664 results on '"Jonathan Golledge"'
Search Results
202. A meta-analysis of randomized controlled trials evaluating the efficacy of smoking cessation interventions in people with peripheral artery disease
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Aaron Drovandi, Jonathan Golledge, and Shivshankar Thanigaimani
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Funnel plot ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Publication bias ,Nicotine replacement therapy ,law.invention ,Clinical trial ,Peripheral Arterial Disease ,chemistry.chemical_compound ,Randomized controlled trial ,chemistry ,law ,Meta-analysis ,medicine ,Physical therapy ,Humans ,Smoking cessation ,Smoking Cessation ,Surgery ,Cardiology and Cardiovascular Medicine ,Varenicline ,business ,Randomized Controlled Trials as Topic - Abstract
Objective This review aimed to systematically pool evidence from randomised clinical trials (RCT) on the efficacy of interventions in assisting smoking cessation in participants with PAD. Methods Publicly available databases were searched for RCTs testing the effect of interventional programs in achieving smoking cessation in participants with PAD who were current smokers. The primary outcome was smoking cessation at the end of follow-up. Meta-analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Risk of bias and publication bias were assessed using a modified version of the Cochrane Collaboration’s tool and funnel plots respectively. Results Six RCTs testing smoking cessation programs comprising physician advice, behavioural counselling from an expert delivered in-person or over the telephone and provision of nicotine replacement therapy and/or varenicline in 558 smokers with PAD were included. Meta-analysis suggested that overall these interventions did not significantly increase the chance of quitting smoking (RR: 1.48 [95% CI 0.84, 2.61]), with low heterogeneity between studies (I2=20%) which were robust in sensitivity analyses. Risk of bias was high, moderate, and low in one, three and two studies respectively. A funnel plot suggested a low risk of publication bias. Conclusion Overall previously tested smoking cessation interventions have not been effective in achieving smoking cessation in people with PAD. Further research is needed to develop and test interventions which can effectively help current smokers with PAD quit.
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- 2022
203. Skeletal muscle microvascular perfusion responses to cuff occlusion and submaximal exercise assessed by contrast‐enhanced ultrasound: The effect of age
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Michelle A. Keske, Kim Greaves, Annelise Lins Menêses, Tom G. Bailey, Michael C. Y. Nam, Jonathan Golledge, Christopher D. Askew, and Chris Anstey
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Adult ,Male ,medicine.medical_specialty ,Physiology ,Isometric exercise ,030204 cardiovascular system & hematology ,lcsh:Physiology ,vascular conductance ,Peripheral Arterial Disease ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Occlusion ,medicine ,Humans ,blood flow ,muscle perfusion ,Plethysmograph ,Ankle Brachial Index ,Muscle, Skeletal ,Reactive hyperemia ,Original Research ,Aged ,Leg ,exercise ,lcsh:QP1-981 ,business.industry ,Microcirculation ,aging ,Age Factors ,Reproducibility of Results ,Skeletal muscle ,Blood flow ,Middle Aged ,reactive hyperemia ,medicine.anatomical_structure ,Regional Blood Flow ,Cardiology ,Female ,business ,Perfusion ,Blood Flow Velocity ,030217 neurology & neurosurgery ,Contrast-enhanced ultrasound - 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., 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. 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).
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- 2020
204. Endotoxin Tolerance in Abdominal Aortic Aneurysm Macrophages, In Vitro: A Case–Control Study
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Karl Schulze, Chaim Y. Meital, Alesiya E. Maynard, Fraser D. Russell, Mark Windsor, Anna Kuballa, S. Coverdale, Jill O'Donnell, Lara T. Meital, Maria Perissiou, Jonathan Golledge, Rebecca Magee, Tom G. Bailey, Christopher D. Askew, and Pankaj Jha
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0301 basic medicine ,medicine.medical_specialty ,Lipopolysaccharide ,Physiology ,Clinical Biochemistry ,Stimulation ,macromolecular substances ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Biochemistry ,environment and public health ,Article ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,abdominal aortic aneurysm ,endotoxin tolerance ,Internal medicine ,medicine ,cardiovascular diseases ,Receptor ,Molecular Biology ,lipid rafts ,business.industry ,lcsh:RM1-950 ,Cell Biology ,abdomianl aortic aneurysm ,macrophages ,enzymes and coenzymes (carbohydrates) ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Endocrinology ,chemistry ,TLR4 ,cardiovascular system ,Tumor necrosis factor alpha ,toll-like receptor 4 (TLR4) ,business ,Oxidative stress - Abstract
Macrophages are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). This study examined the environmentally conditioned responses of AAA macrophages to inflammatory stimuli. Plasma- and blood-derived monocytes were separated from the whole blood of patients with AAA (30&ndash, 45 mm diameter, n = 33) and sex-matched control participants (n = 44). Increased concentrations of pro-inflammatory and pro-oxidant biomarkers were detected in the plasma of AAA patients, consistent with systemic inflammation and oxidative stress. However, in monocyte-derived macrophages, a suppressed cytokine response was observed in AAA compared to the control following stimulation with lipopolysaccharide (LPS) (tumor necrosis factor alpha (TNF-&alpha, ) 26.9 ±, 3.3 vs. 15.5 ±, 3.2 ng/mL, p <, 0.05, IL-6 3.2 ±, 0.6 vs. 1.4 ±, 0.3 ng/mL, p <, 0.01). LPS-stimulated production of 8-isoprostane, a biomarker of oxidative stress, was also markedly lower in AAA compared to control participants. These findings are consistent with developed tolerance in human AAA macrophages. As Toll-like receptor 4 (TLR4) has been implicated in tolerance, macrophages were examined for changes in TLR4 expression and distribution. Although TLR4 mRNA and protein expression were unaltered in AAA, cytosolic internalization of receptors and lipid rafts was found. These findings suggest the inflamed, pro-oxidant AAA microenvironment favors macrophages with an endotoxin-tolerant-like phenotype characterized by a diminished capacity to produce pro-inflammatory mediators that enhance the immune response.
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- 2020
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205. Risk Factors and Mouse Models of Abdominal Aortic Aneurysm Rupture
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Susan K. Morton, Smriti M. Krishna, Jonathan Golledge, and Jiaze Li
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0301 basic medicine ,preclinical imaging ,Review ,030204 cardiovascular system & hematology ,environment and public health ,rupture risk ,lcsh:Chemistry ,Aortic aneurysm ,Mice ,0302 clinical medicine ,Risk Factors ,Aorta, Abdominal ,lcsh:QH301-705.5 ,Spectroscopy ,Cause of death ,Models, Cardiovascular ,General Medicine ,Abdominal aortic aneurysm ,Computer Science Applications ,Biomechanical Phenomena ,Cardiology ,cardiovascular system ,Aortic stiffness ,medicine.medical_specialty ,aortic stiffness ,Aortic Rupture ,peak wall stress ,macromolecular substances ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Aneurysm ,abdominal aortic aneurysm ,medicine.artery ,Internal medicine ,medicine ,Animals ,Humans ,Computer Simulation ,cardiovascular diseases ,Physical and Theoretical Chemistry ,Aortic rupture ,Molecular Biology ,Aorta ,Organic Chemistry ,aneurysm rupture ,medicine.disease ,Aortic wall ,Disease Models, Animal ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Stress, Mechanical ,Aortic Aneurysm, Abdominal - Abstract
Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults. In clinical practice, the most established predictor of AAA rupture is maximum AAA diameter. Aortic diameter is commonly used to assess AAA severity in mouse models studies. AAA rupture occurs when the stress (force per unit area) on the aneurysm wall exceeds wall strength. Previous research suggests that aortic wall structure and strength, biomechanical forces on the aorta and cellular and proteolytic composition of the AAA wall influence the risk of AAA rupture. Mouse models offer an opportunity to study the association of these factors with AAA rupture in a way not currently possible in patients. Such studies could provide data to support the use of novel surrogate markers of AAA rupture in patients. In this review, the currently available mouse models of AAA and their relevance to the study of AAA rupture are discussed. The review highlights the limitations of mouse models and suggests novel approaches that could be incorporated in future experimental AAA studies to generate clinically relevant results.
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- 2020
206. Efficacy of Telmisartan to Slow Growth of Small Abdominal Aortic Aneurysms: A Randomized Clinical Trial
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Dylan R. Morris, Tedy Investigators, Jonathan Golledge, Lori K McDonnell, Tejas P. Singh, Ronald L. Dalman, Jason Jenkins, Joseph V. Moxon, Sophie E. Rowbotham, Robert Fitridge, Jan H.N. Lindeman, Jenna Pinchbeck, and Stephanie M Tomee
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Male ,medicine.medical_specialty ,Diastole ,030204 cardiovascular system & hematology ,Placebo ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Telmisartan ,Adverse effect ,Aged ,Original Investigation ,Aged, 80 and over ,business.industry ,medicine.disease ,Abdominal aortic aneurysm ,Blood pressure ,Treatment Outcome ,Relative risk ,Disease Progression ,Female ,Cardiology and Cardiovascular Medicine ,business ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug ,Aortic Aneurysm, Abdominal - Abstract
Key PointsQuestionDoes telmisartan reduce the growth of small abdominal aortic aneurysms? FindingsIn this placebo-controlled randomized trial of 210 participants, a significant effect of telmisartan on abdominal aortic aneurysm growth rates was not shown. Telmisartan had no effect on requirement for abdominal aortic aneurysm repair or aneurysm rupture. MeaningFurther adequately powered trials are needed to assess the efficacy of medical therapies to slow abdominal aortic aneurysm growth.ImportanceCurrently there is no drug therapy for abdominal aortic aneurysm (AAA). ObjectiveTo test the efficacy of the angiotensin receptor blocker telmisartan in slowing AAA growth in the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. Design, Setting, and ParticipantsA randomized, double-blind, placebo-controlled trial recruited participants between September 6, 2011, and October 5, 2016, to evaluate the efficacy of telmisartan treatment in patients with AAA. Participants with 35- to 49-mm AAAs recruited from Australia, the Netherlands, and the US were randomized 1:1 to receive telmisartan, 40 mg, or identical placebo. Analyses were conducted according to intention-to-treat principles. Final follow-up was conducted on October 11, 2018, and data analysis was performed between June and November 2019. InterventionTelmisartan, 40 mg, or identical placebo. Main Outcomes and MeasuresThe primary outcome of the difference in AAA growth, assessed on core imaging laboratory-read ultrasonographic scanning, was tested with linear mixed-effects models. Other outcomes included effects on blood pressure, computed tomographic (CT)-measured AAA diameter and volume, time to AAA-related events (AAA repair or mortality due to AAA rupture), and health-related quality of life. ResultsOf 300 intended participants, 210 were enrolled and randomized to receive telmisartan (n=107) or placebo (n=103). Of patients included in the intention-to-treat analysis (telmisartan: n=106, placebo: n=101), 183 were men (88%); mean (SD) age was 73.5 (7.9) years. At 1 year, participants receiving telmisartan had mean lower systolic (8.9; 95% CI, 4.1-13.8 mm Hg; P
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- 2020
207. Mouse models for abdominal aortic aneurysm
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Smriti M. Krishna, Yutang Wang, and Jonathan Golledge
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0301 basic medicine ,medicine.medical_specialty ,Aortic Rupture ,macromolecular substances ,Asymptomatic ,Pathogenesis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Aneurysm ,Medicine ,Animals ,Humans ,cardiovascular diseases ,Pharmacology ,Surgical repair ,business.industry ,Perioperative ,medicine.disease ,Thrombosis ,Angiotensin II ,Abdominal aortic aneurysm ,Surgery ,Disease Models, Animal ,030104 developmental biology ,cardiovascular system ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Aortic Aneurysm, Abdominal - Abstract
Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only indicated for large asymptomatic, symptomatic or ruptured aneurysms, is not always durable, and is associated with a risk of serious perioperative complications. As a result, patients with small asymptomatic aneurysms or who are otherwise unfit for surgery are treated conservatively, but up to 70% of small aneurysms continue to grow, increasing the risk of rupture. There is thus an urgent need to develop drug therapies effective at slowing AAA growth. This review describes the commonly used mouse models for AAA. Recent research in these models highlights key roles for pathways involved in inflammation and cell turnover in AAA pathogenesis. There is also evidence for long non-coding RNAs and thrombosis in aneurysm pathology. Further well-designed research in clinically relevant models is expected to be translated into effective AAA drugs. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.
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- 2020
208. Hyperuricemia is independently associated with hypertension in men under 60 years in a general Chinese population
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Christopher G. Sobey, Tingting Qian, Qun Xu, Guang Yang, Jonathan Golledge, Xujuan Hou, Grant R Drummond, Fadi J. Charchar, Yutang Wang, Wenqi Hu, Guang Zhang, and Hui Sun
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Adult ,Male ,medicine.medical_specialty ,China ,Adolescent ,Physical examination ,Hyperuricemia ,030204 cardiovascular system & hematology ,Logistic regression ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,Aged ,Retrospective Studies ,Aged, 80 and over ,Chinese population ,medicine.diagnostic_test ,business.industry ,Confounding ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,Chinese people ,Uric Acid ,Blood pressure ,Cross-Sectional Studies ,chemistry ,Hypertension ,Uric acid ,Female ,business - Abstract
Hyperuricemia has been associated with hypertension, however, whether this association exists across all decades of adult life is unknown. This study aimed to assess the association between hyperuricemia and hypertension in relation to age. This retrospective cross-sectional study included a total of 22,556 adult Chinese people who attended Health Physical Examination in a Chinese hospital. Participants were aged between 18 and 95 years (mean [standard deviation], 45.4 [14.0]). Serum uric acid levels and blood pressure were measured. Associations between serum uric acid and blood pressure, and between hyperuricemia and hypertension diagnosis were analyzed using linear or logistic regression, adjusting for confounding risk factors including age, sex, total cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose. Sub-analysis was stratified by age and sex. Before adjustment, high serum uric acid was associated with higher systolic blood pressure (β = 0.214, P < 0.001) and higher diastolic blood pressure (β = 0.271, P < 0.001). Hyperuricemia was associated with hypertension diagnosis (OR, 1.763; 95% CI, 1.635-1.901; P < 0.001) in an unadjusted analysis. These findings remained significant after adjusting for confounding factors. Sub-analysis suggested that the association between uric acid and blood pressure was weaker in older age groups and the association between hyperuricemia and hypertension was limited to people under 60 years. Hyperuricemia was independently associated with hypertension diagnosis in men but not in women, and the independent association between hyperuricemia and hypertension only presented in men under 60 years. This study suggests that hyperuricemia is independently associated with hypertension in Chinese men under 60 years.
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- 2020
209. Opinions of vascular surgeons and podiatrists in Australia and New Zealand on the use of hyperbaric oxygen therapy for lower limb ulcers
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Aaron Drovandi, Jonathan Golledge, Tejas P. Singh, Torres Woolley, and Malindu E. Fernando
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Research design ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Survey result ,030204 cardiovascular system & hematology ,Lower limb ,Diseases of the endocrine glands. Clinical endocrinology ,Amputation, Surgical ,03 medical and health sciences ,0302 clinical medicine ,Hyperbaric oxygen ,Medicine ,Humans ,Ulcer ,Surgeons ,Hyperbaric Oxygenation ,business.industry ,Australia ,Emerging Technologies, Pharmacology and Therapeutics ,RC648-665 ,Diabetic Foot ,Clinical trial ,Podiatrist ,Lower Extremity ,surveys and questionnaires ,Physical therapy ,business ,New Zealand - Abstract
IntroductionHyperbaric 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 methodsAccredited 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.Results61 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 (pConclusionsVascular surgeons and podiatrists do not feel HBOT has a frequent role in treating lower limb ulcers, but do feel there needs to be a large clinical trial to test its value.
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- 2020
210. Meta-analyses of randomized controlled trials reporting the effect of home foot temperature monitoring, patient education or offloading footwear on the incidence of diabetes-related foot ulcers
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Charith Galappaththy, Evan O. Matthews, Joseph V. Moxon, Chanika Alahakoon, Mal Fernando, Jonathan Golledge, and Peter A Lazzarini
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,MEDLINE ,030209 endocrinology & metabolism ,CINAHL ,law.invention ,Body Temperature ,Weight-Bearing ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Randomized controlled trial ,Patient Education as Topic ,law ,Internal Medicine ,medicine ,Odds Ratio ,Humans ,030212 general & internal medicine ,Randomized Controlled Trials as Topic ,business.industry ,Foot ,Incidence (epidemiology) ,Odds ratio ,Confidence interval ,Diabetic Foot ,Shoes ,Self Care ,Physical therapy ,business ,Foot (unit) ,Patient education - Abstract
Aim: The aim of this study was to perform an up‐to‐date systematic review and meta‐analysis of randomized controlled trials (RCTs) examining the efficacy of home foot temperature monitoring, patient education and offloading footwear in reducing the incidence of diabetes‐related foot ulcers. Methods: A literature search was performed using MEDLINE, PubMed, CINAHL, Scopus and Cochrane databases to identify relevant original studies. Meta‐analyses were performed using intention‐to‐treat principals for worst (main analysis) and best (sub‐analysis) case scenarios. Leave‐one‐out sensitivity analyses were used to assess the consistency of findings. Results: Of 7575 unique records, 17 RCTs involving 2729 participants were included. Four tested home foot temperature monitoring (n = 468), six examined patient education (n = 823) and seven assessed offloading footwear (n = 1438). Participants’ who performed home foot temperature monitoring [odds ratio (OR) 0.51, 95% confidence interval (CI) 0.31 to 0.84; n = 468] and those provided offloading footwear (OR 0.48, 95% CI 0.29 to 0.80; n = 1438) were less likely to develop a diabetes‐related foot ulcer. Patient education programmes did not significantly reduce diabetes‐related foot ulcer incidence (OR 0.59, 95% CI 0.29 to 1.20; n = 823). Sensitivity analyses suggested that offloading footwear findings were consistent, but home foot temperature findings were dependent on the individual inclusion of one trial. All RCTs had either high or unclear risk of bias. Conclusion: This meta‐analysis suggests that offloading footwear is effective in reducing the incidence of diabetes‐related foot ulcers. Home foot temperature monitoring also appears beneficial but larger trials are needed (PROSPERO registration no.: CRD42019135226).
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- 2020
211. Comparison of peak wall stress and peak wall rupture index in ruptured and asymptomatic intact abdominal aortic aneurysms
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V Iyer, Jonathan Golledge, T. C. Gasser, Tejas P. Singh, Jason Jenkins, and Joseph V. Moxon
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Male ,medicine.medical_specialty ,Aortic Rupture ,Finite Element Analysis ,030230 surgery ,Asymptomatic ,03 medical and health sciences ,Aortic aneurysm ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine.artery ,medicine ,Humans ,Aorta, Abdominal ,Aged ,Retrospective Studies ,Aorta ,business.industry ,Confounding ,Case-control study ,Retrospective cohort study ,Odds ratio ,medicine.disease ,Abdominal aortic aneurysm ,Case-Control Studies ,Asymptomatic Diseases ,Cardiology ,Surgery ,Female ,medicine.symptom ,business ,Aortic Aneurysm, Abdominal - Abstract
Background: Previous studies have suggested that finite element analysis (FEA) can estimate the rupture risk of an abdominal aortic aneurysm (AAA); however, the value of biomechanical estimates over measurement of AAA diameter alone remains unclear. This study aimed to compare peak wall stress (PWS) and peak wall rupture index (PWRI) in participants with ruptured and asymptomatic intact AAAs. Methods: The reproducibility of semiautomated methods for estimating aortic PWS and PWRI from CT images was assessed. PWS and PWRI were estimated in people with ruptured AAAs and those with asymptomatic intact AAAs matched by orthogonal diameter on a 1 : 2 basis. Spearman's correlation coefficient was used to assess the association between PWS or PWRI and AAA diameter. Independent associations between PWS or PWRI and AAA rupture were identified by means of logistic regression analyses. Results: Twenty individuals were included in the analysis of reproducibility. The main analysis included 50 patients with an intact AAA and 25 with a ruptured AAA. Median orthogonal diameter was similar in ruptured and intact AAAs (82·3 (i.q.r. 73·5–92·0) versus 81·0 (73·2–92·4) mm respectively; P = 0·906). Median PWS values were 286·8 (220·2–329·6) and 245·8 (215·2–302·3) kPa respectively (P = 0·192). There was no significant difference in PWRI between the two groups (P = 0·982). PWS and PWRI correlated positively with orthogonal diameter (both P
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- 2020
212. Animal models of ischemic limb ulcers: a systematic review and meta-analysis
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Shivshankar Thanigaimani, James Phie, and Jonathan Golledge
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Ischemia ,030204 cardiovascular system & hematology ,Diseases of the endocrine glands. Clinical endocrinology ,Mice ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Clinical significance ,Animal testing ,Pathophysiology/Complications ,Ulcer ,animal experimentation ,Wound Healing ,business.industry ,medicine.disease ,RC648-665 ,Limb ischemia ,Diabetic foot ,Diabetic Foot ,Rats ,Meta-analysis ,Models, Animal ,Rabbits ,Wound healing ,business - Abstract
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.
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- 2020
213. SAT-033 U-Shaped Association of Plasma Testosterone, and No Association of Plasma Estradiol, with Incidence of Any Fracture and Hip Fracture in Older Men
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Leon Flicker, Paul Norman, Jonathan Golledge, Osvaldo Almeida, Graeme Hankey, Jonathan Beilin, Jacqueline Center, Paul Chubb, Helman Alfonso, and Bu Beng Yeap
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medicine.medical_specialty ,Hip fracture ,Male Reproductive Health - from Hormones to Gametes ,business.industry ,Endocrinology, Diabetes and Metabolism ,Incidence (epidemiology) ,Testosterone (patch) ,medicine.disease ,Endocrinology ,Internal medicine ,medicine ,Fracture (geology) ,Reproductive Endocrinology ,business ,AcademicSubjects/MED00250 ,Plasma estradiol - Abstract
Osteoporosis resulting in bone fractures is a major cause of morbidity in older men. Previous studies implicated reduced exposure to estradiol (E2) with increased fracture risk in men. The extent to which circulating androgens contribute to maintenance of bone health is uncertain. We examined associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. We analysed 3,307 community-dwelling men aged 76.8±3.5 years, median follow-up period of 10.6 years. Medical information was collected by questionnaire. Frailty was assessed using the FRAIL scale (1). Early morning plasma testosterone (T), dihydrotestosterone (DHT) and E2 were assayed by mass spectrometry, sex hormone-binding globulin (SHBG) and luteinising hormone (LH) by immunoassay. Incidence of any fracture and hip fracture were determined via data linkage to emergency department presentations and hospital admissions. Risk of fracture according to sex hormone concentrations was analysed. Hazard ratio of fracture according to sex hormone quartiles (Q1-4) was assessed using Cox regression models adjusted for age, medical comorbidities and frailty. In 30,355 participant-years of follow-up, the incidence of any fracture was 1.1% and hip fracture 0.5% per participant per year. Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested non-linear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher concentrations of plasma T, lower E2, higher SHBG and higher LH. In fully-adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Q1: reference group, Q2: fully-adjusted hazard ratio [HR]=0.69, 95% confidence interval [CI]=0.51-0.94, p=0.020; Q3: HR=0.59, CI=0.42-0.83, p=0.002; Q4: 0.85, CI=0.62-1.18, p=0.335). A similar U-shaped association of T was found with incidence of hip fracture (Q1: HR=1.0; Q2: HR=0.60, CI=0.37-0.93, p=0.043; Q3: HR=0.52, CI=0.31-0.88, p=0.015; Q4: HR=1.04, CI=0.65-1.68, p=0.866). DHT, E2 and LH were not associated with incidence of any fracture or hip fracture (all p>0.050). SHBG was not associated with incidence of any fracture, but was associated with hip fracture (Q4 vs Q1: HR=1.76, CI=1.05-2.96, p=0.033). In conclusion, we found a non-linear or U-shaped association of T with fracture risk, with no association of E2. Mid-range plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen may be a biomarker for hormone effects on bone driving fracture risk. A randomised controlled trial of T therapy powered for the outcome of fracture may be warranted and should recruit men with baseline T in the lowest quartile of values. Reference: (1) Hyde Z, et al. J Clin Endocrinol Metab 2010; 95: 3165-3172.
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- 2020
214. Estimating the diagnostic accuracy of the ankle-brachial pressure index for detecting peripheral arterial disease in people with diabetes: A systematic review and meta-analysis
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Peta Ellen Tehan, Christopher Oldmeadow, Angela Searle, Vivienne Chuter, Jonathan Golledge, Lucy Leigh, Stephen M. Twigg, Alex Barwick, and Benjamin Peterson
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Cochrane Library ,Sensitivity and Specificity ,Diabetes Complications ,03 medical and health sciences ,Peripheral Arterial Disease ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Internal Medicine ,medicine ,Diabetes Mellitus ,Humans ,Ankle Brachial Index ,030212 general & internal medicine ,Ultrasonography, Doppler, Color ,medicine.diagnostic_test ,Receiver operating characteristic ,business.industry ,Area under the curve ,Angiography ,Confidence interval ,body regions ,Meta-analysis ,Cohort ,Diagnostic odds ratio ,business - Abstract
Aim: To systematically evaluate research investigating the accuracy of the ankle–brachial index (ABI) for diagnosing peripheral artery disease (PAD) in people with diabetes, as the accuracy is thought to be reduced in this cohort. Methods: A database search of EBSCO Megafile Premier, Embase and The Cochrane Library was conducted to 28 February 2019. Prospective and retrospective investigations of the diagnostic accuracy of the ABI for PAD in people with diabetes using an imaging reference standard were eligible. Sensitivity and specify of the ABI and bivariate meta-analysis against reference tests, or a standard summary receiver operating curve analysis (SROC) was performed. Results: Thirty-three studies met the inclusion criteria. ABI was compared with angiography in 12 studies and with colour duplex ultrasound (CDUS) in 21 studies. A SROC analysis of studies using angiography as the reference standard found a diagnostic odds ratio (DOR) of 9.06 [95% confidence interval (CI) 3.61 to 22.69], and area under the curve (AUC) of 0.76 (95% CI 0.66 to 0.86). Bivariate analysis of studies using CDUS demonstrated mean sensitivity of 0.60 (95% CI 0.48 to 0.71; P = 0.097) and mean specificity of 0.87 (95% CI 0.78 to 0.92; P
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- 2020
215. Association of Serum Lipoprotein (a) With the Requirement for a Peripheral Artery Operation and the Incidence of Major Adverse Cardiovascular Events in People With Peripheral Artery Disease
- Author
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Frank Quigley, Bernie Bourke, Ramesh Velu, Michael J. Bourke, Dick C. Chan, Jason Jenkins, Jonathan Golledge, Sophie E. Rowbotham, Shivshankar Thanigaimani, and Gerald F. Watts
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Arterial disease ,surgical treatment ,Myocardial Infarction ,Disease ,Vascular Medicine ,Risk Assessment ,Peripheral Arterial Disease ,Risk Factors ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Surgical treatment ,Original Research ,Aged ,biology ,Peripheral artery disease ,business.industry ,Incidence (epidemiology) ,Incidence ,lipoprotein (a) ,Lipoprotein(a) ,Middle Aged ,Up-Regulation ,Stroke ,Treatment Outcome ,Peripheral Vascular Disease ,biology.protein ,Cardiology ,Female ,Queensland ,Cardiology and Cardiovascular Medicine ,business ,Vascular Surgical Procedures ,Biomarkers ,Lipoprotein - Abstract
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.
- Published
- 2020
216. Pathogenic mechanisms and the potential of drug therapies for aortic aneurysm
- Author
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Jonathan Golledge, Zamaneh Kassiri, Bo Liu, and David J. Granville
- Subjects
medicine.medical_specialty ,Physiology ,Myocytes, Smooth Muscle ,Review ,030204 cardiovascular system & hematology ,Vascular Remodeling ,Sudden death ,Muscle, Smooth, Vascular ,Extracellular matrix ,03 medical and health sciences ,Aortic aneurysm ,0302 clinical medicine ,Aneurysm ,Physiology (medical) ,medicine.artery ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,Aortic rupture ,030304 developmental biology ,0303 health sciences ,Aorta ,business.industry ,medicine.disease ,Abdominal aortic aneurysm ,Matrix Metalloproteinases ,3. Good health ,Aortic Aneurysm ,Extracellular Matrix ,Clinical trial ,Cardiology ,cardiovascular system ,Disease Progression ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aortic aneurysm is a permanent focal dilation of the aorta. It is usually an asymptomatic disease but can lead to sudden death due to aortic rupture. Aortic aneurysm-related mortalities are estimated at ∼200,000 deaths per year worldwide. Because no pharmacological treatment has been found to be effective so far, surgical repair remains the only treatment for aortic aneurysm. Aortic aneurysm results from changes in the aortic wall structure due to loss of smooth muscle cells and degradation of the extracellular matrix and can form in different regions of the aorta. Research over the past decade has identified novel contributors to aneurysm formation and progression. The present review provides an overview of cellular and noncellular factors as well as enzymes that process extracellular matrix and regulate cellular functions (e.g., matrix metalloproteinases, granzymes, and cathepsins) in the context of aneurysm pathogenesis. An update of clinical trials focusing on therapeutic strategies to slow abdominal aortic aneurysm growth and efforts underway to develop effective pharmacological treatments is also provided.
- Published
- 2020
217. Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice
- Author
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Smriti M. Krishna, Christoph Kleinschnitz, Erik Biros, Con Panousis, Corey S. Moran, Susan K. Morton, Jonathan Golledge, and Sai Wang Seto
- Subjects
Apolipoprotein E ,medicine.medical_specialty ,Apolipoprotein B ,Medizin ,Bradykinin ,ADAM17 Protein ,Mice ,chemistry.chemical_compound ,Apolipoproteins E ,Growth factor receptor ,Internal medicine ,medicine ,Animals ,Aorta, Abdominal ,cardiovascular diseases ,Factor XII ,biology ,Chemistry ,Angiotensin II ,General Medicine ,Kallikrein ,Kinin ,Disease Models, Animal ,Endocrinology ,biology.protein ,cardiovascular system ,Aortic Aneurysm, Abdominal ,circulatory and respiratory physiology - Abstract
Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Chronic inflammation and excessive matrix remodelling are considered important in AAA pathogenesis. Kinins are bioactive peptides important in regulating inflammation. Stimulation of the kinin B2 receptor has been previously reported to promote AAA development and rupture in a mouse model. The endogenous B2 receptor agonist, bradykinin, is generated from the kallikrein–kinin system following activation of plasma kallikrein by Factor XII (FXII). In the current study whole-body FXII deletion, or neutralisation of activated FXII (FXIIa), inhibited expansion of the suprarenal aorta (SRA) of apolipoprotein E-deficient mice in response to angiotensin II (AngII) infusion. FXII deficiency or FXIIa neutralisation led to decreased aortic tumor necrosis factor-α-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-α-converting enzyme) (ADAM-17)) activity, plasma kallikrein concentration, and epithelial growth factor receptor (EGFR) phosphorylation compared with controls. FXII deficiency or neutralisation also reduced Akt1 and Erk1/2 phosphorylation and decreased expression and levels of active matrix metalloproteinase (Mmp)-2 and Mmp-9. The findings suggest that FXII, kallikrein, ADAM-17, and EGFR are important molecular mediators by which AngII induces aneurysm in apolipoprotein E-deficient mice. This could be a novel pathway to target in the design of drugs to limit AAA progression.
- Published
- 2020
218. Abdominal Aortic Aneurysm Pathology and Progress Towards a Medical Therapy
- Author
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Jonathan Golledge, Smriti M. Krishna, Tejas P. Singh, and Joseph V. Moxon
- Subjects
Surgical repair ,medicine.medical_specialty ,business.industry ,macromolecular substances ,medicine.disease ,environment and public health ,Abdominal aortic aneurysm ,Surgery ,law.invention ,Clinical trial ,enzymes and coenzymes (carbohydrates) ,Aortic aneurysm ,Pharmacotherapy ,Randomized controlled trial ,law ,cardiovascular system ,medicine ,cardiovascular diseases ,Elective surgery ,Aortic rupture ,business - Abstract
Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults due to aortic rupture. Surgical repair (either by endovascular or open surgery) is the only treatment for AAA. However, large randomized controlled trials have demonstrated that elective repair of small (
- Published
- 2020
219. Systematic Review and Meta-analysis of Clinical Trials Examining the Benefit of Exercise Programmes Using Nordic Walking in Patients With Peripheral Artery Disease
- Author
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Sebastien Girold, Dylan R. Morris, Khyber Maarij, Jonathan Golledge, Hans Wrang, Joseph V. Moxon, and Jonathan Beard
- Subjects
medicine.medical_specialty ,Arterial disease ,business.industry ,Disease ,030204 cardiovascular system & hematology ,Intermittent claudication ,Test (assessment) ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Meta-analysis ,Physical therapy ,population characteristics ,Medicine ,Surgery ,In patient ,030212 general & internal medicine ,medicine.symptom ,Treadmill ,Cardiology and Cardiovascular Medicine ,business ,human activities - Abstract
Objectives An exercise programme is part of the initial management of peripheral artery disease (PAD). Nordic walking uses poles and a core-focused walking technique to reduce the load on the legs, which may have advantages as an exercise programme for PAD. This systematic review examined the benefit of a Nordic walking programme for treating PAD compared with other programmes. Methods A systematic approach was used to identify clinical trials comparing Nordic walking and control programmes in PAD patients. For inclusion, studies had to report maximum walking distance (MWD) measured with a treadmill test or corridor walking test both at entry and follow up. Study quality was appraised using the Cochrane collaboration tool for assessing risk of bias. An inverse variance weighted meta-analysis was performed to compare improvements in MWD. Results Five independent trials involving 294 patients were identified. In three trials, supervised Nordic walking programmes were compared with supervised standard walking. One trial compared a home based Nordic walking programme with a similar standard walking programme. One trial compared a partly supervised Nordic walking programme with best medical management. Meta-analysis of all data suggested that MWD improvements were similar for patients treated by Nordic and standard walking programmes (standardised mean difference, SMD = 1.31, 95% CI –1.28 to 3.91; p = .322). Findings for completely supervised programmes were similar to the primary analysis (SMD = −0.79, 95% CI –2.81 to 1.24; p = .446) while those from partially supervised or home based programmes favoured Nordic walking (SMD = 4.46, 95% CI 3.39, 5.53; p Conclusions This systematic review suggests no benefit of Nordic over standard walking as supervised exercise for PAD. Favourable results were reported for one home based Nordic walking programme. A larger trial is needed to assess whether this finding can be replicated or not.
- Published
- 2018
220. U-Shaped Relationship of Leukocyte Telomere Length With All-Cause and Cancer-Related Mortality in Older Men
- Author
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Matthew Knuiman, Osvaldo P. Almeida, Mark L. Divitini, John Beilby, Jonathan Golledge, Gillian M. Arscott, Leon Flicker, Jennie Hui, Bu B. Yeap, Paul Norman, Graeme J. Hankey, and Stephen M. Twigg
- Subjects
Oncology ,Senescence ,Male ,Aging ,medicine.medical_specialty ,Lower risk ,Cohort Studies ,Internal medicine ,Cause of Death ,Neoplasms ,medicine ,Leukocytes ,Humans ,Aged ,Aged, 80 and over ,Cancer Death Rate ,Proportional hazards model ,business.industry ,Hazard ratio ,Cancer ,Telomere ,medicine.disease ,Confidence interval ,Quartile ,Cardiovascular Diseases ,Geriatrics and Gerontology ,business - Abstract
Background Telomeres are essential DNA–protein complexes whose attrition results in cellular dysfunction and senescence. Leukocyte telomere length (LTL) correlates with tissue telomere length, representing a biomarker for biological age. However, its predictive value for mortality risk, and for cardiovascular versus cancer deaths, in older adults remains uncertain. Method We studied 3608 community-dwelling men aged 77.0 ± 3.6 years. Leukocyte telomere length was measured using multiplex quantitative PCR, expressed as amount of telomeric DNA relative to single-copy control gene (T/S ratio). Deaths from any cause, cardiovascular disease (CVD), and cancer were ascertained using data linkage. Curve fitting used restricted cubic splines and Cox regression analyses adjusted for age, cardiometabolic risk factors, and prevalent disease. Results There was a U-shaped association of LTL with all-cause mortality. Men with T/S ratio in the middle quartiles had lower mortality (quartiles, Q2 vs Q1, hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.77–0.97, p = .012; Q3 vs Q1 HR = 0.88, CI 0.79–0.99, p = .032). There was no association of LTL with CVD mortality. There was a U-shaped association of LTL with cancer mortality. Men with LTL in the middle quartiles had lower risk of cancer death (Q2 vs Q1, HR = 0.73, CI 0.59–0.90, p = .004; Q3 vs Q1, HR = 0.75, CI 0.61–0.92, p = .007). Conclusions In older men, both shorter and longer LTL are associated with all-cause mortality. A similar U-shaped association was seen with cancer deaths, with no association found for cardiovascular deaths. Further research is warranted to explore the prognostic utility of LTL in ageing.
- Published
- 2019
221. Advanced Glycation End Products and esRAGE Are Associated With Bone Turnover and Incidence of Hip Fracture in Older Men
- Author
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Graeme J. Hankey, Paul Norman, Leon Flicker, Bu B. Yeap, Felix Irrgang, Josephine M. Forbes, Lydia S Lamb, Osvaldo P. Almeida, Jonathan Golledge, Gerald Muench, Timothy M. E. Davis, and Helman Alfonso
- Subjects
Blood Glucose ,Glycation End Products, Advanced ,Male ,0301 basic medicine ,medicine.medical_specialty ,Bone density ,Endocrinology, Diabetes and Metabolism ,Receptor for Advanced Glycation End Products ,Clinical Biochemistry ,Hydroxyapatite binding ,030209 endocrinology & metabolism ,Biochemistry ,Bone remodeling ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,N-terminal telopeptide ,Bone Density ,Predictive Value of Tests ,Risk Factors ,Interquartile range ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,medicine ,Humans ,Aged ,Aged, 80 and over ,Hip fracture ,biology ,Hip Fractures ,business.industry ,Incidence ,Lysine ,Biochemistry (medical) ,Age Factors ,Prognosis ,Pyruvaldehyde ,medicine.disease ,030104 developmental biology ,Osteocalcin ,biology.protein ,Bone Remodeling ,business ,Biomarkers ,Follow-Up Studies - Abstract
Background: Diabetes mellitus is associated with increased fracture risk despite preservation of bone density and reduced bone turnover.Aims: We tested the hypothesis that circulating advanced glycation end products (AGEs) and endogenous secretory receptor for AGEs (esRAGE) differentially modulate bone turnover and predict fracture risk in older men.Participants: A total of 3384 community-dwelling men aged 70 to 89 years.Methods: Collagen type I C-terminal cross-linked telopeptide, N-terminal propeptide of type I collagen (P1NP), and total osteocalcin (TOC) were assayed using immunoassay and undercarboxylated osteocalcin (ucOC) following hydroxyapatite binding. Plasma N-carboxymethyllysine (CML) and esRAGE were assayed using immunoassay. Methylglyoxal and glyoxal were assayed using mass spectrometry. Incident hip fractures were ascertained.Results: Median age was 76.3 years (interquartile range, 74.2 to 79.1 years). Plasma CML was measured in 3011 men, methylglyoxal and glyoxal in 766 men, and esRAGE in 748 men. Plasma CML, methylglyoxal, glyoxal, and esRAGE were similar in men without and with diabetes (all P > 0.05). CML was positively associated with fasting glucose (r = 0.06, P < 0.001), and esRAGE was inversely associated (r = -0.08, P = 0.045). esRAGE was positively associated with bone formation (P1NP, r = 0.17, P < 0.001; ucOC, r = 0.11, P = 0.008; TOC, r = 0.16, P < 0.001). Incident hip fractures occurred in 106 men during follow-up. Men with CML in the third quartile of values had reduced incidence of hip fracture compared with men in the lowest quartile (hazard ratio, 0.49; 95% CI, 0.24 to 0.99; P = 0.045).Conclusions: Glycemia associates positively with CML and reciprocally with esRAGE in older men. Circulating esRAGE modulates bone turnover in older men, whereas CML predicts incidence of hip fracture.
- Published
- 2018
222. Older men with bipolar disorder: Clinical associations with early and late onset illness
- Author
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Osvaldo P. Almeida, Jonathan Golledge, Bu B. Yeap, Graeme J. Hankey, and Leon Flicker
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Bipolar Disorder ,Population ,Late onset ,Comorbidity ,Alcohol use disorder ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Cause of Death ,Odds Ratio ,Prevalence ,medicine ,Humans ,Dementia ,Longitudinal Studies ,Bipolar disorder ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Hazard ratio ,Australia ,medicine.disease ,030227 psychiatry ,Alcoholism ,Suicide ,Psychiatry and Mental health ,Cross-Sectional Studies ,Geriatrics and Gerontology ,Age of onset ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
Objectives: Older adults living with bipolar disorder (BD) include people with early and late onset of symptoms. This study aimed to clarify the cross-sectional and longitudinal clinical associations of BD with early and late onset. Methods: Cohort study of 38 173 men aged 65–85 years followed for up to 17.6 years. We used the Western Australian Data Linkage System to establish the presence of BD, as well as diabetes, cardiovascular and renal diseases, cancer, respiratory and gastrointestinal diseases, alcohol use disorder, dementia, and mortality. The causes of death were recorded according to the International Classification of Diseases. We defined late onset BD using 2 different cut-points: 50 and 60 years. Results: The prevalence of medical morbidities was greater among participants with than without BD, and cardiovascular diseases were more frequent among those with onset before than after 50 years (odds ratio = 1.72, 95% confidence interval = 1.01, 2.94). Bipolar disorder was associated with increased hazard ratio of dementia and death, but there was no difference between early and late onset participants. Death by suicide or accidents occurred exclusively among BD participants with illness onset
- Published
- 2018
223. Anionic nanoliposomes reduced atherosclerosis progression in Low Density Lipoprotein Receptor ( LDLR ) deficient mice fed a high fat diet
- Author
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Jiaze Li, Roby J. Jose, Mahmoud Reza Jaafari, Dawie Liu, Smriti M. Krishna, Jonathan Golledge, Mahdi Hatamipour, Joseph V. Moxon, and Amirhossein Sahebkar
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Physiology ,Clinical Biochemistry ,030204 cardiovascular system & hematology ,Diet, High-Fat ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Scavenger receptor ,Liver X receptor ,Mice, Knockout ,Cholesterol ,Reverse cholesterol transport ,Liver X receptor alpha ,Biological Transport ,Cell Biology ,Atherosclerosis ,Plaque, Atherosclerotic ,SCARB1 ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Liver ,Receptors, LDL ,chemistry ,LDL receptor ,ATP-Binding Cassette Transporters ,lipids (amino acids, peptides, and proteins) ,Lipoprotein - Abstract
Atherosclerosis is a systemic disease characterized by the deposition of cholesterol and inflammatory cells within the arterial wall. Removal of cholesterol from the vessel wall may have an impact on the size and composition of atherosclerotic lesions. Anionic phospholipids or liposome vesicles composed of a lipid bilayer such as nanoliposomes have been suggested as treatments for dyslipidemia. In this study, we investigated the effect of anionic nanoliposomes on atherosclerosis in a mouse model. Low-density lipoprotein receptor knockout mice (Ldlr-/- ) were fed with an atherosclerosis promoting high fat and cholesterol (HFC) diet for 12 weeks. Anionic nanoliposomes including hydrogenated soy phosphatidylcholine (HSPC) and distearoyl phosphatidylglycerol (DSPG) (molar ratio: 1:3) were injected intravenously into HFC-fed Ldlr-/- mice once a week for 4 weeks. Mice receiving nanoliposomes had significantly reduced atherosclerosis within the aortic arch as assessed by Sudan IV staining area (p = 0.007), and reduced intima/media ratio (p = 0.030) and greater collagen deposition within atherosclerosis plaques within the brachiocephalic artery (p = 0.007), compared to control mice. Administration of nanoliposomes enhanced markers of reverse cholesterol transport (RCT) and increased markers of plaque stability in HFC-fed Ldlr-/- mice. Reduced cholesterol accumulation was observed in the liver along with the up-regulation of the major genes involved in the efflux of cholesterol such as hepatic ATP-binding cassette transporters (ABC) including Abc-a1, Abc-g1, Abc-g5, and Abc-g8, Scavenger receptor class B, member 1 (Scarb1), and Liver X receptor alpha (Lxr)-α. Lecithin Cholesterol Acyltransferase activity within the plasma was also increased in mice receiving nanoliposomes. Anionic nanoliposome administration reduced atherosclerosis in HFC-fed Ldlr-/- mice by promoting RCT and upregulating the ABC-A1/ABC-G1 pathway.
- Published
- 2018
224. Risk of dementia associated with psychotic disorders in later life: the health in men study (HIMS)
- Author
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Osvaldo P. Almeida, Jonathan Golledge, Leon Flicker, Bu B. Yeap, Andrew H. Ford, and Graeme J. Hankey
- Subjects
Male ,Risk ,Psychosis ,medicine.medical_specialty ,Comorbidity ,Alcohol use disorder ,03 medical and health sciences ,0302 clinical medicine ,Paraphrenia ,medicine ,Humans ,Dementia ,Longitudinal Studies ,Psychiatry ,Applied Psychology ,Aged ,Aged, 80 and over ,Delusional disorder ,business.industry ,Western Australia ,medicine.disease ,Health Surveys ,030227 psychiatry ,Psychiatry and Mental health ,Psychotic Disorders ,Schizophrenia ,Age of onset ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
BackgroundRecent research has identified several potentially modifiable risk factors for dementia, including mental disorders. Psychotic disorders, such as schizophrenia and delusional disorder, have also been associated with increased risk of cognitive impairment and dementia, but currently available data difficult to generalise because of bias and confounding. We designed the present study to investigate if the presence of a psychotic disorder increased the risk of incident dementia in later life.MethodsProspective cohort study of a community-representative sample of 37 770 men aged 65–85 years who were free of dementia at study entry. They were followed for up to 17.7 years using electronic health records. Clinical diagnoses followed the International Classification of Diseases guidelines. As psychotic disorders increase mortality, we considered death a competing risk.ResultsA total of 8068 (21.4%) men developed dementia and 23 999 (63.5%) died during follow up. The sub-hazard ratio of dementia associated with a psychotic disorder was 2.67 (95% CI 2.30–3.09), after statistical adjustments for age and prevalent cardiovascular, respiratory, gastrointestinal and renal diseases, cancer, as well as hearing loss, depressive and bipolar disorders, and alcohol use disorder. The association between psychotic disorder and dementia risk varied slightly according to the duration of the psychotic disorder (highest for those with the shortest illness duration), but not the age of onset. No information about the use of antipsychotics was available.ConclusionOlder men with a psychotic disorder have nearly three times greater risk of developing dementia than those without psychosis. The pathways linking psychotic disorders to dementia remain unclear but may involve mechanisms other than those associated with Alzheimer's disease and other common dementia syndromes.
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- 2018
225. Risk of major amputation in patients with intermittent claudication undergoing early revascularization
- Author
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Joseph V. Moxon, Jonathan Golledge, Sophie E. Rowbotham, R Velu, Frank Quigley, Lisan Yip, D R Morris, Jason Jenkins, and Jenna Pinchbeck
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Revascularization ,Amputation, Surgical ,Peripheral Arterial Disease ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,medicine ,Humans ,Outpatient clinic ,In patient ,030212 general & internal medicine ,Aged ,Proportional Hazards Models ,Leg ,Proportional hazards model ,business.industry ,Endovascular Procedures ,Intermittent Claudication ,Middle Aged ,Intermittent claudication ,Exercise Therapy ,Surgery ,Amputation ,Relative risk ,medicine.symptom ,business ,Major amputation - Abstract
Background Revascularization is being used increasingly for the treatment of intermittent claudication and yet few studies have reported the long-term outcomes of this strategy. The aim of this study was to compare the long-term outcome of patients with intermittent claudication who underwent revascularization compared with a group initially treated without revascularization. Methods Patients with symptoms of intermittent claudication and a diagnosis of peripheral arterial disease were recruited from outpatient clinics at three hospitals in Queensland, Australia. Based on variation in the practices of different vascular specialists, patients were either treated by early revascularization or received initial conservative treatment. Patients were followed in outpatient clinics using linked hospital admission record data. The primary outcome was the requirement for major amputation. Kaplan–Meier curves, Cox regression and competing risks analyses were used to compare major amputation rates. Results Some 456 patients were recruited; 178 (39·0 per cent) underwent early revascularization and 278 (61·0 per cent) had initial conservative treatment. Patients were followed for a mean(s.d.) of 5·00(3·37) years. The estimated 5-year major amputation rate was 6·2 and 0·7 per cent in patients undergoing early revascularization and initial conservative treatment respectively (P = 0·003). Early revascularization was associated with an increased requirement for major amputation in models adjusted for other risk factors (relative risk 5·40 to 4·22 in different models). Conclusion Patients presenting with intermittent claudication who underwent early revascularization appeared to be at higher risk of amputation than those who had initial conservative treatment.
- Published
- 2018
226. Circulating MicroRNAs as Biomarkers for Acute Ischemic Stroke: A Systematic Review
- Author
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Erik Biros, Diana Thomas Manapurathe, Jonathan Golledge, Joseph V. Moxon, Alex Trollope, and Brittany Dewdney
- Subjects
Adult ,Genetic Markers ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pathology ,Time Factors ,Cochrane Library ,Brain Ischemia ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Blood test ,Circulating MicroRNA ,Myocardial infarction ,Stroke ,Aged ,Cause of death ,medicine.diagnostic_test ,Cerebral infarction ,business.industry ,Rehabilitation ,Middle Aged ,Prognosis ,medicine.disease ,030104 developmental biology ,Molecular Diagnostic Techniques ,Case-Control Studies ,Inclusion and exclusion criteria ,Female ,Surgery ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery - Abstract
Background Acute ischemic stroke is a leading cause of death and disability worldwide. Unlike myocardial infarction, there is no current blood test to diagnose acute ischemic stroke. MicroRNAs (miRNAs) are very stable in the blood and have been suggested as potential diagnostic markers. Materials and Methods This review aimed to systematically assess case–control studies investigating the association of circulating miRNAs with acute ischemic stroke. Medline, CINAHL, Cochrane Library, Web of Science, Scopus, and PubMed were searched for studies that examined the association of circulating miRNAs in patients with acute ischemic stroke. Studies meeting specific inclusion and exclusion criteria (such as blood samples obtained within 24 hours of an acute ischemic stroke) were selected for data extraction. Two authors extracted data from the included studies relevant to the study design, the patient characteristics, and the relative miRNA expression. Results Eight studies were included involving 572 cases and 431 healthy controls. Twenty-two miRNAs (12 upregulated and 10 downregulated) were reported as differentially expressed. Only 1 miRNA, miR-106b, was reported as differentially expressed in at least 2 studies. Significant heterogeneity in the design and methods of the included studies was noted. Conclusions Differential expression of a large number of miRNAs has been reported early following acute ischemic stroke. More research is required in larger patient populations to further evaluate the diagnostic potential of the reported miRNAs.
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- 2018
227. Circulating biomarkers are not associated with endoleaks after endovascular repair of abdominal aortic aneurysms
- Author
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Eugene Ng, Robert Fitridge, Margaret Boult, Ramesh Velu, Joseph V. Moxon, Jonathan Golledge, and Sharon Lazzaroni
- Subjects
Male ,Endoleak ,Computed Tomography Angiography ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Endovascular aneurysm repair ,Aortic aneurysm ,0302 clinical medicine ,Risk Factors ,Prospective Studies ,Registries ,030212 general & internal medicine ,Prospective cohort study ,Homocysteine ,Aged, 80 and over ,medicine.diagnostic_test ,biology ,Endovascular Procedures ,Abdominal aortic aneurysm ,C-Reactive Protein ,Treatment Outcome ,Matrix Metalloproteinase 9 ,Area Under Curve ,Cardiology ,Female ,Radiology ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Aortography ,Fibrin Fibrinogen Degradation Products ,Blood Vessel Prosthesis Implantation ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Aged ,business.industry ,C-reactive protein ,Australia ,Osteoprotegerin ,medicine.disease ,ROC Curve ,Linear Models ,biology.protein ,Surgery ,business ,Complication ,Biomarkers ,Aortic Aneurysm, Abdominal ,Abdominal surgery - Abstract
Objective Endoleak is a common complication of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) but can be detected only through prolonged follow-up with repeated aortic imaging. This study examined the potential for circulating matrix metalloproteinase 9 (MMP9), osteoprotegerin (OPG), D-dimer, homocysteine (HCY), and C-reactive protein (CRP) to act as diagnostic markers for endoleak in AAA patients undergoing elective EVAR. Methods Linear mixed-effects models were constructed to assess differences in AAA diameter after EVAR between groups of patients who did and did not develop endoleak during follow-up, adjusting for potential confounders. Circulating MMP9, OPG, D-dimer, HCY, and CRP concentrations were measured in preoperative and postoperative plasma samples. The association of these markers with endoleak diagnosis was assessed using linear mixed effects adjusted as before. The potential for each marker to diagnose endoleak was assessed using receiver operating characteristic curves. Results Seventy-five patients were included in the study, 24 of whom developed an endoleak during follow-up. Patients with an endoleak had significantly larger AAA sac diameters than those who did not have an endoleak. None of the assessed markers showed a significant association with endoleak. This was confirmed through receiver operating characteristic curve analyses indicating poor diagnostic ability for all markers. Conclusions Circulating concentrations of MMP9, OPG, D-dimer, HCY, and CRP were not associated with endoleak in patients undergoing EVAR in this study.
- Published
- 2018
228. Diabetes Reduces Severity of Aortic Aneurysms Depending on the Presence of Cell Division Autoantigen 1 (CDA1)
- Author
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Philip J. Walker, Terri J. Allen, Leon A. Bach, Jonathan Golledge, Erik Biros, Pacific Huynh, Aozhi Dai, Helen Kiriazis, Yugang Tu, Zhonglin Chai, Jennifer L. Wilkinson-Berka, Mark E. Cooper, Xiao Jun Du, Bryna S.M. Chow, Maria Nataatmadja, Malcolm J. West, Jiaze Li, and Tieqiao Wu
- Subjects
Adult ,Male ,0301 basic medicine ,Apolipoprotein E ,Pathology ,medicine.medical_specialty ,Mice, Knockout, ApoE ,Aortic Rupture ,Endocrinology, Diabetes and Metabolism ,030204 cardiovascular system & hematology ,Autoantigens ,Severity of Illness Index ,Diabetes Mellitus, Experimental ,Mice ,03 medical and health sciences ,Aortic aneurysm ,0302 clinical medicine ,Downregulation and upregulation ,Transforming Growth Factor beta ,Matrix Metalloproteinase 12 ,Diabetes mellitus ,Internal Medicine ,medicine ,Animals ,Humans ,Vasoconstrictor Agents ,Smad3 Protein ,Aortic rupture ,Aged ,Mice, Knockout ,business.industry ,Angiotensin II ,Macrophages ,Middle Aged ,medicine.disease ,Aortic Aneurysm ,030104 developmental biology ,Gene Expression Regulation ,cardiovascular system ,Female ,Collagen ,Signal transduction ,business ,Aortic Aneurysm, Abdominal ,Signal Transduction ,Transforming growth factor - Abstract
Diabetes is a negative risk factor for aortic aneurysm, but the underlying explanation for this phenomenon is unknown. We have previously demonstrated that cell division autoantigen 1 (CDA1), which enhances transforming growth factor-β signaling, is upregulated in diabetes. We hypothesized that CDA1 plays a key role in conferring the protective effect of diabetes against aortic aneurysms. Male wild-type, CDA1 knockout (KO), apolipoprotein E (ApoE) KO, and CDA1/ApoE double-KO (dKO) mice were rendered diabetic. Whereas aneurysms were not observed in diabetic ApoE KO and wild-type mice, 40% of diabetic dKO mice developed aortic aneurysms. These aneurysms were associated with attenuated aortic transforming growth factor-β signaling, reduced expression of various collagens, and increased aortic macrophage infiltration and matrix metalloproteinase 12 expression. In the well-characterized model of angiotensin II–induced aneurysm formation, concomitant diabetes reduced fatal aortic rupture and attenuated suprarenal aortic expansion, changes not seen in dKO mice. Furthermore, aortic CDA1 expression was downregulated ∼70% within biopsies from human abdominal aortic aneurysms. The identification that diabetes is associated with upregulation of vascular CDA1 and that CDA1 deletion in diabetic mice promotes aneurysm formation provides evidence that CDA1 plays a role in diabetes to reduce susceptibility to aneurysm formation.
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- 2018
229. Response to letter about ‘Lack of an effective drug for abdominal aortic aneurysm’
- Author
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Tejas P. Singh, Joseph V. Moxon, Jonathan Golledge, Matthew J. Bown, Anders Wanhainen, and Kevin Mani
- Subjects
0301 basic medicine ,Drug ,medicine.medical_specialty ,Drug trial ,medicine.drug_class ,media_common.quotation_subject ,Antibiotics ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Internal Medicine ,medicine ,Humans ,Statistical dispersion ,media_common ,business.industry ,Kirurgi ,medicine.disease ,Abdominal aortic aneurysm ,Surgery ,030104 developmental biology ,Pharmaceutical Preparations ,Sample size determination ,business ,Aortic Aneurysm, Abdominal - Abstract
[Extract] Dear Sir, We thank Yu and colleagues for their letter 1 about our recent review 2. We agree there was substantial heterogeneity in the design of the past abdominal aortic aneurysm (AAA) drug trials, particularly those testing antibiotics. Whilst Yu et al. have focused on I2, it should be noted that this describes the dispersion of effect sizes and does not completely describe the heterogeneity between studies. The included antibiotic trials had many methodological variations, such as different sample sizes, durations of antibiotic administration and follow‐up protocols, as outlined in Tables 1 and 2 of our review 2.
- Published
- 2019
230. Higher IGFBP3 is associated with increased incidence of colorectal cancer in older men independently of IGF1
- Author
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Yi X. Chan, Ken K. Y. Ho, Helman Alfonso, P. G. Fegan, S. A. P. Chubb, Bu B. Yeap, Graeme J. Hankey, Jonathan Golledge, and Leon Flicker
- Subjects
Male ,0301 basic medicine ,endocrine system ,medicine.medical_specialty ,Colorectal cancer ,Endocrinology, Diabetes and Metabolism ,IGFBP3 ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Risk Factors ,Prostate ,Internal medicine ,medicine ,Humans ,Insulin-Like Growth Factor I ,Prospective cohort study ,Aged ,Aged, 80 and over ,Proportional hazards model ,business.industry ,Incidence ,Incidence (epidemiology) ,Confounding ,Cancer ,medicine.disease ,Insulin-Like Growth Factor Binding Protein 1 ,Insulin-Like Growth Factor Binding Protein 3 ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Colorectal Neoplasms ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Objective: Insulin-like growth factor 1 (IGF1) has anabolic and growth-promoting effects, raising concerns regarding its potential to promote tumour growth. Circulating IGF1 is bound to binding proteins, which modulate bioavailability of IGF1. This study assessed the associations of IGF1 and its binding proteins 1 (IGFBP1) and 3 (IGFBP3) with cancer risk. Design: A prospective cohort study of 4042 men aged >= 70 years. Methods: Plasma total IGF1, IGFBP1 and IGFBP3 were measured between 2001 and 2004. Cancer-related outcomes were assessed until 20 June 2013 using data linkage. Analyses were performed using proportional hazards models with death as a competing risk, and adjustments were made for potential confounders. Results are expressed as subhazard ratios (SHR). Results: There were 907 men who were diagnosed with cancer during a median of 9-year follow-up. Of these, there were 359, 139 and 125 prostate, colorectal and lung cancers, respectively. After adjustments, total IGF1 was not associated with the incidence of any cancer, prostate, lung or colorectal cancer. In the fully-adjusted model, higher IGFBP3 was associated with increased incidence of colorectal cancer (SHR = 1.20, 95% CI 1.01-1.43; P = .041 for every 1 standard deviation increase in IGFBP3) but not other cancers. This effect was not attenuated by inclusion of total IGF1 into the multivariate model (SHR = 1.28, 95% CI 1.03-1.58; P = .025). Neither total IGF1, IGFBP1 nor IGFBP3 were associated with cancer-related deaths. Conclusion: Higher IGFBP3 predicted increased incidence of colorectal cancer in older men independent of conventional risk factors and total IGF1. Further studies are warranted to explore potential underlying mechanisms.
- Published
- 2017
231. Re 'Trends in Lower Extremity Amputation Incidence in European Union 15+ Countries 1990–2017'
- Author
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Peter A Lazzarini, Susanna M. Cramb, Jonathan Golledge, and Yuqi Zhang
- Subjects
Burden of disease ,business.industry ,Incidence ,Incidence (epidemiology) ,Lower extremity amputation ,Outcome measures ,Amputation, Surgical ,Lower Extremity ,Healthcare policy ,Humans ,Medicine ,media_common.cataloged_instance ,Surgery ,European Union ,European union ,Cardiology and Cardiovascular Medicine ,business ,Demography ,media_common - Abstract
[Extract] The accuracy of key burden outcome measures, like lower extremity amputation (LEA) rates, is critical to inform healthcare policy. Hughes et al. recently reported long term trends in national LEA incidence rates using Global Burden of Disease Study (GBD) estimates. The authors reported that Australia had by far the highest national LEA rates of all countries studied. To our knowledge, Australia has never before been reported to have the highest national LEA rates, and the rates appeared at least twofold higher than those previously published.
- Published
- 2021
232. Systematic Review and Meta-Analysis of the Association Between C-Reactive Protein and Major Cardiovascular Events in Patients with Peripheral Artery Disease
- Author
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Tejas P. Singh, Samuel Smith, Joseph V. Moxon, Dylan R. Morris, and Jonathan Golledge
- Subjects
medicine.medical_specialty ,biology ,business.industry ,C-reactive protein ,Hazard ratio ,Disease ,030204 cardiovascular system & hematology ,Cochrane Library ,medicine.disease ,Surgery ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Meta-analysis ,medicine ,biology.protein ,030212 general & internal medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Stroke - Abstract
Background: Patients with peripheral artery disease (PAD) are at substantial risk of cardiovascular events. There is interest in using blood markers, such as C-reactive protein (CRP), to monitor prognosis and treatment efficacy in PAD patients. The aim of this meta-analysis was to assess the association between CRP and major cardiovascular events in PAD patients. Method: Studies evaluating the association between CRP and major cardiovascular events (myocardial infarction, stroke, cardiac revascularisation and mortality) were identified using MEDLINE and the Cochrane library. Studies that did not include participants with PAD, measure CRP, or follow-up patients for cardiovascular events were excluded. Meta-analyses of published adjusted hazard ratios (HR) were conducted using an inverse variance-weighted random effects model, and heterogeneity was assessed with the I2 index. Results: A total of 16 studies involving 5041 participants met the inclusion criteria for the systematic review. Eight studies were included in the meta-analyses. Summary effect estimates were reported as HR comparing higher and lower quantiles, and HR per unit increase in logeCRP. PAD patients with higher CRP had a significantly greater risk of major cardiovascular events compared with those with lower CRP (HR 2.26, 95% CI 1.65–3.09, p < 0.001). The HR for major cardiovascular events was 1.38 (95% CI 1.16–1.63, p < 0.001) per unit increase in logeCRP. Conclusions: The present findings suggest that high circulating CRP is predictive of major cardiovascular events in PAD patients.
- Published
- 2017
233. Longevity Klotho gene polymorphism and the risk of dementia in older men
- Author
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Jonathan Golledge, Bharti Morar, Leon Flicker, Assen Jablensky, Osvaldo P. Almeida, Bu B. Yeap, and Graeme J. Hankey
- Subjects
Male ,Risk ,0301 basic medicine ,Gerontology ,medicine.medical_specialty ,Genotype ,Longevity ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Polymorphism (computer science) ,Internal medicine ,Epidemiology ,Humans ,Medicine ,Dementia ,Risk factor ,Klotho Proteins ,Klotho ,Aged ,Glucuronidase ,Aged, 80 and over ,Polymorphism, Genetic ,business.industry ,Incidence ,Incidence (epidemiology) ,Obstetrics and Gynecology ,medicine.disease ,030104 developmental biology ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
Introduction Klotho variants (KL-VS) have been associated with increased longevity and better cognitive function. It is unclear whether they modulate dementia risk. Methods We recruited 527 men aged 71–87 years who were free of cognitive impairment. We used data linkage to track the onset of dementia over 10 years. KL-VS genotyping (rs9536314 T/G) followed standard procedures. Results The annual rate of dementia was 17.2‰ (95%CI = 14.0–21.1; total = 5053 person-years), and 14.0‰ (95%CI = 10.6–18.4; 3582 person-years), 23.5‰ (95%CI = 16.6–33.2; 1363 person-years) and 46.4‰ (95%CI = 19.3–111.5; 108 person-years) for men with the TT, TG and GG genotypes. Compared with the TT genotype, the sub-hazard ratios of dementia associated with the TG and GG genotypes were 1.6 (95%CI = 1.0, 2.5; p = 0.030) and 3.5 (95%CI = 1.3, 9.1; p = 0.011). Discussion The Klotho KL-VS variant is associated with an increase in the incidence of dementia in older men, in a dose-dependent fashion (intermediate for heterozygosis and highest for homozygosis).
- Published
- 2017
234. Association between metformin prescription and growth rates of abdominal aortic aneurysms
- Author
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Paul Norman, Sophie E. Rowbotham, Joseph V. Moxon, Jason Jenkins, Rhondda E. Jones, Jenna Pinchbeck, Anthony E. Dear, Michael J. Bourke, Gregory J. Anderson, Bernie Bourke, Jonathan Golledge, and Tim Buckenham
- Subjects
Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Cohort Studies ,03 medical and health sciences ,Aortic aneurysm ,0302 clinical medicine ,Diabetes mellitus ,Internal medicine ,Diabetes Mellitus ,medicine ,Humans ,Hypoglycemic Agents ,030212 general & internal medicine ,Medical prescription ,Aged ,business.industry ,Odds ratio ,medicine.disease ,Metformin ,Abdominal aortic aneurysm ,Surgery ,Logistic Models ,Cohort ,Female ,business ,Aortic Aneurysm, Abdominal ,medicine.drug ,Cohort study - Abstract
Background It has been suggested that diabetes medications, such as metformin, may have effects that inhibit abdominal aortic aneurysm (AAA) growth. The aim of this study was to examine the association of diabetes treatments with AAA growth in three patient cohorts. Methods AAA growth was studied using ultrasound surveillance in cohort 1, repeated CT in cohort 2 and more detailed repeat CT in cohort 3. Growth was estimated by the mean annual increase in maximum AAA diameter. Results A total of 1697 patients with an AAA were studied, of whom 118, 39 and 16 patients were prescribed metformin for the treatment of diabetes in cohorts 1, 2 and 3 respectively. Prescription of metformin was associated with a reduced likelihood of median or greater AAA growth in all three cohorts (cohort 1: adjusted odds ratio (OR) 0·59, 95 per cent c.i. 0·39 to 0·87, P = 0·008; cohort 2: adjusted OR 0·38, 0·18 to 0·80, P = 0·011; cohort 3: adjusted OR 0·13, 0·03 to 0·61, P = 0·010). No other diabetes treatment was significantly associated with AAA growth in any cohort. Conclusion These findings suggest a potential role for metformin in limiting AAA growth.
- Published
- 2017
235. High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice
- Author
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Joseph V. Moxon, Smriti M. Krishna, Jonathan Golledge, Sai Wang Seto, Jiaze Li, Roby J. Jose, Paula Clancy, David J. Crossman, Theophilus I. Emeto, and Paul Norman
- Subjects
Male ,0301 basic medicine ,Time Factors ,Apolipoprotein B ,030204 cardiovascular system & hematology ,Thrombospondin 1 ,Aortic aneurysm ,0302 clinical medicine ,immune system diseases ,Risk Factors ,Odds Ratio ,cytokine ,vascular inflammation ,Aorta, Abdominal ,Cells, Cultured ,Ultrasonography ,Mice, Knockout ,biology ,Angiotensin II ,Matricellular protein ,virus diseases ,General Medicine ,Abdominal aortic aneurysm ,Phenotype ,Matrix Metalloproteinase 9 ,Chemokine ,Disease Progression ,cardiovascular system ,Low Density Lipoprotein Receptor-Related Protein-1 ,endocrine system ,medicine.medical_specialty ,Vascular Remodeling ,03 medical and health sciences ,Apolipoproteins E ,Commentaries ,Internal medicine ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,business.industry ,Tumor Suppressor Proteins ,medicine.disease ,Elastin ,Surgery ,Disease Models, Animal ,Collagen Type III ,030104 developmental biology ,Endocrinology ,Receptors, LDL ,Proteolysis ,Commentary ,biology.protein ,business ,Biomarkers ,Aortic Aneurysm, Abdominal ,Lipoprotein - Abstract
Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman’s rho −0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19–0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1−/−ApoE−/−, n=20) and control mice (ApoE−/−, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1−/− ApoE−/− mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1−/−ApoE−/− mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1−/−ApoE−/− mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1−/−ApoE−/− mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.
- Published
- 2017
236. A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms
- Author
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Sophie E. Rowbotham, Jonathan Golledge, Erik Biros, John A. Bingley, and Vikram Iyer
- Subjects
Genetic Markers ,0301 basic medicine ,macromolecular substances ,030204 cardiovascular system & hematology ,Biology ,Bioinformatics ,Original research ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Mirna expression ,microRNA ,Aortic tissue ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Circulating MicroRNA ,cardiovascular diseases ,Epigenetics ,Quality assessment ,medicine.disease ,Abdominal aortic aneurysm ,Phenotype ,030104 developmental biology ,ROC Curve ,Area Under Curve ,Disease Progression ,cardiovascular system ,Cardiology and Cardiovascular Medicine ,Aortic Aneurysm, Abdominal ,Systematic search - Abstract
Background and aims There is increasing interest in identifying novel methods for abdominal aortic aneurysm (AAA) diagnosis. Non-coding RNA molecules such as microRNAs (miRNAs) are stable within the circulation and may serve as biomarkers for AAA. This systematic review aimed to identify miRNAs associated with a diagnosis of human AAA based on currently published original research. Methods A systematic search of the MEDLINE and EMBASE databases identified studies assessing miRNA expression in abdominal aortic tissue or circulating blood from human AAA cases compared to non-aneurysmal controls. Data from included studies were extracted to assess methods and results after independent quality assessment by two reviewers. Results 15 studies were included in this review. 11 studies obtained aortic tissue samples from 195 AAA cases and 104 controls with normal aortas. Nine studies obtained circulating blood samples from 526 AAA cases and 441 controls. miR-21 was differentially expressed in AAA tissue in five separate studies, with four studies reporting upregulation and one reporting downregulation. Seven other miRNAs were differentially expressed in AAA tissue in two separate studies. 15 circulating miRNAs were differentially expressed in two or more separate studies. miR-155 and miR-29b were the only miRNAs differentially expressed in two separate tissue- and blood-based studies. 11 studies offered mechanistic explanations of the role of miRNAs in AAA pathology through exploration of gene targets. Three studies assessed the diagnostic potential of circulating miRNAs with receiver operating characteristic curves. Only one study assessed the prognostic potential of circulating miRNAs in predicting AAA growth. Conclusions Several miRNAs have been found to be associated with human AAA. Their utility as AAA biomarkers requires further investigation.
- Published
- 2017
237. Higher Dihydrotestosterone Is Associated with the Incidence of Lung Cancer in Older Men
- Author
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Yi X. Chan, S. A. Paul Chubb, David J. Handelsman, Jonathan Golledge, Helman Alfonso, P. Gerry Fegan, Leon Flicker, Bu B. Yeap, and Graeme J. Hankey
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Colorectal cancer ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Endocrinology ,Risk Factors ,Prostate ,Internal medicine ,medicine ,Humans ,Testosterone ,Lung cancer ,Aged ,Aged, 80 and over ,Estradiol ,Endocrine and Autonomic Systems ,business.industry ,Incidence ,Incidence (epidemiology) ,Age Factors ,Prostatic Neoplasms ,Cancer ,Dihydrotestosterone ,medicine.disease ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Advancing age is associated with increased cancer incidence, but the role of sex hormones as risk predictors for common cancers in older men remains uncertain. This study was performed to assess associations of testosterone (T), dihydrotestosterone (DHT) and estradiol (E2), with incident prostate, lung and colorectal cancer in community-dwelling older men. Plasma T, DHT and E2 were assayed using liquid chromatography-mass spectrometry between 2001 and 2004 in 3690 men. Cancer outcomes until 20 June 2013 were ascertained using data linkage. Analyses were performed using proportional hazards competing-risks models, and adjustments were made for potential confounding factors including smoking status. Results are expressed as subhazard ratios (SHR). There were 348, 107 and 137 cases of prostate, lung and colorectal cancers respectively during a median of 9.1-year follow-up. Mean T was comparable in current and non-smokers, whilst mean DHT was lower in ex- and current smokers compared to non-smokers. After adjusting for confounders including smoking, higher T or DHT was associated with an increased incidence of lung cancer (SHR = 1.30, 95% CI 1.06-1.60; p = 0.012 per 1 SD increase in T and SHR = 1.29, 95% CI 1.08-1.54; p = 0.004 for DHT). Sex hormones were not associated with prostate or colorectal cancer. In older men, higher T or DHT predict increased incidence of lung cancer over the next decade. Sex hormones are not associated with incident prostate or colorectal cancer. Further studies are warranted to determine if similar associations of sex hormones with lung cancer are present in other populations and to investigate potential underlying mechanisms.
- Published
- 2017
238. Depression Among Nonfrail Old Men Is Associated With Reduced Physical Function and Functional Capacity After 9 Years Follow-up: The Health in Men Cohort Study
- Author
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Keith D. Hill, Osvaldo P. Almeida, Graeme J. Hankey, Bu B. Yeap, Jonathan Golledge, and Leon Flicker
- Subjects
Male ,Gerontology ,medicine.medical_specialty ,Activities of daily living ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Weight loss ,Activities of Daily Living ,Epidemiology ,History of depression ,medicine ,Humans ,Prospective Studies ,030212 general & internal medicine ,Mobility Limitation ,General Nursing ,Depression (differential diagnoses) ,Aged ,Aged, 80 and over ,Depression ,business.industry ,Health Policy ,Western Australia ,General Medicine ,Confidence interval ,Physical Fitness ,Relative risk ,Geriatrics and Gerontology ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
Background Older adults with depression have increased risk of frailty and death. Objective To determine if history of depression hinders future physical and functional capacity. Design, setting, and participants Prospective longitudinal cohort study of 1148 men aged 70-87 years who were living in the Perth metropolitan community in 2001-2004 and completed a follow-up assessment of physical and functional capacity in 2011–2012. Main outcome and measures Outcomes were collected in 2011–2012 and included 4 measures of physical function (timed up-and-go, timed sit-to-stand, functional reach, and step test) and the assessment of basic (activities of daily living) and instrumental activities of daily living. We also collected information on depression and frailty [using the FRAIL (fatigue resistance ambulation illness, and loss of weight) scale] in 2001–2004 and 2011–2012. Frail men at the 2001–2004 were excluded from the analyses. Results Men with history of depression at the 2001–2004 assessment showed significantly worse performance than their counterparts in the timed sit-to-stand and step tests 9 years later. They also had approximately twice the risk of attaining the lowest decile of performance in both tests (analyses adjusted for age, education, and prevalent depressive symptoms). In addition, the adjusted risk ratio of impaired instrumental activities of daily living was 58% (95% confidence interval 15%, 116%) greater for men with than without history of past depression. These associations were particularly robust for men with current depression at the 2001–2004 assessment. Conclusions Nonfrail older men with history of current or past depression showed greater impairment of physical and functional capacity 9 years later. Older men with history of depression may benefit from regular monitoring of physical and occupational function and should be targeted by preventive trials designed to improve function and decrease frailty.
- Published
- 2017
239. Systematic review and meta-analysis of the association between intraluminal thrombus volume and abdominal aortic aneurysm rupture
- Author
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Tejas P. Singh, Joseph V. Moxon, and Jonathan Golledge
- Subjects
Aortic Rupture ,Abdomen ,Humans ,Thrombosis ,Surgery ,Cardiology and Cardiovascular Medicine ,Aortic Aneurysm, Abdominal - Published
- 2020
240. Suicide in older men: The health in men cohort study (HIMS)
- Author
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Bu B. Yeap, Jonathan Golledge, Kieran McCaul, Graeme J. Hankey, Leon Flicker, and Osvaldo P. Almeida
- Subjects
Male ,medicine.medical_specialty ,Substance-Related Disorders ,Epidemiology ,Population ,Poison control ,Suicide prevention ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Humans ,Medicine ,Longitudinal Studies ,030212 general & internal medicine ,Bipolar disorder ,education ,Psychiatry ,Depression (differential diagnoses) ,Aged ,Aged, 80 and over ,Depressive Disorder ,education.field_of_study ,Suicide attempt ,business.industry ,Public Health, Environmental and Occupational Health ,Western Australia ,medicine.disease ,030227 psychiatry ,Suicide ,Mood disorders ,Men's Health ,business ,Cohort study - Abstract
Suicide rates are high in later life, particularly among older men. Mood disorders are known risk factors, but the risk of suicide associated with poor physical health remains unclear. We completed a cohort study of a community representative sample of 38,170 men aged 65–85 in 1996 who were followed for up to 16 years. Data on suicide attempts and completion were obtained from the Western Australia Data Linkage System, as was information about medical and mental health diagnoses. 240 (0.6%) participants had a recorded history of past suicide attempt, most commonly by poisoning (85%). Sixty-nine men died by suicide during follow up (0.3% of all deaths), most often by hanging (50.7%). Age-adjusted competing risk regression showed that past suicide attempt was not a robust predictor of future suicide completion (sub-hazard ratio, SHR = 1.58, 95% CI = 0.39, 6.42), but bipolar (SHR = 7.82, 95% CI = 3.08, 19.90), depressive disorders (SHR = 2.26, 95% CI = 1.14, 4.51) and the number of health systems affected by disease (SHR for 3–4 health systems = 6.02, 95% CI = 2.69, 13.47; SHR for ≥ 5 health systems = 11.18, 95% CI = 4.89, 25.53) were. The population fraction of suicides attributable to having 5 or more health systems affected by disease was 79% (95% CI = 57%, 90%), and for any mood disorder (bipolar or depression) it was 17% (95% CI = 3%, 28%). Older Australian men with multiple health morbidities have the highest risk of death by suicide, even after taking into account the presence of mood disorders. Improving the overall health of the population may be the most effective way of decreasing the rates of suicide in later life.
- Published
- 2016
241. A small animal model for early cerebral aneurysm pathology
- Author
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David S. Anderson, Corey S. Moran, James A. Lee, Laurence A.G. Marshman, Eric P. Guazzo, Leslie Kuma, and Jonathan Golledge
- Subjects
Male ,Pathology ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Mice ,03 medical and health sciences ,Basal (phylogenetics) ,0302 clinical medicine ,Aneurysm ,Physiology (medical) ,Small animal ,medicine ,Animals ,Pathological ,Pancreatic elastase ,Pancreatic Elastase ,business.industry ,Elastase ,Intracranial Aneurysm ,General Medicine ,medicine.disease ,Internal elastic lamina ,Angiotensin II ,Mice, Inbred C57BL ,Disease Models, Animal ,Neurology ,Surgery ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Prior studies, using systemic hypertension and elastase infusion, have induced cerebral aneurysm (CA) formation in mice. However, the CAs induced were rapidly formed, relatively large, and often ruptured. These features are not completely representative of human CAs. We set out to develop a mouse model representative of the early pathological features of human CA. Twenty male C57/BL6 mice were placed in a stereotactic frame. Low dose elastase solution (2μl/min) was manually injected into the right basal cistern. Human angiotensin II (0.11μl/h) was infused subcutaneously. Mice were observed for 2-3weeks prior to euthanasia. Early CA histopathological features including endothelial change (EC) and internal elastic lamina degeneration (IELD) were systematically sought at major cerebral arterial bifurcations. Brains were harvested from 11 of 15 mice, yielding 27 bifurcations. Sub-arachnoid haemorrhage (SAH) without CA formation was observed in one brain. Macroscopic CA without SAH was observed in another brain. Early CA features were observed in 8/11 (73%) brains. All bifurcations with IELD demonstrated EC: where EC was absent, IELD was also absent. EC severity appeared to correlate with IELD severity. EC and IELD were both severe within the CA. Using lower dose elastase solution than previously employed, we developed a model of early CA pathology. Our model demonstrated that the spectrum of known early CA pathology can be created at multiple bifurcations in mice, with EC severity appearing to correlate with IELD severity. This model permits the study of factors which potentially advance or retard the progression of CA formation.
- Published
- 2016
242. Profile of diabetes in men aged 79-97 years: the Western Australian Health in Men Study
- Author
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M. Henze, Leon Flicker, Graeme J. Hankey, Helman Alfonso, Paul Norman, Osvaldo P. Almeida, Bu B. Yeap, S. A. P. Chubb, Jonathan Golledge, and Jill George
- Subjects
Male ,medicine.medical_specialty ,Multivariate analysis ,Heart disease ,Health Status ,Endocrinology, Diabetes and Metabolism ,Psychological intervention ,030209 endocrinology & metabolism ,Physical function ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Surveys and Questionnaires ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,Internal Medicine ,Humans ,Medicine ,030212 general & internal medicine ,Myocardial infarction ,Life Style ,Aged ,Aged, 80 and over ,business.industry ,Western Australia ,Odds ratio ,medicine.disease ,Cross-Sectional Studies ,Quality of Life ,Physical therapy ,Men's Health ,business ,Oral hypoglycaemic - Abstract
Aims To investigate behavioural, physical and biochemical characteristics associated with diabetes in the oldest age group of elderly men. Methods We conducted a cross-sectional analysis of community-dwelling men aged 79–97 years from Perth, Western Australia. Lifestyle behaviours, self-rated health, physical function, and fasting glucose and HbA1c levels were assessed. Results Of 1426 men, 315 had diabetes (22%). Men with diabetes were of similar age to men without (84.9 vs 84.5 years; P=0.14). Only 26.5% of men with diabetes self-rated their health as excellent or very good, compared with 40.6% of men without diabetes (P
- Published
- 2016
243. Rodent Models of Abdominal Aortic Aneurysm: How Far are Mice Men?
- Author
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Lesca M. Holdt, Gabor Gäbel, Lars Maegdefessel, Albert Busch, Daniel Teupser, Jonathan Golledge, Jan H.N. Lindeman, and Bernd H. Northoff
- Subjects
medicine.medical_specialty ,Rodent ,biology ,business.industry ,biology.animal ,medicine ,Surgery ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business ,Abdominal aortic aneurysm - Published
- 2019
244. Relationship Between Disease Specific Quality of Life Measures, Physical Performance, and Activity in People with Intermittent Claudication Caused by Peripheral Artery Disease
- Author
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Anthony S. Leicht, Belinda J. Parmenter, Yorgi Mavros, Jason Jenkins, Jenna Pinchbeck, Maria A. Fiatarone Singh, Marjan Mosalman Haghighi, Roslyn Clapperton, Matthew Hollings, Matthew Dally-Watkins, Lisan Yip, Nicola W. Burton, Jonathan Golledge, Sophie E. Rowbotham, and Yian Noble
- Subjects
Disease specific ,Male ,medicine.medical_specialty ,Arterial disease ,Walk Test ,Disease ,030204 cardiovascular system & hematology ,030230 surgery ,Spearman's rank correlation coefficient ,03 medical and health sciences ,Peripheral Arterial Disease ,0302 clinical medicine ,Quality of life ,medicine ,Humans ,Patient Reported Outcome Measures ,Prospective Studies ,Aged ,business.industry ,Intermittent Claudication ,Middle Aged ,Physical Functional Performance ,Intermittent claudication ,Cross-Sectional Studies ,Physical performance ,Physical therapy ,Quality of Life ,Surgery ,Observational study ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
The aims of this study were firstly to assess the correlation between disease specific measures of quality of life (QOL) and physical performance and activity, and secondly to identify demographic, clinical, functional, and physical activity measures independently associated with QOL in people with intermittent claudication.This was a cross sectional observational study of 198 people with intermittent claudication caused by peripheral artery disease who were recruited prospectively. QOL was assessed with the intermittent claudication questionnaire (ICQ) and the eight-theme peripheral artery disease quality of life questionnaire. Physical performance was assessed with the six minute walk test (6MWT) and short physical performance battery (SPPB), and an accelerometer was used to measure seven day step count. The associations between QOL scores and 6MWT distance, SPPB scores and seven day step count were examined using Spearman Rho's (ρ) correlation and multivariable linear regression.ICQ scores were significantly correlated with 6MWT distance (ρ = 0.472, p .001), all four SPPB scores (balance ρ = 0.207, p = .003; gait speed ρ = 0.303, p .001; chair stand ρ = 0.167, p = .018; total ρ = 0.265, p .001), and seven day step count (ρ = 0.254, p .001). PADQOL social relationships and interactions (ρ = 0.343, p .001) and symptoms and limitations in physical functioning (ρ = 0.355, p .001) themes were correlated with 6MWT distance. The 6MWT distance was independently positively associated with ICQ and both PADQOL theme scores (ICQ: B 0.069, p .001; PADQOL social relationships and interactions: B 0.077, p .001; PADQOL symptoms and limitations in physical functioning: B 0.069, p .001).Longer 6MWT distance independently predicted better physical and social aspects of QOL in people with intermittent claudication supporting its value as an outcome measure.
- Published
- 2019
245. Omega-3 fatty acids decrease oxidative stress and inflammation in macrophages from patients with small abdominal aortic aneurysm
- Author
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Rebecca Magee, Tom G. Bailey, Maria Perissiou, Jonathan Golledge, Lara T. Meital, Christopher D. Askew, Mark Windsor, Anna Kuballa, Karl Schulze, and Fraser D. Russell
- Subjects
0301 basic medicine ,Male ,Antioxidant ,Necrosis ,Lipopolysaccharide ,medicine.medical_treatment ,lcsh:Medicine ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Antioxidants ,Aortic aneurysm ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,lcsh:Science ,chemistry.chemical_classification ,Aged, 80 and over ,Multidisciplinary ,Middle Aged ,Docosahexaenoic acid ,Female ,medicine.symptom ,Oxidation-Reduction ,Polyunsaturated fatty acid ,Sports and Exercise Sciences ,medicine.medical_specialty ,Inflammation ,Article ,03 medical and health sciences ,Internal medicine ,Fatty Acids, Omega-3 ,Humans ,Fatty acids ,Monocytes and macrophages ,Aged ,business.industry ,Macrophages ,lcsh:R ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,chemistry ,lcsh:Q ,business ,Oxidative stress ,Heme Oxygenase-1 ,Aortic Aneurysm, Abdominal - Abstract
Abdominal aortic aneurysm (AAA) is associated with inflammation and oxidative stress, the latter of which contributes to activation of macrophages, a prominent cell type in AAA. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to limit oxidative stress in animal models of AAA. The aim of this study was to evaluate the effect of the n-3 PUFA docosahexaenoic acid (DHA) on antioxidant defence in macrophages from patients with AAA. Cells were obtained from men with small AAA (diameter 3.0–4.5 cm, 75 ± 6 yr, n = 19) and age- matched male controls (72 ± 5 yr, n = 41) and incubated with DHA for 1 h before exposure to 0.1 µg/mL lipopolysaccharide (LPS) for 24 h. DHA supplementation decreased the concentration of tumour necrosis factor-α (TNF-α; control, 42.1 ± 13.6 to 5.1 ± 2.1 pg/ml, p
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- 2019
246. Depletion of CD11c+ dendritic cells in apolipoprotein E-deficient mice limits angiotensin II-induced abdominal aortic aneurysm formation and growth
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Roby J. Jose, Corey S. Moran, Sharon Lazzaroni, Jonathan Golledge, Smriti M. Krishna, and Pacific Huynh
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Apolipoprotein E ,Male ,medicine.medical_specialty ,Apolipoprotein B ,Mice, Knockout, ApoE ,CD11c ,Inflammation ,Vascular Remodeling ,Flow cytometry ,Random Allocation ,Immune system ,Internal medicine ,medicine ,Cytotoxic T cell ,Animals ,Lymphocyte Count ,biology ,medicine.diagnostic_test ,Chemistry ,CD11 Antigens ,Angiotensin II ,General Medicine ,Dendritic Cells ,Atherosclerosis ,Endocrinology ,Cholesterol ,biology.protein ,medicine.symptom ,Leukocyte Elastase ,Aortic Aneurysm, Abdominal - Abstract
Objective: The role of chronic inflammation in abdominal aortic aneurysm (AAA) is controversial. CD11c+ antigen-presenting cells (APCs) (dendritic cells (DCs)) have been reported in human AAA samples but their role is unclear. The effect of conditional depletion of CD11c+ cells on experimental AAA was investigated in the angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE–/–) mouse model. Approach: CD11c-diphtheria toxin (DT or D.tox) receptor (DTR), ovalbumin (OVA) fragment aa 140–386, and enhanced green fluorescent protein (eGFP)-ApoE–/– (CD11c.DOG.ApoE–/–) mice were generated and CD11c+ cell depletion achieved with D.tox injections (8 ng/g body weight, i.p., every-other-day). AAA formation and growth were assessed by measurement of supra-renal aortic (SRA) diameter in vivo by serial ultrasound and by morphometry assessment of harvested aortas at the end of the study. Results: Depletion of CD11c+ cells by administration of D.tox on alternative days was shown to reduce the maximum diameter of AAAs induced by 28 days AngII infusion compared with controls (D.tox, 1.58 ± 0.03 mm vs Vehicle control, 1.81 ± 0.06 mm, P Conclusion: CD11c+ cell-depletion inhibited experimental AAA development and growth associated with down-regulation of circulating effector T cells and attenuated matrix degradation. The findings suggest involvement of autoreactive immune cells in AAA pathogenesis.
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- 2019
247. Associations of plasma IGF1, IGFBP3 and estradiol with leucocyte telomere length, a marker of biological age, in men
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Jennie Hui, Graeme J. Hankey, Stephen M. Twigg, Bu B. Yeap, Ho Ken K Y, Osvaldo P. Almeida, John Beilby, Mark L. Divitini, Chubb S A Paul, Leon Flicker, Gillian M. Arscott, Matthew Knuiman, and Jonathan Golledge
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Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Biological age ,IGFBP3 ,030209 endocrinology & metabolism ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Risk Factors ,Internal medicine ,Linear regression ,medicine ,Leukocytes ,Humans ,IGFBP1 ,Testosterone ,Insulin-Like Growth Factor I ,Aged ,Aged, 80 and over ,Immunoassay ,Estradiol ,General Medicine ,Telomere ,Insulin-Like Growth Factor Binding Protein 1 ,Insulin-Like Growth Factor Binding Protein 3 ,Ageing ,030220 oncology & carcinogenesis ,hormones, hormone substitutes, and hormone antagonists ,Biomarkers ,Hormone - Abstract
Objective Effects of insulin-like growth factor 1 (IGF1) and its binding proteins (IGFBPs) on ageing, and their interaction with sex hormones, remain uncertain. We examined associations of plasma IGF1, IGFBP1, IGFBP3, estradiol and testosterone, with leucocyte telomere length (LTL), a marker of biological age, in 2999 community-dwelling men aged 70–84 years. Methods Plasma IGF1, IGFBP1 and IGFBP3 measured using immunoassay, sex hormones using mass spectrometry. LTL measured by PCR, expressed as ratio of telomeric to single-copy control gene DNA (T/S ratio). Linear regression models adjusted for age and cardio-metabolic risk factors, median splits defined low/high groups. Results Mean age was 76.7 ± 3.2 years. IGF1 and IGFBP3 showed age-adjusted correlations with LTL (coefficient 0.59, P = 0.001 and 0.45, P = 0.013 respectively), IGFBP1 did not. In multivariable-adjusted models IGF1 and IGFBP3 (but not IGFBP1) were associated with LTL (T/S ratio 0.015 higher per 1 s.d. increase in IGF1, P = 0.007, and 0.011 per 1 s.d. IGFBP3, P = 0.049). IGF1 and estradiol were independently associated with longer telomeres (T/S ratio 0.012 higher per 1 s.d. increase in estradiol, P = 0.027, when included in model with IGF1). Testosterone was not associated with LTL. Men with both high IGF1 (>133 µg/L) and high estradiol (>70 pmol/L) had longer LTL compared to men with lower values (multivariable-adjusted T/S ratio 1.20 vs 1.16, P = 0.018). Conclusions Higher IGF1 and IGFBP3 are independently associated with longer telomeres in older men. Additive associations of higher IGF1 and higher estradiol with telomere length are present. Further studies are needed to determine whether these hormonal exposures cooperate to slow biological aging.
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- 2019
248. OR18-2 Higher Plasma Estradiol Concentration Is Independently Associated with Lower Biological Age, Assessed as Leucocyte Telomere Length, in Older Men
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David J. Handelsman, Mark L. Divitini, Jennie Hui, Paul Norman, Bu B. Yeap, Matthew Knuiman, Leon Flicker, Susan V. McLennan, Osvaldo P. Almeida, Jonathan Golledge, Graeme J. Hankey, Gillian M. Arscott, John Beilby, and Stephen M. Twigg
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Male Gonadal Function ,medicine.medical_specialty ,Endocrinology ,Text mining ,business.industry ,Endocrinology, Diabetes and Metabolism ,Internal medicine ,Biological age ,medicine ,Reproductive Endocrinology ,business ,Telomere ,Plasma estradiol - Abstract
Telomeres are essential DNA-protein complexes comprising TTAGGG repeats binding specific proteins, which protect the physical ends of chromosomes from fusion and degradation. Attrition of telomeres results in cellular senescence. Leucocyte telomere length (LTL) reflects lengths of telomeres in various tissues, and shorter LTL is a marker of advancing biological age. Previous work has associated bioactive metabolites of T, dihydrotestosterone (DHT) and estradiol (E2) with LTL in a population of predominantly middle-aged men [1]. However, the relationship of these hormones to biological age in older men was unclear. We aimed to clarify associations of sex hormones with LTL in a cohort of 2,913 community-dwelling men aged 70-89 years. Early morning blood samples were assayed for T, DHT and E2 using mass spectrometry, and for sex hormone-binding globulin (SHBG) using immunoassay. LTL was measured using a multiplex quantitative PCR method and expressed as the amount of telomeric DNA relative to beta-globin, a single copy control gene (T/S ratio). Cross-sectional analyses utilised multivariable linear regression. Mean (±SD) age was 76.7±3.2 years. The average difference per decade of age was T -0.46 nmol/L, DHT -0.11 nmol/L, E2 -7.5 pmol/L, SHBG +10.2 nmol/L, and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r=0.038, p=0.039). After excluding highest and lowest 1% of values, the correlation between E2 and T/S ratio was largely unchanged (r=0.039, p=0.037). SHBG was inversely correlated with T/S ratio (r=-0.053, p=0.004), also unchanged in the trimmed analysis (r=-0.055, p=0.004.) After adjusting for age, BMI, cardiovascular disease, diabetes, alcohol, smoking, physical activity, lipids and hypertension, E2 remained associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, p=0.043). When E2 and SHBG were simultaneously included in the multivariate model, E2 remained positively associated with T/S ratio (coefficient 0.014, p=0.014) and SHBG inversely associated (coefficient -0.013, p=0.037). The magnitude of increase in T/S ratio associated with a 1 SD higher plasma E2 concentration was comparable with having a BMI 3.6 kg/m2 lower, and two thirds that associated with being 3.6 years younger. T, DHT and LH were not associated with LTL in multivariate analyses. To conclude, in older men, neither T nor DHT are associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated. These findings associate activity of the gonadal axis with lower biological age in older men. However, causality cannot be inferred from an observational, cross-sectional study, thus additional research is necessary to determine whether sex hormone exposure modulates male biological ageing. Reference: [1] Yeap BB, et al. J Clin Endocrinol Metab 2016; 101: 1299-1306.
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- 2019
249. Cohort Study Examining the Association Between Blood Pressure and Cardiovascular Events in Patients With Peripheral Artery Disease
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Joseph V. Moxon, Jason Jenkins, Smriti M. Krishna, Frank Quigley, Rhondda E. Jones, Bernie Bourke, Diana Thomas Manapurathe, Jonathan Golledge, Michael J. Bourke, and Sophie E. Rowbotham
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Male ,medicine.medical_specialty ,Time Factors ,Blood Pressure ,Coronary Disease ,030204 cardiovascular system & hematology ,peripheral artery disease ,Vascular Medicine ,Peripheral Arterial Disease ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Clinical Studies ,Prevalence ,Humans ,Medicine ,Prospective Studies ,030212 general & internal medicine ,Myocardial infarction ,Risk factor ,Prospective cohort study ,Stroke ,Aged ,Original Research ,business.industry ,Incidence ,Hazard ratio ,Angiography ,Middle Aged ,medicine.disease ,stroke ,Survival Rate ,myocardial infarction ,Blood pressure ,Peripheral Vascular Disease ,major adverse cardiac event ,Hypertension ,Cohort ,Cardiology ,Female ,Queensland ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies ,Cohort study - Abstract
Background Hypertension is an important risk factor for cardiovascular events in patients with peripheral artery disease; however, optimal blood pressure targets for these patients are poorly defined. This study investigated the association between systolic blood pressure ( SBP ) and cardiovascular events in a prospectively recruited patient cohort with peripheral artery disease. Methods and Results A total of 2773 patients were included and were grouped according to SBP at recruitment (≤120 mm Hg, n=604; 121–140 mm Hg, n=1065; and >140 mm Hg, n=1104). Adjusted Cox proportional hazards analyses suggested that patients with SBP ≤120 mm Hg were at greater risk of having a major cardiovascular event (myocardial infarction, stroke, or cardiovascular death) than patients with SBP of 121–140 mm Hg (adjusted hazard ratio, 1.36; 95% CI, 1.08–1.72; P =0.009). Patients with SBP >140 mm Hg had an adjusted hazard ratio of 1.23 (95% CI, 1.00–1.51; P =0.051) of major cardiovascular events compared with patients with SBP of 121–140 mm Hg. These findings were similar in sensitivity analyses only including patients receiving antihypertensive medications or focused on patients with a minimum of 3 months of follow‐up. Conclusions This cohort study suggests that patients with peripheral artery disease and SBP ≤120 mm Hg are at increased risk of major cardiovascular events. The findings suggest caution in intensive SBP lowering in this patient group.
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- 2019
250. High‐Sensitivity Cardiac Troponin I Improves Cardiovascular Risk Prediction in Older Men: HIMS (The Health in Men Study)
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Osvaldo P. Almeida, Kieran McCaul, Damon A. Bell, Graeme J. Hankey, Samuel D Vasikaran, Nick S.R. Lan, Bu B. Yeap, Leon Flicker, Jonathan Golledge, and Paul Norman
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Male ,medicine.medical_specialty ,Time Factors ,Cardiac troponin ,cardiovascular disease risk factors ,Epidemiology ,Health Status ,risk stratification ,Comorbidity ,030204 cardiovascular system & hematology ,Risk Assessment ,risk prediction ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,cardiovascular disease ,Risk Factors ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Sensitivity (control systems) ,Original Research ,Aged ,Aged, 80 and over ,Framingham Risk Score ,cardiovascular disease prevention ,biology ,troponin ,business.industry ,Incidence ,aging ,Troponin I ,Age Factors ,Western Australia ,Prognosis ,Troponin ,3. Good health ,Primary Prevention ,Cardiovascular Diseases ,Risk stratification ,biology.protein ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Background The Framingham Risk Score estimates the 10‐year risk of cardiovascular events. However, it performs poorly in older adults. We evaluated the incremental benefit of adding high‐sensitivity cardiac troponin I (hs‐cTnI) to the Framingham Risk Score. Methods and Results The HIMS (Health in Men Study) is a cohort study of community‐dwelling men aged 70 to 89 years in Western Australia. Participants were identified from the electoral roll, with a subset undergoing plasma analysis. Hs‐ cTnI (Abbott Architect i2000 SR ) was measured in 1151 men without prior cardiovascular disease. The Western Australia Data Linkage System was used to identify incident cardiovascular events. After 10 years of follow‐up, 252 men (22%) had a cardiovascular event ( CVE +) and 899 did not (CVE–). The Framingham Risk Score placed 148 (59%) CVE + and 415 (46%) CVE– in the high‐risk category. In CVE – men, adding hs‐ cTnI affected the risk categories of 244 (27.2%) men, with 64.8% appropriately reclassified to a lower and 35.2% to a higher category, which decreased the number of high‐risk men in the CVE– to 39%. In CVE + men, adding hs‐ cTnI affected the risk categories of 61 (24.2%), with 50.8% appropriately reclassified to a higher and 49.2% to a lower category and 82.5% remaining above the 15% risk treatment threshold. The net reclassification index was 0.305 ( P cTnI increased the C‐statistic modestly from 0.588 (95% CI , 0.552–0.624) to 0.624 (95% CI , 0.589–0.659) and improved model fit (likelihood ratio test, P Conclusions Adding hs‐ cTnI to the Framingham Risk Score provided incremental prognostic benefit in older men, especially aiding reclassification of individuals into a lower risk category.
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- 2019
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