COVID-19 testing trends: pre-radiation and throughout cancer care

Introduction: Patients presenting for radiation therapy (RT) at a single institution were analysed regarding treatment delays and disparities during the coronavirus disease 2019 (COVID-19) pandemic. Methods: The study was conducted at an urban multidisciplinary cancer centre. In April 2020, the institution's radiation oncology department implemented universal COVID-19 screening protocols prior to RT initiation. COVID-19 testing information on cancer patients planned for RT from 04/2020 to 01/2021 was reviewed. Trends of other lifetime COVID-19 testing and overall care delays were also studied. Results: Two hundred and fifty-four consecutive cancer patients received RT. Median age was 63 years (range 24-94) and 57·9% (n = 147) were Black. Most (n = 107, 42·1%) patients were insured through Medicare. 42·9% (n = 109) presented with stage IV disease. One (0·4%) asymptomatic patient tested positive for COVID-19 pre-RT. The cohort received 975 lifetime COVID-19 tests (median 3 per patient, range 1-18) resulting in 29 positive test results across 21 patients. Sixteen patients had RT delays. Identifying as Hispanic/Latino was associated with testing positive for COVID-19 (p = 0·015) and RT delay (p = 0·029). Conclusion: Most patients with cancer planned for RT tested negative for COVID-19 and proceeded to RT without delay. However, increased testing burden, delays in diagnostic workup and testing positive for COVID-19 may intensify disparities affecting this urban patient population. © The Author(s), 2022. Published by Cambridge University Press.

Neurologic Manifestations of COVID-19

Coronavirus disease (COVID-19) caused by a new coronavirus, SARS-CoV-2, has become a serious health problem throughout the world. Although COVID-19 primarily presents as an acute respiratory tract infection, many neurological findings have also been described in patients. Neurological findings are classified into three groups as central, peripheral nervous system and musculoskeletal system. The most common central nervous system symptom is headache. Encephalitis, encephalopathy, seizures, acute ischemic stroke are also seen. The most common symptoms in the peripheral nervous system are loss of smell and taste. Myalgia, myositis and rhabdomyolysis also can be seen in musculoskeletal system involvement. Awareness of the neurological symptoms by physicians will be beneficial in early diagnosis and treatment of the disease.

Association of the matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of coronavirus disease 2019 (COVID-19); implications of contribution for development of neurological symptoms in the COVID-19 patients.

BACKGROUND: Seemingly, the Matrix metalloproteinases (MMPs) play a role in the etiopathogenesis of coronavirus disease 2019 (COVID-19). Here in this study, we determined the association of MMP9 rs3918242, MMP3 rs3025058, and MMP2 rs243865 polymorphisms with the risk of COVID-19, especially in those with neurological syndrome (NS). METHODS: We enrolled 500 patients with COVID-19 and 500 healthy individuals. To genotype the target SNPs, the Real-time allelic discrimination technique was used. To determine serum levels of MMPs, Enzyme-linked immunosorbent assay (ELISA) was exerted. RESULTS: The MMP9 gene rs3918242 and MMP3 gene rs3025058 SNP were significantly associated with increased COVID-19 risk and susceptibility to COVID-19 with NS. The serum level of MMP-9 and MMP-3 was significantly higher in COVID-19 cases compared with the healthy controls. Serum MMP-9 and MMP-3 levels were also higher in COVID-19 subjects with NS in comparison to the healthy controls. The polymorphisms in MMP genes were not associated with serum level of MMPs. CONCLUSION: MMP9 and MMP3 gene polymorphisms increases the susceptibility to COVID-19 as well as COVID-19 with neurologic syndrome, but they probably have no role in the regulation of serum MMP-9 and MMP-3 levels.

The many facets of CD26/dipeptidyl peptidase 4 and its inhibitors in disorders of the CNS - a critical overview.

Dipeptidyl peptidase 4 is a serine protease that cleaves X-proline or X-alanine in the penultimate position. Natural substrates of the enzyme are glucagon-like peptide-1, glucagon inhibiting peptide, glucagon, neuropeptide Y, secretin, substance P, pituitary adenylate cyclase-activating polypeptide, endorphins, endomorphins, brain natriuretic peptide, beta-melanocyte stimulating hormone and amyloid peptides as well as some cytokines and chemokines. The enzyme is involved in the maintenance of blood glucose homeostasis and regulation of the immune system. It is expressed in many organs including the brain. DPP4 activity may be effectively depressed by DPP4 inhibitors. Apart from enzyme activity, DPP4 acts as a cell surface (co)receptor, associates with adeosine deaminase, interacts with extracellular matrix, and controls cell migration and differentiation. This review aims at revealing the impact of DPP4 and DPP4 inhibitors for several brain diseases (virus infections affecting the brain, tumours of the CNS, neurological and psychiatric disorders). Special emphasis is given to a possible involvement of DPP4 expressed in the brain.While prominent contributions of extracerebral DPP4 are evident for a majority of diseases discussed herein; a possible role of "brain" DPP4 is restricted to brain cancers and Alzheimer disease. For a number of diseases (Covid-19 infection, type 2 diabetes, Alzheimer disease, vascular dementia, Parkinson disease, Huntington disease, multiple sclerosis, stroke, and epilepsy), use of DPP4 inhibitors has been shown to have a disease-mitigating effect. However, these beneficial effects should mostly be attributed to the depression of "peripheral" DPP4, since currently used DPP4 inhibitors are not able to pass through the intact blood-brain barrier.

Human brain organoids to explore SARS-CoV-2-induced effects on the central nervous system.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). In less than three years, an estimated 600 million infections with SARS-CoV-2 occurred worldwide, resulting in a pandemic with tremendous impact especially on economic and health sectors. Initially considered a respiratory disease, COVID-19, along with its long-term sequelae (long-COVID) rather is a systemic disease. Neurological symptoms like dementia or encephalopathy were reported early during the pandemic as concomitants of the acute phase and as characteristics of long-COVID. An excessive inflammatory immune response is hypothesized to play a major role in this context. However, direct infection of neural cells may also contribute to the neurological aspects of (long)-COVID-19. To mainly explore such direct effects of SARS-CoV-2 on the central nervous system, human brain organoids provide a useful platform. Infecting these three-dimensional tissue cultures allows the study of viral neurotropism as well as of virus-induced effects on single cells or even the complex cellular network within the organoid. In this review, we summarize the experimental studies that used SARS-CoV-2-infected human brain organoids to unravel the complex nature of (long)-COVID-19-related neurological manifestations.

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.

Case Study of Transitioning a Clinical Trial from a Clinical Research Facility (CRF) to the Neurology Clinical Service Outpatient Department

Objectives: It was recognised that a later phase extension study was less intense and a potential to transition to the clinical service with support from a coordinator, Epilepsy CNS (Clinical Nurse Specialist) and Neurology fellow. This case study will explore the planning, implementation methods, challenges and successes from the medical, nursing and family perspectives. Method(s): Initial strategic planning will be demonstrated and include a pathway taken to implement the transition. The requirements of the study were assessed, and a model was established of how the study will run in the clinical service. The CNS role was expanded to include research. Teaching and support were provided by the CRF team outlining individual roles and responsibilities. In order to understand the family, medical and nursing experience of research transition, a questionnaire has been completed at the end of study. Result(s): Challenges included new team to research, CNS time, medication accountability management, visit coordination, Covid-19 pandemic impacts on patient visits, and medical responsibilities combining clinical and research care. Collaborative solutions were found overcome these challenges. Positive outcomes: Epilepsy CNS available to families, new CNS skills, and stronger links established between research and clinical. Questionnaires have been analysed to gather data on patient experience, and common themes have been highlighted for considerations to take forward to future trial transitions. Conclusion(s): Overall, it has been a smooth successful transition. This has shifted the culture mindset that research and clinical care running separately. The drug is now approved for use as recommendation on NICE guidelines. The case study is a prime example of research and the clinical service working in unison. Portraying the research journey from early phase to NHS usage.

A case of multisystem inflammatory syndrome in children (MIS-C)

Background/Purpose: MIS-C is uncommon and yet potentially life threatening disorder associated with COVID-19 infection. MIS-C Malaysia Study Group had reported 174 cases, mostly affecting children < 12 years old (93.7%). The fatality rate was 4%. Hereby, we report a case of MIS-C at our adult rheumatology centre. Method(s): Patient's admission note and electrical medical information were reviewed. Result(s): This is a 17 year-old adolescent with underlying obesity (BMI 42 kg/m2). He completed COVID-19 vaccination (Pfizer-BioNTech x 2 doses) in October 2021. In end-February 2022, he presented acutely with recurrent seizures associated with fever (40.3degreeC) and headache. The COVID-19 RTK antigen and PCR tests were positive, and COVID-19 IgM & IgG were negative. At emergency room, he developed haemodynamic instability, needing ventilatory support for respiratory failure and inotropic therapy on Day 1 of illness. The initial diagnosis was severe COVID-19 infection with encephalitis and secondary bacterial infection. Subsequent investigations showed evidence of systemic inflammation with organ dysfunction involving neurological (seizures, CNS vasculitis), cardiac (myocarditis), renal (acute kidney injury) and gastrointestinal (acute livery injury) systems. MIS-C was then diagnosed with early initiation of immunomodulatory treatment (IVIg 2 g/kg and IV methylprednisolone 1-2 mg/kg/day) according to ACR recommendation. Low dose aspirin and high intensity prophylactic SC enoxaparin were prescribed but were discontinued soon due to bleeding tendency. Antimicrobial therapy was continued until microbiological study was proven sterile. With the immunomodulatory treatment, he had rapid clinical and laboratory improvement within first week and was transferred out from ICU on Day 10 of illness. The organ dysfunction was mostly resolved with no sequelae except for high blood pressure requiring antihypertensive. Inflammatory markers were markedly reduced;Serum ferritin reduced from 22,339 to 565.8 mug/L, procalcitonin decreased from 26.7 ng/ml to 1.5 ng/ml and CRP normalised (<5 mg/L). Home discharge was made on Day 16 of illness with oral prednisolone 60 mg daily without antiplatelet. During clinic visit after D30 of illness, he remained asymptomatic with good effort tolerance and normal blood pressure readings. He subsequently completed the high school examination in April 2022 and even enrolled at college later. Oral prednisolone was eventually tapered off at 3rd month of illness with appointments for MRI cardiac and brain scheduled for further assessment. Conclusion(s): MIS-C is a hyperinflammatory syndrome which requires high clinical suspicion as many patients response well to early immunodulatory treatment without sequelae. Long term follow up maybe needed for those with cardiac involvement. (Table Presented).

Neurologic Manifestations of COVID-19.

Coronavirus disease (COVID-19) caused by a new coronavirus, SARS-CoV-2, has become a serious health problem throughout the world. Although COVID-19 primarily presents as an acute respiratory tract infection, many neurological findings have also been described in patients. Neurological findings are classified into three groups as central, peripheral nervous system and musculoskeletal system. The most common central nervous system symptom is headache. Encephalitis, encephalopathy, seizures, acute ischemic stroke are also seen. The most common symptoms in the peripheral nervous system are loss of smell and taste. Myalgia, myositis and rhabdomyolysis also can be seen in musculoskeletal system involvement. Awareness of the neurological symptoms by physicians will be beneficial in early diagnosis and treatment of the disease. Copyright © 2022 Ankara Pediatric Hematology Oncology Training and Research Hospital. All rights reserved.

Multisystem inflammatory syndrome associated with COVID-19 in children: Risk factors of severe life-threatening course of the disease

Background/Purpose: Multisystem inflammatory syndrome in children (MIS-C), associated with COVID-19 infection is a life-threatening condition, required intensive care. The aim of this study was to determine risk factors for severe/life-threatening course of MIS-C. Method(s): The retrospective study included 166 children (99 male, 67 female), aged from 4 months to 17 years (median 8.2 years), who met the WHO criteria for MIS-C. The criterion of severity was the fact of the ICU admission. The analysis of the obtained data was performed using the STATISTICA software package, version 10.0 (StatSoft Inc., USA). Result(s): To assess the factors associated with the severe course of MIS-C, patients were divided into two groups: those who were hospitalized in the ICU (n = 84;50.6%), and those who did not (n = 82;49.4%). Patients with a more severe course of MIS-C were significantly older. They had a high frequency of signs such as rash, edema, hepatomegaly, splenomegaly, neurological and respiratory symptoms. Hypotension/shock and myocardial damage were much more common in patients hospitalized in the ICU. Among the laboratory changes there were significant differences in the levels of hemoglobin, leukocytes and platelets, CRP, creatinine, troponin and D-dimer. The presence of macrophage activation syndrome was higher in patients, admitted in the ICU. Children, required intensive care required high dose corticosteroids and IVIG more often (table 1). FIGURE: 1) The first symptoms of progeria in infancy: scleroderma-like changes in the skin of the lower extremities and stiffness of knee joints at the age of 2 months. 2) Girl at the age of 3 years 5 months. Almost total alopecia with the absence of eyebrows and eyelashes. Pronounced venous pattern in the forehead, nasal bridge and nasolabial triangle. Conclusion(s): MIS-C is potentially a severe life-threatening condition, in which more than half (50.6%) of patients needed the ICU admission. The main factors determining the severity of MIS-C were: cardiovascular, resiratory and central nervous system disorders. It has been found that factors such as hepatomegaly, splenomegaly, D-dimer >2568 ng/ml, troponin >10 pg/ml, make it possible to identify a group of patients with high risk of severe MIS-C who may potentially need hospitalization in the ICU.

COVID-19 and the central nervous system: What is the interplay?

Since the outbreak of COVID-19 in 2019-2020, the highly contiguous disease caused by coronavirus 2 (SARS-CoV-2) spread worldwide in a short life span causing a disastrous effect and nearly 5.8 million deaths until February 2022. This global health crisis caused concerns about the disease's aetiology, epidemiology, and management. Understanding the virus's long-and short-term consequences on diverse human body organs and systems was one of the scientist's concerns despite the virus' respiratory system principal effect. Thus, after reporting neurological symptoms in approximately one-third of hospitalised patients with COVID-19, demonstrating how COVID-19 infects the central nervous system (CNS), causing neurodegenerative diseases in various patients and how the virus affects CNS function became quintessential. There are various mechanisms for COVID-19 pathophysiology, some implicating the potential virus invasion of the blood-brain barrier (BBB). Trans-synaptic and hematogenous routes are the main routes for the virus to pass through the barrier. Binding to the BBB endothelial cells is causing significant alterations in the permeability and integrity properties of the barrier, which cause an elevation of the incidence rate of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis among COVI-19 patients. COVID-19 patients developed neurological manifestations ranging from mild symptoms to severe diseases such as headache and loss of smell, encephalitis and CNS-mediated respiratory distress. However, encephalitis is not a common complication, and it has a significant mortality rate in severely ill patients due to the hyperactivation of the host immune response. Although more investigations are needed, severe COVID-19 patients are considered at a high risk of neurodegenerative disorder as a long-term consequence of SARS-CoV-2 infection. © 2022, Neurotak Publishing. All rights reserved.

Dysregulated Levels of Circulating Autoantibodies against Neuronal and Nervous System Autoantigens in COVID-19 Patients.

BACKGROUND: COVID-19 is a heterogenous disease resulting in long-term sequela in predisposed individuals. It is not uncommon that recovering patients endure non-respiratory ill-defined manifestations, including anosmia, and neurological and cognitive deficit persisting beyond recovery-a constellation of conditions that are grouped under the umbrella of long-term COVID-19 syndrome. Association between COVID-19 and autoimmune responses in predisposed individuals was shown in several studies. AIM AND METHODS: To investigate autoimmune responses against neuronal and CNS autoantigens in SARS-CoV-2-infected patients, we performed a cross-sectional study with 246 participants, including 169 COVID-19 patients and 77 controls. Levels of antibodies against the acetylcholine receptor, glutamate receptor, amyloid ß peptide, alpha-synucleins, dopamine 1 receptor, dopamine 2 receptor, tau protein, GAD-65, N-methyl D-aspartate (NMDA) receptor, BDNF, cerebellar, ganglioside, myelin basic protein, myelin oligodendrocyte glycoprotein, S100-B, glial fibrillary acidic protein, and enteric nerve were measured using an Enzyme-Linked Immunosorbent Assay (ELISA). Circulating levels of autoantibodies were compared between healthy controls and COVID-19 patients and then classified by disease severity (mild [n = 74], severe [n = 65], and requiring supplemental oxygen [n = 32]). RESULTS: COVID-19 patients were found to have dysregulated autoantibody levels correlating with the disease severity, e.g., IgG to dopamine 1 receptor, NMDA receptors, brain-derived neurotrophic factor, and myelin oligodendrocyte glycoprotein. Elevated levels of IgA autoantibodies against amyloid ß peptide, acetylcholine receptor, dopamine 2 receptor, myelin basic protein, and α-synuclein were detected in COVID-19 patients compared with healthy controls. Lower IgA autoantibody levels against NMDA receptors, and IgG autoantibodies against glutamic acid decarboxylase 65, amyloid ß peptide, tau protein, enteric nerve, and S100-B were detected in COVID-19 patients versus healthy controls. Some of these antibodies have known clinical correlations with symptoms commonly reported in the long COVID-19 syndrome. CONCLUSIONS: Overall, our study shows a widespread dysregulation in the titer of various autoantibodies against neuronal and CNS-related autoantigens in convalescent COVID-19 patients. Further research is needed to provide insight into the association between these neuronal autoantibodies and the enigmatic neurological and psychological symptoms reported in COVID-19 patients.

Neurological manifestations of hospitalized COVID-19-infected patients: a single-center cohort study

Background: Although COVID-19 preferentially affects the respiratory system, it has been demonstrated that coronaviruses frequently invade the nervous system. Objectives: We aimed to report the frequency and type of neurological manifestations in hospitalized patients with COVID-19.

CNS Summit 2022

The proceedings contain 66 papers. The topics discussed include: AI-driven COVID-19 mRNA vaccine degradation prediction;evidence-based clinical trial feasibility and protocol design using artificial intelligence;reducing sample sizes by up to 30% in clinical trials for mood disorders via enhanced primary endpoint reliability using audio-visual multimodal machine learning;the development of an automated EEG-based machine learning pipeline for the detection of Alzheimer's disease: a proof of concept for novel clinical trial biomarkers;tools for rapid development of EEG-based pharmacodynamic biomarkers;TWINRCT: novel ai-based solution to reduce sample size of control arms;circadian rhythm-related endpoints derived from actigraphy: validation of SOMNO-ART;and reliability of real world digital end-points of functional neurophysiology.

Spectrum of common and uncommon neurovascular and neurological manifestations of COVID-19 on cross-sectional imaging

COVID-19 is an emerging and re-emerging disease that is caused by SARS CoV-2, a neurotropic virus that frequently involves the central nervous system in ad-dition to the lungs. Findings on neuroimaging can be observed in a significant percentage of active COVID-19 and post-COVID patients, especially those who are/ have been critically ill. Accurate diagnosis of such cases on imaging aids in appropriate patient management and prevention of permanent neurological deficits. The features of CNS involvement in COVID-19 can be broadly categorized as the more common neurovas-cular and relatively uncommon neurological manifes-tations. Several pathophysiological mechanisms have been proposed for the patterns of CNS involvement and corresponding neuroimaging features in COVID-19. We have outlined the pathophysiology and indications for neuroimaging in COVID-19 and extensively discussed the neuroimaging features of the entire spectrum of neurovascular and neurological manifestations, in-cluding the rare and diagnostically challenging ones, through case-based illustrations. As new strains of COVID-19 continue to emerge, radiologists need to be aware of the imaging features of various neurological and neurovascular manifestations of CNS involvement in COVID-19 as timely diagnosis is vital in preventing or limiting permanent neurological deficits in such cases. © 2022, Zita Medical Managent. All rights reserved.

An insight into the immunomodulatory potential of wood oil of Aquilaria malaccensis Lam. with an emphasis into related phytomedicine, biomarkers, pharmacology, and toxicity

Critically endangered Aquilaria malaccensis Lam. is known for highly expensive agarwood with unique aroma. Agarwood has been used as a phytomedicine in chronic degenerative neurological disorders, paralysis, rheumatism, asthma, and others. Its production is dependent naturally or artificially on interaction of endophytic fungi, and by nailing, drilling, and microbial inoculation respectively. The majorly produced biomarkers of terpenes, fatty acids, alkanes, chromones, and flavonoids exhibited several biological activities in congruence to their ethnomedicinal claims. During the pandemic, several in-silico, studies showed the potential of a few sesquiterpene hydrocarbons against covid-19. The review aimed to deliver a comprehensive outline of the immunomodulatory potential of agarwood oil with allied traditional medicinal use, biomarkers, pharmacological evaluation, toxicity, and mechanistic action. The review eventually showed the agarwood oil, extracts, and major biomarkers viz., aromadendrene II, valencene, phytol, octacosane, caryophyllene oxide, b-caryophyllene, hinesol, agarospirol, with immunomodulatory, anti-inflammatory, and allied neural, antidiabetic, antimicrobial activity, toxicity, along with molecular target binding potential against 3CLpro, RDRP, Mpro, PLpro, Spike protein S1 of SARS-CoV2 through in-vitro, in-vivo, in silico studies and limited human clinical trials. The expression of HMGR, ASS, ADXPS, ADXPR, FPS, and WRKY genes of sesquiterpenoid biosynthetic pathways were upregulated for signature aroma and immunomodulatory markers viz., d-guaiene, dodecane, tetracosane, agarospirol, farnesol, and geranylgeraniol acetate as a defensive response. The review would ignite future research on potential immunomodulatory markers viz., caryophyllene oxide, octacosane, heneicosane, agarospirol, n-hexadecanoic acid, a-eudesmol, a-santalol and inoculum guided invitro agarwood production restoring the prized aroma, therapeutic efficacy, and wild population. (c) 2022 SAAB. Published by Elsevier B.V. All rights reserved.