Glucose control and vascular outcomes in type 2 diabetes: Is the picture clear?

The overall impact of glucose lowering on vascular complications and major clinical outcomes, including mortality, in type 2 diabetes is still an open issue. While intensive glucose control has undoubted benefit for microvascular end points, the relationship between glucose-lowering approaches and reduced incidence and/or progression of macrovascular complications is less clear. This review article will discuss the effect of glucose lowering per se as well as the effects of specific glucose-lowering therapies on vascular outcomes in type 2 diabetes. The role of lifestyle changes on cardiovascular outcomes will be also addressed. Recent analyses from large cardiovascular outcome studies (ACCORD, ADVANCE, and VADT) provide new information on factors that modulate the impact of intensive glucose lowering on outcomes, helping to identify the specific clinical characteristics of the patients receiving the intervention that would show a better response.While several studies on cardiovascular outcomes with diabetes drugs are available, they do not clearly highlight a benefit from using a specific medication or will require additional evidence, as for the sodium-glucose cotransporter 2 blockers

Quantifying urban forest structure in Greater Manchester with open-access remote sensing datasets

A growing body of evidence links the adverse impacts of expanding urbanism including increased air pollution, and exposure to heat stress with the removal of vegetation within cities. As the global population is estimated to reach 10 billion by 2050, urban trees and extended green infrastructure are advocated as a remedy to the effects of increasing urbanisation through delivering a multitude of ecosystem services including pollution abatement, reduction of urban heat islands and social benefits. To accurately quantify the services afforded by urban forests, it is vital to measure the extent and structure of urban forests, including through time, in addition for assessing the success of policy to maintain and promote green infrastructure assets. Current ground fieldwork methods rely on plot networks to measure a range of metrics across the tree population; these methods are locally comprehensive however do not fully describe the spatial heterogeneity of the urban fabric, given the limited sampling and often laborious data collection. The increasing availability and access to remote sensing/earth observation datasets provide an opportunity to collate synoptic measurements across large regions. Direct measurements though active sensors, particularly LiDAR, have seen wide adoption when measuring forest structure, however surveys can be expensive, and coverage limited. Fusing LiDAR with satellite imagery though machine learning methods such as Random Forests can drastically increase coverage through capturing complex non linear relationships. A framework is presented to estimate forest structure using open access data and software across Greater Manchester. This workflow estimates three forest structure metrics, canopy cover, canopy height and tree number/density. Random forest models were trained with airborne Environment Agency LiDAR, and predictor variables derived from Sentinel 2 and ancillary climatic and topographic datasets. Results indicate estimates in 2018, mean canopy cover of 14.9% (RMSE = 13.75), mean canopy height of 14.83m (RMSE = 6.14m) and home to ~2.6 million trees (RMSE = 0.95 per pixel). Results appear to illustrate higher canopy cover than i-Tree ground data but lower tree density and canopy heights. Altering input resolution was found to change structure estimations, attributed to methodological issues. Forest structure estimates were found to change from 2018 to 2021 indicating net decreases in canopy cover and number of trees, while average canopy height was found to increase, although change distribution of metrics across boroughs is not equal. Presented methods can augment traditional inventory methods and can assist urban forest/land managers to produce consistent monitoring information to support the sustainability of urban forests worldwide

Quantifying urban forest structure in Greater Manchester with open-access remote sensing datasets

A growing body of evidence links the adverse impacts of expanding urbanism including increased air pollution, and exposure to heat stress with the removal of vegetation within cities. As the global population is estimated to reach 10 billion by 2050, urban trees and extended green infrastructure are advocated as a remedy to the effects of increasing urbanisation through delivering a multitude of ecosystem services including pollution abatement, reduction of urban heat islands and social benefits. To accurately quantify the services afforded by urban forests, it is vital to measure the extent and structure of urban forests, including through time, in addition for assessing the success of policy to maintain and promote green infrastructure assets. Current ground fieldwork methods rely on plot networks to measure a range of metrics across the tree population; these methods are locally comprehensive however do not fully describe the spatial heterogeneity of the urban fabric, given the limited sampling and often laborious data collection. The increasing availability and access to remote sensing/earth observation datasets provide an opportunity to collate synoptic measurements across large regions. Direct measurements though active sensors, particularly LiDAR, have seen wide adoption when measuring forest structure, however surveys can be expensive, and coverage limited. Fusing LiDAR with satellite imagery though machine learning methods such as Random Forests can drastically increase coverage through capturing complex non linear relationships. A framework is presented to estimate forest structure using open access data and software across Greater Manchester. This workflow estimates three forest structure metrics, canopy cover, canopy height and tree number/density. Random forest models were trained with airborne Environment Agency LiDAR, and predictor variables derived from Sentinel 2 and ancillary climatic and topographic datasets. Results indicate estimates in 2018, mean canopy cover of 14.9% (RMSE = 13.75), mean canopy height of 14.83m (RMSE = 6.14m) and home to ~2.6 million trees (RMSE = 0.95 per pixel). Results appear to illustrate higher canopy cover than i-Tree ground data but lower tree density and canopy heights. Altering input resolution was found to change structure estimations, attributed to methodological issues. Forest structure estimates were found to change from 2018 to 2021 indicating net decreases in canopy cover and number of trees, while average canopy height was found to increase, although change distribution of metrics across boroughs is not equal. Presented methods can augment traditional inventory methods and can assist urban forest/land managers to produce consistent monitoring information to support the sustainability of urban forests worldwide

The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease

Endothelium plays a crucial role in the maintenance of vascular tone and structure. Endothelial dysfunction is known to precede overt coronary artery disease. A number of cardiovascular risk factors, as well as metabolic diseases and systemic or local inflammation cause endothelial dysfunction. Nitric oxide (NO) is one of the major endothelium derived vaso-active substances whose role is of prime importance in maintaining endothelial homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. ADMA levels are increased in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic renal failure. A number of studies have reported ADMA as a novel risk marker of cardiovascular disease. Increased levels of ADMA have been shown to be the strongest risk predictor, beyond traditional risk factors, of cardiovascular events and all-cause and cardiovascular mortality in people with coronary artery disease. Interventions such as treatment with L-arginine have been shown to improve endothelium-mediated vasodilatation in people with high ADMA levels. However the clinical utility of modifying circulating ADMA levels remains uncertain

Methodology of a reevaluation of cardiovascular outcomes in the RECORD trial: study design and conduct

Background In 2010, after regulatory review of rosiglitazone licensing, the US Food and Drug Administration (FDA) requested a reevaluation of cardiovascular end points in the RECORD trial.<p></p> Methods Automated screening of the original clinical trial database and manual case report form review were performed to identify all potential cardiovascular and noncardiovascular deaths, and nonfatal myocardial infarction (MI) and stroke events. Search techniques were used to find participants lost to follow-up, and sites were queried for additional source documents. Suspected events underwent blinded adjudication using both original RECORD end point definitions and new FDA end point definitions, before analysis by the Duke Clinical Research Institute.<p></p> Results The reevaluation effort included an additional 328 person-years of follow-up. Automated screening identified 396 suspected deaths, 2,052 suspected MIs, and 468 suspected strokes. Manual review of documents by Duke Clinical Research Institute clinical events classification (CEC) coordinators identified an additional 31 suspected deaths, 49 suspected MIs, and 28 suspected strokes. There were 127 CEC queries issued requesting additional information on suspected deaths; 43 were closed with no site response, 61 were closed with a response that no additional data were available, and additional data were received for 23. Seventy CEC queries were issued requesting additional information for suspected MI and stroke events; 31 were closed with no site response, 20 were closed with a response that no additional data were available, and 19 resulted in additional data.<p></p> Conclusions Comprehensive procedures were used for rigorous event reascertainment and readjudication in a previously completed open-label, global clinical trial. These procedures used in this unique situation were consistent with other common approaches in the field, were enhanced to address the FDA concerns about the original RECORD trial results, and could be considered by clinical trialists designing event readjudication protocols for drug development programs that have been completed.<p></p&gt

Results of a reevaluation of cardiovascular outcomes in the RECORD trial

Background The US Food and Drug Administration (FDA) required a reevaluation of cardiovascular (CV) outcomes in the RECORD trial. This provided an opportunity to assess the implications of event adjudication by 2 groups and quantify the differences as well as to use new FDA end point definitions in development.<p></p> Methods Original data were used to systematically identify all potential deaths, myocardial infarctions (MIs), and strokes. Site investigators were approached for additional source documents and information about participants lost to follow-up. Suspected events were adjudicated using standard procedures, and the results were compared with the original trial outcomes.<p></p> Results Follow-up for mortality was 25,833 person-years, including an additional 328 person-years identified during the reevaluation effort. A total of 184 CV or unknown-cause deaths (88 rosiglitazone, 96 metformin/sulfonylurea), 128 participants with an MI (68 rosiglitazone, 60 metformin/sulfonylurea), and 113 participants with a stroke (50 rosiglitazone, 63 metformin/sulfonylurea) were included. The hazard ratio (HR) for rosiglitazone versus metformin/sulfonylurea for the end point of CV (or unknown cause) death, MI, or stroke was 0.95 (95% CI 0.78-1.17) compared with 0.93 (95% CI 0.74-1.15) for the original RECORD results. Treatment comparisons for MI (HR 1.13, 95% CI 0.80-1.59) and mortality (HR 0.86, 95% CI 0.68-1.08) were also the same compared with the original RECORD results. Sensitivity analyses were also consistent with the original RECORD results. Analyses using the FDA definitions showed similar results.<p></p> Conclusions Only a modest number of additional person-years of follow-up were ascertained from this reevaluation of CV end points in RECORD. Observed HRs and CIs from these analyses using the original RECORD or new FDA end point definitions showed similar treatment effects of rosiglitazone compared with the original RECORD results.<p></p&gt

The outsourcing of social care in Britain : what does it mean for voluntary sector workers?

While recent decades have witnessed a growth in the outsourcing of public services in Britain, the post-1997 UK Labour governments have sought to put in place mechanisms aimed at encouraging long-term collaborative contracting relationships marked by less reliance on cost-based competition. This article explores empirically how far these mechanisms have achieved their aims and thereby acted to protect the employment conditions of staff, and links this exploration to debates concerning the employment implications of organizational reforms within public sectors internationally. It concludes that in terms of bringing income security to the voluntary sector and stability to employment terms and conditions these efforts have been unsuccessful, and consequently casts doubts on more optimistic interpretations of the employment effects of organizational restructuring in the British public sector

Observational study of the association of first insulin type in uncontrolled type 2 diabetes with macrovascular and microvascular disease

<p>Aims: To compare the risk of vascular disease, HbA1c and weight change, between first prescribed insulins in people with type 2 diabetes.</p> <p>Methods: People included in THIN United Kingdom primary care record database who began insulin (2000–2007) after poor control on oral glucose-lowering agents (OGLD) were grouped by the number of OGLDs in their treatment regimen immediately before starting insulin (n = 3,485). Within OGLD group, Cox regression compared macrovascular (all-cause mortality, myocardial infarction, acute coronary syndrome and stroke) and microvascular disease (peripheral neuropathy, nephropathy, and retinopathy) between insulin type (basal, pre-mix or Neutral Protamine Hagedorn, NPH) while ANCOVAs compared haemoglobin A1c (HbA1c) and weight change.</p> <p>Results: Mean follow-up was 3.6 years. Rates of incident macrovascular events were similar when basal insulin was compared to pre-mix or NPH, adjusted hazard ratio versus basal: pre-mix 1.08 (95% CI 0.73, 1.59); NPH 1.00 (0.63, 1.58) after two OGLDs, and pre-mix 0.97 (0.46, 2.02); NPH 0.77 (0.32, 1.86) after three OGLDs. An increased risk of microvascular disease in NPH versus basal after 3 OGLDs, adjusted hazard ratio1.87 (1.04, 3.36), was not seen after two agents or in comparisons of basal and pre-mix. At one year, after two OGLDs, weight increase was less with basal compared with pre-mix. After three OGLDs, mean HbA1c had reduced less in basal versus pre-mix or NPH at 6–8 and at 9–11 months, and versus pre-mix at 12–14 months.</p> <p>Conclusion: We found no difference in the risk of macrovascular events between first insulins in the medium term when started during poor glycaemia control. The increased risk of microvascular events with NPH warrants further study. In certain groups, first use of basal insulin was associated with less gain in weight and decrease in HbA1c compared to other insulins.</p&gt

A study of endothelial function and circulating asymmetric dimethylarginine levels in people with Type 1 diabetes without macrovascular disease or microalbuminuria

<p>Abstract</p> <p>Background</p> <p>Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of endothelial nitric oxide synthase (eNOS) that is associated with endothelial dysfunction, and is a risk marker for cardiovascular disease, a significant problem in Type 1 diabetes. The aim of the present study was to measure circulating ADMA, and define its association with endothelial dysfunction and endothelial markers in people with Type 1 diabetes with low likelihood of macrovascular disease.</p> <p>Methods</p> <p>Sixty-one young people with Type 1 diabetes without macrovascular disease or nephropathy and 62 healthy volunteers underwent brachial artery flow-mediated dilatation (FMD) and assay of plasma ADMA and adhesion molecules.</p> <p>Results</p> <p>Age, gender, BMI, lipid profile and renal function were similar in the two groups. People with Type 1 diabetes had impaired FMD compared to healthy controls (5.0 ± 0.4 vs 8.9 ± 0.4%; p < 0.001). Plasma ADMA levels were significantly lower in the people with diabetes compared to healthy controls (0.52 ± 0.12 vs 0.66 ± 0.20 μmol/l, p < 0.001). Plasma ICAM-1, E-selectin and PAI-1 levels were significantly higher in people with diabetes compared to healthy controls (median 201 (IQR 172–226) vs 180 (156–216) μg/l, p = 0.027; 44.2 (32.6–60.9) vs. 33.1 (22.4–51.0) μg/l; p = 0.003 and 70.8 (33.3–85.5) vs 46.3 (23.9–76.8) μg/l, p = 0.035). Plasma ADMA and VCAM-1 levels were positively correlated (r = 0.37, p = 0.003) in people with diabetes. There was no correlation between the plasma ADMA and FMD.</p> <p>Conclusion</p> <p>ADMA levels are not associated with endothelial dysfunction in young adults with Type 1 diabetes without microalbuminuria or known macrovascular disease. This suggests that the impaired endothelial function in these individuals is not a result of eNOS inhibition by ADMA.</p