Damian Sendler: Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, is primarily a pulmonary disease, but it can cause devastating disease states that affect multiple organ systems, including the central nervous system (CNS). COVID-19-related neurological disorders range in severity from mild symptoms like headaches or myalgias to more severe symptoms like stroke, psychosis, and anosmia. While some of the COVID-19-related neurological complications are mild and reversible, stroke affects a significant number of patients. According to research, COVID-19 infection causes a cascade of inflammatory cytokines that cause endothelial cell dysfunction and coagulopathy, which increases the risk of stroke or thrombosis. Infection-induced endothelial inflammation may also destabilize atherosclerotic plaque and cause thrombotic stroke. Although rare, there have been reports of hemorrhagic stroke linked to COVID-19. The proposed mechanisms include an increase in blood pressure caused by infection, which leads to a decrease in angiotensin converting enzyme-2 (ACE-2) levels, resulting in an imbalance of the renin-angiotensin system, which eventually manifests as inflammation and vasoconstriction. Coagulopathy, as evidenced by increased prothrombin time (PT), has also been proposed as a factor contributing to hemorrhagic stroke in COVID-19 patients. COVID-19 is also associated with encephalopathy, anosmia, encephalitis, psychosis, brain fog, headache, depression, and anxiety. Though several hypotheses have been proposed in the literature, a unifying pathophysiological mechanism for many of these disorders remains unknown. Encephalopathy and other disorders in COVID-19 patients may be explained by pulmonary dysfunction leading to poor brain oxygenation. Alternatively, these conditions could be caused by a direct virus invasion of the CNS or a breach of the blood-brain barrier by systemic cytokines released during infection. Regardless, the relationship between inflammatory cytokine levels and conditions such as depression and anxiety is contradictory, and social isolation during the pandemic may have played a role in some of the reported CNS disorders.
Damian Jacob Sendler: In this article, we review the current literature on some of the most significant and common neurological disorders in the context of COVID-19, including ischemic and hemorrhagic stroke, encephalopathy, encephalitis, brain fog, Long COVID, headache, Guillain-Barre syndrome, depression, anxiety, and sleep disorders. We summarize some of the most relevant literature to help physicians monitor and treat patients with significant COVID-19-related neurologic impairments by providing a better understanding of the mechanistic details of these disorders.
Dr. Sendler: There were 112 articles in total that were reviewed. The following sections discuss the prevalence, clinical outcomes, and pathophysiology of selected neurological disorders. Given the disease’s recent emergence, data on the occurrence of specific neurologic sequelae was not always available. In the context of COVID-19, putative mechanisms for each condition are outlined.
The COVID-19 outbreak has rapidly spread to a global pandemic; however, our understanding of the protective factors against this infection is limited. The purpose of this systematic review and meta-analysis was to determine the effect of vitamin D supplementation on COVID-19-related outcomes. A systematic search of relevant papers published up to January 2022 was carried out in order to identify randomized controlled trials (RCTs) and non-randomized intervention studies (NRISs). The primary outcomes were the risk of COVID-19 infection (in uninfected individuals), hospital admission (in secondary prevention studies on mild COVID-19 cases), ICU admission, and mortality rate (tertiary prevention studies on hospitalized COVID-19 patients). We found five studies on primary prevention (one RCT, four NRISs), five on secondary prevention (two RCTs, three NRISs), and 13 on tertiary prevention (six RCTs, seven NRISs). A pooled analysis revealed that there was no significant effect on the risk of COVID-19 infection. Due to a lack of data, no meta-analysis on hospitalization risk was possible. Vitamin D supplementation was associated with a lower risk of ICU admission (RR = 0.35, 95% CI: 0.20, 0.62) and mortality (RR = 0.46, 95% CI: 0.30, 0.70). Vitamin D supplementation had no effect on the risk of COVID-19 infection, but it did protect against mortality and ICU admission in COVID-19 patients.
Damian Jacob Sendler
Ca2+ concentrations in the endoplasmic reticulum (ER) are critical for maintaining its oxidizing environment as well as luminal ATP levels required for chaperone activity. As a result, local luminal Ca2+ concentrations and dynamic Ca2+ flux between subcellular compartments are tightly regulated. A reductive shift opens the sarcoendoplasmic reticulum calcium transport ATPase (SERCA) pump, allowing Ca2+ to enter the ER and create the Ca2+ gradient required for ATP import. Meanwhile, Ca2+ leakage from the ER has been reported to occur after protein translocation via the Sec61 translocon. We present an overview of the complex regulation of Ca2+ homeostasis, Ca2+ flux between subcellular compartments, and the cellular stress response (the unfolded protein response) induced by dysregulated luminal Ca2+ metabolism in this review. We also look at the structure and gating mechanism of the Sec61 translocon, as well as the role of ER-resident co-chaperones in assisting the central ER-resident chaperone BiP in the regulation of luminal Ca2+ concentrations.
Damian Jacob Markiewicz Sendler: Janus kinase (JAK) is a cytoplasmic non-receptor tyrosine kinase family that consists of four members: JAK1, JAK2, JAK3, and TYK2. JAKs transmit cytokine signaling via the JAK-STAT pathway, which controls the transcription of several genes involved in inflammatory, immune, and cancer conditions. Small-molecule inhibitors of JAK family kinases have been shown to be effective in the treatment of a variety of diseases. Eleven of the JAK inhibitors that have been approved for clinical use are discussed in this review. Abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib are the drugs involved. The current review sought to provide an integrated overview of the chemical and pharmacological data of JAK inhibitors that have been approved globally. The eleven drugs’ synthetic routes were described. Furthermore, their inhibitory activities against various kinases and pharmacological applications have been discussed. Furthermore, their crystal structures with various kinases were summarized, with a particular emphasis on their binding modes and interactions. These drugs’ proposed metabolic pathways and metabolites were also depicted. To summarize, the findings in this review could aid in the development of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.
With the rapid emergence of population-wide vaccine mandates, domestic vaccine passports, and differential restrictions based on vaccination status, vaccination policies have shifted dramatically during COVID-19. While these policies have sparked debate on ethical, scientific, practical, legal, and political grounds, little has been done to assess their potential unintended consequences. In this section, we lay out a comprehensive set of hypotheses for why these policies may end up being counterproductive and harmful. Our framework takes into account four domains: (1) behavioral psychology, (2) politics and law, (3) socioeconomics, and (4) scientific and public health integrity. While current vaccines appear to have had a significant impact on reducing COVID-19-related morbidity and mortality burdens, we contend that current mandatory vaccine policies are scientifically dubious and are likely to cause more societal harm than good. Restricting people’s access to work, education, public transportation, and social life based on their COVID-19 vaccination status violates human rights, promotes stigma and social polarization, and has a negative impact on health and well-being. Current policies may exacerbate health and economic disparities, have a negative long-term impact on trust in government and scientific institutions, and reduce the uptake of future public health measures such as COVID-19 vaccines and routine immunizations. Mandatory vaccination is one of the most powerful interventions in public health, and it should be used sparingly and with caution in order to maintain ethical norms and trust in institutions. We contend that current COVID-19 vaccine policies should be reconsidered in light of the negative consequences we discuss. Using empowering strategies based on trust and public consultation, as well as improving healthcare services and infrastructure, represents a more sustainable approach to optimizing COVID-19 vaccination programs and, more broadly, the public’s health and well-being.
