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Background: Total occlusion of the iliac-femoral tract can cause a variety of life-limiting symp-toms ranging from mild claudication to chronic limb-threatening ischemia. Efforts should be made to revascularize the symptomatic ischemic limb. Currently there are different options in the vascular surgeon's armamentarium to achieve this. The aim of the study was to verify the feasibility and outcomes of inflow hybrid revascularizations combining femoral endarterectomy and recanalization of iliac atherosclerotic occlusion. Methods: A retrospective review was conducted of all hybrid revascularizations involving femoral endarterectomy and endovascular treatment of iliac occlusion. The operations were per-formed in Helsinki University Hospital between January 2013 and December 2018. First, infor-mation about patients' baseline characteristics, indications and details of surgery and technical/ hemodynamic success, and complications and mortality were obtained from the vascular regis-try and patients records. Secondarily, a prospective assessment of mid-term patency was per-formed through follow-up in November 2019. Immediate technical success, 30-day mortality, complications, and patency were considered major outcomes. Hemodynamic improvement, amputation rate, and overall mortality were also assessed.Results: One hundred sixty three iliofemoral occlusions were performed on 147 patients during the period studied. Six patients (3.6%) had infrarenal aortic occlusion, 86 (52.7%) had common iliac, and 128 (78.5%) had external iliac artery occlusion. Technical success rate was 88.3% (n = 144 occlusions recanalized). Primary technical success was somewhat lower in lesions > 90 mm (87.1%) compared to lesions shorter than 90 mm (95.7%; c2 P = 0.06). Iliac stent was deployed in 141 (94.6%) cases, 51 (34.3%) of which were covered stents. Significant resid-ual stenosis remained in 1.2% of cases. Median operative time was 4 hr 34 min (interquartile range 2 hr 43 min) and median estimated blood loss was 743 mL (interquartile range 500 mL). Five patients (3.0%) developed a deep groin infection and 12 (8.1%) suffered any ma-jor cardiovascular event or stroke perioperatively. Primary patency at 30 day, 6 months, 1 year, and 2 years was 98.7%, 98.1%, 96.6%, and 93.7%, respectively. Hemodynamic success was documented in 107 patients (73%). By the end of the follow-up, 7 iliofemoral tracts (11.1%) reoc-cluded, 2 limbs (1.2%) required amputation, and 50 patients (3.0%) died. Conclusions: Good immediate success rate and mid-term patency can be achieved by hybrid revascularization of iliofemoral occlusions. Careful patient selection is mandatory because this pop-ulation often suffers from universal atherosclerosis. The involvement of the aorta represents a sig-nificant determinant of worse long-term patency, although it did not preclude technical success.

Linezolid is an antimicrobial with broad activity against Gram-positive bacteria. Thrombocytopenia is one of its most common side effects often leading to severe complications. The aim of this study is to identify factors related with development of this condition in critically ill patients and to develop and evaluate a predictive machine learning-based model considering easy-to-obtain clinical variables.Data was obtained from the Medical Information Mart for Intensive Care III. Patients who received linezolid for over three days were considered, excluding those under 18 years and/or lacking laboratory data. Thrombocytopenia was considered as a platelet decrease of at least 50% from baseline.Three hundred and twenty patients met inclusion criteria of which 63 developed thrombocytopenia and presented significant greater duration of treatment, aspartate-aminotransferase, bilirubin and international normalized ratio; and lower renal clearance and platelet count at baseline. Thrombocytopenia development was associated with a worse outcome (30 days mortality [OR: 2.77; CI95%: 1.87-5.89; P .001], 60 days mortality [OR: 3.56; CI95%: 2.18-7.26; P .001]). Thrombocytopenia was also correlated with higher length of hospital stays (35.56 [20.40-52.99] vs 22.69 [10.05-38.61]; P .001). Median time until this anomaly was of 23 days (CI95%:19.0-NE). Two multivariate models were performed. Accuracy, sensitivity, specificity and AUROC obtained in the best of them were of 0.75, 0.78, 0.62 and 0.80, respectively.Linezolid associated thrombocytopenia entails greater mortality rates and hospital stays. Although the proposed predictive model has to be subsequently validated in a real clinical setting, its application could identify patients at risk and establish screening and surveillance strategies.

Post‐translational modification of the DNA replication machinery by ubiquitin and SUMO plays key roles in the faithful duplication of the genetic information. Among other functions, ubiquitination and SUMOylation serve as signals for the extraction of factors from chromatin by the AAA ATPase VCP. In addition to the regulation of DNA replication initiation and elongation, we now know that ubiquitination mediates the disassembly of the replisome after DNA replication termination, a process that is essential to preserve genomic stability. Here, we review the recent evidence showing how active DNA replication restricts replisome ubiquitination to prevent the premature disassembly of the DNA replication machinery. Ubiquitination also mediates the removal of the replisome to allow DNA repair. Further, we discuss the interplay between ubiquitinmediated replisome disassembly and the activation of CDK1 that is required to set up the transition from the S phase to mitosis. We propose the existence of a ubiquitin–CDK1 relay, where the disassembly of terminated replisomes increases CDK1 activity that, in turn, favors the ubiquitination and disassembly of more replisomes. This model has important implications for the mechanism of action of cancer therapies that induce the untimely activation of CDK1, thereby triggering premature replisome disassembly and DNA damage., Ramón y Cajal Fellowship from MINECO (RYC-2016-20705), co-funded by European Regional Development Funds (FEDER) to Emilio Lecona; by grants from the Spanish Ministry of Science, Innovation and Universities (RTI2018-102204-B-I00, co-financed with European FEDER funds) and the European Research Council (ERC-617840) to Oscar Fernandez-Capetillo; fellowships from Fundacion Ramon Areces-UAM and LaCaixa Foundation to Pablo Valledor (LCF/BQ/ES18/11670008)

Chemical inhibitors of the deubiquitinase USP7 are currently being developed as anticancer agents based on their capacity to stabilize P53. Regardless of this activity, USP7 inhibitors also generate DNA damage in a p53-independent manner. However, the mechanism of this genotoxicity and its contribution to the anticancer effects of USP7 inhibitors are still under debate. Here we show that, surprisingly, even if USP7 inhibitors stop DNA replication, they also induce a widespread activation of CDK1 throughout the cell cycle, which leads to DNA damage and is toxic for mammalian cells. In addition, USP7 interacts with the phosphatase PP2A and supports its active localization in the cytoplasm. Accordingly, inhibition of USP7 or PP2A triggers very similar changes of the phosphoproteome, including a widespread increase in the phosphorylation of CDK1 targets. Importantly, the toxicity of USP7 inhibitors is alleviated by lowering CDK1 activity or by chemical activation of PP2A. Our work reveals that USP7 limits CDK1 activity at all cell cycle stages, providing a novel mechanism that explains the toxicity of USP7 inhibitors through untimely activation of CDK1., Spanish Ministry of Science, Innovation and Universities (RTI2018-102204-B-I00, co-financed with European FEDER funds) and the European Research Council (ERC-617840) to OF; a grant from the Spanish Ministry of Science, Innovation and Universities (RTI2018-095582-B-I00, co-financed with European FEDER funds) to MM; a grant from MINECO (BFU2014-55168-JIN)

The aim of this work was to analyze outer membrane porin-encoding genes (ompK35 and ompK36) in a collection of OXA-48 producing Klebsiella pneumoniae, to assess the effect of porin alterations on the susceptibility to ceftazidime/avibactam, and to describe a screening methodology for phenotypic detection of OXA-48-producing K. pneumoniae with disrupted porins. Antimicrobial susceptibility was tested by Microscan and Etest. The genomes of 81 OXA-48-producing K. pneumoniae were sequenced. MLST, detection of antimicrobial resistance genes, and analysis of ompK35 and ompK36 were performed in silico. Tridimensional structures of the OmpK36 variants were assessed. Receiver operating characteristics curves were built to visualize the performance ability of a disk diffusion assay using carbapenems and cefoxitin to detect OmpK36 functional alterations. A wide variety of OmpK36 alterations were detected in 17 OXA-48-producing K. pneumoniae isolates. All displayed a high-level meropenem resistance (MIC ≥ 8 mg/L), and some belonged to high-risk clones, such as ST15 and ST147. Alterations in ompK35 were also observed, but they did not correlate with high-level meropenem resistance. All isolates were susceptible to ceftazidime/avibactam and porin alterations did not affect the MICs of the latter combination. Cefoxitin together with ertapenem/meropenem low inhibition zone diameters (equal or lower than 16 mm) could strongly suggest alterations affecting OmpK36 in OXA-48-producing K. pneumoniae. OXA-48-producing K. pneumoniae with porin disruptions are a cause of concern, ceftazidime/avibactam showed good in vitro activity against them, so this combination could be positioned as the choice therapy to combat the infections caused by this difficult-to-treat isolates.

This paper introduces a method for the distribution of any and all population-based metaheuristics. It improves on the naive approach, independent multiple runs, while adding negligible overhead. Existing methods that coordinate instances across a cluster typically require some compromise of more complex design, higher communication loads, and solution propagation rate, requiring more work to develop and more resources to run. The aim of the new method is not to achieve state-of-the-art results, but rather to provide a better baseline method than multiple independent runs. The main concept of the method is that one of the instances receives updates with the current best solution of all other instances. This work describes the general approach and its particularization to both genetic algorithms and ant colony optimization for solving Traveling Salesman Problems (TSPs). It also includes extensive tests on the TSPLIB benchmark problems of resulting quality of the solutions and anytime performance (solution quality versus time to reach it). These tests show that the new method yields better solutions for about two thirds of the problems and equivalent solutions in the remaining third, and consistently exhibits better anytime performance.

Over 30 years, evolutionary multi- and many-objective optimization (EMO/EMaO) algorithms have been extensively applied to find well-distributed Pareto-optimal (PO) solutions in a single run. However, in real-world problems, the PO front may not always be a single continuous hyper-surface, rather several irregularities may exist involving disjointed surfaces, holes within the surface, or patches of mixed-dimensional surfaces. When a set of trade-off solutions are obtained by EMO/EMaO algorithms, there may exist less dense or no solutions (we refer as 'gaps') in certain parts of the front. This can happen for at least two reasons: (i) gaps naturally exist in the PO front, or (ii) no natural gaps exists, but the chosen EMO/EMaO algorithm is not able to find any solution in the apparent gaps. To make a confident judgement, we propose a three-step procedure here. First, we suggest a computational procedure to identify gaps, if any, in the EMO/EMaO-obtained PO front. Second, we propose a computational method to identify well-distributed gap-points in the gap regions. Third, we apply a focused EMO/EMaO algorithm to search for possible representative trade-off points in the gaps. We then propose two metrics to qualitatively establish whether a gap truly exists in the obtained dataset, and if yes, whether the gap naturally exists on the true Pareto-set. Procedures are supported by results on two to five-objective test problems and on a five-objective scheduling problem from a steel-making industry.

The aim of this paper is to analyse, model, and solve the rescheduling problem in dynamic permutation flow shop environments while considering several criteria to optimize. Searching optimal solutions in multiobjective optimization problems may be difficult as these objectives are expressing different concepts and are not directly comparable. Thus, it is not possible to reduce the problem to a single-objective optimization, and a set of efficient (nondominated) solutions, a so-called Pareto front, must be found. Moreover, in manufacturing environments, disruptive changes usually emerge in scheduling problems, such as machine breakdowns or the arrival of new jobs, causing a need for fast schedule adaptation. In this paper, a mathematical model for this type of problem is proposed and a restarted iterated Pareto greedy (RIPG) metaheuristic is used to find the optimal Pareto front. To demonstrate the appropriateness of this approach, the algorithm is applied to a benchmark specifically designed in this study, considering three objective functions (makespan, total weighted tardiness, and steadiness) and three classes of disruptions (appearance of new jobs, machine faults, and changes in operational times). Experimental studies indicate the proposed approach can effectively solve rescheduling tasks in a multiobjective environment.

In multi-objective optimisation problems, optimal decisions need to be made in the presence of trade-offs among conflicting objectives which may sometimes be expressed in different units of measure...

Summary The AAA+ ATPase VCP regulates the extraction of SUMO and ubiquitin-modified DNA replication factors from chromatin. We have previously described that active DNA synthesis is associated with a SUMO-high/ubiquitin-low environment governed by the deubiquitylase USP7. Here, we unveil a functional cooperation between USP7 and VCP in DNA replication, which is conserved from Caenorhabditis elegans to mammals. The role of VCP in chromatin is defined by its cofactor FAF1, which facilitates the extraction of SUMOylated and ubiquitylated proteins that accumulate after the block of DNA replication in the absence of USP7. The inactivation of USP7 and FAF1 is synthetically lethal both in C. elegans and mammalian cells. In addition, USP7 and VCP inhibitors display synergistic toxicity supporting a functional link between deubiquitylation and extraction of chromatin-bound proteins. Our results suggest that USP7 and VCPFAF1 facilitate DNA replication by controlling the balance of SUMO/Ubiquitin-modified DNA replication factors on chromatin., Graphical abstract, Highlights • VCP and USP7 control the SUMO/ubiquitin landscape during DNA replication • VCP is recruited by FAF1 to chromatin-associated SUMO/ubiquitylated proteins • FAF1 recognizes both SUMO and ubiquitin on target proteins • The control of DNA replication by VCPFAF1 and USP7 is evolutionarily conserved, Chromatin at DNA replication forks is SUMO-rich and ubiquitin-poor. Franz et al. report that FAF1 is a dual reader of SUMO and ubiquitin targeting VCP to extract DNA replication factors from chromatin in C. elegans and human cells. Together with USP7, VCPFAF1 controls the SUMO/ubiquitin landscape during replication.

SUMMARYTo ensure a faithful segregation of chromosomes, DNA must be fully replicated before mitotic entry. However, how cells sense the completion of DNA replication and to what extent this is linked to the activation of the mitotic machinery remains poorly understood. We previously showed that USP7 is a replisome-associated deubiquitinase with an essential role in DNA replication. Here, we reveal that USP7 inhibition leads to the ubiquitination of MCM7, a hallmark of DNA replication termination. In addition, USP7 inhibition leads to the ubiquitination of additional replisome components such as POLD1, which are displaced from replisomes. Surprisingly, this premature termination of DNA replication occurs concomitant to a generalized activation of CDK1 throughout the entire cell cycle, which impairs chromosome segregation and is toxic for mammalian cells. Accordingly, the toxicity of USP7 inhibitors is alleviated by CDK1 inhibition. Our work sheds light into the mechanism of action of USP7 inhibitors and provides evidence to the concept that DNA replication termination is coupled to the activation of the mitotic program.

Metaheuristics include a wide range of optimization algorithms. Some of them are very well known and with proven value, as they solve successfully many examples of combinatorial NP-hard problems. Some examples of Metaheuristics are Genetic Algorithms (GA), Simulated Annealing (SA) or Ant Colony Optimization (ACO). Our company is devoted to making steel and is the biggest steelmaker in the world. Combining several industrial processes to produce 84.6 million tones (public official data of 2015) involves huge effort. Metaheuristics are applied to different scenarios inside our operations to optimize different areas: logistics, production scheduling or resource assignment, saving costs and helping to reach operational excellence, critical for our survival in a globalized world. Rather than obtaining the global optimal solution, the main interest of an industrial company is to have "good solutions", close to the optimal, but within a very short response time, and this latter requirement is the main difference with respect to the traditional research approach from the academic world. Production is continuous and it cannot be stopped or wait for calculations, in addition, reducing production speed implies decreasing productivity and making the facilities less competitive. Disruptions are common events, making rescheduling imperative while foremen wait for new instructions to operate. This position paper explains the problem of the time response in our industrial environment, the solutions we have investigated and some results already achieved.

In transactional systems, the objectives of quality of service regarding are often specified by Service Level Objectives (SLOs) that stipulate a response time to be achieved for a percentile of the transactions. Usually, there are different client classes with different SLOs. In this paper, we extend a technique that enforces the fulfilment of the SLOs using admission control. The admission control of new user sessions is based on a response-time model. The technique proposed in this paper dynamically adapts the model to changes in workload characteristics and system configuration, so that the system can work autonomically, without human intervention. The technique requires no knowledge about the internals of the system; thus, it is easy to use and can be applied to many systems. Its utility is demonstrated by a set of experiments on a system that implements the TPC-App benchmark. The experiments show that the model adaptation works correctly in very different situations that include large and small changes in response times, increasing and decreasing response times, and different patterns of workload injection. In all this scenarios, the technique updates the model progressively until it adjusts to the new situation and in intermediate situations the model never experiences abnormal behaviour that could lead to a failure in the admission control component.

Swarm Intelligence metaheuristics, and among them Ant Colony Optimization (ACO), have been successfully applied worldwide to solve multiple examples of combinatorial NP-hard problems, giving good solutions in a reasonable period of time (an essential requirement in real life applications). Our company is dedicated to produce steel, being the biggest steelmaker in the World. The impact of a good sequencing in our daily production results is critical. Sequencing requires to take into consideration the most relevant parameters that influence along the material transformation process, being this a really difficult task to do manually or with other traditional methods. After the successful use of the Ant System (AS) algorithm to sequence several of our Galvanizing production lines, we have studied the potential benefit of moving from the classical AS algorithm to an Ant Colony System (ACS), a promising variation of the ACO metaheuristics family. In this paper, we present the work done in order to apply the ACO techniques to an industrial problem. More specifically, we exhibit a comparison between AS and ACS variants, the results obtained and the conclusions drawn from such comparison.