Viral replication of thymidine kinase deleted (tk⁻) vaccinia virus (VV) is attenuated in resting normal cells, enabling cancer selectivity, however, replication potency of VV-tk⁻ appears to be diminished in cancer cells. Previously, we found that wild-type herpes simplex virus (HSV)-tk (HSV-tk) disappeared in most of the recombinant VV after multiple screenings, and only a few recombinant VV containing naturally mutated HSV-tk remained stable. In this study, VV-tk of western reserve (WR) VV was replaced by A167Y mutated HSV-tk (HSV-tk_418m), to alter nucleoside selectivity from broad spectrum to purine exclusive selectivity. WOTS-418 remained stable after numerous passages. WOTS-418 replication was significantly attenuated in normal cells, but cytotoxicity was almost similar to that of wild type WR VV in cancer cells. WOTS-418 showed no lethality following a 5 × 10⁸ PFU intranasal injection, contrasting WR VV, which showed 100% lethality at 1 × 10⁵ PFU. Additionally, ganciclovir (GCV) but not BvdU inhibited WOTS-418 replication, confirming specificity to purine nucleoside analogs. The potency of WOTS-418 replication inhibition by GCV was > 10-fold higher than that of our previous truncated HSV-tk recombinant OTS-412. Overall, WOTS-418 demonstrated robust oncolytic efficacy and pharmacological safety which may delegate it as a candidate for future clinical use in OV therapy.

BACKGROUND The Inverse Care Law stipulates that healthcare resources are unevenly distributed and tend to vary inversely with actual clinical needs. Hybrid approaches, which deliberately combine in-person and virtual care, may help counteract this phenomenon in various settings, including rural healthcare, by leveraging clinician capacity across geographic regions. However, the literature on the potential of hybrid approaches to primary care has not been comprehensively mapped. OBJECTIVE This scoping review aimed to map the international evidence on applications of the hybrid approach to primary care and examine its impacts across the domains of the Quadruple Aim framework for quality improvement. METHODS We conducted a scoping review following the PRISMA extension for Scoping Reviews and the five-stage framework by Levac et al. MEDLINE, Scopus, Embase, and CINAHL were searched for studies published from 2020 onward, supplemented by a grey literature search. We included literature describing hybrid approaches to outpatient care involving primary care clinicians. Outcomes were mapped across the Quadruple Aim domains of patient experience, clinician and non-clinical staff experience, clinical impact, and economic impact. RESULTS Of 3,504 unique records screened, 24 peer-reviewed studies and 8 grey literature sources were included. Peer-reviewed studies were predominantly conducted in North America (16/24) and in rural or remote settings (15/24). Hybrid approaches varied considerably in design and implementation but commonly used virtual-first models and interdisciplinary teams combining off-site physicians with locally based clinicians. Clinical impact was the most frequently assessed domain (13/24) and showed the most consistently favourable findings (11/13), followed by patient experience (6/8 studies reporting favourable findings). Clinician experience showed mixed findings, while economic impact was infrequently evaluated. CONCLUSIONS Hybrid approaches show promise as an innovative way to address gaps in healthcare access and mitigate workforce maldistribution in hard-to-serve regions, with reported benefits spanning multiple domains of the Quadruple Aim. However, evidence regarding economic impact remains limited, highlighting an important area for future research. CLINICALTRIAL NA