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Introduction More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI.Methods and analysis EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI.Ethics and dissemination EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials.Trial registration number NCT04165369.

Preferential enrichment (PE) is a crystallization process, starting from either a racemic of slightly enantio-enriched solution (ca. +5%) that results in a high enantiomeric excess in the liquid phase (>+90%ee) and a slight opposite excess in the deposited crystals (−2 to −5%ee). The mechanism(s) of this symmetry-breaking phenomenon is (are) still a matter of debate since it eludes rationalization by phase diagram formalism. In this publication, we thoroughly reinvestigate the PE phenomenon of arginine fumarate by using a new approach: the process is monitored by introducing isotopically labeled arginine enantiomers into the crystallization medium to better understand the mass exchanges during crystallization. These experiments are supported by chiral HPLC-MS/MS. This study permits re-evaluating the criteria that were thought mandatory to perform PE. In particular, we show that PE occurs by a continuous exchange between the solution and the crystals and does not require the occurrence of a solvent-mediated solid–solid phase transition.

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.

Objectives: Arterial hypertension, when exacerbated by excessive dietary salt intake, worsens the morbidity and mortality rates associated with cardiovascular and renal diseases. Stimulation of the apelinergic system appears to protect against several circulatory system diseases, but it remains unknown if such beneficial effects are conserved in severe hypertension. Therefore, we aimed at determining whether continuous infusion of apelinergic ligands (i.e., Apelin-13 and Elabela) exerted cardiorenal protective effects in spontaneously hypertensive (SHR) rats receiving high-salt diet.Methods: A combination of echocardiography, binding assay, histology, and biochemical approaches were used to investigate the cardiovascular and renal effects of Apelin-13 or Elabela infusion over 6 weeks in SHR fed with normal-salt or high-salt chow.Results: High-salt intake upregulated the cardiac and renal expression of APJ receptor in SHR. Importantly, Elabela was more effective than Apelin-13 in reducing high blood pressure, cardiovascular and renal dysfunctions, fibrosis and hypertrophy in high-salt fed SHR. Unlike Apelin-13, the beneficial effects of Elabela were associated with a counter-regulatory role of the ACE/ACE2/neprilysin axis of the renin-angiotensin-aldosterone system (RAAS) in heart and kidneys of salt-loaded SHR. Interestingly, Elabela also displayed higher affinity for APJ in the presence of high salt concentration and better resistance to RAAS enzymes known to cleave Apelin-13.Conclusion: These findings highlight the protective action of the apelinergic system against salt-induced severe hypertension and cardiorenal failure. As compared with Apelin-13, Elabela displays superior pharmacodynamic and pharmacokinetic properties that warrant further investigation of its therapeutic use in cardiovascular and kidney diseases.

Electron delocalization and aromaticity was comparatively evaluated in recently synthesized figure‐eight molecules made of two condensed U‐shaped polycyclic aromatic hydrocarbon moieties connected either by two single bonds or by two para‐phenylene groups. The selected examples include molecules that incorporate eight‐membered and sixteen‐membered rings, as well as a doubly [5]helicene‐bridged (1,4)cyclophane. We probe whether some electron delocalization could occur through the stereogenic single bonds in these molecules: Is aromaticity purely (semi‐)local, or possibly also global in these molecules? It was concluded that the situation can go from a purely (semi‐)local character when the dihedral angle at the connecting single bonds is large, such as in biphenyl, to a predominantly (semi‐)local character with a minor global contribution when the dihedral angle is small, such as in the para‐phenylene connectors of the [5] helicene‐bridged cyclophane. [ABSTRACT FROM AUTHOR]

Background and Aims: Recruitment maneuvers may be used during anesthesia as part of perioperative protective ventilation strategy. However, the hemodynamic effect of recruitment maneuvers remain poorly documented in this setting. Material and Methods: This was a prospective observational study performed in operating theatre including patients scheduled for major vascular surgery. Patients were monitored with invasive arterial pressure and esophageal doppler. After induction of general anesthesia, before surgery began, preload optimization based on stroke volume (SV) variation following fluid challenge was performed. Then, an alveolar recruitment maneuver (ARM) through stepwise increase in positive end expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) was performed. Hemodynamic data were noted before, during, and after the alveolar recruitment maneuver. Results: ARM through stepwise increase in PEEP and CPAP were applied in 22 and 14 preload independent patients, respectively. Relative changes in SV during ARMs were significantly greater in the ARMCPAPgroup (-39 ± 20%) as compared to the ARMPEEPgroup (-15 ± 22%; P= 0.002). The difference (95% CI) in relative decrease in SV between ARMCPAPand ARMPEEPgroups was -24% (-38 to -9; P= 0.001). Changes in arterial pressure, cardiac index, pulse pressure variation, peak velocity, and corrected flow time measures were not different between groups. Conclusion: During anesthesia, in preload independent patients, ARMs through CPAP resulted in a significantly greater decrease in SV than stepwise increase in PEEP. During anesthesia, ARM should be used cautiously.

Objectives: Cardiovascular diseases (CVD) remain the leading cause of morbimortality in patients with chronic kidney disease (CKD). The aim of this study was to assess the cardiovascular impact of the pharmacological inhibition of soluble epoxide hydrolase (sEH), which metabolizes the endothelium-derived vasodilatory and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acid (DHETs), in the 5/6 nephrectomy (Nx) mouse model.Methods and Results: Compared to sham-operated mice, there was decrease in EET-to-DHET ratio 3 months after surgery in vehicle-treated Nx mice but not in mice treated with the sEH inhibitor t-AUCB. Nx induced an increase in plasma creatinine and in urine albumin-to-creatinine ratio as well as the development of kidney histological lesions, all of which were not modified by t-AUCB. In addition, t-AUCB did not oppose Nx-induced blood pressure increase. However, t-AUCB prevented the development of cardiac hypertrophy and fibrosis induced by Nx, as well as normalized the echocardiographic indices of diastolic and systolic function. Moreover, the reduction in endothelium-dependent flow-mediated dilatation of isolated mesenteric arteries induced by Nx was blunted by t-AUCB without change in endothelium-independent dilatation to sodium nitroprusside.Conclusion: Inhibition of sEH reduces the cardiac remodelling, and the diastolic and systolic dysfunctions associated with CKD. These beneficial effects may be mediated by the prevention of endothelial dysfunction, independent from kidney preservation and antihypertensor effect. Thus, inhibition of sEH holds a therapeutic potential in preventing type 4 cardiorenal syndrome.

Silicon (Si) is known to alleviate many nutritional stresses. However, in Brassica napus, which is a highly S-demanding species, the Si effect on S deficiency remains undocumented. The aim of this study was to assess whether Si alleviates the negative effects of S deficiency on Brassica napus and modulates root sulfate uptake capacity and S accumulation. For this, Brassica napus plants were cultivated with or without S and supplied or not supplied with Si. The effects of Si on S content, growth, expression of sulfate transporter genes (BnaSultr1.1; BnaSultr1.2) and sulfate transporters activity in roots were monitored. Si supply did not mitigate growth or S status alterations due to S deprivation but moderated the expression of BnaSultr1.1 in S-deprived plants without affecting the activity of root sulfate transporters. The effects of Si on the amount of S taken-up and on S transporter gene expression were also evaluated after 72 h of S resupply. In S-deprived plants, S re-feeding led to a strong decrease in the expression of both S transporter genes as expected, except in Si-treated plants where BnaSultr1.1 expression was maintained over time. This result is discussed in relation to the similar amount of S accumulated regardless of the Si treatment.

Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of NaV channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC50. These five alkaloids were then assayed using the Na+ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na+ currents elicited by the hNav1.2 and hNav1.6 channels, with IC50 values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block NaV channels, with promising therapeutical applications.

Abstract Catecholamines, in concert with fluid resuscitation, have long been recommended in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has emerged, trending toward decatecholaminization. Contextually, it is time to re-examine the “maintaining blood pressure” paradigm by identifying safer and life-saving alternatives. We put in perspective the emerging and growing knowledge on a promising alternative avenue: the apelinergic system. This target exhibits invaluable pleiotropic properties, including inodilator activity, cardio-renal protection, and control of fluid homeostasis. Taken together, its effects are expected to be greatly beneficial for patients in septic shock.

In this paper, we report a study on the nucleation behavior of potassium sulfate (K2SO4) from aqueous solutions under the influence of unfocused nanosecond laser pulses. The objective is to contribute to the general understanding of the Non-Photochemical Laser-Induced Nucleation (NPLIN) mechanism. First, the influence of several parameters such as supersaturation as well as laser parameters (pulse energy, number of pulses, and laser polarization) on induction time, probability of nucleation and mean number of crystals in comparison with spontaneous nucleation was investigated. Then, we examined the influence of gas composition (i.e., degassing and gas bubbling (CO2 and N2)) of the supersaturated solutions on the NPLIN kinetics, showing no correlation between gas content (or nature) on the crystallization behavior. Our study questions the role of impurities within the solution regarding the mechanism of laser-induced nucleation.