EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

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. 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. 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

The CB1 receptor antagonist AM251 impairs reconsolidation of pavlovian fear memory in the rat basolateral amygdala

We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder.This work was conducted within the Behavioural and Clinical Neuroscience Institute, a joint initiative funded by the Wellcome Trust and the UK Medical Research Council, in the Department of Psychology at the University of Cambridge. This work was funded by a UK Medical Research Council programme grant (no. G1002231) awarded to BJE and ALM. PR was supported by a Department of Physiology and Pharmacology Fellowship at the Sapienza University of Rome, and an Italian Society of Pharmacology Fellowship. ALM is the Ferreras-Willetts Fellow in Neuroscience at Downing College, Cambridge. The manuscript was partly prepared while ALM was an Erskine Visiting Cambridge Fellow at the University of Canterbury, Christchurch, New Zealand

Synthesis and in-vitro anti-proliferative with antimicrobial activity of new coumarin containing heterocycles hybrids

Abstract A series of new coumarin-N-heterocyclic hybrids, coumarin-quinolines 7a–e, coumarin-acridines 10b,c and coumarin-neocryptolepines 13b,c were synthesized and evaluated for their anticancer and antimicrobial activities. The structures of all synthesized hybrids were confirmed by FT-IR, 1H-NMR, 13C-NMR, and MS spectrometry. The anti-proliferative activity of hybrids 7a–e, 10c and 13c were bio-evaluated using MTT-assay against colon (CaCo-2), lung (A549), breast (MDA-MB-231), and hepatocellular carcinoma (HepG-2) human cancer cell lines using doxorubicin as a reference drug. The results demonstrated that, all hybrids displayed moderate to good anti-proliferative activity against the cell lines. The most active hybrids were 7a–d and 10c against CaCo-2 cancer cell line with IC50: 57.1, 52.78, 57.29, 51.95 and 56.74 µM, and selectivity index 1.38, 1.76, 2.6, 1.96 and 0.77; respectively. While, 7a,d were potent against A549 cancer cell line with IC50: 51.72, 54.8 µM and selectivity index 1.5, 0.67; respectively. Moreover, 7c showed the most potency against MDA-MB-231 cancer cell line with IC50: 50.96 µM and selectivity index 2.20. Interestingly, docking results revealed that binding energy of the current compounds showed marked affinity values ranging from -6.54 to -5.56 kcal with interactions with the reported key amino acid SER 79. Furthermore, the antimicrobial activity of the synthesized hybrids 7a–e, 10b,c, 13b and 13c were evaluated against Gram‐positive and Gram‐negative bacterial and fungal strains. The hybrids 10b, 13b, 10c, and 13c exhibited broad-spectrum antibacterial activity against E.coli, S. mutans, and S. aureus with MIC from 3.2 to 66 µM, this hybrids also displayed antifungal activity against C. albicans with MIC values ranging from 0.0011 to 29.5 µM. In-silico investigation of the pharmacokinetic properties indicated that tested hybrids had high GI absorption, low Blood Brain Barrier (BBB) permeability in addition to cell membrane penetrability

C-BREEZE 1: Efficacy and safety of ruzasvir 60 mg plus uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis c virus (HCV) genotype (GT)1, 2, 3, 4, or 6 infection.

Background: Ruzasvir (RZR, MK‐8408, an NS5A inhibitor) plus uprifosbuvir (UPR, MK‐3682, an NS5B uridine nucleotide polymerase inhibitor) in combination with grazo‐ previr (GZR, an NS3/4A inhibitor) as a three‐drug regimen has demonstrated promising efficacy in people with HCV GT1, 2, 3, 4, or 6 infection. Given the high efficacy of the three‐drug regimen, the aim of this trial was to evaluate the safety and efficacy of a two‐drug regimen of RZR 60 mg + UPR 450 mg without ribavirin for 12 weeks. Methods: A Phase 2, open‐label, multi‐arm clinical trial was conducted in adults with GT1‐6 chronic HCV infection who were treatment‐naive or treatment‐experienced with interferon ± RBV and either had no cirrhosis or compensated cirrhosis (NCT02759315). All participants received RZR 60 mg + UPR 450 mg once daily for 12 weeks. The primary objectives were the assessment of efficacy (sustained virologic response at 12 weeks after the end of study therapy [HCV RNA \u3c15 IU/mL]), and safety and tolerability. Resistance‐associated substitutions (RASs) were assessed using next‐generation sequencing (15% sensitivity threshold). Results: One hundred sixty participants were enrolled (GT1a, n=54; GT1b, n=15; GT2, n=29; GT3, n=39; GT4, n=20; GT5, n=0; GT6 n=3), 50 (31%) of whom had cirrhosis. All participants had HCV RNA \u3c15 IU/mL at the end of treatment. Results to date are based on 149 participants who received 12 weeks of therapy and have at least 8 weeks of post‐therapy follow‐up (Table) One cirrhotic treatment naïve participant with GT1a infection and baseline NS5A Q30H and Y93H RASs relapsed with detectable treatment‐emergent Q30L and M28G. Nine treatment naïve participants with GT3 infection relapsed, two of whom had baseline NS5A S62T and/or A30L RASs; all nine developed treatment‐emergent Y93H. Treatment was generally well tolerated. The most frequent drug‐related adverse events in all participants were fatigue (6.3%), diarrhea (5.6%), nausea (4.3%), and headache (3.8%). Conclusions: The two‐drug combination of RZR 60 mg + UPR 450 mg for 12 weeks was well tolerated and has promising efficacy in GT1, 2, and 4 infection. However, the efficacy in GT3 infection was lower, particularly in cirrhotic participants (6/9 GT3 failures had cirrhosis). Viro‐ logic failure in participants with GT3 infection was not clearly associated with presence of baseline RASs, but was associated with treatment‐emergent NS5A RASs. Higher doses of RZR in a two‐drug combination with UPR may be needed to optimize efficacy against some HCV genotypes. Complete SVR12 results will be presented