A Machine Learning Model for the Prediction of COVID-19 Severity Using RNA-Seq, Clinical, and Co-Morbidity Data.

The premise for this study emanated from the need to understand SARS-CoV-2 infections at the molecular level and to develop predictive tools for managing COVID-19 severity. With the varied clinical outcomes observed among infected individuals, creating a reliable machine learning (ML) model for predicting the severity of COVID-19 became paramount. Despite the availability of large-scale genomic and clinical data, previous studies have not effectively utilized multi-modality data for disease severity prediction using data-driven approaches. Our primary goal is to predict COVID-19 severity using a machine-learning model trained on a combination of patients' gene expression, clinical features, and co-morbidity data. Employing various ML algorithms, including Logistic Regression (LR), XGBoost (XG), Naïve Bayes (NB), and Support Vector Machine (SVM), alongside feature selection methods, we sought to identify the best-performing model for disease severity prediction. The results highlighted XG as the superior classifier, with 95% accuracy and a 0.99 AUC (Area Under the Curve), for distinguishing severity groups. Additionally, the SHAP analysis revealed vital features contributing to prediction, including several genes such as COX14, LAMB2, DOLK, SDCBP2, RHBDL1, and IER3-AS1. Notably, two clinical features, the absolute neutrophil count and Viremia Categories, emerged as top contributors. Integrating multiple data modalities has significantly improved the accuracy of disease severity prediction compared to using any single modality. The identified features could serve as biomarkers for COVID-19 prognosis and patient care, allowing clinicians to optimize treatment strategies and refine clinical decision-making processes for enhanced patient outcomes.

Islatravir: evaluation of clinical development for HIV and HBV.

INTRODUCTION: Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits HIV RT through multiple mechanisms. Contrary to all approved NtRTIs, islatravir retains a 3'OH group. In vitro and clinical data show that ISL is an ultrapotent investigational drug with high tolerability. AREAS COVERED: The historical development of islatravir and its mechanisms of HIV and HBV inhibition and resistance are covered. Additionally, the outcomes of Phase I and Phase II clinical trials are discussed. EXPERT OPINION: Current first-line antiretroviral therapy, preexposure, and postexposure prophylactic interventions are highly effective in maintaining low or undetectable viral load. Despite these measures, an unusually high rate of new infections every year warrants developing novel antivirals that can suppress drug-resistant HIV and improve compliance. ISL, an NRTTI once deemed a long-acting drug, was placed on a clinical hold. The outcome of ongoing clinical trials with a reduced ISL dose will decide its future clinical application. Additionally, MK-8527, which inhibits HIV via same mechanism as that of ISL may supersede ISL. Data on ISL inhibition of HBV are scarce, and preclinical data show dramatically lower ISL efficacy against HBV than currently preferred nucleos(t)ide drugs, indicating that ISL may not be a potent anti-HBV drug.

Potential therapeutic targets for Mpox: the evidence to date.

INTRODUCTION: The global Mpox (MPX) disease outbreak caused by the Mpox virus (MPXV) in 2022 alarmed the World Health Organization (WHO) and health regulation agencies of individual countries leading to the declaration of MPX as a Public Health Emergency. Owing to the genetic similarities between smallpox-causing poxvirus and MPXV, vaccine JYNNEOS, and anti-smallpox drugs Brincidofovir and Tecovirimat were granted emergency use authorization by the United States Food and Drug Administration. The WHO also included cidofovir, NIOCH-14, and other vaccines as treatment options. AREAS COVERED: This article covers the historical development of EUA-granted antivirals, resistance to these antivirals, and the projected impact of signature mutations on the potency of antivirals against currently circulating MPXV. Since a high prevalence of MPXV infections in individuals coinfected with HIV and MPXV, the treatment results among these individuals have been included. EXPERT OPINION: All EUA-granted drugs have been approved for smallpox treatment. These antivirals show good potency against Mpox. However, conserved resistance mutation positions in MPXV and related poxviruses, and the signature mutations in the 2022 MPXV can potentially compromise the efficacy of the EUA-granted treatments. Therefore, MPXV-specific medications are required not only for the current but also for possible future outbreaks.

Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak.

Attributes contributing to the current monkeypox virus (MPXV) outbreak remain unknown. It has been established that mutations in viral proteins may alter phenotype and pathogenicity. To assess if mutations in the MPXV DNA replication complex (RC) contribute to the outbreak, we conducted a temporal analysis of available MPXV sequences to identify mutations, generated a DNA replication complex (RC) using structures of related viral and eukaryotic proteins, and structure prediction method AlphaFold. Ten mutations within the RC were identified and mapped onto the RC to infer role of mutations. Two mutations in F8L (RC catalytic subunit), and two in G9R (a processivity factor) were ∼100% prevalent in the 2022 sequences. F8L mutation L108F emerged in 2022, whereas W411L emerged in 2018, and persisted in 2022. L108 is topologically located to enhance DNA binding affinity of F8L. Therefore, mutation L108F can change the fidelity, sensitivity to nucleoside inhibitors, and processivity of F8L. Surface exposed W411L likely affects the binding of regulatory factor(s). G9R mutations S30L and D88 N in G9R emerged in 2022, and may impact the interaction of G9R with E4R (uracil DNA glycosylase). The remaining six mutations that appeared in 2001, reverted to the first (1965 Rotterdam) isolate. Two nucleoside inhibitors brincidofovir and cidofovir have been approved for MPXV treatment. Cidofovir resistance in vaccinia virus is achieved by A314T and A684V mutations. Both A314 and A684 are conserved in MPXV. Therefore, resistance to these drugs in MPXV may arise through similar mechanisms.