Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

The r(33) electro-optic coefficient of Er:LiNbO3

By exploiting a Mach\u2013Zehnder interferometer, the r33 electro-optic coefficient of erbium-bulk-doped lithium niobate crystals grown by the Czochralski technique was measured depending on the erbium content. The r33 coefficient decreases with the erbium concentration. Such a trend has been connected with both the reduction of the lattice parameter, measured by high resolution x-ray diffraction, and the increase of lattice defects

Self-confined beams in erbium-doped lithium niobate

We experimentally investigate the formation of self-confined beams in lithium niobate crystals which are doped in the bulk with erbium. Samples have been grown by the Czochralski method with erbium nominal concentrations varying in the range 0.0\u20130.7 mol% in the melt. The speeds of beam confinement depend on the applied bias and on the beam intensity, as expected, but on the doping level as well. The erbium incorporation influences both the electro-optic coefficient and the photovoltaic field. A very general dependence of the confined beam waist on the refractive index change was experimentally derived, valid now for every lithium niobate crystal, independent on its growing procedure or doping

Ultrafast science and development at the Artemis facility

The Artemis facility for ultrafast XUV science is constructed around a high average power carrier-envelope phasestabilised system, which is used to generate tuneable pulses across a wavelength range spanning the UV to the far infrared, few-cycle pulses at 800nm and short pulses of XUV radiation produced through high harmonic generation. The XUV pulses can be delivered to interaction stations for materials science and atomic and molecular physics and chemistry through two vacuum beamlines for broadband XUV or narrow-band tuneable XUV pulses. The novel XUV monochromator provides bandwidth selection and tunability while preserving the pulse duration to within 10 fs. Measurements of the XUV pulse duration using an XUV-pump IR-probe technique demonstrate that the XUV pulselength is below 30 fs for a 28 fs drive laser pulse. The materials science station, which contains a hemispherical electron analyser and five-axis manipulator cooled to 14K, is optimised for photoemission experiments with the XUV. The end-station for atomic and molecular physics and chemistry includes a velocity-map imaging detector and molecular beam source for gas-phase experiments. The facility is now fully operational and open to UK and European users for twenty weeks per year. Some of the key new scientific results obtained on the facility include: the extension of HHG imaging spectroscopy to the mid-infrared; a technique for enhancing the conversion efficiency of the XUV by combining two laser fields with non-harmonically related wavelengths; and observation of D₃⁺ photodissociation in intense laser fields