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Background: A significant proportion of the global population has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at some point since the onset of the pandemic. Although most individuals who develop coronavirus disease 2019 (COVID-19) recover without complications, about 6% have persistent symptoms, referred to as post-COVID-19 condition (PCC). Intervention studies investigating treatments that potentially alleviate PCC-related symptoms and thus aim to mitigate the global public health burden and healthcare costs linked to PCC are desperately needed. The PYCNOVID trial investigates the effects of Pycnogenol®, a French maritime pine bark extract with anti-inflammatory and antioxidative properties, versus placebo on patient-reported health status in people with PCC. Methods: This is a single-center, placebo-controlled, quadruple blind, randomized trial. We aim to randomly assign 150 individuals with PCC (1:1 ratio) to receive either 200 mg Pycnogenol® or placebo daily for 12 weeks. Randomization is stratified for duration of PCC symptoms (≤ 6 months versus > 6 months) and presence of symptomatic chronic disease(s). The primary endpoint is perceived health status at 12 weeks (EuroQol—Visual Analogue Scale) adjusted for baseline values and stratification factors. Secondary endpoints include change in self-reported PCC symptoms, health-related quality of life, symptoms of depression and anxiety, cognitive function, functional exercise capacity, physical activity measured with accelerometry, and blood biomarkers for endothelial health, inflammation, coagulation, platelet function, and oxidative stress. Investigators, study participants, outcome assessors, and data analysts are blinded regarding the intervention assignment. Individuals with PCC were involved in the design of this study. Discussion: This is the first trial to investigate the effects of Pycnogenol® versus placebo on patient-reported health status in people with PCC. Should the trial proof clinical effectiveness, Pycnogenol® may serve as a therapeutic approach to mitigate symptoms associated with PCC. Trial registration: The study is registered at ClinicalTrials.gov. :NCT05890534, June 6, 2023. [ABSTRACT FROM AUTHOR]

There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out to date, with seven of those being randomized placebo-controlled studies. This systematic review and meta-analysis covers the literature from the outbreak of SARS-CoV-2 in late 2019 until January 2024. Search terms related to fluvoxamine, such as its trade names and chemical names, along with words related to COVID-19, such as SARS-CoV-2 and coronavirus, were used in literature databases including PubMed, Google Scholar, Scopus, and the ClinicalTrials.gov database from NIH, to identify the trials used in the subsequent analysis. Clinical deterioration and death data were extracted from these studies where available and used in the meta-analysis. A total of 7153 patients were studied across 14 studies (both open-label and double-blind placebo-controlled). 681 out of 3553 (19.17%) in the standard care group and 255 out of 3600 (7.08%) in the fluvoxamine-treated group experienced clinical deterioration. The estimated average log odds ratio was 1.087 (95% CI 0.200 to 1.973), which differed significantly from zero (z = 2.402, p = 0.016). The seven placebo-controlled studies resulted in a log odds ratio of 0.359 (95% CI 0.1111 to 0.5294), which differed significantly from zero (z = 3.103, p = 0.002). The results of this study identified fluvoxamine as effective in preventing clinical deterioration, and subgrouping analysis suggests that earlier treatment with a dose of 200 mg or above provides the best outcomes. We hope the outcomes of this study can help design future studies into respiratory viral infections and potentially improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Aims Methods and Results Conclusions We investigated the presence of SARS‐CoV‐2 in free‐ranging wildlife populations in Northeastern Minnesota on the Grand Portage Indian Reservation and Isle Royale National Park.One hundred twenty nasal samples were collected from white‐tailed deer, moose, grey wolves and black bears monitored for conservation efforts during 2022–2023. Samples were tested for viral RNA by RT‐qPCR using the CDC N1/N2 primer set. Our data indicate that no wildlife samples were positive for SARS‐CoV‐2 RNA.Continued surveillance is therefore crucial to better understand the changing landscape of zoonotic SARS‐CoV‐2 in the Upper Midwest. [ABSTRACT FROM AUTHOR]

The Omicron variant and its sub-lineages are the only current circulating SARS-CoV-2 viruses worldwide. In this study, the conformational stability of the isolated Receptor Binding Domain (RBD) of Omicron's spike protein is examined in detail. The parent Omicron lineage has over ten mutations in the ACE2 binding region of the RBD that are specifically associated with its β hairpin loop domain. It is demonstrated through biophysical molecular computations that the mutations in the β hairpin loop domain significantly increase the intra-protein interaction energies of intra-loop and loop–RBD interactions. The interaction energy increases include the formation of new hydrogen bonds in the β hairpin loop domain that help stabilize this critical ACE2 binding region. Our results also agree with recent experiments on the stability of Omicron's core β barrel domain, outside of its loop domain, and help demonstrate the overall conformational stability of the Omicron RBD. It is further shown here through dynamic simulations that the unbound state of the Omicron RBD remains closely aligned with the bound state configuration, which was not observed for the wild-type RBD. Overall, these studies demonstrate the significantly increased conformational stability of Omicron over its wild-type configuration and raise a number of questions on whether conformational stability could be a positive selection feature of SARS-CoV-2 viral mutational changes. [ABSTRACT FROM AUTHOR]

Background: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) immune response is crucial for disease management, although diminishing immunity raises the possibility of reinfection. Methods: We examined the immunological response to SARS‐CoV‐2 in a cohort of convalescent COVID‐19 patients in matched samples collected at 1 and 6−8 months after infection. The peripheral blood mononuclear cells were isolated from enrolled study participants and flow cytometry analysis was done to assess the lymphocyte subsets of naive, effector, central memory, and effector memory CD4+ or CD8+ T cells in COVID‐19 patients at 1 and 6−8 months after infection. Immunophenotypic characterization of immune cell subsets was performed on individuals who were followed longitudinally for 1 month (n = 44) and 6−8 months (n = 25) after recovery from COVID infection. Results: We observed that CD4 +T cells in hospitalized SARS‐CoV‐2 patients tended to decrease, whereas CD8+ T cells steadily recovered after 1 month, while there was a sustained increase in the population of effector T cells and effector memory T cells. Furthermore, COVID‐19 patients showed persistently low B cells and a small increase in the NK cell population. Conclusion: Our findings show that T cell responses were maintained at 6−8 months after infection. This opens new pathways for further research into the long‐term effects in COVID‐19 immunopathogenesis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case emphasizes the significance of COVID‐19 in pediatric patients presenting with unusual hepatic manifestations, urging clinicians to broaden their diagnostic lens. The unexpected elevation of SARS‐CoV‐2 antibodies and the effective use of N‐acetyl cysteine highlight the importance of adaptability in treatment strategies. This case report presents a unique manifestation of severe hepatic involvement in a 4‐year‐old girl with thalassemia minor and COVID‐19. Despite the absence of prominent respiratory symptoms, the patient exhibited jaundice, elevated liver enzymes, and coagulopathy. Initial suspicion of viral hepatitis was replaced by the discovery of significantly elevated SARS‐CoV‐2 antibodies. A multidisciplinary approach, including gastroenterology consultation and an extensive workup, was pivotal in ruling out alternative etiologies. Unconventional use of N‐acetyl cysteine contributed to clinical improvement, highlighting the need for adaptable treatment strategies. This case underscores the importance of heightened awareness in recognizing atypical presentations of COVID‐19 in pediatric patients, especially those with underlying health conditions. Further exploration into nuanced manifestations and treatment approaches is warranted for comprehensive clinical management. [ABSTRACT FROM AUTHOR]

Abstract: The legal neuropsychological assessment of individuals following infection with the Coronavirus disease 2019 (COVID-19) who exhibit potential symptoms of the Post-COVID-Syndrome (PCS) not only requires adherence to local regulations but also consideration of general professional guidelines. The assessment of PCS proves challenging both for the individual and the evaluator in the presence of ambiguous functional deficits or causal relationships. This article offers an overview of pathogenetic findings relevant to legal assessment and reflects on current German regulations and frameworks. In Germany, the legal neuropsychological assessment of PCS should align with guidelines of the Gesellschaft für Neuropsychologie (GNP) and integrate published neurological criteria. As PCS research rapidly advances, an interdisciplinary professional exchange is vital for further refining the legal neuropsychological assessment of PCS. [ABSTRACT FROM AUTHOR]

Background: This review aims to study the clinical characteristics, diagnostic results, treatments, and outcomes in patients with heterotopic ossification following COVID-19 infection. Methods: A literature search for eligible articles was conducted using MEDLINE/Pubmed, Global Health, and Scopus databases (January 12th, 2023), including all case reports and case series from any country and language. The criteria for inclusion in this review were cases of COVID-19 infection subsequently developing heterotopic ossification. Results: This systematic review analysed 15 reports (n = 20 patients) documenting cases of heterotopic ossification following COVID-19 infection. 80% of the patients were male, with a median age of 59 years. All patients required intensive care unit stay with an average duration of 48.5 days. Mechanical ventilation was necessary for all patients and 30% of them underwent tracheostomy. Common symptoms included stiffness and pain, most frequently affecting multiple locations (70%), with the hips and shoulders being predominantly involved. X-rays were the most commonly used imaging modality, followed by computed tomography. Although treatment was given, some of the patients continued to experience symptoms, particularly stiffness. Conclusion: 20 patients who developed heterotopic ossification after COVID-19 have been reported, the majority of which had at least two independent risk factors for this condition. The link between those two clinical entities is therefore uncertain, requiring further investigation. It is nonetheless important to suspect heterotopic ossification in patients with severe COVID-19 infection, prolonged immobilisation, mechanical ventilation, who develop joint pain and stiffness, as this condition can significantly impact patients' quality of life. Protocol registration: CRD42023393516. [ABSTRACT FROM AUTHOR]

A non-structural SARS-CoV-2 protein, PLpro, is involved in post-translational modifications in cells, allowing the evasion of antiviral immune response mechanisms. In this study, potential PLpro inhibitory drugs were designed using QSAR, molecular docking, and molecular dynamics. A combined QSAR equation with physicochemical and Free-Wilson descriptors was formulated. The r2, q2, and r2test values were 0.833, 0.770, and 0.721, respectively. From the equation, it was found that the presence of an aromatic ring and a basic nitrogen atom is crucial for obtaining good antiviral activity. Then, a series of structures for the binding sites of C111, Y268, and H73 of PLpro were created. The best compounds were found to exhibit pIC50 values of 9.124 and docking scoring values of −14 kcal/mol. The stability of the compounds in the cavities was confirmed by molecular dynamics studies. A high number of stable contacts and good interactions over time were exhibited by the aryl-thiophenes Pred14 and Pred15, making them potential antiviral candidates. [ABSTRACT FROM AUTHOR]

Immunomodulatory therapy has been extensively studied in randomized clinical trials for the treatment of patients hospitalized for COVID-19 with inconsistent findings. Guideline committees, reviewing the same clinical trial data, have generated different recommendations for immunomodulatory therapy. We hypothesize that trial design differences, specifically whether the study utilized an open-label or placebo-controlled design, accounted for the inconsistent mortality effects reported in clinical trials of immunomodulator therapies for COVID-19. We reviewed COVID-19 treatment guidelines (World Health Organization [WHO], Infectious Diseases Society of America [IDSA] and The National Institutes of Health [NIH]) and identified the meta-analyses associated with glucocorticoids, IL-6 inhibitors, JAK kinase inhibitors, and complement C5a inhibitors that were available to the guideline authors at the time recommendations were either made or updated. We identified a meta-analysis for each of the immunomodulator classes that are included in current COVID-19 treatment guidelines: glucocorticoids [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499–518] (cited 419), IL-6 antagonists [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499–518] (cited 419), JAK inhibitors [Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, et al. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022;6:CD015209] (cited 34), and complement C5a inhibitors [Tsai CL, Lai CC, Chen CY, Lee HS. The efficacy and safety of complement C5a inhibitors for patients with severe COVID-19: A systematic review and meta-analysis. Expert Rev Anti Infect Ther. 2023;21:77–86] (cited 1). Using the same randomized clinical trials, we evaluated the four meta-analyses accounting for trial design: placebo-controlled or open-label. Glucocorticoids (Risk Ratio [RR] 0.91 [95% CI, 0.49–1.69]), IL-6 inhibitors sarilumab (RR 1.17 [95% CI, 0.96–01.43]), and tocilizumab (RR 0.95 [95% CI, 0.76–1.19]) did not reduce mortality in placebo-controlled trials, whereas baricitinib did confer a large survival benefit (RR 0.65 [95% CI, 0.52–0.81]). The complement C5a inhibitor, vilobelimab, also reduced mortality in a single placebo-controlled trial (RR 0.76 [95% CI, 0.57–1.0]). Placebo-controlled trial evidence indicates that baricitinib should be the first choice immunomodulator for patients hospitalized for COVID-19 who require any form of oxygen support—low- or high-flow oxygen, non-invasive or invasive ventilation. Vilobelimab warrants study in a large placebo-controlled trial. Treatment guidelines for future pandemics should prioritize the results of placebo-controlled trials. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has had an enormous impact on the experiences of patients across all health disciplines, especially those of cancer patients. The study aimed to understand the experiences of cancer patients who underwent surgery during the first two waves of the pandemic at Guy’s Cancer Centre, which is a large tertiary cancer centre in London. Methods: A mixed-methods approach was adopted for this study. Firstly, a survey was co-designed by the research team and a patient study group. Patients who underwent surgery during the COVID-19 pandemic were invited to take part in this survey. Results were analysed descriptively. Three discussion groups were then conducted to focus on the main themes from the survey findings: communication, COVID-19 risk management and overall experience. These discussion groups were transcribed verbatim and underwent a thematic analysis using the NVivo software package. Results: Out of 1657 patients invited, a total of 250 (15%) participants took part in the survey with a mean age of 66 (SD 12.8) and 52% females. The sample was representative of a wide range of tumour sites and was reflective of those invited to take part. Overall, the experience of the cancer patients was positive. They felt that the safety protocols implemented at the hospital were effective. Communication was considered key, and patients were receptive to a change in the mode of communication from in-person to virtual. Conclusions: Despite the immense challenges faced by our Cancer Centre, patients undergoing surgery during the first two waves of the COVID-19 pandemic had a generally positive experience with minimal disruptions to their planned surgery and ongoing care. Together with the COVID-19 safety precautions, effective communication between the clinical teams and the patients helped the overall patient experience during their surgical treatment. [ABSTRACT FROM AUTHOR]

Introduction During the COVID-19 pandemic, a significant number of individuals experienced persistent symptoms, collectively termed post-COVID-19 condition (PCC) by the World Health Organization. While civilian prevalence has been extensively studied, little is known about PCC in military personnel. This article highlights the need for increased awareness, documentation, and research on PCC within the military context, utilizing the Defense Health Agency database. Materials and Methods A keyword search of the PubMed, CINAHL, and Web of Science databases was performed utilizing the keywords: military, post-COVID conditions, long COVID-19, and post-COVID19 syndrome. A five-stage integrative review framework was used to analyze 40 reports and research articles published from 2019 to 2023 to assess the current state of PCC research, including epidemiology, severe acute respiratory syndrome coronavirus 2 variants, pathophysiology, and prevalence in military personnel. Results Our review revealed a notable gap in research on PCC within the military population, with only a few mentions in the literature. A key finding was the association between immunization status, symptom severity, and ethnicity in PCC development. Conclusion To comprehensively address PCC in military personnel, it is imperative to foster both awareness and documentation. Creating a centralized Defense Health Agency-DoD repository for active duty service members with PCC diagnoses offers a valuable opportunity to conduct trend analysis, identify missed cases, and better understand the individual and military readiness implications of this condition. Additionally, to address the educational needs of clinicians, it is essential to develop continuing medical education and continuing nursing education programs focusing on PCC signs, symptoms, and their impact on readiness. Furthermore, randomized controlled trials and longitudinal experimental clinical trials are essential for monitoring service members over time, providing valuable insights into the course of PCC and potential interventions. These research endeavors collectively contribute to improving the health, readiness, and care of military personnel affected by PCC. [ABSTRACT FROM AUTHOR]

Background: The causative agent of the COVID‐19 pandemic, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is of zoonotic origin and has shown reverse zoonotic transmissibility. Objectives: The aim of this cross‐sectional study was to investigate the serological and molecular prevalence of SARS‐CoV‐2 infection in the domestic cat (Felis catus) population from Latvia in natural conditions and subsequently perform viral genome analysis. Methods: Oropharyngeal and rectal swabs and blood samples were collected from 273 domestic cats during the second wave of COVID‐19 infection in Latvia. Molecular prevalence was determined by using reverse transcriptase‐polymerase chain reaction (RT‐PCR). Serum samples were analysed via double antigen enzyme‐linked immunosorbent assay targeting the antibody against the nucleocapsid protein of SARS‐CoV‐2. Positive swab samples were analysed using whole viral genome sequencing and subsequent phylogenetic analysis of the whole genome sequencing data of the samples was performed. Results: The overall SARS‐CoV‐2 RT‐PCR positivity and seroprevalence was 1.1% (3/273) and 2.6% (7/273), respectively. The SARS‐CoV‐2 genome sequences from three RT‐PCR positive cats were assigned to the three common lineages (PANGOLIN lineage S.1.; B.1.177.60. and B.1.1.7.) circulating in Latvia during the particular period of time. Conclusions: These findings indicate that feline infection with SARS‐CoV‐2 occurred during the second wave of the COVID‐19 pandemic in Latvia, yet the overall prevalence was low. In addition, it seems like no special 'cat' pre‐adaptations were necessary for successful infection of cats by the common lineages of SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

The aim of this scoping review was to examine the national and international literature on the response of adult Hospital at Home (HAH) services to the global Covid-19 pandemic and explore key themes to emerge and make recommendations for further research. The databases were searched using agreed search terms and Arksey and O'Malley's scoping review framework was utilized and papers were identified and analyzed for common themes. Thirty-one papers were included in the review. Of the papers included, general adult medicine was the largest service group (n = 15) with geriatric services the next largest (n = 12). Most papers were European in origin (n = 19). Key themes to emerge include (1) similar outcomes for HAH patients compared with traditional inpatient care, (2) expansion of capacity for inpatient care due to HAH use, (3) growth of virtual monitoring in HAH setting, (4) reduction in infection transmission in HAH setting, and (5) cost reduction due to HAH utilization. Hospital at home demonstrated good outcomes for both patients with Covid-19 and other conditions during the pandemic. These services also expanded capacity during a global healthcare crisis. Remote monitoring played a major role in the expansion of capacity and the reduction of infection transmission during the pandemic. Although some papers discuss how HAH is more cost effective than traditional hospital, more work is needed around this as many of the patients may not have been as sick as those admitted to traditional hospital during the pandemic. [ABSTRACT FROM AUTHOR]

In the last twenty years, three deadly zoonotic coronaviruses (CoVs)—namely, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2—have emerged. They are considered highly pathogenic for humans, particularly SARS-CoV-2, which caused the 2019 CoV disease pandemic (COVID-19), endangering the lives and health of people globally and causing unpredictable economic losses. Experiments on wild-type viruses require biosafety level 3 or 4 laboratories (BSL-3 or BSL-4), which significantly hinders basic virological research. Therefore, the development of various biosafe CoV systems without virulence is urgently needed to meet the requirements of different research fields, such as antiviral and vaccine evaluation. This review aimed to comprehensively summarize the biosafety of CoV engineering systems. These systems combine virological foundations with synthetic genomics techniques, enabling the development of efficient tools for attenuated or non-virulent vaccines, the screening of antiviral drugs, and the investigation of the pathogenic mechanisms of novel microorganisms. [ABSTRACT FROM AUTHOR]

People living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccines, but fewer studies have examined cellular immune responses to the vaccinations. Here, we used an activation-induced marker (AIM) assay to quantify SARS-CoV-2 spike-specific CD4+ and CD8+ T cells generated by two and three doses of COVID-19 vaccines in 50 PLWH receiving antiretroviral therapy, compared to 87 control participants without HIV. In a subset of PLWH, T-cell responses were also assessed after post-vaccine breakthrough infections and/or receipt of a fourth vaccine dose. All participants remained SARS-CoV-2 infection-naive until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to a Nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 control participants after the third vaccine dose. Multivariable regression analyses were used to investigate the relationships between sociodemographic, health- and vaccine-related variables, vaccine-induced T-cell responses, and breakthrough infection risk. We observed that a third vaccine dose boosted spike-specific CD4+ and CD8+ T-cell frequencies significantly above those measured after the second dose (all p < 0.0001). Median T-cell frequencies did not differ between PLWH and controls after the second dose (p > 0.1), but CD8+ T-cell responses were modestly lower in PLWH after the third dose (p = 0.02), an observation that remained significant after adjusting for sociodemographic, health- and vaccine-related variables (p = 0.045). In PLWH who experienced a breakthrough infection, median T-cell frequencies increased even higher than those observed after three vaccine doses (p < 0.03), and CD8+ T-cell responses in this group remained higher even after a fourth vaccine dose (p = 0.03). In multivariable analyses, the only factor associated with an increased breakthrough infection risk was younger age, which is consistent with the rapid increase in SARS-CoV-2 seropositivity that was seen among younger adults in Canada after the initial appearance of the Omicron variant. These results indicate that PLWH receiving antiretroviral therapy mount strong T-cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection. [ABSTRACT FROM AUTHOR]

It has not yet been fully established that there is coronavirus disease 2019 (COVID-19) involvement in the synovial fluid and it remains a topic of debate. The aim of this study was to evaluate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in knee joint synovial fluid of patients with COVID-19. This retrospective study was conducted with an initial screening of patients who were admitted to a tertiary pandemic hospital due to COVID-19 symptoms, and underwent treatment for COVID-19 between March and June 2020. A total of 2476 patients were hospitalized or received treatment for a possible diagnosis of COVID-19. While the RT-PCR test was positive in 318 patients (12.8%), 2158 (87.2%) were computed tomography positive but reverse transcription-polymerase chain reaction (RT-PCR) negative. Twelve patients were consulted due to acute joint effusion. Of five patients with knee joint effusion and a positive RT-PCR test, the synovial tissue RT-PCR test was positive in only one patient. This paper is the first to show the presence of SARS-CoV-2 in synovial fluid. This can be considered of importance for the determination and elimination of the route of transmission, thereby preventing further development and spread of the disease. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is the virus that causes the new global pandemic, which has already resulted in millions of deaths, affecting the world's health and economy. Probiotics have shown benefits in a variety of diseases, including respiratory infections, and may be beneficial in the adjunctive treatment of COVID-19. This study analyzed the effectiveness of probiotics as adjunctive treatment in reducing symptoms of patients with COVID-19, through a systematic review with meta-analysis. The EMBASE (Elsevier), Pubmed, Scopus, Web of Science and International Clinical Trials Registry Platform (ICTRP) were searched through March 16, 2022. The risk ratio (RR) with 95% confidence intervals (CIs) was estimated using a fixed-effect model. RoB 2 and ROBINS I were used to assess the risk of bias of the included studies. Nine studies were included (7 clinical trials and 2 cohorts), of which three clinical trials comprised the meta-analysis. Results showed that probiotics were associated with a significant 51% reduction in symptoms reported by COVID-19 patients (RR 0.49, 95% CI 0.40–0.61). There was a significant improvement in cough (RR 0.56, 95% CI 0.37–0.83), headaches (RR 0.17, 95% CI 0.05–0.65), and diarrhea (RR 0. 33, 95% CI 0.12–0.96) of patients on probiotic therapy. These findings suggest that probiotic supplementation is effective in improving symptoms of COVID-19. [ABSTRACT FROM AUTHOR]

Scientists and researchers have been searching for drugs targeting the main protease (Mpro) of SARS-CoV-2, which is crucial for virus replication. This study employed a virtual screening based on molecular docking to identify benzoylguanidines from an in-house chemical library that can inhibit Mpro on the active site and three allosteric sites. Molecular docking was performed on the LaSMMed Chemical Library using 88 benzoylguanidine compounds. Based on their RMSD values and conserved pose, three potential inhibitors (BZG1, BZG2, and BZG3) were selected. These results indicate that BZG1 and BZG3 may bind to the active site, while BZG2 may bind to allosteric sites. Molecular dynamics data suggest that BZG2 selectively targets allosteric site 3. In vitro tests were performed to measure the proteolytic activity of rMpro. The tests showed that BZG2 has uncompetitive inhibitory activity, with an IC50 value of 77 µM. These findings suggest that benzoylguanidines possess potential as Mpro inhibitors and pave the way towards combating SARS-Cov-2 effectively. [ABSTRACT FROM AUTHOR]

Pregnant persons are at increased risk of severe COVID-19 illness. Bivalent mRNA COVID-19 vaccination is recommended for everyone, including pregnant persons. However, data are limited on the safety of bivalent mRNA COVID-19 vaccination during pregnancy. To evaluate and summarize reports to the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system, among pregnant persons who received bivalent mRNA COVID-19 vaccine. VAERS U.S. reports of adverse events (AEs) in pregnant persons who received the bivalent mRNA COVID-19 vaccine from 9/1/2022–03/31/2023 were identified. Clinicians reviewed all reports and available medical records. AEs of these reports were compared with AEs reported to VAERS following monovalent mRNA COVID-19 booster vaccination in pregnancy. VAERS received 136 reports for pregnant persons who received bivalent mRNA COVID-19 vaccine; 87 (64 %) after BNT162b2 (Pfizer-BioNTech), and 48 (35 %) after mRNA-1273 (Moderna); 28 (20.6 %) reports were classified as serious. The most common pregnancy-specific outcomes reported included 12 (8.8 %) spontaneous abortions (<20 weeks gestation), 6 (4.4 %) episodes of preterm delivery, and 5 (3.7 %) reports of preeclampsia. One stillbirth (≥20 weeks gestation) was reported. No maternal or infant deaths were reported. There were 6 reports of AEs in infants, which included 3 reports of admissions to the neonatal intensive care unit: two infants with low birth weight, and one infant with a patent ductus arteriosus and patent foramen ovale. Non-pregnancy-specific adverse events were mostly COVID-19 infection and systemic reactions (e.g., headache, fatigue). Pregnancy-specific conditions were reported less frequently after bivalent mRNA COVID-19 vaccination compared to monovalent mRNA COVID-19 booster vaccination (3rd and 4th dose). Based on this review of reports to VAERS, the safety profile of bivalent mRNA COVID-19 vaccination in pregnant persons was comparable to that observed for monovalent mRNA COVID-19 booster vaccination (3rd and 4th dose) in pregnant persons. [ABSTRACT FROM AUTHOR]

• Estimates incidence of COVID-19 infection, hospitalization, & deaths in Japan. • Examines potential impact of Fall 2023 COVID-19 vaccine on clinical outcomes. • Target population for COVID-19 vaccination is adults ≥18 years in Japan. • Fall 2023 vaccine may reduce COVID-19 infections, hospitalizations, & deaths. The study objective was to estimate the incidence of COVID-19 infection, hospitalization, and deaths in Japan from September 2023 to August 2024 and potential impact of a monovalent XBB.1.5 variant–adapted Fall 2023 COVID-19 vaccine (modified version: XBB monovalent) for adults aged ≥18 years on these outcomes. A previously developed Susceptible-Exposed-Infected-Recovered model for the United States (US) was adapted to Japan. The numbers of symptomatic infections, COVID-19–related hospitalizations, and deaths were calculated. Given differences in vaccination coverage, masking practices and social mixing patterns between the US and Japan, all inputs were updated to reflect the Japanese context. Vaccine effectiveness (VE) values are hypothetical, but predicted based on existing VE values of bivalent BA.4/BA.5 boosters against BA.4/BA.5 in Japan, from the VERSUS test-negative case-control study. Sensitivity analyses were performed. The base case model predicts overall that there will be approximately 35.2 million symptomatic COVID-19 infections, 690,000 hospitalizations, and 62,000 deaths in Japan between September 2023 and August 2024. If an updated COVID-19 vaccine is offered to all adults aged 18 years and older in Fall 2023, the model predicts that 7.3 million infections, 275,000 hospitalizations and 26,000 deaths will be prevented. If vaccines are only given to those aged 65 years and older, only 2.9 million infections, 180,000 hospitalizations and 19,000 deaths will be prevented. Sensitivity analysis results suggest that hospitalizations and deaths prevented are most sensitive to initial VE against infection and hospitalizations, and the waning rate associated with VE against infection. Symptomatic infections prevented was most sensitive to initial VE against infection and VE waning. Results suggest that a Fall 2023 COVID-19 vaccine would reduce total numbers of COVID-19–related infections, hospitalizations, and deaths. [ABSTRACT FROM AUTHOR]

Objective: The novel coronavirus caused a disease that mainly affected the respiratory system. The effect of severe acute respiratory syndrome coronavirus 2 on the hypot halam ic–pi tuita ry–ad renal axis is unknown. This study assesses the prognostic accuracy of serum cortisol levels and prediction tools in predicting mortality rates in patients with coronavirus disease 2019 (COVID-19). Methods: We prospectively analyzed 106 inpatients (53 COVID-19 positive, 53 non-COVID-19; mean 59.9 ± 17.3 years; 38 males and 68 females) with serum cortisol and adrenocorticotropic hormone levels compared with prognostic scores. Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores determined the disease’s severity. The predictive value of serum cortisol, APACHE, and SOFA on mortality was assessed using receiver operating characteristic curve analysis and the area under the curve (AUC). Results: No significant age or sex differences were found between groups. Serum cortisol levels were similar. The APACHE-II scores in the COVID-19 group were higher than in the other group, while SOFA scores showed no significant difference. The AUC for the APACHE-II score in predicting mortality was 0.765 (95% CI 0.672-0.842), with an optimal cutoff (>9) demonstrating 62.5% sensitivity and 86.7% specificity for overall participants. No correlation was found between serum cortisol levels and prediction tools such as APACHE-II and SOFA. Conclusion: The measurement of serum cortisol did not provide additional prognostic information beyond that established by the APACH-II score. This study highlights the significance of assessing novel prognostic tools for predicting outcomes in hospitalized patients with COVID-19. [ABSTRACT FROM AUTHOR]

As for all single-stranded, positive-sense RNA (+RNA) viruses, intracellular RNA synthesis relies on extensive remodeling of host cell membranes that leads to the formation of specialized structures. In the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus causing COVID-19, endoplasmic reticulum membranes are modified, resulting in the formation of double-membrane vesicles (DMVs), which contain the viral dsRNA intermediate and constitute membrane-bound replication organelles. The non-structural and transmembrane protein nsp3 is a key player in the biogenesis of DMVs and, therefore, represents an interesting antiviral target. However, as an integral transmembrane protein, it is challenging to express for structural biology. The C-terminus of nsp3 encompasses all the membrane-spanning, -interacting, and -remodeling elements. By using a cell-free expression system, we successfully produced the C-terminal region of nsp3 (nsp3C) and reconstituted puri fied nsp3C into phospholipid nanodiscs, opening the way for structural studies. Negativestain transmission electron microscopy revealed the presence of nsp3C oligomers very similar to the region abutting and spanning the membrane on the cytosolic side of DMVs in a recent subtomogram average of the SARS-CoV-2 nsp3-4 pore (1). AlphaFoldpredicted structural models fit particularly well with our experimental data and support a pore-forming hexameric assembly. Altogether, our data give unprecedented clues to understand the structural organization of nsp3, the principal component that shapes the molecular pore that spans the DMVs and is required for the export of RNA in vivo. IMPORTANCE Membrane remodeling is at the heart of intracellular replication for single-stranded, positive-sense RNA viruses. In the case of coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), this leads to the formation of a network of double-membrane vesicles (DMVs). Targeting DMV biogenesis offers promising prospects for antiviral therapies. This requires a better understanding of the molecular mechanisms and proteins involved. Three non-structural proteins (nsp3, nsp4, and nsp6) direct the intracellular membrane rearrangements upon SARS-CoV-2 infection. All of them contain transmembrane helices. The nsp3 component, the largest and multi-functional protein of the virus, plays an essential role in this process. Aiming to understand its structural organization, we used a cell-free protein synthesis assay to produce and reconstitute the C-terminal part of nsp3 (nsp3C) including transmembrane domains into phospholipid nanodiscs. Our work reveals the oligomeric organization of one key player in the biogenesis of SARS-CoV-2 DMVs, providing basis for the design of future antiviral strategies. [ABSTRACT FROM AUTHOR]

Aims: Adherence to pharmacological interventions in clinical trials is crucial for accurate identification of beneficial and adverse outcomes. The ways in which adherence to interventions should be reported in trial publications are described in the Template for Intervention Description and Replication (TIDieR), a 12‐item extension of the Consolidated Standards of Reporting Trials reporting guidelines. The objective of this study was to assess compliance with TIDieR Items 11 and 12 of randomized controlled trials (RCTs) of interventions in SARS‐CoV‐2 infection published in 5 selected journals during 2021. Methods: We assessed pharmacological interventions for SARS‐CoV‐2 infection reported in RCTs published in 2021 in the Annals of Internal Medicine, The BMJ, JAMA, The Lancet and The New England Journal for Medicine for compliance with TIDieR items addressing intervention adherence (Items 11 and 12). We calculated proportional adherence for pharmacological and comparator interventions where available. Results: We found 75 eligible RCTs. Twenty‐eight (37%) reported results of SARS‐CoV‐2 vaccinations. Compliance with Items 11 and 12 could be assessed in 71 of these 75. Of the 71 RCTs, 37 (52%) reported how adherence was assessed (Item 11), and 70 reported adherence rates (Item 12). Only 1 of the 71 RCTs (1.4%, 0–7.6%) fully complied with TIDieR Items 11 and 12. Conclusion: Half of RCTs of SARS‐CoV‐2 pharmacological interventions published in leading medical journals in 2021 complied with reporting of how adherence assessments were made and almost none complied with both TIDieR Items 11 and 12. The implications for interpretation, application and replication of findings based on these publications warrant consideration. [ABSTRACT FROM AUTHOR]

Aims To monitor severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA contamination in vehicles operating in England during the pandemic, to better understand transmission risk of SARS-CoV-2 on public transport. Methods and results We collected 1314 surface samples between December 2020 and April 2022 on trains and buses managed by five different transport operators. The presence of SARS-CoV-2 RNA was investigated through reverse transcription polymerase chain reaction (RT-PCR). SARS-CoV-2 RNA was found on 197 (15%) of the 1314 surfaces sampled, including seat head rests, handholds, and air extract grilles, but the levels of RNA recovered on those samples (median value of 23.4, interquartile range: 14.3–35.4, N gene copies per extraction) made the presence of infectious virus at the time of sampling extremely unlikely. However, detection rates varied over time with peaks broadly coinciding with times of high community transmission, when it was more likely that people infected with SARS-CoV-2 were travelling on public transport. Conclusion During the pandemic, and as in other public spaces, low levels of SARS-CoV-2 RNA were found on surfaces associated with public transport. [ABSTRACT FROM AUTHOR]

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a member of a class of highly pathogenic coronaviruses. The large family of coronaviruses, however, also includes members that cause only mild symptoms, like human coronavirus‐229E (HCoV‐229E) or OC43 (HCoV‐OC43). Unravelling how molecular (and cellular) pathophysiology differs between highly and low pathogenic coronaviruses is important for the development of therapeutic strategies. Methods: Here, we analysed the transcriptome of primary human bronchial epithelial cells (PBEC), differentiated at the air–liquid interface (ALI) after infection with SARS‐CoV‐2, SARS‐CoV, Middle East Respiratory Syndrome (MERS)‐CoV and HCoV‐229E using bulk RNA sequencing. Results: ALI‐PBEC were efficiently infected by all viruses, and SARS‐CoV, MERS‐CoV and HCoV‐229E infection resulted in a largely similar transcriptional response. The response to SARS‐CoV‐2 infection differed markedly as it uniquely lacked the increase in expression of immediate early genes, including FOS, FOSB and NR4A1 that was observed with all other coronaviruses. This finding was further confirmed in publicly available experimental and clinical datasets. Interfering with NR4A1 signalling in Calu‐3 lung epithelial cells resulted in a 100‐fold reduction in extracellular RNA copies of SARS‐CoV‐2 and MERS‐CoV, suggesting an involvement in virus replication. Furthermore, a lack in induction of interferon‐related gene expression characterised the main difference between the highly pathogenic coronaviruses and low pathogenic viruses HCoV‐229E and HCoV‐OC43. Conclusion: Our results demonstrate a previously unknown suppression of a host response gene set by SARS‐CoV‐2 and confirm a difference in interferon‐related gene expression between highly pathogenic and low pathogenic coronaviruses. [ABSTRACT FROM AUTHOR]

Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC50, CC50) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios of reported unbound peak plasma concentrations, (Cmax)/EC50, were used to predict the potential in vivo efficacy. The 20 drugs with the highest ratios were retested in human Calu-3 and Caco-2 cells, and their CC50 was determined in an expanded panel of cell lines. Many of the 20 drugs with the highest ratios were inactive in human Calu-3 and Caco-2 cells. Antivirals effective in controlled clinical trials had unbound Cmax/EC50 ≥ 6.8 in Calu-3 or Caco-2 cells. EC50 of nucleoside analogs were cell dependent. This approach and earlier availability of more relevant cultures could have reduced the number of unwarranted clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: The interferon pathway plays a critical role in triggering the immune response to SARS-CoV-2, and these gene variants may be involved in the severity of COVID-19. This study aimed to analyze the frequency of three gene variants of OAS and RNASEL with the occurrence of COVID-19 symptoms and disease outcome. Methods: This cross-sectional study included 104 patients with SARS-CoV-2 infection, of which 34 were asymptomatic COVID-19, and 70 were symptomatic cases. The variants rs486907 (RNASEL), rs10774671 (OAS1), rs1293767 (OAS2), and rs2285932 (OAS3) were screened and discriminated using a predesigned 5′-nuclease assay with TaqMan probes. Results: Patients with the allele C of the OAS2 gene rs1293767 (OR = 0.36, 95% CI: 0.15–0.83, p = 0.014) and allele T of the OAS3 gene rs2285932 (OR = 0.39, 95% CI: 0.2–0.023, p = 0.023) have lower susceptibility to developing symptomatic COVID-19. The genotype frequencies (G/G, G/C, and C/C) of rs1293767 for that comparison were 64.7%, 29.4%, and 5.9% in the asymptomatic group and 95.2%, 4.8%, and 0% in severe disease (p < 0.05). Conclusions: Our data indicate that individuals carrying the C allele of the OAS2 gene rs1293767 and the T allele of the OAS3 gene rs2285932 are less likely to develop symptomatic COVID-19, suggesting these genetic variations may confer a protective effect among the Mexican study population. Furthermore, the observed differences in genotype frequencies between asymptomatic individuals and those with severe disease emphasize the potential of these variants as markers for disease severity. These insights enhance our understanding of the genetic factors that may influence the course of COVID-19 and underscore the potential for genetic screening in identifying individuals at increased risk for severe disease outcomes. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion New tools have been developed to distinguish the COVID‐19 diagnosis from other viral infections presenting similar symptomatology and mitigate the lack of sensitivity of molecular testing. We previously identified a specific “sandglass” aspect on the white blood cells (WBC) scattergram of COVID‐19 patients, as a highly reliable COVID‐19 screening test (sensitivity: 85.9%, specificity: 83.5% and positive predictive value: 94.3%). We then decided to validate our previous data in a multicentric study.This retrospective study involved 817 patients with flu‐like illness, among 20 centers, using the same CBC instrument (XN analyzer, SYSMEX, Japan). After training, one specialist per center independently evaluated, under the same conditions, the presence of the “sandglass” aspect of the WDF scattergram, likely representing plasmacytoid lymphocytes.Overall, this approach showed sensitivity: 59.0%, specificity: 72.9% and positive predictive value: 77.7%. Sensitivity improved with subgroup analysis, including in patients with lymphopenia (65.2%), patients presenting symptoms for more than 5 days (72.3%) and in patients with ARDS (70.1%). COVID‐19 patients with larger plasmacytoid lymphocyte cluster (>15 cells) more often have severe outcomes (70% vs. 15% in the control group).Our findings confirm that the WBC scattergram analysis could be added to a diagnostic algorithm for screening and quickly categorizing symptomatic patients as either COVID‐19 probable or improbable, especially during COVID‐19 resurgence and overlapping with future influenza epidemics. The observed large size of the plasmacytoid lymphocytes cluster appears to be a hallmark of COVID‐19 patients and was indicative of a severe outcome. Furthers studies are ongoing to evaluate the value of the new hematological parameters in combination with WDF analysis. [ABSTRACT FROM AUTHOR]

Objective: To identify all post-BNT162b2 vaccination (BioNTech and Pfizer) events during the ensuing 12 months in patients with systemic lupus erythematosus (SLE) from the Immuno-Rheumatology Department at Cayetano Heredia Hospital's cohort, Lima, Perú. Methods: A 12-month follow-up study was conducted from the first dose of immunization with the BNT162b2 vaccine, which was given between May and June 2021, to SLE patients from this cohort. Results: The initial population was constituted by 100 patients (100 patients received the 1st dose, 90 the 2nd dose, and 85 the 3rd dose of this vaccine); 33 patients presented a SLE reactivation (flare), 9% (9/100) post 1st dose, 26.6% (24/90) post 2nd dose, and 16.4% (14/85) post 3rd dose. The most common types of flare were articular (26) and renal (14) with 5/33 (15.1%) requiring hospitalization for flare management. A negative association with flare occurrence was found between the use of hydroxychloroquine RR 0.43 (0.21–0.85) and the opposite was the case for azathioprine RR 2.70 (1.39–5.25). During follow-up, 26 patients developed SARS-CoV-2 infection of whom three required hospitalization, one of whom died. Conclusions: 33 of 100 SLE patients immunized with BNT162b2 vaccine against SARS-CoV-2, presented SLE flares (47 episodes in total); 5 of these patients required in-hospital management and all fully recovered; 26 patients had SARS-CoV-2 infection; three required hospitalization, one died. [ABSTRACT FROM AUTHOR]

Objective: Despite an increasing number of studies, there is as yet no definite treatment developed for the coronavirus disease 2019 (COVID-19). In this clinical trial, we examined the efficacy of a novel herbal antiviral preparation in critically ill COVID-19 patients. Materials and Methods: A total number of 120 ICU-admitted patients with a diagnosis of COVID-19 pneumonia were recruited to the trial. Participants were equally randomized to receive either the novel antiviral preparation sublingually, for up to two consecutive weeks or till discharge, or placebo. Clinical and laboratory parameters as well as survival rates were compared between the two groups. Results: The cumulative incidence of death throughout the study period was 8.33% in the intervention group and 60% in the placebo group (risk ratio: 0.14; 95% confidence interval [CI], 0.05 to 0.32; p<0.001). On day 7, several parameters including white blood cells (WBCs) count, C-reactive protein, and SpO2 were improved for the treatment group compared with the placebo group (p-values of 0.05, 0.01, and <0.001, respectively). Conclusion: This preparation might be suggested as a potentially promising COVID-19 treatment. [ABSTRACT FROM AUTHOR]

Aim: To systematically review the evidence on Covid‐19 infection risk, severity and vaccination uptake among children and adolescents by socioeconomic status. Methods: We conducted a systematic literature review, using the PubMed database. We searched for articles published from January 2020 to January 2022 using "MeSH" words and titles. The key terms were "COVID", "social status", "socioeconomic factor" and "children". We also searched secondary sources such as published reports and other databases. Results: The search identified 15 relevant articles and reports. This review shows that children of lower socioeconomic status have a higher risk of COVID‐19 infection and a higher risk of being hospitalised. Mortality in a global setting was also higher in children with low socioeconomic status, though not observed in high‐resourced countries. These children are also less likely to be vaccinated against the SARS‐CoV‐2 virus. Conclusions: The higher risk of COVID‐19 infection and hospitalisation and lower vaccination coverage in children and adolescents from lower socioeconomic backgrounds demonstrate health disparities also in young age. These disparities should inform health authorities in planning for future pandemics. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization has declared Omicron as the fifth variant of concern with more than 50 mutations, particularly in the spike protein. Given increased viral infectivity due to mutations, worldwide genomic surveillance and detection of severe acute respiratory syndrome 2 (SARSCoV- 2) is essential. The present study aimed to track Omicron lineage BA.2.40 in West Kalimantan, Indonesia. Methods: In May-August 2022, nasopharyngeal swab samples (n=3,642) were collected from international travelers to West Kalimantan (active surveillance), and patients hospitalized due to SARS-CoV-2 infection (baseline surveillance). The samples were tested for Omicron lineages based on ORF1ab, N, and HV69-70del genes, followed by whole-genome sequencing. The sequences were then identified using two genomic databases, aligned against the reference genome (Wuhan/Hu-1/2019), and then compared with BA.2.40 lineage detected across the world. Phylogenetic analysis between the samples and other SARS-CoV-2 isolates was performed using molecular evolutionary genetics analysis software. Results: Based on the genomic databases, 10 isolates were identified as BA.2.40. All samples tested positive for the ORF1ab and N genes, but negative for the HV69-70del gene, which is a marker to detect the Omicron variant. Phylogenetic analysis showed the isolates were closely related to an isolate from Malaysia, an area dominated by BA.2.40. Conclusion: Omicron lineage BA.2.40 has no HV69-70 deletion in the spike protein, a marker used to screen for the Omicron variant. BA.2.40 showed a high similarity to an isolate from Malaysia and was detected only during certain periods, indicating the effect of internationally imported cases. [ABSTRACT FROM AUTHOR]

Coronaviruses are highly transmissible and pathogenic viruses for humans and animals. The vast quantity of information collected about SARS-CoV-2 during the pandemic helped to unveil details of the mechanisms behind the infection, which are still largely elusive. Recent research demonstrated that different class I/II human leukocyte antigen (HLA) alleles might define an individual susceptibility to SARS-CoV-2 spreading, contributing to the differences in the distribution of the infection through different populations; additional studies suggested that the homolog of the HLA in cats, the feline leukocyte antigen (FLA), plays a pivotal role in the transmission of viruses. With these premises, this study aimed to exploit a bioinformatic approach for the prediction of the transmissibility potential of two distinct feline coronaviruses (FCoVs) in domestic cats (feline enteric coronavirus (FeCV) and feline infectious peritonitis virus (FIPV)) using SARS-CoV-2 as the reference model. We performed an epitope mapping of nonapeptides deriving from SARS-CoV-2, FeCV, and FIPV glycoproteins and predicted their affinities for different alleles included in the three main loci in class I FLAs (E, H, and K). The predicted complexes with the most promising affinities were then subjected to molecular docking and molecular dynamics simulations to provide insights into the stability and binding energies in the cleft. Results showed the FLA proteins encoded by alleles in the FLA-I H (H*00501 and H*00401) and E (E*01001 and E*00701) loci are largely responsive to several epitopes deriving from replicase and spike proteins of the analyzed coronaviruses. The analysis of the most affine epitope sequences resulting from the prediction can stimulate the development of anti-FCoV immunomodulatory strategies based on peptide drugs. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has necessitated rapid research to aid in the understanding of the disease and the development of novel therapeutics. One option is to conduct controlled human infection trials (CHITs). In this article I examine the history of deliberate human infection and CHITs and their utilization prior to the COVID-19 pandemic, key ethical considerations of CHITs in the COVID-19 setting, an analysis of the World Health Organization's (WHO) Key criteria for the ethical acceptability of COVID-19 human challenge studies, and a review of the two COVID-19 CHITs that have already commenced, their compliance with the WHO criteria and other ethical considerations. [ABSTRACT FROM AUTHOR]

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infections that were first detected in Wuhan, China, at the end of 2019 led to the state of the global COVID-19 pandemic declared by the World Health Organization in March 2020. Thus, the world faces a new challenge to control the spread of the virus. The pandemic highlighted the need for rapid detection of infections that would be able to accurately screen the population much more rapidly and economically than the gold standard molecular biology-based tools such as quantitative real-time reverse transcription polymerase chain reaction. Such screening measures would be able to isolate infected individuals, including those showing no symptoms, and provide early treatments before more serious complications develop, thus allowing for the spread of infections to be better controlled without the implementation of socioeconomically crippling lockdowns. In this review, we present a comprehensive overview of the major advances in the use of electrolyte-gated field effect transistor-based biosensors for the detection of viruses, including their use for SARS-CoV-2 detection. We describe the main types of bioreceptors used for the detection of viruses in general and those used for COVID-19 in detail. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome (SARS)-coronavirus (CoV), Middle Eastern respiratory syndrome (MERS)-CoV, and SARS-CoV-2 have seriously threatened human life in the 21st century. Emerging and re-emerging β-coronaviruses after the coronavirus disease 2019 (COVID-19) epidemic remain possible highly pathogenic agents that can endanger human health. Thus, pan-β-coronavirus vaccine strategies to combat the upcoming dangers are urgently needed. In this study, four LNP-mRNA vaccines, named O, D, S, and M, targeting the spike protein of SARS-CoV-2 Omicron, Delta, SARS-CoV, and MERS-CoV, respectively, were synthesized and characterized for purity and integrity. All four LNP-mRNAs induced effective cellular and humoral immune responses against the corresponding spike protein antigens in mice. Furthermore, LNP-mRNA S and D induced neutralizing antibodies against SARS-CoV and SARS-CoV-2, which failed to cross-react with MERS-CoV. Subsequent evaluation of sequential and cocktail immunizations with LNP-mRNA O, D, S, and M effectively elicited broad immunity against SARS-CoV-2 variants, SARS-CoV, and MERS-CoV. A direct comparison of the sequential with cocktail regimens indicated that the cocktail vaccination strategy induced more potent neutralizing antibodies and T-cell responses against heterotypic viruses as well as broader antibody activity against pan-β-coronaviruses. Overall, these results present a potential pan-β-coronavirus vaccine strategy for improved preparedness prior to future coronavirus threats. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is an infection caused by SARS-CoV-2. Genome-wide association studies (GWASs) have suggested a strong association of genetic factors with the severity of the disease. However, many of these studies have been completed in European populations, and little is known about the genetic variability of indigenous peoples' underlying infection by SARS-CoV-2. The objective of the study is to investigate genetic variants present in the genes AQP3, ARHGAP27, ELF5L, IFNAR2, LIMD1, OAS1 and UPK1A, selected due to their association with the severity of COVID-19, in a sample of indigenous people from the Brazilian Amazon in order to describe potential new and already studied variants. We performed the complete sequencing of the exome of 64 healthy indigenous people from the Brazilian Amazon. The allele frequency data of the population were compared with data from other continental populations. A total of 66 variants present in the seven genes studied were identified, including a variant with a high impact on the ARHGAP27 gene (rs201721078) and three new variants located in the Amazon Indigenous populations (INDG) present in the AQP3, IFNAR2 and LIMD1 genes, with low, moderate and modifier impact, respectively. [ABSTRACT FROM AUTHOR]

Severely ill patients with COVID-19 are challenging to sedate and often require high-dose sedation and analgesic regimens. Ketamine can be an effective adjunct to facilitate sedation of critically ill patients but its effects on sedation level and inflammation in COVID-19 patients have not been studied. This retrospective, observational cohort study evaluated the effect of ketamine infusions on inflammatory biomarkers and clinical outcomes in mechanically ventilated patients with SARS-CoV-2 infection. A total of 186 patients were identified (47 received ketamine, 139 did not). Patients who received ketamine were significantly younger than those who did not (mean (standard deviation) 59.2 (14.2) years versus 66.3 (14.4) years; P = 0.004), but there was no statistically significant difference in body mass index (P = 0.25) or sex distribution (P = 0.91) between groups. Mechanically ventilated patients who received ketamine infusions had a statistically significant reduction in Richmond Agitation-Sedation Scale score (–3.0 versus –2.0, P < 0.001). Regarding inflammatory biomarkers, ketamine was associated with a reduction in ferritin (P = 0.02) and lactate (P = 0.01), but no such association was observed for C-reactive protein (P = 0.27), lactate dehydrogenase (P = 0.64) or interleukin-6 (P = 0.87). No significant association was observed between ketamine administration and mortality (odds ratio 0.971; 95% confidence interval 0.501 to 1.882; P = 0.93). Ketamine infusion was associated with improved sedation depth in mechanically ventilated COVID-19 patients and provided a modest anti-inflammatory benefit but did not confer benefit with respect to mortality or intensive care unit length of stay. [ABSTRACT FROM AUTHOR]

The rapid genetic evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the coronavirus disease 2019 (COVID-19) pandemic has greatly challenged public health authorities worldwide, including in Mauritania. Despite the presence of the virus in Mauritania, only one study described its genomic variation during the course of the epidemic. The purpose of the present study was to document the genomic pattern of SARS-CoV-2 variants from clinical isolates during the COVID-19 outbreak in Mauritania, from September to November 2021. The whole genomes from 54 SARS-CoV-2 strains detected in nasopharyngeal swabs with a cycle threshold value ≤ 30 were successfully sequenced using next-generation sequencing (NGS) and the Illumina protocol. The mean genome coverage (±standard deviation) was 96.8% (±3.7). The most commonly identified clade was 21J (57.4%), followed by 21D (16.7%), 20A (11.1%), and 20B (9.2%). At the level of lineages, the majority of the samples were Delta variants with the sub-lineage AY.34 (or B.1.617.2.34). Among the 54 SARS-CoV-2 isolates that were successfully sequenced, 33 (61.1%) came from vaccinated individuals, and 21 (38.9%) were from unvaccinated individuals. Several SARS-CoV-2 variants were present in Mauritania between September and November 2021. As Mauritania, like many West African countries, is resource-limited regarding viral genome sequencing facilities, establishment of mutualized sub-regional sequencing platforms will be necessary to ensure continuous monitoring of mutations in viral genomes and track potential reduction in COVID-19 vaccine efficacy, increased transmissibility, and disease severity. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has been a major challenge worldwide for the past years with high morbidity and mortality rates. While vaccination was the cornerstone to control the pandemic and disease spread, concerns regarding safety and adverse events (AEs) have been raised lately. A cross-sectional study was conducted between January 1st and January 22nd, 2022, in six Arabic countries namely Saudi Arabia, Egypt, Syria, Libya, Iraq, and Algeria. We utilized a self-administered questionnaire validated in Arabic which encompassed two main parts. The first was regarding sociodemographic data while the second was about COVID-19 vaccination history, types, doses, and experienced AEs. A multistage sampling was employed in each country, involving the random selection of three governorates from each country, followed by the selection of one urban area and one rural area from each governorate. We included the responses of 1564 participants. The most common AEs after the first and second doses were local AEs (67.9% and 46.6%, respectively) followed by bone pain and myalgia (37.6% and 31.8%, respectively). After the third dose, the most common AEs were local AEs (45.7%) and fever (32.4%). Johnson and Johnson, Sputnik Light, and Moderna vaccines showed the highest frequency of AEs. Factors associated with AEs after the first dose included an increase in age (aOR of 61–75 years compared to the 12–18 years group: 2.60, 95% CI: 1.59–4.25, p = 0.001) and male gender (OR: 0.72, 95% CI: 0.63–0.82, p < 0.001). The cumulative post-vaccination COVID-19 disease was reported with Sinovac (16.1%), Sinopharm (15.8%), and Johnson and Johnson (14.9) vaccines. History of pre-vaccination SARS-CoV-2 infection significantly increases the risk of post-vaccination COVID-19 after the first, second, and booster doses (OR: 3.09, CI: 1.9–5.07, p < 0.0001; OR: 2.56, CI: 1.89–3.47, p < 0.0001; and OR: 2.94, CI: 1.6–5.39, p = 0.0005 respectively). In conclusion, AEs were common among our participants, especially local AEs. Further extensive studies are needed to generate more generalizable data regarding the safety of different vaccines. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has been a major challenge worldwide for the past years with high morbidity and mortality rates. While vaccination was the cornerstone to control the pandemic and disease spread, concerns regarding safety and adverse events (AEs) have been raised lately. A cross-sectional study was conducted between January 1st and January 22nd, 2022, in six Arabic countries namely Saudi Arabia, Egypt, Syria, Libya, Iraq, and Algeria. We utilized a self-administered questionnaire validated in Arabic which encompassed two main parts. The first was regarding sociodemographic data while the second was about COVID-19 vaccination history, types, doses, and experienced AEs. A multistage sampling was employed in each country, involving the random selection of three governorates from each country, followed by the selection of one urban area and one rural area from each governorate. We included the responses of 1564 participants. The most common AEs after the first and second doses were local AEs (67.9% and 46.6%, respectively) followed by bone pain and myalgia (37.6% and 31.8%, respectively). After the third dose, the most common AEs were local AEs (45.7%) and fever (32.4%). Johnson and Johnson, Sputnik Light, and Moderna vaccines showed the highest frequency of AEs. Factors associated with AEs after the first dose included an increase in age (aOR of 61–75 years compared to the 12–18 years group: 2.60, 95% CI: 1.59–4.25, p = 0.001) and male gender (OR: 0.72, 95% CI: 0.63–0.82, p < 0.001). The cumulative post-vaccination COVID-19 disease was reported with Sinovac (16.1%), Sinopharm (15.8%), and Johnson and Johnson (14.9) vaccines. History of pre-vaccination SARS-CoV-2 infection significantly increases the risk of post-vaccination COVID-19 after the first, second, and booster doses (OR: 3.09, CI: 1.9–5.07, p < 0.0001; OR: 2.56, CI: 1.89–3.47, p < 0.0001; and OR: 2.94, CI: 1.6–5.39, p = 0.0005 respectively). In conclusion, AEs were common among our participants, especially local AEs. Further extensive studies are needed to generate more generalizable data regarding the safety of different vaccines. [ABSTRACT FROM AUTHOR]

Background: COVID-19 is an abnormal host response to the SARS-CoV-2 infection, which is associated with endothelial dysfunction and multi-organ failure. Atorvastatin has been proposed to reduce COVID-19 severity and mortality in chronic and de-novo users. Methods: This randomized double-blind trial included 220 COVID-19 patients admitted to Mansoura University's isolation hospital in Egypt. One hundred and ten cases were given 40 mg of atorvastatin once daily for 28 days (group A), while 110 received a placebo (group B). All patients received treatment as per hospital protocol. The primary outcome is all-cause mortality at 28 days. We also tracked 6-month mortality, time to clinical improvement, the risk of invasive mechanical ventilation, acute kidney injury, potential adverse events, and hospital and intensive care length of stay. Results: The 28-day all-cause mortality was 52/104 (50%) in group A vs. 54/103 (52.4%) in group B, odds ratio (OR) = 0.907 (0.526, 1.565), P = 0.727; adjusted OR = 0.773 (0.407, 1.47), P = 0.433. Six-month mortality occurred in 53/102 (52%) and 59/79 (60.8%) in group A vs. B, respectively, P = 0.208. Among hospital survivors in group A vs. group B, the median time to clinical improvement was 10 days (7–14) vs. 10 (7–15), P = 0.715; the duration of hospital stay was 10 days (7–14) vs. 10 (8–17), P = 0.378. Discontinuation was higher in group B (four vs. one), but statistically insignificant, P = 0.369. Conclusions: In adults with severe or critical COVID-19, atorvastatin did not reduce the risk of 28-day or 6-month mortality and did not shorten the length of hospital stay or time to clinical improvement. Trial registration Clinical Trial Registry (NCT04952350) on July 1st, 2021. https://clinicaltrials.gov/ct2/show/NCT04952350 [ABSTRACT FROM AUTHOR]

With SARS-CoV-2 continuing to evolve, there is a need to adapt COVID-19 vaccines to enhance mucosal immunity and better address immune-evasive variants. This pilot study was performed in mice and rhesus macaques to compare Advax-adjuvanted monovalent and bivalent recombinant spike protein vaccines, including when delivered via a combination of intramuscular (IM) and intrapulmonary (IPM) or oral routes. Mice were first used to compare the immunogenicity of monovalent and bivalent vaccines containing a variety of spike protein variants. Then, rhesus macaques (n = 23) were divided into 5 groups to receive COVID-19 vaccines via different routes. Clinical signs, local vaccination site reactions, body weight, food consumption, serum, alveolar lavage, nasal and oral antibody levels, and nasal and alveolar lavage virus loads were assessed in response to a heterologous Omicron BA.5 virus challenge. The Wuhan + Mu bivalent vaccine gave the most broadly cross-neutralizing antibody responses. Robust serum neutralizing antibodies against Wuhan, Delta and Lambda variants were obtained, but BA.5 neutralizing antibodies were not detectable pre-challenge. Overall, the IM x3 and the IM x2 plus oral x2 vaccines delivered the best protection, with reduced lung virus load versus unimmunized controls across Days 2, 4 and 7. Advax-adjuvanted monovalent or bivalent recombinant spike protein vaccines given via parenteral and/or mucosal routes protected against a heterologous BA.5 challenge, despite absent serum BA.5 neutralizing antibody, pre-challenge. The possibility of using an oral Advax-adjuvanted protein booster to provide broad protection against newer SARS-CoV-2 variants warrants further investigation. [ABSTRACT FROM AUTHOR]

The emergence of corona virus disease 2019 (COVID-19), resulting from Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has left an indelible mark on a global scale, causing countless infections and fatalities. This investigation delves into the role of the SARS-CoV-2 nucleocapsid (N) protein within the HEK293 cells, shedding light on its influence over apoptosis, interferon signaling, and cytokines production. The N gene was amplified, inserted into the pAdTrack-CMV vector, and then transfected to the HEK293 cells. Changes in the expression of IRF3, IRF7, IFN-β, BAK, BAX, and BCL-2 genes were evaluated. The levels of proinflammatory cytokines of IL-6, IL-12, IL-1β, and TNF-α were also determined. The N protein exhibited an anti-apoptotic effect by modulating critical genes associated with apoptosis, including BAK, BAX, and BCL-2. This effect potentially prolonged the survival of infected cells. The N protein also played a role in immune evasion by suppressing the interferon pathway, evidenced by the downregulation of essential interferon regulatory factors of IRF3 and IRF7, and IFN-β expression. The N protein expression led to a substantial increase in the production of proinflammatory cytokines of IL-6, IL-12, IL-1β, and TNF-α. The N protein emerged as a versatile factor and was exerted over apoptosis, interferon signaling, and cytokine production. These findings carry potential implications for the development of targeted therapies to combat COVID-19 and mitigate its global health impact. [ABSTRACT FROM AUTHOR]

The emergence of SARS-CoV-2 variants alters the efficacy of existing immunity towards the viral spike protein, whether acquired from infection or vaccination. Mutations that impact N -glycosylation of spike may be particularly important in influencing antigenicity, but their consequences are difficult to predict. Here, we compare the glycosylation profiles and antigenicity of recombinant viral spike of ancestral Wu-1 and the Gamma strain, which has two additional N -glycosylation sites due to amino acid substitutions in the N-terminal domain (NTD). We found that a mutation at residue 20 from threonine to asparagine within the NTD caused the loss of NTD-specific antibody COVA2-17 binding. Glycan site-occupancy analyses revealed that the mutation resulted in N -glycosylation switching to the new sequon at N20 from the native N17 site. Site-specific glycosylation profiles demonstrated distinct glycoform differences between Wu-1, Gamma, and selected NTD variant spike proteins, but these did not affect antibody binding. Finally, we evaluated the specificity of spike proteins against convalescent COVID-19 sera and found reduced cross-reactivity against some mutants, but not Gamma spike compared to Wuhan spike. Our results illustrate the impact of viral divergence on spike glycosylation and SARS-CoV-2 antibody binding profiles. [ABSTRACT FROM AUTHOR]

• Five compounds: (2 S)−4´,7-dimethoxyflavan (CDS1), (2 S)−4´‑hydroxy-7-methoxyflavan (CDS2), hippadine (CDS3), (2 R)−4´‑hydroxy-5,7-dimethoxyflavan (CDS4) and hippacine (CDS5) were isolated from C. distichum. • The compounds inhibit the proteolytic and the deubiquitinating activities of the papain-like protease of two coronavirus species: Mers-CoV and Sars-CoV2. • The studied compounds exert their inhibitory effect through competitive and non-competitive inhibition mechanisms. • These compounds also induced the instability of the enzymes by reducing their melting temperature. Highly pathogenic coronaviruses, including the Middle East Respiratory Syndrome Coronavirus (Mers-CoV) and Severe Acute Respiratory Syndrome Coronavirus-2 (Sars-CoV2), have recently emerged and represent a serious threat to global health. Accordingly, a search for potent inhibitors against coronavirus diseases is warranted. Therefore, this study aimed at identifying potential inhibitors from Crinum distichum against the papain-like protease (PLpro), an important antiviral target due to its essential role in viral replication. A bacterial expression system was used for the recombinant expression of Mers-CoV-PLpro and Sars-CoV2-PLpro which was used to assess the inhibitory effect of compounds isolated from C. distichum against their proteolytic and deubiquitinating (DUB) activities. Then, the inhibition mechanism of hit compounds was determined through enzyme kinetic studies. Protein-ligand stability was assessed by Differential Scanning Fluorometry and Molecular docking was used to predict the possible molecular interactions. Five compounds, namely (2 S)-4´,7-dimethoxyflavan (CDS1), (2 S)-4´‑hydroxy-7-methoxyflavan (CDS2), Hippadine (CDS3), (2 R)-4´‑hydroxy-5,7-dimethoxyflavan (CDS4) and Hippacine (CDS5) were tested in this study. They markedly inhibited both the proteolytic and deubiquitinating activities of CoV-PLpro. Their IC 50 values were in the low micromolar range. The most potent inhibitors were CDS3 and CDS4, with IC 50 values of 9.28 and 6.45 µM, and 11.63 and 6.10 µM against the proteolytic and DUB activities of Mers-CoV-PLpro and Sars-CoV2-PLpro, respectively. They exert their inhibitory effect through competitive and non-competitive inhibition mechanisms. These compounds induced the instability of the enzymes by reducing their melting temperature and molecular docking analysis revealed several molecular interactions between the compounds and various amino acids of the enzymes. Overall, our findings suggest C. distichum active constituents to be promising candidates for development into potential inhibitors against coronavirus. [ABSTRACT FROM AUTHOR]

Studies on the development of effective and cost-effective oral drugs are the new priority of the pharmaceutical industry for the prevention and treatment of COVID-19. This work was based on the computational analysis of physicochemical parameters, pharmacokinetic and toxicological measurements, molecular docking and in silico measurement of the antiviral activity of 12 repositionable drugs. The Molinspiration platform (physical-chemical parameters), pkCSM® (absorption, distribution, metabolism and excretion), OSIRIS Property Explorer® (toxicological measurements), Seam® (Docking with the RdRp protein) and AVCpred server® (antiviral activity) were used. Considering the 12 selected repositionable drugs, molecular anchoring data with the RdRp protein, only the drug tilorone had lower binding energy than the control used in this study (Molnupiravir). Ledipasvir, daclatasvir and piperaquine showed the best percentage of antiviral inhibition considering the control pattern. ADMETox data showed that piperaquine has a high toxicological potential for mutagenesis, tumorigenesis and irritant effects. The findings of this study indicate that ledipasvir and daclatasvir showed greatest potential for inhibition RdRp and action against COVID-19. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lasted from March 2020 to May 2023, infecting over 689 million and causing 6.9 million deaths globally. SARS-CoV-2 enters human cells via the spike protein binding to ACE2 receptors, leading to viral replication and an exaggerated immune response characterized by a "cytokine storm." This review analyzes the COVID-19 pathogenesis, strains, risk factors for severe disease, and vaccine types and effectiveness. A systematic literature search for 2020–2023 was conducted. Results show the cytokine storm underlies COVID-19 pathogenesis, causing multiorgan damage. Key viral strains include Alpha, Beta, Gamma, Delta, and Omicron, differing in transmissibility, disease severity, and vaccine escape. Risk factors for severe COVID-19 include older age, obesity, and comorbidities. mRNA, viral vector, and inactivated vaccines effectively prevent hospitalization and death, although new variants exhibit some vaccine escape. Ongoing monitoring of emerging strains and vaccine effectiveness is warranted. This review provides updated information on COVID-19 pathogenesis, viral variants, risk factors, and vaccines to inform public health strategies for containment and treatment. [ABSTRACT FROM AUTHOR]

Since its discovery in Wuhan, China, in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly around the world with being declared a pandemic in March 2020 by the World Health Organization (WHO). Comorbidities are one of the most concerning clinical considerations for mortality. Materials and Methods: This was a retrospective observational study conducted at the All India Institute of Medical Sciences in Patna, Bihar, from June 2020 to December 2020. It included adult patients who succumbed to coronavirus disease 2019 (COVID-19) during this period, and their relevant information, such as demographic information hospital stay duration, haematological parameters and comorbidities, was gathered. Results: The mean age of the study group was 63.5 (11.8) years. Of 150 cases, 126 men (about 84 per cent) and 24 women were involved (16 per cent). In our study, hypertension (HTN) was shown to be the most frequent comorbidity at 68.7% (103/150), followed by diabetes mellitus (DM) at 61.3% (92/150). The most prevalent haematological disorder identified in our investigation was anaemia and leucocytosis. Conclusion: The categorisation of patients who would need extra measures including early hospitalisation, heightened monitoring and intense therapy would be made easier by identifying patient traits and conditions. [ABSTRACT FROM AUTHOR]