bluuebunny/crossref_metadata_2025_split huggingface dataset:
A proteomics workflow reveals predictive autoantigens in idiopathic pulmonary fibrosis
Authors: Leuschner Gabriela , Mayr Christoph H. , Ansari Meshal , Seeliger Benjamin , Frankenberger Marion , Kneidinger Nikolaus , Hatz Rudolf A. , Hilgendorff Anne , Prasse Antje , Behr Jürgen , Mann Matthias , Schiller Herbert B. 
Published: February 2021

AbstractRationaleThe diagnosis of idiopathic pulmonary fibrosis (IPF) requires exclusion of known underlying autoimmunity, as present in interstitial lung diseases associated with connective tissue diseases (CTD-ILD). However, autoantibodies of unknown significance have been repeatedly detected in IPF patients.ObjectivesWe aimed to characterize autoreactivities in IPF patients beyond clinically established autoimmune panels by establishing an unbiased assay for de novo discovery of autoantigens in different forms of ILD and healthy controls.MethodsWe developed the proteomic Differential Antigen Capture (DAC) assay, capturing patient antibodies from plasma, followed by affinity purification of lung proteins coupled to mass spectrometry. Plasma antibodies from patients with IPF (n=35), CTD-ILD (n=24) and age-matched controls (n=32) were analyzed and validated in an independent cohort (IPF: n=40; CTD-ILD: n=20). Plasma antibody binding profiles were associated with clinical meta-data including diagnosis, lung function and transplant free survival.Measurements and Main ResultsWe identified 586 putative autoantigens in both study cohorts with a broad heterogeneity among disease entities and cohorts. The prevalence of autoantibodies was higher in IPF compared to CTD-ILD. We identified a predictive autoimmune signature that was significantly associated with reduced transplant free survival in IPF. In particular, presence of autoantibodies to Thrombospondin 1 (THBS1) was associated with a significantly reduced survival in patients with IPF (p=0.002), independent of the study cohort, suggesting clinical relevance as predictive biomarker.ConclusionsUnbiased proteomic profiling reveals that the overall prevalence of autoantibodies is similar in IPF and CTD-ILD patients and identifies novel IPF specific autoantigens associated with patient survival.
Lesion Symptom Mapping of Domain-Specific Cognitive Impairments using Routine Imaging in Stroke
Authors: Moore Margaret Jane , Demeyere Nele 
Published: February 2021

AbstractBackground and PurposeThis large-scale lesion-symptom mapping study aimed to investigate the necessary neuro-anatomical substrates of 5 cognitive domains frequently affected post stroke: Language, Attention, Praxis, Number, and Memory. This study aims to demonstrate the validity of using routine clinical brain imaging from a large, real-world patient cohort for lesion-symptom mapping.MethodsBehavioural cognitive screening data from the Oxford Cognitive Screen and routine clinical neuroimaging from 573 acute patients was used in voxel-based lesion-symptom mapping analyses. Patients were classed as impaired or not on each of the subtests within 5 cognitive domains.ResultsDistinct patterns of lesion damage were associated with different domains. Language functions were associated with damage to left hemisphere fronto-temporal areas. Visuo-spatial functions were associated with damage to posterior occipital areas (Visual Field) and the right temporo-parietal region (Visual Neglect). Different memory impairments were linked to distinct voxel clusters within the left insular and opercular cortices. Deficits which were not associated with localised voxels (e.g. praxis, executive function) represent distributed functions.ConclusionThe standardised, brief Oxford Cognitive Screen was able to reliably differentiate distinct neural correlates critically involved in supporting domain-specific cognitive abilities. By demonstrating and replicating known brain anatomy correlates within real-life clinical cohorts using routine CT scans, we open up VLSM techniques to a wealth of clinically relevant studies which can capitalise on using existing clinical brain imaging.
Ultrasensitive assay for saliva-based SARS-CoV-2 antigen detection
Authors: Ren A , Sohaei D , Zacharioudakis I , Sigal GB , Stengelin M , Mathew A , Campbell C , Padmanabhan N , Romero D , Joe J , Soosaipillai A , Kulasingam V , Mazzulli T , Li XA , McGeer A , Diamandis EP , Prassas I 
Published: February 2021

AbstractWidespread SARS-CoV-2 testing is highly valuable for identifying asymptomatic/pre-symptomatic individuals to slow community disease transmission. However, there remains a technological gap for highly reliable, easy, and quick SARS-CoV-2 diagnostic tests that are suitable for frequent mass testing. Compared to the conventional nasopharyngeal (NP) swab-based tests, saliva-based methods are attractive due to easier and safer sampling protocols. Despite its merits in rapid turn-around-time and high throughput compared to traditional PCR-based technologies, the widespread use of saliva-based SARS-CoV-2 rapid antigen tests is hindered by limited analytical sensitivity of current methods. Here, we report the first ultrasensitive, saliva-based SARS-CoV-2 antigen assay with an analytical sensitivity of < 0.32 pg/ml, corresponding to 4 viral RNA copies/µl, which is comparable to that of PCR-based tests. Using the novel electrochemiluminescence (ECL)-based S-PLEX immunoassay, we measured the SARS-CoV-2 nucleocapsid (N) antigen concentration in 105 saliva samples obtained from non-COVID-19 and COVID-19 patients. Our assay displayed absolute specificity and high sensitivity (90.2%), where it correctly identified samples with viral loads up to 35 CT cycles by saliva-based PCR. Paired NP swab-based PCR results were also obtained for 86 cases for comparison. Our assay showed high concordance with saliva-based and NP swab-based PCR in samples with negative (< 0.32 pg/ml) and strongly positive (> 2 pg/ml) N antigen concentrations. Our study unveiled the ultrasensitivity and specificity of the saliva-based S-PLEX assay, demonstrating its clinical value as a high throughput, complementary alternative to PCR-based techniques. The novel technique is especially valuable in cases where compliance to frequent swabbing may be problematic (e.g. schools, nursing homes, etc.).
Repurposing Colchicine for the Management of COVID-19: A Systematic Review and Meta-analysis
Authors: Mohanty Rashmi Ranjan , Meher Bikash Ranjan , Padhy Biswa Mohan , Das Smita 
Published: February 2021

AbstractMany anti-inflammatory drugs like, tocilizumab, N-acetylcystiene and etolizumab has been repurposed for the management of COVID-19 with variable success. Colchicine exhibits anti-inflammatory activity by tubulin disruption and inhibition of leucocyte-mediated inflammatory activities like production of superoxide and release of various cytokines which are central to the pathophysiology of COVID-19. So, this systematic review and meta-analysis assessed the currently available data on the use of colchicine for the treatment of COVIDLJ19. A total of 3 studies (2 RCTS and 1 observational study) including 402 patients were included out of which 194 patients received colchicine. The random effect model showed the overall pooled OR to be 0.32 (95%CI: 0.18 to 0.56) for the primary outcome (Clinical deterioration) which was statistically significant (p <0.0001). Also there was increase in adverse effect (diarrhoea) with use of colchicine as suggested by the pooled OR (OR=4.56, 95%CI: 2.04 to 10.15, P=0.0002). With the limited number of available studies, it has shown statistically significant reduction in clinical deterioration in COVID-19. Though there was an increase in adverse effect in the form of diarrhoea, it was mild and self-limiting.
Chyawanprash for the prevention of COVID-19 infection among healthcare workers: A Randomized Controlled Trial
Authors: Gupta Arun , Madan Amit , Yadav Babita , Mundada Pallavi , Singhal Richa , Pandey Yogesh Kumar , Agarwal Riju , Tripathi Arunabh , Rana Rakesh , Sharma B. S. , Rao BCS , Bharti  , Srikanth Narayanam , Dhiman K. S. 
Published: February 2021

AbstractBackgroundCoronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are at high risk of exposure, the standard of care is personal protection from getting infected. Whether Ayurvedic rasayana drug like Chyawanprash can prevent symptomatic infection in frontline health care workers is unknown.ObjectiveTo evaluate the effect of the combination of Chyawanprash and Standard Preventive Regimen compared to the use of Standard Preventive Regimen alone on the proportion of RT-PCR confirmed COVID-19 infections among frontline healthcare workers (HCWs).MethodsAn open-label randomized controlled trial was conducted in the HCWs between 25 to 60 years age currently working in an environment with chance of direct exposure to COVID-19 cases. The interventions to be compared in this trial were Standard Preventive Regimen as per institutional guidelines and based on their roles (Group I) and Ayurvedic Intervention viz., Chyawanprash 12 g twice for 30 days from day of randomization plus Standard Preventive Regimen (Group II). The incidence of RT PCR confirmed COVID-19 cases in both groups, was the primary outcome measure. Evaluation of the safety of the study drug (by any statistically significant change in various biochemical and hematological parameters and occurrence of any adverse drug reactions); incidence of any other infective diseases (bacterial /viral/ fungal / etc.) like upper respiratory tract illness during the study period and any change in the immunoglobulins like IgG, IgM and IgE and inflammatory markers like TNF alpha, IL-6 and IL-10 were the secondary outcome measures.ResultsOut of 193 participants who completed the study, no participant in both groups was COVID-19 positive at the end of one month. In post intervention follow-up, 4 subjects in Group I and 2 subjects in Group II were COVID-19 positive. No adverse drug reaction or any serious adverse event was reported during the study. No clinically significant change in the safety parameters was observed before and after the study. Statistically significant rise in Serum IgG level was seen in Group II but other inflammatory and immune markers did not show statistically significant difference.ConclusionChyawanprash was well tolerated by all the participants in the intervention group but to prove its adaptogenic effect and efficacy as an add-on to the standard care in preventing the occurrence of COVID-19, clinical trial for longer duration with larger sample size is needed.Trial registrationClinical Trials Registry of India vide CTRI/2020/05/025275 dated 20/05/2020Date of IEC approval19.5.2020
Clinical validation of the quantitative Siemens SARS-CoV-2 spike IgG assay (sCOVG) reveals improved sensitivity and a good correlation with virus neutralization titers
Authors: Irsara Christian , Egger Alexander E. , Prokop Wolfgang , Nairz Manfred , Loacker Lorin , Sahanic Sabina , Pizzini Alex , Sonnweber Thomas , Holzer Barbara , Mayer Wolfgang , Schennach Harald , Loeffler-Ragg Judith , Bellmann-Weiler Rosa , Hartmann Boris , Tancevski Ivan , Weiss Günter , Binder Christoph J. , Anliker Markus , Griesmacher Andrea , Hoermann Gregor 
Published: February 2021

AbstractObjectivesSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections cause Coronavirus Disease 2019 (COVID-19) and induce a specific antibody response. Serological assays detecting IgG against the receptor binding domain (RBD) of the spike (S) protein are useful to monitor the immune response after infection or vaccination. The objective of our study was to evaluate the clinical performance of the Siemens SARS-CoV-2 IgG (sCOVG) assay.MethodsSensitivity and specificity of the Siemens sCOVG test were evaluated on 178 patients with SARS-CoV-2-infection and 160 pre-pandemic samples in comparison with its predecessor test COV2G. Furthermore, correlation with virus neutralization titers was investigated on 134 samples of convalescent COVID-19 patients.ResultsSpecificity of the sCOVG test was 99.4% and sensitivity was 90.5% (COV2G assay 78.7%; p<0.0001). S1-RBD antibody levels showed a good correlation with virus neutralization titers (r=0.843; p<0.0001) and an overall qualitative agreement of 98.5%. Finally, median S1-RBD IgG levels increase with age and were significantly higher in hospitalized COVID-19 patients (median levels general ward: 25.7 U/ml; intensive care: 59.5 U/ml) than in outpatients (3.8 U/ml; p<0.0001).ConclusionsPerformance characteristics of the sCOVG assay have been improved compared to the predecessor test COV2G. Quantitative SARS-CoV-2 S1-RBD IgG levels could be used as a surrogate for virus neutralization capacity. Further harmonization of antibody quantification might assist to monitor the humoral immune response after COVID-19 disease or vaccination.
The interaction between lifetime depression severity and BMI is related to altered activation pattern in the right inferior frontal gyrus during food anticipation
Authors: Manelis A , Halchenko YO , Satz S , Ragozzino R , Lucero M , Swartz HA , Levine MD 
Published: February 2021

ABSTRACTBackgroundDepression and obesity often co-occur but the underlying neural mechanisms for this bidirectional link are not well understood. Using fMRI, we examined how the relationship between Body Mass Index (BMI) and dimensional lifetime depression severity was associated with brain activation during food anticipation and pleasant/unpleasant rating.Methods90 participants (48 healthy controls, 42 with unipolar depression (UD), 69 female, age=28.5±6.6) were fMRI-scanned while performing the Food and Object Cued Encoding task consisting of food/object anticipation and food/object pleasant/unpleasant rating phases.ResultsThe analysis across all participants revealed a significant BMI-by-lifetime depression severity interaction on RIFG activation during food anticipation (p<0.0125). Most symptomatic and overweight/obese individuals with UD showed decreased right inferior frontal gyrus (RIFG) activation during food anticipation, while less symptomatic and/or normal-weight individuals with UD showed increased RIFG activation during food anticipation. RIFG activation during food anticipation was negatively correlated with RIFG activation during pleasant/unpleasant rating (r= -0.63, p<0.001). Individuals with UD who showed higher RIFG activation for food items during pleasant/unpleasant rating reported liking or wanting those food items less than those with lower RIFG activation (p<0.05).ConclusionsThe IFG is involved in emotion regulation and response inhibition necessary to control appetitive behavior. Greater RIFG activation during pleasant/unpleasant rating of food coupled with low ratings of food liking and wanting could be associated with inhibition of cognitive and emotional response to food in UD. This process may be cognitively challenging and stressful thus putting affected individuals with UD at risk for weight gain and worsening of depression.
SARS-CoV-2 shedding dynamics across the respiratory tract, sex and disease severity for adult and pediatric COVID-19
Authors: Chen Paul Z. , Bobrovitz Niklas , Premji Zahra , Koopmans Marion , Fisman David N. , Gu Frank X. 
Published: February 2021

BackgroundSARS-CoV-2 shedding dynamics influence the risk of transmission and clinical manifestations of COVID-19. Yet, the relationships between SARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) and age, sex and COVID-19 severity remain unclear.MethodsUsing systematic review, we developed a dataset of case characteristics (age, sex and COVID-19 severity) and quantitative respiratory viral loads (rVLs). We then conducted stratified analyses to assess SARS-CoV-2 shedding across disease course, COVID-19 severity, the respiratory tract, sex and age groups (aged 0 to 17 years, 18 to 59 years, and 60 years or older).ResultsThe systematic dataset included 1,266 adults and 136 children with COVID-19. In the URT, adults with severe COVID-19 had higher rVLs at 1 day from symptom onset (DFSO) than adults (P = 0.005) or children (P = 0.017) with nonsevere illness. Between 1-10 DFSO, severe adults had comparable rates of SARS-CoV-2 clearance from the URT as nonsevere adults (P = 0.479) and nonsevere children (P = 0.863). In the LRT, severe adults showed higher rVLs post-symptom onset than nonsevere adults (P = 0.006). In the analyzed period (4-10 DFSO), severely affected adults had no significant trend in SARS-CoV-2 clearance from LRT (P = 0.105), whereas nonsevere adults showed a clear trend (P < 0.001). After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of the duration of respiratory shedding. The estimated accuracy for using URT shedding as a prognostic indicator for COVID-19 severity was up to 65%, whereas it was up to 81% for LRT shedding.ConclusionsHigh, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. After symptom onset, severe cases tended to have slightly higher URT shedding than their nonsevere counterparts. Disease severity, rather than age or sex, predicted SARS-CoV-2 kinetics. LRT specimens more accurately prognosticate COVID-19 severity than do URT specimens.FundingNatural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, NSERC Senior Industrial Research Chair and the Toronto COVID-19 Action Fund.
COVID-BioB Cohort Study: the neutralizing antibody response to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for virus control and survival
Authors: Dispinseri Stefania , Secchi Massimiliano , Pirillo Maria Franca , Tolazzi Monica , Borghi Martina , Brigatti Cristina , De Angelis Maria Laura , Baratella Marco , Bazzigaluppi Elena , Venturi Giulietta , Sironi Francesca , Canitano Andrea , Marzinotto Ilaria , Tresoldi Cristina , Ciceri Fabio , Piemonti Lorenzo , Negri Donatella , Cara Andrea , Lampasona Vito , Scarlatti Gabriella 
Published: February 2021

ABSTRACTUnderstanding how antibody to SARS-CoV-2 evolve during infection may provide important insight into therapeutic approaches to prevent fatal COVID-19 illness and vaccines. Here, we profile the antibody response of 162 well-characterized COVID-19 symptomatic patients followed longitudinally for up to eight months from symptom onset. Using two newly developed assays we detect SARS-CoV-2 neutralization and antibodies binding to Spike antigens and nucleoprotein as well as to Spike S2 antigen of seasonal beta-coronaviruses, and to hemagglutinin of the H1N1 flu virus. Presence of neutralizing antibodies withing the first weeks from symptom onset correlates with time to a negative swab result (p=0.002) while lack of neutralization with an increased risk of a fatal disease outcome (HR 2.918, 95%CI 1.321-6.449; p=0.008). Neutralizing antibody titers progressively drop after 5-8 weeks but are still detectable up to 8 months in the majority of recovered patients regardless of age or co-morbidities. IgG to Spike antigens are the best correlate of neutralization. Antibody responses to seasonal coronaviruses are temporary boosted and parallel those to SARS-CoV-2 without dampening the specific response or worsening disease progression. Thus, a compromised immune response to the Spike rather than an enhanced one is a major trait of patients with critical conditions. Patients should be promptly identified and immediately start therapeutic interventions aimed at restoring their immunity.
COVID-19 associated autoimmunity is a feature of severe respiratory disease - a Bayesian analysis
Authors: Trahtemberg Uriel , Rottapel Robert , dos Santos Claudia C , Di Battista Alex P , Slutsky Arthur S. , Baker Andrew J , Fritzler Marvin J 
Published: February 2021

AbstractBackgroundSerological and clinical features with similarities to systemic autoimmunity have been reported in severe COVID-19, but there is a lack of studies that include contemporaneous controls who do not have COVID-19.MethodsObservational cohort study of adult patients admitted to an intensive care unit with acute respiratory failure. Patients were divided into COVID+ and COVID− based on SARS-CoV-2 PCR from nasopharyngeal swabs and/or endotracheal aspirates. No COVID-19 specific interventions were given. The primary clinical outcome was death in the ICU within 3 months; secondary outcomes included in-hospital death and disease severity measures. Measurements including autoantibodies, were done longitudinally. ANOVA and Fisher’s exact test were used with α=0.05, with a false discovery rate of q=0.05. Bayesian analysis was performed to provide credible estimates of the possible states of nature compatible with our results.Results22 COVID+ and 20 COVID− patients were recruited, 69% males, median age 60.5 years. Overall, 64% had anti-nuclear antibodies, 38% had antigen-specific autoantibodies, 31% had myositis related autoantibodies, and 38% had high levels of anti-cytokine autoantibodies. There were no statistically significant differences between COVID+ and COVID− for any of the clinical or autoantibody parameters. A specific pattern of anti-nuclear antibodies was associated with worse clinical severity for both cohorts.ConclusionsSevere COVID+ patients have similar humoral autoimmune features as comparably ill COVID− patients, suggesting that autoantibodies are a feature of critical illness regardless of COVID-19 status. The clinical significance of autoimmune serology and the correlation with severity in critical illness remains to be elucidated.
Host-virus chimeric events in SARS-CoV2 infected cells are infrequent and artifactual
Authors: Yan Bingyu , Chakravorty Srishti , Mirabelli Carmen , Wang Luopin , Trujillo-Ochoa Jorge L. , Chauss Daniel , Kumar Dhaneshwar , Lionakis Michail S. , Olson Matthew R , Wobus Christiane E. , Afzali Behdad , Kazemian Majid 
Published: February 2021

AbstractPathogenic mechanisms underlying severe SARS-CoV2 infection remain largely unelucidated. High throughput sequencing technologies that capture genome and transcriptome information are key approaches to gain detailed mechanistic insights from infected cells. These techniques readily detect both pathogen and host-derived sequences, providing a means of studying host-pathogen interactions. Recent studies have reported the presence of host-virus chimeric (HVC) RNA in RNA-seq data from SARS-CoV2 infected cells and interpreted these findings as evidence of viral integration in the human genome as a potential pathogenic mechanism. Since SARS-CoV2 is a positive sense RNA virus that replicates in the cytoplasm it does not have a nuclear phase in its life cycle, it is biologically unlikely to be in a location where splicing events could result in genome integration. Here, we investigated the biological authenticity of HVC events. In contrast to true biological events such as mRNA splicing and genome rearrangement events, which generate reproducible chimeric sequencing fragments across different biological isolates, we found that HVC events across >100 RNA-seq libraries from patients with COVID-19 and infected cell lines, were highly irreproducible. RNA-seq library preparation is inherently error-prone due to random template switching during reverse transcription of RNA to cDNA. By counting chimeric events observed when constructing an RNA-seq library from human RNA and spike-in RNA from an unrelated species, such as fruit-fly, we estimated that ~1% of RNA-seq reads are artifactually chimeric. In SARS-CoV2 RNA-seq we found that the frequency of HVC events was, in fact, not greater than this background “noise”. Finally, we developed a novel experimental approach to enrich SARS-CoV2 sequences from bulk RNA of infected cells. This method enriched viral sequences but did not enrich for HVC events, suggesting that the majority of HVC events are, in all likelihood, artifacts of library construction. In conclusion, our findings indicate that HVC events observed in RNA-sequencing libraries from SARS-CoV2 infected cells are extremely rare and are likely artifacts arising from either random template switching of reverse-transcriptase and/or sequence alignment errors. Therefore, the observed HVC events do not support SARS-CoV2 fusion to cellular genes and/or integration into human genomes.