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Telemonitoring and telerehabilitation have shown promise in delivering individualized healthcare remotely. We introduce STASISM, a sensor-based telerehabilitation and telemonitoring system, in this work. This platform has been created to facilitate individualized telerehabilitation and telemonitoring for those who need rehabilitation or ongoing monitoring. To gather and analyze pertinent and validated physiological, kinematic, and environmental data, the system combines a variety of sensors and data analytic methodologies. The platform facilitates customized rehabilitation activities based on individual needs, allows for the remote monitoring of a patient’s progress, and offers real-time feedback. To protect the security of patient data and to safeguard patient privacy, STASISM also provides secure data transmission and storage. The platform has the potential to significantly improve the accessibility and efficacy of telerehabilitation and telemonitoring programs, enhancing patients’ quality of life and allowing healthcare professionals to provide individualized care outside of traditional clinical settings.

Nirsevimab is a monoclonal antibody that binds to the respiratory syncytial virus (RSV) fusion protein. During the Phase 2b (NCT02878330) and MELODY (NCT03979313) clinical trials, infants received one dose of nirsevimab or placebo before their first RSV season. In this pre-specified analysis, isolates from RSV infections were subtyped, sequenced and analyzed for nirsevimab binding site substitutions; subsequently, recombinant RSVs were engineered for microneutralization susceptibility testing. Here we show that the frequency of infections caused by subtypes A and B is similar across and within the two trials. In addition, RSV A had one and RSV B had 10 fusion protein substitutions occurring at >5% frequency. Notably, RSV B binding site substitutions were rare, except for the highly prevalent I206M:Q209R, which increases nirsevimab susceptibility; RSV B isolates from two participants had binding site substitutions that reduce nirsevimab susceptibility. Overall, >99% of isolates from the Phase 2b and MELODY trials retained susceptibility to nirsevimab. Nirsevimab binds the respiratory syncytial virus (RSV) fusion protein and has been tested for RSV prevention in clinical trials. Here, the authors analyse RSV from infections and show that binding site substitutions are rare and that over 99% of isolates remain susceptible to nirsevimab.

This study aimed to evaluate the feasibility of using serious games for the (tele)rehabilitation of children with disabilities affected by the Ukrainian war. Additionally, it provides requirements for technologies that can be used in war-affected areas. Structured interviews and Likert scale assessments were conducted on-site and remotely with patients of the tertiary care facility in Ukraine. All participants used the telerehabilitation platform for motor and cognitive training. Nine serious games were employed, involving trunk tilts, upper limb movements, and head control. By mid-September 2023, 186 positive user experiences were evident, with 89% expressing interest in continued engagement. The platform’s accessibility, affordability, and therapeutic benefits were highlighted. The recommendations from user feedback informed potential enhancements, showcasing the platform’s potential to provide uninterrupted rehabilitation care amid conflict-related challenges. This study suggests that serious games solutions that suit the sociopolitical and economic context offer a promising solution to rehabilitation challenges in conflict zones. The positive user experiences towards using the platform with serious games indicate its potential in emergency healthcare provision. The findings emphasize the role of technology, particularly serious gaming, in mitigating the impact of armed conflicts on children’s well-being, thereby contributing valuable insights to healthcare strategies in conflict-affected regions. Requirements for technologies tailored to the context of challenging settings were defined.

Currently, influenza vaccine manufacturers need to produce 1-5 x 107 PFU of each vaccine strain to fill one dose of the current live-attenuated-influenza-vaccine (LAIV). To make a single dose of inactivated vaccine (15 ug of each hemagglutinin), the equivalent of 1010 PFU of each vaccine strains need to be grown. This high dose requirement is a major drawback for manufacturing as well as rapidly sourcing sufficient doses during a pandemic. Using our computer-aided vaccine platform Synthetic Attenuated Virus Engineering (SAVE), we created a vaccine candidate against pandemic H1N1 A/CA/07/2009 (CodaVax-H1N1) with robust efficacy in mice and ferrets, and is protective at a much lower dose than the current LAIV. CodaVax-H1N1 is currently in Phase I/II clinical trials. The hemagglutinin (HA) and neuraminidase (NA) gene segments of A/California/07/2009 (H1N1) (CA07) were \"de-optimized\" and a LAIV was generated ex silico using DNA synthesis. In DBA/2 mice, vaccination at a very low dose (100 or approximately 1 PFU) with CodaVax-H1N1 prevented disease after lethal challenge with wild-type H1N1. In BALB/c mice, as little as 103 PFU was protective against lethal challenge with mouse-adapted H1N1. In ferrets, CodaVax-H1N1 was more potent compared to currently licensed LAIV and still effective at a low dose of 103 PFU at preventing replication of challenge virus.

BackgroundOncolytic viruses (OVs) of multiple species have been demonstrated to induce beneficial changes in the tumor microenvironment (TME), increasing immune cell infiltration and activating stimulatory immune responses, which ultimately support induction of an anti-tumor immune response. The majority of OVs are attenuated by either gene deletion or mutations and then armed with immunomodulatory transgenes to promote anti-tumor immune responses. Here, we describe a next-generation OV that is rationally attenuated via codon-pair deoptimization and capable of activating anti-tumor immune responses in a mouse model of triple-negative breast cancer without the need of transgenes.MethodsHemagglutinin and neuraminidase genes of influenza virus strain A/California/07/2009 were codon-pair deoptimized using an algorithm to design synthetic viral genomes, yielding CodaLytic, a genetically stable OV with over 600 silent mutations across the two genes. For in vivo studies, EMT6 cells were implanted into inguinal mammary fad pads and treated intratumorally with CodaLytic three times a week for up to 4 weeks for efficacy studies or for up to 5 doses for pharmacodynamic readouts. Tumor infiltrating immune cells were characterized by flow cytometry or RNA was isolated for transcriptomic analysis. Anti-tumor memory was assessed by intravenous EMT6 rechallenge and interferon-γ ELISpot in splenocytes of long-term survivors.ResultsCodaLytic treatment of orthotopic EMT6 tumors led to dose-dependent tumor growth retardation and increased survival with significant tumor growth inhibition of 60% and 40–60% complete regressions at 108 pfu/dose across repeat experiments. Intravenous rechallenge of long-term survivors led to a 27-fold reduction in lung nodule formation (colony mean 0.75 vs 19.92 in naïve control animals, p = 0.005). Anti-tumor efficacy after CodaLytic treatment was accompanied by a change in the composition of the tumor immune infiltrate with significant increases in CD4+ T, B and NK cells and increased gene expression of interferon-γ, MHC-II and CCL-5. Further evidence of induction of anti-tumor immunity was an EMT6-specific interferon-γ recall response in splenocytes from long-term survivors.ConclusionsThese data demonstrate the induction of innate and adaptive changes in the TME and anti-tumor efficacy after intratumoral treatment of EMT6 tumors with CodaLytic. Additional holistic gene expression analysis is ongoing to further characterize the mechanisms of immune activation. Taken together with preclinical safety data and demonstrated clinical safety and immunogenicity of this attenuated influenza virus after intranasal administration in healthy individuals, CodaLytic is a promising immunotherapeutic to be further developed as monotherapy and in combination with immune checkpoint inhibitors or other modalities.Ethics ApprovalAll animal studies were conducted in compliance with protocol 2019-01-17-COD-1, approved by the Mispro Biotech Services Institutional Animal Care and Use Committee.

Experimental and bioinformatic studies of transcription initiation by RNA polymerase II (RNAP2) have revealed a mechanism of RNAP2 transcription initiation less uniform across gene promoters than initially thought. However, the general transcription factor TFIIB is presumed to be universally required for RNAP2 transcription initiation. Based on bioinformatic analysis of data and effects of TFIIB knockdown in primary and transformed cell lines on cellular functionality and global gene expression, we report that TFIIB is dispensable for transcription of many human promoters, but is essential for herpes simplex virus-1 (HSV-1) gene transcription and replication. We report a novel cell cycle TFIIB regulation and localization of the acetylated TFIIB variant on the transcriptionally silent mitotic chromatids. Taken together, these results establish a new paradigm for TFIIB functionality in human gene expression, which when downregulated has potent anti-viral effects.

Successfully combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity. Here, we describe COVI-VAC, the only live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine currently in clinical development. COVI-VAC was developed by recoding a segment of the viral spike protein with synonymous suboptimal codon pairs (codon-pair deoptimization), thereby introducing 283 silent (point) mutations. In addition, the furin cleavage site within the spike protein was deleted from the viral genome for added safety of the vaccine strain. Except for the furin cleavage site deletion, the COVI-VAC and parental SARS-CoV-2 amino acid sequences are identical, ensuring that all viral proteins can engage with the host immune system of vaccine recipients. COVI-VAC was temperature sensitive in vitro yet grew robustly (>10⁷ plaque forming units/mL) at the permissive temperature. Tissue viral loads were consistently lower, lung pathology milder, and weight loss reduced in Syrian golden hamsters (Mesocricetus auratus) vaccinated intranasally with COVI-VAC compared to those inoculated with wild-type (WT) virus. COVI-VAC inoculation generated spike IgG antibody levels and plaque reduction neutralization titers similar to those in hamsters inoculated with WT virus. Upon challenge with WT virus, COVI-VAC vaccination reduced lung challenge viral titers, resulted in undetectable virus in the brain, and protected hamsters from almost all SARS-CoV-2–associated weight loss. Highly attenuated COVI-VAC is protective at a single intranasal dose in a relevant in vivo model. This, coupled with its large-scale manufacturing potential, supports its potential use in mass vaccination programs.