Acute kidney injury: a post-COVID-19 complication in children and adolescents / Lesão renal aguda: uma complicação pós-COVID-19 em crianças e adolescentes

ABSTRACT Objective: To describe cases of acute kidney injury (AKI) in children diagnosed with COVID-19, associated risk factors, clinical aspects and outcome of cases. Methods: Retrospective study, carried out in a pediatric hospital between March 2020 and September 2021, with patients with COVID-19 who were diagnosed with AKI, studying information present in medical records such as comorbidities, age, gender and use of nephrotoxic medications. Results: We studied 40 cases, and male individuals were significantly more affected (62.5%; p=0.025). AKI was a severe complication of COVID-19 infection, with 100% of the sample requiring admission to the Intensive Care Unit and 22.5% dying. The most prevalent comorbidities analyzed in this study were epilepsy, cerebral palsy and heart disease. Most patients were classified according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria as KDIGO 1 (42.5%), and required orotracheal intubation (67.5%). The frequency of use of nephrotoxic medications and need for dialysis was low, with percentages of 35 and 17.5%, respectively. Among the children who died, 70.4% had some comorbidity and 88.8% received invasive ventilation. Conclusions: AKI in children with COVID-19 infection is associated with severe conditions. Despite the severity, most patients were discharged alive from the hospital.

RESUMO Objetivo: Descrever casos de lesão renal aguda (LRA) em crianças diagnosticadas com COVID-19, associando fatores de risco, aspectos clínicos e evolução dos casos. Métodos: Estudo retrospectivo, realizado em hospital pediátrico entre março de 2020 e setembro de 2021, com pacientes com COVID-19 diagnosticados com LRA, que examinou informações presentes em prontuários como comorbidades, idade, sexo e uso de medicações nefrotóxicas. Resultados: Foram estudados 40 casos, sendo o sexo masculino significativamente mais acometido (62,5%; p=0,025). A LRA foi uma complicação grave da infecção por COVID-19, com 100% da amostra necessitando de internação na Unidade de Terapia Intensiva e 22,5% indo a óbito. As comorbidades mais prevalentes analisadas neste estudo foram epilepsia, paralisia cerebral e cardiopatia. A maioria dos pacientes foi classificada pelos critérios Kidney Disease: Improving Global Outcomes (KDIGO) como KDIGO 1 (42,5%) e necessitou de intubação orotraqueal (67,5%). A frequência de uso de medicamentos nefrotóxicos e necessidade de diálise foi baixa, com percentuais de 35 e 17,5%, respectivamente. Entre as crianças que faleceram, 70,4% apresentavam alguma comorbidade e 88,8% receberam ventilação invasiva. Conclusões: A LRA em crianças com infecção por COVID-19 está associada a quadros graves, apesar de a maior parte dos pacientes ter recebido alta hospitalar.

Approaching Pharmacological Space: Events and Components.

The pharmacological space comprises all the dynamic events that determine the bioactivity (and/or the metabolism and toxicity) of a given ligand. The pharmacological space accounts for the structural flexibility and property variability of the two interacting molecules as well as for the mutual adaptability characterizing their molecular recognition process. The dynamic behavior of all these events can be described by a set of possible states (e.g., conformations, binding modes, isomeric forms) that the simulated systems can assume. For each monitored state, a set of state-dependent ligand- and structure-based descriptors can be calculated. Instead of considering only the most probable state (as routinely done), the pharmacological space proposes to consider all the monitored states. For each state-dependent descriptor, the corresponding space can be evaluated by calculating various dynamic parameters such as mean and range values.The reviewed examples emphasize that the pharmacological space can find fruitful applications in structure-based virtual screening as well as in toxicity prediction. In detail, in all reported examples, the inclusion of the pharmacological space parameters enhances the resulting performances. Beneficial effects are obtained by combining both different binding modes to account for ligand mobility and different target structures to account for protein flexibility/adaptability.The proposed computational workflow that combines docking simulations and rescoring analyses to enrich the arsenal of docking-based descriptors revealed a general applicability regardless of the considered target and utilized docking engine. Finally, the EFO approach that generates consensus models by linearly combining various descriptors yielded highly performing models in all discussed virtual screening campaigns.

Feasibility and Effectiveness of Vaccines for COVID-19: An Umbrella Review.

Introduction: In January 2020, WHO declared the 2019 Coronavirus Disease (COVID-19) a pandemic. Though COVID-19 vaccines are recommended, ongoing surveillance is crucial due to potential unforeseen events. Evaluation of long-term effectiveness and safety and addressing emerging variants are vital. This study integrates systematic reviews to assess COVID-19 vaccine efficacy, immunogenicity, and safety comprehensively. Methods: This study was an umbrella review study on the feasibility and effectiveness of vaccines for COVID-19. We conducted a comprehensive search in PubMed, Web of Sciences, and Scopus, using MeSH terms and keywords related to COVID-19 vaccines. Inclusion criteria comprised peer-reviewed systematic reviews and meta-analyses in English, focusing on feasibility and effectiveness. Exclusion criteria targeted non-systematic reviews exclusively on vaccine safety and duplicates. Two independent reviewers screened and resolved discrepancies. Data extraction included key details. Methodological quality was assessed using the ROBIS tool. Data synthesis involves narrative and, if applicable, quantitative synthesis (meta-analysis). Reporting followed PRISMA guidelines. Results: A total of 32 systematic reviews were included in the study, of which 20 also conducted a meta-analysis. The studies investigated in the included reviews ranged from 7 to 74. The included articles were conducted in various countries around the globe. The findings indicated that COVID-19 vaccines are generally safe and effective for individuals with various medical conditions. The overall risk of bias for the included studies was assessed as low risk. Conclusion: The study outcomes indicated that mRNA vaccines exhibit a higher incidence of adverse events but demonstrate greater efficacy. Conversely, inactivated and protein subunit vaccines are safer but exhibit lower efficiency. Moreover, the vaccine is considered safe for individuals with specific conditions such as inflammatory bowel disease, solid organ transplant recipients, children, pregnant individuals, and those with hematologic problems. Ultimately, the acceptance of the COVID-19 vaccine among individuals is influenced by various factors, including geographic, socioeconomic, and pandemic-related considerations.

Full-length nanopore sequencing of circular RNA landscape in peripheral blood cells following sequential BNT162b2 mRNA vaccination.

Circular RNAs (circRNA) lack 5' or 3' ends; their unique covalently closed structures prevent RNA degradation by exonucleases. These characteristics provide circRNAs with high pharmaceutical stability and biostability relative to current standard-of-care linear mRNAs. CircRNA levels are reportedly associated with certain human diseases, making them novel disease biomarkers and a noncanonical class of therapeutic targets. In this study, the endogenous circRNAs underlying the response to BNT162b2 mRNA vaccination were evaluated. To this end, peripheral blood samples were subjected to full-length sequencing of circRNAs via nanopore sequencing and transcriptome sequencing. Fifteen samples, comprising pre-, first, and second vaccination cohorts, were obtained from five healthcare workers with no history of SARS-CoV-2 infection or previous vaccination. A total of 4706 circRNAs were detected; following full-length sequencing, 4217 novel circRNAs were identified as being specifically expressed during vaccination. These circRNAs were enriched in the binding motifs of stress granule assemblies and SARS-CoV-2 RNA binding proteins, namely poly(A) binding protein cytoplasmic 1 (PABPC1), pumilio RNA binding family member 1 (PUM1), and Y box binding protein 1 (YBX1). Moreover, 489 circRNAs were identified as previously reported miRNA sponges. The differentially expressed circRNAs putatively originated from plasma B cells compared to circRNAs reported in human blood single-cell RNA sequencing datasets. The pre- and post-vaccination differences observed in the circRNA expression landscape in response to the SARS-CoV-2 BNT162b2 mRNA vaccine.

Development of aptamer-based lateral flow devices for rapid detection of SARS-CoV-2 S protein and uncertainty assessment.

The outbreak and spread of COVID-19 have highlighted the urgent need for early diagnosis of SARS-CoV-2. Nucleic acid testing as an authoritative tool, is cumbersome, time-consuming, and easy to cross-infect, while the available antibody self-testing kits are deficient in sensitivity and stability. In this study, we developed competitive aptamer-based lateral flow devices (Apt-LFDs) for the quantitative detection of SARS-CoV-2 spike (S) protein. Molecular docking simulation was used to analyze the active binding sites of the aptamer to S protein, guiding complementary DNA (cDNA) design. Then a highly efficient freezing strategy was applied for the conjugation of gold nanoparticles (AuNPs) and DNA probes. Under optimal conditions, the linear range of the constructed Apt-LFDs was 0.1-1 µg/mL, and the limit of detection (LOD) was 51.81 ng/mL. The cross-reactivity test and stability test of the Apt-LFDs showed good specificity and reliability. The Apt-LFDs had recoveries ranging from 89.45 % to 117.12 % in pharyngeal swabs. Notably, the uncertainty of the analytical result was evaluated using a "bottom-up" approach. At a 95 % confidence level, the uncertainty report of (453.37±54.86) ng/mL with k = 2 was yielded. Overall, this study provides an important reference for the convenient and reliable detection of virus proteins based on LFDs.

Enhanced performance of impedimetric immunosensors to detect SARS-CoV-2 with bare gold nanoparticles and graphene acetic acid.

Immunosensors based on electrical impedance spectroscopy allow for label-free, real-time detection of biologically relevant molecules and pathogens, without requiring electro-active materials. Here, we investigate the influence of bare gold nanoparticles (AuNPs), synthesized via laser ablation in solution, on the performance of an impedimetric immunosensor for detecting severe acute respiratory syndrome coronavirus (SARS-CoV-2). Graphene acetic acid (GAA) was used in the active layer for immobilizing anti-SARS-CoV-2 antibodies, owing to its high density of carboxylic groups. Immunosensors incorporating AuNPs exhibited superior performance compared to those relying solely on GAA, achieving a limit of detection (LoD) of 3 x 10-20 g/mL to detect the Spike Receptor Binding Domain (RBD) protein of SARS-CoV-2 and of 2 PFU/mL for inactivated virus. Moreover, these immunosensors presented high selectivity against the H1N1 influenza virus. We anticipate that this platform will be versatile and applicable in the early diagnosis of various diseases and viral infections, thereby facilitating Point-of-Care testing.

Cognitive function and brain structure in COVID-19 survivors: The role of persistent symptoms.

Persistent COVID-19 symptoms post-acute state have been shown to have a significant negative impact on brain structure and function. In this study, we conducted magnetic resonance imaging (MRI) of the whole brain in 43 working-age adults (mean age: 44.79±10.80; range: 24-65 years) with a history of COVID-19 (731.17±312.41 days post-diagnosis), and also assessed their cognitive function (processing speed, attention, working memory, executive function, and recognition memory), mental health, and sleep quality. MRI data were processed using FSL to derive regional volumes for bilateral nucleus accumbens, caudate, pallidum, putamen, thalamus, amygdala, and hippocampus, and total grey matter, white matter, and cerebral spinal fluid volume, and analysed in relation to persistent COVID-19 symptom load, mental health, and sleep quality. Higher persistent COVID-19 symptom load was significantly associated with smaller putamen volume, lower response accuracy on working memory, executive function, and recognition memory tasks, as well as a longer time to complete the executive function task, and poorer mental health and sleep quality. Smaller putamen fully mediated the relationship between persistent COVID-19 symptom load and lower executive function. Further research is required to confirm whether reduced putamen volume and its association with poor executive function persists in COVID-19 survivors in the long term.

SARS-CoV-2 detection in COVID-19 patients' sample using Wooden quoit conformation structural aptamer (WQCSA)-Based electronic bio-sensing system.

The COVID-19 epidemic and its continuous spread pose a serious threat to public health. Coronavirus strains known as SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) variants have undergone genomic changes. The severity of the symptoms, the efficiency of vaccinations, and the transmission capacity of the virus can be impacted by these alterations. Point-of-care diagnostic assays can identify particular genetic or protein sequences that are exclusive to each variety. Currently, ultrafast, responsive, and accurate antibody detection faces several challenges. Here, we outline the fabrication, implementation, and sensing performance benchmarking of an ultrafast (5 s) and inexpensive (0.15 USD) assay with label-free sensing of SARS-CoV-2 S (Spike)/N (Nucleocapsid) protein and other variants in real patient samples. A label-free DNA aptameric capacitive bio-sensing device was used to detect SARS-CoV-2 variants. Our novel, cutting-edge bio-sensing device contains a Wooden quoits conformation structural aptamer (WQCSA)-based inter-digitated capacitor electronic (WQCSA-IDCE) system. WQCSA-aptamer was used as a switch-turn on response to achieve ultrasensitivity in the variable area of the SARS-CoV-2. The molecular beacon (MB) method was also used to measure the fluorescently colored SARS-CoV-2 S/N protein. These sensors can be used with several types of label-free DNA aptamers to act as rapid, affordable, and label-free biosensors for a variety of critical acute respiratory virus syndrome disorders.

Plasmon-enhanced fluorescence and electrochemical aptasensor for SARS-CoV-2 Spike protein detection.

In this work, we combined plasmon-enhanced fluorescence and electrochemical (PEF-EC) transduction mechanisms to realize a highly sensitive dual-transducer aptasensor. To implement two traducers in one biosensor, a novel large-scale nanoimprint lithography process was introduced to fabricate gold nanopit arrays (AuNpA) with unique fringe structures. Light transmitting through the AuNpA samples exhibited a surface plasmon polariton peak overlapping with the excitation peak of the C7 aptamer-associated fluorophore methylene blue (MB). We observed a five and seven-times higher average fluorescence intensity over the AuNpA and fringe structure, respectively, in comparison to a plane Au film. Furthermore, the MB fluorophore was simultaneously utilized as a redox probe for electrochemical investigations and is described here as a dual transduction label for the first time. The novel dual transducer system was deployed for the detection of SARS-CoV-2 Spike protein via a C7 aptamer in combination with a strand displacement protocol. The PEF transducer exhibited a detection range from 1 fg/mL to 10 ng/mL with a detection limit of 0.07 fg/mL, while the EC traducer showed an extended dynamic range from 1 fg/mL to 100 ng/mL with a detection limit of 0.15 fg/mL. This work provides insights into an easy-to-perform, large-scale fabrication process for nanostructures enabling plasmon-enhanced fluorescence, and the development of an advanced but universal aptasensor platform.

Bridging basic science and applied diagnostics: Comprehensive viral diagnostics enabled by graphene-based electronic biosensor technology advancements.

This study presents a graphene field-effect transistor (gFET) biosensor with dual detection capabilities for SARS-CoV-2: one RNA detection assay to confirm viral positivity and the other for nucleocapsid (N-)protein detection as a proxy for infectiousness of the patient. This technology can be rapidly adapted to emerging infectious diseases, making an essential tool to contain future pandemics. To detect viral RNA, the highly conserved E-gene of the virus was targeted, allowing for the determination of SARS-CoV-2 presence or absence using nasopharyngeal swab samples. For N-protein detection, specific antibodies were used. Tested on 213 clinical nasopharyngeal samples, the gFET biosensor showed good correlation with RT-PCR cycle threshold values, proving its high sensitivity in detecting SARS-CoV-2 RNA. Specificity was confirmed using 21 pre-pandemic samples positive for other respiratory viruses. The gFET biosensor had a limit of detection (LOD) for N-protein of 0.9 pM, establishing a foundation for the development of a sensitive tool for monitoring active viral infection. Results of gFET based N-protein detection corresponded to the results of virus culture in all 16 available clinical samples and thus it also proved its capability to serve as a proxy for infectivity. Overall, these findings support the potential of the gFET biosensor as a point-of-care device for rapid diagnosis of SARS-CoV-2 infection and indirect assessment of infectiousness in patients, providing additional information for clinical and public health decision-making.

Choroiditis following severe acute respiratory syndrome coronavirus 2 infection in unvaccinated identical twins

ABSTRACT Unvaccinated identical twins developed bilateral anterior uveitis soon after the onset of coronavirus disease 2019 symptoms. During follow-up, both patients developed choroiditis, and one twine developed posterior scleritis and serous retinal detachment. Prompt treatment with oral prednisone ameliorated the lesions, and no recurrence was observed at the 18-month follow-up. Choroiditis may rarely be associated with severe acute respiratory syndrome coronavirus 2 infection, and it responds well to corticosteroid therapy. Although the exact mechanism is unknown, we hypothesize that the virus may act as an immunological trigger for choroiditis.

A human monoclonal antibody neutralizing SARS-CoV-2 Omicron variants containing the L452R mutation.

The effectiveness of SARS-CoV-2 therapeutic antibodies targeting the spike (S) receptor-binding domain (RBD) has been hampered by the emergence of variants of concern (VOCs), which have acquired mutations to escape neutralizing antibodies (nAbs). These mutations are not evenly distributed on the RBD surface but cluster on several distinct surfaces, suggesting an influence of the targeted epitope on the capacity to neutralize a broad range of VOCs. Here, we identified a potent nAb from convalescent patients targeting the receptor-binding domain of a broad range of SARS-CoV-2 VOCs. Except for the Lambda and BA.2.86 variants, this nAb efficiently inhibited the entry of most tested VOCs, including Omicron subvariants BA.1, BA.2, XBB.1.5, and EG.5.1 and to a limited extent also BA.4/5, BA.4.6, and BQ.1.1. It bound recombinant S protein with picomolar affinity, reduced the viral load in the lung of infected hamsters, and prevented the severe lung pathology typical for SARS-CoV-2 infections. An X-ray structure of the nAb-RBD complex revealed an epitope that does not fall into any of the conventional classes and provided insights into its broad neutralization properties. Our findings highlight a conserved epitope within the SARS-CoV-2 RBD that should be preferably targeted by therapeutic antibodies and inform rational vaccine development.IMPORTANCETherapeutic antibodies are effective in preventing severe disease from SARS-CoV-2 infection and constitute an important option in pandemic preparedness, but mutations within the S protein of virus variants (e.g., a mutation of L452) confer resistance to many of such antibodies. Here, we identify a human antibody targeting the S protein receptor-binding domain (RBD) with an elevated escape barrier and characterize its interaction with the RBD functionally and structurally at the atomic level. A direct comparison with reported antibodies targeting the same epitope illustrates important differences in the interface, providing insights into the breadth of antibody binding. These findings highlight the relevance of an extended neutralization profiling in combination with biochemical and structural characterization of the antibody-RBD interaction for the selection of future therapeutic antibodies, which may accelerate the control of potential future pandemics.

Clinical, epidemiological, and molecular characteristics of SARS-CoV-2 Infections among healthcare workers at a research center in the amazon region of BRAZIL from 2020 to 2022.

The coronavirus disease-2019 (COVID-19) pandemic has affected different sectors of society, and healthcare workers have been particularly impacted. This study aimed to describe the clinical, epidemiological, and molecular characteristics of SARS-CoV-2 infections among healthcare workers in Evandro Chagas Institute, a research reference center in Brazil, from October 2020 to July 2022. 845 samples were collected from individuals who presented clinical symptoms of respiratory infection. Nasopharyngeal positive samples were submitted through genome sequencing. Clinical, epidemiological, and the SARS-CoV-2 lineages (or variants) were analyzed. SARS-CoV-2 positivity was detected in 31.8% (269/845) of samples with a higher prevalence of females (60.2%). The highest SARS-CoV-2 positivity rates were reported in March 2021 (39%), January 2022 (65%), and July 2022 (56%). On clinical symptoms, arthralgia, chills, and diarrhea were statistically significantly detected in 2020; fever, runny nose, and arthralgia in 2021; runny nose, and cough in 2022. On molecular analysis of SARS-CoV-2, 66 samples (25.3%, 66/269) were sequenced and the most prevalent lineage was the Omicron, representing 57.6%. Studies on the epidemiological and clinical characteristics of HCW are essential to propose control measures and work management since research centers play a major role in surveillance to identify and monitor infectious diseases.

Factors associated with the development, severity, and resolution of post COVID-19 condition in adults living in Canada, January 2020 to August 2022.

OBJECTIVES: We aimed to characterize the burden of post COVID-19 condition (PCC) among adults in Canada and identify factors associated with its occurrence, severity, and resolution. METHODS: We used self-report data from a population-based cross-sectional probability survey of adults in Canada conducted between April and August 2022. Incidence and prevalence of PCC were estimated using confirmed infections, as well as confirmed and suspected combined. Multivariable modeling using confirmed cases identified associated factors. RESULTS: As of August 2022, 17.2% (95% CI 15.7, 18.8) of adults with confirmed infections and 16.7% (95% CI 15.5, 18.0) of adults with confirmed or suspected infections experienced PCC, translating to 3.3% (95% CI 3.0, 3.6) and 4.4% (95% CI 4.1, 4.8) of all adults, respectively. Age less than 65 years (aORs of 1.75 to 2.14), more pre-existing comorbidities (aORs of 1.75 to 3.57), and a more severe initial infection (aORs of 3.52 to 9.69) were all associated with higher odds of PCC, while male sex at birth (aOR = 0.54, 95% CI 0.41, 0.70), identifying as Black (aOR = 0.23, 95% CI 0.11, 0.51), and being infected after 2020 (aORs of 0.24 to 0.55) were associated with lower odds. Those residing in a rural area (aOR = 2.31, 95% CI 1.35, 3.93), or reporting a disability (aOR = 2.87, 95% CI 1.14, 7.25), pre-existing chronic lung condition (aOR = 5.47, 95% CI 1.85, 16.12) or back problem (aOR = 2.34, 95% CI 1.26, 4.36), or PCC headache (aOR = 2.47, 95% CI 1.60, 3.83) or weakness (aOR = 2.27, 95% CI 1.41, 3.68) had higher odds of greater limitations in daily activities, while males had lower odds (aOR = 0.54, 95% CI 0.34, 0.85). Two or more pre-existing chronic conditions (aHRs from 0.33 to 0.38), or PCC symptoms relating to the heart (aHR = 0.25, 95% CI 0.07, 0.90), brain fog (aHR = 0.44, 95% CI 0.23, 0.86), or stress/anxiety (aHR = 0.48, 95% CI 0.24, 0.96) were associated with a decreased rate of symptom resolution. CONCLUSION: Over the first two and a half years of the pandemic, a substantial proportion of infected adults in Canada reported PCC. Females and people with comorbidities were disproportionately impacted.

RéSUMé: OBJECTIFS: Nous avons cherché à caractériser le fardeau du syndrome post-COVID-19 (SPC) chez les adultes au Canada et à identifier les facteurs associés à son apparition, sa gravité et sa résolution. MéTHODES: Nous avons utilisé les données d'auto-évaluation d'une enquête probabiliste transversale basée sur la population d'adultes au Canada menée entre avril et août 2022. L'incidence et la prévalence du SPC ont été estimées à l'aide d'infections confirmées, ainsi que d'infections confirmées et soupçonnées combinées. La modélisation multivariée à l'aide des cas confirmés a permis d'identifier des facteurs leur étant associés. RéSULTATS: En août 2022, 17,2% (IC à 95%: 15,7, 18,8) des adultes atteints d'infections confirmées et 16,7% (IC à 95%: 15,5, 18,0) des adultes atteints d'infections confirmées ou soupçonnées ont développé un SPC, soit 3,3% (IC à 95%: 3,0, 3,6) et 4,4% (IC à 95%: 4,1, 4,8) de tous les adultes, respectivement. Être âgé de moins de 65 ans (aRC de 1,75 à 2,14), un plus grand nombre de comorbidités préexistantes (aRC de 1,75 à 3,57) et une infection initiale plus grave (aRC de 3,52 à 9,69) étaient tous associés à une probabilité plus élevée de SPC, alors qu'être un garçon à la naissance (aRC = 0,54, IC à 95%: 0,41, 0,70), s'identifier comme Noir (aRC = 0,23, IC à 95%: 0,11, 0,51) et le fait d'être infecté après 2020 (aRC de 0,24 à 0,55) étaient associés à des probabilités plus faibles. Les personnes résidant dans une région rurale (aRC = 2,31, IC à 95%: 1,35 à 3,93) ou déclarant une incapacité (aRC = 2,87, IC à 95%: 1,14 à 7,25), une affection pulmonaire chronique préexistante (aRC = 5,47, IC à 95%: 1,85 à 16,12), des problèmes de dos (aRC = 2,34, IC à 95%: 1,26 à 4,36), des maux de tête liés au SPC (aRC = 2,47, IC à 95%: 1,60 à 3,83) ou une faiblesse liée au SPC (aRC = 2,27, IC à 95%: 1,41, 3,68) avaient une probabilité plus élevée de limitations plus importantes des activités quotidiennes, tandis que les hommes avaient une probabilité plus faible (aRC = 0,54, IC à 95%: 0,34, 0,85). Le fait d'avoir deux maladies chroniques préexistantes ou plus (aRR de 0,33 à 0,38) ou des symptômes de SPC liés au cœur (aRR = 0,25, IC à 95%: 0,07, 0,90), au brouillard cérébral (aRR = 0,44, IC à 95%: 0,23, 0,86) ou au stress/anxiété (aRR = 0,48, IC à 95%: 0,24, 0,96) étaient associés à une diminution du taux de résolution des symptômes. CONCLUSION: Au cours des deux premières années et demie de la pandémie, une proportion importante d'adultes infectés au Canada a déclaré un SPC. Les femmes et les personnes avec des comorbidités ont été touchées de manière disproportionnée.

Virologic Response and Safety of Ibuzatrelvir, a Novel SARS-CoV-2 Antiviral, in Adults With COVID-19.

BACKGROUND: Despite effective vaccines and treatments for COVID-19, clinical burden persists. An unmet need exists for additional effective agents with safety profiles allowing use across a broad population. Ibuzatrelvir is an orally bioavailable SARS-CoV-2 Mpro inhibitor that has demonstrated in vitro antiviral activity and low potential for safety concerns, including drug-drug interactions. METHODS: This phase 2b, double-blind, randomized clinical trial enrolled US adults aged 18‒<65 years with symptomatic COVID-19 and no risk factors for severe disease. Participants were randomized 1:1:2:2 to receive 100, 300, or 600 mg ibuzatrelvir or placebo orally twice daily for 5 days. Nasopharyngeal specimens were collected on Days 1 (baseline), 3, 5, 10, 14, and 21; adverse events (AEs) were recorded through Day 33. The primary endpoint was change in SARS-CoV-2 RNA level (viral load [VL]) from baseline to Day 5 among participants with baseline VL ≥4 log10 copies/mL. RESULTS: Of 240 enrollees, 237 received ≥1 dose and 199 were included in the primary analysis. Placebo-adjusted least squares mean (80% CI) change from baseline in VL at Day 5 was significant across all doses: 100 mg, ‒0.7 (‒1.1, ‒0.3) log10 copies/mL, P=0.02; 300 mg, ‒0.8 (‒1.3, ‒0.3) log10 copies/mL, P=0.01; and 600 mg, ‒1.2 (‒1.5, ‒0.8) log10 copies/mL, P<0.0001. AEs occurred in similar percentages of participants across groups. No deaths from any cause or treatment-related serious AEs occurred through Day 33, and no participants reported dysgeusia. CONCLUSIONS: All 3 ibuzatrelvir doses were associated with robust antiviral activity and an acceptable safety profile, supporting continued clinical development. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05799495.

Design, synthesis, and biological evaluation of dithiocarbamate derivatives as SARS-CoV-2 Mpro inhibitors.

SARS-CoV-2 continues to mutate, spread, and impact public health and daily life. The main protease (Mpro) is essential for the replication and maturation of SARS-CoV-2, making it an ideal target for anti-coronaviral drug discovery and development due to its high conservation and lack of homologous proteases in humans. Herein, we designed and synthesized a series of dithiocarbamate derivatives as potent SARS-CoV-2 Mpro inhibitors. Notably, compound L2 exhibited an IC50 value of 9.1 ± 2.0 nM against SARS-CoV-2 Mpro, underscoring its potential as a promising candidate for anti-coronaviral therapy and justifying further research and development.

Identification of catechin as main protease inhibitor of SARS-CoV-2 Omicron variant using molecular docking, molecular dynamics, PCA, DCCM, MM/GBSA and ADMET profiling.

The Omicron variant of SARS-CoV-2 spreads more rapidly than other variants and can affect even vaccinated individuals. The Omicron variant main protease (Mpro), crucial for viral replication and transcription, is an attractive target for antiviral drug discovery. This research aims to investigate non-toxic flavonoids that follow Lipinski's rule of five (RO5) and inhibit the Omicron variant Mpro. Molecular docking was performed on 35 flavonoids screened by analysing their medicinal values and adherence to RO5. Catechin (2-(3,4-dihydroxyphenol) chroman-3,5,7-triol), a non-toxic natural compound having predicted toxicity class 6 and LD50 value 10,000 mg/kg, exhibited a docking score of -7.1 kcal/mol with Mpro. The Mpro-catechin complex remained stable during 250 ns MD simulations. The post-MD free energy (MM/GBSA) calculations showed a binding energy of -20.5 kcal/mol, indicating strong interactions with the active amino acid residues. These findings suggest that catechin is a promising drug candidate against the Omicron variant.

Serum proteome reveals distinctive molecular features of H7N9- and SARS-CoV-2-infected patients.

The coronavirus disease 2019 (COVID-19) pandemic has reminded us of human infections with the H7N9 virus and has raised questions related to the clinical and molecular pathophysiological diversity between the two diseases. Here, we performed a proteomic approach on sera samples from patients with H7N9-virus or SARS-CoV-2-virus infection and healthy controls. Compared to SARS-CoV-2, H7N9-virus infection caused elevated neutrophil concentrations, T cell exhaustion, and increased cytokine/interleukin secretion. Cell-type deconvolution and temporal analysis revealed that T cells and neutrophils could regulate the core immunological trajectory and influence the prognosis of patients with severe H7N9-virus infection. Elevated tissue-enhanced proteins combined with alterations of clinical biochemical indexes suggested that H7N9 infection induced more severe inflammatory organ injury and dysfunction in the liver and intestine. Further mechanical analysis revealed that the high concentration of neutrophils might impact the intestinal enterocyte cells through cytokine-receptor interaction, leading to intestinal damage in patients with H7N9-virus infection.

Induction of IGHV3-53 public antibodies with broadly neutralising activity against SARS-CoV-2 including Omicron subvariants in a Delta breakthrough infection case.

BACKGROUND: Emergence of SARS-CoV-2 variants that escape neutralising antibodies hampers the development of vaccines and therapeutic antibodies against SARS-CoV-2. IGHV3-53/3-66-derived public antibodies, which are generally specific to the prototype virus and are frequently induced in infected or vaccinated individuals, show minimal affinity maturation and high potency against prototype SARS-CoV-2. METHODS: Monoclonal antibodies isolated from a Delta breakthrough infection case were analysed for cross-neutralising activities against SARS-CoV-2 variants. The broadly neutralising antibody K4-66 was further analysed in a hamster model, and the effect of somatic hypermutations was assessed using the inferred germline precursor. FINDINGS: Antibodies derived from IGHV3-53/3-66 showed broader neutralising activity than antibodies derived from IGHV1-69 and other IGHV genes. IGHV3-53/3-66 antibodies neutralised the Delta variant better than the IGHV1-69 antibodies, suggesting that the IGHV3-53/3-66 antibodies were further maturated by Delta breakthrough infection. One IGHV3-53/3-66 antibody, K4-66, neutralised all Omicron subvariants tested, including EG.5.1, BA.2.86, and JN.1, and decreased the viral load in the lungs of hamsters infected with Omicron subvariant XBB.1.5. The importance of somatic hypermutations was demonstrated by the loss of neutralising activity of the inferred germline precursor of K4-66 against Beta and Omicron variants. INTERPRETATION: Broadly neutralising IGHV3-53/3-66 antibodies have potential as a target for the development of effective vaccines and therapeutic antibodies against newly emerging SARS-CoV-2 variants. FUNDING: This work was supported by grants from AMED (JP23ym0126048, JP22ym0126048, JP21ym0126048, JP23wm0125002, JP233fa627001, JP223fa627009, JP24jf0126002, and JP22fk0108572), and the JSPS (JP21H02970, JK23K20041, and JPJSCCA20240006).

In silico exploration of phytocompounds from AYUSH-64 medicinal plants against SARS CoV-2 RNA-dependent RNA polymerase.

BACKGROUND: The AYUSH 64 formulation helps to treat mild to moderate cases of COVID-19. Although several drugs have been proposed to combat COVID-19, no medication is available for SARS-CoV-2 infection. The RNA-dependent RNA polymerase (RdRp) is the pivotal enzyme of SARS-CoV-2 replication, so it could be considered a better drug target for experimental studies. OBJECTIVE: The AYUSH-64 formulation plants exhibited multiple therapeutic properties; thus, the present study aims to screen the phytocompounds of these plants against SARS CoV2 RdRp to identify specific compounds that could potentially affect COVID-19 infection. MATERIALS AND METHODS: PatchDock and AutoDock tools were used for docking experiments. MD simulations and Density Functional Theory (DFT) calculations of protein-ligand Picroside-I and Remdesivir complexes were carried out in GROMACS v2019.4 and Gaussian 09 software, respectively. RESULTS: Among the tested, five phytocompounds (Picroside I, Oleanolic acid, Arvenin I, II, and III) from AYUSH-64 medicinal plants showed possible binding with RdRp catalytic residues (Ser759, Asp760, and Asp761). Of these, Picroside I exhibited hydrogen bond interactions with NTP entry channel residues (Arg553 and Arg555). The MM-PBSA free energy, RMSD, Rg, PCA, and RMSF analysis suggested that the Picroside I complex showed stable binding interactions with RdRp in the 50 ns simulation. In addition to this, Picroside I revealed its robust and attractive nature toward the target protein, as confirmed by DFT. CONCLUSION: The results of this study have proposed that Picroside I from AYUSH 64 medicinal plant compounds was the selective binder of catalytic and NTP entry channel residues of SARS-CoV2 RdRp thereby; it may considered as a potential inhibitor of SARS-CoV2 RdRp.