Modifiable contributing factors to COVID-19: A comprehensive review.

The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual's dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19. The current study identifies eighty immune system dysfunction-enabling toxic stressors and behaviors (hereafter called modifiable contributing factors (CFs)) that also link directly to COVID-19. Each CF is assigned to one of the five categories in the CF taxonomy shown in Section 3.3.: Lifestyle (e.g., diet, substance abuse); Iatrogenic (e.g., drugs, surgery); Biotoxins (e.g., micro-organisms, mycotoxins); Occupational/Environmental (e.g., heavy metals, pesticides); Psychosocial/Socioeconomic (e.g., chronic stress, lower education). The current study shows how each modifiable factor contributes to decreased immune system capability, increased inflammation and coagulation, and increased neural damage and neurodegeneration. It is unclear how real progress can be made in combatting COVID-19 and other similar diseases caused by viral variants without addressing and eliminating these modifiable CFs.

Towards effective COVID­19 vaccines: Updates, perspectives and challenges (Review).

In the current context of the pandemic triggered by SARS-COV-2, the immunization of the population through vaccination is recognized as a public health priority. In the case of SARS­COV­2, the genetic sequencing was done quickly, in one month. Since then, worldwide research has focused on obtaining a vaccine. This has a major economic impact because new technological platforms and advanced genetic engineering procedures are required to obtain a COVID­19 vaccine. The most difficult scientific challenge for this future vaccine obtained in the laboratory is the proof of clinical safety and efficacy. The biggest challenge of manufacturing is the construction and validation of production platforms capable of making the vaccine on a large scale.

Vaccine development for zoonotic viral diseases caused by positive­sense single­stranded RNA viruses belonging to the Coronaviridae and Togaviridae families (Review).

Outbreaks of zoonotic viral diseases pose a severe threat to public health and economies worldwide, with this currently being more prominent than it previously was human history. These emergency zoonotic diseases that originated and transmitted from vertebrates to humans have been estimated to account for approximately one billion cases of illness and have caused millions of deaths worldwide annually. The recent emergence of severe acute respiratory syndrome coronavirus-2 (coronavirus disease 2019) is an excellent example of the unpredictable public health threat causing a pandemic. The present review summarizes the literature data regarding the main vaccine developments in human clinical phase I, II and III trials against the zoonotic positive-sense single-stranded RNA viruses belonging to the Coronavirus and Alphavirus genera, including severe acute respiratory syndrome, Middle east respiratory syndrome, Venezuelan equine encephalitis virus, Semliki Forest virus, Ross River virus, Chikungunya virus and O'nyong-nyong virus. That there are neither vaccines nor effective antiviral drugs available against most of these viruses is undeniable. Therefore, new explosive outbreaks of these zoonotic viruses may surely be expected. The present comprehensive review provides an update on the status of vaccine development in different clinical trials against these viruses, as well as an overview of the present results of these trials.

A Selective Histamine H4 Receptor Antagonist, JNJ7777120, Role on glutamate Transporter Activity in Chronic Depression.

Glutamate release and reuptake play a key role in the pathophysiology of depression. glutamatergic nerves in the hippocampus region are modulated by histaminergic afferents. Excessive accumulation of glutamate in the synaptic area causes degeneration of neuron cells. The H4 receptor is defined as the main immune system histamine receptor with a pro-inflammatory role. To understand the role of this receptor, the drug JNJ7777120 was used to reveal the chronic depression-glutamate relationship. We have important findings showing that the H4 antagonist increases the glutamate transporters' instantaneous activity. In our experiment, it has been shown that blocking the H4 receptor leads to increased neuron cell viability and improvement in behavioral ability due to glutamate. Therefore, JNJ can be used to prevent neurotoxicity, inhibit membrane phospholipase activation and free radical formation, and minimize membrane disruption. In line with our findings, results have been obtained that indicate that JNJ will contribute to the effective prevention and treatment of depression.

Disinfectant-induced hormesis: An unknown environmental threat of the application of disinfectants to prevent SARS-CoV-2 infection during the COVID-19 pandemic?

Massive additional quantities of disinfectants have been applied during the COVID-19 pandemic as infection preventive and control measures. While the application of disinfectants plays a key role in preventing the spread of SARS-CoV-2 infection, the effects of disinfectants applied during the ongoing pandemic on non-target organisms remain unknown. Here we collated evidence from multiple studies showing that chemicals used for major disinfectant products can induce hormesis in various organisms, such as plants, animal cells, and microorganisms, when applied singly or in mixtures, suggesting potential ecological risks at sub-threshold doses that are normally considered safe. Among other effects, sub-threshold doses of disinfectant chemicals can enhance the proliferation and pathogenicity of pathogenic microbes, enhancing the development and spread of drug resistance. We opine that hormesis should be considered when evaluating the effects and risks of such disinfectants, especially since the linear-no-threshold (LNT) and threshold dose-response models cannot identify or predict their effects.

Contributing factors common to COVID­19 and gastrointestinal cancer.

The devastating complications of coronavirus disease 2019 (COVID­19) result from the dysfunctional immune response of an individual following the initial severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS­CoV­2 exploits the dysfunctional immune system to trigger a chain of events, ultimately leading to COVID­19. The authors have previously identified a number of contributing factors (CFs) common to myriad chronic diseases. Based on these observations, it was hypothesized that there may be a significant overlap between CFs associated with COVID­19 and gastrointestinal cancer (GIC). Thus, in the present study, a streamlined dot­product approach was used initially to identify potential CFs that affect COVID­19 and GIC directly (i.e., the simultaneous occurrence of CFs and disease in the same article). The nascent character of the COVID­19 core literature (~1­year­old) did not allow sufficient time for the direct effects of numerous CFs on COVID­19 to emerge from laboratory experiments and epidemiological studies. Therefore, a literature­related discovery approach was used to augment the COVID­19 core literature­based 'direct impact' CFs with discovery­based 'indirect impact' CFs [CFs were identified in the non­COVID­19 biomedical literature that had the same biomarker impact pattern (e.g., hyperinflammation, hypercoagulation, hypoxia, etc.) as was shown in the COVID­19 literature]. Approximately 2,250 candidate direct impact CFs in common between GIC and COVID­19 were identified, albeit some being variants of the same concept. As commonality proof of concept, 75 potential CFs that appeared promising were selected, and 63 overlapping COVID­19/GIC potential/candidate CFs were validated with biological plausibility. In total, 42 of the 63 were overlapping direct impact COVID­19/GIC CFs, and the remaining 21 were candidate GIC CFs that overlapped with indirect impact COVID­19 CFs. On the whole, the present study demonstrates that COVID­19 and GIC share a number of common risk/CFs, including behaviors and toxic exposures, that impair immune function. A key component of immune system health is the removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.

Disinfectant-induced hormesis: An unknown environmental threat of the application of disinfectants to prevent SARS-CoV-2 infection during the COVID-19 pandemic?☆

Massive additional quantities of disinfectants have been applied during the COVID-19 pandemic as infection preventive and control measures. While the application of disinfectants plays a key role in preventing the spread of SARS-CoV-2 infection, the effects of disinfectants applied during the ongoing pandemic on non-target organisms remain unknown. Here we collated evidence from multiple studies showing that chemicals used for major disinfectant products can induce hormesis in various organisms, such as plants, animal cells, and microorganisms, when applied singly or in mixtures, suggesting potential ecological risks at sub-threshold doses that are normally considered safe. Among other effects, sub-threshold doses of disinfectant chemicals can enhance the proliferation and pathogenicity of pathogenic microbes, enhancing the development and spread of drug resistance. We opine that hormesis should be considered when evaluating the effects and risks of such disinfectants, especially since the linear-no-threshold (LNT) and threshold dose-response models cannot identify or predict their effects. Graphical abstract Image 1 Disinfectants that are widely applied during the COVID-19 pandemic have the potential to induce hormetic responses in non-target organisms, suggesting risks to environmental health at sub-threshold doses.

Erratum to "Why are we vaccinating children against COVID-19?" [Toxicol. Rep. 8C (2021) 1665-1684 / 1193].

[This corrects the article DOI: 10.1016/j.toxrep.2021.08.010.].

Why are we vaccinating children against COVID-19?

This article examines issues related to COVID-19 inoculations for children. The bulk of the official COVID-19-attributed deaths per capita occur in the elderly with high comorbidities, and the COVID-19 attributed deaths per capita are negligible in children. The bulk of the normalized post-inoculation deaths also occur in the elderly with high comorbidities, while the normalized post-inoculation deaths are small, but not negligible, in children. Clinical trials for these inoculations were very short-term (a few months), had samples not representative of the total population, and for adolescents/children, had poor predictive power because of their small size. Further, the clinical trials did not address changes in biomarkers that could serve as early warning indicators of elevated predisposition to serious diseases. Most importantly, the clinical trials did not address long-term effects that, if serious, would be borne by children/adolescents for potentially decades. A novel best-case scenario cost-benefit analysis showed very conservatively that there are five times the number of deaths attributable to each inoculation vs those attributable to COVID-19 in the most vulnerable 65+ demographic. The risk of death from COVID-19 decreases drastically as age decreases, and the longer-term effects of the inoculations on lower age groups will increase their risk-benefit ratio, perhaps substantially.

Immune response (IgG) following full inoculation with BNT162b2 COVID­19 mRNA among healthcare professionals.

Soon after the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) pandemic in December, 2019, numerous research teams, assisted by vast capital investments, achieved vaccine development in a fraction of time. However, almost 8 months following the initiation of the European vaccination programme, the need for prospective monitoring of the vaccine­induced immune response, its determinants and related side­effects remains a priority. The present study aimed to quantify the immune response following full vaccination with the BNT162b2 coronavirus disease 2019 (COVID­19) mRNA vaccine by measuring the levels of immunoglobulin G (IgG) titers in healthcare professionals. Moreover, common side­effects and factors associated with IgG titers were identified. For this purpose, blood samples from 517 individuals were obtained and analysed. Blood sampling was performed at a mean period of 69.0±23.5 days following the second dose of the vaccine. SARS­CoV­2 IgG titers had an overall mean value of 4.23±2.76. Females had higher titers than males (4.44±2.70 and 3.89 ±2.84, respectively; P=0.007), while non­smokers had higher titers than smokers (4.48±2.79 and 3.80±2.64, respectively; P=0.003). An older age was also associated with lower antibody titers (P<0.001). Moreover, the six most prevalent adverse effects were pain at the injection site (72.1%), generalized fatigue (40.5%), malaise (36.3%), myalgia (31,0%), headache (25.8%) and dizziness/weakness (21.6%). The present study demonstrated that the immune response after receiving the BNT162b2 COVID­19 mRNA vaccine is dependent on various modifiable and non­modifiable factors. Overall, the findings of the present study highlight two key aspects of the vaccination programs: First, the need for prospective immunosurveillance studies in order to estimate the duration of immunity, and second, the need to identify those individuals who are at a greater risk of developing low IgG titers in order to evaluate the need for a third dose of the vaccine.

Challenges and Scientific Prospects of the Newest Generation of mRNA-Based Vaccines against SARS-CoV-2.

In the context of the current COVID-19 pandemic, traditional, complex and lengthy methods of vaccine development and production would not have been able to ensure proper management of this global public health crisis. Hence, a number of technologies have been developed for obtaining a vaccine quickly and ensuring a large scale production, such as mRNA-based vaccine platforms. The use of mRNA is not a new concept in vaccine development but has leveraged on previous knowledge and technology. The great number of human resources and capital investements for mRNA vaccine development, along with the experience gained from previous studies on infectious diseases, allowed COVID-19 mRNA vaccines to be developed, conditionally approved and commercialy available in less than one year, thanks to decades of basic research. This review critically presents and discusses the COVID-19 mRNA vaccine-induced immunity, and it summarizes the most common anaphylactic and autoimmune adverse effects that have been identified until now after massive vaccination campaigns.

Erratum to "COVID-19 pandemic and alcohol consumption: Impacts and interconnections" [Toxicol. Rep. 8C (2021) 529 - 535/1078].

[This corrects the article DOI: 10.1016/j.toxrep.2021.03.005.].

Erratum to "Safety of COVID-19 vaccines administered in the EU: Should we be concerned?" [Toxicol. Rep. 8C (2021) 871-879/1111].

[This corrects the article DOI: 10.1016/j.toxrep.2021.04.003.].

Safety of COVID-19 vaccines administered in the EU: Should we be concerned?

The COVID-19 pandemic has had an unprecedented and devastating impact on public health, society and economics around the world. As a result, the development of vaccines to protect individuals from symptomatic COVID-19 infections has represented the only feasible health tool to combat the spread of the disease. However, at the same time the development and regulatory assessment of different vaccines has challenged pharmaceutical industries and regulatory agencies as this process has occurred in the shorter time ever though. So far, two mRNA and two adenovirus-vectored vaccines have received a conditional marketing authorisation in the EU and other countries. This review summarized and discusses the assessment reports of the European Medicine Agency (EMA) concerning the safety of the 3 vaccines currently used in the EU (Pfizer, Moderna and Astra-Zeneca). A particular focus has been paid to safety information from pre-clinical (animal) and clinical (phase 3 trials) studies. Overall, the most frequent adverse effects reported after the administration of these vaccines consisted of local reactions at the injection site (sore arm and erythema) followed by non-specific systemic effects (myalgia, chills, fatigue, headache, and fever), which occurred soon after vaccination and resolved shortly. Rare cases of vaccine-induced immune thrombotic thrombocytopenia have been reported for Vaxzevria. Data on long-term studies, interaction with other vaccines, use in pregnancy/breast-feeding, use in immunocompromised subjects, and in subjects with comorbidities, autoimmune or inflammatory disorders are still missing for these vaccines. Therefore, careful follow-up and surveillance studies for continued vaccine safety monitoring will be needed to ascertain the potential risks of such adverse events or diseases. In conclusion, the benefits and risks of current COVID-19 vaccines must be weighed against the real possibility of contract the disease and develop complications and long-term sequels; all this on the basis of the available scientific evidence and in the absence of unmotivated biases.

Current and innovative methods for the diagnosis of COVID­19 infection (Review).

The Coronavirus Disease 2019 (COVID­19) pandemic has forced the scientific community to rapidly develop highly reliable diagnostic methods in order to effectively and accurately diagnose this pathology, thus limiting the spread of infection. Although the structural and molecular characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) were initially unknown, various diagnostic strategies useful for making a correct diagnosis of COVID­19 have been rapidly developed by private research laboratories and biomedical companies. At present, rapid antigen or antibody tests, immunoenzymatic serological tests and molecular tests based on RT­PCR are the most widely used and validated techniques worldwide. Apart from these conventional methods, other techniques, including isothermal nucleic acid amplification techniques, clusters of regularly interspaced short palindromic repeats/Cas (CRISPR/Cas)­based approaches or digital PCR methods are currently used in research contexts or are awaiting approval for diagnostic use by competent authorities. In order to provide guidance for the correct use of COVID­19 diagnostic tests, the present review describes the diagnostic strategies available which may be used for the diagnosis of COVID­19 infection in both clinical and research settings. In particular, the technical and instrumental characteristics of the diagnostic methods used are described herein. In addition, updated and detailed information about the type of sample, the modality and the timing of use of specific tests are also discussed.

Back to basics in COVID-19: Antigens and antibodies-Completing the puzzle.

The outbreak of the coronavirus disease 2019 (COVID-19) has gathered 1 year of scientific/clinical information. This informational asset should be thoroughly and wisely used in the coming year colliding in a global task force to control this infection. Epidemiology of this infection shows that the available estimates of SARS-CoV-2 infection prevalence largely depended on the availability of molecular testing and the extent of tested population. Within molecular diagnosis, the viability and infectiousness of the virus in the tested samples should be further investigated. Moreover, SARS-CoV-2 has a genetic normal evolution that is a dynamic process. The immune system participates to the counterattack of the viral infection by pathogen elimination, cellular homoeostasis, tissue repair and generation of memory cells that would be reactivated upon a second encounter with the same virus. In all these stages, we still have knowledge to be gathered regarding antibody persistence, protective effects and immunological memory. Moreover, information regarding the intense pro-inflammatory action in severe cases still lacks and this is important in stratifying patients for difficult to treat cases. Without being exhaustive, the review will cover these important issues to be acknowledged to further advance in the battle against the current pandemia.

COVID-19 pandemic and alcohol consumption: Impacts and interconnections.

Alcohol consumption is associated with multiple diseases and might contribute to vulnerability to SARS-CoV-2 infection. It can also catalyze exacerbations of mental and organic illnesses and predispose to behaviors with an increased risk of infection, severity of disease but also independently of sociopathic behavior and violence. Globally, millions of premature deaths from excessive alcohol consumption occur each year. This paper discusses the effects of increased alcohol consumption and the most important consequences on the health of the population during the social isolation and lockdown during current COVID-19 pandemic.

Thrombosis and Haemostasis challenges in COVID-19 - Therapeutic perspectives of heparin and tissue-type plasminogen activator and potential toxicological reactions-a mini review.

The coronavirus disease (COVID)-19 pandemic is a major challenge for the health systems worldwide. Acute respiratory distress syndrome (ARDS), is one of the most common complications of the COVID-19 infection. The activation of the coagulation system plays an important role in the pathogenesis of ARDS. The development of lung coagulopathy involves thrombin generation and fibrinolysis inhibition. Unfractionated heparin and its recently introduced counterpart low molecular weight heparin (LMWH), are widely used anticoagulants with a variety of clinical indications allowing for limited and manageable physio-toxicologic side effects while the use of protamine sulfate, heparin's effective antidote, has made their use even safer. Tissue-type plasminogen activator (tPA) is approved as intravenous thrombolytic treatment. The present narrative review discusses the use of heparin and tPA in the treatment of COVID-19-induced ARDS and their related potential physio-toxicologic side effects. The article is a quick review of articles on anticoagulation in COVID infection and the potential toxicologic reactions associated with these drugs.