Real-world, Multicenter Experience With Meropenem-Vaborbactam for Gram-Negative Bacterial Infections Including Carbapenem-Resistant Enterobacterales and Pseudomonas aeruginosa

Background: We aimed to describe the clinical characteristics and outcomes of patients treated with meropenem-vaborbactam (MEV) for a variety of gram-negative infections (GNIs), primarily including carbapenem-resistant Enterobacterales (CRE). Methods: This is a real-world, multicenter, retrospective cohort within the United States between 2017 and 2020. Adult patients who received MEV for ≥72 hours were eligible for inclusion. The primary outcome was 30-day mortality. Classification and regression tree analysis (CART) was used to identify the time breakpoint (BP) that delineated the risk of negative clinical outcomes (NCOs) and was examined by multivariable logistic regression analysis (MLR). Results: Overall, 126 patients were evaluated from 13 medical centers in 10 states. The most common infection sources were respiratory tract (38.1%) and intra-abdominal (19.0%) origin, while the most common isolated pathogens were CRE (78.6%). Thirty-day mortality and recurrence occurred in 18.3% and 11.9%, respectively. Adverse events occurred in 4 patients: nephrotoxicity (n = 2), hepatoxicity (n = 1), and rash (n = 1). CART-BP between early and delayed treatment was 48 hours (P = .04). MEV initiation within 48 hours was independently associated with reduced NCO following analysis by MLR (adusted odds ratio, 0.277; 95% CI, 0.081-0.941). Conclusions: Our results support current evidence establishing positive clinical and safety outcomes of MEV in GNIs, including CRE. We suggest that delaying appropriate therapy for CRE significantly increases the risk of NCOs

Understanding elevated lactate level in a large-scale perfusion process to improve performance

Operational differences between the development lab and the GMP manufacturing facility can present challenges when developing a scalable process that conforms to the intended facility. Differences in the media storage conditions and metabolite sampling method between the bench scale and manufacturing scale perfusion processes were found to contribute to discrepancies in process parameters and ultimately lower productivity during scale-up runs. Unlike the bench scale runs, perfusion media was prepared and stored in an air-sparged vessel prior to being fed into a 500L bioreactor. Media air sparging resulted in elevated media pH, which consequently altered the dissolved amino acid and metal ion levels in the media prior to being fed into the reactor. During a subsequent run, the pH level was controlled during air-sparging. Productivity from the 500L process with pH-controlled media storage was higher than the 500L process with uncontrolled pH during media storage. Additionally, lactate levels were lower for the 500L scale process when pH was controlled during media storage. Comparing the 500L scale process to the 3L scale process used in development, measured lactate concentration levels during all 500L scale runs were elevated relative to the lactate concentrations measured during the 3L development runs. A key difference between development and 500L runs was the procedure used to measure lactate, specifically the difference in timing between drawing the sample and measurement. This difference combined with the fact that the 500L runs were performed in pressurized vessels led to the discrepancy in measured lactate levels during the process. The mechanism involved is likely related to CHO cell regulatory volume decrease (RVD).1 When CHO cells are withdrawn from a pressurized reactor, they undergo osmotic swelling followed by efflux of ions such as potassium and chloride as well as organic osmolytes such as amino acids, glucose and lactate. This efflux is known to occur over only a few minutes; therefore, a delay of such time in metabolite measurements can lead to a discrepancy between scale-up and development data. Careful consideration must be given to differences not only in the process (e.g. media storage), but also in the methods utilized to gather process parameter data. Because adjustments to the cell culture conditions affecting cell productivity are made based on measurements of process parameters (e.g. pH level), discrepancies in the data acquisition methods for these parameters can indirectly affect cell productivity if not carefully evaluated. [1] Sarkadi, B., Attisan, L., Grinstein, S., Buchwald, M., Rothstein, A., “Volume Regulation of Chinese Hamster Ovary Cells in Aniisoosmotic Media”, Biochimica et Biophysica Acta, 774 (1984) 159-168

Electronic Structure Calculations in Arbitrary Electrostatic Environment

Modeling of electronic structure of molecules in electrostatic environments is of considerable relevance for surface-enhanced spectroscopy and molecular electronics. We have developed and implemented a novel approach to the molecular electronic structure in arbitrary electrostatic environments that is compatible with standard quantum chemical methods and can be applied to medium-sized and large molecules. The scheme denoted CheESE (chemistry in electrostatic environments) is based on the description of molecular electronic structure subject to a boundary condition on the system/environment interface. Thus, it is particularly suited to study molecules on metallic surfaces. The proposed model is capable of describing both electrostatic effects near nanostructured metallic surfaces and image-charge effects. We present an implementation of the CheESE model as a library module and show example applications to neutral and negatively charged molecules.Chemistry and Chemical Biolog

Persistent fluid flows defined by active matter boundaries

Biological systems achieve precise control over ambient fluids through the self-organization of active protein structures including flagella, cilia, and cytoskeletal networks. In active structures individual proteins consume chemical energy to generate force and motion at molecular length scales. Self-organization of protein components enables the control and modulation of fluid flow fields on micron scales. The physical principles underlying the organization and control of active-matter driven fluid flows are poorly understood. Here, we apply an optically-controlled active-matter system composed of microtubule filaments and light-switchable kinesin motor proteins to analyze the emergence of persistent flow fields in a model active matter system. Using light, we form contractile microtubule networks of varying shape. We analyze the fluid flow fields generated by a wide range of microtubule network geometries and explain the resulting flow fields within a unified theoretical framework. We specifically demonstrate that the geometry of microtubule flux at the boundary of contracting microtubule networks predicts the steady-state fluid flow fields across polygonal network geometries through finite-element simulations. Our work provides a foundation for programming microscopic fluid-flows with controllable active matter and could enable the engineering of versatile and dynamic microfluidic devices

Real Time Animation of Virtual Humans: A Trade-off Between Naturalness and Control

Virtual humans are employed in many interactive applications using 3D virtual environments, including (serious) games. The motion of such virtual humans should look realistic (or ‘natural’) and allow interaction with the surroundings and other (virtual) humans. Current animation techniques differ in the trade-off they offer between motion naturalness and the control that can be exerted over the motion. We show mechanisms to parametrize, combine (on different body parts) and concatenate motions generated by different animation techniques. We discuss several aspects of motion naturalness and show how it can be evaluated. We conclude by showing the promise of combinations of different animation paradigms to enhance both naturalness and control

Emissions of C&D refuse in landfills: a European case

ABSTRACT: A field study was developed in a new landfill for refuse from construction and demolition (C&D) material recovery plants of small size (4 Ha.) in Europe, with the aim of evaluating the liquid and gas emissions in this type of facility at a large scale. It included characterization of the materials, monitoring leachate and gas quantity and composition. Besides thermometers, piezometers and sampling ports were placed in several points within the waste. This paper presents the data obtained for five years of the landfill life. The materials disposed were mainly made up of wood and concrete, similar to other C&D debris sites, but the amount of gypsum drywall (below 3% of the waste) was significantly smaller than other available studies, where percentages above 20% had been reported. Leachate contained typical C&D pollutants, such as different inorganic ions and metals, some of which exceeded other values reported in the literature (conductivity, ammonium, lead and arsenic). The small net precipitation in the area and the leachate recirculation into the landfill surface help explain these higher concentrations, thus highlighting the impact of liquid to solid (L/S) ratio on leachate characteristics. In contrast to previous studies, neither odor nuisances nor significant landfill gas over the surface were detected. However, gas samples taken from the landfill inside revealed sulfate reducing and methanogenic activity

Design of a decision support system for multiobjective activity planning and programming using global bacteria optimization

The success of any project lies in a great manner on keeping costs in the estimated values, as well as meeting customer required due date. Therefore, there is a current need of developing an information system that facilitates the creation and managing of projects and their processes, including costing schemes, as well as monitoring an optimizing project’s makespan. In order to address this situation a user-friendly information system (IS) was developed. This IS includes an optimization module that reduces the project’s execution time, thus, minimizing costs and ultimately providing the manager with the right tools for the correct development of the project. Therefore, a better planning of activities in a reduced time is accomplished. In this way, the project manager is equipped with a decision support system (DSS) that allows a better decision making and, thanks to this performance optimization, a cost-effective solution can be delivered to the company. The optimization module is the main innovative component in this IS, considering that addresses the problem as a multiobjective one, considering at the same time makespan and cost. This module is based on global bacteria optimization (GBO). This becomes the most relevant improvement when compared to other ISs in the market

Mitogen-Activated Protein Kinase 14 Promotes AKI

An improved understanding of pathogenic pathways may identify novel acute kidney injury (AKI) therapeutic approaches. Unbiased LC-MS/MS protein expression profiling combined with focused data mining identified MAP3K14 and non-canonical NFκB activation at the crossroads of the enriched pathways MAPK, ubiquitin-mediated proteolysis, chemokines, NFκB and apoptosis in the kidney cortex of experimental toxic AKI. In AKI the upstream kinase MAP3K14, the NFκB DNA binding heterodimer RelB/NFκB2, and proteins involved in NFκB2 p100 ubiquitination and proteasomal processing to p52, such as Ube2m and cullin1 were up-regulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in experimental and human AKI. In vivo evidence of MAP3K14 activation in experimental folic acid-induced AKI consisted of NFκB2 p100 processing to p52, nuclear location and DNA binding of RelB and NFκB2. MAP3K14 activity-deficient aly/aly mice were protected from kidney dysfunction, inflammation and apoptosis in AKI induced by folic acid and from lethality in cisplatin-induced AKI. MAP3K14 siRNA targeting in cultured tubular cells decreased inflammation and cell death. Bone marrow transplantation experiments where consistent with a protective effect of renal cell MAP3K14 targeting. Cell culture and in vivo studies identified chemokines MCP-1, RANTES and CXCL10 as MAP3K14 targets in tubular cells, thus identifying potential mediators of the deleterious effect of MAP3K14 in kidney injury. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target