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Aims/hypothesisThis is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19).MethodsThe CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days.ResultsWe included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th–75th percentile) 28.4 (25.0–32.4) kg/m2. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5–14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors.Conclusions/interpretationIn patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period.Trial registrationClinicaltrials.gov identifier: NCT04324736

Lower-extremity arterial disease (LEAD) is a major endemic disease with an alarming increased prevalence worldwide. It is a common and severe condition with excess risk of major cardiovascular events and death. It also leads to a high rate of lower-limb adverse events and non-traumatic amputation. The American Diabetes Association recommends a widespread medical history and clinical examination to screen for LEAD. The ankle brachial index (ABI) is the first non-invasive tool recommended to diagnose LEAD although its variable performance in patients with diabetes. The performance of ABI is particularly affected by the presence of peripheral neuropathy, medial arterial calcification, and incompressible arteries. There is no strong evidence today to support an alternative test for LEAD diagnosis in these conditions. The management of LEAD requires a strict control of cardiovascular risk factors including diabetes, hypertension, and dyslipidaemia. The benefit of intensive versus standard glucose control on the risk of LEAD has not been clearly established. Antihypertensive, lipid-lowering, and antiplatelet agents are obviously worthfull to reduce major cardiovascular adverse events, but few randomised controlled trials (RCTs) have evaluated the benefits of these treatments in terms of LEAD and its related adverse events. Smoking cessation, physical activity, supervised walking rehabilitation and healthy diet are also crucial in LEAD management. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in LEAD management. The revascularization strategy should take into account several factors including anatomical localizations of lesions, medical history of each patients and operator experience. Further studies, especially RCTs, are needed to evaluate the interest of different therapeutic strategies on the occurrence and progression of LEAD and its related adverse events in patients with diabetes.

The Antarctic Circumpolar Current (ACC) is a major driver of global ocean circulation and climate. To better understand the interplay between long-term atmospheric and ocean variability in the Southern Ocean since the late Miocene, we present sea surface temperature (SST) and carbonate preservation records from the Subantarctic Eastern South Pacific (IODP Site U1543), along with an extended ACC strength record from Central South Pacific Site U1541. We focus on long-term eccentricity-scale variations showing decreased (increased) SST with enhanced (reduced) CaCO 3 preservation, and stronger (weaker) ACC strength, particularly during the Pliocene. These changes coincide with stronger (weaker) South Pacific SST gradients, possible northward (southward) migration of Southern Ocean fronts, strengthened (weakened) westerlies, and atmospheric CO 2 release. These patterns contrast with Pleistocene glacial-interglacial cycles. Reduced Pacific-Atlantic exchange through the Drake Passage may have weakened Atlantic Meridional Overturning Circulation during warming at Site U1543 across the intensification of Northern Hemisphere Glaciation. Simultaneous stronger ACC and higher CaCO 3 deposition in the high-latitude Pacific suggest a strengthened basin-wide Pacific overturning circulation during parts of the Pliocene. Long-term cooling coincided with enhanced Antarctic Circumpolar Current strength and better carbonate preservation indicating major reorganization of Pacific circulation. During initial Northern Hemisphere Glaciation, the eastern South Pacific warmed.

Millennial-scale variations in the strength and position of the Antarctic Circumpolar Current exert considerable influence on the global meridional overturning circulation and the ocean carbon cycle. The mechanistic understanding of these variations is still incomplete, partly due to the scarcity of sediment records covering multiple glacial-interglacial cycles with millennial-scale resolution. Here, we present high-resolution current strength and sea surface temperature records covering the past 790,000 years from the Cape Horn Current as part of the subantarctic Antarctic Circumpolar Current system, flowing along the Chilean margin. Both temperature and current velocity data document persistent millennial-scale climate variability throughout the last eight glacial periods with stronger current flow and warmer sea surface temperatures coinciding with Antarctic warm intervals. These Southern Hemisphere changes are linked to North Atlantic millennial-scale climate fluctuations, plausibly involving changes in the Atlantic thermohaline circulation. The variations in the Antarctic Circumpolar Current system are associated with atmospheric CO 2 changes, suggesting a mechanistic link through the Southern Ocean carbon cycle. The strength of the Cape-Horn Current, as traced in the sediment cores, varies with sea surface temperature in the Eastern South Pacific. Changes in this current are also associated with North Hemisphere cooling events and atmospheric CO2 outgassing.

Aims/hypothesisTenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up.MethodsWe used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors.ResultsWe monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly.Conclusions/interpretationIn individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.

Chen et al. recently related the skin autofluorescence (SAF) of Advanced Glycation End-products to subclinical cardiovascular disease in the 3001 participants from the general population (Rotterdam study), with a particularly close relationship for the 413 subjects with diabetes. Because conventional vascular risk factors do not capture the risk in diabetes very well, this relationship may help to select high-risk individuals for the screening of silent myocardial ischemia, which has yet to prove its benefit in randomized controlled trials. Among 477 patients with uncontrolled and/or complicated Type 2 Diabetes, we measured the SAF ten years ago, and we registered new revascularizations during a 54-months follow-up. The patients with SAF > 2.6 Arbitrary units (AUs), the median population value, experienced more revascularizations of the coronary (17/24) and lower-limb arteries (13/17) than patients with a lower SAF, adjusted for age, sex, diabetes duration, vascular complications, and smoking habits: HR 2.17 (95% CI: 1.05–4.48), p = 0.035. The SAF has already been reported to predict cardiovascular events in three cohorts of people with diabetes. We suggest that its measurement may help to improve the performance of the screening before vascular explorations and revascularizations.

We analyzed the cross-sectional and prospective relationships between the accumulation of advanced glycation end products (AGE), assessed by skin autofluorescence (AF) and frailty and its components. A total of 423 participants of the Bordeaux sample of the Three-City study 75 years of age or older in 2009-2010 were included in the cross-sectional analysis. Among them, 255 initially non-frail participants were re-examined 4 years later. Skin AF (arbitrary units (AU)) was measured using the AGE Reader. Frailty was defined using Fried's criteria. Associations were assessed with logistic regression models. Mean skin AF at baseline was 2.81 ±0.68 AU and 16.8% participants were frail. Adjusted for sociodemographic and health characteristics, skin AF was associated neither with prevalent frailty as a whole (Odds Ratio (OR) = 1.2; 95% Confidence Interval: 0.8-1.9) nor with any of its components. Among 255 non-frail participants, 32 became frail over 4 years. In multivariate analyses, skin AF was not associated with incident frailty as a whole (OR = 1.0; 0.5-2.0) but with a doubled risk of incident exhaustion (OR = 2.0; 1.2-3.6) and low energy expenditure (OR = 2.0; 1.1-3.7). No association was observed with other criteria. In French older community-dwellers aged 75 years and over, the accumulation of AGEs evaluated by skin AF was not associated with prevalent or incident frailty but with the 4-year risk of exhaustion and low energy expenditure. Further studies with larger samples are needed to confirm our results.

Background Cardiovascular disease (CVD) and nontraumatic lower-limb amputation (LLA) each results in reduced life expectancy in patients with type 1 diabetes, but the differential burden between these conditions is unknown. We compared the effects of CVD and LLA on the risk of mortality in people with type 1 diabetes. Methods We used pooled data from the SURGENE, GENEDIAB, and GENESIS prospective cohorts. Data were divided into: 1/absence of CVD (myocardial infarction and/or stroke) nor LLA, 2/history of CVD alone without LLA, 3/LLA alone without CVD or 4/both conditions at baseline. Participants with baseline history of peripheral artery disease were excluded from groups 1 and 2. The study endpoint was any death occurring during follow-up, regardless of the causes. Results Among 1169 participants (male 55%, age 40 ± 13 years, diabetes duration 23 ± 11 years), CVD, LLA or both were present at baseline in 49 (4.2%), 62 (5.3%) and 20 (1.7%) subjects, respectively. All-cause death occurred in 304 (26%) participants during 17-year follow-up, corresponding to 18,426 person-years and an incidence rate of 16 (95%CI, 15–18) per 1000 person-years. The risk of death increased in individuals with baseline history of CVD (adjusted HR 2.00 [95% CI 1.34–3.01], p = 0.0008) or LLA (2.26 [1.56–3.28], p < 0.0001), versus no condition, with an additive effect in people with both conditions (5.32 [3.14–9.00], p < 0.0001). No incremental risk of death was observed in people with CVD versus LLA (0.87 [0.54–1.41]). Compared with no condition, CVD and LLA were similarly associated with reduced life expectancy during follow-up: 2.79 (95% CI 1.26–4.32) and 3.38 (1.87–4.88) years, respectively. Combined conditions expose to 7.04 (4.76–9.31) less years of life expectancy (all p < 0.0001). Conclusions CVD and LLA conferred a similar burden regarding mortality in type 1 diabetes population. Our findings encourage a careful consideration of people with type 1 diabetes and LLA as usually recommended for those with CVD, in terms of management of risk factors, treatments and prevention.

Background Most guidelines recommend a systematic screening of asymptomatic high risk patients with diabetes for silent ischemia, but the clinical benefit of this strategy has not been demonstrated compared with the simple control of cardiovascular risk factors. We sought to determine whether referring asymptomatic diabetic patients for screening of silent ischemia decreases the risk of cardiovascular events compared with usual care. Methods DYNAMIT was a prospective, randomized, open, blinded end-point multicenter trial run between 2000 and 2005, with a 3.5 year mean follow-up in ambulatory care in 45 French hospitals. The study included 631 male and female with diabetes aged 63.9 ± 5.1 years, with no evidence of coronary artery disease and at least 2 additional cardiovascular risk factors, receiving appropriate medical treatment. The patients were randomized centrally to either screening for silent ischemia using a bicycle exercise test or Dipyridamole Single Photon Emission Computed Tomography (N = 316), or follow-up without screening (N = 315). The main study end point was time to death from all causes, non-fatal myocardial infarction, non-fatal stroke, or heart failure requiring hospitalization or emergency service intervention. The results of a meta-analysis of DYNAMIT and DIAD, a similar study, are also presented. Results The study was discontinued prematurely because of difficulties in recruitment and a lower-than expected event rate. Follow-up was complete for 98.9% patients regarding mortality and for 97.5% regarding the main study end point. Silent ischemia detection procedure was positive or uncertain in 68 (21.5%) patients of the screening group. There was no significant difference between the screening and the usual care group for the main outcome (hazard ratio = 1.00 95%CI 0.59 to 1.71). The meta-analysis of these and DIAD results gave similar results, with narrower confidence intervals for each endpoint. Conclusions These results suggest that the systematic detection of silent ischemia in high-risk asymptomatic patients with diabetes is unlikely to provide any major benefit on hard outcomes in patients whose cardiovascular risk is controlled by an optimal medical treatment. Trial registration ClinicalTrials.gov: NCT00627783