scholarly journals Optimizing Antiviral Therapy for COVID-19 With Learned Pathogenic Model

Author(s):  
Abhishek Dutta

Abstract COVID-19 together with variants have caused an unprecedented amount of mental and economic turmoil with ever increasing fatality and no proven therapies in sight. The healthcare industry is racing to find a cure with multitude of clinical trials underway to access the efficacy of repurposed antivirals, however the much needed insights into the dynamics of pathogenesis of SARS-CoV-2 and corresponding pharmacology of antivirals are lacking. This paper introduces systematic pathological model learning of COVID-19 dynamics followed by derivative free optimization based multi objective drug rescheduling. The pathological model learnt from clinical data of severe COVID-19 patients treated with Remdesivir could additionally predict immune T cells response and resulted in a dramatic reduction in Remdesivir dose and schedule leading to lower toxicities, however maintaining a high virological efficacy.

2020 ◽  
Vol 178 ◽  
pp. 65-74
Author(s):  
Ksenia Balabaeva ◽  
Liya Akmadieva ◽  
Sergey Kovalchuk

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra J. Spencer ◽  
Paul F. McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D. Bissett ◽  
...  

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.


2021 ◽  
Author(s):  
Faruk Alpak ◽  
Yixuan Wang ◽  
Guohua Gao ◽  
Vivek Jain

Abstract Recently, a novel distributed quasi-Newton (DQN) derivative-free optimization (DFO) method was developed for generic reservoir performance optimization problems including well-location optimization (WLO) and well-control optimization (WCO). DQN is designed to effectively locate multiple local optima of highly nonlinear optimization problems. However, its performance has neither been validated by realistic applications nor compared to other DFO methods. We have integrated DQN into a versatile field-development optimization platform designed specifically for iterative workflows enabled through distributed-parallel flow simulations. DQN is benchmarked against alternative DFO techniques, namely, the Broyden–Fletcher–Goldfarb–Shanno (BFGS) method hybridized with Direct Pattern Search (BFGS-DPS), Mesh Adaptive Direct Search (MADS), Particle Swarm Optimization (PSO), and Genetic Algorithm (GA). DQN is a multi-thread optimization method that distributes an ensemble of optimization tasks among multiple high-performance-computing nodes. Thus, it can locate multiple optima of the objective function in parallel within a single run. Simulation results computed from one DQN optimization thread are shared with others by updating a unified set of training data points composed of responses (implicit variables) of all successful simulation jobs. The sensitivity matrix at the current best solution of each optimization thread is approximated by a linear-interpolation technique using all or a subset of training-data points. The gradient of the objective function is analytically computed using the estimated sensitivities of implicit variables with respect to explicit variables. The Hessian matrix is then updated using the quasi-Newton method. A new search point for each thread is solved from a trust-region subproblem for the next iteration. In contrast, other DFO methods rely on a single-thread optimization paradigm that can only locate a single optimum. To locate multiple optima, one must repeat the same optimization process multiple times starting from different initial guesses for such methods. Moreover, simulation results generated from a single-thread optimization task cannot be shared with other tasks. Benchmarking results are presented for synthetic yet challenging WLO and WCO problems. Finally, DQN method is field-tested on two realistic applications. DQN identifies the global optimum with the least number of simulations and the shortest run time on a synthetic problem with known solution. On other benchmarking problems without a known solution, DQN identified compatible local optima with reasonably smaller numbers of simulations compared to alternative techniques. Field-testing results reinforce the auspicious computational attributes of DQN. Overall, the results indicate that DQN is a novel and effective parallel algorithm for field-scale development optimization problems.


Author(s):  
Martin Perez-Santos ◽  
Maricruz Anaya-Ruiz ◽  
Gabriela Sanchez-Esgua ◽  
Luis Villafaña-Diaz ◽  
Diana Barron-Villaverde

PD-L1 and ICOS are immune control points in cancer and their presence in cancer tends to have a poor prognosis. WO2019122882 patent describes a bispecific antibody that targets PDL-1/ICOS with the potential application of cancer treatment. WO2019122882 patent describes a bispecific antibody with antitumor efficacy in CT26 model through of the depletion of TReg cells and improved ratio of CD8+ T cells: TReg in tumor microenvironment. The anti-PDL-1/ICOS antibody is new; however, only preclinical assays are shown using colon carcinoma model. So far, there are no reports of clinical trials to evaluate the safety, toxicity and efficacy, but it will be of great interest to analyze in the future if this antibody surpasses the action of the combinatorial therapy in cancer.


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