The immunization of healthcare workers in the early stages of the rollout of COVID-19 vaccines was prioritized in order to ensure uninterrupted medical care provision. At the same time the increasing number of available COVID-19 vaccines may trigger hesitancy towards the decision to get vaccinated. Thus, accumulating reliable information on the adverse events following immunization may educate and urge the general population to receive a COVID-19 vaccine. The present study aimed to evaluate the adverse events (AEs) following immunization with any of the available COVID-19 vaccine among Bulgarian healthcare workers (HCWs). A cross-sectional study among HCWs in Plovdiv, Bulgaria was conducted in the period March – September 2021. Through a semi-structured online questionnaire, the participants reported the adverse events following the administration of the first and second dose of a COVID-19 vaccine. A total of 253 respondents, vaccinated with one of the available vaccines against COVID-19 took part in the study. Of them 71.9% were females, and 75.9% received mRNA-based vaccines, while 24.1% received a viral-vector based vaccine. Overall 91.6% and 82.6% of all participants reported at least one local AE after the first and second dose of a COVID-19 vaccine. The share of respondents reporting at least one systemic AE after the first and second dose of a COVID-19 vaccine was 59.7% and 62.4% respectively. The most common local AE was pain at the injection spot (84.0%), while the most common systemic AEs were fatigue (54.9%), chills (43.2%), and headache (41.7%). The mRNA-based vaccines versions seem to cause higher prevalence of local AEs, while the vector-based vaccines were linked with increased prevalence of systemic AEs. Female HCWs and the younger age group were associated with an increased risk of adverse events generally. Our results added more evidence that mRNA-based and viral-vector based vaccines are generally safe. The reported adverse events were mild, although they occurred in a high share of the respondents. No serious AEs attributable to the vaccines were reported.

Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in close vicinity as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.

This work presents the results of a comprehensive physico-chemical and biological study of hu-mic substances samples – an extract of humic and fulvic acids. The performed loss on drying test showed a 22 times different dry matter content between EHS and FA. The morphology and dis-tribution of particles in the dry residue of the samples assessed using the methods of optical and digital microscopy demonstrated differences in the qualitative features of the microstructures of their surfaces and granulometries. Shimadzu X-ray fluorescence spectrometry revealed Si (8.1 and 1.7%), P (33.5 and 2.7%), S (4.3 and 59.5%), K (1.35 and 2.5%), Ca (10.9 and 3.2%), Mn (0.27 and 0.06%), Fe (11 and 0.05%), Cu (0.16 and 0.45%), Zn (0.06 and 0.02%) in the dry residues of the EHS and FA samples, respectively. A high intensity of the X-ray fluorescence signal for Fe atoms in the EHS sample was demonstrated. The FT-IR spectra for EHS and FA are characterized by simi-lar vibration frequencies that are characteristic of the chromone derivatives (1-benzopyran-4-one). The UV absorption spectrum is characterized by max = 281 nm for FA. The EHS solution showed a fluorescence maximum at em = 560 nm at ex = 280 nm. Using the DLS method, nanoparticles of 1 nm and 200 nm were detected in EHS and FA diluted solutions, which are likely to condition the biochemical and physical properties of humic acids. Using the Spiro-tox-test method, the absence of the toxic effect of humic acids on the cell model of ciliates Sp. am-bigua was established. When the cell model was incubated in a solution of a toxicant of the fluo-roquinolone group, a decrease in toxicity was demonstrated when diluted with the EHS solu-tion. The results of the study of the antiviral activity of EHS and FA showed that the study ob-jects in the culture of Vero-E6 cells, in doses non-toxic to cells, suppress the reproduction of the SARS-CoV-2 virus both in the study of the virucidal effect and in the study of the antiviral activ-ity according to the therapeutic and prophylactic model scheme of injection. The results obtained suggest that standardized drugs based on humic acids may open up new perspectives in their biomedical application as antiviral drugs.

Aims: Spironolactone is a steroidal mineralocoricosteroid receptor antagonist (MRA) used for treatment of resistant hypertension, heart failure and edema. It exerts class specific adverse effects that are shared by other MRAs. Additionally, it exerts unique “off target” steroidal effects that include gynecomastia, impotence and loss of libido in males and menstrual irregularity in females. Together, these have led to a poor tolerability and limited use despite positive results in many randomized, controlled clinical trials. We review the off-target effects of spironolactone that may summate with its MRA action to provide an advantageous profile for prevention or treatment of patients with COVID-19. Methods: Literature review using PubMed Central. Results: The blockade by spironolactone of the androgen receptor should diminish the expression of transmembrane protease serine 2 (TMPRSS2) that has an androgen promoter while its MRA action should enhance the expression of protease nexin1 (PN1) that inhibits furin and plasmin. TMPRSS2, furin and plasmin cooperated to process the SARS-CoV-2 spike protein to increase its high affinity binding to the angiotensin converting enzyme 2 (ACE2) and thereby promote viral cell entry. Its actions as an MRA may reduce inflammation and preserve pulmonary, cardiac and vascular functions. Its anti-plasmin action may combat hemostatic dysfunction. Conclusion: The hypothesis that the off-target effects of spironolactone summate with its MRA actions to provide special benefits for COVID-19 is worthy of direct investigation and clinical trial.

Biosensors are measurement devices that can sense several biomolecules, and are widely used for the detection of relevant clinical pathogens such as bacteria and viruses, showing outstanding results. Because of the latent existing risk of facing another pandemic like the one we are living due to COVID-19, researchers are constantly looking forward to developing new technologies for diagnosis and treatment of infections caused by different bacteria and viruses. Regarding that, nanotechnology has improved biosensors design and performance through the development of materials and nanoparticles that enhance their affinity, selectivity, and efficacy in detecting these pathogens, such as employing nanoparticles, graphene quantum dots, and electrospun nanofibers. Therefore, this work aims to present a comprehensive review that exposes how biosensors work in terms of bacterial and viral detection, and the nanotechnological features that are contributing to achieving a faster yet still efficient COVID-19 diagnosis at the point-of-care.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing pandemic of coronavirus disease 2019 (COVID-19). The worldwide transmission of COVID-19 from human to human is spreading like wildfire, affecting almost every country in the world. In the past 100 years, the globe did not face microbial pandemic similar in scale to COVID-19. Taken together, both previous outbreaks of other members of the coronavirus family (SARS-CoV and MERS-CoV) did not produce even 1% of the global harm already inflicted by COVID-19. There are also four other CoVs capable of infecting humans (HCoVs), which circulate continuously in the human population, but their phenotypes are generally mild, and these HCoVs received relatively little attention. These dramatic differences between infection with HCoVs, SARS-CoV, MERS-CoV, and SARS-CoV-2 raise many questions, such as: Why is COVID-19 transmitted so quickly? Is it due to the some specific features of the viral structure? Are there some specific human (host) factors? Are there some environmental factors? The aim of this review is to collect and concisely summaries the possible and logic answers to these questions.

The aim of this study was to assess the key laboratory features displayed by coronavirus disease 2019 (COVID-19) inpatients which associated with mild, moderate, severe and fatal course of the disease and, through longitudinal follow-up, to understand the dynamics of COVID-19 pathophysiology. All SARS-CoV-2 positive patients admitted to the University Hospital in Motol between March and June 2020 were included in this study. Severe course of COVID-19 was associated with elevation of proinflammatory markers, efflux of immature granulocytes into peripheral blood, activation of CD8 T cells, which infiltrate lungs, and transient liver disease. In particular, the elevation of serum gamma-glutamyl transferase (GGT) and histological signs of cholestasis were highly specific for patients with severe disease. In contrast, patients with fatal course of COVID-19 failed to upregulate markers of inflammation, showed dyscoordination of immune response and progressed towards acute kidney failure. COVID-19 is a disease with multi-organ affinity characterized by activation of innate and cellular adaptive immunity. Biliary lesion with elevation of GGT and organ-infiltration of IL-6 producing cells are defining characteristic for patients with fulminant disease.

Background: Over 900,000 cases of COVID-19 and 23,000 deaths have been reported till 13 July in India. Preserving the limited healthcare workforce is part of the strategy against the pandemic. Mortality and morbidity data have a role in customising this strategy. At this time, there is no published study on COVID-related mortality among doctors or other healthcare workers in India. Methods: A multi-pronged search was made for all reported deaths linked with COVID-19 among doctors in India. Details of COVID-linked deaths reported by mainstream media and by multiple professional social media sources were collected, screened, verified and analysed. Violent deaths occurring in the setting of pandemic-related work were separately listed. Deaths from other diseases were excluded. Results: Among 108 COVID-linked deaths among doctors, there were four pandemic-related violent deaths including three road accidents and a suicide. Of the 104 non-violent deaths, 55.5% were below 60 years of age, while 29.6% and 21% were below the age of 50 and 40 respectively. The average age at death was 56.3 (range 22 - 96). Over half of the deaths occurred among general practitioners, while surgical specialties accounted for 27% of the mortality. The geographic distribution of deaths of doctors correlated with the reported number of COVID-19 patients in each state. The total number of COVID-related healthcare worker deaths was 136, out of which eight (5.8%) were violent, and occurred in young individuals with an average age of 27.8 years. Conclusions: The majority of the 104 COVID-related non-violent deaths among doctors (55.5%) occurred below the age of 60. The average at death was 56.6 years. The states with highest number of COVID-19 cases had greater number of doctor deaths. Violent deaths among young healthcare workers in the setting of the pandemic requires special attention.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that causes the new Coronavirus disease (COVID-19). The symptoms range from mild to severe with a higher incidence of severe cases seen in patients with risk factors such as older age and comorbidities. COVID-19 is mainly spread through the inhalation of respiratory droplets from coughing or sneezing or via contact with droplet-contaminated surfaces. Paramedics should be aware that some aerosol generating procedures (AGPs) may put them at a higher risk of contracting the virus via possible airborne transmission. The use of remote triage clinical assessment is likely to increase as a result of the pandemic. There is no curative drug treatment for the virus and some medications may exacerbate its effects or make patients more susceptible to it. Paramedics should accept that feeling stressed by the pandemic is a natural response. Official guidelines and advice are evolving continually as the evidence on SARS-CoV-2 and COVID-19 grows. Paramedics should keep up to date with the latest clinical guidance from their employers.

The replication of species A rotaviruses (RVAs) and other RNA viruses involves recruitment of and inter-action with the cellular organelles lipid droplets (LDs), both physically and functionally. Inhibition of en-zymes involved in the cellular fatty acid biosynthesis pathway or of cellular lipases that degrade LDs re-duces the functions of ‘viral factories’ (viroplasms for rotaviruses or replication compartments of other RNA viruses) and decreases the production of infectious progeny virus. Similarly, disturbance of the cellular lipid homeostasis in various ways blocks the replication of flaviviruses (hepatitis C viruses, Zikavirus, others), HIV-1, SARS-CoV-2, picornaviruses, noroviruses, influenza viruses and other negative-strand RNA viruses.

Introduction: On March 11, 2020, the World Health Organization (WHO) declared Coronavirus disease 2019 (COVID-19) as a pandemic. The spread of the Delta variant of coronavirus started in June 2021 and accounted for the fifth peak of COVID-19 in Iran in July 2021. According to reports from other countries, vaccination protects against severe diseases caused by COVID-19, including the Delta variant. Studies have also shown that vaccination provides strong protection against SARS-CoV-2 infection, COVID-19-related hospitalization, and mortality. This retrospective cohort study was designed based on the medical care monitoring center (MCMC) database of Sayyad Shirazi Hospital.Methods: The following patient data were extracted for this study: demographic characteristics, signs and symptoms, ICU admission, need for aggressive oxygen therapy, including intubation, mortality, and vaccination status. Results: Being vaccinated was associated with a 4.14-fold increase in survival (adjusted OR=4.14; 95% CI: 2.22 to 7.69; P<0.01), and individuals in a younger age group demonstrated a 5.58-fold higher likelihood of surviving (adjusted OR=5.58; 95% CI: 4.25 to 8.14; P<0.01). The risk of severe COVID-19 was significantly lower in vaccinated individuals, showing a 3.12-fold decrease in risk (adjusted OR=3.12; 95% CI: 2.06 to 4.72; P<0.01), and in younger age groups, the risk exhibited a 3.28-fold decrease (adjusted OR=3.28; 95% CI: 2.66 to 4.04; P<0.01).Conclusion: The present results suggest that receiving at least one dose of COVID-19 vaccine had a significant relationship with decreased COVID-19 severity and mortality in vaccinated patients compared to unvaccinated patients.

Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from the infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn, increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules each of which can downregulate ACE2, while the infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19 associated neurological disorders.

More than 600 Healthcare workers died due to COVID-19 infection until January 2022 in Ecuador. Even though the COVID-19 vaccines are safe, local, and systemic reactions were reported among physicians. This study aims to analyze the Adverse events (AEs) of COVID-19 vaccines with an emphasis on homologous and heterologous booster doses. An electronic survey was performed in Quito- Ecuador, directed to physicians who were vaccinated with the three doses of COVID-19 vaccines. 210 participants were analyzed after administering any doses of the vaccines. At least one AE was identified in 60.0% (126/210) of the sample after the first dose, 52.40% (110/210) after the second dose, and 75.2% (158/210) after the booster dose. The most frequent AEs were localized pain, myalgia, headache, and fever. At least one drug was used in 44.3% of the population after the first dose, 37.1% after the second dose, and 63.8% in the booster dose. Heterol-ogous booster produces more AEs compared with homologous booster (80.1% vs. 53.8%), and 77.3% of participants reported that interfered with daily activities. Similar studies agree that reactogenicity occurs mainly with heterologous vaccination compared to ho-mologous vaccination. This situation affected physicians’ performance in daily activities and led them to use medication for the symptoms

SARS-CoV-2 belongs to the group of RNA viruses with a pronounced tendency to mutate. Omicron BA.2.75 is a subvariant believed to be able to suppress the currently dominant BA.5. Omicron BA.2.75 is characterized by a greater infectivity compared to earlier Omicron variants. However, Gibbs energy of biosynthesis of virus particles is slightly less negative compared to those of other variants. Thus, the multiplication rate of Omicron BA.2.75 is lower than that of other variants. This leads to slower accumulation of newly formed virions and less damage to host cells, indicating evolution of SARS-CoV-2 towards decreasing pathogenicity.

The transcriptional response of human blood leukocytes to SARS-CoV-2 infection was investigated focusing on the differences between mild and severe cases and between age subgroups. Weighted gene co-expression network analysis and comparative gene expression analysis were used. Three transcriptional modules positively associated with the traits of interest and their respective high hierarchy genes were identified. Enrichment analyses showed that the yellow module, associated with severe cases and older patients, had an overrepresentation of genes involved in inflammatory and innate immune responses, and neutrophil activation. The magenta and black modules, associated with disease severity and younger patients, contained genes related to innate immunity and inflammation and genes that regulate those responses. Subnetworks for these modules were constructed using genes enriched for innate immunity, inflammation, immunoregulation and differentially expressed genes (severe vs. mild). Their analysis evidenced that immunoregulatory functions are more activated in the modules associated with younger patients, what may help to explain the better disease course and faster recovery observed in younger COVID-19 patients. Comparative gene expression analysis between severe and mild groups, followed by gene enrichment and normalized gene expression analyses, revelated a set of 23 potential biomarkers for COVID-19 severity, of which 13 are newly described.

Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors influence COVID-19 by applying the Adverse Outcome Pathway (AOP) framework well-established in regulatory toxicology. This framework aims to model the sequence of events starting from an initial interaction of a stressor with the organism and the progress through key biological events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 patients have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.

Currently, SARS-CoV-2 infection which is the causative agent for COVID-19 disease is a worldwide pandemic with more than 100 million global cases and more than 2.0 million deaths (as of January, 2021). While several vaccines for prevention of COVID-19 have already been registered by the regulatory authorities, the problem is that the substitution rate of this virus is estimated to be one change per 2 weeks, thus mutations could arise that threaten the efficacy of vaccines. Unfortunately, there is no current evidence from random clinical trials to recommend any specific post-exposure treatment for patients with suspected or confirmed COVID-19 disease. Here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated harmless viruses might interact in patients infected with pathogenic virus. During SIT, the patient benefits from superinfection with an apathogenic double-stranded RNA (dsRNA) virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). The safety of orally administered acid-resistant IBDV strain R903/78 reverse engineered viral drug candidate was demonstrated in 10 stage IV cancer patients who exhausted all conventional therapy. Following repeated oral administration of the virus up to 10⁹ infectious units (IU)/ dose, only mild flu-like side effects were reported in some patients. Proof-of-principle efficacy was demonstrated in an early COVID-19 patient who was successfully treated with 3x10⁶ IU of an attenuated IBDV vaccine. A small scale dose-finding Phase I safety study is proposed.

To understand lung damage caused by COVID-19, we deduced two-phase lung damage mechanisms. After the lungs are infected with SARS-CoV-2 virus, the affected lung tissue swells and surface properties of pulmonary capillaries change, resulting in an increased flow resistance of affected capillaries. If a sufficient number of capillaries are affected by the infection, the swelling and increased cell wall adhesion collectively raise pulmonary vascular resistance. The increased vascular resistance further increases the dwell times of WBCs in affected capillaries and nearly capillaries. When pulmonary pressure is sufficiently higher, WBCs are forced to squeeze into interstitial spaces or alveolar spaces when local pressures are higher than what the capillaries can withstand. When more and more WBCs are dynamically retained, the flow resistance of more capillaries rises, pulmonary vascular resistance rises, and pulmonary pressure rises. The rise in the pulmonary pressure in turn results in elevated capillary pressures. When capillary pressures around the alveoli are sufficiently high, they cause interstitial pressures to change from normally negative values to positive values. The positive pressures cause fluid leakage to the alveolar space and thus degrade lung function. Tissue swelling, and occupation of WBCs in interstitial spaces and alveolar spaces further reduce compressible volume, and thus cause further rise in the pulmonary vascular resistance and pulmonary pressure. When the pulmonary pressure has reached a critical point as in the second phase, the blood breaks capillary walls and squeezes through interstitial spaces to reach alveolar spaces, resulting in irreversible lung damages. The available free volume in the thorax cage, organ usable capacities, temperature and humid are expected to have great impacts on degree of lung damages. The free volume in the thorax cage, lung usable surplus capacity, and other organ usable capacities determine the arrival time of last-phase irreversible damage. The mechanisms imply that the top priority for protecting lungs is maintaining pulmonary micro-circulation and preserving organ functions in the entire disease course while controlling viral reproduction should be stressed in the earliest time possible. The mechanisms also explain leukecytes are recruited and migrated into inflamed tissues by increasing their dwell times caused by increased local flow resistance.

Coronavirus disease 2019 (COVID-19) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in tremendous morbidity and mortality worldwide. A major underlying cause of COVID-19 mortality is a hyperinflammatory cytokine storm in severe/critically ill patients. Although many clinical trials are testing the efficacy of targeting inflammatory cytokines/chemokines in COVID-19 patients, the critical inflammatory mediator initiating COVID-19 patient death is undefined. Here we suggest that the immunopathological pathway leading to COVID-19 mortality can be divided into three stages with distinct clinical features that can be used to guide therapeutic strategies. Our interpretation of the recently published clinical trials from COVID-19 patients suggests that the clinical efficacy in preventing COVID-19 mortality using IL-1 blockade is subjected to notable caveats, while that for IL-6 blockade is suboptimal. We discuss critical factors in determining appropriate inflammatory cytokine/chemokine targets, timing, and combination of treatments to prevent COVID-19 mortality.

After the appearance of first cases of ‘pneumonia of unknown origin’ in the Wuhan city, China, during late 2019, the disease progressed fast. Its cause was identified as a novel coronavirus, named provisionally 2019-nCoV. Subsequently, an official name was given as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) by the International Committee on Taxonomy of Viruses (ICTV) study group. The World Health Organization (WHO) named the Coronavirus disease-2019 as COVID-19. The epidemics of COVID-2019 have been recorded over 113 countries/territories/areas apart from China and filched more than 4292 humans, affecting severely around 1,18,326 cases in a short span. The status of COVID-2019 emergency revised by the WHO within 42 days from Public Health International Emergency (January 30, 2020) to a pandemic (March 11, 2020). Nonetheless, the case fatality rate (CFR) of the current epidemic is on the rise (between 2-4%), relatively is lower than the previous SARS-CoV (2002/2003) and MERS-CoV (2012) outbreaks. Even though investigations are on its way, the researchers across the globe have assumptions of animal-origin of current SARS-CoV-2. A recent case report provides evidence of mild COVID-2019 infection in a pet dog that acquired COVID-2019 infection from his owner in Hong Kong. The news on travellers associated spread across the globe have also put many countries on alert with the cancellation of tourist visa to all affected countries and postponement of events where international visits were required. A few diagnostic approaches, including quantitative and differential real-time polymerase chain reaction assays, have been recommended for the screening of the individuals at risk. In the absence of any selective vaccine against SARS-CoV-2, re-purposed drugs are advocated in many studies. This article discourse the current worldwide situation of COVID-2019 with information on virus, epidemiology, host, the role of animals, effective diagnosis, therapeutics, preventive and control approaches making people aware on the disease outcomes.

Approximately 10–20% of individuals suffering from COVID-19 develop prolonged symptoms known as long COVID or post-COVID condition (LC). This review aimed to assess healthcare resource use (HCRU) and healthcare costs associated with LC. Because LC is not clearly defined and often remains undiagnosed, studies reporting on long-term follow-up of individuals with a COVID-19 diagnosis were also included. Among the 41 publications included, 36 reported on HCRU and 16 on costs. Individuals with LC had significantly elevated HCRU and healthcare cost vs controls without a COVID-19 diagnosis over ≥15 months, with a 7.6%–13.1% increase in total healthcare costs per person per month as assessed by difference-in-difference analysis. Among studies that did not specifically refer to LC, having a COVID-19 diagnosis was associated with a significant 4–10% increase in long-term total HCRU over 6–8 months and a 1.3- to 2.9-fold relative increase in total healthcare costs over 6 months. Due to the heterogeneity of included studies, high-quality evidence is needed to better understand the economic burden of LC. In the absence of effective treatments, prioritizing prevention of acute COVID-19, e.g., through vaccination, may be crucial for preventing LC and the associated long-term HCRU and medical spending.

Since December 2019, the COVID-19 virus has rapidly spread worldwide, prompting the World Health Organization (WHO) to declare it a pandemic and advocate for the widespread use of face masks to mitigate transmission. In this review, we delve into the potential impact of prolonged face mask use on temporomandibular joint (TMJ) health, an area that has garnered limited attention amidst COVID-19 research. Research has revealed that improper mask fit, and constant readjustment can lead to TMJ abnormalities. Similarly, there is a demonstrated correlation between continuous mask usage and increased incidence of headaches, temporomandibular pain, and diminished quality of life. Many studies have highlighted discomfort in the preauricular area, headaches, TMJ noises, headache, jaw pain, and muscle fatigue, as well as dermatological disorders that have been attributed to prolonged mask wear and its impact on TMJ. Our study catalyzes future research endeavors, urging a deeper exploration of the implications of long-term mask wear, not only in the context of the COVID-19 pandemic but also among occupational groups regularly exposed to extended mask use. By unraveling the complexities of TMJ health in the face of evolving preventive measures, we aim to enhance our understanding and safeguard the well-being of mask-wearers worldwide.

COVID-19 was an inflammatory pneumonia caused by a respiratory infection with a coronavirus named SARS-CoV-2. Severely ill COVID-19 patients could die of acute pulmonary and systemic inflammation. Thus, there was a theory that long COVID-19 shared many similarities with systemic autoimmune diseases. There was also a theory that the SARS-CoV-2 virus could infect many cell- and tissue-types distributed throughout multiple organ systems of the body. I aim to review the above theories using unbiased high-throughput datasets cataloguing gene expression. Studies reviewed used the technology of next generation sequencing, either as bulk tissue RNA sequencing, or as single-cell RNAs sequencing; ingenious methods for signal deconvolution were then used to identify individual cell types. Datasets reviewed suggested that severe COVID-19 induced expression of genes associated with pro-inflammatory signaling, tissue development or remodeling, scarring, or cell death. The datasets also provided evidence for several inflammatory syndromes associated with COVID-19, such as neuronal COVID, acute respiratory disease syndrome, vascular inflammation, or multisystem inflammatory syndrome. Indeed, inflammatory signal during severe COVID-19 was reported in many cell types, for example in structural cells, in infiltrating immune cells, in the vascular system, or in circulating cells in the blood. There was also frequently a change in proportions of immune cell-types in the blood, epithelial cells in the lungs, or among infiltrating immune cells.

People with sickle cell disease (SCD) are at greater risk of severe illness and death from respiratory infections, including COVID-19 than people without SCD (Centers for Disease Control and Prevention, USA). Vaso-occlusive crises (VOC) in SCD and severe SARS-CoV-2 infection are both characterized by thrombo-inflammation mediated by endothelial injury, complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion, and activation of the coagulation cascade. Notably, lipid mediators, including thromboxane A2, significantly increase in severe COVID-19 and SCD. In addition, the release of thromboxane A2 from endothelial cells and macrophages stimulates platelets to release microvesicles which are harbingers of multicellular adhesion and thrombo-inflammation. Currently, there are limited therapeutic strategies targeting platelet-neutrophil activation and thrombo-inflammation in either SCD or COVID-19 during acute crisis. However, due to many similarities between the pathobiology of thrombo-inflammation in SCD and COVID-19, therapies targeting one disease may likely be effective in the other. Therefore, the preclinical and clinical research spurred by the COVID-19 pandemic, including clinical trials of anti-thrombotic agents, are potentially applicable to VOC. Here, we first outline the parallels between SCD and COVID-19; second, review the role of lipid mediators in the pathogenesis of these diseases and lastly, examine the therapeutic targets and potential treatments for the two diseases.

The less virulent human (h) coronaviruses (CoVs) 229E, NL63, OC43, and HKU1 cause mild, self-limiting respiratory tract infections, while the more virulent SARS-CoV-1, MERS-CoV, and SARS-CoV-2 have caused severe outbreaks. The CoV envelope (E) protein, an important contributor to the pathogenesis of severe hCoVs infections, may provide insight into this disparate severity of the disease. We, therefore, generated full-length E protein models for SARS-CoV-1, -2, MERS-CoV, HCoV-229E, and HCoV-NL63 and docked C-terminal peptides of each model to the PDZ domain of the human PALS1 protein. The PDZ-binding motif (PBM) of the SARS-CoV-1, -2, and MERS-CoV models adopted a more flexible, extended coil while the HCoV-229E and HCoV-NL63 models adopted a less flexible alpha helix. All the E peptides docked to PALS1 occupied the same binding site and the more virulent hCoV E peptides generally interacted more stably with PALS1 than the less virulent ones. We propose that the increased flexibility of the PBM in more virulent hCoVs may permit more stable binding to various host proteins, thereby possibly contributing to more severe disease. This is the first paper to model full-length 3D structures for both more virulent and less virulent hCoVs E proteins, providing novel insights for possible drug and/or vaccine development.

This study aimed to evaluate the mixed and homogeneous application of the inactivated SARS-CoV-2 vaccine CoronaVac (CV) and the mRNA vaccine BNT162b2 (BNT). This prospective cohort study included 235 health care workers, who had received two prime shots with CoronaVac. They were divided into three cohorts after the third month: Cohort-I (CV/CV); Cohort-II (CV/CV/CV) and Cohort-III (CV/CV/BNT). Anti-S-RBD-IgG and total an-ti-spike/anti-nucleocapsid-IgG antibody concentrations were examined in vaccinated health workers at the 1st, 3rd and 6th months following the second dose of the vaccination. The mean age of 235 health care workers who participated in the project was 39.51±10.39 (min-max: 22-64). At the end of the 6th month, no antibodies were detected in 16.7% of Cohort-I participants, and anti-S-RDB IgG levels showed a decrease of 60% compared to the levels of the 3rd month. The antibody concentrations of the 6th month were found to have increased by an average of 5.13 times compared to the 3rd-month levels in the Cohort-II and 20.4 times in Cohort-III. The heterologous vaccination strategy “CoronaVac and BNT162b2 regimen” is able to induce a stronger immunity and it will help remove inequalities in the developing world where CoronaVac was the initial prime.

Abstract Introduction:The Robert Koch Institute (RKI) managed the exchange of cross-border contact tracing data between public health authorities (PHA) in Germany and abroad during the COVID-19 pandemic. Aim: We aimed to describe the extent of RKI cross-border contact tracing and the challenges experienced. Methods:We analysed cross-border COVID-19 contact tracing events from 03 February to 05 April 2020 using information exchanged through the European “Early Warning Response System” (EWRS) as well as communication with International Health Regulation (IHR) national focal points. We described events by PHA involved, number of contact persons and exposure context. Results:The RKI processed 467 events, initiating contact to PHA 1,099 times (median 1, IQR [1;2]) and sharing data on 5,099 contact persons. Of 327 (70%) events with known exposure context, most common reported were exposures on aircraft 64 (14%), on cruise ships 24 (5%) and exposures related to non-transport contexts 210 (45%). Cruise ship and aircraft exposures yielded higher median numbers of authorities contacted (10[2;16], 4[2;11]) and contact persons (60 [9;269], 2[1;3]) than non-transport related exposures (1[1;6] and 1[1;2]), respectively. The median time spend on contact tracing activities was the highest for cruise ships: 5 days [IQR 3;9]. Conclusion:In the current COVID-19 pandemic cross-border contact tracing is considered a critical component of the outbreak response. While the majority of international contact tracing activities did not relate to exposure events in transport, they contributed substantially to the workload. The numerous communications highlight the need for fast and efficient global outbreak communication channels between PHA.

As the world endures the coronavirus disease 2019 (COVID-19) pandemic, conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs.

The coronavirus disease caused by SARS-CoV-2 (known as COVID 19) is highly contagious and has spread rapidly over 200 countries over last three months. WHO suggested urgent escalation in testing, isolation and contact tracing, as the "backbone" of managing the pandemic. Globally, the detection of SARS-CoV-2 in patients are done by RT-PCR and blood antibody-based testing. In addition to the existing processes, flow-cytometry could be used as a high-throughput and efficient diagnostic method for detection of COVID 19. The suspected COVID 19 samples can be analyzed using ‘Indirect flow cytometry’, with the specific primary antibody and fluorescent tagged secondary antibodies. The fluorescence signal can distinguish the infected v/s non-infected samples. In the present article, we have summarized the applications of Flow virometry to study various viruses and have proposed possible application in the detection of COVID 19.

Background: The mortality and severity in COVID-19 is increased in patients with comorbidities. The aim of this study was to evaluate the unknown risk of severity and mortality in COVID-19 patients with underlying kidney and liver diseases. Method: We retrieved data on the clinical features and primary composite end point of COVID-19 patients released from inception till 16^th of April 2020 from Medline and Embase. The data on two comorbidities, liver diseases and chronic kidney disease, present in COVID-19 were pooled and statistically analysed to explain the associated severity and mortality rate. Results: 142 abstracts were screened, and 41 full articles were then read. In total, 22 studies including 5595 COVID-19 patients were included in this study with case fatality rate of 16%. The prevalence of liver diseases and CKD were 3% (95%CI; 2%-3%) and 1% (95%CI; 1%-2%) respectively. In patients with COVID-19 and underlying liver diseases, 57.33% (43/75) cases were severe with 17.65% mortality. While in CKD patients with COVID-19, 83.93% (47/56) severity and 53.33% (8/15) mortality were reported. Conclusion: This study found an increased risk of severity and mortality in COVID-19 patients with liver diseases and CKD. This will allow for better clinical management and inform more stringent preventative measures for this group of patients.

Evidence suggests that COVID-19 infection increases the risk of type 1 (T1D) and type 2 diabetes (T2D). Diabetes, in turn, increases COVID-19 susceptibility and contributes to increased COVID-19 morbidity and mortality. Oxidative stress (OxS) has emerged as a common factor driving the pathogenesis of diabetes and COVID-19 caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). The mechanistic links between OxS, T2D, and COVID-19 have primarily been studied in adults and will be summarized in this review. However, we suggest that studying these interconnections in children and young adults is critical since early intervention is optimal for improving outcomes. At the height of the pandemic, COVID-19 was a leading cause of death in children and young people, and people in this age group are as susceptible to COVID-19 as adults and the elderly. Glutathione (GSH) is the primary water-soluble intracellular antioxidant and can be deficient in both diabetes and COVID-19. GSH is a tripeptide containing cysteine (CYS), glutamic acid (GLU), and glycine (GLY). Strategies to increase GSH levels may be beneficial in helping to manage COVID-19-induced diabetes as well as diabetes-induced COVID-19 risk. Dietary supplementation with GlyNAC may be optimal since it contains two metabolic GSH precursors, i.e., n-acetyl-l-cysteine (NAC) and GLY.

Determining the genetic contribution of susceptibility to severe SARS-CoV-2 infection outcomes is important for public health measures and individualized treatment. Through intense research on this topic, several hundred genes have been implicated as possibly contributing to the severe infection phenotype(s); however, the findings are complex and appear to be population-dependent. We aimed to determine the contribution of human rare genetic variants associated with a severe outcome of SARS-CoV-2 infections and their burden in the Slovenian population. A panel of 517 genes associated with severe SARS-CoV-2 infection were obtained through an extensive review of the literature, and additionally included target genes identified by the COVID-19 Host Genetic Initiative, as well as the curated Research COVID-19 associated genes from PanelApp, England Genomics. Whole genome sequencing was performed using PCR-free WGS on DNA from 60 patients hospitalized due to severe COVID-19 disease, and the identified rare genomic variants were analyzed and classified according to the ACMG criteria. Background prevalence in the general Slovenian population was determined by comparison with sequencing data from 8025 individuals included in the Slovenian genomic database (SGDB). Results show that several rare pathogenic/likely pathogenic genomic variants in genes CFTR, MASP2, MEFV, TNFRSF13B, and RNASEL likely contribute to the severe infection outcomes in our patient cohort. These results represent an insight into the Slovenian genomic diversity associated with severe COVID-19 outcome.

Many ailments can be diagnosed while they are asymptomatic, meaning that the patient has no signs or symptoms of a progressing disease. If caught in their initial stage of formation, these maladies can be effectively treated, leading to successful outcomes; curative therapies can halt illnesses from advancing, thus improving the quality of life, and long-term survival of the patient. Still cutting-edge upgrades in precision technologies are necessary for early, reliable, affordable, and rapid disease detection, but also are vital for the well-being of people and the future of global public health. The emerging role and utility of non-invasive and repeatable diagnostic test approaches for detection of health conditions has been liquid biopsies based on genomic biomarkers. As such, biological fluids permit any measurable molecular indicator or signature (e.g., proteins), to provide valuable information on individual’s wellness and/or disease. Among the bodily secretions used for non-invasive diagnostics is sputum, a complex viscous gel-like biopolymeric network, that has gained growing recognition as a rich source of biomarkers of airway infections, pulmonary diseases, and serves as a determinant to reveal other illnesses. As per the World Health Organization, the burden of respiratory conditions is exacerbated by factors, ranging from considerable subjection to air pollution and occupational contaminants, to tobacco smoking and second-hand smoke, in addition to poor socio-economic status. Due to the likely increase of these determinants, respiratory tract ailments are on the rise, affecting the health of many individuals, in addition to putting stress on healthcare facilities and services worldwide. We therefore highlight the need to use expectorated or induced sputum specimens as a routine sample source for testing valuable protein biomarkers to diagnose these chronic maladies, to predict inflammation and disease progression, as well as monitor the effectiveness of treatments. Further, we discuss the urgency for fast and reliable point-of-care methods to detect and quantify crucial protein biomarkers in sputum specimens, and limitations faced when dealing with their complex matrices.

SARS-CoV-2 virulence is known to increase with lowering of environmental temperature and solar ultraviolet radiation; therefore, we have focused our real-world nationwide study concerning with COVID-19 trends and dynamics on the coldest seasons of the year in Italy, the Western country hardest hit at the onset of the pandemic, comparing the autumn-winter of 2020 (before mass vaccination but when the emergency machinery was fully operative in terms of tracing and swabs) with the autumn-winter of 2021 (after mass vaccination), and analyzing the mortality burden by age groups and life stages in the years 2019 (pre-COVID-19), 2020 (before mass vaccination) and 2021 (after mass vaccination). Methods: During the state of national health emergency, the Civil Defense Department released the aggregate data coming from the Higher Institute of Health, the Ministry of Health, the Italian Regions, and the Independent Provinces, to inform the population (58.85 million people) about the pandemic situation, daily. Among these data there were the number of contagions, performed swabs, hospitalizations in Intensive Care Units (ICU), non-ICU patients, and deaths. By means of a team effort, we have collected and elaborated all these data, comparing the COVID-19 pandemic in Italy during the autumn-winter of 2020 with the autumn-winter of 2021. Moreover, we have extracted from the database of the National Institute of Statistics the total number of annual deaths in Italy during the years 2019, 2020 and 2021, comparing them to each other in order to evaluate the mortality burden attributable to COVID-19. Results: From the autumn-winter of 2020 to the autumn-winter of 2021, the contagions increased by ≈285%, however against a ≈290% increase in the performed swabs; therefore, the mean positivity rate passed from 8.74% before mass vaccination to 8.59% after mass vaccination. The unprecedent vaccination campaign allowed a ≈251% abatement in COVID-19 deaths, and a reduction of ≈224% and ≈228% in daily ICU and non-ICU hospitalizations due to COVID-19, respectively. Regarding COVID-19 deaths, in 2020 there was a mortality excess of ≈14.3% quantifiable in 105,900 more deaths compared to 2019, the pre-COVID-19 year; 103,183 out of 105,900 deaths occurred in older adults (≥60 years), which is equivalent to ≈97.4%, while in adults over 50, the segment of population just below older adults, in 2020 there were 2807 more deaths than in 2019. Surprisingly, from the analysis of our data, it is emerged that under the age of 40 in the years 2019, 2020 and 2021 there were 7103, 6808 and 7165 deaths, respectively. This means that in subjects under 40 during 2020 there were 295 fewer deaths than in 2019, while during 2021 there were 357 more deaths than in 2020, equivalent to ≈5.2% more. Conclusions: COVID-19 is a potential life-threatening disease mainly in older adults, as they are the most vulnerable due to inherent immunosenescence and inflammaging. Extensive vaccination in this segment of population with up-to-date vaccines is the means to reduce deaths, hospitalizations, and ICU pressure in the public interest. In the event of future threats, a new mass vaccination campaign must not be implemented without taking into account the individual age; it should primarily be aimed at people over 60 and at patients of any age with immune deficits, and secondly at people over 50. COVID-19 vaccination shows a favorable benefit-risk balance in older adults, while this balance falls under the age of 40; this younger segment of population should be therefore exempt from any mandatory vaccination.

After three years of the onset of the pandemic, there is scarce evidence about how COVID-19 disease affect the female reproductive system, and consequently, the menstrual cycle. Since the common causes of secondary amenorrhea are considered as exclusion criteria in the studies about menstrual changes following SARS-CoV-2 infection, the prevalence of this event and the influencing factors in formerly menstruating women remains unknown. A retrospective observational cross-sectional study was conducted on Spanish adult women (N= 17,512), using an online survey; a subpopulation of SARS-CoV-2-infected-formerly menstruating women was included in the present analysis (n= 72). Collected data included general characteristics, medical history, and specific information about COVID-19 disease. 38.9% of the respondents experienced menstrual-related disturbances after suffering from the COVID-19 disease, unexpected vaginal bleeding being the most common (20.8%). Other alterations related with the length – “shorter” by 12.5% − and the flow − “heavier than usual” 30.3% − of the menstrual bleeding were reported. The binary logistic regression showed that being a perimenopausal woman (AOR 4.608, CI 95%, 1.018 – 20.856, p = 0.047) and having heavy menstrual bleeding (AOR 4.857, CI 95%, 1.239 – 19.031, p=0.023) are influential factors. This evidence could help health professionals to provide scientifically up-to-date information to their patients, empowering them to actively manage their reproductive health, especially in those societies where menstrual health is still a taboo.

All severe cases of SARS-CoV-2 infections are characterized by a high risk of disease progression towards ARDS, leading to bad outcome. Respiratory symptoms in COVID-19 patients often do not correspond to disease’s worsening. A dysregulated host response to the large viral load could play a key role in the disease progression. In our sample median age was 74 years (72-75) and 54% were men. Median period of hospitalization was 9 days. Firstly, we observed an asynchronous trend of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) in 764 selected among 963 patients who were consecutively recruited in two hospitals (Cannizzaro, S. Marco) in Catania, Italy. NLR values in deceased patients showed an increase from baseline over time. By contrast, CRP tended to fall from baseline to median day of hospitalization in all four subgroups, but steeply increased at the end of hospitalization only in ICU-admitted patients. Then we evaluated the relationships between NLR and CRP as continuous variables with PaO2/FiO2 ratio (P/F). Finally, we made mediation and moderation analyses to determine the link between inflammation (CRP), immune system (neutrophils and lymphocytes) and respiratory failure (P/F). CRP, neutrophils and P/F are linked in the same pathogenetic chain leading to respiratory failure.

Studies have shown that COVID-19 patients with prediabetes frequently present with high plasma glucose levels on hospital admission. However, whether the glycemic abnormalities are temporary or persist after recovery from the illness is unclear. We conducted a prospective cohort study of 69 COVID-19 patients with prediabetes (HbA1c 5.7-6.4%) who were admitted to a tertiary care hospital in Chennai, India, from May to October 2020 and were discharged alive. Over a mean follow-up of 146.6 (SD: 72.5) days, the mean fasting plasma glucose rose by 16.8 mg/dl (from 119.3-136.1 mg/dl), 2-hr post-prandial glucose by 61.0 mg/dl (from 176.2-237.2 mg/dl), and HbA1c by 0.6% (5.9-6.5%). Of the 49 (84.5%) patients who were discharged with glucose-lowering medications, 40 (81.6%) continued taking them at the first follow-up visit (mean of 50.1 days from admission), and 39 (79.6%) continued taking them at the second follow-up visit (mean of 114.3 days from first the follow-up visit). In addition, 12.1% of patients developed new-onset diabetes after recovery from the illness. Continuous monitoring of glycemia and detecting new-onset diabetes in COVID-19 patients with prediabetes after recovery are essential, as the metabolic effects of SARS-CoV-2 persist for several months.

The goal of this paper is to contribute the perspective of a systems engineer to the effort to fight pandemics. The availability of low latency case data and effectiveness of social distancing suggest there is sufficient control for successful smoothing and targeting almost any desired level of low or high cases and immunity. This control proceeds from spontaneous public reaction to caseloads and news as well as government mediated recommendations and orders. We simulate multi-step and intermittent-with-feedback partial unlock of social distancing for rapidly-spreading moderate-mortality epidemics and pandemics similar to COVID-19. Optimized scenarios reduce total cases and therefore deaths typically 8% and up to 30% by controlling overshoot as groups cross the herd immunity threshold, or lower thresholds to manage medical resources and provide economic relief. We analyze overshoot and provide guidance on how to damp it. However, we find overshoot damping, whether from expert planning or natural public self-isolation, increases the likelihood of transition to an endemic disease. An SIR model is used to evaluate scenarios that are intended to function over a wide variety of parameters. The end result is not a case trajectory prediction, but a prediction of which strategies produce near-optimal results over a wide range of epidemiological and social parameters. Overshoot damping perversely increases the chance a pathogen will transition to an endemic disease, so we briefly describe the undershoot conditions that promote transition to endemic status.

Viruses rely on host cells to replicate their genomes and assemble new viral particles. Thus, they have evolved intricate mechanisms to exploit host factors. Host cells, in turn, have developed strategies to inhibit viruses, resulting in a nuanced interplay of co-evolution between virus and host. This dynamic often involves competition for resources crucial for both host cell survival and virus replication. Iron and iron-containing cofactors, including iron-sulfur clusters, are known to be a heavily battled resource during bacterial infections where control over iron can tug the war in favor of the pathogen or the host. It is logical to assume that viruses also engage in this competition. Surprisingly, our knowledge about how viruses utilize iron (Fe) and iron-sulfur (FeS) clusters remains limited. The handful of reviews on this topic primarily emphasize the significance of iron in supporting the host immune response against viral infections. The aim of this review, however, is to organize our current understanding of how viral proteins utilize FeS clusters, to give perspectives on what questions to ask next and to propose important avenues for future investigations.

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction. There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner. Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

Background: The epidemiological situation generated by COVID-19 has cast into sharp relief the delicate balance between public health priorities and the economy, with businesses obliged to toe a line between employee health and continued production. In an effort to detect as many cases as possible, isolate contacts, cut transmission chains and limit the spread of the virus in the workplace, mass testing strategies have been implemented in both public health and industrial contexts to minimize the risk of disruption in activity. Objective: To evaluate the economic impact of mass workplace testing strategy as carried out by a large automotive company in Catalonia in terms of health and healthcare resource savings. Methodology: Analysis of health costs and impacts based on the estimation of mortality and morbidity avoided because of screening and the resulting savings in healthcare costs. Results: The economic impact of the mass workplace testing strategies (using both PCR and RAT tests) was approximately €10.44 per test performed or €5,575.49 per positive detected. 38% of this figure corresponds to savings derived from better use of health resources (hospital beds, ICU beds and follow-up of infected cases), while the remaining 62% corresponds to improved health rates due to avoided morbidity and mortality. In scenarios with higher positivity rates and a greater impact of the infection on health and the use of health resources, these results could be up to ten times higher (€130.24 per test performed or €69,565.59 per positive detected). Conclusion: In the context of COVID-19, preventive actions carried out by the private sector to safeguard industrial production also have concomitant public benefits in the form of savings in healthcare costs. Thus, governmental bodies need to recognize the value of implementing such strategies in private settings and facilitate them through, for example, subsidies.

The spread of the infection caused by the new coronavirus SARS-CoV-2 (COVID-19) became pandemic on March 11, 2020. From the time of the first cases (in November 2019, Wuhan, China), to date, a large number of COVID-19 observations have been accumulated in different age groups of patients both in China and abroad. Published scientific data allows us to conclude that children suffer from COVID-19 much less often than adults and tolerate the disease in a milder form, often appear to be asymptomatic. There is currently no final answer why children are less susceptible to this virus; however, scientists are increasingly inclined to consider a complex effect of the immune response and components of the renin-angiotensin system (RAS), which according to recent studies affects not only the cardiovascular system, but is also responsible for the activation of inflammatory reactions. A hypothesis of genetic predisposition to the development of severe forms of COVID-19 has recently been made. We conducted a search for publications in the databases and showed current scientific ideas about COVID-19 pathogenesis and factors influencing the disease development in childhood. Childhood immunity may have several protective features against SARS-CoV-2: immaturity of particular elements of the innate immune response, constitutional lymphocytosis with a shift towards anti-inflammatory Th2-response, as well as "trained" immunity. The influence of renin-angiotensin system reactions in this review is shown from two perspectives: expression of ACE2 receptors and polymorphisms of certain genes of this system. It was established that ACE2 transmembrane protein is not only the entry point for the virus but also plays a regulatory role, turning the pro-inflammatory vasoconstrictor angiotensin II into anti-inflammatory angiotensin (1-7), which has vasodilating properties. Higher ACE2 content in children compared with adults helps maintain balance in the renin-angiotensin system and prevents the development of complications. It was also shown that the presence of certain genetic polymorphisms (AGTR1, AGTR2, ACE2, ACE) could determine the imbalance inside the RAS, leading to more pronounced reactions of alveolocytes, vascular endothelium and smooth muscle fibers in response to SARS-CoV-2 infection due to a shift towards vasoconstrictor, proliferative and profibrotic mechanisms.

We tested the possibility of using “adverse events count” (AEC) as a drug-risk indicator and side-effect severity indicator. Data from 3938 adverse event (AE) reports for COVID-19 vaccines (Comirnaty, Moderna, Vaxzevria, and Janssen) and 6869 AE reports for other medicines were collected from the Bulgarian Drug Agency database (01.01.2018–31.03.2022). AEC was modeled with zero-adjusted negative binomial (ZANBI) and zero-adjusted Poisson inverse Gaussian (ZAPIG) regression models, which account for zero absence and overdispersion. The models’ fit was checked with residual diagnostic plots and parametric correspondence to normality. Explanatory variables were: age, sex, sequence number (order of submission), severity of AE, and vaccine type. Average AEC was higher in severe vs. non-severe AE, and in females vs. males; it decreased with age and was lower in Comirnaty than other vaccines. Variability of AEC for COVID-19 data decreased with sequence number in severe AE and increased in non-severe AE. Full ZANBI models had greater sensitivity than parametric ZANBI or ZAPIG models. Results showed correlation between AEC and AE severity, suggesting AEC as a simple and reliable measure of drug-risk and side-effect severity for clinicians and regulators, especially for COVID-19 vaccines.

Global rapidly evolving events, e.g., COVID-19, are usually followed by countermeasures and policies. As a reaction, the public tends to express their emotions on social media platforms. Therefore, predicting emotional responses to events is critical to put a plan to avoid risky behaviors. This paper proposes a machine learning-based framework to detect public emotions based on social media posts in response to specific events. It presents a precise measurement of population-level emotions which can aid governance in monitoring public response and guide it to put in place strategies such as targeted monitoring of mental health, to react to a rise in negative emotions in response to lockdowns, or information campaigns, for instance in response to elevated rates of fear in response to vaccination programs. We evaluate our framework by extracting 15,455 tweets. We annotate and categorize the emotions into 11 categories based on Plutchik’s study of emotion and extract the features using a combination of Bag of Words and Term Frequency-Inverse Document Frequency. We filter 813 COVID-19 vaccine-related tweets and use them to demonstrate our framework’s effectiveness. Numerical evaluation of emotions prediction using Random Forest and Logistic Regression shows that our framework predicts emotions with an accuracy up to 95%.

-529391451442Citation: To be added by editorial staff during production. Academic Editor: Firstname Lastname Received: date Revised: date Accepted: date Published: date Copyright: © 2023 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).0Citation: To be added by editorial staff during production. Academic Editor: Firstname Lastname Received: date Revised: date Accepted: date Published: date Copyright: © 2023 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Abstract: SARS-CoV-2 vaccination offered the opportunity to get out of the pandemic and thereby worldwide health, social, and economic disasters. However, in addition to efficacy, safety is an important issue for any vaccine. The mRNA-based vaccine platform is considered to be safe but side effects are being reported more frequently as more and more people around the world become treated. Myo-pericarditis is the major, but not the only cardiovascular complication of this vaccine, hence it is important not to underestimate other side effects. We report a case series of patients affected by cardiac arrhythmias post mRNA vaccine from our clinical practice and the literature. Reviewing the official vigilance database emerged that heart rhythm disorders after Covid vaccination are not uncommon and deserve more clinical and scientific attention. Since Covid vaccine is the only vaccination to have been related to this side effect questions arose about whether these vaccines could affect heart conduction. Although the risk-benefit is clearly in favor of vaccination heart rhythm disorders are not a negligible issue and there are red flags in the literature about the risk of post-vaccination malignant arrhythmias in some predisposed patients. In light of these findings, we investigated the potential mechanism for the Covid vaccine to impact on cardiac electrophysiology and cause heart rhythm disorders.

Coronavirus disease 2019 (COVID-19) has detrimental multi-system consequences. Symptoms may appear during the acute phase of infection, but literature on long-term recovery of young adults after mild-to-moderate infection is lacking. Heart rate variability (HRV) allows observation of autonomic nervous system (ANS) modulation post SARS-CoV-2 infection. Additionally, physical activity (PA) helps improve ANS modulation, where investigation of PA influence on ANS recovery is vital to reduce risk and severity of symptoms. Clinicians may use this research to aid development of non-medication interventions. At baseline, 18 control (CT) and 20 post-COVID-19 (PCOV) participants were observed where general amnamnesis was performed, followed by HRV and PA assessment. 10 CT and 7 PCOV subjects returned for follow-up (FU) evaluation 6 weeks after complete immunization (2 doses) and assessments were repeated. Over the follow-up period, decrease in sympathetic (SNS) activity (mean heart rate: p=0.0024, CI=-24.67- -3.26; SNS index: p=0.0068, CI=-2.50- -0.32) and increase in parasympathetic (PNS) activity (mean RR:p=0.0097, CI=33.72-225.51; PNS index: p=0.0091, CI=-0.20-1.47) were observed. At follow-up, HRV was not different between groups (p>0.05). Additionally, no differences were observed in PA between moments and groups. This study provides evidence of ANS recovery after SARS-CoV-2 insult in young adults over a follow-up period, independent of changes in PA.

With the advent of COVID19, the attitude of health authorities around the world, led mainly by the West, demanded a level of proof as evidence for cheap, non-patented remedies while promoting expensive, patented, and untested remedies by using emergency use authorization and special provisions afforded to the status of a pandemic emergency. Western science has neither a tested nor a valid historical basis of a logical system that informs to authenticate scientific practices. Here we use a logical heuristic derived from ancient Buddhist logic, which is consistent with the conduct of modern science. We applied the heuristic to show that enough evidence was available for using cost-effective early therapies such as vitamin D supplementation as a public health measure during the first half of 2020. Strong supporting evidence has since accumulated. Apart from political and financial decisions incompatible with science and other conflicts of interest, a critical barrier to evaluating and approving early therapies appears to be the fallacy that the randomized controlled trial (RCT) is the superior proof method in medical hypotheses, including those for nutrients. Logically, no reason exists why properly designed retrospective, ecological, and naturalistic studies with adequate sample sizes and applied appropriate statistical methods would not be as valid as RCTs, especially when elucidating a causative factor instead of treatment. That assertion is particularly true for nutrient deficiencies, interventions, and other cost-effective therapies. Leading health authorities’ failure or refusal to consider other study types (because of either poor logic or vested interest) probably contributed to the spread of misinformation, symptomatic disease, complications, and deaths from COVID19. Partial immunity derived from vaccines and the later development of more contagious variants—and thus a sense of acceptance that SARS-CoV-2 had progressed from a pandemic to an endemic—shows the hollowness of the initial promotions and mandates of vaccines as a cure. Adequate knowledge was available in 2020 to advise that SARS-CoV-2 will continue to mutate, with variants emerging a few times per year, making the vaccine less effective. Emerging evidence confirms that natural immunity better protects against new variants than vaccination against the spike protein. Had vitamin D been adopted as part of the public health measure through a broader supplementation program in 2020 or even today (through sun exposure or as a prophylactic or adjunct therapy early on), the viral spread and symptomatic disease may have been suppressed, with minimal lockdowns and quarantine, and economic harm. The pandemic could have been halted with a significantly reduced need for hospitalization, complications, and deaths, potentially saving millions of lives.

The intensive care units in North West London are part of one of the oldest critical carenetworks in the UK, forming a mature and established strategic alliance to shareresources, experience and knowledge for the benefit of its patients. North WestLondon saw an early surge in COVID-19 admissions, which urgently threatened thecapacity of some of its intensive care units even before the UK government announcedlockdown. The pre-existing relationships and culture within the network allowed itsmembers to unite and work rapidly to develop agile and innovative solutions, protectingany individual unit from becoming overwhelmed, and ultimately protecting its patients.Within a short 50-day period 223 patients were transferred within the network todistribute pressures. This unprecedented number of critical care transfers, combinedwith the creation of extra capacity and new pathways, allowed the region to continue tooffer timely and unrationed access to critical care for all patients who would benefitfrom admission. This extraordinary response is a testament to the power and benefitsof a regionally networked approach to critical care, and the lessons learned maybenefit other healthcare providers, managers and policy makers, especially in regionscurrently facing new outbreaks of COVID-19.

RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) is shown to block replication of the SARS-CoV-2 virus and has been granted Fast Track Designation by the US FDA for the treatment of Critical COVID-19 with Respiratory Failure. We describe the clinical course of the first patient treated with this investigational medication in an open label manner -- a 54 year old patient suffering antibody-mediated rejection of his double lung transplant who contracted COVID-19 with respiratory failure refractory to all currently available therapies. He received three infusions of RLF-100 under an FDA-approved emergency use IND. Within 24 hours of the third infusion, substantial improvement in oxygen saturation and radiographic improvement in characteristic COVID-19 pneumonitis was noted. He was discharged from intensive care at that point and scheduled for discharge to home at 1 week on room air. Despite an intervening hospitalization for trauma, he remains alive and free of respiratory failure at 28 days post treatment.

C-type lectin CD209/DC-SIGN and CD209L/L-SIGN proteins are distinct cell adhesion and pathogen recognition receptors that mediate cellular interactions and recognize a wide range of pathogens including, viruses such as SARS, SARS-CoV-2, bacteria, fungi and parasites. Pathogens exploit CD209L family proteins to promote infection and evade the immune recognition system. CD209L and CD209 are widely expressed in SARS-CoV-2 target organs and can contribute to infection and pathogenesis. CD209L family receptors are highly susceptible to alternative splicing and genomic polymorphism, which may influence virus tropism and transmission in vivo. The carbohydrate-recognition domain (CRD) and the neck/repeat region represent the key features of CD209L family proteins that are also central to facilitating cellular ligand interactions and pathogen recognition. While, the neck/repeat region is involved in oligomeric dimerization, the CRD recognizes the mannose containing structures present on specific glycoproteins such as those found on the SARS-CoV-2 spike protein. Considering the role of CD209L and related proteins in diverse pathogen recognition, this review article discusses the recent advances in the cellular and biochemical characterization of CD209 and CD209L and their roles in viral uptake, which has important implications in understanding the host-pathogen interaction, the viral pathobiology and driving vaccine development of SARS-CoV-2.

Long COVID comprises persistent symptoms which extend beyond four weeks post-SARS-CoV-2 infection. The potential association between long COVID and the endorsement of COVID-19 conspiracy theories has not been explored, particularly in Arab countries where high endorsement of these theories has been reported. This study aimed to explore the association between endorsing COVID-19 conspiracy theories and the prevalence of self-reported long COVID symptoms among adults in Jordan and Kuwait in addition to other Arab countries. The study employed a cross-sectional design using an electronic self-administered survey in Arabic language. Recruitment utilized snowball sampling via social media and the survey was distributed in July 2024. The survey instrument included sections on demographic information, the history of COVID-19 infection, and vaccination status. Long COVID manifestations were assessed using a score reflecting the frequency and intensity of ten recognized long COVID symptoms with subsequent categorization into three categories: low, middle, and high. The beliefs in COVID-19 conspiracy theories were measured via a 5-point Likert scale across five items. The final study sample comprised 756 respondents, the majority of whom self-reported a history of confirmed COVID-19 diagnosis at least once (n = 493, 65.2%). The results indicated a neutral average attitude towards COVID-19 conspiracy theories (mean score = 15.18±4.64 out of 30.00). Participants with high conspiracy theories scores were significantly more likely to report high (aOR = 6.85, 95% CI: 2.90–16.13, p &lt; 0.001) and middle long COVID symptoms (aOR = 2.82, 95% CI: 1.32–6.06, p = 0.008) compared to those with lower scores. Additional predictors of higher long COVID reporting included female sex and lower self-reported household income. Frequent COVID-19 infections and hospitalizations were also associated with higher long COVID symptom reporting. The study results revealed a significant correlation between the endorsement of COVID-19 conspiracy theories and the higher frequency and magnitude of long COVID symptom reporting. The findings also highlighted the influence of sociodemographic factors and COVID-19 infection history on long COVID reporting, which suggests that public health strategies should address these factors to mitigate long COVID challenges effectively.

Rapid development and deployment of vaccines greatly reduced mortality and morbidity during the COVID-19 pandemic. The most widely used COVID-19 vaccines approved by national regulatory authorities require intramuscular administration. SARS-CoV-2 initially infects the upper respiratory tract where the infection can be eliminated with little or no symptoms by an effective immune response. Failure to eliminate SARS-CoV-2 in the upper respiratory tract results in lower respiratory tract infections that can lead to severe disease and death. Presently used intramuscularly administered COVID-19 vaccines are effective in reducing severe disease and mortality but are not entirely able to prevent asymptomatic and mild infections as well as person to person transmission of the virus. Individual and population differences also influence susceptibility to infection and the propensity to develop severe disease. This article provides a perspective on the nature and the mode of delivery COVID-19 vaccines that can optimize protective immunity in the upper respiratory tract to reduce infections and virus transmission as well as severe disease.

The COVID-19 pandemic drew public attention back to the living conditions related to housing, access to green areas in close neighbourhood and nearby recreation. Several studies confirm that visiting green spaces improved the health and wellbeing in times of crisis. This representative study for the metropolitan area of Vienna, Austria’s capital, confirms the high relevance of contact with nature, particularly for citizens to cope with the negative consequences and perceived stress, anxiety, nervousness and many other negative symptoms experienced during the health crisis. It highlights the importance of nearby smaller but also medium to large scale green areas in cities for health and wellbeing of the population. Moreover, it specifically adds novel insights on age effects in use and perception of urban green spaces during COVID-19 pandemic. The online panel survey (n=1012) was conducted in summer 2021. In order to obtain a representative sample reflective of the population’s characteristics, a (stratified) random sample was selected by applying the quota method. The objective was to obtain a sample which represented gender, age and regional distribution of the population of the City of Vienna as well as the immediately surrounding local communities. Interestingly, particularly young people spent more time outside in green areas during the pandemic, discovered novel spaces for the first time and stated a high relevance of contact with nature for their wellbeing. Elderly people above sixty five, on the contrary, stayed more frequently at home. Significant differences are visible between the age groups also with regard to negative symptoms experienced in case of restricted access to green areas due to strict pandemic measures such as lockdowns and quarantine. All age groups, however, similarly acknowledged the importance of green areas for their physical, mental and emotional health in general during the pandemic.

This study continued the analysis of immunization with the receptor binding domain (RBD) associated with the adjuvants Dimethyldioctadecylammonium bromide (DDA) and Saponin (Sap) (RBD+DDA/Sap) or Aluminum hydroxide (AH) and outer membrane vesicles (OMVs) of Neisseria meningitidis (RBD+AH/OMV); from adult to old age and assessed maternal-fetal transference of antibodies. Outbred Swiss mice were immunized with 2 intramuscular (IM) doses with the antigenic preparations RBD+DDA/Sap, RBD+AH/OMV or RBD alone. The humoral immune response was evaluated using ELISA, avidity-ELISA, Immunoblotting and a Omicron-surrogate-neutralization assay (BA.1), while the cellular immune response was analyzed by ELISpot. Our previous work studied the IgG response; here, we verified that IgM levels were higher right after the immunization doses, but, as IgG, it persisted until 368 days after the immunization. The avidity of IgM increased from low to intermediate-to-high after the booster dose. RBD+DDA/Sap presented neutralizing indexes against Omicron at days 47 and 176, while RBD+AH/OMV showed neutralization on days 21, 47 and 176. Cellular response, measured 465 days after immunization, revealed IFN-Y and IL-4 secretion. The offspring of RBD+DDA/Sap had detectable antibodies, which decreased around 45 days after birth, the last point we analyzed. The results suggested that DDA/Sap is a promising adjuvant mixture to enhance humoral and cellular immune response against SARS-CoV-2, improving maternal-fetal transference of antibodies; cross-reactivity with Omicron variant; and the maintenance of antibodies for a long period.

Since the spread of the deadly virus SARS-CoV2 in late 2019, researchers have restlessly been seeking for unraveling how the virus factually enters the host cells. Some proteins on each side of the interaction between the virus and the host cells are involved as the major contributors to this process: 1- the nano-machine Spike protein on behalf of the virus, 2- angiotensin converting enzyme II, the mono-carboxypeptidase and the key component of renin angiotensin system on behalf of the host cell, 3- some host proteases and proteins exploited by SARS-CoV2, In this review, the complex process of SARS-CoV2 entrance into the host cells with the contribution of the involved host proteins as well as the sequential conformational changes in the Spike protein tending to increase the probability of complexification of the latter with angiotensin converting enzyme II, the receptor of the virus on the host cells, are discussed. Besides, the release of the catalytic ectodomain of angiotensin converting enzyme II as its soluble form in the extracellular space and its positive or negative impact on the infectivity of the virus are considered.

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations, characterized by distinct interactomes – namely protein assemblies - under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation's influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly and disease.

Although most cases of COVID-19 are paucisymptomatic, severe disease is characterized by immune dysregulation, with a decreased type I interferon response, increased inflammatory indicators, surging IL-6, IL-10 and TNFα suggestive of cytokine storm, progressive lymphopenia, and abnormal blood clotting. Factors determining susceptibility to severe disease are poorly understood, although mortality correlates with increasing age and co-morbidities including diabetes and cardiovascular disease (CVD). Pyridoxal 5'-phosphate (PLP) tends to be insufficient in populations particularly vulnerable to COVID-19, including the elderly, the institutionalized, and people with diabetes and CVD, and PLP becomes further depleted during infection and inflammation. In turn, low PLP results in immune imbalance, as PLP is an essential cofactor in pathways regulating cytokine production, in particular type I interferons and IL-6, and in lymphocyte trafficking and endothelial integrity. Furthermore, normalizing PLP levels attenuates abnormalities in platelet aggregation and clot formation. Finally, PLP insufficiency induces excess secretion of renin and angiotensin, and hypertension. In inflammatory disease, pharmacological doses of PLP decrease circulating TNFα, IL-6 and D-dimer, and animal studies demonstrate that supplemental PLP shortens the duration and severity of viral pneumonia. Severe COVID-19 manifests as an imbalance in the immune response and the clotting system. Pharmacological PLP supplementation may therefore mitigate COVID-19 symptoms by alleviating both the immune suppression underlying viral spread and the pathological hypersecretion of inflammatory cytokines, as well as directly bolstering endothelial integrity and preventing hypercoagulability.

Coronavirus Disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a “cytokine storm,” and neuroinflammation. COVID-19’s upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy Bodies made of α-Synuclein protein encoded by synuclein alpha (SNCA). This study presents the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN’s Ingenuity Pathway Analysis, the study identifies the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream Effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.

COVID-19 sepsis immune response remains unclear. Here we propose a new perspective in host response against pathogenic proteins that may lead to a vaccine design by polymerization of antigens of <70 kDa. In COVID-19, initial Th1 response kills infected cells releasing viral proteins. SARS-CoV-2 viral structural proteins are Spike (140 kDa), Nucleocapsid (50 kDa), Membrane (25 kDa) and Envelope (10 kDa). B cell receptor cannot capture antigens >70 kDa. The Spike protein (140 kDa) cannot be captured by B cells and triggers inflammatory Th1 response via the macrophages. Only proteins with a size <70 kDa can activate B cell receptor and trigger Th2 adaptative humoral response. Moreover, M-25 kDa and E-12 kDa glycoproteins can activate IgM-BCR like oligovalent or monovalent antigens. The sustained infected cells lysis overfeeds high levels of viral proteins <70 kDa, increases B cells activation and, in the shift from Th1 to Th2 immune response, triggers the cytokine storm. The continuous BCR activation increases IL-10 releasing and may lead to immune paralysis.