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Summary: Background: Cardiac surgery invariably triggers acute kidney stress causing adverse renal outcomes. The AKITA study evaluated the efficacy and safety of RMC-035, a novel analogue of alpha-1-microglobulin, for reducing cardiac surgery-associated kidney injury. Methods: In this randomised double-blind placebo-controlled phase 2a study, we randomly assigned (1:1) adult hospitalised patients undergoing open-chest cardiac surgery at high risk for acute kidney injury (AKI) at 21 sites in North America and Europe to receive either RMC-035 (1.3 or 0.65 mg/kg) or placebo (1:1) for 2 days (5 intravenous infusions), stratified by region and renal function. Eligible patients had at least one pre-defined AKI risk factor. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR]

Objective: Ischemic mitral regurgitation (MR) is generally associated with very poor outcomes and disappointing results, despite a seemingly perfect initial repair and optimal revascularization. We previously published our intermediate-term results of posterior leaflet augmentation without follow-up extending beyond 4 years. Our objective is to assess long-term durability of the repair, survival, and the causes of late mortality. Methods: Ninety-one patients with severe (4+) Carpentier Type IIIb ischemic MR underwent repair in a single center between 2003 and 2022 by method of posterior leaflet extension using a patch of bovine pericardium and a true-sized remodeling annuloplasty ring, with or without surgical revascularization. Serial echocardiography was performed over the years to ascertain valve competence and degree of ventricular remodeling, in addition to telephone follow-up and chart reviews. Results: The average age of patients was 67 ± 9.6 years. Mean follow-up was 8 ± 5 years with some extending to almost 20 years. One-, 5-, and 10-year freedom from recurrent significant MR, characterized as moderate or severe MR, was 98.6%, 85.5%, and 71.3%, respectively. Thirty-day mortality was 6.5%. One-, 5-, and 10-year survival was 85.5%, 64.4%, and 43.3%, respectively. Of all the mortalities, only 17.5% were proven to be directly cardiac related. Conclusions: The suggested repair technique offers satisfactory long-term outcomes with minimal residual regurgitation in surviving patients when used in context of ischemic MR. Despite durable repair, we have discovered that poor long-term survival is not directly related to cardiovascular causes.

This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of t-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by t-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids.

Introduction Acute kidney injury (AKI) is a common complication after cardiac surgery (CS) and is associated with adverse short-term and long-term outcomes. Alpha-1-microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme binding and mitochondrial-protective mechanisms. RMC-035 is a modified, more soluble, variant of A1M and has been proposed as a novel targeted therapeutic protein to prevent CS-associated AKI (CS-AKI). RMC-035 was considered safe and generally well tolerated when evaluated in four clinical phase 1 studies.Methods and analysis This is a phase 2, randomised, double-blind, adaptive design, parallel group clinical study that evaluates RMC-035 compared with placebo in approximately 268 cardiac surgical patients at high risk for CS-AKI. RMC-035 is administered as an intravenous infusion. In total, five doses will be given. Dosing is based on presurgery estimated glomerular filtration rate (eGFR), and will be either 1.3 or 0.65 mg/kg.The primary study objective is to evaluate whether RMC-035 reduces the incidence of postoperative AKI, and key secondary objectives are to evaluate whether RMC-035 improves postoperative renal function compared with placebo. A blinded interim analysis with potential sample size reassessment is planned once 134 randomised subjects have completed dosing. An independent data monitoring committee will evaluate safety and efficacy data at prespecified intervals throughout the trial. The study is a global multicentre study at approximately 30 sites.Ethics and dissemination The trial was approved by the joint ethics committee of the physician chamber Westfalen-Lippe and the University of Münster (code ‘2021-778 f-A’) and subsequently approved by the responsible ethics committees/relevant institutional review boards for the participating sites. The study is conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal.Trial registration number NCT05126303.

Iron is an essential micronutrient for citrus, playing an important role in photosynthesis and yield. The aim of this paper was to evaluate the tolerance to Fe deficiency of five citrus rootstocks: sour orange (S), Carrizo citrange (C), Citrus macrophylla (M), Troyer citrange (T), and Volkamer lemon (V). Plants were grown for 5 weeks in nutrient solution that contained the following Fe concentrations (in µM): 0, 5, 10, 15, and 20. At the end of the experiment, biomass (dry weight—DW), leaf area, total leaf chlorophyll (CHL), and the activity of root chelate reductase (FCR) were recorded. Additionally, the mineral composition of roots (R) and shoots (S) was evaluated. Principal component analysis was used to study the relationships between all parameters and, subsequently, the relations between rootstocks. In the first component, N-S, P-S, Ca-S, Cu-S, Zn-S, Mn-S, Zn-R, and Mn-R concentrations were related to leaf CHL and FCR. Increases in leaf CHL, Mg-R, and DW (shoots and roots) were inversely related to Cu-R, which was shown in the second component. The values obtained were consistent for V10, C15, and C20, but in contrast for S0 and S5. In conclusion, micronutrient homeostasis in roots and shoots of all rootstocks were affected by Fe stress conditions. The Fe/Cu ratio was significantly related to CHL, which may be used to assist rootstock performance.

Acute scrotal pain (ASP) requiring surgical exploration is common in the pediatric population, but little has been reported on this subject with regard to the adult population. The aim of this study was to investigate the demographic and clinical characteristics and outcomes of scrotal explorations performed on adult patients. Patients over 21 years of age who underwent surgical exploration for ASP with suspected testicular torsion (TT) at 14 French hospitals between January 2005 and December 2019 were included in this study. The main outcome measures were demographic characteristics, pathology found during scrotal exploration, and perioperative outcomes. Logistic regression was used to perform univariate and multivariate analyses to identify predictors of TT. Data for 1329 men were analyzed. The median age was 30 (interquartile range [IQR]: 25–35; range: 21–89) years. Regarding the clinical examination, 867 (65.2%) patients presented with an elevation of the testicle, 613 (46.1%) patients with scrotal edema or erythema, and 211 (15.9%) patients with nausea or vomiting. Operative findings identified TT in only 684 (51.5%) patients, epididymo-orchitis in 112 (8.4%) patients, a tumor in 16 (1.2%) patients, and no causes in 475 (35.7%) patients. Orchiectomy for nonviable testes was required in 101 (7.6%) patients. In multivariate analysis, an elevation of the testicle, erythema/swelling, and the presence of nausea/vomiting were found to be associated with the occurrence of TT. Testicular torsion is not exclusive to children and adolescents, so must be considered in males of any age with acute scrotal findings. However, one-third of scrotal explorations in adults did not lead to a diagnosis.

Abstract The homogenization of agricultural landscapes has led to a decrease in pollinator diversity and abundance. In response to this decline, farmers have implemented agroecological measures, which, in meadows, aim at providing more floral resources. These measures are the availability of unmown floral strips, delayed mowing, and discouraging the use of the conditioner, a device known to harm insects. The aim of our study was to investigate the cascade of effects of these agroecological measures on honey bee colony development and winter survival. We (1) determined the effect of these measures on colony size during the nectar and pollen collecting season in spring and summer, (2) evaluated the effect of spring and summer colony sizes on autumn size, and (3) described the effect of colony size in autumn on winter mortality. In this study, 300 honey bee colonies were monitored over three years in three cantons of Switzerland. Colony size was defined by the numbers of brood cells and of adult workers. Honey bee colony size in summer and autumn was improved by agroecological measures on meadows and likely contributed to the increased overwintering success. This study is a first step toward the targeted identification of viable agroecological measures on temporary meadows that can be implemented to promote honey bee colonies health in the agricultural landscape.

Abstract Background Few studies have measured frailty as a potential reason for foregoing transcatheter aortic valve replacement (TAVR) in older adults with severe aortic stenosis (AS). This study sought to determine the impact of frailty and other clinician-cited reasons on restricted mean survival time (RMST). Methods An analysis of the McGill Frailty Registry was conducted between 2014 and 2018 at the McGill University Health Center Structural Valve Clinic. Consecutive nonsurgical patients referred for TAVR were included. In those that underwent balloon aortic valvuloplasty or medical management, the primary clinician-cited reason for foregoing TAVR was codified. Vital status was ascertained at 1 year and analysed using RMST and Kaplan-Meier analyses. Results The study consisted of 373 patients with a mean age of 82.4 years, of which 233 underwent TAVR and 140 did not. Patients who did not undergo TAVR were more likely to be nonagenarians, with left ventricular dysfunction, chronic kidney disease, dementia, disability, depression, malnutrition, and frailty. The primary clinician-cited reason was: comorbidity in 34%, frailty in 23%, procedural feasibility and risks in 16%, and mild or unrelated symptoms in 27%. Compared to the TAVR group, 1-year RMST was reduced by 2.0 months in the medical management group (95% CI 1.2, 2.7) and by 1.1 months in the valvuloplasty group (95% CI -0.2, 2.5). Conclusions Patients with severe AS referred for TAVR may never undergo the procedure on the basis of comorbidity, frailty, procedural issues, and symptoms. The best treatment decision is one that follows from multi-disciplinary assessment encompassing frailty.

Background The Essential Frailty Toolset (EFT) was shown to be easy to use and predictive of adverse events in patients undergoing aortic valve replacement procedures. The objective of this study was to evaluate the EFT in patients undergoing coronary artery bypass grafting procedures. Methods and Results The McGill Frailty Registry prospectively included patients ≥60 years of age undergoing urgent or elective isolated coronary artery bypass grafting between 2011 and 2018 at 2 hospitals. The preoperative EFT was scored 0 to 5 points as a function of timed chair rises, Mini‐Mental Status Examination, serum albumin, and hemoglobin. The primary outcome was all‐cause mortality assessed by Cox proportional hazards regression. The cohort consisted of 500 patients with a mean age of 71.4 ± 6.4 years, of which 27% presented with acute coronary syndromes requiring urgent surgery. The mean EFT was 1.3 ± 1.1 points, 132 (26%) were nonfrail, 298 (60%) were prefrail, and 70 (14%) were frail. Over a median follow‐up of 4.0 years, 78 deaths were observed. In nonfrail, prefrail, and frail patients, survival at 1 year was 98%, 95%, and 91%, and at 5 years was 89%, 83%, and 63% (P

Telomerase reactivation is responsible for telomere preservation in about 90% of cancers, providing cancer cells an indefinite proliferating potential. Telomerase consists of at least two main subunits: a catalytic reverse transcriptase protein (hTERT) and an RNA template subunit. Strategies to inhibit hTERT expression seem promising for cancer treatment. Previous works showed that all-trans retinoic acid (ATRA) induces hTERT repression in acute promyelocytic leukemia cells, resulting in their death. Here, we investigated the effects of ATRA in a subset of breast cancer cell lines. The mutational status of hTERT promoter and the methylation patterns at a single CpG resolution were assessed. We observed an inverse relationship between hTERT expression after ATRA treatment and the methylation level of a specific CpG at chr5: 1,300,438 in a region of hTERT gene at −5 kb of the transcription initiation site. This observation highlighted the significance of this region, whose methylation profile could represent a promising biomarker to predict the sensitivity to ATRA-induced hTERT repression in specific breast cancer subtypes. As hTERT repression promotes drug-induced cell death, checking the methylation status of this unique region and the specific CpG included can help in decision-making to include ATRA in combination therapy and contributes to a better clinical outcome.

We study the photo-induced insulator-metal transition in VO2, correlating threshold and dynamic evolution with excitation wavelength. In high-quality single crystal samples, we find that switching can only be induced with photon energies above the 670-meV gap. This contrasts with the case of polycrystalline films, where formation of the metallic state can also be triggered with photon energies as low as 180 meV, well below the bandgap. Perfection of this process may be conducive to novel schemes for optical switches, limiters and detectors, operating at room temperature in the mid-IR.

The lack of understanding of complex food-web interactions has been a major gap in the history of biological control. In particular, a better understanding of the functioning of pest food-webs and how they vary between native and invaded geographical ranges is of prime interest for biological control research and associated integrated pest management. Technical limitations associated with the deciphering of complex food-webs can now be largely overcome by the use of high throughput DNA sequencing techniques such as Illumina MiSeq. We tested the efficiency of this next generation sequencing technology in a metabarcoding approach, to study aphid food-webs using the cabbage aphid as model. We compared the variations in structure and composition of aphid food-webs in the species’ native range (United Kingdom, UK) and in an invaded range (New Zealand, NZ). We showed that Illumina MiSeq is a well suited technology to study complex aphid food-webs from aphid mummies. We found an unexpectedly high top down pressure in the NZ cabbage aphid food-web, which coupled to a large ratio of consumer species / prey species and a lack of potential inter-specific competition between primary parasitoids, could cause the NZ food-web to be more vulnerable than the UK one. This study also reports for the first time the occurrence of a new hyperparasitoid species in NZ, as well as new associations between hyperparasitoids parasitoids and the cabbage aphid in this country. We conclude that the complexity of aphid food-webs in agricultural systems could often be underestimated, particularly at higher trophic levels; and that the use of high throughput DNA sequencing tools, could largely help to overcome this impediment.

Lipoprotein(a), or Lp(a), significantly increased alkaline phosphatase activity, release of phosphate, calcium deposition, hydroxyapatite, cell apoptosis, matrix vesicle formation, and phosphorylation of signal transduction proteins; increased expression of chondro-osteogenic mediators; and decreased SOX9 and matrix Gla protein (p

Directed cell motion in response to an external chemical gradient occurs in many biological phenomena such as wound healing, angiogenesis, and cancer metastasis. Chemotaxis is often characterized by the accuracy, persistence, and speed of cell motion, but whether any of these quantities is physically constrained by the others is poorly understood. Using a combination of theory, simulations, and 3D chemotaxis assays on single metastatic breast cancer cells, we investigate the links among these different aspects of chemotactic performance. In particular, we observe in both experiments and simulations that the chemotactic accuracy, but not the persistence or speed, increases with the gradient strength. We use a random walk model to explain this result and to propose that cells' chemotactic accuracy and persistence are mutually constrained. Our results suggest that key aspects of chemotactic performance are inherently limited regardless of how favorable the environmental conditions are.

This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of t-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by t-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids.

Important cellular processes such as migration, differentiation, and development often rely on precise timing. Yet, the molecular machinery that regulates timing is inherently noisy. How do cells achieve precise timing with noisy components? We investigate this question using a first-passage-time approach, for an event triggered by a molecule that crosses an abundance threshold and that is regulated by either an accumulating activator or a diminishing repressor. We find that either activation or repression outperforms an unregulated strategy. The optimal regulation corresponds to a nonlinear increase in the amount of the target molecule over time, arises from a tradeoff between minimizing the timing noise of the regulator and that of the target molecule itself, and is robust to additional effects such as bursts and cell division. Our results are in quantitative agreement with the nonlinear increase and low noise of mig-1 gene expression in migrating neuroblast cells during Caenorhabditis elegans development. These findings suggest that dynamic regulation may be a simple and powerful strategy for precise cellular timing.