SARS-CoV-2/COVID-19 associated pediatric acute-onset neuropsychiatric syndrome a case report of female twin adolescents.

"Pediatric acute-onset neuropsychiatric syndrome", or PANS, is a rare syndrome characterized by an acute onset of obsessive-compulsive disorder (OCD), and/or severely restricted food intake accompanied by a variety of neuropsychiatric symptoms. To our knowledge, this is the first case report of twin adolescents with COVID-19-associated PANS. Dizygotic twin sisters in late teens, with abrupt and acute onset of severely restrictive food intake, weight loss, OCD, anxiety with intermittent auditory and visual hallucinations, depression, attention deficit, and sleep disturbances, simultaneously accompanied by milder neurologic symptoms such as hand tremor, tinnitus, dizziness, headache, and weakness of proximal muscles, were applied to child and adolescent psychiatry clinic. The only relevant agent underlying those neuropsychiatric and somatic complaints was COVID-19, and it was validated with laboratory testing, such as positive IgG titers of SARS-CoV-2 and negative biomarkers for other possible bacterial or viral agents. Generalized epileptic anomaly and a vermian/folial atrophy in the cerebellum were detected in further evaluations. Treatment options consisted of psychotropic agents, antibiotics, antiepileptic, and intravenous immunoglobulin transfusion finely treated the neuropsychiatric symptoms. Clinicians should consider SARS-CoV-2 as a potential agent, when a child presents with abrupt onset, dramatic neuropsychiatric symptoms also consisting of PANS, even in asymptomatic patients or with mild respiratory symptoms.

Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences.

COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19. This systematic review highlights the detailed therapeutic implication of naturally occurring glycyrrhizin and its related derivatives against COVID-19. Glycyrrhizin has already been established for blocking different biomolecular targets related to the SARS-CoV-2 replication cycle. In this article, several experimental and theoretical evidences of glycyrrhizin and related derivatives have been discussed in detail to evaluate their potential as a promising therapeutic strategy against COVID-19. Moreover, the implication of glycyrrhizin in traditional Chinese medicines for alleviating the symptoms of COVID-19 has been reviewed. The potential role of glycyrrhizin and related compounds in affecting various stages of the SARS-CoV-2 life cycle has also been discussed in detail. Derivatization of glycyrrhizin for designing potential lead compounds along with combination therapy with other anti-SARS-CoV-2 agents followed by extensive evaluation may assist in the formulation of novel anti-coronaviral therapy for better treatment to combat COVID-19.

Complex Hallucinations in Hospitalized Rehabilitation Patients With COVID-19.

Objectives: To explore the characteristics of hallucinations in hospitalized rehabilitation patients with COVID-19. Design: Retrospective review using medical records of patients with COVID-19 and admitted to the acute inpatient rehabilitation unit (ARU). Setting: A public hospital in southern California, specializing in rehabilitation medicine. Participants: Patients with COVID-19 and hallucinations who were consecutively admitted from January 1st to April 30th, 2021. Interventions: Not applicable. Main Outcome Measures: Types and themes of hallucinations. Results: Eight of the 37 patients (21.6%) admitted to the ARU with COVID-19 exhibited hallucinations. All were Hispanic and 7 of them were men; their average age was 56.5 (range: 38-71). Seven patients had COVID-19 pneumonia and 1 developed respiratory distress secondary to Guillain-Barre Syndrome. One patient had posterior reversible encephalopathy syndrome. The average length of stay in the intensive care unit (ICU) was 31.3 days (range: 8-48). Most of the hallucinations occurred during their ICU stay and 2 continued to their ARU stay. All recalled details of hallucinations with 7 exhibiting visual hallucinations, consistent with peduncular hallucinosis with or without auditory and/or tactile components. One patient experienced tactile hallucinations. The themes of hallucinations identified to reflect the contents of the hallucinations were patients' comfort-seeking, fearfulness, and seeing deceased family members. All patients had impaired cognition at the ARU admission but improved at discharge. Four patients had depressed mood/anxiety and 1 had depressed mood alone but without a history of psychiatric illness. ICU delirium was documented in 5 patients. The negative experience of hallucinations seemed to affect their participation of the ARU stay. Conclusions: More than 20% of patients with COVID-19 who were transferred to attend inpatient rehabilitation exhibited hallucinations. It remains uncertain if these hallucinations were related to the SARS-CoV-2 infection. Multidisciplinary rehabilitation team should be aware to support patients with COVID-19 who experience hallucinations.

Navigating the cellular landscape in tissue: Recent advances in defining the pathogenesis of human disease.

Over the past decade, our understanding of human diseases has rapidly grown from the rise of single-cell spatial biology. While conventional tissue imaging has focused on visualizing morphological features, the development of multiplex tissue imaging from fluorescence-based methods to DNA- and mass cytometry-based methods has allowed visualization of over 60 markers on a single tissue section. The advancement of spatial biology with a single-cell resolution has enabled the visualization of cell-cell interactions and the tissue microenvironment, a crucial part to understanding the mechanisms underlying pathogenesis. Alongside the development of extensive marker panels which can distinguish distinct cell phenotypes, multiplex tissue imaging has facilitated the analysis of high dimensional data to identify novel biomarkers and therapeutic targets, while considering the spatial context of the cellular environment. This mini-review provides an overview of the recent advancements in multiplex imaging technologies and examines how these methods have been used in exploring pathogenesis and biomarker discovery in cancer, autoimmune and infectious diseases.

Neurological and psychological effects of long COVID in a young population: A cross-sectional study.

Aim: We evaluated the long-term clinical status of pediatric patients after testing positive for COVID-19. We hypothesized that there are similar symptoms to those that have been described in adults and children and that pediatric patients with neurophysiologic symptoms still present 3-5 months after infection have psychological consequences that interfere with their adaptive functioning. Method: We recruited 322 COVID-19-positive pediatric patients, between 1.5 and 17 years old, from the outpatient clinic for COVID-19 follow-up. Neurological symptoms were analyzed at onset, after 1 month, and after 3-5 months. A psychological assessment with standardized questionnaires was also conducted to determine the impact of the disease. Results: At the onset of COVID-19, 60% of the total sample exhibited symptoms; this decreased after 1 month (20%) but stabilized 3-5 months after disease onset (22%). Prevailing long-COVID neurological symptoms were headache, fatigue, and anosmia. In the 1.5-5-year-old subgroup, internalizing problems emerged in 12% of patients. In the 6-18-year-old subgroup, anxiety and post-traumatic stress showed significant associations with neurological symptoms of long COVID. Conclusions: These data demonstrate that long COVID presents various broad-spectrum symptoms, including psychological and long-lasting cognitive issues. If not treated, these symptoms could significantly compromise the quality of life of children and adolescents.

Intraventricular CNS aspergillosis in a patient with prior history of COVID-19: Case report and review of literature.

Introduction and importance: Although some immunocompetent patients have developed invasive aspergillosis, the vast majority of cases are seen in immunocompromised patients. COVID-19 infection has been proposed to cause immune dysfunction or suppression, which predisposes patients to fungal co-infections such as mucormycosis and aspergillosis. Case presentation: A 58-year-old woman was admitted to the hospital with confusion, dysarthria, and loss of consciousness. The patient had a 1-month prior history of severe COVID-19 infection. A computerized tomography (CT) scan and a magnetic resonance imaging (MRI) revealed an intraventricular lesion with perilesional edema and a significant midline shift, which was initially thought to be an intraventricular tumor. Following a posterior parietal craniotomy, the lesion was resected via a transcortical approach from the posterior parietal region to the right lateral ventricle. Histopathological findings confirmed intraventricular aspergillosis (IVA). The patient was treated with intravenous amphotericin B for two months and discharged with oral variconazole for 4 months. Discussion: Covid-19 infections can result in- dissemination of fungal diseases such as aspergillosis. As a minor component of cerebral aspergillosis with a poor prognosis, intraventricular aspergillosis necessitates prompt treatment, which includes surgical resection and the administration of anti-fungal medications. Conclusion: Infection with COVID-19 causes immune dysfunction, which leads to fungal co-infection, including CNS aspergillosis. As a result, all COVID-19 patients who present with acute neurologic symptoms should have CNS aspergillosis considered in their differential diagnosis.

Isolated arteritis misdiagnosed as bilateral orbital tumors in a patient with acute ischemic stroke.

Vasculitis is a heterogeneous group of disorders characterized by multifocal segmental inflammation of the small and medium vessels of the central nervous system. The predominant symptoms of cerebral vasculitis are stroke, headache, and encephalopathy. Additional symptoms include seizures, cranial nerve palsies, and myelopathy. Imaging techniques play a crucial role in identifying the diagnosis of vasculitis and demonstrating brain involvement. An 89-year-old woman with permanent atrial fibrillation developed an embolic stroke. In treatment, intravenous thrombolysis and thrombectomy with complete antegrade reperfusion of the left middle cerebral artery was used, without the clinical effectiveness. Brain MRI revealed bilateral oval lesions in medial parts of the orbits, which were initially misinterpreted as orbital tumors. Final diagnosis confirmed thickened arterial walls as orbital changes due to inflammatory arteritis. Ten days later, follow-up MRI was performed and showed complete regression of the orbital masses. Primary central nervous system vasculitis, manifesting as acute ischemic stroke, may be reversible with early systemic thrombolytic treatment.

Neurological manifestations by sex and age group in COVID-19 inhospital patients.

Introduction: Neurological manifestations have been associated with a poorer prognosis in COVID-19. However, data regarding their incidence according to sex and age groups is still lacking. Methods: This retrospective multicentric cohort collected data from 39 Brazilian hospitals from 17 cities, from adult COVID-19 admitted from March 2020 to January 2022. Neurological manifestations presented at hospital admission were assessed according to incidence by sex and age group. Results: From 13,603 COVID-19 patients, median age was 60 years old and 53.0% were men. Women were more likely to present with headaches (22.4% vs. 17.7%, p < 0.001; OR 1.36, 95% confidence interval [CI] 1.22-1.52) than men and also presented a lower risk of having seizures (OR 0.43, 95% CI 0.20-0.94). Although delirium was more frequent in women (6.6% vs. 5.7%, p = 0.020), sex was not associated with delirium in the multivariable logistc regresssion analysis. Delirium, syncope and coma increased with age (1.5% [18-39 years] vs. 22.4% [80 years or over], p < 0.001, OR 1.07, 95% CI 1.06-1.07; 0.7% vs. 1.7%, p = 0.002, OR 1.01, 95% CI 1.00-1.02; 0.2% vs. 1.3% p < 0.001, OR 1.04, 95% CI 1.02-1.06), while, headache (26.5% vs. 7.1%, OR 0.98, 95% CI 0.98-0.99), anosmia (11.4% vs. 3.3%, OR 0.99, 95% CI] 0.98-0.99 and ageusia (13.1% vs. 3.5%, OR 0.99, CI 0.98-0.99) decreased (p < 0.001 for all). Conclusion: Older COVID-19 patients were more likely to present delirium, syncope and coma, while the incidence of anosmia, ageusia and headaches decreased with age. Women were more likely to present headache, and less likely to present seizures.

Intraparenchymal fiberoptic intracranial pressure monitoring and decompressive craniectomy in meningioma case with critical intracranial pressure: A case report during COVID-19 pandemic.

Introduction: Meningioma is a slow-growing tumor that can cause neurological emergency due to intracranial hypertension. The definitive therapy is indeed emergency resection, but it is not always possible in several countries due to limited capacity and/or capability of the emergency operating room. The use of intraparenchymal fiberoptic intracranial pressure (ICP) monitoring and decompressive craniectomy (DC) in cases of brain tumors might be possible, but it is uncommon. We report a meningioma patient in whom immediate meningioma resection was considered too risky due to intensive care unit (ICU) shortage during COVID-19 pandemic and, therefore, underwent these procedures as life-saving measures. Case presentation: A 24-year-old man was brought to the emergency room with a chief complaint of seizure. Physical examination was notable for decreased consciousness (Glasgow Coma Scale (GCS) 11) and a dilated left pupil with intact light reflex. A contrasted Brain CT Scan revealed extra-axial mass on the left sphenoid with extensive tentacle edema, which pushed the midline structures 2 cm toward the contralateral side. Discussion: The patient was diagnosed with Left Sphenoid Meningioma. We decided to perform intraparenchymal fiberoptic ICP monitor insertion and DC considering the situation, device availability, safety, and efficacy. The patient slowly regained consciousness in the recovery room after the procedure. The best-observed GCS was 12. Two weeks afterward, the patient came back to our outpatient clinic neurologically intact. The patient was then planned for elective tumor resection. Conclusion: ICP monitoring and DC are not commonly performed on brain tumor cases. However, in suboptimal situations, these procedures might save lives. The present case showed that ICP monitor and DC were helpful in times of ICU shortage.

Health effects and known pathology associated with the use of E-cigarettes.

In recent years, new nicotine delivery methods have emerged, and many users are choosing electronic cigarettes (e-cigarettes) over traditional tobacco cigarettes. E-cigarette use is very popular among adolescents, with more than 3.5 million currently using these products in the US. Despite the increased prevalence of e-cigarette use, there is limited knowledge regarding the health impact of e-cigarettes on the general population. Based on published findings by others, E-cigarette is associated with lung injury outbreak, which increased health and safety concerns related to consuming this product. Different components of e-cigarettes, including food-safe liquid solvents and flavorings, can cause health issues related to pneumonia, pulmonary injury, and bronchiolitis. In addition, e-cigarettes contain alarmingly high levels of carcinogens and toxicants that may have long-lasting effects on other organ systems, including the development of neurological manifestations, lung cancer, cardiovascular disorders, and tooth decay. Despite the well- documented potential for harm, e-cigarettes do not appear to increase susceptibility to SARS-CoV- 2 infection. Furthermore, some studies have found that e-cigarette users experience improvements in lung health and minimal adverse effects. Therefore, more studies are needed to provide a definitive conclusion on the long-term safety of e-cigarettes. The purpose of this review is to inform the readers about the possible health-risks associated with the use of e-cigarettes, especially among the group of young and young-adults, from a molecular biology point of view.

Thermal dysregulation in patients with multiple sclerosis during SARS-CoV-2 infection. The potential therapeutic role of exercise.

Thermoregulation is a homeostatic mechanism that is disrupted in some neurological diseases. Patients with multiple sclerosis (MS) are susceptible to increases in body temperature, especially with more severe neurological signs. This condition can become intolerable when these patients suffer febrile infections such as coronavirus disease-2019 (COVID-19). We review the mechanisms of hyperthermia in patients with MS, and they may encounter when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Finally, the thermoregulatory role and relevant adaptation to regular physical exercise are summarized.

The impact of lymphoid memory cells in different ages of COVID-19 patients.

Coronaviruses are highly pathogenic and transmissible viruses. The SARS-CoV-2 virus that emerged in December 2019 is increasingly recognized as a serious, worldwide public health concern. Respiratory infections and the hyper-inflammatory response induced by SARS-CoV-2 play a key role in disease severity and death in infected COVID-19 patients. However, much uncertainty still exists about the pathogenesis and various effects of COVID-19 on immune system. It seems that memory T cells can reduce the severity of COVID-19 infection by inducing a protective immune response. Memory T cells along with protective antibodies are the main defenses and also protective barrier against recurrent COVID-19 infection. The role of Memory T cells varies in different ages and the severity of COVID-19 infection varies between children, adults and the elderly. Furthermore, the aim of this review is to evaluate the role of memory cells in mild, moderate and severe infected COVID-19 patients with different ages.

In silico identification of potential inhibitors against main protease of SARS-CoV-2 6LU7 from Andrographis panniculata via molecular docking, binding energy calculations and molecular dynamics simulation studies.

BACKGROUND: The ongoing global outbreak of new corona virus (SARS-CoV-2) has been recognized as global public health concern since it causes high morbidity and mortality every day. Due to the rapid spreading and re-emerging, we need to find a potent drug against SARS-CoV-2. Synthetic drugs, such as hydroxychloroquine, remdisivir have paid more attention and the effects of these drugs are still under investigation, due to their severe side effects. Therefore, the aim of the present study was performed to identify the potential inhibitor against main protease SARS-CoV-2 6LU7. OBJECTIVE: In this study, RO5, ADME properties, molecular dynamic simulations and free binding energy prediction were mainly investigated. RESULTS: The molecular docking study findings revealed that andrographolide had higher binding affinity among the selected natural diterpenoids compared to co-crystal native ligand inhibitor N3. The persistent inhibition of Ki for diterpenoids was analogous. Furthermore, the simulations of molecular dynamics and free binding energy findings have shown that andrographolide possesses a large amount of dynamic properties such as stability, flexibility and binding energy. CONCLUSION: In conclusion, findings of the current study suggest that selected diterpenoids were predicted to be the significant phytonutrient-based inhibitor against SARS-CoV-2 6LU7 (Mpro). However, preclinical and clinical trials are needed for the further scientific validation before use.

Pediatrics COVID-19 and neurological manifestations: Single tertiary centre experience.

IMPORTANCE: Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome that is caused by a novel coronavirus 2 (SARS-CoV-2). It originated in China late December 2019 and was declared a global pandemic on March 12, 2020. Most reports of COVID-19 cases either presented with neurological manifestations or complications involve adults. Only few cases were reported in pediatric patients. OBJECTIVE: To report COVID-19 pediatric cases with neurological manifestations and identify the wide spectrum of its manifestations. DESIGN SETTING AND PARTICIPANTS: This was a retrospective, observational case series. Data of pediatric patients infected by SARS-CoV-2 presenting with neurological manifestations at King Abdullah Specialized Children Hospital in King Abdulaziz Medical City in Riyadh were collected from May 23 to June 30, 2020. RESULTS: We encountered 5 COVID-19 cases with neurological manifestations. Three patients who were previously healthy had new-onset neurological symptoms. Symptoms and signs included encephalopathy, ataxia, headache, seizure, papilledema, ophthalmoplegia, hyporeflexia, and different clinical spectra, such as Miller Fisher syndrome, meningoencephalitis, and idiopathic intracranial hypertension. Other patients attending our center were incidentally found to be SARS-CoV-2-positive, which caused a delay in the investigations required to reach diagnosis. CONCLUSIONS AND RELEVANCE: Our cases highlight the wide clinical spectrum of neurological manifestations in COVID-19 patients. Given the paucity of information about pediatric COVID-19 cases with neurological symptoms, we here reported these cases to shed light on the association between SARS-CoV-2 and neurological presentation. Moreover, our study indicates that many investigations are being delayed and could affect diagnosis and treatment.

Cerebral Micro-Structural Changes in COVID-19 Patients - An MRI-based 3-month Follow-up Study.

BACKGROUND: Increasing evidence supported the possible neuro-invasion potential of SARS-CoV-2. However, no studies were conducted to explore the existence of the micro-structural changes in the central nervous system after infection. We aimed to identify the existence of potential brain micro-structural changes related to SARS-CoV-2. METHODS: In this prospective study, diffusion tensor imaging (DTI) and 3D high-resolution T1WI sequences were acquired in 60 recovered COVID-19 patients (56.67% male; age: 44.10 ± 16.00) and 39 age- and sex-matched non-COVID-19 controls (56.41% male; age: 45.88 ± 13.90). Registered fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were quantified for DTI, and an index score system was introduced. Regional volumes derived from Voxel-based Morphometry (VBM) and DTI metrics were compared using analysis of covariance (ANCOVA). Two sample t-test and Spearman correlation were conducted to assess the relationships among imaging indices, index scores and clinical information. FINDINGS: In this follow-up stage, neurological symptoms were presented in 55% COVID-19 patients. COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers (corrected p value <0.05). Global GMV, GMVs in left Rolandic operculum, right cingulate, bilateral hippocampi, left Heschl's gyrus, and Global MD of WM were found to correlate with memory loss (p value <0.05). GMVs in the right cingulate gyrus and left hippocampus were related to smell loss (p value <0.05). MD-GM score, global GMV, and GMV in right cingulate gyrus were correlated with LDH level (p value <0.05). INTERPRETATION: Study findings revealed possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting the long-term consequences of SARS-CoV-2. FUNDING: Shanghai Natural Science Foundation, Youth Program of National Natural Science Foundation of China, Shanghai Sailing Program, Shanghai Science and Technology Development, Shanghai Municipal Science and Technology Major Project and ZJ Lab.

PKU and COVID19: How the pandemic changed metabolic control.

BACKGROUND: COVID19 pandemic urged the need to take severe measures for reducing the epidemic spread. Lockdowns were imposed throughout countries and even Inborn errors of metabolism (IEMs) affected patients had to face it and adapt, with management strategies changes coming along. Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism causing, when not treated, blood Phe increases and consequent central nervous system (CNS) damage. Dietary intervention is the main recognized treatment and must be maintained long-life, however adherence is often suboptimal in adulthood. Aim of this study was to evaluate whether and how the pandemic had impacted PKUs metabolic control and what factors may have played a role as potential modifiers. METHODS: Patients ≥4 yo and in follow-up at our Metabolic Clinic were enrolled in this study, divided into subgroups according to age (GROUP A < 12 yo; GROUP B ≥ 12 yo). Videoconsults were conducted on a minimum monthly basis and collected DBS were studied and compared to previous year same time-period in order to evaluate possible changes. RESULTS: 39% of patients (n = 121) increased the number of performed DBS. "Non-compliant" patients were reduced (11-3%) with a - 14% of patients with mean Phe levels >600 umol/l and a - 8% of patients with 100% DBS above same level. GROUP A maintained substantially unchanged metabolic control among two analyzed time-periods. On the contrary, GROUP B demonstrated significant reductions in mean blood Phe concentrations (p < 0.0001) during the pandemic (mean 454 umol/l, SD ± 252, vs. 556.4 umol/l, SD ± 301). DISCUSSION: COVID19 pandemic strongly impacted people's life with lifestyle habits changing consistently. PKU patients had to adapt their dietary restrictions to the new environment they were exposed to and, if younger patients could have been less exposed (meals strictly according to diet plan independently from setting), adolescent and adults strongly reflected the obligation to stay home by showing better metabolic control. Multiple factors could have played a role in that and the availability of teleconsultancy may have contributed allowing easier connections, but our data demonstrate how the pandemic and the environment can strongly impact PKUs adherence to treatment and how removing distance barriers can ameliorate and optimize metabolic compliance.

A comparative genomics-based study of positive strand RNA viruses emphasizing on SARS-CoV-2 utilizing dinucleotide signature, codon usage and codon context analyses.

The novel corona virus disease or COVID-19 caused by a positive strand RNA virus (PRV) called SARS-CoV-2 is plaguing the entire planet as we conduct this study. In this study a multifaceted analysis was carried out employing dinucleotide signature, codon usage and codon context to compare and unravel the genomic as well as genic characteristics of the SARS-CoV-2 isolates and how they compare to other PRVs which represents some of the most pathogenic human viruses. The main emphasis of this study was to comprehend the codon biology of the SARS-CoV-2 in the backdrop of the other PRVs like Poliovirus, Japanese encephalitis virus, Hepatitis C virus, Norovirus, Rubella virus, Semliki Forest virus, Zika virus, Dengue virus, Human rhinoviruses and the Betacoronaviruses since codon usage pattern along with the nucleotide composition prevalent within the viral genome helps to understand the biology and evolution of viruses. Our results suggest discrete genomic dinucleotide signature within the PRVs. Some of the genes from the different SARS-CoV-2 isolates were also found to demonstrate heterogeneity in terms of their dinucleotide signature. The SARS-CoV-2 isolates also demonstrated a codon context trend characteristically dissimilar to the other PRVs. The findings of this study are expected to contribute to the developing global knowledge base in countering COVID-19.

Nicotinic cholinergic system and COVID-19: In silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions.

SARS-CoV-2 infection was announced as a pandemic in March 2020. Since then, several scientists have focused on the low prevalence of smokers among hospitalized COVID-19 patients. These findings led to our hypothesis that the Nicotinic Cholinergic System (NCS) plays a crucial role in the manifestation of COVID-19 and its severe symptoms. Molecular modeling revealed that the SARS-CoV-2 Spike glycoprotein might bind to nicotinic acetylcholine receptors (nAChRs) through a cryptic epitope homologous to snake toxins, substrates well documented and known for their affinity to the nAChRs. This binding model could provide logical explanations for the acute inflammatory disorder in patients with COVID-19, which may be linked to severe dysregulation of NCS. In this study, we present a series of complexes with cholinergic agonists that can potentially prevent SARS-CoV-2 Spike glycoprotein from binding to nAChRs, avoiding dysregulation of the NCS and moderating the symptoms and clinical manifestations of COVID-19. If our hypothesis is verified by in vitro and in vivo studies, repurposing agents currently approved for smoking cessation and neurological conditions could provide the scientific community with a therapeutic option in severe COVID-19.

Enhancing innate immunity against virus in times of COVID-19: Trying to untangle facts from fictions.

INTRODUCTION: In light of the current COVID-19 pandemic, during which the world is confronted with a new, highly contagious virus that suppresses innate immunity as one of its initial virulence mechanisms, thus escaping from first-line human defense mechanisms, enhancing innate immunity seems a good preventive strategy. METHODS: Without the intention to write an official systematic review, but more to give an overview of possible strategies, in this review article we discuss several interventions that might stimulate innate immunity and thus our defense against (viral) respiratory tract infections. Some of these interventions can also stimulate the adaptive T- and B-cell responses, but our main focus is on the innate part of immunity. We divide the reviewed interventions into: 1) lifestyle related (exercise, >7 h sleep, forest walking, meditation/mindfulness, vitamin supplementation); 2) Non-specific immune stimulants (letting fever advance, bacterial vaccines, probiotics, dialyzable leukocyte extract, pidotimod), and 3) specific vaccines with heterologous effect (BCG vaccine, mumps-measles-rubeola vaccine, etc). RESULTS: For each of these interventions we briefly comment on their definition, possible mechanisms and evidence of clinical efficacy or lack of it, especially focusing on respiratory tract infections, viral infections, and eventually a reduced mortality in severe respiratory infections in the intensive care unit. At the end, a summary table demonstrates the best trials supporting (or not) clinical evidence. CONCLUSION: Several interventions have some degree of evidence for enhancing the innate immune response and thus conveying possible benefit, but specific trials in COVID-19 should be conducted to support solid recommendations.