- Identification of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir -
The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans and become pandemic. Its high mortality rate of up to 35 % and the absence of effective targeted therapies call for the development of antiviral drugs for this pathogen. Since the beginning of the SARS-CoV-2 pandemic, extensive research has focused on identifying protease inhibitors for the treatment of SARS-CoV-2. Our intention was therefore to assess whether these protease inhibitors are viable options for combating MERS-CoV. To that end, we used previously established protease assays to quantify inhibition of the SARS-CoV-2 and MERS-CoV main proteases. Furthermore, we selected MERS-CoV-Mpro mutants resistant against nirmatrelvir, the most effective inhibitor of this protease, with a safe, surrogate virus-based system, and suggest putative resistance mechanisms. Notably, nirmatrelvir demonstrated effectiveness against various viral proteases, illustrating its potential as a broad-spectrum coronavirus inhibitor. To adress the inherent resistance of MERS-CoV-Mpro to ensitrelvir, we applied directed mutagenesis to a key ensitrelvir-interacting residue and provided structural models.
- Sex-Specific Systemic Inflammatory Responses in Mice Infected with a SARS-CoV-2-like Virus and Femur Fracture -
This study investigates the systemic inflammatory response in mice infected with a murine coronavirus (MHV), which shares a common genus with SARS-CoV-2, and sustaining a fracture. The study reveals that the combined inflammatory incidents of MHV infection and fracture disrupt the systemic immune response in both female and male mice, likely leading to immune dysregulation, altered cell recruitment, and disruption of the typical inflammatory cascade. Notably, the study uncovers sex-specific responses that modulate circulating immune factors. Females exhibit elevated levels of inflammatory factors, whereas males demonstrate a diminished response. This divergence is mirrored in cell populations, suggesting that the quantity of immune factors released may contribute to these discrepancies. The findings suggest that an overproduction of proinflammatory cytokines may induce a dysregulated immune response, contributing to the observed poorer prognosis in comorbid cases. These insights could pave the way for therapeutic advancements and treatment strategies aimed at reducing mortality rates in COVID-19 patients with fractures.
- In field use of water samples for genomic surveillance of ISKNV infecting tilapia fish in Lake Volta, Ghana -
Viral outbreaks are a constant threat to aquaculture, limiting production for better global food security. A lack of diagnostic testing and monitoring in resource-limited areas hinders the capacity to respond rapidly to disease outbreaks and to prevent viral pathogens becoming endemic in fisheries productive waters. Recent developments in diagnostic testing for emerging viruses, however, offers a solution for rapid in situ monitoring of viral outbreaks. Genomic epidemiology has furthermore proven highly effective in detecting viral mutations involved in pathogenesis and assisting in resolving chains of transmission. Here, we demonstrate the application of an in-field epidemiological tool kit to track viral outbreaks in aquaculture on farms with reduced access to diagnostic labs, and with non-destructive sampling. Inspired by the "lab in a suitcase" approach used for genomic surveillance of human viral pathogens and wastewater monitoring of COVID19, we evaluated the feasibility of real-time genome sequencing surveillance of the fish pathogen, Infectious spleen and kidney necrosis virus (ISKNV) in Lake Volta. Viral fractions from water samples collected from cages holding Nile tilapia (Oreochromis niloticus) with suspected ongoing ISKNV infections were concentrated and used as a template for whole genome sequencing, using a previously developed tiled PCR method for ISKNV. Mutations in ISKNV in samples collected from the water surrounding the cages matched those collected from infected caged fish, illustrating that water samples can be used for detecting predominant ISKNV variants in an ongoing outbreak. This approach allows for the detection of ISKNV and tracking of the dynamics of variant frequencies, and may thus assist in guiding control measures for the rapid isolation and quarantine of infected farms and facilities.
- Towards ultra-low-cost smartphone microscopy -
The outbreak of COVID-19 exposed the inadequacy of our technical tools for home health surveillance, and recent studies have shown the potential of smartphones as a universal optical microscopic imaging platform for such applications. However, most of them use laboratory-grade optomechanical components and transmitted illuminations to ensure focus tuning capability and imaging quality, which keeps the cost of the equipment high. Here we propose an ultra-low-cost solution for smartphone microscopy. To realize focus tunability, we designed a seesaw-like structure capable of converting large displacements on one side into small displacements on the other (reduced to [~]9.1%), which leverages the intrinsic flexibility of 3D printing materials. We achieved a focus-tuning accuracy of [~] 5 m, which is 40 times higher than the machining accuracy of the 3D-printed lens holder itself. For microscopic imaging, we use an off-the-shelf smartphone camera lens as the objective and the built-in flashlight as the illumination. To compensate for the resulting image quality degradation, we developed a learning-based image enhancement method. We use the CycleGAN architecture to establish the mapping from smartphone microscope images to benchtop microscope images without pairing. We verified the imaging performance on different biomedical samples. Except for the smartphone, we kept the full costs of the device under 4 USD. We think these efforts to lower the costs of smartphone microscopes will benefit their applications in various scenarios, such as point-of-care testing, on-site diagnosis, and home health surveillance.
- Social isolation, mental health, and use of digital interventions in youth during the COVID-19 pandemic: a nationally representative survey -
Summary Background: Public health measures to curb SARS-CoV-2 transmission rates may have negative psychosocial consequences in youth. Digital interventions may help to mitigate these effects. We investigated the associations between social isolation, cognitive preoccupation, worries, and anxiety, objective social risk indicators, psychological distress as well as use of, and attitude towards, mobile health (mHealth) interventions in youth during the COVID-19 pandemic. Methods: Data were collected as part of the âMental Health And Innovation During COVID-19 Surveyâ âa cross-sectional panel study including a representative sample of individuals aged 16 to 25 years (N=666; Mage 21·3) (assessment period: 07.05.-16.05.2020). Outcomes: Overall, 38% of youth met criteria for moderate psychological distress and 30% felt âoftenâ or âvery oftenâ socially isolated, even after most restrictive infection control measures had been lifted. Social isolation, COVID-19-related worries and anxiety, and objective risk indicators were associated with psychological distress, with evidence of dose-response relationships for some of these associations. For instance, psychological distress was progressively more likely to occur as levels of social isolation increased (reporting âneverâ as reference group: âoccasionallyâ: adjusted odds ratio [aOR] 9·1, 95% confidence interval [CI] 4·3 â 19·1, p<0·001; âoftenâ: aOR 22·2, CI 9·8 â 50·2, p<0·001;âvery oftenâ: aOR 42·3, CI 14·1 â 126·8, p<0·001). There was evidence that psychological distress, worries, and anxiety were associated with a positive attitude towards using digital interventions, whereas high levels of psychological distress, worries, and anxiety were associated with actual use. Interpretation: Public health measures during pandemics may be associated with poor mental health in youth. Digital interventions may help mitigate the negative psychosocial impact given there is an objective need and subjective demand.
- Failure to protect: COVID infection control policy privileges poor-quality evidence -
The failure to immediately recognize the urgent need to control airborne spread of COVID-19, including use of adequate personal protective equipment for an airborne pathogen, represents a major medical error that cost âan enormous number of livesâ. Made in the face of significant scientific evidence and a clear requirement to adhere to a precautionary approach, it has still not been fully remedied. To understand the substantial, ongoing gap between science and policy, we carried out an in-depth investigation of an illustrative publication authored by prominent authorities in the fields of Public Health and Infection Prevention and Control, describing a trial of medical masks and N95 respirators for the prevention of COVID-19. Although it was portrayed as among the highest quality evidence available within the Evidence-Based Medicine decision-making paradigm, we found this work to be deeply flawed to the extent that it does not meet basic standards of scientific rigour. Extensive prior work in the respiratory protection field â sufficiently well-established to be incorporated into both national standards and specific recommendations made to address infection control failures in SARS â was ignored. Randomization was compromised, with a statistically significant correlation between female sex and allocation to the higher-risk arm of the trial. Significant conflicts of interest in favour of the reported finding that medical masks are noninferior to N95 respirators in preventing COVID-19 transmission were not disclosed. Prespecified analyses were omitted, and the finding of noninferiority is entirely a product of inappropriate alterations to the trial that were not prospectively registered. Despite numerous flaws biasing the outcome towards a finding of noninferiority, re-analysis using the prespecified approach and noninferiority criterion unambiguously reverses the reported outcome of the trial.
- The Last Confirmed Case is Not the Last Infection and Catastrophic Outbreaks do Not Require Transmission -
Efforts to prevent transmission of the infectious agent that causes an infectious disease in its capacity as a pathogen are praised and victory is declared after the last case of the expected outcomes of the event in which this disease occurs is confirmed. After all, it is assumed that such expected outcomes of the event in which the pathogen causes the infectious disease are manifestations of this disease and therefore that the last confirmed case in which such outcomes are observed is the last case of infection. But the results obtained while forging the path to immunological concepts which have eluded us since the birth of the repeatedly proven germ theory with the method by which Einstein approximated astronomical reality conceptually while developing General Relativity reveal that outcomes of the event in which the pathogen causes the infectious disease are not manifestations of this disease but rather consequences of the comanifestation of different diseases in the spectrum of the infectious disease. These results enable us to account for the differences between such outcomes which, for instance, in patients with COVID-19 that the current theory of infectious disease pathogenesis expects to produce outcomes that affect the upper respiratory disease, include unexpected conditions such as the chronic ones seen in Long COVID patients and in patients with mpox, which this theory logically deduced to be a skin-affecting disease, include deadly conditions like encephalitis with the consequence that outcomes with such deadly conditions are attributed to underlying conditions even after Spainâs health ministry reported deaths from such outcomes in healthy individuals. And the consequence of the same results is that the last cases of expected outcomes such as those that affect the skin of individuals who are infected with the mpox virus are not the last cases of infection but rather the last cases in which such outcomes appear as the sterile causes of the non-infectious diseases that co-manifest with the infectious disease for the emergence of such outcomes disappear from the population in which undetected spread of the infectious agent occurred long before the widespread appearance of such expected outcomes that called attention to this pathogen or an earlier form of the pathogen, such as the smallpox virus, which is assumed to have been eradicated. It follows in the reality which was visualized to obtain these results that even as the disappearance of such outcomes is being celebrated, the sterile causes of non-infectious diseases which co-manifest with the infectious disease for the emergence of unexpected deadly outcomes, such as those with encephalitis and toxic shock, may be appearing in the population which is already harboring the pathogen silently. And without exciting cause or warning, such deadly outcomes will become widespread in our populations and will decimate them if the only treatments available at the time are still those that reduce viral replication which are unable to bring about the remission of such outcomes. Instead of celebrating the disappearance of cases when the sterile causes of the non-infectious diseases that co-manifest with mpox for the emergence of those expected skin-affecting outcomes disappear, we ought to quickly elucidate the conditions that permit the immunological mechanisms of infection and vaccination to bring about uneventful exposure to such sterile causes even after deadly outcomes of such events have already appeared as achieved, in some cases, by the vaccines of William Coley and Julius Wagner-Jauregg even at a time when nothing was known about the nature of such immunological mechanisms and the remission that followed therapeutic infection in such cases was attributed to fever.
- Genome-wide Bioinformatics Analysis of Human Protease Capacity for Proteolytic Cleavage of the SARS-CoV-2 Spike Glycoprotein -
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) primarily enters the cell by binding the virusâs spike (S) glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface, followed by proteolytic cleavage by host proteases. Studies have identified furin and TMPRSS2 proteases in priming and triggering cleavages of the S glycoprotein, converting it into a fusion-competent form and initiating membrane fusion, respectively. Alternatively, SARS-CoV-2 can enter the cell through the endocytic pathway, where activation is triggered by lysosomal cathepsin L. However, other proteases are also suspected to be involved in both entry routes. In this study, we conducted a genome-wide bioinformatics analysis to explore the capacity of human proteases in hydrolyzing peptide bonds of the S glycoprotein. Predictive models of sequence specificity for 169 human proteases were constructed and applied to the S glycoprotein together with the method for predicting structural susceptibility to proteolysis of protein regions. After validating our approach on extensively studied S2â and S1/S2 cleavage sites, we applied our method to each peptide bond of the S glycoprotein across all 169 proteases. Our results indicate that various members of the PCSK, TTSP, and kallikrein families, as well as specific coagulation factors, are capable of cleaving S2â or S1/S2 sites. We have also identified a potential cleavage site of cathepsin L at the K790 position within the S2â loop. Structural analysis suggests that cleavage of this site induces conformational changes similar to the cleavage at the R815 (S2â) position, leading to the exposure of the fusion peptide and subsequent fusion with the membrane. Other potential cleavage sites and the influence of mutations in common SARS-CoV-2 variants on proteolytic efficiency are discussed.
- Murine Alveolar Macrophages Rapidly Accumulate Intranasally Administered SARS-CoV-2 Spike Protein leading to Neutrophil Recruitment and Damage -
The trimeric SARS-CoV-2 Spike protein mediates viral attachment facilitating cell entry. Most COVID-19 vaccines direct mammalian cells to express the Spike protein or deliver it directly via inoculation to engender a protective immune response. The trafficking and cellular tropism of the Spike protein in vivo and its impact on immune cells remains incompletely elucidated. In this study we inoculated mice intranasally, intravenously, and subcutaneously with fluorescently labeled recombinant SARS-CoV-2 Spike protein. Using flow cytometry and imaging techniques we analyzed its localization, immune cell tropism, and acute functional impact. Intranasal administration led to rapid lung alveolar macrophage uptake, pulmonary vascular leakage, and neutrophil recruitment and damage. When injected near the inguinal lymph node medullary, but not subcapsular macrophages, captured the protein, while scrotal injection recruited and fragmented neutrophils. Wide-spread endothelial and liver Kupffer cell uptake followed intravenous administration. Human peripheral blood cells B cells, neutrophils, monocytes, and myeloid dendritic cells all efficiently bound Spike protein. Exposure to the Spike protein enhanced neutrophil NETosis and augmented human macrophage TNF- and IL-6 production. Human and murine immune cells employed C-type lectin receptors and Siglecs to help capture the Spike protein. This study highlights the potential toxicity of the SARS-CoV-2 Spike protein for mammalian cells and illustrates the central role for alveolar macrophage in pathogenic protein uptake.
- Gut microbiome remains stable following COVID-19 vaccination in healthy and immuno-compromised individuals -
The bidirectional interaction between the immune system and the gut microbiota is a key contributor to various host physiological functions. Immune-associated diseases such as cancer and autoimmunity, as well as the efficacy of immunomodulatory therapies, have been linked to microbiome variation. While COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.
- Donât Say Itâs Over: The Perceived Epidemic Stage and Covid Preventive Behaviour -
The risks for people during the epidemic are evolving. For COVID-19 pandemic one important feature was its multiwave pattern, where, within each wave, the pandemic dynamic could be described as the curve. This study aimed to explore how peopleâs perceptions of such a pandemic process associates with the risk perceptions and the preventive behaviour. A sample of 1,343 university students in the beginning of COVID-19 pandemic have assessed the pandemic stage, perceived risks, mental health and trust to different bodies in regard to pandemic. They also reported their involvement in the COVID topic and a wide range of implemented behaviour. The study participants differed in their perception of the pandemic stage despite being in the same environment. The belief that the curve pick is left behind was associated with the less perceived risk and decrease in preventive behaviour implementation, while there was no difference in the perception of risks or behaviour between belief in living the period in the epidemic peak or the beginning of the wave. The lack of COVID involvement, distrust to authorities and official COVID information were associated with the less perceived risk and preventive behaviour. Mental health characteristics were significantly associated with the social preventive behaviours - the higher depression level was the predictor of the decreasing of communication with other people while the anxiety was the predictor of more risky behaviour due to increase in face-to-face communication. Overall the perception that the epidemic wave is on its final stage could be an independent predictor of more risky behaviour. Communication of the epidemic dynamic should be provided with extreme caution.
- Memory B cells dominate the early antibody-secreting cell response to SARS-CoV-2 mRNA vaccination in naive individuals independently of their antibody affinity -
Memory B cells (MBCs) formed over the individual's lifetime constitute nearly half of the adult peripheral blood B cell repertoire in humans. To assess their response to novel antigens, we tracked the origin and followed the differentiation paths of MBCs in the early anti-S response to mRNA vaccination in SARS-CoV-2-naïve individuals on single-cell and monoclonal antibody level. Newly generated and pre-existing MBCs differed in their differentiation paths despite similar levels of SARS-CoV-2 and common corona virus S-reactivity. Pre-existing highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody secreting cells (ASCs). In contrast, newly generated MBCs derived from naïve precursors showed strong signs of antibody affinity maturation before differentiating into ASCs. Thus, although pre-existing human MBCs have an intrinsic propensity to differentiate into ASCs, the quality of the anti-S antibody and MBC response improved through the clonal selection and affinity maturation of naïve precursors.
- Design of SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model -
The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. In this study, we designed and synthesized 85 noncovalent PLpro inhibitors that bind to the newly discovered Val70Ub site and the known BL2 groove pocket. Potent compounds inhibited PLpro with inhibitory constant Ki values from 13.2 to 88.2 nM. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 microM. Oral treatment with Jun12682 significantly improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.
- Substrate recognition and selectivity in SARS-CoV-2 main protease: Unveiling the role of subsite interactions through dynamical nonequilibrium molecular dynamics simulations -
The main protease (Mpro) of the SARS-CoV-2 coronavirus employs a cysteine-histidine dyad in its active site to catalyse hydrolysis of the viral polyproteins. It is well established that binding of the substrate P1-Gln in the S1 subsite of Mpro active site is crucial for catalysis and this interaction has been employed to inform inhibitor design; however, how Mpro dynamically recognises and responds to substrate binding remains difficult to probe by experimental methods. We thus employed the dynamical nonequilibrium molecular dynamics (D-NEMD) approach to probe the response of Mpro to systematic substrate variations. The results emphasise the importance of P1-Gln for initiating a productive enzymatic reaction. Specifically, substituting P1-Gln with alanine disrupts the conformations of the Cys145 and His41 dyad, causing Cys145 to transition from the productive gauche conformation to the non-productive trans conformation. Importantly, our findings indicate that Mpro exhibits dynamic responses to substrate binding and likely to substrate-mimicking inhibitors within each of the S4-S2' subsites. The results inform on the substrate selectivity requirements and shed light on the observed variations in hydrolytic efficiencies of Mpro towards different substrates. Some interactions between substrate residues and enzyme subsites involve more induced fit than others, implying that differences in functional group flexibility may optimise the binding of a substrate or inhibitor in a particular subsite.
- High-throughput ML-guided design of diverse single-domain antibodies against SARS-CoV-2 -
Treating rapidly evolving pathogenic diseases such as COVID-19 requires a therapeutic approach that accommodates the emergence of viral variants over time. Our machine learning (ML)-guided sequence design platform combines high-throughput experiments with ML to generate highly diverse single-domain antibodies (VHHs) that bind and neutralize SARS-CoV-1 and SARS-CoV-2. Crucially, the model, trained using binding data against early SARS-CoV variants, accurately captures the relationship between VHH sequence and binding activity across a broad swathe of sequence space. We discover ML-designed VHHs that exhibit considerable cross-reactivity and successfully neutralize targets not seen during training, including the Delta and Omicron BA.1 variants of SARS-CoV-2. Our ML-designed VHHs include thousands of variants 4-15 mutations from the parent sequence with significantly improved activity, demonstrating that ML-guided sequence design can successfully navigate vast regions of sequence space to unlock and future-proof potential therapeutics against rapidly evolving pathogens.
Effect of Metformin in Reducing Fatigue in Long COVID in Adolescents - Conditions: Long COVID
Interventions: Drug: Metformin; Other: Placebo
Sponsors: Trust for Vaccines and Immunization, Pakistan
Not yet recruiting
A Randomized Trial Evaluating a mRNA VLP Vaccineâs Immunogenicity and Safety for COVID-19 - Conditions: COVID-19; SARS-CoV-2 Infection
Interventions: Biological: AZD9838; Biological: Licensed mRNA vaccine
Sponsors: AstraZeneca
Not yet recruiting
âThe Effect of Aerobic Exercise and Strength Training on Physical Activity Level, Quality of Life and Anxiety-Stress Disorder in Young Adults With and Without Covid-19â - Conditions: COVID-19
Interventions: Behavioral: Aerobic Exercise and Strength Training
Sponsors: Pamukkale University
Active, not recruiting
Safety Study of SLV213 for the Treatment of COVID-19. - Conditions: COVID-19
Interventions: Other: Placebo for SLV213; Drug: SLV213
Sponsors: National Institute of Allergy and Infectious Diseases (NIAID)
Not yet recruiting
Vale+TĂș Salud: Corner-Based Randomized Trial to Test a Latino Day Laborer Program Adapted to Prevent COVID-19 - Conditions: COVID-19
Interventions: Behavioral: COVID-19 Group Problem Solving; Behavioral: Standard of Care; Behavioral: Booster session
Sponsors: The University of Texas Health Science Center, Houston; National Institute on Minority Health and Health Disparities (NIMHD)
Recruiting
Collection of Additional Biological Samples From Potentially COVID-19 Patients for Monitoring of Biological Parameters Carried Out as Part of the Routine - Conditions: SARS CoV 2 Infection
Interventions: Diagnostic Test: RIPH2
Sponsors: CerbaXpert
Not yet recruiting
Promoting Engagement and COVID-19 Testing for Health - Conditions: COVID-19
Interventions: Behavioral: COVID-19 Test Reporting; Behavioral: Personalized Nudges via Text Messaging; Behavioral: Non-personalized Nudges via Text Messaging
Sponsors: Emory University; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Morehouse School of Medicine; Georgia Institute of Technology
Not yet recruiting
Mitigating Mental and Social Health Outcomes of COVID-19: A Counseling Approach - Conditions: Social Determinants of Health; Mental Health Issue; COVID-19
Interventions: Behavioral: Individual counseling; Behavioral: Group counseling; Other: Resources
Sponsors: Idaho State University
Not yet recruiting
Development and Qualification of Methods for Analyzing the Mucosal Immune Response to COVID-19 - Conditions: Certain Disorders Involving the Immune Mechanism
Interventions: Biological: Sampling; Biological: PCR (polymerase chain reaction) SARS-CoV-2
Sponsors: University Hospital, Tours
Not yet recruiting
Water-based Activity to Enhance Recovery in Long COVID - Conditions: Long COVID
Interventions: Behavioral: WATER+CT; Behavioral: Usual Care
Sponsors: VA Office of Research and Development
Not yet recruiting
Performance Evaluation of the Lucira COVID-19 & Flu Test - Conditions: COVID-19; Influenza
Interventions: Device: Lucira COVID-19 & Flu Test
Sponsors: Lucira Health Inc
Completed
Efficacy of Two Therapeutic Exercise Modalities for Patients With Persistent COVID - Conditions: Persistent COVID-19
Interventions: Other: exercise programe
Sponsors: Facultat de ciencies de la Salut Universitat Ramon Llull
Recruiting
Molecular mechanisms of dexamethasone actions in COVID-19: Ion channels and airway surface liquid dynamics - The COVID-19 pandemic has been a global health crisis of unprecedented magnitude. In the battle against the SARS-CoV-2 coronavirus, dexamethasone, a widely used corticosteroid with potent anti-inflammatory properties, has emerged as a promising therapy in the fight against severe COVID-19. Dexamethasone is a synthetic glucocorticoid that exerts its therapeutic effects by suppressing the immune system and reducing inflammation. In the context of COVID-19, the severe form of the disease is oftenâŠ
Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma - CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.
Antiviral Effects of Pyrroloquinoline Quinone through Redox Catalysis To Prevent Coronavirus Infection - The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease (COVID-19) is ongoing. Therefore, effective prevention of virus infection is required. Pyrroloquinoline quinone (PQQ), a natural compound found in various foods and human breast milk, plays a role in various physiological processes and is associated with health benefits. In this study, we aimed to determine the effects of PQQ on preventing coronavirus infections using a proxy Feline InfectiousâŠ
Dobrava hantavirus and coinciding SARS-CoV-2 infection mimicking thrombotic microangiopathy and responding to a single dose of eculizumab - The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has refocused scientific interest on gaining insight into the pathophysiology of systemic viral diseases. Complement activation has been characterized as a driver of endothelial injury and microvascular thrombosis in acute respiratory distress syndrome as well as hantavirus hemorrhagic fever with renal syndrome. On this occasion, we wish to report a case of severe hantavirus disease with coinciding SARS-CoV-2âŠ
Cardiovascular safety pharmacology of ivermectin assessed using the isoflurane-anesthetized beagle dogs: ICH S7B follow-up study - Antiparasitic ivermectin has been reported to induce cardiovascular adverse events, including orthostatic hypotension, tachycardia and cardiopulmonary arrest, of which the underlying pathophysiology remains unknown. Since its drug repurposing as an antiviral agent is underway at higher doses than those for antiparasitic, we evaluated the cardiovascular safety pharmacology of ivermectin using isoflurane-anesthetized beagle dogs (n=4). Ivermectin in doses of 0.1 followed by 1 mg/kg wasâŠ
Ligand concentration determines antiviral efficacy of silica multivalent nanoparticles - We have learned from the recent COVID-19 pandemic that the emergence of a new virus can quickly become a global health burden and kill millions of lives. Antiviral drugs are essential in our fight against viral diseases, but most of them are virus-specific and are prone to viral mutations. We have developed broad-spectrum antivirals based on multivalent nanoparticles grafted with ligands that mimic the target of viral attachment ligands (VALs). We have shown that when the ligand has aâŠ
Broad-spectrum antiviral activity of two structurally analogous CYP3A inhibitors against pathogenic human coronaviruses in vitro - Coronaviruses pose a permanent risk of outbreaks, with three highly pathogenic species and strains (SARS-CoV, MERS-CoV, SARS-CoV-2) having emerged in the last twenty years. Limited antiviral therapies are currently available and their efficacy in randomized clinical trials enrolling SARS-CoV-2 patients has not been consistent, highlighting the need for more potent treatments. We previously showed that cobicistat, a clinically approved inhibitor of Cytochrome P450-3A (CYP3A), has direct antiviralâŠ
Protection effects of mice liver and lung injury induced by coronavirus infection of Qingfei Paidu decoction involve inhibition of the NLRP3 signaling pathway - CONCLUSIONS: To sum up, our current study demonstrated that QFPD treatment has the capacity to alleviate infection-related symptoms, mitigate tissue damage in infected organs, and suppress viral replication in coronavirus-infected mice. The protective attributes of QFPD in coronavirus-infected mice are plausibly associated with its modulation of the NLRP3 signaling pathway. We further infer that QFPD holds substantial promise in the context of coronavirus infection therapy.
A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection - Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysisâŠ
Chemical Composition of Thyme (Thymus vulgaris) Extracts, Potential Inhibition of SARS-CoV-2 Spike Protein-ACE2 Binding and ACE2 Activity, and Radical Scavenging Capacity - Water and ethanol extracts of dried thyme (Thymus vulgaris) were analyzed for chemical composition, inhibition of the SARS-CoV-2 spike protein-ACE2 interaction, inhibition of ACE2 activity, and free radical scavenging capacity. Thirty-two compounds were identified in water extract (WE) and 27 were identified in ethanol extract (EE) of thyme through HPLC-MS. The WE (33.3 mg/mL) and EE (3.3 mg/mL) of thyme inhibited the spike protein-ACE2 interaction by 82.6 and 86.4%, respectively. The thyme WEâŠ
Pre-pandemic Executive Function Protects Against Pandemic Anxiety in Children with and Without Autism Spectrum Disorder - The COVID-19 pandemic may have exacerbated depression, anxiety, and executive function (EF) difficulties in children with autism spectrum disorder (ASD). EF skills have been positively associated with mental health outcomes. Here, we probed the psychosocial impacts of pandemic responses in children with and without ASD by relating pre-pandemic EF assessments with anxiety and depression symptoms several months into the pandemic. We found that pre-pandemic inhibition and shifting difficulties,âŠ
Implementing PCR testing in general practice-a qualitative study using normalization process theory - CONCLUSION: In its current form, the added diagnostic value of using POC PCR testing in general practice was not sufficient for the professionals to justify the increased work connected to the usage of the diagnostic procedure in daily practice.
Inhibition of bradykinin in SARS-CoV-2 infection: a randomised, double-blind trial of icatibant compared with placebo (ICASARS) - SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes.These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kininâŠ
Antiviral peptides inhibiting the main protease of SARS-CoV-2 investigated by computational screening and in vitro protease assay - The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays an important role in viral replication and transcription and received great attention as a vital target for drug/peptide development. Therapeutic agents such as small-molecule drugs or peptides that interact with the Cys-His present in the catalytic site of Mpro are an efficient way to inhibit the protease. Although several emergency-approved vaccines showed good efficacy and drastically dropped theâŠ
Plant-Derived Natural Compounds as an Emerging Antiviral in Combating COVID-19 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human virus that burst at Wuhan in China and spread quickly over the world, leading to millions of deaths globally. The journey of this deadly virus to different mutant strains is still ongoing. The plethora of drugs and vaccines have been tested to cope up this pandemic. The herbal plants and different spices have received great attention during pandemic, because of their anti-inflammatory, and immunomodulatory properties inâŠ