Acoustic cell washing and raman spectroscopy technologies To address cell therapy bioprocess challenges

Many organizations are confronting the challenges of economically ensuring the manufacture of safe and efficacious cell therapy products. These processes often depend on devices and methods that were developed for only related applications, such as blood cell processing or scientific research. Thus, we are in a window of opportunity to tailor innovative technologies to address the emerging specialized needs of cell therapy manufacturing. The most frequent unit operation is to wash cells between process stages, such as from DMSO containing cryopreservation medium to culture expansion medium. In particular for relatively small-scale autologous cell therapy processing, cell washing is imperfectly performed by closed system blood cell centrifuges or filters. We previously developed an acoustic cell separation device, widely used for over 15 years in CHO cell perfusion cultures. This technology acts as a non-fouling filter for months of operation, by using the forces generated in ultrasonic standing wave fields. These forces separate cells from medium based on differences in density and compressibility. Greater than 99.9% cell washing with 95% washed cell recovery efficiencies have been provided by our device. We also have recently enhanced the acoustic technology to perfuse 100 million cell/mL cultures, maintaining \u3e99% cell separation efficiencies. This provides an alternative high performance closed manufacturing system, to perfuse, concentrate and wash cells, with no physical filter barrier or mechanical moving parts. While many clinical trials have had few adverse events, the great promise of cellular therapies comes with grave risks, such as from potentially oncogenic pluripotent cells present in embryonic stem cell derived populations. There is an urgent need for process analytical technologies to non-invasively monitor mammalian cell populations and improve the reliability of manufactured cell products. This includes to monitor both the expected differentiation as well as to detect unexpected cells in the process. Recently, technological advances have led to an explosive growth in the capabilities of Raman spectroscopy, increasing the potential for novel applications. We are developing the use of this spectroscopic technique to track cell development, by measuring macromolecular changes in cell samples from cultures where stem cells are differentiated towards insulin-producing cells for the treatment of diabetes. Raman spectroscopy has great potential to provide continuous on-line assessment of cell quality during the manufacture of cell-derived therapeutic cells

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

US hegemony and the origins of Japanese nuclear power : the politics of consent

This paper deploys the Gramscian concepts of hegemony and consent in order to explore the process whereby nuclear power was brought to Japan. The core argument is that nuclear power was brought to Japan as a consequence of US hegemony. Rather than a simple manifestation of one state exerting material ‘power over' another, bringing nuclear power to Japan involved a series of compromises worked out within and between state and civil society in both Japan and the USA. Ideologies of nationalism, imperialism and modernity underpinned the process, coalescing in post-war debates about the future trajectory of Japanese society, Japan's Cold War alliance with the USA and the role of nuclear power in both. Consent to nuclear power was secured through the generation of a psychological state in the public mind combining the fear of nuclear attack and the hope of unlimited consumption in a nuclear-fuelled post-modern world

Strategic network formation through peering and service agreements

We introduce a game theoretic model of network formation in an effort to understand the complex system of business relationships between various Internet entities (e.g., Autonomous Systems, enterprise networks, residential customers). In our model we are given a network topology of nodes and links where the nodes act as the players of the game, and links represent potential contracts. Nodes wish to satisfy their demands, which earn potential revenues, but may have to pay their neighbors for links incident to them. We incorporate some of the qualities of Internet business relationships, including customer-provider and peering contracts. We show that every Nash equilibrium can be represented by a circulation flow of utility with certain constraints. This allows us to prove bounds on the prices of anarchy and stability. We also focus on the quality of equilibria achievable through centralized incentives.Network formation Contract formation Price of anarchy Price of stability Algorithmic game theory