Edinburgh Type Research Articles

Exploration of Metabolomic Markers Associated With Declining Kidney Function in People With Type 2 Diabetes Mellitus.

Metabolomics, the study of small molecules in biological systems, can provide valuable insights into kidney dysfunction in people with type 2 diabetes mellitus (T2DM), but prospective studies are scarce. We investigated the association between metabolites and kidney function decline in people with T2DM. The Edinburgh Type 2 Diabetes Study, a population-based cohort of 1066 men and women aged 60 to 75 years with T2DM. We measured 149 serum metabolites at baseline and investigated individual associations with baseline estimated glomerular filtration rate (eGFR), incident chronic kidney disease [CKD; eGFR <60 mL/min/(1.73 m)2], and decliner status (5% eGFR decline per year). At baseline, mean eGFR was 77.5 mL/min/(1.73 m)2 (n = 1058), and 216 individuals had evidence of CKD. Of those without CKD, 155 developed CKD over a median 7-year follow-up. Eighty-eight metabolites were significantly associated with baseline eGFR (β range -4.08 to 3.92; PFDR < 0.001). Very low density lipoproteins, triglycerides, amino acids (AAs), glycoprotein acetyls, and fatty acids showed inverse associations, while cholesterol and phospholipids in high-density lipoproteins exhibited positive associations. AA isoleucine, apolipoprotein A1, and total cholines were not only associated with baseline kidney measures (PFDR < 0.05) but also showed stable, nominally significant association with incident CKD and decline. Our study revealed widespread changes within the metabolomic profile of CKD, particularly in lipoproteins and their lipid compounds. We identified a smaller number of individual metabolites that are specifically associated with kidney function decline. Replication studies are needed to confirm the longitudinal findings and explore if metabolic signals at baseline can predict kidney decline.

Combining serum metabolomic profiles with traditional risk factors improves 10-year cardiovascular risk prediction in people with type 2 diabetes.

To identify a group of metabolites associated with incident cardiovascular disease (CVD) in people with type 2 diabetes and assess its predictive performance over-and-above a current CVD risk score (QRISK3). A panel of 228 serum metabolites was measured at baseline in 1066 individuals with type 2 diabetes (Edinburgh Type 2 Diabetes Study) who were then followed up for CVD over the subsequent 10 years. We applied 100 repeats of Cox least absolute shrinkage and selection operator to select metabolites with frequency >90% as components for a metabolites-based risk score (MRS). The predictive performance of the MRS was assessed in relation to a reference model that was based on QRISK3 plus prevalent CVD and statin use at baseline. Of 1021 available individuals, 255 (25.0%) developed CVD (median follow-up: 10.6 years). Twelve metabolites relating to fluid balance, ketone bodies, amino acids, fatty acids, glycolysis, and lipoproteins were selected to construct the MRS that showed positive association with 10-year cardiovascular risk following adjustment for traditional risk factors [hazard ratio (HR) 2.67; 95% confidence interval (CI) 1.96, 3.64]. The c-statistic was 0.709 (95%CI 0.679, 0.739) for the reference model alone, increasing slightly to 0.728 (95%CI 0.700, 0.757) following addition of the MRS. Compared with the reference model, the net reclassification index and integrated discrimination index for the reference model plus the MRS were 0.362 (95%CI 0.179, 0.506) and 0.041 (95%CI 0.020, 0.071), respectively. Metabolomics data might improve predictive performance of current CVD risk scores based on traditional risk factors in people with type 2 diabetes. External validation is warranted to assess the generalizability of improved CVD risk prediction using the MRS.

Comparison of the clinical efficacy of three internal fixation methods in the treatment of Edinburgh type IB fractures of the proximal clavicle

ABSTRACT Clavicle fractures are one of the most common fractures and usually occur in the medial third of the clavicle. The study explored the efficacy of three internal fixation methods to treat Edinburgh IB fractures of the proximal clavicle. 68 patients with Edinburgh IB fractures of the proximal clavicle were divided into T-shaped plate group, double-miniature steel plate group and memory alloy embracing device group. Postoperative complications, return time to work, and fracture healing time were recorded. The clinical efficacy was evaluated by Constant-Murley score of shoulder joint, Visual Analogue Scale (VAS) score of pain, and arm-shoulder-hand dysfunction score. The operative time of the memory alloy embracing device group was significantly better than T-shaped plate group and double-miniature steel plate group. The length of surgical incision in the double-miniature steel plate group was significantly shorter than that in the T-shaped plate group and the memory alloy embracing device group. The hospitalization cost and recovery time of the double-plate and memory alloy hug groups were lower than those of the T-plate group. The double-miniature steel plate group and the memory alloy embracing device group were significantly better than the T-shaped plate group at two weeks after operation. Satisfactory clinical results can be obtained by using T-shaped plate, double-miniature steel plate and memory alloy embracing device in the treatment of Edinburgh IB fracture of proximal clavicle. However, the double-miniature steel plate group has the advantages of small incision, low cost, and quick postoperative recovery, and has more early advantages.

Risk of dementia associated with body mass index, changes in body weight and waist circumference in older people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study.

To determine the relationship of dementia with preceding body mass index (BMI), changes in body weight and waist circumference in older people with type 2 diabetes. In the Edinburgh Type 2 Diabetes Study (1064 men and women with type 2 diabetes, aged 60-75), body weight, waist circumference and BMI were measured at baseline and after 4 years in a subgroup (n= 821). Percentage body weight and waist circumference change over 4 years were calculated. Data on incident dementia was recorded during a median follow-up time of 10.84 years. Survival models considering a range of co-variables and/or death as a competing risk were used to estimate the risks of dementia associated with each weight-related variable. A total of 105 incident dementia events were recorded. When compared with people in the lowest BMI group (<25 kg/m2 ), risk of dementia was lower in intermediate BMI groups (25-29.9kg/m2 , HR 0.44, p= 0.002; 30-34.9kg/m2 , HR 0.41, p= 0.001) and the highest BMI group (≧35 kg/m2 , HR 0.35, p= 0.001). In the weight change subgroup, 78 incident dementia events were recorded between years 4 and 10. Body weight loss over 5% (compared with ≦5%) was associated with higher incidence of dementia (HR 2.06, p= 0.010). The association between waist circumference change and dementia was not significant. Both a lower BMI and weight loss over a period of years are indicative of increased dementia risk for older people with type 2 diabetes, while waist circumference changes may be less informative.

Abstract 10457: Improved 10-Year Cardiovascular Risk Prediction Combining Serum Metabolites With Traditional Cardiovascular Risk Factors in People With Type 2 Diabetes: Edinburgh Type 2 Diabetes Study

Introduction: Cardiovascular disease (CVD) is the leading cause of death for people with type 2 diabetes (T2D). The predictive performance of existing CVD risk scores in T2D populations is suboptimal. Metabolomics is a promising method of identifying novel biomarkers which might improve risk prediction. We aimed to identify a group of metabolites associated with incident CVD in people with T2D and assess its predictive performance over-and-above a current CVD risk score (QRISK3). Methods: In 1,066 individuals with T2D (Edinburgh Type 2 Diabetes Study), a panel of 228 serum metabolites was measured at baseline and incident CVD events were identified over the subsequent 10 years. We applied 100 repeats of Cox LASSO (least absolute shrinkage and selection operator) to select metabolites with frequency &gt;90% as candidate components for a metabolites-based risk score (MRS). The MRS was calculated using the linear predictor in an unpenalized Cox regression model where only candidate metabolites were included. The predictive performance of the MRS was assessed in relation to a reference score which refitted components of QRISK3 plus prevalent CVD and statin use at baseline. Predictive metrics were internally validated using 500-repeat bootstrapping. Results: In 1,021 available individuals (mean age 67.9 years, 51.7% male), 255 people developed CVD (25.0%) during a median of 10.6 years of follow-up. Twelve metabolites relating to fluid balance, ketone bodies, amino acids, fatty acids, glycolysis and lipoproteins were selected to construct the MRS. C-statistics were 0.673 (95%CI 0.642, 0.704) for the MRS alone and 0.718 (95%CI 0.689, 0.747) for the reference score, increasing slightly to 0.736 (95%CI 0.707, 0.764) for the combination of the two. The improved prediction by combining the MRS with the reference score was internally validated in bootstrapping samples, where the C-statistics for the reference score and the combination were 0.679 (95%CI 0.650, 0.708) vs. 0.699 (95%CI 0.671, 0.728) separately. Conclusions: Metabolomics data might improve predictive performance of current CVD risk scores based on traditional risk factors in people with T2D. External validation is warranted to assess the generalizability of improved CVD risk prediction using the MRS.

Serum metabolomic profiles associated with subclinical and clinical cardiovascular phenotypes in people with type 2 diabetes

BackgroundAtherosclerotic cardiovascular diseases (CVD) is the leading cause of death in diabetes, but the full range of biomarkers reflecting atherosclerotic burden and CVD risk in people with diabetes is unknown. Metabolomics may help identify novel biomarkers potentially involved in development of atherosclerosis. We investigated the serum metabolomic profile of subclinical atherosclerosis, measured using ankle brachial index (ABI), in people with type 2 diabetes, compared with the profile for symptomatic CVD in the same population.MethodsThe Edinburgh Type 2 Diabetes Study is a cohort of 1,066 individuals with type 2 diabetes. ABI was measured at baseline, years 4 and 10, with cardiovascular events assessed at baseline and during 10 years of follow-up. A panel of 228 metabolites was measured at baseline using nuclear magnetic resonance spectrometry, and their association with both ABI and prevalent CVD was explored using univariate regression models and least absolute shrinkage and selection operator (LASSO). Metabolites associated with baseline ABI were further explored for association with follow-up ABI and incident CVD.ResultsMean (standard deviation, SD) ABI at baseline was 0.97 (0.18, N = 1025), and prevalence of CVD was 35.0%. During 10-year follow-up, mean (SD) change in ABI was + 0.006 (0.178, n = 436), and 257 CVD events occurred. Lactate, glycerol, creatinine and glycoprotein acetyls levels were associated with baseline ABI in both univariate regression [βs (95% confidence interval, CI) ranged from − 0.025 (− 0.036, − 0.015) to − 0.023 (− 0.034, − 0.013), all p < 0.0002] and LASSO analysis. The associations remained nominally significant after adjustment for major vascular risk factors. In prospective analyses, lactate was nominally associated with ABI measured at years 4 and 10 after adjustment for baseline ABI. The four ABI-associated metabolites were all positively associated with prevalent CVD [odds ratios (ORs) ranged from 1.29 (1.13, 1.47) to 1.49 (1.29, 1.74), all p < 0.0002], and they were also positively associated with incident CVD [ORs (95% CI) ranged from 1.19 (1.02, 1.39) to 1.35 (1.17, 1.56), all p < 0.05].ConclusionsSerum metabolites relating to glycolysis, fluid balance and inflammation were independently associated with both a marker of subclinical atherosclerosis and with symptomatic CVD in people with type 2 diabetes. Additional investigation is warranted to determine their roles as possible etiological and/or predictive biomarkers for atherosclerotic CVD.

Higher baseline inflammatory marker levels predict greater cognitive decline in older people with type 2 diabetes: year 10 follow-up of the Edinburgh Type 2 Diabetes Study

Aims/hypothesisWe aimed to determine the longitudinal association of circulating markers of systemic inflammation with subsequent long-term cognitive change in older people with type 2 diabetes.MethodsThe Edinburgh Type 2 Diabetes Study is a prospective cohort study of 1066 adults aged 60 to 75 years with type 2 diabetes. Baseline data included C-reactive protein, IL-6, TNF-α fibrinogen and neuropsychological testing on major cognitive domains. Cognitive testing was repeated after 10 years in 581 participants. A general cognitive ability score was derived from the battery of seven individual cognitive tests using principal component analysis. Linear regression was used to determine longitudinal associations between baseline inflammatory markers and cognitive outcomes at follow-up, with baseline cognitive test results included as covariables to model cognitive change over time.ResultsFollowing adjustment for age, sex and baseline general cognitive ability, higher baseline fibrinogen and IL-6 were associated with greater decline in general cognitive ability (standardised βs = −0.059, p=0.032 and −0.064, p=0.018, respectively). These associations lost statistical significance after adjustment for baseline vascular and diabetes-related covariables. When assessing associations with individual cognitive tests, higher IL-6 was associated with greater decline in tests of executive function and abstract reasoning (standardised βs = 0.095, p=0.006 and −0.127, p=0.001, respectively). Similarly, raised fibrinogen and C-reactive protein levels were associated with greater decline in processing speed (standardised βs = −0.115, p=0.001 and −0.111, p=0.001, respectively). These associations remained statistically significant after adjustment for the diabetes- and vascular-related risk factors.Conclusions/interpretationHigher baseline levels of inflammatory markers, including plasma IL-6, fibrinogen and C-reactive protein, were associated with subsequent cognitive decline in older people with type 2 diabetes. At least some of this association appeared to be specific to certain cognitive domains and to be independent of vascular and diabetes-related risk factors.Graphical abstract

Retinal arteriolar tortuosity and fractal dimension are associated with long-term cardiovascular outcomes in people with type 2 diabetes

Aims/hypothesisOur aim was to determine whether quantitative retinal traits in people with type 2 diabetes are independently associated with incident major cardiovascular events including CHD and stroke.MethodsA total of 1066 men and women with type 2 diabetes, aged 65–74 years, were followed up over 8 years in the population-based Edinburgh Type 2 Diabetes Study. Using retinal photographs taken at baseline and specialist software, a number of quantitative retinal traits were measured, including arteriolar and venular widths and tortuosity as well as fractal dimension (a measure of the branching pattern complexity of the retinal vasculature network). Incident CHD events occurring during follow-up included fatal and non-fatal myocardial infarction, first episodes of angina and coronary interventions for CHD. Incident cerebrovascular events included fatal and non-fatal stroke or transient ischaemic attack. Cox proportional hazard regression analyses were performed to identify the association of the retinal traits with cardiovascular events in the population with retinal data available (n = 1028).ResultsA total of 200 participants had an incident cardiovascular event (139 CHD and 61 cerebrovascular events). Following adjustment for age and sex, arteriolar tortuosity and fractal dimension were associated with cerebrovascular events (HR 1.27 [95% CI 1.02, 1.58] and HR 0.74 [95% CI 0.57, 0.95], respectively), including with stroke alone (HR 1.30 [95% CI 1.01, 1.66] and HR 0.73 [95% CI 0.56, 0.97], respectively). These associations persisted after further adjustment for established cardiovascular risk factors (HR 1.26 [95% CI 1.01, 1.58] and HR 0.73 [95% CI 0.56, 0.94], respectively). Associations generally reduced in strength after a final adjustment for the presence of diabetic retinopathy, but the association of fractal dimension with incident cerebrovascular events and stroke retained statistical significance (HR 0.73 [95% CI 0.57, 0.95] and HR 0.72 [95% CI 0.54, 0.97], respectively). Associations of retinal traits with CHD were generally weak and showed no evidence of statistical significance.Conclusions/interpretationArteriolar tortuosity and fractal dimension were associated with incident cerebrovascular events, independent of a wide range of traditional cardiovascular risk factors including diabetic retinopathy. These findings suggest potential for measurements of early retinal vasculature change to aid in the identification of people with type 2 diabetes who are at increased risk from stroke.Graphical abstract

Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in type 2 diabetes: The Edinburgh Type 2 Diabetes Study.

BackgroundType 2 diabetes (T2D) is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non‐alcoholic fatty liver disease (NAFLD). However, the absolute risk of progression is low. So, it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk‐stratification tools are suboptimal and perform worse in people with diabetes.AimsTo determine whether the addition of complementary biomarker(s) to current NAFLD risk‐stratification tools in people with T2D could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC.MethodsThe Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with T2D (n = 1066, age 60–75 at baseline). Cases of cirrhosis and HCC were identified over 11 years of follow‐up. Biomarkers were measured at baseline and year 1 and association with incident disease was assessed using logistic regression.ResultsOf existing risk‐stratification scores tested, the Fibrosis‐4 (FIB‐4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut‐point ≥ 50 μ g/L) to FIB‐4 (cut‐point ≥ 1.3) maintained a false negative rate of ≤25% and reduced the number of people incorrectly identified as “high risk” for incident disease by ∼50%.ConclusionsThe addition of hyaluronic acid to FIB‐4 reduced the proportion of people inappropriately identified as “high risk” for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with T2D. These findings require a validation in independent cohorts.

Retinal venular tortuosity and fractal dimension predict incident retinopathy in adults with type 2 diabetes: the Edinburgh Type 2 Diabetes Study

Aims/hypothesisOur aim was to determine whether a range of prespecified retinal vessel traits were associated with incident diabetic retinopathy in adults with type 2 diabetes.MethodsIn the prospective observational cohort Edinburgh Type 2 Diabetes Study of 1066 adults with type 2 diabetes, aged 60–75 years at recruitment, 718 were free from diabetic retinopathy at baseline. Baseline retinal traits including vessel widths, tortuosity (curvature) and fractal dimensions (network complexity), were quantified using fundus camera images and semiautomated software, and analysed using logistic regression for their association with incident diabetic retinopathy over 10 years.ResultsThe incidence of diabetic retinopathy was 11.4% (n = 82) over 10 years. After adjustment for a range of vascular and diabetes-related risk factors, both increased venular tortuosity (OR 1.51; 95% CI 1.15, 1.98; p = 0.003) and decreased fractal dimension (OR 0.75; 95% CI 0.58, 0.96; p = 0.025) were associated with incident retinopathy. There was no evidence of an association with arterial tortuosity, and associations between measurements of vessel widths and retinopathy lost statistical significance after adjustment for diabetes-related factors and vascular disease. Adding venular tortuosity to a model including established risk factors for diabetic retinopathy (HbA1c, BP and kidney function) improved the discriminative ability (C statistic increased from 0.624 to 0.640, p = 0.013), but no such benefit was found with fractal dimension.Conclusions/interpretationIncreased retinal venular tortuosity and decreased fractal dimension are associated with incident diabetic retinopathy, independent of classical risk factors. There is some evidence that venular tortuosity may be a useful biomarker to improve the predictive ability of models based on established retinopathy risk factors, and its inclusion in further risk prediction modelling is warranted.Graphical abstract

Depression as a risk factor for dementia in older people with type 2 diabetes and the mediating effect of inflammation

Aims/hypothesisWe aimed to determine the association of depression with dementia risk in people with type 2 diabetes, and to explore the possible mediating role of inflammation in this relationship.MethodsThe Edinburgh Type 2 Diabetes Study is a prospective cohort of 1066 men and women with type 2 diabetes aged 60–75 years. Cox proportional hazards regression analysis was used to investigate the association between depression, assessed at baseline, and subsequent risk of dementia over 10 years. Depression was defined using the Hospital Anxiety and Depression Scale, while incident dementia was defined using medical records, prescription data and death certificates. The potential mediating effect of systemic inflammation was assessed by adjusting models for a generalised inflammation factor, derived from four inflammatory markers measured at baseline (C-reactive protein, IL-6, TNF-α and fibrinogen), and carrying out an exploratory mediation analysis.ResultsDementia developed in 105 participants over a median follow-up of 10.6 years. After adjusting for age and sex, depression was associated with over a 2.5-fold increase in risk of dementia (HR 2.59 [95% CI 1.62, 4.15]). Additional adjustment for the generalised inflammation factor and other covariates did not attenuate the size of association between depression and incident dementia and mediation analysis showed that it was not a mediator. Adjusted logistic regression models showed cross-sectional associations of C-reactive protein and IL-6 with depression.Conclusions/interpretationDepression is an important risk factor for dementia in people with type 2 diabetes. Some inflammatory markers were associated with depression, but systemic inflammation does not appear to mediate the relationship between depression and dementia.Graphical abstract

Non-invasive risk scores do not reliably identify future cirrhosis or hepatocellular carcinoma in Type 2 diabetes: The Edinburgh type 2 diabetes study.

The incidence of cirrhosis and hepatocellular carcinoma (HCC) is increased in Type 2 diabetes, primarily secondary to non-alcoholic fatty liver disease (NAFLD). European guidelines recommend screening for NAFLD in Type 2 diabetes. American guidelines, while not advocating a screening protocol, suggest using non-invasive markers of fibrosis for risk-stratification and guiding onward referral. To test the ability of individual fibrosis scores and the European screening algorithm to predict 11-year incident cirrhosis/HCC in an asymptomatic community cohort of older people with Type 2 diabetes. The Edinburgh Type 2 Diabetes Study investigated men and women with Type 2 diabetes (n = 1066, aged 60-75 at baseline). Liver markers were measured at baseline and year 1; steatosis and fibrosis markers were calculated according to independently published calculations. During 11 years of follow-up, cases of cirrhosis and HCC were identified. Forty-three out of 1059 participants with no baseline cirrhosis/HCC developed incident disease. All scores were significantly associated with incident liver disease by odds ratio (P < .05). The ability of the risk-stratification tools to accurately identify those who developed incident cirrhosis/HCC was poor with low-positive predictive values (5-46%) and high false-negative and -positive rates (up to 60% and 77%) respectively. When fibrosis risk scores were used in conjunction with the European algorithm, they performed modestly better than when applied in isolation. In a cohort with a moderately low incidence of cirrhosis/HCC, existing risk scores did not reliably identify participants at high risk. Better prediction models for cirrhosis/HCC in people with Type 2 diabetes are required.

EVALUATION THE SIGN OF UNION, DURATION OF SURGERY AND POST-OPERATIVE SKIN COMPLICATION IN MID SHAFT CLAVICLE FRACTURE.

INTRODUCTION: It is impossible to support and immobilize a fracture of middle 3rd of clavicle in an adult by external means with figure-of-eight bandages. Clavicle fractures accounts for approximately 2.6% of all fractures in adults2 10% to 15% in children and comprise about 30 -40% of all shoulder girdle injuries and 5% fractures occurs in medial end. The goal of clavicle fracture treatment is to achieve bony union while minimizing dysfunction, morbidity, and cosmetic deformity. Definitive indications for acute surgical intervention include skin tenting, open fractures, the presence of neurovascular compromise, multiple trauma, or floating shoulder. Outside of these indications, the management of displaced fractures of the mid shaft (Edinburgh type 2B) remains somewhat controversial. Recent literature is challenging the traditional belief that mid- shaft clavicle fractures uniformly heal without functional deficit. &#x0D; MATERIAL AND METHODS: Patients included were cases of mid shaft clavicle fractures. 30 patients with mid shaft clavicle fractures were included in the study.All patients above 18 years of age were included in the study falling into Robinson’s type 2 B1 (Mid shaft simple displaced and single butterfly fragment fracture), type 2 B2 (Mid shaft segmental fracture) classification. The patients were selected randomly and were divided in the following two groups of 15 patients each: Group A: 15 patients treated by anatomical locking compression plate (LCP) by open technique. Group B: 15 patients treated by minimal invasive percutaneous osteosynthesis (MIPO) technique. All patients were operated as early as possible once the patient was declared fit for the surgery by the physician. Open reduction and internal fixation with LCP was done.&#x0D; RESULTS: A total of 30 patients were included in the study. In group A 15 patients treated by anatomical locking compression plate (LCP) by open technique and in group B 15 patients treated by minimal invasive percutaneous osteosynthesis (MIPO) technique. In Group A, 7 (46.7%) patients had operative time of 80-100 minutes whereas 6 (40%) and 2 (13.3%) patients had operative time of 100-120 and 120-140 minutes respectively. The mean operative time was 104.9 ± 13.52mins. In Group B, 6 (40%) patients had operative time of 80-100 minutes whereas 8 (53.4%) and 1 (6.6%) patients had operative time of 100-120 and 120-140 minutes respectively. The mean operative time was 106.5 ± 11.72mins. The mean duration for radiological union in Group A was 12.7 ± 4.61 weeks. Majority of the patients (60%) achieved radiological union in &lt;12 weeks while 6 (40%) patients achieved union in 12-24 weeks. In Group B, majority of the patients (66.7%) achieved radiological union in &lt;12 weeks while 5 (33.3%) patients achieved union in 12-24 weeks. The mean duration for radiological union in Group B was 12.1 ± 6.68 weeks.&#x0D; CONCLUSION: MIPOs can used to preserve the biology at the fracture site, to maximise the healing potential of the bone, and to facilitate early and pain free recovery and MIPPO technique with the application of LCP offered an ideal combination in terms of bone fixation and soft-tissue sparing.

Decreased iron stores are associated with cardiovascular disease in patients with type 2 diabetes both cross-sectionally and longitudinally

Background and aimsThe possible contribution of iron to cardiovascular complications of type 2 diabetes (T2D) has been scarcely investigated. We aimed to study whether serum ferritin is linked to prevalent/incident cardiovascular disease (CVD) in T2D. MethodsThe prevalence of coronary heart disease (CHD), cerebrovascular disease (CEVD) and CVD was evaluated in the SIDIAP study (n = 38,617) and prevalence and 7-year incidence were analysed in the Edinburgh Type 2 Diabetes Study (ET2DS) (n = 821). Logistic and Cox regressions were used to describe associations between serum ferritin and CVD adjusting for confounding variables. ResultsIncrease of 1 SD unit in log-ferritin was associated with lower CVD prevalence in fully-adjusted models (ET2DS odds ratio (OR) 95% confidence interval (CI): 0.81 (0.68–0.96), p = 0.018; SIDIAP study: 0.91 (0.88–0.94), p < 0.001). In ET2DS, ferritin in the highest (vs. the lowest) quintile was associated with lower incidence of CVD (fully adjusted HR 95% CI: 0.46 (0.26–0.83), p = 0.010). This association persisted after removing subjects with CVD at baseline (n = 536) (HR 95% CI: 0.34 (0.14–0.81), p = 0.016). ConclusionsLow iron status was associated with CVD risk in T2D. This pattern was consistent in populations at different cardiovascular risk. Low iron status seems to be harmful for cardiovascular health in T2D and it may be a target for intervention.

Comparison of non-traditional biomarkers, and combinations of biomarkers, for vascular risk prediction in people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study

Background and aimsWe aimed at comparing the impact of multiple non-traditional biomarkers (ankle brachial pressure index (ABI), N-terminal pro-brain natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin (hs-cTnT), gamma-glutamyl transpeptidase (GGT) and four markers of systemic inflammation), both individually and in combination, on cardiovascular risk prediction, over and above traditional risk factors incorporated in the QRISK2 score, in older people with type 2 diabetes. MethodsWe conducted a prospective study of 1066 men and women aged 60–75 years with type 2 diabetes mellitus, living in Lothian, Scotland. ResultsAfter 8 years, 205 cardiovascular events occurred. Higher levels of hs-cTNT and NT-proBNP and lower ABI at baseline were associated with increased risk of CV events, independently of traditional risk factors (basic model). The C statistic of 0.722 (95% CI 0.681, 0.763) for the basic model increased on addition of individual biomarkers, most markedly for hs-cTnT (0.732; 0.690, 0.774)). Models including different combinations of biomarkers had even greater C statistics, with the highest for ABI, hs-cTnT and GGT combined (0.740; 0.699, 0.781). ConclusionsIndividually, hs-cTnT appeared to be the most promising biomarker in terms of improving vascular risk prediction in people with type 2 diabetes, over and above traditional risk factors incorporated in the QRISK2 score. Combining several non-traditional biomarkers added further predictive value, and this approach merits further investigation when developing cost effective risk prediction tools for use in clinical practice.

Cardiovascular disease biomarkers are associated with declining renal function in type 2 diabetes

Aims/hypothesisWe investigated whether biochemical cardiovascular risk factors and/or markers of subclinical cardiovascular disease were associated with the development of reduced renal function in people with type 2 diabetes.MethodsA cohort of 1066 Scottish men and women aged 60–74 years with type 2 diabetes from the Edinburgh Type 2 Diabetes Study were followed up for a median of 6.7 years. New-onset reduced renal function was defined as two eGFRs <60 ml−1 min−1 (1.73 m)−2 at least 3 months apart with a > 25% decline from baseline eGFR. Ankle brachial pressure index (ABI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) were measured at baseline. Pulse wave velocity (PWV) and carotid intima media thickness were measured 1 year into follow-up. Data were analysed using Cox proportional hazards models.ResultsA total of 119 participants developed reduced renal function during follow-up. ABI, PWV, NT-proBNP and hsTnT were all associated with onset of decline in renal function following adjustment for age and sex. These associations were attenuated after adjustment for additional diabetes renal disease risk factors (systolic BP, baseline eGFR, albumin:creatinine ratio and smoking pack-years), with the exception of hsTnT which remained independently associated (HR 1.51 [95% CI 1.22, 1.87]). Inclusion of hsTnT in a predictive model improved the continuous net reclassification index by 0.165 (0.008, 0.286).Conclusions/interpretationOur findings demonstrate an association between hsTnT, a marker of subclinical cardiac ischaemia, and subsequent renal function decline. Further research is required to establish the predictive value of hsTnT and response to intervention.

BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes.

Both type 2 diabetes (T2DM) and Bβ448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BβArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BβArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BβArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BβArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bβ448Lys was longer than Bβ448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bβ448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bβ448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies.

Urinary peptidomics in a rodent model of diabetic nephropathy highlights epidermal growth factor as a biomarker for renal deterioration in patients with type 2 diabetes

Many diabetic patients suffer from declining renal function without developing albuminuria. To identify alternative biomarkers for diabetic nephropathy (DN) we performed urinary peptidomic analysis in a rodent model in which hyperglycemia and hypertension synergize to promote renal pathologic changes consistent with human DN. We identified 297 increased and 15 decreased peptides in the urine of rats with DN compared with controls, including peptides derived from proteins associated with DN and novel candidate biomarkers. We confirmed by ELISA that one of the parent proteins, urinary epidermal growth factor (uEGF), was more than 2-fold reduced in rats with DN in comparison with controls. To assess the clinical utility of uEGF we examined renal outcomes in 642 participants from the Edinburgh Type 2 Diabetes Study who were normoalbuminuric and had preserved renal function at baseline. After adjustment for established renal risk factors, a lower uEGF to creatinine ratio was associated with new-onset estimated glomerular filtration rate less than 60 ml/min per 1.73m(2) (odds ratio 0.48; 95% confidence interval, 0.26-0.90), rapid (over 5% per annum) decline in renal function (odds ratio 0.44; 95% confidence interval, 0.27-0.72) or the composite of both outcomes (odds ratio 0.38; 95% confidence interval, 0.24-0.62). Thus, the utility of a low uEGF to creatinine ratio as a biomarker of progressive decline in renal function in normoalbuminuric patients should be assessed in additional populations.

Long-term results following polydioxanone sling fixation technique in unstable lateral clavicle fracture.

Neer type II (Edinburgh type 3B) fractures of the lateral clavicle are unstable fractures. The optimal management of these fractures remains controversial with many surgical techniques described in the literature. Our study reports the long-term results of a modified suture (1.5-mm polydioxanone cord) and sling technique for these fractures to avoid complications associated with current techniques in the literature. Over a 5-year period, 23 patients who were (12 males, 11 females; 14 left, 9 right) with a mean age of 42 years were treated with this technique. At last follow-up, the mean Oxford score was 45.1 (range 36-48); the mean SPADI score was 7.4 (range 0-32.3); and the mean Constant score was 91.5 (range 71-100). There were one non-union and no malunion. All patients in our series, except one, returned to their pre-injury activity level. This modified suture fixation technique is safe, technically simple to perform and cheap. It achieves excellent rates of fracture union without the complications associated with other fixation methods in the literature.

Clinically significant chronic liver disease in people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

Background: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations.Aims: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease.Design: Prospective cohort study.Methods: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources.Results: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (all P < 0.001).Conclusions: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools.