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Preventive actions for scientific misconduct and questionable research practice must be taken at an institutional level but also by scientists themselves as part of their role of science managers. We have proposed the concept of “Ethical and Efficient Research Management” and a panoply of easy to use tools which are designed to favour ethical behaviour, sound data and robust methods. Through the example of the processes “Arrival” and “Departure of a co-worker”, we show here that flow charts can help visualize critical steps in an activity and how to manage these steps in an ethical and efficient way.

Healthcare product procurement accounts for around 50% of the French healthcare system's greenhouse gas emissions. This lesson learned from the publication of the Shift Project's work in November 2021 has been a catalyst within the healthcare system, accelerating the consideration and implementation of actions aimed at reducing the environmental impact of the healthcare system, before, during and after care. In addition to their carbon footprint, healthcare products have a wide range of environmental impacts, including on water, air and soil, throughout their entire life cycle. We have chosen to divide this life cycle into four main stages: from research and development to production, distribution and market access, use and finally end-of-life management. Analysis of the regulatory framework at each stage and of existing initiatives described in the literature or by those in the field have structured and fuelled our thinking. We found that existing regulations focus exclusively on the health risk, with little or no consideration of the environmental risk, which is in itself a health risk. Furthermore, the implementation of certain structuring actions during the first 3 stages of the life cycle would make it possible to simplify or even eliminate the major problem of waste management associated with the end-of-life of healthcare products. With this in mind, we have produced 9 recommendations to ensure that the environmental impact of healthcare products is better taken into account throughout their life cycle., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Imeglimin, a glucose-lowering agent targeting mitochondrial bioenergetics, decreases reactive oxygen species (ROS) overproduction and improves glucose homeostasis. We investigated whether this is associated with protective effects on metabolic syndrome-related left ventricular (LV) and vascular dysfunctions., Methods: We used Zucker fa/fa rats to assess the effects on LV function, LV tissue perfusion, LV oxidative stress and vascular function induced by imeglimin administered orally for 9 or 90 days at a dose of 150 mg/kg twice daily., Results: Compared to untreated animals, 9- and 90-day imeglimin treatment decreased LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased LV tissue perfusion and decreased LV ROS production. Simultaneously, imeglimin restored acetylcholine-mediated coronary relaxation and mesenteric flow-mediated dilation. One hour after imeglimin administration, when glucose plasma levels were not yet modified, imeglimin reduced LV mitochondrial ROS production and improved LV function. Ninety-day imeglimin treatment reduced related LV and kidney fibrosis and improved kidney function., Conclusion: In a rat model, mimicking Human metabolic syndrome, imeglimin immediately countered metabolic syndrome-related cardiac diastolic and vascular dysfunction by reducing oxidative stress/increased NO bioavailability and improving myocardial perfusion and after 90-day treatment myocardial and kidney structure, effects that are, at least in part, independent from glucose control., Competing Interests: Marianne Lachaux, Matthieu Soulié, Mouad Hamzaoui, Anaëlle Bailly, Lionel Nicol, Isabelle Rémy‐Jouet, Sylvanie Renet, Cathy Vendeville, Christelle Monteil, Vincent Richard and Paul Mulder (being the guarantor) have nothing to declare. Pascale Gluais‐Dagorn and Sophie Hallakou‐Bozec are employee Poxel SA., (© 2020 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Background: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes., Methods and Results: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating., Conclusions: These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.

Aim: To determine whether non-steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome-related end-organ, i.e. cardiac, damage., Materials and Methods: In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non-steroidal MR antagonist finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods)., Results: Long-term (90 days) finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relationship, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relationship. Simultaneously, long-term finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short-term (7 days) finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short-term finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio-availability, were increased., Conclusions: In rats with metabolic syndrome, the non-steroidal MR antagonist finerenone opposed metabolic syndrome-related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/increased NO bioavailability, as well as long-term effects, such as modifications in the myocardial structure., (© 2018 John Wiley & Sons Ltd.)

Objectives: The current study addressed the hypothesis that the local decrease in endothelin-1 (ET-1) bioavailability during sustained flow increases contributes to endothelium-dependent, flow-mediated dilatation (FMD) of conduit arteries and is altered in presence of cardiovascular risk factors., Methods and Results: In nine young healthy individuals, the decrease in local ET-1 plasma levels and radial artery FMD in response to hand skin heating (from 34 to 44 °C) was not affected by endothelin type A (ETA) receptor blockade, achieved using the brachial infusion of BQ-123 (100 nmol/min per l of forearm), as compared with physiological saline (0.9% NaCl) infusion. In contrast, endothelin type B (ETB) receptor blockade with BQ-788 (10 nmol/min per l) suppressed the decrease in plasma ET-1 during heating and reduced FMD, without altering nitric oxide release. The coinfusion of BQ-123 did not affect the inhibitory effect of ETB receptor blockade on the decrease in ET-1 plasma levels during heating but prevented the reduction in FMD. Basal radial artery parameters, systemic hemodynamics, and endothelium-independent dilatation to glyceryl trinitrate were not modified by ETA and/or ETB blockade. In a general population of 40 participants without treatment or major cardiovascular diseases, including the nine healthy individuals, the reduction in endothelin-1 level during heating was correlated with FMD (r = -0.55, P < 0.001) and decreased with increased age (r = 0.49, P = 0.001), mean arterial blood pressure (r = 0.48, P = 0.002), and total cholesterol level (r = 0.37, P = 0.024)., Conclusion: The uptake of endothelin-1 by ETB receptors contributes to conduit artery FMD, preventing its vasoconstrictor action mediated by ETA receptors. The alteration of this mechanism by cardiovascular risk factors may contribute to endothelial dysfunction.

Background: Enhanced heart rate observed in metabolic syndrome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocardial O2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown., Methods: We assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg · kg(-1) · d(-1))., Results: Delayed short-term (4 days) and long-term (90 days) HRR induced by S38844 reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased myocardial tissue perfusion, decreased myocardial oxidized glutathione levels, and preserved cardiac output, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relation, although only long-term S38844 opposed LV collagen accumulation. Long-term S38844 improved flow-induced endothelium-dependent dilatation of mesenteric arteries, while metabolic parameters, such as plasma glucose levels, and Hb1c, were never modified., Conclusions: In rats with MS, HRR induced by the If inhibitor S38844 improved LV diastolic function and endothelium-dependent vascular dilatation, independent from modifications in metabolic status. Moreover, this improvement in cardiac function involves not only immediate effects such as improved myocardial perfusion and reduced oxidative stress but also long-term effects such as modifications in the myocardial structure.

This study addressed the hypothesis that inhibition of the EETs degrading enzyme soluble epoxide hydrolase affords renal protection in the early stage of diabetic nephropathy. The renal effects of the sEH inhibitor t-AUCB (10mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Compared with non-treated HFD mice, HFD mice treated with t-AUCB had a decreased EET degradation, as shown by their higher plasma EETs-to-DHETs ratio, and an increased EET production, as shown by the increase in EETs+DHETs levels, which was associated with induction of CYP450 epoxygenase expression. Both agents similarly reduced fasting glycemia but only t-AUCB prevented the increase in the urinary albumine-to-creatinine ratio in HFD mice. Histopathological analysis showed that t-AUCB reduced renal inflammation, which was associated with an increased mRNA expression of the NFκB inhibitor Iκ≡ and related decrease in MCP-1, COX2 and VCAM-1 expressions. Finally, there was a marginally significant increase in reactive oxygen species production in HFD mice, together with an enhanced NOX2 expression. Both agents did not modify these parameters but t-AUCB increased the expression of the antioxidant enzyme superoxide dismutase 1. These results demonstrate that, independently from its glucose-lowering effect, sEH inhibition prevents microalbuminuria and renal inflammation in overweight hyperglycemic mice, suggesting that this pharmacological strategy could be useful in the management of diabetic nephropathy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow-mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD.

Background: Middle molecular weight uraemic toxins are considered to play an important role in vascular dysfunction and cardiovascular outcomes in end-stage renal disease (ESRD) patients. Recent dialysis techniques based on convection, specifically high-efficiency on-line haemodiafiltration (HDF), enhance the removal of middle molecular weight toxins and reduce all-cause mortality in haemodialysis (HD) patients. However, the mechanisms of these improved outcomes remain to be established., Methods: This prospective study randomly assigned 42 ESRD patients to switch from high-flux HD to high-efficiency on-line HDF (n=22) or to continue HD (n=20). Brachial artery endothelium-dependent flow-mediated dilatation, central pulse pressure, carotid artery intima-media thickness (IMT), internal diastolic diameter and distensibility and circulating markers of uraemia, inflammation and oxidative stress were blindly assessed before and after a 4-month follow-up., Results: Brachial flow-mediated dilatation and carotid artery distensibility increased significantly in the HDF group compared with HD, while carotid IMT and diameter remained similar. HDF decreased predialysis levels of the uraemic toxins β2-microglobulin, phosphate and blood TNFα mRNA expression. Oxidative stress markers were not different between the HD and HDF groups. Blood mRNA expression of protein kinase C β2, an endothelial NO-synthase (eNOS) inhibitor, decreased significantly with HDF., Conclusions: High-efficiency on-line HDF prevents the endothelial dysfunction and stiffening of the conduit arteries in ESRD patients compared with high-flux HD. HDF decreases uraemic toxins, vascular inflammation, and is associated with subsequent improvement in eNOS functionality. These results suggest that reduced endothelial dysfunction may be an intermediate mechanism explaining the beneficial outcomes associated with HDF.