Medical Rehabilitation and Infectious Diseases in Children

Today, medical rehabilitation is undergoing significant transformation. The new system built around the biopsychosocial model includes assessment of physical constraints and rehabilitation diagnosis, determination of rehabilitation potential, formulation of goals and objectives of individual interventions, development of rehabilitation plans, and progress evaluation. All of these rehabilitation components can be implemented using a personalized, problem-oriented, multidisciplinary approach, which is now being actively introduced into clinical practice. The current pandemic of the novel coronavirus infection has demonstrated that medical rehabilitation is crucial for convalescents. However, its principles and techniques have not been fully elaborated yet. This review describes the current state of medical rehabilitation of children with or after infectious diseases and identifies its avenues and prospects.Copyright © 2022 Obstetrics, Gynecology and Reproduction. All rights reserved.

Expect the Unexpected: Invasive Central Nervous System (Cns) Aspergillosis in Non-Neutropenic Patients - a Case Series of 15 Patients from India

Intro: Invasive aspergillosis of CNS is a severe form of aspergillosis & is associated with high mortality. Most of these cases are suspected & diagnosed in neutropenic patients. We hereby describe a series of 15 patients with CNS aspergillosis in non-neutropenic patients from a tertiary care hospital in India. Method(s): All patients with clinical & radiological features suggestive of CNS aspergillosis were screened for microbiological evidence of invasive aspergillosis, either by demonstration of hyphae by microscopy or histology, culture or galactomannan assay. Patients demographic details, clinical features, risk factors, diagnosis, management & outcome details were documented. Finding(s): A total of 15 patients were found to have CNS aspergillosis, 5 isolated CNS infections & 10 showing concomitant CNS & pulmonary aspergillosis in one between January 2021 to July 2022. The average age was 41.46+/-14.6y, with majority being male. Among the risk factors, most common ones were fungal sinusitis (46.6%), steroid use (40%), COVID-19 (33.3%). One patient had history of endoscopic sinus repair, another had h/o lung abscess. Most common symptoms of CNS aspergillosis were headache (73.3%), fever (60%), altered sensorium (53.3%) & seizures (47.6%). Radiologically, the common findings included ring enhancing lesion, s/o cerebral abscesses were observed in four patients. Direct microscopy s/o fungal hyphae were reported in 5 patients, with 4 culture positives. Average serum galactomannan was 1, while CSF galactomannan showed better sensitivity with mean CSF galactomannan being 2.53. Almost all patients were treated with Voriconazole based on weight, but showed high mortality of 60% even after initiation of therapy. Complete resolution were seen in only two patients, while 4 patients remaining static in improvement during 6 months follow up. Conclusion(s): Invasive CNS aspergillosis must be suspected even with nonneutropenic patients with newer emerging risk factors like steroid use, COVID-19 & h/o fungal sinusitis presenting with clinical & radiological manifestations.Copyright © 2023

NO CSF BIOMARKER EVIDENCE OF PERSISTING CNS INFECTION AFTER SARS-CoV-2 INFECTION

Background: Neurocognitive symptoms are common in acute as well as convalescent (post-acute sequelae of COVID-19 [PASC]) COVID-19, but mechanisms of CNS pathogenesis are unclear. The aim of this study was to investigate cerebrospinal fluid (CSF) biomarker evidence of CNS infection, immune activation and neuronal injury in convalescent compared with acute infection. Method(s): We included 68 (35% female) patients >=18 years with CSF sampled during acute (46), 3-6 months after (22) SARS-CoV-2 infection or both (17), and 20 (70% female) healthy controls from longitudinal studies. The 22 patients sampled only at 3-6 months were recruited in a PASC protocol. CSF N-Ag was analyzed using an ultrasensitive antigen capture immunoassay platform (S-PLEX SARS-CoV-2 N Kit, Meso Scale Diagnostics, LLC. Rockville, MD). Additional analyses included CSF beta2-microglobulin (beta2M)], IFN-gamma, IL-6, TNF-alpha neurofilament light (NfL), and total and phosphorylated tau. Log-transformed CSF biomarkers were compared using ANOVA (Tukey post-hoc test). Result(s): Patients sampled during acute infection had moderate (27) or severe (19) COVID-19. In patients sampled at 3-6 months, corresponding initial severity was 10 (mild), 14 (moderate), and 15 (severe). At 3-6 months, 31/39 patients reported neurocognitive symptoms;8/17 patients also sampled during acute infection reported full recovery after 3-6 months. CSF biomarker results are shown in Figure 1. SARS-CoV-2 RNA was universally undetectable. N-Ag was detectable only during acute infection (32/35) but was undetectable in all follow up and control samples. Significantly higher CSF concentrations of beta2M (p< 0.0001), IFN-gamma (p=0.02), IL-6 (p< 0.0001) and NfL (p=0.04) were seen in acute compared to post-infection. Compared to controls, beta2M (p< .0001), IL-6 (p< 0.0001) and NfL (p=0.005) were significantly higher in acute infection. No biomarker differences were seen post-infection compared with controls. No differences were seen in CSF GFAp, t-tau or p-tau. Conclusion(s): We found no evidence of residual infection (RNA, N-Ag), inflammation (beta2M, IL-6, IFN-gamma, TNF-alpha), astrocyte activity (GFAp) or neuronal injury (NfL, tau) 3-6 months after initial COVID-19, while significantly higher concentrations of several markers were found during acute infection, suggesting that PASC may be a consequence of earlier injury rather than active CNS damage. CSF beta2M, IL-6, IFN-gamma and NfL were significantly lower after 3-6 months than during acute COVID-19 and not different from healthy controls. (Figure Presented).

Pain in Covid-19 and Features of Pathogenetic Molecular Mechanisms

Although it has been almost three years since the World Health Organization (WHO) declared a pandemic, COVID-19 is still an unsolved problem, thereby attracting great scientific interest. The disease has a heterogeneous clinical picture with multiple manifestations from different organs and systems. Currently, COVID-19 is perceived as a polysyndromic inflammatory disease involving not only the respiratory system, but also the musculoskeletal system, the cardiovascular system, the skin, the excretory and the nervous system, and is accompanied by a number of hematological, gastrohepatoenterological and endocrine disorders. Various pain phenomena also appear in the clinical presentation of the disease, often as a single manifestation or in combination with symptoms from different organs and systems. The pathogenesis of pain is complex and there is still no consensus on the exact driving mechanisms. Several different signaling pathways play an important role in the generation of pain impulses and perception. They are different for different types of pain. At this stage, the role of angiotensin-converting enzyme 2 (ACE), the renin-angiotensin system (RAC), angiotensin 2 receptors (AT2R), direct neuronal invasion of the virus, the involvement of pro-inflammatory cytokines, hypoxia, the involvement of macrophages, is discussed. as well as the role of overactivity of the immune system, causing the so-called "cytokine storm". Pain is the result of complex biochemical processes influenced to varying degrees by biological, physiological and social factors. Our knowledge at this stage remains scarce and is the subject of many studies on the key pathogenic mechanisms. Therefore, the purpose of this review is to describe the known mechanisms for the occurrence and persistence of pain in patients with COVID-19, as well as to classify the pain phenomena and present its most common localizations. The diagnosis and treatment of COVID-19 and associated pain should be carried out by a multidisciplinary team of specialists, given the heterogeneous clinical presentation of the disease.Copyright © 2023 Medical Information Center. All rights reserved.

Is There a Rendezvous for SARS-CoV-2 and Agmatine?

The catastrophe of the ongoing COVID-19 pandemic is caused by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). The respiratory system appears to be ground zero in the majority of the patients. However, many other organs can get infected by cytokines, chemokines and other mediators released in response to the presence of the virus. The neurotropism by the SARS-CoV-2 is established beyond doubt. In addition to non-specific symptoms, the symptoms specific to central and/or peripheral nervous system diseases as well as neuromuscular diseases have been observed in numerous clinical cases. These observations and the experiences with other coronavirus infections earlier and flu pandemics raise concerns not only about the neurological effects in active disease but also about the long-term effects generated by the infection, immune and inflammatory functions. The knowledge of biological actions of agmatine in the backdrop of physiological events instigated by invading SARS-CoV-2 and host's response, especially in neural events, focuses on the possible overlaps of biomolecular pathways at a number of instances. This is not surprising since the factors stimulated during SARS-CoV-2 infection are the disease-generating neuroinflammatory components altered by agmatine. Hence, we hypothesize the possible beneficial role of agmatine in SARS-CoV-2 infection. Based on a narrative review of the literature, agmatine can be proposed as a plausible beneficial candidate for supporting treatment of SARS-CoV-2 infection and for addressing post-infection neurological complications.Copyright © 2022 Bentham Science Publishers.

Neurological manifestations associated with SARS-CoV-2 infection: an updated review

SARS-CoV-2 is a single-stranded RNA virus that belongs to the group of seven coronaviruses that affect humans, and its infection causes the COVID-19 disease. The association between the COVID-19 condition and risk factors of neurological manifestations is unclear to date. This review aims to update the main neurological manifestations associated with SARS-CoV-2 disease. First, we present the hypothesis of the neuroinvasion mechanisms of SARS-CoV-2. Then, we discuss the possible symptoms related to patients with COVID-19 infection in the central and peripheral nervous systems, followed by the perspectives of diagnosis and treatment of possible neurological manifesta-tions. The hypothesis of the neuroinvasion mechanism includes direct routes, as the virus crosses the blood-brain barrier or the ACE2 receptor pathway role, and indirect pathways, such as malfunctions of the immune system and vascular system dysregulation. Various studies report COVID-19 consequences, such as neuroanatomic alterations and cognitive impairment, besides peripheral condi-tions, such as anosmia, ageusia, and Guillain Barre Syndrome. However, the het-erogeneity of the studies about neurologic damage in patients after COVID-19 infection precludes any generalization of current findings. Finally, new studies are necessary to understand the adequate diagnosis, therapeutic method of early treatment, and risk group of patients for neurological manifestations of COVID-19 post-infection.Copyright © 2023, Instituto de Investigaciones Clinicas. All rights reserved.

Melanized (dematiaceous) fungal infections simulating skin cancer in African organ transplant recipients

Fungi are the most frequent skin infections in organ transplant recipients (OTRs) and usually present as superficial mycoses. Deeper infections are much less common, potentially more serious and the incidence is higher in the first few months post-transplant. We report two African OTRs with deep fungal infections caused by dematiaceous (melanized, pigmented or black) fungi, who both presented with suspected skin malignancies. A 60-year-old Nigerian man developed a painful, ulcerated, amelanotic, bleeding nodule on his right fourth toe 2 months after renal transplantation. Clinical differential diagnoses included Kaposi sarcoma (KS), amelanotic acral melanoma and subungual squamous cell carcinoma (SCC). However, histology showed pseudoepitheliomatous hyperplasia, extensive mixed inflammation, multinucleated giant cells and pigmented septate hyphae with rounded 'budding' forms. Periodic acid-Schiff, Grocott and Masson-Fontana stains were positive, and Alcian blue stain was negative, consistent with infection by a dematiaceous fungus. Fungal 18S polymerase chain reaction (PCR) was positive and culture identified Nigrograna mackinnonii. Treatment with oral itraconazole was supervised virtually during the COVID-19 pandemic. After 6 months there was minimal response and he opted for amputation of the digit. A 61-year-old Nigerian man presented 2 months after renal transplantation with a 2-cm diameter nodule on his left thigh at the site of a previous burn. This failed to respond to antibiotics. Magnetic resonance imaging was suggestive of possible malignancy, but surgery was deferred because of the COVID-19 pandemic. Two months later the lesion was 5 cm in diameter and verrucous with an 8-cm sessile, purplish plaque on his right forearm. Atypical KS, lymphoma and chronic burns-associated SCC were all considered. However, histology from both lesions was similar to the first patient. Fungal culture and 18S PCR confirmed infection with the dematiaceous fungus Alternaria alternata. At his request, the right thigh lesion was excised. The lesion on his forearm has partially responded to 8 months of ongoing oral itraconazole. In our African OTR cohort, KS is more common than deep fungal infection. However, despite this suspicion of skin malignancy, both patients had phaeohyphomycoses caused by dematiaceous fungi. Characterized by the presence of melanin in their cell walls, > 130 species of these plant pathogens and soil saprophytes are implicated in human disease, particularly in immunocompromised individuals. Although localized skin diseases (phaeohyphomycoses, chromoblastomycosis and mycetoma) are the most common manifestations, rare disseminated, central nervous system and pulmonary infections may prove fatal. Although uncommon, deep fungal infection should be considered in atypical skin lesions in OTRs;histology, tissue culture and fungal PCR are critical to confirming this diagnosis.

HD-tDCS in acute and long-term COVID-19

Symposium title: The potential role of tDCS in the management of Post-Acute Sequelae of SARS-COV-2 (PASC) Symposium description: The novel SARS-CoV-2 virus has infected millions of people worldwide. Post-infectious symptoms, referred to as Post-Acute Sequelae of SARS-CoV-2 (PASC), affect a large and growing segment of survivors, lasting months or even years without recovery. With continuous COVID-19 infections, PASC is a growing problem for public health. Therefore, effective and accessible treatment options need to be evaluated urgently. PASC symptoms are multi-systemic and can vary by the individual in clinical presentation, and its underlying pathological mechanisms remain uncharacterized. tDCS is a well-tolerated and extensively characterized noninvasive neuromodulation technique, and is effective in targeting the neuropsychiatric symptoms that define PASC (i.e., fatigue, cognitive, pain, emotional) including in other post-viral conditions. In addition, tDCS may have a larger role in the management of persisting respiratory symptoms. We will provide an overview of the theoretical basis and work to date supporting tDCS as a tool for PASC management, and present initial findings from recently completed and ongoing clinical trials. When COVID-19 first emerged, many researchers were focused on its impact on the lungs. As we have learned more about SARS-CoV-2 and resulting COVID-19, we have discovered that patients present a greater complexity in the context of the neurotrauma and the pulmonary lesions can become an aggravation of the neuroinvasion of the coronavirus and originate from cerebral injury. Recently, it has been suggested that noninvasive brain stimulation could be a valuable tool for the management of the early and postacute phase of patients with COVID-19. This session will present the results of our investigation of the High-definition transcranial direct current stimulation effects during the acute and chronic recovery phase from COVID-19. The prognostic factors and clinical predictors that contribute to greater response to treatment will be presented and directions for future research will be discussed. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: HD-tDCS, Coronavirus disease, Noninvasive brain stimulation, Long COVID-19Copyright © 2023

An Unusual Case Presentation of MOG-Positive Acute Disseminated Encephalomyelitis (ADEM) in a Preschool Child

Introduction: An unusual case presentation of MOG-positive Acute Disseminated Encephalomyelitis (ADEM) in a preschool child following meta-pneumo viral infection responded to the combination of immune modulatory treatment with a favourable outcome. Material: Three-year-old female child presented with acute encephalopathy, high fever, vomiting, starring episodes, floppiness, and left abducent nerve palsy with rapid deteriorating GCS necessitating intubation and ventilation. Two weeks earlier, she was treated for suspected CNS infection with 10 days of antibiotics in the PICU with a positive meta-pneumo-virus. On admission, she had a GCS score of 6 with left-sided increased tone, bilateral hyperreflexia, and bilateral extensor response and on Day 14 demonstrated hyperkinetic movements of the upper and lower limbs. Method(s): Serum MOG antibody positive, CSF MOG low positive, metabolic investigations, Mycoplasma, EBV, Influenza, corona PCR, SARS-COV-2 Antibody, viral CSF panel unremarkable. MRI brain demonstrated T2 hyperintense signal in bilateral medial thalami and brain stem with a normal spine. Progressive changes were shown on repeated MRI Brains on day 4 and day 14 suggestive of multifocal changes involving deep cortical and subcortical white matter bilaterally with a new short segment of the spinal lesion at the T8 level. Repeated EEG and ambulatory EEG showed a diffusely slow background with intermittent slow runs of slow waves suggestive of generalized cerebral dysfunction. Result(s): After receiving the combination of high pulse steroids with a taper over 10 weeks, IVIG and 10 cycles of plasmapheresis she demonstrated gradual and remarkable clinical improvement over 10-12 weeks with a minimal focal neurological deficit. Conclusion(s): Initial differentiating CNS infection, metabolic disease and ADEM may be clinically challenging. Her clinical presentation, investigations and imaging were in keeping with the diagnosis of MOG-positive ADEM. Previous CNS infection may be related. MOG-positive ADEM treated with the early combination of immunomodulation may lead to positive clinical outcomes.

Brain phaeohyphomycosis secondary to immunosuppressant therapy due to Rhinocladiella mackenziei

Two cases of Rhinocladiella mackenziei have been noted in our institute, the first case in 2015 (post-renal transplant) and the second case in 2021 (post-COVID infection). Both the patients had received immunosuppressants for varying dura-tion. Both the cases presented to the hospital with neurological deficit secondary to brain abscess. On initial assessment, the melanized fungus was noted which was later identified as Rhinocladiella on culture and further confirmed with molecular meth-ods. Both the cases were treated with injection of L AmB, voriconazole and 5FC for a prolonged duration and later discharged when the condition improved. The renal transplant patient was advised lifelong voriconazole since he would continue to be on immunosuppressants. To our knowledge, the second patient diagnosed post-COVID could be the first case report of invasive dematiaceous fungal infection in an apparently immunocompetent individual. Both cases also highlight the challenges in man-agement such as designing an appropriate regimen, deciding the optimum duration of antifungal therapy, and managing the toxicities associated with long-term antifungal use. R. mackenziei is a frequently fatal melanized neurotropic fungus known to carry almost 100% mortality despite the combination of antifungal agents and surgery. Central nervous system infections due to R. mackenziei have been exclusively reported from the Middle East, except for cases recently reported from India.

Neuromodulatory Effects of Sars-Cov2 on Blood Brain Barrier Integrity and Function: E-Poster Viewing

Introduction: Autopsies of COVID-19 patients demonstrate the presence of SARS-CoV-2 in the brain endothelium, cerebrospinal fluid, glial cells, and neuronal tissue;while emerging clinical data suggest that ~40% of COVID-19 patients develop neurological symptoms. We examined the effects of SARS-COV-2 RBD spike protein on blood brain barrier (BB) integrity, and on the expression of tight junction proteins (TJP) that maintain BBB permeability and function. Materials / Methods: Primary human BMVEC were treated with recombinant SARS-COV-2 Spike protein (BEI Resources Inc) for 24-48 hrs, followed by immunofluorescent staining to quantify ACE2 receptor expression. Pro-inflammatory cytokines were quantified in culture supernatants using BioLegend's LEGENDLplexTM bead-based immunoassay. Additionally, a well validated 2D in-vitro BBB model was used to examine the effects of SARS-COV-2 on BBB integrity as measured by transendothelial electrical resistance (TEER) across the membrane, and TJ protein gene expression levels were measured using real time quantitative PCR. Result(s): Data demonstrates that primary human BMVEC express the ACE2 receptor and treatment with SARS-COV-2 spike protein significant increases in ACE2 receptor expression. We observed a significant increase in the levels of the pro-inflammatory cytokines TNF-alpha (p<0.01), IL-6 (p<0.0001), IL-10 (p<0.05), IL-23 (p<0.05) and IL-33 (p<0.01) in BMVEC treated with SARS-COV-2 spike protein compared to untreated controls. A 30% (p<0.05) decrease in TEER occurred in the BBB treated with SARS-COV-2 spike protein as compared to untreated controls, and SARS-COV-2 decreased TJP expression. Data demonstrates that SARS-COV-2 treatment decreased gene expression for the TJPs- ZO-1 (52%;p<0.05), ZO-2 (92%;p<0.001), Claudin-5 (97%;p<0.001) and JAM-2 (45%;p<0.05) as compared to untreated controls. Discussion(s): SARS COV-2 mediates its effects via the ACE2 receptor and therefore an increase in ACE2 expression on BMVEC suggests that neuroinvasion by SARS- COV2 is mediated via endothelial inflammation. Further, SARS-COV-2 induced levels of pro-inflammatory cytokines IL-6, TNF-alpha, IL-8, and IL-10 corroborates the induction of a neuroinflammatory response, confirming hypercytokinemia, which may underlie neuroinflammation in COVID-19 associated encephalopathy. Our data suggest that the significant decrease in TJP gene expression levels directly affect BBB integrity and function thus enabling neuro-invasion and potential subsequent COVID-19 associated neuropathology. Conclusion(s): BMVEC have a paracrine-autocrine role in maintaining CNS homeostasis and the SARS-COV2 associated endothelial cell dysfunction preludes the neuropathology observed in COVID-19 infected patients. Potentially, anti-cytokine based therapeutics may be effective in treating patients with COVID- 19 associated neurological disease. Acknowledgements: Authors gratefully acknowledge funding from SUNY Research Seed Grant Program 2019-20 -RFP #20-03-COVID that was crucial to obtain data for this pilot project. Learning Objectives: Examine the basic neuromodulatory mechanisms that underlie SARS-COV-2 mediated neuropathology. Keywords: SARS-COV2;transendothelial electrical resistance;Blood Brain Barrier;permeability, Tight junction Copyright © 2022

Findings on PET/CT-PET/MR secondary to central and peripheral nervous system infection by SARS-CoV-2

Introduction: SARS-CoV-2 infection worldwide has affected about 232,075,351 people and caused at least 4,752,988 deaths according to WHO data. It has been considered that the organ of predilection for involvement by this infection is the lung, but according to the literature, 36.4% of patients have evidenced CNS involvement and 8.9% of the SNP. Material(s) and Method(s): An intentional search of the literature was carried out in different medical databases such as Pubmed, Ovid, BMJ, Clinical Key, ScienceDirect, entering keywords such as COVID-19, brain, SARS-CoV-2 infection, PET/CT, PET/RM encephalopathy, accompanied by Boolean operators such as AND, OR and NOT. Result(s): To date, numerous case reports, case series, and observational studies have been published using different PET/CT or PET/MRI radiotracers with different findings. Conclusion(s): PET/CT or PET/MRI with 2-[18F]FDG or [18F]FDOPA has shown to be a useful tool to detect and understand the disease process in those patients with SARS-CoV-2 neuro-infection in cases of normal structural images. Copyright © 2022 Sociedad Neurologica Argentina

Early Permissiveness of Central Nervous System Cells to Measles Virus Infection Is Determined by Hyperfusogenicity and Interferon Pressure.

The cessation of measles virus (MeV) vaccination in more than 40 countries as a consequence of the COVID-19 pandemic is expected to significantly increase deaths due to measles. MeV can infect the central nervous system (CNS) and lead to lethal encephalitis. Substantial part of virus sequences recovered from patients' brain were mutated in the matrix and/or the fusion protein (F). Mutations of the heptad repeat domain located in the C terminal (HRC) part of the F protein were often observed and were associated to hyperfusogenicity. These mutations promote brain invasion as a hallmark of neuroadaptation. Wild-type F allows entry into the brain, followed by limited spreading compared with the massive invasion observed for hyperfusogenic MeV. Taking advantage of our ex vivo models of hamster organotypic brain cultures, we investigated how the hyperfusogenic mutations in the F HRC domain modulate virus distribution in CNS cells. In this study, we also identified the dependence of neural cells susceptibility on both their activation state and destabilization of the virus F protein. Type I interferon (IFN-I) impaired mainly astrocytes and microglial cells permissiveness contrarily to neurons, opening a new way of consideration on the development of treatments against viral encephalitis.

Proteome and phosphoproteome analyses of SARS-CoV-2-infected humanized K18-ACE2 mice reveal hyperactive phenotype of circulating platelets

Background: Platelets are effectors of hemostasis and play a major role in coordinating immune and inflammatory activities. Suitable animal models are needed to study COVID-19-associated coagulopathy and platelet effector functions in COVID-19, which are currently poorly understood. Aim(s): We aimed to characterize alterations of platelets isolated from K18-hACE2 transgenic mice infected with SARS-CoV-2. Method(s): Heterozygous K18-hACE2 (human ACE2) and C57BL/6J mice were used to study SARS-CoV-2 infectivity. Lung infection, infiltration, and platelet aggregation were characterized with histology and immunohistochemistry. Platelet response to SARS-CoV-2 infection was quantified by mass spectrometry analysis of proteomics and phosphoproteomics. Western blotting, ELISA, and multiplex plasma profiling were performed to validate the proteomics and phosphoproteomics data. Result(s): SARS-CoV-2 inoculated (10E6PFU, i.n.) K18-hACE2 mice started to lose weight at 4 days post-infection (dpi) and showed 90% lethality at 7-dpi in association with viral neuroinvasion. Histopathologic findings of infected K18-hACE2 mice included progressive lymphohistiocytic interstitial pneumonia with absence of diffuse alveolar damage. Lungs of infected K18-hACE2 mice (2-/ 4-dpi) showed mild increase in CD61+ aggregates compared to sham mice, but no overt tissue thrombosis. Gene ontology and pathway analyses of platelet proteomics and phosphoproteomics revealed that SARS-CoV-2 infection significantly upregulates the complement-coagulation cascades (F2/12/13, Tfpi, C1ra, Cd55, C4bp) and platelet activation-adhesion-degranulation proteins (Vwf, Itgb3/5, Selp, Pecam1) and chemokine (Pf4, Cxcl5/12) signaling at 2-dpi. However, interferon (Ddx58, Trim25, Mapk3) signaling was dominant at 4-dpi. Activation of proteomics and phosphoproteomics protein markers were highly correlated with platelet activation and interferon signaling at 2-/ 4-dpi, respectively. Plasma chemokine (e.g., Ccl8 and Pf4) and cytokines (e.g., IL6) were significantly elevated at 2-/ 4-dpi. SARS-CoV-2 spike protein was abundant at 2-/ 4-dpi in the lungs but not in platelets and kidneys, which correlated with no infectious virus in the serum. Conclusion(s): Platelet re-programming towards activation-degranulation-aggregation is likely attributable to a pneumonia-induced elevated circulatory factors (e.g., cytokines)-driven response rather than direct platelet infection.

Pharmacological Potential of Flavonoids against Neurotropic Viruses.

Flavonoids are a group of natural compounds that have been described in the literature as having anti-inflammatory, antioxidant, and neuroprotective compounds. Although they are considered versatile molecules, little has been discussed about their antiviral activities for neurotropic viruses. Hence, the present study aimed to investigate the pharmacological potential of flavonoids in the face of viruses that can affect the central nervous system (CNS). We carried out research from 2011 to 2021 using the Pubmed platform. The following were excluded: articles not in the English language, letters to editors, review articles and papers that did not include any experimental or clinical tests, and papers that showed antiviral activities against viruses that do not infect human beings. The inclusion criteria were in silico predictions and preclinical pharmacological studies, in vitro, in vivo and ex vivo, and clinical studies with flavonoids, flavonoid fractions and extracts that were active against neurotropic viruses. The search resulted in 205 articles that were sorted per virus type and discussed, considering the most cited antiviral activities. Our investigation shows the latest relevant data about flavonoids that have presented a wide range of actions against viruses that affect the CNS, mainly influenza, hepatitis C and others, such as the coronavirus, enterovirus, and arbovirus. Considering that these molecules present well-known anti-inflammatory and neuroprotective activities, using flavonoids that have demonstrated both neuroprotective and antiviral effects could be viewed as an alternative for therapy in the course of CNS infections.

Rotavirus meningitis in an adult with transient aphasia.

We identified an additional case of documented Rotavirus meningitis in an adult with full medical history. A previously healthy 37-year-old patient presented herself for transient aphasia associated with fever and headaches at the end of a one-week history of gastroenteritis. Cerebrospinal fluid (CSF) analysis revealed lymphocytic meningitis, and treatment with aciclovir was initiated. Rotavirus A reverse transcription-polymerase chain reaction (RT-PCR) was positive in CSF and the patient's stools in favor of Rotavirus meningitis. Testing for other viruses was negative. Magnetic resonance imaging (MRI) showed no signs of encephalitis. Aphasia was resolutive in less than 12 hours, and no neurological symptoms relapsed. All symptoms evolved favorably despite aciclovir discontinuation. Viral sequencing methods have recently identified unexpected viruses as potential causative agents in meningitis, including Rotavirus. We confirm the detectability of Rotavirus in the analysis of CSF in the context of Rotavirus gastroenteritis in an adult. This case suggests postviral headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome may be linked to previously undetected direct viral infection of the central nervous system. Therefore, clinicians should consider Rotavirus meningitis in diagnosing meningitis associated with gastroenteritis in adults.