Viremia defined as detectable SARS-CoV-2 RNA in the blood is a potential marker of disease severity and prognosis in COVID-19 patients. Here, we determined the frequency of viremia in serum of two independent COVID-19 patient cohorts within the German National Pandemic Cohort Network (German: Nationales Pandemie Kohorten Netzwerk, NAPKON) with diagnostic RT-PCR against SARS-CoV-2. A cross-sectional cohort with 1122 COVID-19 patients (German: Sektorenuebergreifende Platform, SUEP) and 299 patients recruited in a high-resolution platform with patients at high risk to develop severe courses (German: Hochaufloesende Plattform, HAP) were tested for viremia. Our study also involved a comprehensive analysis and association of serological, diagnostic, and clinical parameters of the NAPKON medical dataset. Prevalence of viremia at the recruitment visit was 12.8% (SUEP) and 13% (HAP), respectively. Serological analysis revealed that viremic patients had lower levels of SARS-CoV-2 specific antibodies as well as lower neutralizing antibodies compared to aviremic patients. Viremia was associated with severity (<0.0001 SUEP; 0.002 HAP) and mortality of COVID-19 (both cohorts <0.0001) compared to aviremic patients. While rare, viremia was also detected in patients with mild disease (0.7%). In patients of the SUEP cohort with acute kidney disease (p = 0.0099) and hematooncological conditions (p = 0.0091), viremia was detected more frequently. Compared to the aviremic group, treatment with immunomodulating drugs as well as elevated levels of inflammatory markers in the blood was more frequent in the viremic group. In conclusion, our analysis revealed that detectable viremia correlates with hyperinflammatory conditions and higher risk for severe COVID-19 disease.

The antiviral agent, remdesivir, is adenosine analogue which is currently also used as anti-coronavirus disease 2019. Remdesivir also had anti-inflammatory effect which reduced pro-inflammatory cytokine production, and inhibition of the cyclic GMP-AMP synthase-STING pathway.

We evaluated the antiarthritic effects of remdesivir in a mouse model of High-fat diet (HFD) collagen-induced arthritis (CIA) and in fibroblast-like synoviocytes from patients with RA. Type II collagen was administered to DBA/1J mice to induce CIA. Vehicle or remdesivir was injected subcutaneously three times a week. During 7 weeks of treatment, the arthritis score and incidence were evaluated twice a week. Flow cytometry and confocal imaging were used to evaluate CD4 + T cells in the spleen. FLSs from patients with RA were stimulated in vitro with remdesivir and tumor necrosis factor (TNF)-α, and western blotting was used to measure the expression of STING and necroptosis-related markers.

Remdesivir administration suppressed the incidence and progression of arthritis in mice with CIA. Histological analysis revealed lower inflammation and cartilage damage scores in remdesivir-treated than in vehicle groups. Interleukin (IL)-17 + CD4 + T-cell differentiation was inhibited in the remdesivir-treated group. Furthermore, IL-17/-6/-1β, monocyte chemoattractant protein -1, and TNF-α expression was reduced in the remdesivir group. In vitro, remdesivir suppressed the expression of STING, nuclear factor-κB, RIPK3, and phosphorylated MLKL in RA-FLSs under TNF-α stimulation.

The antiviral agent remdesivir suppressed arthritis by regulating Th cell differentiation, pro-inflammatory cytokine expression, the STING pathway, and necroptosis.

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone significant genomic mutations, contributing to resistance against existing 2019 coronavirus disease (COVID-19) treatments. In a previous study, we identified N-0385, a potent host-directed inhibitor of transmembrane serine protease 2 (TMPRSS2), which has therapeutic efficacy towards SARS-CoV-2 infection. However, in further evaluation of its preclinical druggability, N-0385 displayed unfavorable pharmacokinetic properties, including high bioavailability (99 %) following intranasal (IN) administration. This can lead to substantial systemic exposure and potential adverse effects due to off-target interactions. Here, we designed a library of peptidomimetic compounds with P3 site modifications on an optimized scaffold. We sought to maintain sub-nanomolar potency against TMPRSS2 (Kis < 2 nM), reduce pseudovirus infection, while addressing the lack of selectivity and excessive lung uptake. Notably, inhibitor 9, which contains Asp at the P3 position, achieved a two-fold increase in TMPRSS2 inhibitory potency (Ki = 0.13 ± 0.03 nM), a >700-fold selectivity over Factor Xa (FXa), and showed superior selectivity against other proteases (matriptase, transmembrane serine protease 6 (TMPRSS6), thrombin, furin, and tPA). Despite concerns about the role of FXa in the coagulation cascade, compound 9 had no impact on coagulation or thrombolysis 2 h after in vitro treatment. In the air-liquid interface (ALI) model of the lung epithelium, compound 9 displayed a 1.5-fold decrease in permeability compared to N-0385 and demonstrated sustained stability in lungs (11 h) and plasma (13 h). Taken together, our data demonstrate that continued optimization of this type of inhibitors will lead to improved therapeutics for the treatment of SARS-CoV-2 infection by IN administration.

Emergence of viruses cause unprecedented challenges and thus leading to wide-ranging consequences today. The world has faced massive disruptions like COVID-19 and continues to suffer in terms of public health and world economy. Fighting with this emergence of viruses and its reemergence plays a critical role in the health care industry. Identification of novel virus-drug associations is a vital step in drug discovery. Prediction and prioritization of novel virus-drug associations through computational approaches is an alternative and best choice considering the cost and risk of biological experiments. This study proposes a method, KR-AEVDA that relies on k-nearest neighbor based reliable negative sample selection and autoencoder based feature extraction to explore promising virus-drug associations for further experimental validation. The method analyzes complex relationships among drugs and viruses by investigating similarity and association data between drugs and viruses. It generates feature vectors from the similarity data, and reliable negative samples are extracted through an effective distance-based algorithm from the unlabeled samples in the dataset. Then high level features are extracted via an autoencoder and is fed to an ensemble classifier for inferring novel associations. Experimental results on three different datasets showed that KR-AEVDA reliably attained better performance than other state-of-the-art methods. Molecular docking is carried out between the top-predicted drugs and the crystal structure of the SARS-CoV-2's main protease to further validate the predictions. Case studies for SARS-CoV-2 illustrate the effectiveness of KR-AEVDA in identifying potential virus-drug associations.

SARS-CoV-2 is a neurotrophic and pro-inflammatory virus, with several acute and more persistent neuropsychiatric sequelae reported. There are limited data from African cohorts and few acute illness biomarkers of persistent neuropsychiatric symptoms.

To examine the association of neuropsychiatric outcomes with clinical illness severity, systemic inflammation, cardiovascular and renin-angiotensin-system (RAS) biomarkers. Second, to determine the prevalence of neuropsychiatric symptoms in a cohort of South African SARS-CoV-2 PCR positive patients at least six months following infection/hospitalization.

SARS-CoV-2 PCR positive patients were recruited prospectively from Cape Town, South Africa, including hospitalized patients from ancestral, beta and delta-dominant COVID-19 waves (pre-vaccine rollout); and asymptomatic/mild SARS-CoV-2 positive patients. The 96-protein O-link inflammation and cardiovascular panels, RAS fingerprinting, and antibody responses were measured in serum samples collected at peak severity and recovery (>3 months post-infection). Telephonic interviews were conducted at least six months post infection/hospitalization. Validated measures employed were: WHO Self-Report Questionnaire (SRQ-20), Generalized Anxiety Disorder Scale (GAD-7), Chalder Fatigue Scale (CFS-11) and Telephonic Montreal Cognitive Assessment (T-MoCA).

Ninety-seven participants completed telephonic interviews. The median (IQR) age was 48 (37-59) years, and 54 % were female. There were no significant associations between neuropsychiatric outcomes and illness severity, systemic inflammation, cardiovascular and/or renin-angiotensin-system (RAS) biomarkers from either peak illness or recovery samples. More than half of this SA COVID-19 cohort had one or more persistent neuropsychiatric symptoms >6 months post vaccine-naïve infection. On the T-MoCA, 44 % of participants showed evidence of cognitive and/or memory impairments.

The high prevalence of persistent neuropsychiatric symptoms in this African cohort supports ongoing attention to long COVID. Acute and early serum protein biomarkers were not associated with persistent neuropsychiatric outcomes post-COVD-19.

Neutralizing autoantibodies against type I interferons were strongly linked to severe COVID-19 in unvaccinated patients; however, this has yet to be evaluated in vaccinated individuals.

To analyze how these autoantibodies influences disease variability in vaccine breakthrough COVID-19 pneumonia patients.

Clinical and laboratory data; autoantibodies blocking interferon-α2 and -ω; and humoral response to SARS-CoV-2 vaccine were collected from all vaccinated COVID-19 pneumonia patients admitted from April 2021 to December 2022 at Bellvitge University Hospital, Spain.

458 patients developed COVID-19 pneumonia despite an appropriate antibody response to SARS-CoV-2 vaccination. Autoantibodies neutralizing interferons were significantly more prevalent in patients with critical pneumonia compared to those with milder forms (8.8 % vs. 3.6 %; p = 0.037). Having these autoantibodies was an independent predictor for critical COVID-19 pneumonia (OR 2.88 [95 %CI 1.18-6.98]).

Vaccination considerably reduces the severity of COVID-19; however, patients with type I interferon autoantibodies remain at increased risk of severe disease.

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately impacted immunocompromised hosts, leading to higher morbidity and mortality. The clinical outcomes have varied based on the degree of immunosuppression, treatment availability, severe acute respiratory syndrome coronavirus 2 variants, and vaccination status. This review discusses the evolving epidemiology, clinical presentation, treatment, and prevention strategies for COVID-19 in immunocompromised populations, including patients living with human immunodeficiency virus, solid organ transplant, and hematopoietic stem cell transplant recipients.

Inborn errors of immunity (IEI) are congenital disorders of the immune system. Due to impaired immune system, they are at a higher risk to develop a more severe COVID-19 course compared to general population.

Herein, we aimed to systematically review various aspects of IEI patients infected with SARS-CoV-2. Moreover, we performed a meta-analysis to determine the frequency of COVID-19 in patients with different IEI.

Embase, Web of Science, PubMed, and Scopus were searched introducing terms related to IEI and COVID-19.

3646 IEI cases with a history of COVID-19 infection were enrolled. The majority of patients had critical infections (1013 cases, 27.8%). The highest frequency of critical and severe cases was observed in phenocopies of IEI (95.2%), defects in intrinsic and innate immunity (69.4%) and immune dysregulation (23.9%). 446 cases (12.2%) succumbed to the disease and the highest mortality was observed in IEI phenocopies (34.6%). COVID-19 frequency in immunodeficient patients was 11.9% (95% CI: 8.3 to 15.5%) with innate immunodeficiency having the highest COVID-19 frequency [34.1% (12.1 to 56.0%)]. COVID-19 case fatality rate among IEI patients was estimated as 5.4% (95% CI: 3.5-8.3%, n = 8 studies, I2 = 17.5%).

IEI with underlying defects in specific branches of the immune system responding to RNA virus infection experience a higher frequency and mortality of COVID-19 infection. Increasing awareness about these entities and underlying genetic defects, adherence to prophylactic strategies and allocating more clinical attention to these patients could lead to a decrease in COVID-19 frequency and mortality in these patients.

Widespread vaccination, hybrid immunity, and reduced pathogenicity with circulating Omicron variants have decreased the rate of severe coronavirus disease 2019 (COVID-19) outcomes in the general population. Certain patients with COVID-19 remain at high risk for severe outcomes. Clinicians must individualize treatments based on expected benefits and relative harms for patients with mild-to-moderate COVID-19. Guideline-directed therapy for severe and critical COVID-19 has remained static over the last couple of years. Data on immunomodulatory agents have improved our understanding of the management of severe and critical COVID-19, yet uncertainty remains on the role and timing of these agents in the Omicron era.

The SARS-CoV-2 outbreak highlights the persistent vulnerability of humanity to epidemics and emerging microbial threats, emphasizing the lack of time to develop disease-specific treatments. Therefore, it appears beneficial to utilize existing resources and therapies. Computational drug repositioning is an effective strategy that redirects authorized drugs to new therapeutic purposes. This strategy holds significant promise for newly emerging diseases, as drug discovery is a lengthy and expensive process. Through this study, we present an ensemble method based on the convolutional neural network integrated with genetic algorithm and deep forest classifier for virus-drug association prediction (CGDVDA). We generated feature vectors by combining drug chemical structure and virus genomic sequence-based similarities, and extracted prominent deep features by applying the convolutional neural network. The convoluted features are optimized using the genetic algorithm and classified using the ensemble deep forest classifier to predict novel virus-drug associations. The proposed method predicts drugs for COVID-19 and other viral diseases in the dataset. The model could achieve ROC-AUC scores of 0.9159 on fivefold cross-validation. We compared the performance of the model with state-of-the-art approaches and classifiers. The experimental results and case studies illustrate the efficacy of CGDVDA in predicting drugs against viral infectious diseases.

To compare the effects of treatments for mild or moderate (that is, non-severe) coronavirus disease 2019 (covid-19).

Systematic review and network meta-analysis.

Covid-19 Living Overview of Evidence Repository (covid-19 L-OVE) by the Epistemonikos Foundation, a public, living repository of covid-19 articles, from 1 January 2023 to 19 May 2024. The search also included the WHO covid-19 database (up to 17 February 2023) and six Chinese databases (up to 20 February 2021). The analysis included studies identified between 1 December 2019 and 28 June 2023.

Randomised clinical trials in which people with suspected, probable, or confirmed mild or moderate covid-19 were allocated to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.

After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias was assessed by use of a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, following GRADE guidance, drug treatments were classified in groups from the most to the least beneficial or harmful.

Of 259 trials enrolling 166 230 patients, 187 (72%) were included in the analysis. Compared with standard care, two drugs probably reduce hospital admission: nirmatrelvir-ritonavir (25 fewer per 1000 (95% confidence interval 28 fewer to 20 fewer), moderate certainty) and remdesivir (21 fewer per 1000 (28 fewer to 7 fewer), moderate certainty). Molnupiravir and systemic corticosteroids may reduce hospital admission (low certainty). Compared with standard care, azithromycin probably reduces time to symptom resolution (mean difference 4 days fewer (5 fewer to 3 fewer), moderate certainty) and systemic corticosteroids, favipiravir, molnupiravir, and umifenovir probably also reduce duration of symptoms (moderate to high certainty). Compared with standard care, only lopinavir-ritonavir increased adverse effects leading to discontinuation.

Nirmatrelvir-ritonavir and remdesivir probably reduce admission to hospital, and systemic corticosteroids and molnupiravir may reduce admission to hospital. Several medications including systemic corticosteroids and molnupiravir probably reduce time to symptom resolution.

This review was not registered. The protocol is publicly available in the supplementary material.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) prolonged the coronavirus disease 2019 (COVID-19) pandemic. The continued development of novel pan-variant therapeutics to treat currently circulating and future VOCs is critically important. Photomedicine may offer broadly applicable, pan-variant treatments. In this study, we show that visible light centered around 425 nm inactivates each of the five SARS-CoV-2 VOC lineages that have been identified by the World Health Organization (Alpha, Beta, Delta, Gamma, and Omicron) in cell-free suspensions in a dose-dependent manner, including bamlanivimab-resistant variants. Specifically, 60 J/cm2 of 425 nm light reduced SARS-CoV-2 titers by >4 log10 relative to unilluminated controls. We observed that 425 nm light inactivates SARS-CoV-2 through restricted entry to host cells. In addition, a non-cytotoxic dosing regimen of 32 J/cm2 of 425 nm light reduced infectious virus titers in well-differentiated air-liquid interface (ALI) human airway epithelial (HAE) cells infected with the Beta, Delta, and Omicron variants that incorporate mutations associated with immune evasion and/or increased transmissibility. Infectious SARS-CoV-2 titers were reduced when dosing began during the early stages of infection or in more established infections. Finally, we translated these findings to the RD-X19, a novel medical device that emits 425 nm light; our results showed that the RD-X19 restricted spike binding to ACE-2 and reduced SARS-CoV-2 titers in cell-free suspensions (by >2 log10) and in the ALI HAE model (by >1 log10). These findings indicate that photomedicine utilizing 425 nm visible light may serve as a novel, pan-variant treatment modality for COVID-19.IMPORTANCEThe continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of variants that can evade public health measures, including vaccines and therapeutics. Thus, the continued development of broadly applicable measures to supplement current public health measures and standards of care remains critical. Photomedicine is one such approach. In this study, we show that non-ultraviolet visible light can inactivate each SARS-CoV-2 variant of concern (VOC) by preventing entry to host cells. Furthermore, visible light reduced the amount of virus produced in an infection model of the human airway at multiple stages of infection, demonstrating the antiviral capability of visible light. This study provides preclinical support for the development of visible light to serve as a SARS-CoV-2 countermeasure and warrants further investigation.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with endothelial dysfunction, which may also compromise the microcirculation within ocular tissues. This prospective study evaluated associations between radial peripapillary capillary (RPC) vessel density (VD) and systemic treatment, age, hypoxia, D-dimer, and interleukin-6 (IL-6) levels in patients recovering from coronavirus disease 2019 (COVID-19) related pneumonia.

Sixty-three individuals who were admitted to the hospital due to COVID-19 bilateral pneumonia underwent ophthalmic examination two months post-discharge. RPC VD was measured using optical coherence tomography angiography. Associations with age, arterial hypertension, and systemic treatment (dexamethasone, remdesivir, and oxygen therapy), oxygen saturation, D-dimer, and IL-6 levels were evaluated. The control group comprised 43 control participants with no history of COVID-19 who attended routine ophthalmic examinations.

No ophthalmic abnormalities were detected. RPC VD did not differ significantly with hypertension or systemic treatment with dexamethasone and remdesivir. However, patients receiving oxygen therapy had higher RPC VD. A borderline inverse correlation was observed between inferior RPC VD and age. There were no correlations between RPC VD and oxygen saturation. Significant inverse correlations were found between nasal RPC and mean RPC with D-dimer levels and between inferior RPC VD and IL-6 levels. No significant differences in RPC parameters were observed when comparing the COVID-19 group with controls.

Hypertension or systemic treatment had no significant effect on RCP VD. However, VD in specific RPC areas correlated inversely with D-dimer and IL-6 levels, highlighting the need for monitoring peripapillary microvasculature for potential long-term ocular effects of COVID-19.

Aqueous two-phase systems (ATPS) have been used to purify a range of biomolecules, including small molecules, monoclonal antibodies, viruses, and whole cells. They are known for selective separations, creating a stabilizing, low-shear environment, and high yields. Recently, as biomanufacturing attempts to adopt continuous processing, attention has shifted to ATPS for its ability to operate fully continuously while incurring lower costs than many chromatographic methods. But despite 60 years of exploration and development, the complex network of interlinked driving forces controlling these separations has prevented robust development of process understanding, and most ATPS separations are still optimized using slow and costly manual screening methods. As a result, industry has been unwilling to adopt ATPS. Fortunately, a growing body of literature is developing statistical and mechanistic models of ATPS to predict liquid-liquid equilibria and separations with reduced experimental burden. This review surveys the application of these models to ATPS, comparing their progress and potential to promote rapid development of bioseparations in the near and long term. The discussion evaluates the adaptability of statistical tools, like response surface methodology and artificial neural networks, and contrasts it with the process understanding generated through application of semi-empirical thermodynamic models. Strategies are explored to automate optimization of separations for new biomolecules using these models to create artificial data. By understanding the landscape of models applied to ATPS, this review will start a discussion about bringing this technology closer to commercialization and enabling continuous processing on a broader scale.

Biomedical research often utilizes Cox regression for the analysis of time-to-event data. The pervasive use of frequentist inference for these analyses implicates that the evidence for or against the presence (or absence) of an effect cannot be directly compared and that researchers must adhere to a predefined sampling plan. As an alternative, the use of Bayes factors improves upon these limitations, which is especially important for costly and time-consuming biomedical studies. However, Bayes factors involve their own difficulty of specifying priors for the parameters of the statistical model. In this article, we develop data-driven priors centered around zero for Cox regression tailored to nine subfields in biomedicine. To this end, we extracted hazard ratios and associated [Formula: see text] confidence intervals from the abstracts of large corpora of already existing studies within the nine biomedical subfields. We used these extracted data to inform priors for the nine subfields. All of our suggested priors are Normal distributions with means of 0 and standard deviations closely scattered around 1. We propose that researchers use these priors as reasonable starting points for their analyses.

The JAK family, particularly JAK3, plays a crucial role in immune signaling and inflammatory responses. Dysregulated JAK3 activation in SARS-CoV-2 infections has been associated with severe inflammation and respiratory complications, making JAK inhibitors a viable therapeutic option. However, their use raises concerns regarding immunosuppression, which could increase susceptibility to secondary infections. While long-term adverse effects are less of a concern in acute COVID-19 treatment, patient selection and monitoring remain critical. Furthermore, adverse effects associated with oral JAK3 inhibitors necessitate the exploration of alternative strategies to optimize therapeutic efficacy while minimizing risks. This review highlights the role of JAK3 in immune and epithelial cells, examines the adverse effects of oral JAK3 inhibitors in COVID-19 and other treatments, and discusses alternative therapeutic strategies for improving patient outcomes.

A series of novel Mpro inhibitors was designed and synthesized to combat the coronavirus, such as HCoV-OC43 and SARS-CoV-2, and several compounds showed comparable antiviral activity to nirmatrelvir. Among them, an octahydroindole-based peptidomimetic covalent inhibitor 28f showed strong inhibitory activity against Mpros and exhibited broad-spectrum anticoronavirus activity with EC50 values ranging from 0.027 to 4.41 μM. Besides, this compound displayed potent antiviral activity against EV71. Compared to FB2001, 28f displayed better pharmacokinetic properties, and the value of oral bioavailability in CD-1 mice and Beagle dogs was improved to 10.4 and 10.2%, respectively. In addition, oral treatment with 28f could significantly reduce the viral loads of HCoV-OC43 in mice, and compound 28f could also effectively reduce lung viral loads in a K18-hACE2 transgenic mouse model without ritonavir. Taken together, compound 28f is a promising orally bioavailable broad-spectrum antiviral drug candidate that deserves further research.

Nuclear export protein 1, also known as XPO1, plays a crucial role in cellular homeostasis and assists in the nucleocytoplasmic transfer of ribonucleic acids (RNAs) and proteins. In addition, this nuclear export receptor is essential for the export of a variety of cargo molecules, such as proteins implicated in the immune response, tumor suppression, and cell cycle regulation. XPO1 has emerged as a promising target to disrupt the life cycles of multiple viruses and treat cancers. In our current work, we used a computational approach consisting of pharmacophore-assisted virtual screening complemented by molecular docking, molecular dynamics, and solvation-based free-energy studies to identify new inhibitors of the XPO1 protein. The identified compounds displayed highly stable RMSD plots, hydrogen bonding interactions, and relatively good binding affinities in both docking and free energy studies. These molecules were validated in vitro against SARS-CoV-2 and cancer cell lines. The study identified novel inhibitors of the XPO1 protein with both antiviral and anticancer activities.

Measles, hepatitis C, and COVID-19 are significant human diseases caused by RNA viruses. While vaccines exist to prevent infections, there are a small number of currently available therapeutic agents that can effectively treat these diseases after infection occurs. This study explores a new therapeutic strategy using a small molecule designated polyprenyl immunostimulant (PI) to increase innate immune responses and combat viral infections. Using a multi-disciplinary approach, this study quantifies the effects of PI in mice and THP-1 cells using flow cytometry to identify immune phenotypic markers and mass spectroscopy to monitor the metabolomic profiles of immune cells perturbed by PI treatment. The metabolomic studies identified that sphinganine and ceramide, which are precursors of sphingosine-1-phosphate (S1P), were the common metabolites upregulated in THP-1 and mice blood. Sphingosine-1-phosphate can mediate the trafficking of T cells, whereas ceramide can signal the activation and proliferation of T cells, thereby modulating the mammalian host's immunity. To demonstrate proof-of-principle, a case study was conducted to examine the benefit of administering PI to improve the outcomes of a feline co-infected with two distinct RNA viruses-feline leukemia virus and feline infectious peritonitis virus. Both viruses produce deadly symptoms that closely resemble RNA viruses that infect humans. The results identify quantifiable cellular and metabolic markers arising from PI treatment that can be used to establish a platform measuring the efficacy of PI in modulating the innate immune system.

A major hindrance to the identification of new drug targets and the large-scale testing of new or existing compound libraries against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is that research on the virus is restricted to biosafety level 3 (BSL-3) laboratories. In such cases, BSL-2 surrogate systems or chimeric and attenuated versions of the virus are developed for safer, faster, and cheaper examination of the stages of the virus life cycle and specific drug targets. In this study, we describe a BSL-2 chimeric viral system utilizing a Sindbis virus background as a tool to study one such target, the SARS-CoV-2 Envelope (E) protein channel activity. This protein is fully conserved between SARS-CoV and SARS-CoV-2 variants of concern (VOCs), except for a threonine to isoleucine mutation in the Omicron variant, making the E ion channel domain an attractive antiviral target for combination therapy. Using a BSL-2-chimeric system, we have been able to show similar inhibition profiles using channel inhibitors as previously reported for E-channel inhibition in authentic SARS-CoV-2. This system has the potential to allow faster initial screening of E-channel inhibitors and can be useful in developing broad-spectrum antivirals against viral channel proteins.IMPORTANCEDespite its importance in viral infections, no antivirals exist against the ion channel activity of the SARS-CoV-2 Envelope (E) protein. The E protein is highly conserved among SARS-CoV-2 variants, making it an attractive target for antiviral therapies. Research on SARS-CoV-2 is restricted to BSL-3 laboratories, creating a bottleneck for screening potential antiviral compounds. This study presents a BSL-2 chimeric system using a Sindbis virus background to study the ion channel activity of the E protein. This novel BSL-2 system bypasses this limitation, offering a safer and faster approach for the initial screening of ion channel inhibitors. By replicating the channel inhibition profiles of authentic SARS-CoV-2 in a more accessible system, this research paves the way for the development of broad-spectrum antivirals against viral channel proteins, potentially expediting the discovery of life-saving treatments for COVID-19 and other viral diseases.

Procalcitonin (PCT) is recognized as an inflammatory biomarker, often elevated in COVID-19 pneumonia alongside other biomarkers. Understanding its association with severe outcomes and comparing its predictive ability with other biomarkers is crucial for clinical management.

This retrospective multicenter observational study aimed to investigate the association between PCT levels and adverse outcomes in hospitalized COVID-19 patients. Additionally, it sought to compare the predictive performance of various biomarkers.

The study analyzed data from the Society of Critical Care Medicine (SCCM) Viral Infection and Respiratory Illness Universal Study (VIRUS) registry, comprising COVID-19 patients hospitalized across multiple Mayo Clinic sites between March 2020 and June 2022.

A total of 7851 adult COVID-19 patients were included. Patients were categorized into 6 groups based on the worst WHO ordinal scale. Multivariate models were constructed using peak biomarker levels within 72 hours of admission, adjusted for confounders.

Elevated PCT levels were independently associated with increased odds of adverse outcomes, including ICU admission (adjusted odds ratio [aOR] 1.32, 95%CI 1.27-1.38), IMV requirement (aOR 1.35, 95%CI: 1.28-1.42), and in-hospital mortality (aOR 1.30, 95%CI: 1.22-1.37). A 3.48-fold increase in IMV requirement and 3.55 times increase in in-hospital mortality were noted with peak PCT ⩾ 0.25 ng/ml. Similar associations were observed with other biomarkers like NLR (AUC 0.730), CRP, IL-6, LDH (AUC 0.800), and D-dimer (AUC 0.719). Models incorporating NLR, LDH, D-dimer, and PCT demonstrated the highest predictive accuracy, with a combined model exhibiting an area under the curve (AUC) of 0.826 (95%CI 0.803-0.849).

Higher PCT levels were significantly linked to worse outcomes in COVID-19 patients, emphasizing its potential as a prognostic marker. Biomarker-based predictive models, particularly those including PCT, showed promising utility for risk assessment and clinical decision-making. Further prospective studies are warranted to validate these findings on a larger scale.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the coronavirus disease 2019 (COVID-19) pandemic, continues to pose global health challenges despite the availability of approved vaccines and antiviral drugs. The emergence of new variants of SARS-CoV-2 and ongoing post-COVID complications necessitate continuous exploration of effective treatments. Kaurenoic acid (KA) is a tetracyclic diterpenoid isolated from plants of the Copaifera genus and has been previously recognized for its anti-inflammatory, antibacterial, antifungal, and antitumor properties. However, there is a lack of knowledge about the in vitro effects of KA on viruses. Here, we evaluated its effect on SARS-CoV-2 replication for the first time.

KA demonstrated a high selective index of 16.1 against SARS-CoV-2 and robust effectiveness against the B.1.617.2 (Delta) and BA.2 (Omicron) variants. Mechanistically, KA was shown to impair the post-entry steps of viral replication. In a subgenomic replicon system, we observed a decrease in viral RNA synthesis in different cell lines. Using an infectious virus, a larger reduction in the release of SARS-CoV-2 virions was observed. We suggest that KA interacts with SARS-CoV-2 proteases through molecular docking.

In conclusion, KA emerges as an inhibitor of SARS-CoV-2 proteases and, consequently, its replication cycle. It could be a good candidate for further investigation in clinical assays against SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) global health crisis, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented unprecedented challenges to global healthcare systems, leading to rapid advances in treatment development. This review comprehensively examines the current therapeutic approaches for managing COVID-19, including direct-acting antivirals, immunomodulators, anticoagulants, and adjuvant therapies, as well as emerging and experimental approaches. Direct-acting antivirals target various stages of the viral life cycle, offering specific intervention points, while immunomodulators aim to modulate the host's immune response, reducing disease severity. Anticoagulant therapies address the coagulopathy frequently observed in severe cases, and adjuvant treatments provide supportive care to improve overall outcomes. We also explore the challenges and limitations of implementing these treatments, such as drug resistance, variable patient responses, and access to therapies, especially in resource-limited settings. The review also discusses future perspectives, including the potential of next-generation vaccines, personalized medicine, and global collaboration in shaping future COVID-19 treatment paradigms. Continuous innovation, combined with an integrated and adaptable approach, will be crucial to effectively managing COVID-19 and mitigating the impact of future pandemics.

The single nucleotide polymorphism rs12979860 is associated with the production of IFNλ4, a type III interferon, which offers protection from viral infection via its proinflammatory properties. We investigated if a genetically determined increase in IFNλ4 affects disease progression in SARS-CoV-2. This prospective, single-center study involved critically ill SARS-CoV-2 patients admitted to the intensive care unit. We performed genotyping for rs12979860 and analyzed daily laboratory data. Genotype frequencies were compared with an external validation cohort. Critically ill individuals with COVID-19 (n = 184; 29.3% women) were included. Median age was 63 years. The TT genotype was present in 11%, CT in 48% and CC in 41%. At baseline, CRP, ferritin, transferrin and neopterin did not differ significantly between groups. Longitudinal analysis revealed significant genotype-dependent differences in CRP, ferritin and neopterin with the highest peak in TT patients after 10-15 days. A higher need for renal replacement therapy (31.6% vs. 11.7%, p = 0.044) and mechanical ventilation (22 days vs. 15 days, p = 0.018) was observed in the TT group. The SNP rs12979860 near IFNL4 is associated with distinct inflammatory trajectories in critically ill COVID-19 patients. Genetic determinants of the immune response influence the severity of inflammation and clinical outcomes in severe COVID-19.

In November 2020, the Food and Drug Administration issued an Emergency Use Authorization for baricitinib, a Janus Kinase protein inhibitor, for hospitalized children and adults with COVID-19 requiring supplemental oxygen, but safety data for this pediatric indication is lacking.

This retrospective case series describes patients aged younger than 21 years treated with baricitinib for severe COVID-19 between 2021 and 2022. Patient characteristics, treatments, adverse events, reasons for early discontinuation of baricitinib, durations of oxygen supplementation and hospitalization, and complications were recorded.

There were 37 patients who received baricitinib. Median age was 16 years (range 1-20). All had a comorbidity (59% obesity, 5% malignancy), and 76% were cared for in the intensive care unit. All received remdesivir (median 5 days; range: 2-11), and 34 (92%) received corticosteroids (median 6 days; range: 1-10). Median duration of baricitinib was 6 days (range 3-14). Baricitinib was discontinued early for clinical improvement (2), and adverse events (7; 6 elevated liver enzymes [only 1 meeting discontinuation criteria), 1 thrombocytosis]). One patient had deep vein thrombosis without pulmonary embolism, 5 patients had concurrent infections (4 bacterial, 1 fungal, 2 herpes simplex virus reactivation). All adverse events were resolved. There were no deaths. Median hospitalization was 7 days (range 2-108) and mechanical ventilation was 4.5 days (range 1-86 days). Two patients (5%) were discharged with supplemental oxygen and one with a tracheostomy.

Baricitinib appears safe in children hospitalized for severe COVID-19. Most early baricitinib discontinuation for abnormal laboratory studies was secondary to provider caution.

Severe coronavirus outbreaks, including SARS, MERS, and COVID-19, have underscored the urgent need for effective antiviral therapies. This study evaluated the antiviral activity of biflavanones isolated from Ouratea spectabilis-specifically ouratein (Our-) A, B, C, and D-against murine hepatitis virus (MHV-3) and human SARS-CoV-2. Cells infected with MHV-3 or SARS-CoV-2 were treated with ourateins, and viral replication was assessed using plaque assays. Mice infected with MHV-3 were treated with Our-D either orally or intraperitoneally. Key assessments included leukocyte counts, cytokine and chemokine levels, histological analysis, and survival rates. The mechanism of action was explored through in silico and in vitro studies focused on the binding and inhibition of the main protease (Mpro). Our-D significantly inhibited the replication of both viruses, with a selective index of 2.5 for MHV-3 and 14.9 for SARS-CoV-2. In vivo, Our-D reduced leukocyte infiltration in the lungs, decreased CCL2 levels, increased IL-10, and lowered plasma IL-6 and CXCL1 levels. Additionally, Our-D mitigated lung damage, partially restored betacoronavirus-induced lymphopenia, and reduced viral loads in the lungs, heart, and spleen, ultimately improving survival in mice. In silico studies revealed that Our-A and Our-C had strong binding affinity for Mpro, and both significantly inhibited Mpro activity in vitro, unlike Our-D. Our-D protected mice from coronavirus infection by modulating the inflammatory response and reducing viral loads, with minimal effect on Mpro inhibition, suggesting alternative mechanisms for its antiviral activity.

There is limited evidence on clinical outcomes and treatment pattern in Japanese patients with severe chronic kidney disease (CKD), hospitalized for coronavirus disease-2019 (COVID-19). We aimed to describe patient characteristics, treatment pattern, and clinical outcomes in Japanese patients with severe CKD, hospitalized for COVID-19 who received remdesivir (RDV).

We used the anonymized claims database from Medical Data Vision Co., Ltd., Japan. The analysis included patients aged ≥ 18 years with severe CKD, hospitalized for moderate to severe COVID-19, and administered ≥ 1 dose of RDV between October 2021 and September 2023. All-cause inpatient mortality, disease progression, and recovery up to 56 days from hospitalization were evaluated.

Data of 847 patients were analyzed (mean age 73.0 ± 14.1 years). Median (Q1-Q3) time to RDV initiation was 1.0 day (1.0-2.0) from hospitalization and treatment duration was 5.0 days (3.0-5.0). At RDV initiation, 44.27% patients required non-invasive positive pressure ventilation/high or low flow oxygen; 4.25% required invasive mechanical ventilation/extracorporeal membrane oxygenation/intensive care unit hospitalization. Proportion of patients with all-cause mortality was 11.45% (stage 4, 14.89%; stage 5, 10.47%) by 28 days and 12.28% (stage 4, 16.49%; stage 5, 11.08%) by 56 days. At 28 days, 12.28% had disease progression and 72.14% recovered.

Most patients with severe CKD received RDV immediately after hospitalization. The majority of patients recovered by 28 days. The study provided insights into RDV treatment in inpatient settings, which could contribute to the discussion on standard of care in this population in Japan.

Enteroviruses (EV) usually cause acute, mild, self-limiting disease. Chronic infections with EVs are rare, and typically occur in patients with immunodeficiency, posing a high risk of severe outcomes. We report a rare case of chronic diarrhea caused by coxsackievirus A1 (CVA1) (from EV-C species) infection in a patient with a common variable immunodeficiency, who was on treatment with pooled intravenous immunoglobulin (IVIG) from the Netherlands. To explore treatment options, we assessed the presence of neutralizing antibodies (nAbs) against CVA1 in pooled IVIG from South Africa, where EV-Cs are prevalent, and tested the antiviral efficacy of US Food and Drug Administration-approved drugs like fluoxetine, itraconazole, ribavirin, and remdesivir (RDV) against CVA1 in vitro. Both Dutch and South African IVIG showed low nAb titers against CVA1. The patient, treated with Dutch IVIG, also received a combination of amantadine and fluoxetine, which were discontinued due to side effects. Among the drugs tested, only RDV significantly inhibited CVA1 replication in rhabdomyosarcoma (RD) cells. This in vitro efficacy was not reflected by a favorable clinical response after treatment of the patient with RDV. In concordance with unfavorable antiviral response in the patient, preliminary tests on a co-culture model containing isogenic human intestinal cells and intestinal fibroblasts showed no significant reduction in CVA1 RNA copies after RDV administration. In conclusion, our results showed that repurposing of drugs that have shown in vitro efficacy does not translate well to the patients, and this is also reflected in a more physiologically relevant model of the human intestine.

The coronavirus disease 2019 (COVID-19) pandemic has exerted a catastrophic impact on public health. Meanwhile, the seasonal influenza outbreak overlaps with the current pandemic wave. There is still an urgent need to develop effective therapeutic agents for the treatment of co-infection of multiple respiratory viruses. This study aimed to investigate antiviral effects of EIDD-2801, an orally bioavailable ribonucleoside analog, and its potent therapeutic effects in co-infection of multiple respiratory viruses.

BALB/c mice and hamsters were infected with IFV or SARS-CoV-2, then were dosed orally with EIDD-2801 to measure the antiviral effects of EIDD-2801. Viral replication and mRNA transcription were evaluated by quantitative polymerase chain reaction (qPCR) and protein expression by Western Blot. Influenza viral titer was assessed using EID50 assay.

EIDD-2801 was found to be significantly effective against influenza A virus and influenza B virus. The antiviral activity against SARS-CoV-2 and further co-infection with influenza virus was also distinct. EIDD-2801 had potent antiviral effects against multiple respiratory viruses both in vitro and in vivo.

This study demonstrated that the small-molecule compound EIDD-2801, an orally available broad-spectrum antiviral agent, significantly inhibited the infection of influenza virus and SARS-CoV-2 and effectively protected animals from lethal influenza virus co-infection.

The COVID-19 pandemic, caused by the virus SARS-CoV-2 infection, has underscored the critical importance of rapid and accurate therapeutics. The neutralization of SARS-CoV-2 is paramount in controlling the spread and impact of COVID-19. In this context, the integration of aptamers and aptamer-related nanotherapeutics presents a valuable and scientifically significant approach. Despite the potential, current reviews in this area are often not comprehensive and specific enough to encapsulate the full scope of therapeutic principles, strategies, advancements, and challenges. This review aims to fill that gap by providing an in-depth examination of the role of aptamers and their related molecular medicine in COVID-19 therapeutics. We first introduce the unique properties, selection, and recognition mechanism of aptamers to bind with high affinity to various targets. Next, we delve into the therapeutic potential of aptamers, focusing on their ability to inhibit viral entry and replication, as well as modulate the host immune response. The integration of aptamers with nucleic acid nanomedicine is explored. Finally, we address the challenges and future perspectives of aptamer and nucleic acid nanomedicine in COVID-19 therapeutics, including issues of stability, delivery, and manufacturing scalability. We conclude by underscoring the importance of continued research and development in this field to meet the ongoing challenges posed by COVID-19 and potential future pandemics. Our review will be a valuable resource for researchers and clinicians interested in the latest developments at the intersection of molecular biology, nanotechnology, and infectious disease management.

Long covid describes a syndrome of persistent symptoms following COVID-19 and is responsible for substantial healthcare and economic burden. Currently, no effective treatments have been established. Ashwagandha (Withania somnifera (L.) Dunal) is a medicinal herb traditionally used in India for its immune-strengthening and anti-inflammatory properties. Withanolides, a family of steroid-derived molecules unique to Ashwagandha, have been shown to modulate inflammatory pathways in animal models, and several small randomised trials in humans support its effectiveness for reducing symptoms that are also associated with long covid. Therefore, this study aims to assess whether Ashwagandha is effective and safe for improving functional status and reducing symptom burden in adults living with long covid.

A randomised double-blind placebo-controlled trial will be performed at participating general practice (GP) surgeries and long covid clinics across the UK. Individuals diagnosed with long covid will be screened for eligibility and then randomised 1:1 to take 1000 mg daily of Ashwagandha root extract tablets (standardised to <0.9% withanolides) or matching placebo tablets for 3 months (target, n = 2500). Monthly online surveys will be performed to collect patient-reported outcomes, and monthly safety monitoring, including liver function tests, will be conducted by clinical site teams. The primary outcome of the Post-COVID Functional Status Scale score at 3 months will be assessed by baseline-adjusted ordinal logistic regression, according to a pre-published statistical analysis plan. The secondary outcomes included validated quality of life and long covid symptom scales, work status and productivity and adverse events. The trial has been approved as a Clinical Trial of an Investigational Medicinal Produce by the Medicines and Healthcare Regulatory Authority and by the NHS Research Ethics Committee and Health Research Authority.

Treatments for long covid are urgently needed. This trial will robustly evaluate the safety and efficacy of a candidate treatment with a promising efficacy and safety profile. If found to be effective, the findings will likely influence treatment guidelines and improve health outcomes in those living with long covid.

This trial was pre-registered on 15/08/2022: ISRCTN12368131.