Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection.

The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring the need for a dynamic platform for the rapid development of pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing the treatment of numerous diseases with unprecedented potency, duration of effect, and safety. Through the systematic screening of hundreds of oligonucleotide sequences, we identified fully chemically stabilized siRNAs and ASOs that target regions of the SARS-CoV-2 genome conserved in all variants of concern, including delta and omicron. We successively evaluated candidates in cellular reporter assays, followed by viral inhibition in cell culture, with eventual testing of leads for in vivo antiviral activity in the lung. Previous attempts to deliver therapeutic oligonucleotides to the lung have met with only modest success. Here, we report the development of a platform for identifying and generating potent, chemically modified multimeric siRNAs bioavailable in the lung after local intranasal and intratracheal delivery. The optimized divalent siRNAs showed robust antiviral activity in human cells and mouse models of SARS-CoV-2 infection and represent a new paradigm for antiviral therapeutic development for current and future pandemics.

Can Adverse Childhood Experiences Heighten Risk for Problematic Internet and Smartphone Use? Findings from a College Sample.

BACKGROUND: College students are among the heaviest users of smartphones and the Internet, and there is growing concern regarding problematic Internet (PIU) and smartphone use (PSU). A subset of adverse childhood experiences, household dysfunction [(HHD) e.g.; parental substance use, mental illness, incarceration, suicide, intimate partner violence, separation/divorce, homelessness], are robust predictors of behavioral disorders; however, few studies have investigated the link between HHD and PIU and PSU and potential protective factors, such as social support, among students. METHODS: Data are from a diverse California student sample (N = 1027). The Smartphone Addiction Scale-Short Version and Internet Addiction Test assessed dimensions of addiction. Regression models tested associations between students' level of HHD (No HHD, 1-3 HHD, ≥4 HHD) and PSU and PIU, and the role of extrafamilial social support in these relationships, adjusting for age, gender, ethnicity, SES, employment loss due to COVID-19, and depression. RESULTS: Compared to students reporting no HHD, students with ≥4 HHD had twice the odds (AOR: 2.03, 95% CI: 1.21-3.40) of meeting criteria for PSU, while students with 1-3 HHD and ≥4 HHD had three and six times the odds of moderate to severe PIU (AORs: 2.03-2.46, CI:1.21-3.96) after adjusting for covariates. Extrafamilial social support was inversely associated with PIU and moderated the HHD-PSU association for students with 1-3 HHD. CONCLUSION: Students exposed to HHD may be especially vulnerable to developing behavioral addictions such as PSU and PIU. Extrafamilial social support offset the negative effects of HHD for PSU among the moderate risk group; implications for prevention efforts are discussed.