Associations of microvascular complications with all-cause death in patients with diabetes and COVID-19:the CORONADO, ABCD Covid-19 audit and AMERICADO study groups

AIM: To provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD‐19. MATERIALS AND METHODS: We analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID‐19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all‐cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID‐19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer. RESULTS: Among 2951 CORONADO, 3387 ABCD COVID‐19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all‐cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66‐3.83), OR 1.24 (95% CI 1.00‐1.56) and OR 1.66 (95% CI 1.40‐1.95) in the CORONADO, the ABCD COVID‐19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all‐cause death during hospital stay in the CORONADO, the ABCD COVID‐19 diabetes national audit and the AMERICADO studies: adjusted OR ((adj)OR) 2.57 (95% CI 1.69‐3.92), (adj)OR 1.22 (95% CI 1.00‐1.52) and (adj)OR 1.33 (95% CI 1.15‐1.53), respectively. In meta‐analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all‐cause death during hospital stay of 2.05 (95% CI 1.42‐2.97), which decreased to 1.62 (95% CI 1.19‐2.119) after adjustment for age and sex, and to 1.50 (1.12‐2.02) after hypertension and CVD were further added to the model. CONCLUSION: Microvascular burden is associated with an increased risk of death in patients hospitalized for COVID‐19

The catastrophic flash-flood event of 8–9 September 2002 in the Gard region, France: a first case study for the Cévennes–Vivarais Mediterranean Hydrometeorological Observatory

The Cévennes–Vivarais Mediterranean Hydrometeorological Observatory (OHM-CV) is a research initiative aimed at improving the understanding and modeling of the Mediterranean intense rain events that frequently result in devastating flash floods in southern France. A primary objective is to bring together the skills of meteorologists and hydrologists, modelers and instrumentalists, researchers and practitioners, to cope with these rather unpredictable events. In line with previously published flash-flood monographs, the present paper aims at documenting the 8–9 September 2002 catastrophic event, which resulted in 24 casualties and an economic damage evaluated at 1.2 billion euros (i.e., about 1 billion U.S. dollars) in the Gard region, France. A description of the synoptic meteorological situation is first given and shows that no particular precursor indicated the imminence of such an extreme event. Then, radar and rain gauge analyses are used to assess the magnitude of the rain event, which was particularly remarkable for its spatial extent with rain amounts greater than 200 mm in 24 h over 5500 km2. The maximum values of 600–700 mm observed locally are among the highest daily records in the region. The preliminary results of the postevent hydrological investigation show that the hydrologic response of the upstream watersheds of the Gard and Vidourle Rivers is consistent with the marked space–time structure of the rain event. It is noteworthy that peak specific discharges were very high over most of the affected areas (5–10 m3 s−1 km−2) and reached locally extraordinary values of more than 20 m3 s−1 km−2. A preliminary analysis indicates contrasting hydrological behaviors that seem to be related to geomorphological factors, notably the influence of karst in part of the region. An overview of the ongoing meteorological and hydrological research projects devoted to this case study within the OHM-CV is finally presented

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired

Genetic and environmental factors study of type 2 diabetes complications

Le diabète de type 2 (DT2) représente un enjeu de santé publique au regard de ses complications, qui sont des maladies complexes, où interagissent des déterminants génétiques et environnementaux.L'objectif de ce travail était d'étudier ces déterminants dans trois populations indépendantes de patients DT2 en couplant études transversales (DIAB2NEPHROGENE) et longitudinales (SURDIAGENE et DIABHYCAR) totalisant 7767 sujets. Via une approche gène-candidat, nous avons focalisé nos recherches sur le système des peptides natriurétiques, le gène NPR3 (codant le récepteur de clairance aux peptides natriurétiques) et les apports sodés puis la voie métabolique des hormones sexuelles, le gène CYP19A1 (codant l’aromatase) et les concentrations de stéroïdes sexuels. Nous avons montré que l'allèle G du rs2270915 du NPR3 est un allèle de risque de pression artérielle (PA) plus élevée et de moindre sensibilité pressive à la réduction sodée qui ne confère pas d'augmentation significative de risque d'évènements cardiovasculaires (ECV) contrairement au rs6889608. Enfin, la survie sans ECV est significativement modulée par les apports en sel avec un risque de morbi-mortalité réduit chez les sujets diabétiques consommant le plus de sel malgré un niveau de PA plus élevé.Nous avons confirmé que le sexe masculin est un facteur de risque pour la néphropathie diabétique (ND) mais également pour la survenue d'ECV. Nous avons montré, chez les hommes, que des concentrations plus élevés d'oestradiol s'associent à une prévalence plus importante de ND mais ne se traduisent pas par une augmentation des événements rénaux oucardiovasculaires. CYP19A1 n'est associé ni avec les niveaux d'oestradiol, ni avec la prévalence ou la sévérité de la ND. Deux SNP s'associent toutefois significativement avec la survenue d'insuffisance rénale chronique terminale.Au total, nous avons identifié dans 2 voies métaboliques distinctes des déterminants génétiques de complications du DT2 ainsi qu'une interaction gène-environnement.Type 2 diabetes (T2D) is a public health issue because of vascular and renal complications, which are complex diseases with interaction between genetic and environmental determinants.The objective of this work was to study these determinants in three independent populations of T2D patients by coupling cross-sectional (DIAB2NEPHROGENE) and longitudinal studies (SURDIAGENE and DIABHYCAR). Through a candidate-gene approach, we first focused on the natriuretic peptides system, NPR3 gene and sodium intake and then on the metabolic pathway of sex hormones, CYP19A1 gene (coding for aromatase) and sex steroid levels.Our first results showed that NPR3 rs2270915 G Allele was associated with high blood pressure (BP) and a reduced salt-sensitivity of BP. However, this SNP was not associated with any significant risk of cardio-vascular events (CVE) or death, at variance with rs6889608. Ultimately, CVE-free survival was impacted by salt intake with a reduced risk of morbi-mortality in those patients having the greatest intake, though a higher BP.In our second study, we confirmed that male gender was a risk factor for diabetic nephropathy (DN), but also for the occurrence of CVE. In men, we showed higher levels of estradiol (E2) associated with a higher prevalence of ND but without any significant increase in renal or CVE during follow-up. CYP19A1 variants were not associated with either E2 levels or the prevalence of ND. However, 2 SNPs tested, were significantly associated with the occurrence of end stage renal failure. Altogether, we have identified 2 different metabolic ways contributing to the genetic determinants of complications associated with T2D including a gene-environment interaction

Relation entre fonction respiratoire, microbiologie bronchique et présence de dilatations des bronches chez les malades atteints de bronchopneumopathie chronique obstructive

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Active targeting of brain tumors using nanocarriers.

International audienceThe delivery of drugs to brain tumors is limited by the presence of the blood-brain barrier (BBB) separating the blood from the cerebral parenchyma. An understanding of the specific mechanisms of the brain capillary endothelium has led to the development of various strategies to enhance the penetration of drugs into the brain tissue. Active targeting is a non-invasive approach, which consists in transporting drugs to target organs using site-specific ligands. Drug-loaded nanocarriers capable of recognizing brain capillary endothelial cells and cerebral tumoral cells have shown promising potential in oncology. Endogenous and chimeric ligands binding to carriers or receptors of the BBB have been directly or indirectly conjugated to nanocarriers. This review indexes the main targeted colloidal systems used for drug delivery to the brain. Their pharmacological behavior and their therapeutic effect are discussed