BACKGROUND: Molnupiravir and nirmatrelvir-ritonavir are orally administered pharmacotherapies for mild to moderate COVID-19. However, the effectiveness of these drugs among very old (≥80 years), hospitalised patients remains unclear, limiting the risk-benefit assessment of these antivirals in this specific group. This study investigates the effectiveness of these antivirals in reducing mortality among this group of hospitalised patients with COVID-19.
METHODS: Using a territory-wide public healthcare database in Hong Kong, a target trial emulation study was conducted with data from 13 642 eligible participants for the molnupiravir trial and 9553 for the nirmatrelvir-ritonavir trial. The primary outcome was all-cause mortality. Immortal time and confounding bias was minimised using cloning-censoring-weighting approach. Mortality odds ratios were estimated by pooled logistic regression after adjusting confounding biases by stabilised inverse probability weights.
RESULTS: Both molnupiravir (HR: 0.895, 95% CI: 0.826-0.970) and nirmatrelvir-ritonavir (HR: 0.804, 95% CI: 0.678-0.955) demonstrated moderate mortality risk reduction among oldest-old hospitalised patients. No significant interaction was observed between oral antiviral treatment and vaccination status. The 28-day risk of mortality was lower in initiators than non-initiators for both molnupiravir (risk difference: -1.09%, 95% CI: -2.29, 0.11) and nirmatrelvir-ritonavir (risk difference: -1.71%, 95% CI: -3.30, -0.16) trials. The effectiveness of these medications was observed regardless of the patients\' prior vaccination status.
CONCLUSIONS: Molnupiravir and nirmatrelvir-ritonavir are moderately effective in reducing mortality risk among hospitalised oldest-old patients with COVID-19, regardless of their vaccination status.

Despite the potential of neutralizing antibodies in the management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), clinical research on its efficacy in Chinese patients remains limited. This study is aimed at investigating the therapeutic effect of combination of antiviral therapy with neutralizing monoclonal antibodies for recurrent persistent SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion. A prospective study was conducted on Chinese patients who were treated with antiviral nirmatrelvir/ritonavir therapy and the neutralizing antibody tixagevimab-cilgavimab (tix-cil). The primary outcome was the rate of recurrent SARS-CoV-2 infection. Five patients with lymphoma experienced recurrent SARS-CoV-2 pneumonia and received tix-cil treatment. All patients had a history of CD20 monoclonal antibody use within the year preceding SARS-CoV-2 infection, and two patients also had a history of Bruton\'s tyrosine kinase (BTK) inhibitor use. These patients had notably low lymphocyte counts and exhibited near depletion of B cells. All five patients tested negative for serum SARS-CoV-2 IgG and IgM antibodies. None of the patients developed reinfection with SARS-CoV-2 pneumonia after antiviral and tix-cil treatment during the 6-month follow-up period. In conclusion, the administration of antiviral and SARS-CoV-2-neutralizing antibodies showed encouraging therapeutic efficacy against SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion, along with the potential preventive effect of neutralizing antibodies for up to 6 months.

Adenosine is a neuro- and immunomodulator that functions via G protein-coupled cell surface receptors. Several microbes, including viruses, use the adenosine signaling pathway to escape from host defense systems. Since the recent research developments in its role in health and disease, adenosine and its signaling pathway have attracted attention for targeting to treat many diseases. The therapeutic role of adenosine has been extensively studied for neurological, cardiovascular, and inflammatory disorders and bacterial pathophysiology, but published data on the role of adenosine in viral infections are lacking. Therefore, the purpose of this review article was to explain in detail the therapeutic role of adenosine signaling against viral infections, particularly COVID-19 and HIV. Several therapeutic approaches targeting A2AR-mediated pathways are in development and have shown encouraging results in decreasing the intensity of inflammatory reaction. The hypoxia-adenosinergic mechanism provides protection from inflammation-mediated tissue injury during COVID-19. A2AR expression increased remarkably in CD39 + and CD8 + T cells harvested from HIV patients in comparison to healthy subjects. A combined in vitro treatment performed by blocking PD-1 and CD39/adenosine signaling produced a synergistic outcome in restoring the CD8 + T cells funstion in HIV patients. We suggest that A2AR is an ideal target for pharmacological interventions against viral infections because it reduces inflammation, prevents disease progression, and ultimately improves patient survival.

Coronavirus disease-2019 (COVID-19) has caused continuous effects on the global public, especially for susceptible and vulnerable populations like pregnant women. COVID-19-related studies and publications have shown blowout development, making it challenging to identify development trends and hot areas by using traditional review methods for such massive data. Aimed to perform a bibliometric analysis to explore the status and hotspots of COVID-19 in obstetrics. An online search was conducted in the Web of Science Core Collection (WOSCC) database from January 01, 2020 to November 31, 2022, using the following search expression: (((TS= (\"COVID 19\" OR \"coronavirus 2019\" OR \"coronavirus disease 2019\" OR \"SARS-CoV-2\" OR \"2019-nCoV\" OR \"2019 novel coronavirus\" OR \"SARS coronavirus 2\" OR \"Severe Acute Respiratory Syndrome Coronavirus-2\" OR \"SARS-COV2\")) AND TS= (\"obstetric*\" OR \"pregnancy*\" OR \"pregnant\" OR \"parturition*\" OR \"puerperium\"))). VOSviewer version 1.6.18, CiteSpace version 6.1.R6, R version 4.2.0, and Rstudio were used for the bibliometric and visualization analyses. 4144 articles were included in further analysis, including authors, titles, number of citations, countries, and author affiliations. The United States has contributed the most significant publications with the leading position. \"Sahin, Dilek\" has the largest output, and \"Khalil, Asma\" was the most influential author with the highest citations. Keywords of \"Cov,\" \"Experience,\" and \"Neonate\" with the highest frequency, and \"Systematic Review\" might be the new research hotspots and frontiers. The top 3 concerned genes included ACE2, CRP, and IL6. The new research hotspot is gradually shifting from the COVID-19 mechanism and its related clinical research to reviewing treatment options for pregnant women. This research uniquely delves into specific genes related to COVID-19\'s effects on obstetrics, a focus that has not been previously explored in other reviews. Our research enables clinicians and researchers to summarize the overall point of view of the existing literature and obtain more accurate conclusions.

In patients with severe acute respiratory syndrome coronavirus 2 (which causes coronavirus disease 2019 [COVID-19]), oxidative stress (OS) is associated with disease severity and death. OS is also involved in the pathogenesis of atherosclerosis (AS). Previous studies have shown that geniposide has anti-inflammatory and anti-viral properties, and can protect cells against OS. However, the potential target(s) of geniposide in patients with COVID-19 and AS, as well as the mechanism it uses, are unclear. We combined pharmacology and bioinformatics analysis to obtain geniposide against COVID-19/AS targets, and build protein-protein interaction network to filter hub genes. The hub genes were performed an enrichment analysis by ClueGO, including Gene Ontology and KEGG. The Enrichr database and the target microRNAs (miRNAs) of hub genes were predicted through the MiRTarBase via Enrichr. The common miRNAs were used to construct the miRNAs-mRNAs regulated network, and the miRNAs\' function was evaluated by mirPath v3.0 software. Two hundred forty-seven targets of geniposide were identified in patients with COVID-19/AS comorbidity by observing the overlap between the genes modulated by geniposide, COVID-19, and AS. A protein-protein interaction network of geniposide in patients with COVID-19/AS was constructed, and 27 hub genes were identified. The results of enrichment analysis suggested that geniposide may be involved in regulating the OS via the FoxO signaling pathway. MiRNA-mRNA network revealed that hsa-miR-34a-5p may play an important role in the therapeutic mechanism of geniposide in COVID-19/AS patients. Our study found that geniposide represents a promising therapy for patients with COVID-19 and AS comorbidity. Furthermore, the target genes and miRNAs that we identified may aid the development of new treatment strategies against COVID-19/AS.

OBJECTIVE: In this study, we aim to explore the efficacy of paxlovid on reducing mortality of COVID-19 patients in clinical setting, especially whether paxlovid modifies the risk of death in these severe and critical patients.
METHODS: Our retrospective cohort study was conducted on the medical records of patients, consecutively admitted for COVID-19 to five hospitals in Chongqing, China from Dec 8, 2022 to Jan 20, 2023. Based on whether patients received paxlovid during their hospitalization, patients were grouped as paxlovid group and non-paxlovid group. We used 1:1 ratio propensity score matching (PSM) in our study to adjust for confounding factors and differences between groups. Statistical analysis were performed by SPSS 23.0. The differences in 28-day mortality between these two groups and its influencing factors were the main results we focused on.
RESULTS: There were 1018 patients included in our study cohort. With 1:1 ratio PSM, each of the paxlovid group and non-paxlovid group included 237 patients. The results showed that patients using paxlovid have a lower 28-day mortality in overall population either before PSM (OR 0.594, 95% CI 0.385-0.917, p = 0.019) or after PSM (OR 0.458, 95% CI 0.272-0.774, p = 0.003) with multivariable adjusted logistic regression models. Meanwhile, in severe subgroup, it showed similar findings.With paxlovid treatment, it showed a significantly lower 28-day mortality in severe subgroup both before PSM (28% vs.41%, p = 0.008) and after PSM (19% vs.32%, p = 0.007).
CONCLUSIONS: Paxlovid can significantly reduce the risk of 28-day mortality in overall population and severe subgroup patients.This study distinguished the severe subgroup patients with COVID-19 who benefit more from paxlovid treatment.

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SARS-CoV-2 has still been threatening global public health with its emerging variants. Our previous work reported lead compound JZD-07 that displayed good 3CLpro inhibitory activity. Here, an in-depth structural optimization for JZD-07 was launched to obtain more desirable drug candidates for the therapy of SARS-CoV-2 infection, in which 54 novel derivatives were designed and synthesized by a structure-based drug design strategy. Among them, 24 compounds show significantly enhanced 3CLpro inhibitory potencies with IC50 values less than 100 nM, and 11 compounds dose-dependently inhibit the replication of the SARS-CoV-2 delta variant. In particular, compound 49 has the most desirable antiviral activity with EC50 of 0.272 ± 0.013 μM against the delta variant, which was more than 20 times stronger than JZD-07. Oral administration of 49 could significantly reduce the lung viral copies of mice, exhibiting a more favorable therapeutic potential. Overall, this investigation presents a promising drug candidate for further development to treat SARS-CoV-2 infection.