The scientific community is focused on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease 2019 (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data, we compare within-host viral dynamics of SARS-CoV-2 with analogous dynamics of MERS-CoV and SARS-CoV. Our quantitative analyses using a mathematical model revealed that the within-host reproduction number at symptom onset of SARS-CoV-2 was statistically significantly larger than that of MERS-CoV and similar to that of SARS-CoV. In addition, the time from symptom onset to the viral load peak for SARS-CoV-2 infection was shorter than those of MERS-CoV and SARS-CoV. These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2–3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies.

Background: Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials. Methods and findings: A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (p-value < 0.001). The mean decay rates were 1.17 d⁻¹ (95% CI: 1.06 to 1.27 d⁻¹), 0.777 d⁻¹ (0.716 to 0.838 d⁻¹), and 0.450 d⁻¹ (0.378 to 0.522 d⁻¹) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies). Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome. We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation. Conclusions: In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.

In this study, a channel and feature selection methodology is devised for brain‐computer interface (BCI) applications using functional near‐infrared spectroscopy (fNIRS). A graph convolutional network (GCN) is employed to select the appropriate and correlated fNIRS channels. Furthermore, in the feature extraction phase, the performance of two filter‐based feature selection algorithms, (i) the minimum redundancy maximum relevance (mRMR) and (ii) ReliefF, is investigated. The five most commonly used temporal statistical features (i.e., mean, slope, maximum, skewness, and kurtosis) are used, whereas the conventional support vector machine (SVM) is utilized as a classifier for training and testing. The proposed methodology is validated using an available online dataset of motor imagery (left‐ and right‐hand), mental arithmetic, and baseline tasks. First, the efficacy of the proposed methodology is shown for two‐class BCI applications (i.e., left‐ vs. right‐hand motor imagery and mental arithmetic vs. baseline). Second, the proposed framework is applied to four‐class BCI applications (i.e., left‐ vs. right‐hand motor imagery vs. mental arithmetic vs. baseline). The results show that the number of appropriate channels and features was significantly reduced, resulting in a significant increase in classification accuracy for both two‐class and four‐class BCI applications, respectively. Furthermore, both mRMR (i.e., 87.8% for motor imagery, 87.1% for mental arithmetic, and 78.7% for four‐class) and ReliefF (i.e., 90.7% for motor imagery, 93.7% for mental arithmetic, and 81.6% for four‐class) yielded high average classification accuracy (p < 0.05). However, the results of the ReliefF algorithm are more stable and significant.

The rapid expansion of diverse networks has created a growing need to integrate multiple heterogeneous structures to effectively capture both inter- and intra-entity relationships. This integration helps preserve the intrinsic meaning of complex biological interactions. Network-based approaches have been highly effective in predicting node labels and uncovering hidden associations between entities. These methods have been widely applied in areas such as user-item recommendations, gene-gene interactions, and lncRNA-disease association prediction. In this study, we present GMFLDA, an advanced machine learning framework for inferring lncRNA-disease associations (LDA) by synergizing graph convolutional networks (GCNs) with deep matrix factorization. Specifically, GCNs are leveraged to extract and encode high-fidelity feature representations of lncRNAs and diseases, while deep matrix factorization, implemented via a multi-layer perceptron, facilitates the discovery of potential disease-associated lncRNAs. Our model exhibits outstanding predictive performance, achieving AUCs of 0.9183 and 0.9057 in leave-one-out and five-fold cross-validation experiments, respectively. Extensive comparative evaluations demonstrate that GMFLDA surpasses four state-of-the-art methods, underscoring its superior predictive capability. We anticipate that GMFLDA will serve as a powerful computational tool for biomarker discovery, significantly accelerating the identification of disease-associated lncRNAs while mitigating the time and cost constraints of traditional wet-lab experiments.

Cancer virotherapy is studied in mathematical modeling to improve tumor elimination. Since various oncolytic viruses are used for cancer therapy and virus selection is an important research problem, we, therefore, constructed deterministic and stochastic models of cancer-virus dynamics. We investigated virus characteristic parameter sensitivities using a reproduction ratio. Locally and globally asymptotically stable equilibrium points that are respectively related to therapy failure/partial success and therapy failure were determined. A stochastic system was derived from the deterministic model. Tumor extinction probabilities depending on changing parameter values were investigated. Results suggest that viruses with high infection rates and optimal cytotoxicity are effective for cancer treatment.

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.