Dysosmia and dysgeusia as differential diagnostics for clinical triaging of COVID-19 cases (preprint)

Smell and taste disorders are recognized as frequent, and often the only, signs occurring in the early phase of SARS-Cov-2 infection and in many cases perdure as post-viral symptoms. This evidence raised a general reconsideration of chemosensory deficits, further suggesting that their appearance can be considered as a discriminative and predictive tool to detect COVID-19 cases. In this study, encompassing the first and second pandemic wave, participants estimated their olfactory and gustatory sensitivity, plus they were administered the validated Brief Smell Identification Test (BSIT). We observed that smell and taste impairments were mainly experienced by COVID-19-positive subjects with comparable severity of respiratory symptoms as non-COVID-19 patients. In addition, we noticed that the diagnostic power of subjective olfactory assessments upon SARS-Cov-2 infection is comparable to quantitative evaluation, suggesting that self-reporting could be adopted as the first line of intervention, anticipating more exhaustive procedures aimed at containing COVID-19 diffusion and consequently preserving general health. Overall, results from this work share similarity with other studies, therefore further underlying that olfactory and gustatory disbalance can be distinctive hallmarks in COVID-19 continuum.

Revisiting Fiscal Deficit Sustainability and Revenue-Expenditure Nexus in India (preprint)

With the onset of the COVID-19 pandemic, the issue of fiscal sustainability has emerged as one of the most challenging issues for both developing and developed countries. In this backdrop, it is imperative to examine fiscal deficit sustainability, particularly in federal countries like India, where both Central and State governments are continuously borrowing and debt is at relatively high levels. Therefore, the core objective of the study is to empirically investigate the fiscal deficit sustainability in India by employing Gregory-Hansen cointegration approach. In addition, the study also aims at determining the causal relationship between government expenditures and revenues using Toda-Yamamoto Granger non-causality test. The result supports the evidence of “weak” fiscal deficit sustainability for both governments, individually. Further, result also supports the “spend-tax hypothesis” for both governments. Therefore, the present study suggests that there is a dire need for fiscal consolidation along with prudent fiscal policies for lowering the size of fiscal deficit, optimizing the implementation of monetary and exchange rate policies and promoting private sector-led growth.

Infection-induced vascular inflammation in COVID-19 links focal microglial dysfunction with neuropathologies through IL-1/IL-6-related systemic inflammatory states (preprint)

COVID-19 is associated with diverse neurological abnormalities, which predict poor outcome in patients. However, the mechanisms whereby infection-induced inflammation could affect complex neuropathologies in COVID-19 are unclear. We hypothesized that microglia, the resident immune cells of brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy-, protein- and mRNA data sets in post-mortem mirror blocks of brain and peripheral organ samples from COVID-19 cases. Nanoscale microscopy, single-cell RNA sequencing and analysis of inflammatory and metabolic signatures revealed distinct mechanisms of microglial dysfunction associated with cerebral SARS-CoV-2 infection. We observed focal loss of microglial P2Y12R at sites of virus-associated vascular inflammation together with dysregulated microglia-vascular-astrocyte interactions, Cx3Cr1-fractalkine axis deficits and mitochondrial failure in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction occurs at sites of excessive synapse- and myelin phagocytosis and loss of glutamatergic terminals. While central and systemic viral load is strongly linked in individual patients, the regionally heterogenous microglial reactivity in the brain correlated with the extent of central and systemic inflammation related to IL-1 / IL-6 via virus-sensing pattern recognition receptors (PRRs) and inflammasome activation pathways. Thus, SARS-CoV-2-induced central and systemic inflammation might lead to a primarily glio-vascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

Proteomic landscape of astrocytes and pericytes infected with HIV/SARS-CoV-2 mono/co-infection, impacting on neurological complications (preprint)

Background Although most individuals recover from coronavirus disease 2019 (COVID-19) within a few weeks, some people continue to experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Majority of patients with PASC develop neurological disorders like brain fog, fatigue, mood swings, sleep disorders, loss of smell and test among others collectively called neuro-PASC. While the people living with HIV (PWH) do not have a higher risk of developing severe disease and mortality/morbidity due to COVID-19. As a large section of PWH suffered from HIV-associated neurocognitive disorders (HAND), it is essential to understand the impact of neuro-PASC on people with HAND. In pursuit of this, we infected HIV/SARS-CoV-2 alone or together in primary human astrocytes and pericytes and performed proteomics to understand the impact of co-infection in the central nervous system.Methods Primary human astrocytes and pericytes were infected with SARS-CoV-2 or HIV or HIV + SARS-CoV-2. The concentration of HIV and SARS-CoV-2 genomic RNA in the culture supernatant was quantified using reverse transcriptase quantitative real time polymerase chain reaction (RT-qPCR). This was followed by a quantitative proteomics analysis of mock, HIV, SARS-CoV-2, and HIV + SARS-CoV-2 infected astrocytes and pericytes to understand the impact of the virus in CNS cell types.Results Both healthy and HIV-infected astrocytes and pericytes support abortive/low level of SARS-CoV-2 replication. In both mono-infected and co-infected cells, we observe a modest increase in the expression of SARS-CoV-2 host cell entry factors (ACE2, TMPRSS2, NRP1, and TRIM28) and inflammatory mediators (IL-6, TNF-α, IL-1β and IL-18). Quantitative proteomic analysis has identified uniquely regulated pathways in mock vs SARS-CoV-2, mock vs HIV + SARS-CoV-2, and HIV vs HIV + SARS-CoV-2 infected astrocytes and pericytes. The gene set enrichment analysis revealed that the top ten enriched pathways are linked to several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.Conclusions Our study emphasizes the significance of long-term monitoring of patients co-infected with HIV and SARS-CoV-2 to detect and understand the development of neurological abnormalities. By unraveling the molecular mechanisms involved, we can identify potential targets for future therapeutic interventions.

Analysis of risk factors for seizures and short-term reoccurrence of seizures in febrile children with SARS-CoV-2 infection: an observational study (preprint)

Background:With the epidemic of the Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) variant Omicron, its accompanying neurological manifestations have gradually attracted attention.The main objective of this study was to compare seizures in febrile children with and without coronavirus disease 2019(COVID-19) and to conduct a short-term follow-up in the COVID-19 positive group to investigate the risk factors for short-term recurrence of seizures in children with febrile seizures(FS). Methods: Retrospective analysis of patients admitted to the Children's Hospital of Chongqing Medical University for fever and seizures between October 1 and December 30, 2022.Based on the results of SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR), the patients were divided into a COVID-19 positive group and a COVID-19 negative group.Moreover,we followed up patients in the COVID-19-positive group for 3 months using outpatient or telephone follow-up, and the main content of follow-up included whether the patients had seizures after discharge and whether there were neurological abnormalities. Results:Compared with the COVID-19-negative group, the COVID-19-positive group had a higher proportion of seizure duration ≥ 15 minutes(18.7%VS5.1%;P=0.001), seizure ≥ 2 time(54.4%VS41.0%;P=0.024), status epilepticus(15.4%VS5.1%;P=0.005), and Electroencephalogram (EEG) abnormalities(29.4%VS13.6%;P=0.016).Seizures ≥2 time[P=0.015,OR(95% CI)=4.632(1.347-15.928)], peak temperature ≤39°C[P=0.001,OR(95% CI)=6.296(2.059-19.254)], and history of convulsions[P=0.005,OR(95% CI)=5.628(1.707-18.550)] were risk factors for recurrence of seizures within a short period of time in children with covid-19 infected febrile convulsions.In the COVID-19 positive group, three patients died and four patients had residual cognitive or motor dysfunction. Conclusions:The seizures were more severe in the COVID-19 positive group compared to the COVID-19 negative group.In addition, patients with COVID-19 who present with seizures and persistent impaired consciousness need to be alerted to serious neurological disorders such as acute necrotizing encephalopathy.

The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms (preprint)

Background: The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody response with various Long COVID (LC) phenotypes prior to vaccination are not known. The capacity of antibodies to cross neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. Methods: We measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected during the early waves of the COVID-19 pandemic, prior to wide-spread rollout of SARS-CoV-2 vaccines. Cross sectional regression models adjusted for various clinical covariates and longitudinal mixed effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms in general, as well as LC phenotypes. Results: We identified several novel relationships between SARS-CoV-2 antibody neutralization and the presence of LC symptoms. Specifically, we show that, although neutralizing antibody responses to the original, infecting strain of SARS-CoV-2 were not associated with LC in cross-sectional analyses, cross-neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of LC and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with LC phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants. Conclusions: Our findings suggest that relationships between various immune responses and LC are likely complex but may involve the breadth of antibody neutralization responses.

The effects of COVID-19 on cognitive performance in a community-based cohort: A COVID Symptom Study Biobank observational study (preprint)

Background Cognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored. Methods Cognitive performance (working memory, attention, reasoning, motor control) was assessed in participants of a voluntary biobank in July, 2021 (Round 1), and April, 2022 (Round 2). Participants, drawn from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds. Findings 3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, {beta} = -0.14 standard deviations, SDs) than negative controls. Deficits were largest for positive individuals with [≥] 12 weeks of symptoms (N = 495, {beta} = -0.22 SDs). Effects were comparable to hospital presentation during illness (N = 281, {beta} = -0.31 SDs), and 10 years age difference (60-70 years vs. 50-60 years, {beta} = -0.21 SDs) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection. Interpretation Cognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms. Funding Chronic Disease Research Foundation, Wellcome Trust, National Institute for Health and Care Research, Medical Research Council, British Heart Foundation, Alzheimer's Society, European Union, COVID-19 Driver Relief Fund, French National Research Agency.

Neurological manifestations of Multisystem Inflammatory Syndrome in children (MIS-C) associated with SARS-CoV-2 infection: A clinico-demographic profile with short-term outcome in patients admitted to a tertiary care hospital in Eastern India. (preprint)

Background: In April 2020, a novel syndrome termed multisystem inflammatory syndrome in children (MIS-C), related to SARS-CoV-2 infection was first described. This syndrome has a wide spectrum of systemic involvement, has shown to include the nervous system as well. Our study aims to obtain a baseline clinical and demographic profile of varied neurological manifestations of MIS-C. It also aims to delineate a profile of short-term outcome in these patients with regards to residual neurological sequelae. Methods: A single-centre, retrospective, observational and hospital based study for 5 months was conducted among patients in the age group from 1 month to 12 years, with MIS-C with co-existing neurological symptoms. The subjects who had pre-existing neurological diseases were excluded from the study. A total of 34 subjects were collected. Post-discharge, each patient was followed up for a period of 1 month. The residual neurological deficits, if any, at discharge and follow-up. Results: The neurological complication found were Acute Symptomatic Seizure (29.4%), Aseptic Meningitis (23.5%), Encephalitis (11.8%), Guillain-Barré Syndrome (11.8%), Miller-Fisher Syndrome (2.9%), ADEM (8.8%), Autoimmune Encephalitis (8.8%) and Acute Haemorrhaegic Stroke (2.9%). 11.8% expired and 50% required P.I.C.U admissions. 23.5% had residual neurological deficit at discharge and 8.8% at follow-up after 1 month of discharge. Conclusions: In spite of great variability in manifestations, prognosis is favourable if early aggressive treatment is initiated.

Blood-brain barrier disruption in Long COVID-associated cognitive impairment (preprint)

Vascular disruption has been heavily implicated in COVID-19 pathogenesis and may predispose the neurological sequelae associated with the condition now known as long COVID. To date, no studies have objectively assessed blood-brain barrier (BBB) function in individuals with neurological complications stemming from prior SARS-CoV-2 infection. Here, we explored the neurobiological effects of SARS-CoV-2 infection in humans with acute infection (n = 76) and those with persistent long COVID with and without neurological impairment. Following acute infection, patients with neurological impairment had increased serum S100β, indicative of BBB disruption. Furthermore, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in long COVID patients (n = 32), we observed elevated BBB permeability in distinct neuroanatomical regions including the frontal cortex, occipital lobe and temporal lobes which correlated with global brain volume and white matter volume deficits in patients with neurological impairment. Patients with neurological impairment had increased levels of blood-based biomarkers including GFAP, TGFβ and IL8 with levels of TGFβ that correlated with BBB permeability and structural brain changes. Peripheral blood mononuclear cells isolated from unaffected and long COVID patients had persistent upregulation of inflammatory markers including IFNA/G and showed increased adhesion to human brain endothelial cells in vitro. Finally, exposure of endothelial cells to serum from long COVID patients induced increases in ICAM-1, VCAM-1 and TNF irrespective of neurological sequelae. Together, these data suggest that sustained systemic inflammation and persistent localised BBB dysfunction is a feature of long COVID-associated neurological impairment. Importantly, this may also be therapeutically relevant in the treatment and clinical management of this patient group.

Brain imaging and neuropsychological assessment of individuals recovered from mild to moderate SARS-CoV-2 infection (preprint)

Importance: As SARS-CoV-2 infections have been shown to affect the central nervous system, it is crucial to investigate associated alterations of brain structure and neuropsychological sequelae to help address future health care needs. Objective: To determine whether a mild to moderate SARS-CoV-2 infection is associated with alteration of brain structure detected by magnetic resonance imaging (MRI) and neuropsychological deficits. Design, Setting and Participants: Following a case-control design, 223 non-vaccinated individuals with a positive polymerase chain reaction test (PCR) for SARS-CoV-2 obtained between 1 March and 31 December 2020 received MRI and neuropsychological assessments within the framework of the Hamburg City Health Study (median 9.7 months after testing). Two hundred twenty-three healthy controls, examined prior to the SARS-CoV-2 pandemic, were drawn from the main study and matched for age, sex, education and cardiovascular risk factors. Exposure: Infection with SARS-CoV-2 confirmed by a positive PCR. Main Outcomes and Measures: Primary study outcomes were advanced diffusion MRI measures of white matter microstructure, cortical thickness, white matter hyperintensity load and neuropsychological test scores. Results: The present analysis included 223 individuals recovered from mainly mild to moderate SARS-CoV-2 infections (100 female/123 male, age [years], mean +- SD, 55.54 +- 7.07) and 223 matched healthy controls (93 female/130 male, 55.74 +- 6.60). Among all 11 MR imaging markers tested, significant differences between groups were found in global measures of mean diffusivity and extracellular free-water which were both elevated in the white matter of post-SARS-CoV-2 individuals comparing to matched controls (free-water: 0.148 +- 0.018 vs. 0.142 +- 0.017, P

Monoclonal Antibodies for Treatment of SARS-CoV-2 Infection During Pregnancy (preprint)

IMPORTANCE Monoclonal antibody (mAb) treatment decreases hospitalization and death in high-risk outpatients with mild to moderate COVID-19. However, no studies have evaluated adverse events and effectiveness of mAbs in pregnant persons compared to no mAb treatment. OBJECTIVE To determine the frequency of drug-related adverse events and obstetric-associated safety outcomes after treatment with mAb compared to no mAb treatment, and the association between mAb treatment and a composite of 28-day COVID-19-related hospital admission or emergency department visit, COVID-19-associated delivery, or mortality. DESIGN, SETTING, PARTICIPANTS Propensity-score matched cohort study of persons aged 12 years of age or older with a pregnancy episode and any documented positive SARS-CoV-2 test (polymerase chain reaction or antigen test) in the UPMC health system from April 30, 2021 to January 21, 2022. EXPOSURES Bamalanivmab and etesevimab, casirivimab and imdevimab, or sotrovimab treatment compared to no mAb treatment. MAIN OUTCOMES AND MEASURES Drug-related adverse events, obstetric-associated safety outcomes among persons who delivered, and a risk-adjusted composite of 28-day COVID-19-related hospital admission or ED visit, COVID-19-associated delivery, or mortality. RESULTS Among 944 pregnant persons (median [IQR] age 30 [26, 33] years, White (79.5%, N=750), median [IQR] Charlson Comorbidity Index Score 0 (0,0)), 552 persons received mAb treatment (58%). Median gestational age at COVID-19 diagnosis or treatment was 179 days (IQR: 123, 227), and most persons received sotrovimab (69%, N=382). Of those with known vaccination status, 178 (62%) were fully vaccinated. Drug-related adverse events were uncommon (N=8, 1.4%), and there were no differences in any obstetric-associated outcome among 276 persons who delivered. After propensity score matching, the frequency of the composite 28-day COVID-19-associated outcome was 4.0 per 100 persons (95% CI 1.9, 6.2) in mAb-treated compared to 3.7 per 100 persons (95% CI 1.7, 5.8) in non-treated controls (risk difference = 0.31 per 100 persons [95% CI -2.6, 3.3). There were no deaths among mAb-treated patients compared to 1 death in the non-treated controls (p = 0.24). There were more non-COVID-19-related hospital admissions in the mAb-treated persons (risk difference 2.8 per 100 persons (95% CI 1.1, 4.5)). CONCLUSIONS AND RELEVANCE In pregnant persons with mild to moderate COVID-19, adverse events after mAb treatment were mild and rare. There was no difference in obstetric-associated safety outcomes between mAb treatment and no treatment among persons who delivered. MAb treatment was associated with similar 28-day COVID-19-associated outcomes and more non-COVID-19-related hospital admissions compared to no mAb treatment. Key Points QUESTION Among pregnant persons with COVID-19, is monoclonal antibody (mAb) treatment associated with drug-related adverse events, similar frequency of obstetric-associated safety outcomes, and improved COVID-19-related clinical outcomes compared to no mAb treatment? FINDINGS In 944 pregnant persons with COVID-19, drug-related adverse events were mild and infrequent. Obstetric-associated safety outcomes were similar between mAb treatment and no treatment. There was no evidence of difference in risk of COVID-19-related hospital admission, COVID-19-associated delivery, or mortality between mAb treatment and no mAb treatment. MEANING In pregnant persons with mild to moderate COVID-19, adverse events after mAb treatment were uncommon, and there was no difference in obstetric-associated safety outcomes between mAb treatment and no treatment. MAb treatment was associated with similar 28-day risk of a COVID-19-associated outcome and more non-COVID-19-related hospital admissions compared to no mAb treatment.

Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: update of a living systematic review and meta-analysis (preprint)

ABSTRACT BACKGROUND Debate about the level of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues. The amount of evidence is increasing and study designs have changed over time. We updated a living systematic review to address three questions: (1) Amongst people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) What is the infectiousness of asymptomatic and presymptomatic, compared with symptomatic, SARS-CoV-2 infection? (3) What proportion of SARS-CoV-2 transmission in a population is accounted for by people who are asymptomatic or presymptomatic? METHODS AND FINDINGS The protocol was first published on 1 April 2020 and last updated on 18 June 2021. We searched PubMed, Embase, bioRxiv and medRxiv, aggregated in a database of SARS-CoV-2 literature, most recently on 6 July 2021. Studies of people with PCR-diagnosed SARS-CoV-2, which documented symptom status at the beginning and end of follow-up, or mathematical modelling studies were included. Studies restricted to people already diagnosed, of single individuals or families, or without sufficient follow-up were excluded. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with a bespoke checklist and modelling studies with a published checklist. All data syntheses were done using random effects models. Review question (1): We included 130 studies. Heterogeneity was high so we did not estimate a mean proportion of asymptomatic infections overall (interquartile range 14-50%, prediction interval 2-90%), or in 84 studies based on screening of defined populations (interquartile range 20-65%, prediction interval 4-94%). In 46 studies based on contact or outbreak investigations, the summary proportion asymptomatic was 19% (95% CI 15-25%, prediction interval 2-70%). (2) The secondary attack rate in contacts of people with asymptomatic infection compared with symptomatic infection was 0.32 (95% CI 0.16-0.64, prediction interval 0.11-0-95, 8 studies). (3) In 13 modelling studies fit to data, the proportion of all SARS-CoV-2 transmission from presymptomatic individuals was higher than from asymptomatic individuals. Limitations of the evidence include high heterogeneity and high risks of selection and information bias in studies that were not designed to measure persistently asymptomatic infection, and limited information about variants of concern or in people who have been vaccinated. CONCLUSIONS Based on studies published up to July 2021, most SARS-CoV-2 infections were not persistently asymptomatic and asymptomatic infections were less infectious than symptomatic infections. Summary estimates from meta-analysis may be misleading when variability between studies is extreme and prediction intervals should be presented. Future studies should determine the asymptomatic proportion of SARS-CoV-2 infections caused by variants of concern and in people with immunity following vaccination or previous infection. Without prospective longitudinal studies with methods that minimise selection and measurement biases, further updates with the study types included in this living systematic review are unlikely to be able to provide a reliable summary estimate of the proportion of asymptomatic infections caused by SARS-CoV-2. REVIEW PROTOCOL Open Science Framework ( https://osf.io/9ewys/ ) AUTHOR SUMMARY Why was this study done? ▪ The proportion of people who will remain asymptomatic throughout the course of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (covid-19), is debated. ▪ Studies that assess people at just one time point overestimate the proportion of true asymptomatic infection because those who go on to develop covid-19 symptoms will be wrongly classified as asymptomatic, but other types of study might underestimate the proportion if, for example, people with symptoms are more likely to be included in a study population. ▪ The number of published studies about SARS-CoV-2 is increasing continuously, types of studies are changing and, since 2021, vaccines have become available, and variants of concern have emerged. What did the researchers do and find? ▪ We updated a living systematic review through 6 July 2021, using automated workflows that speed up the review processes, and allow the review to be updated when relevant new evidence becomes available. ▪ In 130 studies, we found an interquartile range of 14-50% (prediction interval 2-90%) of people with SARS-CoV-2 infection that was persistently asymptomatic; owing to heterogeneity, we did not estimate a summary proportion. ▪ Contacts of people with asymptomatic SARS-CoV-2 infection are less likely to become infected than contacts of people with symptomatic infection (risk ratio 0.38, 95% CI 0.16-0.64, prediction interval 0.11-0.95, 8 studies). What do these findings mean? ▪ Up to mid-2021, most people with SARS-CoV-2 were not persistently asymptomatic and asymptomatic infection was less infectious than symptomatic infection. ▪ In the presence of high between-study variability, summary estimates from meta-analysis may be misleading and prediction intervals should be presented. ▪ Future studies about asymptomatic SARS-CoV-2 infections caused by variants of concern and in people with immunity following vaccination or previous infection should be specifically designed, using methods to minimise biases in the selection of study participants and in ascertainment, classification and follow-up of symptom status.

SARS-CoV-2 Infection of Microglia Elicits Pro-inflammatory Activation and Apoptotic Cell Death (preprint)

Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes various neurological symptoms in coronavirus disease 2019 (COVID-19) patients. The most dominant immune cells in the brain are microglia. Yet, the relationship between neurological manifestations, neuroinflammation, and host immune response of microglia to SARS-CoV-2 has not been well characterized. Here, we report that SARS-CoV-2 can directly infect human microglia, eliciting M1-like pro-inflammatory responses, followed by cytopathic effects. Specifically, SARS-CoV-2 infected human microglial clone 3 (HMC3), leading to inflammatory activation and cell death. RNA-seq analysis also revealed that ER stress and immune responses were induced in the early and apoptotic processes in the late phase of viral infection. SARS-CoV-2-infected HMC3 showed the M1 phenotype and produced pro-inflammatory cytokines such as interleukin (IL)-1{beta}, IL-6, and tumour necrosis factor (TNF-), but not the anti-inflammatory cytokine IL-10. After this pro-inflammatory activation, SARS-CoV-2 infection promoted both intrinsic and extrinsic death receptor-mediated apoptosis in HMC3. Using K18-hACE2 transgenic mice, murine microglia were also infected by intranasal inoculation of SARS-CoV-2. This infection induced the acute production of pro-inflammatory microglial IL- 6 and TNF- and provoked a chronic loss of microglia. Our findings suggest that microglia are potential mediators of SARS-CoV-2-induced neurological problems and, consequently, can be targets of therapeutic strategies against neurological diseases in COVID-19 patients.

AstraZeneca COVID-19 vaccine: A possible risk factor for Stroke, Case Series (preprint)

Cerebrovascular accident (CVA) is one of the commonest neurological deficits. There is a well-known association between COVID-19 and stroke. We present a case series of Sudanese patients who developed CVA after receiving the AstraZeneca COVID-19 vaccine suggesting a relationship between the vaccine and CVA.

Visual Interpretation of Brain Hypometabolisms Related to Neurological Long COVID: A French Multicentric Experience (preprint)

This multicenter study aims to provide a qualitative and consensual description of brain 18 F-FDG PET images in patients with suspected neurological long COVID, regarding the previously reported pattern involving olfactory bulbs and other limbic/paralimbic regions, as well as the brainstem and cerebellum. Methods: From the beginning of August 2021 to the end of October 2021, brain 18 F-FDG PET exams of patients referred for suspected neurological long COVID with positive reverse transcription polymerase chain reaction (RT-PCR) and/or serology for the SARS-CoV-2 infection were retrospectively reviewed in three French Nuclear Medicine departments. Experimented nuclear physicians from each department had to classify according to the same visual interpretation analysis brain 18 F-FDG PET scans as being normal, mildly to moderate (incomplete or moderately hypometabolic), or severely affected within the previously reported long COVID hypometabolic pattern. Results: On the 143 brain 18 F-FDG PET performed during this period 3 months, 53% of scans were visually interpreted as normal, 31% as mildly to moderate and 16% as severely affected according to the COVID hypometabolic pattern. Importantly, this specific hypometabolic pattern is reported as identical in the three Nuclear Medicine departments. Typical illustrative examples are provided to help nuclear physicians in the interpretation of long COVID pattern. Conclusion: The proposed PET metabolic pattern is easily identified at visual interpretation in clinical routine in part of patients with suspicion of neurological long COVID, requiring special consideration for fronto-basal paramedian regions, the brainstem and cerebellum.

Adipsic Hypernatremia with Neurologic Manifestations in a Patient with Severe COVID-19 Pneumonia: A Case Report (preprint)

This report describes a case of a 50-year-old man with hypertension who was admitted with a history of fever, chills, and shortness of breath and tested positive for COVID-19. Shortly after resolving his ARDS, he developed an adipsic hypernatremia with associated confusion, lethargy, and weakness.

AstraZeneca COVID-19 vaccine: A possible risk factor for Stroke, Case Series from Sudan (preprint)

Cerebrovascular accident (CVA) is one of the commonest neurological deficits. There is a well-known association between COVID-19 and stroke. We present a case series of Sudanese patients who developed CVA after receiving the AstraZeneca COVID-19 vaccine suggesting a relationship between the vaccine and CVA.

AstraZeneca COVID-19 vaccine: A possible risk factor for Stroke, Case Series from Sudan (preprint)

Cerebrovascular accident (CVA) is one of the commonest neurological deficits. There is a well-known association between COVID-19 and stroke. We present a case series of Sudanese patients who developed CVA after receiving the AstraZeneca COVID-19 vaccine suggesting a relationship between the vaccine and CVA.

Outcomes and Risk Factors of Patients With COVID-19 and Cancer (ONCORONA): A Sub-Study of the Philippine CORONA Study (preprint)

Background and Objectives: A study conducted in China on patients with COVIID 19 revealed that cancer conferred a five times increased risk for needing intensive care admission and mortality. Furthermore, data from two big registry studies showed that the presence of active cancer was associated with mortality. No data was collected from the Philippines, a developing country with a different healthcare system. Thus, the investigators conducted a sub study on the participants of the Philippine COVID-19 Outcomes (CORONA) study with a history of cancer and their clinical outcomes (i.e. mortality, respiratory failure, and intensive care unit admission).Methodology: Multi-Center, Retrospective Cohort Design.Results: A total of 10, 881 patients were included in the study; out of which, 244 had a history of cancer. After adjusting to the different confounding variables of interest, having cancer was significantly associated with the following outcomes: have 75% increased odds of having severe/critical COVID-19 at nadir (CI 95% 1.32, 2.33; p <0.001), have 136% increased odds of in-hospital mortality (CI 95% 1.75, 3.18; p <0.001), have 109% increased odds of respiratory failure (CI 95% 1.55, 2.83; p <0.001), have 98% increased odds of being admitted to ICU (CI 95% 1.47, 2.67; p <0.001). Additionally, after adjusting to the different confounding variables of interest, having cancer was significantly associated with the following time-to-event outcomes: 72% increase in hazard of in-hospital mortality (CI 95% 1.37, 2.16; p <0.001), 65% increase in hazard of respiratory failure (CI 95% 1.31, 2.08; p <0.001), and 57% increase in hazard of being admitted to ICU (CII 95% 1.24, 1.97; p <0.001).Conclusion: A history of cancer conferred poorer clinical outcomes on adult, hospitalized patients who were infected with COVID-19. Other demographic and clinical risk factors associated with cancer patients infected with COVID-19 are; older age, female sex, multiple co-morbidities, and having more respiratory symptoms and neurologic manifestations.Clinical Trial Registration Details: The study protocol was registered in ClinicalTrials.gov (NCT04386083)Funding Information: This study has not received any grant or funding from third-party organizations.Declaration of Interests: All authors declare no conflict of interest.Ethics Approval Statement: Our protocol was mainly endorsed by the Single Joint Research Ethics Board of the Department of Health, Philippines (SJREB-2020–24) for which the following institutions were included: Cagayan Valley Medical Center, Tuguegarao City; Jose R. Reyes Memorial Medical Center, Manila; Ospital ng Makati, Makati City; Perpetual Succour Hospital, Cebu City; Philippine Heart Center, Quezon City; Southern Isabela Medical Center, Santiago City; Southern Philippines Medical Center, Davao City; Western Visayas Medical Center, Iloilo City; and Zamboanga City Medical Center, Zamboanga City. Moreover, the authors were able to receive approval from the following local institutional review boards (code): Asian Hospital and Medical Center, Muntinlupa City (2020- 010-A); Baguio General Hospital and Medical Center, Baguio City (BGHMC-ERC-2020–13); Capitol Medical Center, Quezon City; Cardinal Santos Medical Center, San Juan City (CSMC REC 2020–020); Chong Hua Hospital, Cebu City (IRB 2420–04); De La Salle Medical and Health Sciences Institute, Cavite (2020–23-02-A); Dr. Jose N. Rodriguez Memorial and Sanitarium Hospital, Caloocan City; Dr. Pablo O. Torre Memorial Hospital (Riverside Medical Center), Bacolod City; East Avenue Medical Center, Quezon City (EAMC IERB 2020- 38); Jose B. Lingad Memorial Regional Hospital, City of San Fernando, Pampanga; Lung Center of the Philippines, Quezon City (LCP-CT-010–2020); Manila Doctors Hospital, Manila (MDH IRB 2020–006); Makati Medical Center, Makati City (MMC IRB 2020–054); Medical Center Manila, Manila (MMERC 2020–09); New Era General Hospital, Quezon City; Northern Mindanao Medical Center, Cagayan de Oro City (025–2020); Quirino Memorial Medical Center, Quezon City (QMMC REB GCS 2020–28); Philippine General Hospital, Manila (2020–314-01 SJREB); Research Institute for Tropical Medicine, Muntinlupa City (RITM IRB 2020–16); San Lazaro Hospital, Manila; San Juan De Dios Educational Foundation Inc. Hospital, Pasay City (SJRIB 2020–0006); Southern Isabela Medical Center, Santiago City (2020–03); Southern Philippines Medical Center (SPMC), Davao City (P20062001); St. Luke’s Medical Center, Quezon City (SL–20116); St. Luke’s Medical Center, Bonifacio Global City, Taguig City (SL–20116); The Medical City, Pasig City; University of the East Ramon Magsaysay Memorial Medical Center, Inc, Quezon City (0835/E/2020/063); University of Santo Tomas Hospital, Manila (UST-REC-2020–04-071-MD); Veterans Memorial Medical Center, Quezon City (VMMC- 2020–025); Vicente Sotto Memorial Medical Center, Cebu City (VSMMC-REC-O-2020–048).

Encephalopathy as a prognostic factor in adults with acute disseminated encephalomyelitis following COVID-19 (preprint)

Numerous reports support the possible occurrence of acute disseminated encephalomyelitis (ADEM) following COVID-19. Herein, we report a case of ADEM in a 53 years-old man two weeks after SARS-CoV-2 infection. We reviewed the reports of adult cases of ADEM and its variant acute necrotizing hemorrhagic leukoencephalitis (ANHLE) to check for possible prognostic factors and clinical/epidemiological peculiarities. We performed a descriptive analysis of clinical and cerebrospinal fluid data. Ordinal logistic regressions were performed to check the effect of clinical variables and treatments on ADEM/ANHLE outcomes. We also compared ADEM and ANHLE patients. We identified a total of 20 ADEM (9 females, median age 53.5 years) and 23 ANHLE (11 females, median age 55 years). Encephalopathy was present in 80% of ADEM and 91.3% of ANHLE patients. We found that the absence of encephalopathy predicts a better clinical outcome in ADEM (OR = 0.027, 95%CI 0.001–0.611, p = 0.023), also when correcting for the other variables (OR = 0.032, 95%CI 0.001–0.995, p = 0.05). Conversely, we identified no significant prognostic factor in ANHLE patients. ANHLE patients showed a trend towards a worse clinical outcome (lower proportion of good/complete recovery, 4.5% vs 16.7%) and higher mortality (36.4% vs 11.1%) as compared to ADEM. Compared to pre-pandemic ADEM, we observed a higher median age of people with post-COVID-19 ADEM and ANHLE, a shorter interval between infection and neurological symptoms, and a worse prognosis both in terms of high morbidity and mortality. Despite being affected by the retrospective nature of the study, these observations provide new insights into ADEM/ANHLE following SARS-CoV-2 infection.