Multiscale modeling of HBV infection integrating intra- and intercellular viral propagation to analyze extracellular viral markers.

Chronic infection with hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. Thus, quantifying and understanding the dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, such study requires repeated liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because liver biopsy is potentially morbid and not common during hepatitis B treatment. We here aimed to develop a noninvasive method for quantifying cccDNA in the liver using surrogate markers in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations, integrates experimental data from in vitro and in vivo investigations. By applying this model, we roughly predicted the amount and dynamics of intrahepatic cccDNA within a certain range using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The noninvasive quantification of cccDNA using our proposed method holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions.

Multiscale modeling of HBV infection integrating intra- and intercellular viral propagation for analyzing extracellular viral markers.

Chronic infection of hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. The quantifying and understanding dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, it requires a liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because of the ethical aspect. We here aimed to develop a non-invasive method for quantifying cccDNA in the liver using surrogate markers present in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations (PDEs), integrates experimental data from in vitro and in vivo investigations. By applying this model, we successfully predicted the amount and dynamics of intrahepatic cccDNA using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The non-invasive quantification of cccDNA using our proposed methodology holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions.

Effect of 3-week preoperative rehabilitation on pain and daily physical activities in patients with severe osteoarthritis undergoing total knee arthroplasty.

Background: We hypothesized that 3 weeks of preoperative rehabilitation could improve postoperative pain in patients undergoing total knee arthroplasty (TKA). Aim: This study aimed to evaluate the effects of 3 weeks of preoperative rehabilitation on postoperative pain after TKA. Methods: This prospective cohort study included 29 subjects (41 knees) divided into two groups: the preoperative rehabilitation group included 14 subjects (20 knees) and the control group included 15 subjects (21 knees). All subjects were scheduled for unilateral or bilateral TKA. The preoperative rehabilitation group completed a 90-min rehabilitation program 3 days per week for 3 weeks before their TKA. The rehabilitation included body weight exercise, resistance exercise, and cycle ergometer exercise. The control group did not undergo any rehabilitation prior to TKA. We assessed the patients using Western Ontario and McMaster Universities' Osteoarthritis Index (WOMAC) and recorded their physical activity of walking, standing, sitting, and lying down at study entry and/or before TKA and 1 month after TKA. Results: The WOMAC total and WOMAC pain scores were significantly lower after 3-weeks of rehabilitation, but before TKA and 1 month after surgery were significantly lower in the preoperative rehabilitation group than in the control group. The time spent walking, standing, sitting, and lying down for 12 h did not change after TKA in the preoperative rehabilitation group. In contrast, in the control group, the time spent in walking and standing positions decreased and the time in the sitting position increased after TKA (p < 0.05). Conclusion: We found that 3-week preoperative training reduced knee pain and helped maintain physical activity after surgery in patients with severe osteoarthritis who underwent TKA.

[Remdesivir for COVID-19].

Remdesivir is a direct-acting antiviral agent that inhibits viral RNA synthesis developed by Gilead Sciences, Inc. in the United States. It has been shown to have antiviral activity against single-stranded RNA viruses, including coronaviruses, in cell culture systems and animal models, and has been developed as a therapeutic agent for Ebola virus infection since 2015. however, to date, it has not been approved in any country. A novel coronavirus infection (COVID-19) was identified in Wuhan, Hubei Province, China in Dec, 2019, and is a respiratory disease characterized by fever, cough, and dyspnea. In severe cases, it may cause serious pneumonia, multi-organ failure and death. Gilead Sciences, Inc. U.S. embarked on the development of COVID-19 as a therapeutic drug, using remdesivir, which has shown in vitro and in vivo antiviral activities against MERS-CoV and SARS-CoV, which are single-stranded RNA coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). The in vitro antiviral activity of remdesivir against SARS-CoV-2, which causes COVID-19, was confirmed and clinical studies were initiated in February 2020. Based on the results of clinical studies conducted by the National Institute of Allergy and Infectious Diseases (NIAID) and Gilead Sciences, Inc. and experience of administration from a compassionate use, an exceptional approval system based on the "Pharmaceuticals and Medical Devices Act" was also approved in Japan as of May 7, 2020 for the indication of "infections caused by SARS-CoV-2." In this article, the background of the development and clinical results of remdesivir are described.

Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection.

The duration of viral shedding is determined by a balance between de novo infection and removal of infected cells. That is, if infection is completely blocked with antiviral drugs (100% inhibition), the duration of viral shedding is minimal and is determined by the length of virus production. However, some mathematical models predict that if infected individuals are treated with antiviral drugs with efficacy below 100%, viral shedding may last longer than without treatment because further de novo infections are driven by entry of the virus into partially protected, uninfected cells at a slower rate. Using a simple mathematical model, we quantified SARS-CoV-2 infection dynamics in non-human primates and characterized the kinetics of viral shedding. We counterintuitively found that treatments initiated early, such as 0.5 d after virus inoculation, with intermediate to relatively high efficacy (30-70% inhibition of virus replication) yield a prolonged duration of viral shedding (by about 6.0 d) compared with no treatment.

Anticancer Activity of ZnO Nanoparticles against Human Small-Cell Lung Cancer in an Orthotopic Mouse Model.

Small-cell lung cancer, a highly malignant form of lung cancer, often responds to first-line treatments but relapses in most cases with resistance to further treatments. We tested zinc oxide (ZnO) nanoparticles against small-cell lung cancer and other cancer cell lines, in light of reported anticancer effects in vitro Because of a strong safety record, ZnO nanoparticles are frequently used in biomedical research, including in cellular imaging and drug delivery, and have been used for many years in several commercial products such as skin care agents. Strikingly, ZnO nanoparticles were genotoxic against small-cell lung cancer cells, resulting in low viability, even in cells orthotopically grafted onto mouse models. However, the nanoparticles were less cytotoxic against normal lung-derived cells and did not elicit observable adverse effects after intravenous administration. ZnO nanoparticles were also found to induce highly reactive oxygen species and DNA leakage from nuclei. This study is the first comprehensive evaluation of the anticancer effects of ZnO nanoparticles in vitro and in vivo and highlights new therapeutic opportunities against small-cell lung cancer.

Distribution and toxicity evaluation of ZnO dispersion nanoparticles in single intravenously exposed mice.

ZnO nanoparticles (NPs) have been widely used in various commercial products. Application of ZnO NPs is expected to apply to cancer diagnosis and therapy, used as drug delivery carriers. In the present study, the lethal dose 50 (LD50) of intravenously administered ZnO NPs (0.3 mg/kg) was calculated in mice. Blood kinetics and tissue distribution of a toxic dose of ZnO NPs (0.2 mg/kg, 0.05 mg/kg) were investigated after intravenous exposure. In addition, 8-hydroxy-2'-deoxyguanosine (8-OHdG) was evaluated. Following the injection, ZnO NPs were rapidly removed from the blood and distributed to organs. Pulmonary emphysema was observed pathologically study in mice at 3 days after the 0.2 mg/kg dose and at 6 days after the 0.05 mg/kg dose. ZnO NPs were mainly accumulated in the lung and spleen within 60 min. From the long-term tissue distribution study, the liver showed peak concentration at 6 days, and spleen peaked at 1 day. The lungs kept high levels until 6 days. Tissue distribution and pathological study showed that the spleen, liver, and lungs are target organs for ZnO NPs. Accumulation in the liver and spleen may be due to the phagocytosis by macrophages. A dose-dependent increase in 8-OHdG was observed in mice treated with ZnO NPs. This study is the first to show information on kinetics and target organs following intravenous ZnO injection.