Genetic consequences of effective and suboptimal dosing with mutagenic drugs in a hamster model of SARS-CoV-2 infection.

Mutagenic antiviral drugs have shown promise against multiple viruses, but concerns have been raised about whether their use might promote the emergence of new and harmful viral variants. Recently, genetic signatures associated with molnupiravir use have been identified in the global SARS-COV-2 population. Here, we examine the consequences of using favipiravir and molnupiravir to treat SARS-CoV-2 infection in a hamster model, comparing viral genome sequence data collected from (1) untreated hamsters, and (2) from hamsters receiving effective and suboptimal doses of treatment. We identify a broadly linear relationship between drug dose and the extent of variation in treated viral populations, with a high proportion of this variation being composed of variants at frequencies of less than 1 per cent, below typical thresholds for variant calling. Treatment with an effective dose of antiviral drug was associated with a gain of between 7 and 10 variants per viral genome relative to drug-free controls: even after a short period of treatment a population founded by a transmitted virus could contain multiple sequence differences to that of the original host. Treatment with a suboptimal dose of drug showed intermediate gains of variants. No dose-dependent signal was identified in the numbers of single-nucleotide variants reaching frequencies in excess of 5 per cent. We did not find evidence to support the emergence of drug resistance or of novel immune phenotypes. Our study suggests that where onward transmission occurs, a short period of treatment with mutagenic drugs may be sufficient to generate a significant increase in the number of viral variants transmitted.

Epibulbar osseous choristoma: case report and review of the literature.

Epibulbar osseous choristoma is a choristomatous lesion of the conjunctiva containing bone. Originally called epibulbar osteoma, this lesion was first described by von Graefe in 1863. We discuss a case of a 4-year-old patient who presented with an epibulbar lesion consistent histopathologically with an epibulbar osseous choristoma, and report a review of the literature. The differential diagnosis of osseous choristoma should include classical limbal dermoids, epithelial inclusion cysts, prolapsed orbital fat, papillomas, dermolipomas, and complex choristomas. Although the rarest of epibulbar choristomas, 51 epibulbar osteomas have now been reported in the medical literature. Most commonly, this variety of choristoma presents as an isolated epibulbar lesion within the supratemporal quadrant but may occur in other locations on the surface of the globe and possibly in conjunction with other choristomatous tissue as much as 10% of the time. Frequently, they may involve the muscle or have dense attachments to the underlying sclera. Osseous choristomas most likely represent congenital lesions with a potential for slow growth but may occur in association with trauma. Options for management include observation or surgical excision. When surgery is contemplated, preoperative radiographic imaging may be helpful for assessing adhesion to the sclera or extraocular muscles.