Preclinical Evaluation of a Novel Once-a-Day Brimonidine Ophthalmic Nanosuspension.

Purpose: This article aims to describe a preclinical proof of concept for a novel once-a-day (OD) brimonidine ophthalmic nanosuspension. Methods: The preclinical proof of concept was established using New Zealand white rabbits as animal models. Dose-finding, multiple-dose efficacy, ocular pharmacokinetic, and hemodynamic studies were performed in normotensive rabbits. Steroid-induced ocular hypertension model in rabbits was used to study efficacy in glaucomatous pathophysiology. The test (0.35% OD suspension) and reference (0.15% three times a day [TID] solution) were compared. Results: The intraocular pressure (IOP) reduction was sustained for 0.35% and 0.5% strengths but not for other lower strengths tested or reference strengths. A 0.35% OD suspension reduced IOP >2 mmHg after 24 h of dosing, which was not seen with the reference. After multiple dosing, 0.35% OD suspension reduced IOP by 4-6 mmHg after 24 h, which was comparable to the 0.15% TID reference solution. An ocular pharmacokinetic study showed that the brimonidine was rapidly absorbed and distributed throughout the eye after topical administration. Concentration was higher in tissues with high α2 receptors, such as cornea-conjunctiva, iris/ciliary body, and choroid/retina. The steady-state concentrations in these organs were also significant after 24 h of the last dose. There was an indication of increased plasma levels, so a hemodynamic study was performed to assess any adverse effects. All hemodynamic parameters were normal and no new unusual safety findings were observed. Conclusions: The study demonstrated that the novel brimonidine 0.35% ophthalmic nanosuspension is both safe and effective when administered OD and is comparable to the marketed reference formulation administered TID.

Fractal-fractional mathematical modeling and forecasting of new cases and deaths of COVID-19 epidemic outbreaks in India.

Fractional-order derivative-based modeling is very significant to describe real-world problems with forecasting and analyze the realistic situation of the proposed model. The aim of this work is to predict future trends in the behavior of the COVID-19 epidemic of confirmed cases and deaths in India for October 2020, using the expert modeler model and statistical analysis programs (SPSS version 23 & Eviews version 9). We also generalize a mathematical model based on a fractal fractional operator to investigate the existing outbreak of this disease. Our model describes the diverse transmission passages in the infection dynamics and affirms the role of the environmental reservoir in the transmission and outbreak of this disease. We give an itemized analysis of the proposed model including, the equilibrium points analysis, reproductive number R 0 , and the positiveness of the model solutions. Besides, the existence, uniqueness, and Ulam-Hyers stability results are investigated of the suggested model via some fixed point technique. The fractional Adams Bashforth method is applied to solve the fractal fractional model. Finally, a brief discussion of the graphical results using the numerical simulation (Matlab version 16) is shown.

Deep Learning-Based Spermatogenic Staging Assessment for Hematoxylin and Eosin-Stained Sections of Rat Testes.

In preclinical toxicology studies, a "stage-aware" histopathological evaluation of testes is recognized as the most sensitive method to detect effects on spermatogenesis. A stage-aware evaluation requires the pathologist to be able to identify the different stages of the spermatogenic cycle. Classically, this evaluation has been performed using periodic acid-Schiff (PAS)-stained sections to visualize the morphology of the developing spermatid acrosome, but due to the complexity of the rat spermatogenic cycle and the subtlety of the criteria used to distinguish between the 14 stages of the cycle, staging of tubules is not only time consuming but also requires specialized training and practice to become competent. Using different criteria, based largely on the shape and movement of the elongating spermatids within the tubule and pooling some of the stages, it is possible to stage tubules using routine hematoxylin and eosin (H&E)-stained sections, thereby negating the need for a special PAS stain. These criteria have been used to develop an automated method to identify the stages of the rat spermatogenic cycle in digital images of H&E-stained Wistar rat testes. The algorithm identifies the spermatogenic stage of each tubule, thereby allowing the pathologist to quickly evaluate the testis in a stage-aware manner and rapidly calculate the stage frequencies.

Existence theory and numerical analysis of three species prey-predator model under Mittag-Leffler power law.

In this manuscript, the fractional Atangana-Baleanu-Caputo model of prey and predator is studied theoretically and numerically. The existence and Ulam-Hyers stability results are obtained by applying fixed point theory and nonlinear analysis. The approximation solutions for the considered model are discussed via the fractional Adams Bashforth method. Moreover, the behavior of the solution to the given model is explained by graphical representations through the numerical simulations. The obtained results play an important role in developing the theory of fractional analytical dynamic of many biological systems.

On a comprehensive model of the novel coronavirus (COVID-19) under Mittag-Leffler derivative.

The major purpose of the presented study is to analyze and find the solution for the model of nonlinear fractional differential equations (FDEs) describing the deadly and most parlous virus so-called coronavirus (COVID-19). The mathematical model depending of fourteen nonlinear FDEs is presented and the corresponding numerical results are studied by applying the fractional Adams Bashforth (AB) method. Moreover, a recently introduced fractional nonlocal operator known as Atangana-Baleanu (AB) is applied in order to realize more effectively. For the current results, the fixed point theorems of Krasnoselskii and Banach are hired to present the existence, uniqueness as well as stability of the model. For numerical simulations, the behavior of the approximate solution is presented in terms of graphs through various fractional orders. Finally, a brief discussion on conclusion about the simulation is given to describe how the transmission dynamics of infection take place in society.