Convergent evolution of the SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant

In late 2022, although the SARS-CoV-2 Omicron subvariants have highly diversified, some lineages have convergently acquired amino acid substitutions at five critical residues in the spike protein. Here, we illuminated the evolutionary rules underlying the convergent evolution of Omicron subvariants and the properties of one of the latest lineages of concern, BQ.1.1. Our phylogenetic and epidemic dynamics analyses suggest that Omicron subvariants independently increased their viral fitness by acquiring the convergent substitutions. Particularly, BQ.1.1, which harbors all five convergent substitutions, shows the highest fitness among the viruses investigated. Neutralization assays show that BQ.1.1 is more resistant to breakthrough BA.2/5 infection sera than BA.5. The BQ.1.1 spike exhibits enhanced binding affinity to human ACE2 receptor and greater fusogenicity than the BA.5 spike. However, the pathogenicity of BQ.1.1 in hamsters is comparable to or even lower than that of BA.5. Our multiscale investigations provide insights into the evolutionary trajectory of Omicron subvariants.

Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and accelerates recovery from clinical aspects of COVID-19

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622, a novel inhibitor of SARS-CoV-2 main protease (Mpro, also known as 3C-like protease), decreases viral load and ameliorates the disease severity in SARS-CoV-2-infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to sub-micromolar concentrations in cells. Oral administration of S-217622 demonstrated eminent pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern (VOCs), including the highly pathogenic Delta variant and the recently emerged Omicron variant. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase II/III clinical trial, possesses remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

SARS-CoV-2 bearing a mutation at the S1/S2 cleavage site exhibits attenuated virulence and confers protective immunity

Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) possesses a discriminative polybasic cleavage motif in its spike protein that is recognized by host furin protease. Proteolytic cleavage activates the spike protein and influences both the cellular entry pathway and cell tropism of SARS-CoV-2. Here, we investigated the impact of the furin cleavage site on viral growth and pathogensis using a hamster animal model infected with SARS-CoV-2 variants bearing mutations at the furin cleavage site (S gene mutants). In the airway tissues of hamsters, the S gene mutants exhibited a low growth property. In contrast to parental pathogenic SARS-CoV-2, hamsters infected with the S gene mutants showed no body weight loss and only a mild inflammatory response, indicating the attenuated variant nature of S gene mutants. We reproduced the attenuated growth of S gene mutants in primary differenciated human airway epithelial cells. This transient infection was enough to induce protective neutralizing antibodies crossreacting with different SARS-CoV-2 lineages. Consequently, hamsters inoculated with S gene mutants showed resistance to subsequent infection with both the parental strain and the currently emerging SARS-CoV-2 variants belonging to lineages B.1.1.7 and P.1. Together, our findings revealed that the loss of the furin cleavage site causes attenuation in the airway tissues of SARS-CoV-2 and highlights the potential benefits of S gene mutants as potential immunogens.

Construction Case with an Electronic Hospital Formulary to Be Able to Do Rapid Retrieval Using a Portable Terminal iPhone® / 医薬品情報学

<b>Objective: </b>The hospital is changing its formulary reference from paper-based to intranet.  There was concern that both paper-based and intranet versions of the formulary would be necessary.  Revising the paper-based hospital formulary each time package inserts are revised is difficult.  For your review we report on the creation of the iPhone® electronic formulary which enables rapid off-line formulary retrieval and easy updates while at the same time providing low cost service in a light device.<br><b>Methods: </b>The CSV (Comma Separated Value) of the hospital formulary dictionary was made using a standard personal computer.  The CSV data file was converted using JAMES2DIC into a HTML file format.  Next, the converted HTML file is transformed into the EPWING (Electronic Publishing WING) format using EBStudio.  Finally, we forward the EPWING dictionary file from the personal computer to the iPhone®.  The retrieval becomes possible by using EBPocket for iOS of EPWING/electronic book viewer software for the iPhone®.  The number of items was assumed to be 29 items thought for a lot of inquiries to exist.<br><b>Results: </b>We compared the paper-based formulary with the iPhone® electronic formulary.  As a result, the iPhone4® electronic formulary shortened the retrieval time, was smaller, lighter, and excellent at a lower price.<br><b>Conclusion: </b>The iPhone4® electronic formulary enables the user to perform complex full-text searches and retrieve information at a much higher speed than is possible with paper based formularies.  It has the additional advantage of seamless integration and deployment of formulary additions or reference material revisions.  We believe we have successfully created a practical electronic formulary.

Evaluation of the effect of analgesics for cancer patients using their pain descriptions

<b>Purpose</b>: The present study aims to evaluate the effect of analgesics in cancer patients based on their pain descriptions. <b>Methods</b>: The relationship between the words that patients used to describe their pain due to cancer and the efficacy of treatment with analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) or opioids was evaluated. <b>Results</b>: We recorded 529words that were used by 164patients to describe their pain and pain quality and classified them into 108types of pain.For patients who used the actual word 'dull' or one with a similar meaning, treatment with opioids was effective. However, treatment with opioids was less effective in patients who used words such as "numb" and "tingling". <b>Conclusion</b>: We were able to gain a good understanding of cancer pain by listening to the actual words that patients used when complaining of pain. These findings suggested that we could choose a suitable medication through evaluation of the actual words cancer patients used to describe their pain and successfully relieve their pain. Palliat Care Res 2009: 4(1): 207-213