Integro-differential approach for modeling the COVID-19 dynamics - Impact of confinement measures in Italy

The COVID-19 pandemic has overwhelmed the life and security of most of the world countries, and especially of the Western countries, without similar experiences in the recent past. In a first phase, the response of health systems and governments was disorganized, but then incisive, also driven by the fear of a new and dramatic phenomenon. In the second phase, several governments, including Italy, accepted the doctrine of “coexistence with the virus” by putting into practice a series of containment measures aimed at limiting the dramatic sanitary consequences while not jeopardizing the economic and social stability of the country. Here, we present a new mathematical approach to modeling the COVID-19 dynamics that accounts for typical evolution parameters (i.e., virus variants, vaccinations, containment measurements). Reproducing the COVID-19 epidemic spread is an extremely challenging task due to the low reliability of the available data, the lack of recurrent patterns, and the considerable amount and variability of the involved parameters. However, the adoption of fairly uniform criteria among the Italian regions enabled to test and optimize the model in various conditions leading to robust and interesting results. Although the regional variability is quite large and difficult to predict, we have retrospectively obtained reliable indications on which measures were the most appropriate to limit the transmissibility coefficients within detectable ranges for all the regions. To complicate matters further, the rapid spread of the English variant has upset contexts where the propagation of contagion was close to equilibrium conditions, decreeing success or failure of a certain measure. Finally, we assessed the effectiveness of the zone assignment criteria, highlighting how the reactivity of the measures plays a fundamental role in limiting the spread of the infection and thus the total number of deaths, the most important factor in assessing the success of epidemic management.

In silico drug repurposing in COVID-19: A network-based analysis.

The SARS-CoV-2 pandemic is a worldwide public health emergency. Despite the beginning of a vaccination campaign, the search for new drugs to appropriately treat COVID-19 patients remains a priority. Drug repurposing represents a faster and cheaper method than de novo drug discovery. In this study, we examined three different network-based approaches to identify potentially repurposable drugs to treat COVID-19. We analyzed transcriptomic data from whole blood cells of patients with COVID-19 and 21 other related conditions, as compared with those of healthy subjects. In addition to conventionally used drugs (e.g., anticoagulants, antihistaminics, anti-TNFα antibodies, corticosteroids), unconventional candidate compounds, such as SCN5A inhibitors and drugs active in the central nervous system, were identified. Clinical judgment and validation through clinical trials are always mandatory before use of the identified drugs in a clinical setting.

Assessing the impact of data-driven limitations on tracing and forecasting the outbreak dynamics of COVID-19.

The availability of the epidemiological data strongly affects the reliability of several mathematical models in tracing and forecasting COVID-19 pandemic, hampering a fair assessment of their relative performance. The marked difference between the lethality of the virus when comparing the first and second waves is an evident sign of the poor reliability of the data, also related to the variability over time in the number of performed swabs. During the early epidemic stage, swabs were made only to patients with severe symptoms taken to hospital or intensive care unit. Thus, asymptomatic people, not seeking medical assistance, remained undetected. Conversely, during the second wave of infection, total infectives included also a percentage of detected asymptomatic infectives, being tested due to close contacts with swab positives and thus registered by the health system. Here, we compared the outcomes of two SIR-type models (the standard SIR model and the A-SIR model that explicitly considers asymptomatic infectives) in reproducing the COVID-19 epidemic dynamic in Italy, Spain, Germany, and France during the first two infection waves, simulated separately. We found that the A-SIR model overcame the SIR model in simulating the first wave, whereas these discrepancies are reduced in simulating the second wave, when the accuracy of the epidemiological data is considerably higher. These results indicate that increasing the complexity of the model is useless and unnecessarily wasteful if not supported by an increased quality of the available data.

SAveRUNNER: an R-based tool for drug repurposing.

BACKGROUND: Currently, no proven effective drugs for the novel coronavirus disease COVID-19 exist and despite widespread vaccination campaigns, we are far short from herd immunity. The number of people who are still vulnerable to the virus is too high to hamper new outbreaks, leading a compelling need to find new therapeutic options devoted to combat SARS-CoV-2 infection. Drug repurposing represents an effective drug discovery strategy from existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. RESULTS: We developed a network-based tool for drug repurposing provided as a freely available R-code, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), with the aim to offer a promising framework to efficiently detect putative novel indications for currently marketed drugs against diseases of interest. SAveRUNNER predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-associated proteins in the human interactome through the computation of a novel network-based similarity measure, which prioritizes associations between drugs and diseases located in the same network neighborhoods. CONCLUSIONS: The algorithm was successfully applied to predict off-label drugs to be repositioned against the new human coronavirus (2019-nCoV/SARS-CoV-2), and it achieved a high accuracy in the identification of well-known drug indications, thus revealing itself as a powerful tool to rapidly detect potential novel medical indications for various drugs that are worth of further investigation. SAveRUNNER source code is freely available at https://github.com/giuliafiscon/SAveRUNNER.git , along with a comprehensive user guide.

SAveRUNNER: A network-based algorithm for drug repurposing and its application to COVID-19.

The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity (i.e., SARS), comorbidity (e.g., cardiovascular diseases), or for their association to drugs tentatively repurposed to treat COVID-19 (e.g., malaria, HIV, rheumatoid arthritis). Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments (e.g., chloroquine, hydroxychloroquine, tocilizumab, heparin), as well as a new combination therapy of 5 drugs (hydroxychloroquine, chloroquine, lopinavir, ritonavir, remdesivir), actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies (e.g., anti-IFNγ, anti-TNFα, anti-IL12, anti-IL1ß, anti-IL6), and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.