Unraveling the enigma of long COVID: novel aspects in pathogenesis, diagnosis, and treatment protocols.

Long COVID, now unmistakably identified as a syndromic entity encompassing a complex spectrum of symptoms, demands immediate resolution of its elusive pathogenic underpinnings. The intricate interplay of diverse factors presents a complex puzzle, difficult to resolve, and thus poses a substantial challenge. As instances of long COVID manifest by repeated infections of SARS-CoV-2 and genetic predisposition, a detailed understanding in this regard is needed. This endeavor is a comprehensive exploration and analysis of the cascading pathogenetic events driven by viral persistence and replication. Beyond its morbidity, long COVID, more disabling than fatal, exacts one of the most substantial tolls on public health in contemporary times, with the potential to cripple national economies. The paper introduces a unified theory of long COVID, detailing a novel pathophysiological framework that interlinks persistent SARS-CoV-2 infection, autoimmunity, and systemic vascular pathology. We posit a model where viral reservoirs, immune dysregulation, and genetic predispositions converge to perpetuate disease. It challenges prevailing hypotheses with new evidence, suggesting innovative diagnostic and therapeutic approaches. The paper aims to shift the paradigm in long COVID research by providing an integrative perspective that encapsulates the multifaceted nature of the condition. We explain the immunological mechanisms, hypercoagulability states, and viral reservoirs in the skull that feed NeuroCOVID in patients with long COVID. Also, this study hints toward a patient approach and how to prioritize treatment sequences in long COVID patients in hospitals and clinics.

Intranasal Route: A Nasocerebral Approach against SARS-CoV-2 in NeuroCOVID.

The nasal cavity is a prime site for viral load of SARS-CoV-2 in COVID-19, as is evident from the fact that this area has been used for sample collection for the diagnosis of COVID-19. The nasal cavity has a connection with the brain across the cribriform plate which has been reported to be a route of SARS-CoV-2 to the olfactory apparatus and the brain. Targeting the SARS-CoV-2 in the nasal cavity in patients presenting with COVID-19 and long-COVID can result in the prevention and treatment of neurological deficits and therefore needs to be prioritized as a route of potential significance.

Novel, thalidomide-like, non-cereblon binding drug tetrafluorobornylphthalimide mitigates inflammation and brain injury.

BACKGROUND: Quelling microglial-induced excessive neuroinflammation is a potential treatment strategy across neurological disorders, including traumatic brain injury (TBI), and can be achieved by thalidomide-like drugs albeit this approved drug class is compromised by potential teratogenicity. Tetrafluorobornylphthalimide (TFBP) and tetrafluoronorbornylphthalimide (TFNBP) were generated to retain the core phthalimide structure of thalidomide immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure. TFBP/TFNBP were hence designed to retain beneficial anti-inflammatory properties of IMiDs but, importantly, hinder cereblon binding that underlies the adverse action of thalidomide-like drugs. METHODS: TFBP/TFNBP were synthesized and evaluated for cereblon binding and anti-inflammatory actions in human and rodent cell cultures. Teratogenic potential was assessed in chicken embryos, and in vivo anti-inflammatory actions in rodents challenged with either lipopolysaccharide (LPS) or controlled cortical impact (CCI) moderate traumatic brain injury (TBI). Molecular modeling was performed to provide insight into drug/cereblon binding interactions. RESULTS: TFBP/TFNBP reduced markers of inflammation in mouse macrophage-like RAW264.7 cell cultures and in rodents challenged with LPS, lowering proinflammatory cytokines. Binding studies demonstrated minimal interaction with cereblon, with no resulting degradation of teratogenicity-associated transcription factor SALL4 or of teratogenicity in chicken embryo assays. To evaluate the biological relevance of its anti-inflammatory actions, two doses of TFBP were administered to mice at 1 and 24 h post-injury following CCI TBI. Compared to vehicle treatment, TFBP reduced TBI lesion size together with TBI-induction of an activated microglial phenotype, as evaluated by immunohistochemistry 2-weeks post-injury. Behavioral evaluations at 1- and 2-weeks post-injury demonstrated TFBP provided more rapid recovery of TBI-induced motor coordination and balance impairments, versus vehicle treated mice. CONCLUSION: TFBP and TFNBP represent a new class of thalidomide-like IMiDs that lower proinflammatory cytokine generation but lack binding to cereblon, the main teratogenicity-associated mechanism. This aspect makes TFBP and TFNBP potentially safer than classic IMiDs for clinical use. TFBP provides a strategy to mitigate excessive neuroinflammation associated with moderate severity TBI to, thereby, improve behavioral outcome measures and warrants further investigation in neurological disorders involving a neuroinflammatory component.

The immune paradox of SARS-CoV-2: Lymphocytopenia and autoimmunity evoking features in COVID-19 and possible treatment modalities.

SARS-CoV-2 causes multiorgan damage to vital organs and tissue that are known to be due to a combination of tissue tropisms and cytokine-mediated damage that it can incite in COVID-19. The effects of SARS-Co-2 on the lymphocytes and therefore on the immune response have attracted attention recently in COVID-19 to understand its effects in causing a chronic state of ongoing infection with Long-COVID. The associated lymphopaenia and autoimmune disease state, which is an apparent paradox, needs to be researched to dissect possible mechanisms underlying this state. This paper attempts to unravel the aforesaid immune paradox effects of SARS-CoV-2 on the lymphocytes and discusses appropriate treatment modalities with antiviral drugs and nutraceuticals which could prove virucidal in SARS-CoV-2 seeding monocytes and lymphocytes in patients with COVID-19 and Long-COVID. Importantly it proposes a new in vitro treatment modality of immune regulating cells that can help patients fight the lymphopaenia associated with COVID-19 and Long-COVID.

Underlying Causes and Treatment Modalities for Neurological Deficits in COVID-19 and Long-COVID.

With reports of diverse neurological deficits in the acute phase of COVID-19, there is a surge in neurological findings in Long-COVID─a protracted phase of SARS-CoV-2 infection. Very little is known regarding the pathogenic mechanisms of Neuro-COVID in the above two settings in the current pandemic. Herein, we hint toward the possible molecular mechanism that can contribute to the signs and symptoms of patients with neurological deficits and possible treatment and prevention modalities in the acute and chronic phases of COVID-19.

Activity of a Novel Anti-Inflammatory Agent F-3,6'-dithiopomalidomide as a Treatment for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6'-dithiopomalidomide (F-3,6'-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6'-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6'-DP. F-3,6'-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6'-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6'-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

Differential diagnosis and pathogenesis of the neurological signs and symptoms in COVID-19 and long-COVID syndrome.

Neurological features have now been reported very frequently in the ongoing COVID-19 pandemic caused by SARS-CoV-2. The neurological deficits associated features are observed in both acute and chronic stages of COVID-19 and they appear to overlap with wide-ranging symptoms that can be attributed to being of non-neural origins, thus obscuring the definitive diagnosis of neuro-COVID. The pathogenetic factors acting in concert to cause neuronal injury are now emerging, with SARS-CoV-2 directly affecting the brain coupled with the neuroinflammatory factors have been implicated in the causation of disabilities in acute COVID-19 and patients with Long-COVID syndrome. As the differentiation between a neural origin and other organ-based causation of a particular neurological feature is of prognostic significance, it implores a course of action to this covert, yet important neurological challenge.

Correlating Biochemical and Structural Changes in the Brain with Clinical Features in COVID-19.

With emerging reports of the deleterious effects of SARS-CoV-2 reflecting as neurological deficits in COVID-19, the biochemical and morphological changes it casts on the brain are also being investigated. This is an important niche of research as it is expected to predict and relate the neurological clinical features in the acute phase and chronic syndromic forms of COVID-19. Here debated are the biochemical and structural changes that can be related to the neurological manifestations in COVID-19.

Innovations in surgery between the past and future: A narrative review of targeted literature.

Innovation is the introduction of a new method or technology designed to change the way things are done. History is full of remarkable innovations in surgery over the years as surgeons have always been innovating and pioneering latest techniques and equipment that can benefit the mankind. Though persistent, progress has been far from uniform. Despite all the bells and whistles that these innovations bring to the table, the little acknowledged fact is that they are only accessible to a very small proportion of the global population. Five billion people on this planet do not even have access to an operating room when needed. It has been reported that conditions requiring surgery are responsible for one-third of all the deaths in the world. The current narrative review was planned to focus on the importance of innovations in surgery, to highlight the problems that were faced by resource-restricted countries in the past, and the necessity of innovative solutions to improve global surgical care in the future.

Pathways and Pathogenesis of Hearing Deficits, Tinnitus, and Vertigo in COVID-19.

COVID-19 has been shown to affect the ear and has led to hearing deficits, tinnitus, and vertigo. Very little is known regarding the mechanisms and targets of SARS-CoV-2 that cause the above symptoms. Anatomical extensions from the areas of viral loads to the middle ear appear to enable the SARS-CoV-2 to cause either an inflammatory response or a direct effect on the lining epithelium leading to temporary hearing and equilibrium-related symptoms in COVID-19. Herein the anatomical continuity from the areas of viral loads to the middle and internal ear is debated to uncover the possible covert routes used by SARS-CoV-2 to affect the hearing and equilibrium in COVID-19.

Chronic long-COVID syndrome: A protracted COVID-19 illness with neurological dysfunctions.

After almost a year of COVID-19, the chronic long-COVID syndrome has been recognized as an entity in 2021. The patients with the long-COVID are presenting with ominous neurological deficits that with time are becoming persistent and are causing disabilities in the affected individuals. The mechanisms underlying the neurological syndrome in long-COVID have remained obscure and need to be actively researched to find a resolution for the patients with long-COVID. Here, the factors like site of viral load, the differential immune response, neurodegenerative changes, and inflammation as possible causative factors are debated to understand and investigate the pathogenesis of neuro-COVID in long-COVID syndrome.

Targeting Neuroinvasion by SARS-CoV-2: Emerging Trends in Drug and Antibody Delivery to Combat COVID-19.

Because SARS-CoV-2 uses the nasal cavity as a major route of entry to the human body, nasal administration of drugs and antibodies directed against the virus can prove to be effective for not only pulmonary COVID-19 but also prevention of potential early neuroinvasion caused by this virus. With recent reports of the potential application of antibody-laden nasal spray for the treatment of COVID-19, proposed here is the use of drugs recently proven to be effective against SARS-CoV-2 to be administered via inhalation route using a modified transcribrial device reported previously for its use against Naegleria fowleri, to target SARS-CoV-2 in our fight against COVID-1.

Docking Prediction of Levodopa in the Receptor Binding Domain of Spike Protein of SARS-CoV-2.

Levodopa is a prodrug that is converted into dopamine, which replenishes the deficient dopamine in the brain of patients suffering from Parkinsonism. We hypothesize that levodopa may interact with the receptor binding domain of the SARS-CoV-2 and may act as a physical impediment to the viral entry into the host cell.

'Targeting the feast of a sleeping beast': Nutrient and mineral dependencies of encysted Acanthamoeba castellanii.

Acanthamoeba spp. cause a corneal infection, Acanthamoeba keratitis (AK), and a cerebral infection, granulomatous amoebic encephalitis (GAE). Though aggressive chemotherapy has been able to kill the active trophozoite form of Acanthamoeba, the encysted form of this parasite has remained problematic to resist physiological concentrations of drugs. The emergence of encysted amoeba into active trophozoite form poses a challenge to eradicate this parasite. Acanthamoeba trophozoites have active metabolic machinery that furnishes energy in the form of ATPs by subjecting carbohydrates and lipids to undergo pathways including glycolysis and beta-oxidation of free fatty acids, respectively. However, very little is known about the metabolic preferences and dependencies of an encysted trophozoite on minerals or potential nutrients that it consumes to live in an encysted state. Here, we investigate the metabolic and nutrient preferences of the encysted trophozoite of Acanthamoeba castellanii and the possibility to target them by drugs that act on calcium ion dependencies of the encysted amoeba. The experimental assays, immunostaining coupled with bioinformatics tools show that the encysted Acanthamoeba uses diverse nutrient pathways to obtain energy in the quiescent encysted state. These findings highlight potential pathways that can be targeted in eradicating amoebae cysts successfully.