cardiovascular events (risk ratio, 1.14 [95% CI, 0.83-1.57]; P=0.54) or cardiovascular death (risk ratio, 0.92 [95% CI, 0.53-1.59]; P=0.71). Human genetic studies reported variants predisposing to low arterial sclerostin expression were associated with a high risk of cardiovascular events. Overall, past research suggests a cardiovascular protective role of sclerostin but findings have been inconsistent, possibly due to variations in study design, the unique populations and models studied, and the heterogeneous methods used.

Editor's Choice - A Systematic Review and Meta-Analysis of the Incidence and Risk Factors for Re-admission to Hospital in People with Diabetes Related Foot Disease.

OBJECTIVE: The aim of this study was to systematically review the incidence and risk factors for 30 day re-admission to hospital following an index admission to treat diabetes related foot disease (DFD). DATA SOURCES: A literature search was conducted using Medline/PubMed, Scopus, Cochrane Library, and CINAHL databases. METHODS: The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Studies that reported the rate of total or DFD related 30 day re-admissions were included. Meta-analysis was performed using a random effects model to calculate the pooled mean (95% confidence interval [CI]) of the proportion of patients re-admitted to hospital within 30 days. Meta-regression was performed to determine the association between risk factors and 30 day re-admission. RESULTS: Sixteen retrospective studies with a total of 124 683 participants were included. The mean total 30 day re-admission rate was 22.0% (95% CI 17.0 - 27.0%) while the mean DFD related 30 day re-admission rate was 10.0% (95% CI 7.0 - 15.0%). Meta-regression found that greater prevalence of peripheral neuropathy (p = .045) was associated with a higher rate of any 30 day re-admission, and male sex (p = .023) and private health insurance (p = .048) were associated with lower rates of any 30 day re-admission. Coronary artery disease (p= .025) was associated with a higher rate of DFD related re-admission. All studies had low or moderate risk of bias. CONCLUSION: This systematic review suggested that about one fifth of patients with DFD are re-admitted to hospital within 30 days, of which about half are to treat DFD. Risk factors for re-admission included female gender, peripheral neuropathy, lack of private health insurance, and coronary artery disease.

Association Between Serum MicroRNAs and Abdominal Aortic Aneurysm Diagnosis and Growth.

OBJECTIVE: This study aimed to examine the association between serum microRNAs (miRNAs) and diagnosis and growth of abdominal aortic aneurysm (AAA), and to test their diagnostic and prognostic value. METHODS: The expression levels of 800 miRNA tags were assessed in 108 patients with AAA, 12 age and sex matched healthy controls (HCs), and 12 patients with peripheral artery disease (PAD) using NanoString technology. Findings were assessed in an independent sample of 66 patients with AAA and 29 age and sex matched HCs by reverse transcriptase polymerase chain reaction. AAA growth was assessed by a median of three (interquartile range [IQR] 2, 3) repeat ultrasound scans over a median follow up of 1.1 (IQR 1.0, 2.0) years. The association between the miRNA and AAA diagnosis and growth was examined by regression and linear mixed effects analyses. The diagnostic and prognostic potential of the miRNAs were examined using area under the receiver operator characteristic curve (AUC), net re-classification index (NRI), and Cox hazard analyses. RESULTS: In comparison with HCs, a model combining clinical risk factors, let-7b-5p and miR-548n had an AUC of 98.0% (95% confidence interval [CI] 95.6 - 100.0; p = .003) for diagnosing AAA, which was a significant improvement over clinical risk factors alone (NRI 1.74; 95% CI 1.61 - 1.87; p < .001). Compared with PAD, a model combining clinical risk factors and miR-548n had an AUC of 99.6% (95% CI 98.9 - 100.0, p = .037) for diagnosing AAA, which was a significant improvement over clinical risk factors alone (NRI 1.79, 95% CI 1.68 - 1.91; p < .001). In the longitudinal cohort, none of the miRNAs were able to predict the likelihood of reaching surgical threshold diameter better than clinical risk factors alone. CONCLUSION: Serum let-7b-5p and miR548n significantly improved the ability to diagnose AAA. None of the miRNAs had independent prognosis value in predicting AAA growth.

Rates of Stroke in Patients With Different Presentations of Carotid Artery Stenosis.

OBJECTIVE: Carotid artery stenosis may present without the classical symptoms of transient ischaemic attack or stroke but the rates of stroke for these presentations is unknown. The aim of this study was to examine the rates of stroke in patients with different presentations of carotid artery stenosis. METHODS: A multicentre prospective cohort study was conducted across three Australian vascular centres with low rates of surgical treatment of patients without transient ischaemic attack or stroke. Patients with a 50 - 99% carotid artery stenosis presenting with non-focal symptoms (e.g., dizziness or syncope; n = 47), prior contralateral carotid endarterectomy (n = 71), prior ipsilateral symptoms more than six months earlier (n = 82), and no symptoms (n = 304) were recruited. The primary outcome was ipsilateral ischaemic stroke. Secondary outcomes were any ischaemic stroke and cardiovascular death. Data were analysed using Cox proportional hazard and Kaplan-Meier analyses. RESULTS: Between 2002 and 2020, 504 patients were enrolled (mean age 71 years, 30% women) and followed for a median of 5.1 years (interquartile range 2.5, 8.8; 2 981 person years). Approximately 82% were prescribed antiplatelet therapy, 84% were receiving at least one antihypertensive drug, and 76% were prescribed a statin at entry. After five years the incidence of ipsilateral stroke was 6.5% (95% confidence interval [CI] 4.3 - 9.5). There were no statistically significant differences in the annual rate of ipsilateral stroke among people with non-focal symptoms (2.1%; 95% CI 0.8 - 5.7), prior contralateral carotid endarterectomy (0.2%; 0.03 - 1.6) or ipsilateral symptoms > 6 months prior (1.0%; 0.4 - 2.5) compared with those with no symptoms (1.2%; 0.7 - 1.8; p = .19). There were no statistically significant differences in secondary outcomes across groups. CONCLUSION: This cohort study showed no large differences in stroke rates among people with different presentations of carotid artery stenosis.