bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival and outcomes of tocilizumab use in severe and critically ill COVID-19 patients not responding to steroids
Authors: Assu Shiraz , Bhasin Deepak , Sekhri Kavita , Sampley Supriya , Singh Harpal , Kaur Gurleen 
Published: December 2021

AbstractBackgroundMortality and morbidity are highest in severe and critically ill patients with COVID -19 pneumonia. We used interleukin-6 (IL-6) receptor inhibitor, tocilizumab in the above patients who failed to show any clinical improvement after initial treatment with steroids.MethodsThis is a retrospective observational study conducted at a tertiary care hospital in India. Severe and critical COVID-19 patients, who got admitted to intensive care unit and subsequently received tocilizumab were included. Patients who worsened clinically or had no change in oxygen requirement even after 24hrs of receiving intravenous methylprednisolone at a dose of 1-2mg/kg/day received a maximum total dose of 800mg of intravenous tocilizumab. The day 28 all-cause mortality and progression to mechanical ventilation were the primary outcome measures. Clinical improvement and oxygen requirements after tocilizumab administration along with trends in inflammatory markers and secondary infections rates were also noted.ResultsA total of 51 patients who did not show clinical improvement even after 24 hours of intravenous steroids had received tocilizumab. In these patients, there was a significant decrease in oxygen requirement and clinical progression by day 7 of tocilizumab administration. Baseline median values of CRP (114.2 mg/L), IL-6 (69.8 pg/ml) and neutrophil-lymphocyte ratio (12.4) in these patients were elevated. Out of these, only CRP showed a significant decrease after the drug administration. 13 (26.5%) of the 49 patients on non-invasive oxygen support progressed to mechanical ventilation and the day 28 all-cause mortality was 10/51(19.6%). 10(19.6%) of the 51 patients had life threatening infections.ConclusionEarly and timely administration of tocilizumab is a viable option in selected severe and critical COVID-19 patients who do not respond to initial steroids. When given along with steroids, a high suspicion of secondary infections should be kept.
Deviations in Predicted COVID-19 cases in the US during early months of 2021 relate to rise in B.1.526 and its family of variants
Authors: Nandakishore P. , Liu M. , R. Prakash , Gourneni S. , Sukumaran R. , Berman J.M. , Iyer S. , Glorioso C. 
Published: December 2021

AbstractObjectiveTo investigate the abrogation of COVID-19 case declines from predicted rates in the US in relationship to viral variants and mutations.DesignEpidemiological prediction and time series study of COVID-19 in the US by State.SettingCommunity testing and sequencing of COVID-19 in the US.ParticipantsTime series US COVID-19 case data from the Johns Hopkins University CSSE database. Time series US Variant and Mutation data from the GISAID database.Main outcome measuresPrimary outcomes were statistical modeling of US state deviations from epidemiological predictions, percentage of COVID-19 variants, percentage of COVID-19 mutations, and reported SARS-CoV-2 infections.ResultsDeviations in epidemiological predictions of COVID-19 case declines in the North Eastern US in March 2021 were highly positively related to percentage of B.1.526 (Iota) lineage (p < 10e − 7) and B.1.526.2 (p < 10 − 8) and the T95I mutation (p < 10e − 9). They were related inversely to B.1.427 and B.1.429 (Epsilon) and there was a trend for association with B.1.1.7 (Alpha) lineage.ConclusionDeviations from accurate predictive models are useful for investigating potential immune escape of COVID-19 variants at the population level. The B.1.526 and B.1.526.2 lineages likely have a high potential for immune escape and should be designated as variants of concern. The T95I mutation which is present in the B.1.526, B.1.526.2, and B.1.617.2 (Delta) lineages in the US warrants further investigation as a mutation of concern.
The influence of new SARS-CoV-2 variant Omicron (B.1.1.529) on vaccine efficacy, its correlation to Delta Variants: a computational approach
Authors: Ranjan Prashant , Neha  , Devi Chandra , Devar Kaviyapriya Arulmozhi , Das Parimal 
Published: December 2021

AbstractThe newly discovered COVID variant B.1.1.529 in Botswana has more than 30 mutations in spike and many other in non-spike proteins, far more than any other SARS-CoV-2 variant accepted as a variant of concern by the WHO and officially named Omicron, and has sparked concern among scientists and the general public. Our findings provide insights into structural modification caused by the mutations in the Omicrons receptor-binding domain and look into the effects on interaction with the hosts neutralising antibodies CR3022, B38, CB6, P2B-2F6, and REGN, as well as ACE2R using an in silico approach. We have employed secondary structure prediction, structural superimposition, protein disorderness, molecular docking, and MD simulation to investigate host-pathogen interactions, immune evasion, and transmissibility caused by mutations in the RBD region of the spike protein of the Omicron variant and compared it to the Delta variants (AY.1, AY.2, & AY.3) and wild type. Computational analysis revealed that the Omicron variant has a higher binding affinity for the human ACE2 receptor than the wild and Delta (AY.1 and AY.2 strains), but lower than the Delta AY.3 strain. MD simulation and docking analysis suggest that the omicron and Delta AY.3 were found to have relatively unstable and compact RBD structures and hampered interactions with antibodies more than wild and Delta (AY.1 and AY.2), which may lead to relatively more pathogenicity and antibody escape. In addition, we observed lower binding affinity of Omicron for human monoclonal antibodies (CR3022, B38, CB6, and P2B2F6) when compared to wild and Delta (AY.1 & AY.2). However, the binding affinity of Omicron RBD variants for CR3022, B38, and P2B2F6 antibodies is lower as compared to Delta AY.3, which might promote immune evasion and reinfection and needs further experimental investigation.
Identifying protein sites contributing to vaccine escape via statistical comparisons of short-term molecular dynamics simulations
Authors: Rajendran Madhusudan , Ferran Maureen C. , Babbitt Gregory A. 
Published: December 2021

AbstractThe identification of viral mutations that confer escape from antibodies is crucial for understanding the interplay between immunity and viral evolution. We describe a molecular dynamics (MD) based approach that scales well to a desktop computer with a high-end modern graphics processor and enables the user to identify protein sites that are prone to vaccine escape in a viral antigen. We first implement our MD pipeline to employ site-wise calculation of Kullback-Leibler divergence in atom fluctuation over replicate sets of short-term MD production runs thus enabling a statistical comparison of the rapid motion of influenza hemagglutinin (HA) in both the presence and absence of three well-known neutralizing antibodies. Using this simple comparative method applied to motions of viral proteins, we successfully identified in silico all previously empirically confirmed sites of escape in influenza HA, predetermined via selection experiments and neutralization assays. Upon the validation of our computational approach, we then surveyed potential hot spot residues in the receptor binding domain of the SARS-CoV-2 virus in the presence of COVOX-222 and S2H97 antibodies. We identified many single sites in the antigen-antibody interface that are similarly prone to potential antibody escape and that match many of the known sites of mutations arising in the SARS-CoV-2 variants of concern. In the omicron variant, we find only minimal adaptive evolutionary shifts in the functional binding profiles of both antibodies. In summary, we provide a fast and accurate computational method to monitor hot spots of functional evolution in antibody binding footprints.
Intranasal immunization with a vaccinia virus vaccine vector expressing pre-fusion stabilized SARS-CoV-2 spike fully protected mice against lethal challenge with the heavily mutated mouse-adapted SARS2-N501YMA30 strain of SARS-CoV-2
Authors: Kibler Karen V. , Szczerba Mateusz , Lake Douglas , Roeder Alexa J. , Rahman Masmudur , Hogue Brenda G. , Wong Lok-Yin Roy , Perlman Stanley , Li Yize , Jacobs Bertram L. 
Published: December 2021

AbstractThe Omicron SARS-CoV-2 variant has been designated a variant of concern because its spike protein is heavily mutated. In particular, Omicron spike is mutated at 5 positions (K417, N440, E484, Q493 and N501) that have been associated with escape from neutralizing antibodies induced by either infection with or immunization against the early Washington strain of SARS-CoV-2. The mouse-adapted strain of SARS-CoV-2, SARS2-N501YMA30, contains a spike that is also heavily mutated, with mutations at 4 of the 5 positions in Omicron spike associated with neutralizing antibody escape (K417, E484, Q493 and N501). In this manuscript we show that intranasal immunization with a pre-fusion stabilized Washington strain spike, expressed from a highly attenuated, replication-competent vaccinia virus construct, NYVAC-KC, fully protected mice against disease and death from SARS2-N501YMA30. Similarly, immunization by scarification on the skin fully protected against death, but not from mild disease. This data demonstrates that Washington strain spike, when expressed from a highly attenuated, replication-competent poxvirus, administered without parenteral injection can fully protect against the heavily mutated mouse-adapted SARS2-N501YMA30.
The cellular characterisation of SARS-CoV-2 spike protein in virus-infected cells using Receptor Binding Domain-binding specific human monoclonal antibodies
Authors: Chan Conrad En-Zuo , Ng Ching-Ging , Lim Angeline Pei-Chew , Seah Shirley Lay-Kheng , Chye De-Hoe , Wong Steven Ka-Khuen , Lim Jie-Hui , Lim Vanessa Zi-Yun , Lai Soak-Kuan , Wong Pui-San , Leong Kok-Mun , Liu Yi-Chun , Sugrue Richard J , Tan Boon-Huan 
Published: December 2021

AbstractA human monoclonal antibody panel (PD4, PD5, PD7, SC23 and SC29) was isolated from the B cells of convalescent patients and used to examine the S protein in SARS-CoV-2- infected cells. While all five antibodies bound conformational-specific epitopes within SARS-CoV-2 Spike (S) protein, only PD5, PD7, and SC23 were able to bind to the Receptor Binding Domain (RBD). Immunofluorescence microscopy was used to examine the S protein RBD in cells infected with the Singapore isolates SARS-CoV-2/0334 and SARS-CoV-2/1302. The RBD-binders exhibited a distinct cytoplasmic staining pattern that was primarily localised within the Golgi complex and was distinct from the diffuse cytoplasmic staining pattern exhibited by the non-RBD binders (PD4 and SC29). These data indicated that the S protein adopted a conformation in the Golgi complex that enabled the RBD recognition by the RBD-binders. The RBD-binders also recognised the uncleaved S protein indicating that S protein cleavage was not required for RBD recognition. Electron microscopy indicated high levels of cell-associated virus particles, and multiple cycle virus infection using RBD-binder staining provided evidence for direct cell-to-cell transmission for both isolates. Although similar levels of RBD-binder staining was demonstrated for each isolate, the SARS-CoV-2/1302 exhibited slower rates of cell-to-cell transmission. These data suggest that a conformational change in the S protein occurs during its transit through the Golgi complex that enables RBD recognition by the RBD-binders, and suggests that these antibodies can be used to monitor S protein RBD formation during the early stages of infection.ImportanceThe SARS CoV-2 spike (S) protein receptor binding domain (RBD) mediates the attachment of SARS CoV-2 to the host cell. This interaction plays an essential role in initiating virus infection and the S protein RBD is therefore a focus of therapeutic and vaccine interventions. However, new virus variants have emerged with altered biological properties in the RBD that can potentially negate these interventions. Therefore an improved understanding of the biological properties of the RBD in virus-infected cells may offer future therapeutic strategies to mitigate SARS CoV-2 infection. We used physiologically relevant antibodies that were isolated from the B cells of convalescent COVID19 patients to monitor the RBD in cells infected with SARS CoV-2 clinical isolates. These immunological reagents specifically recognise the correctly folded RBD and were used to monitor the appearance of the RBD in SARS CoV-2-infected cells and identified the site where the RDB first appears.
Outbreak of COVID-19 among vaccinated and unvaccinated homeless shelter residents — Sonoma County, California, July 2021
Authors: Bukatko Aleksandr , Lobato Mark N. , Mosites Emily , Stainken Cameron , Reihl Katheryn , Deldari Mojgan , Bell John M. , Morris Mary Kate , Wadford Debra A. , Harriman Kathleen , Mase Sundari 
Published: December 2021

AbstractIn July 2021, the Sonoma County Health Department was alerted to three cases of COVID-19 among residents of a homeless shelter in Santa Rosa, California. Among 153 shelter residents, 83 (54%) were fully vaccinated; 71 (86%) vaccinated residents had received the Janssen COVID-19 vaccine and 12 (14%) received an mRNA (Pfizer BioNTech or Moderna) COVID-19 vaccine. Within 1 month, 116 shelter residents (76%) received positive SARS-CoV-2 test results, including 66 fully vaccinated residents and 50 not fully vaccinated. 9 fully vaccinated and 1 unvaccinated were hospitalized for COVID-19. All hospitalized cases had at least one underlying medical condition. Two deaths occurred, one in a vaccinated resident and one in a non-vaccinated resident. Specimens from 52 residents underwent whole genome sequencing; all were identified as SARS-CoV-2, Delta Variant AY.13 lineage. Additional mitigation measures are needed in medically vulnerable congregate setting where limited resources make individual quarantine and isolation not feasible.
Racial and ethnic disparities in COVID-19 disease incidence independent of comorbidities, among people with HIV in the US
Authors: Bender Ignacio RA , Shapiro AE , Nance RM , Whitney BM , Delaney JAC , Bamford L , Wooten D , Karris M , Mathews WC , Kim HN , Van Rompaey SE , Keruly JC , Burkholder G , Napravnik S , Mayer KH , Jacobson J , Saag MS , Moore RD , Eron JJ , Willig AL , Christopoulos KA , Martin J , Hunt PW , Crane HM , Kitahata MM , Cachay E ,   for the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS)
Published: December 2021

ABSTRACTObjectivesTo define the incidence of clinically-detected COVID-19 in people with HIV (PWH) in the US and evaluate how racial and ethnic disparities, comorbidities, and HIV-related factors contribute to risk of COVID-19.DesignObservational study within the CFAR Network of Integrated Clinical Systems cohort in 7 cities during 2020.MethodsWe calculated cumulative incidence rates of COVID-19 diagnosis among PWH in routine care by key characteristics including race/ethnicity, current and lowest CD4 count, and geographic area. We evaluated risk factors for COVID-19 among PWH using relative risk regression models adjusted with disease risk scores.ResultsAmong 16,056 PWH in care, of whom 44.5% were Black, 12.5% were Hispanic, with a median age of 52 years (IQR 40-59), 18% had a current CD4 count < 350, including 7% < 200; 95.5% were on antiretroviral therapy, and 85.6% were virologically suppressed. Overall in 2020, 649 PWH were diagnosed with COVID-19 for a rate of 4.94 cases per 100 person-years. The cumulative incidence of COVID-19 was 2.4-fold and 1.7-fold higher in Hispanic and Black PWH respectively, than non-Hispanic White PWH. In adjusted analyses, factors associated with COVID-19 included female sex, Hispanic or Black identity, lowest historical CD4 count <350 (proxy for CD4 nadir), current low CD4/CD8 ratio, diabetes, and obesity.ConclusionsOur results suggest that the presence of structural racial inequities above and beyond medical comorbidities increased the risk of COVID-19 among PWHPWH with immune exhaustion as evidenced by lowest historical CD4 or current low CD4:CD8 ratio had greater risk of COVID-19.
Current state of the evidence on community treatments for people with complex emotional needs: a scoping review
Authors: Ledden Sarah , Rains Luke Sheridan , Schlief Merle , Barnett Phoebe , Fung Ching Brian Chi , Hallam Brendan , Günak Mia Maria , Steare Thomas , Parker Jennie , Labovitch Sarah , Oram Sian , Pilling Steve , Johnson Sonia ,   CEN Mental Health Policy Research Group
Published: December 2021

AbstractBackgroundImproving the quality of care in community settings for people with ‘Complex Emotional Needs’ (CEN - our preferred working term for services for people with a “personality disorder” diagnosis or comparable needs) is recognised internationally as a priority. Plans to improve care should be rooted as far as possible in evidence. We aimed to take stock of the current state of such evidence, and identify significant gaps through a scoping review of published investigations of outcomes of community-based psychosocial interventions designed for CEN.MethodsWe conducted a scoping review with systematic searches. We searched six bibliographic databases, including forward and backward citation searching, and reference searching of relevant systematic reviews. We included studies using quantitative methods to test for effects on any clinical, social, and functioning outcomes from community-based interventions for people with CEN.ResultsWe included 226 papers in all (209 studies). Little relevant literature was published before 2000. Since then, publications per year and sample sizes have gradually increased, but most studies are relatively small, including many pilot or uncontrolled studies. Most studies focus on symptom and self-harm outcomes of various forms of specialist psychotherapy: most result in outcomes better than from inactive controls and similar to other specialist psychotherapies. We found large evidence gaps.Adaptation and testing of therapies for significant groups (e.g. people with comorbid psychosis, bipolar disorder, post-traumatic stress disorder or substance misuse; older and younger groups; parents) have for the most part only reached a feasibility testing stage. We found little evidence regarding interventions to improve social aspects of people’s lives, peer support or ways of designing effective services.ConclusionsCompared with other longer term mental health problems that significantly impair functioning, the evidence base on how to provide high quality care for people with CEN is very limited. There is good evidence that people with CEN can be effectively helped when specialist therapies are available and they are able to engage with them. However, a much more methodologically robust and substantial literature addressing a much wider range of research questions is urgently needed to optimise treatment and support across this group.
Proteogenomic analysis of aneuploidy reveals divergent types of gene expression regulation across cellular pathways
Authors: Cheng Pan , Zhao Xin , Katsnelson Lizabeth , Moya Raquel , Shwetar Jasmine , Fenyö David , Davoli Teresa 
Published: December 2021

AbstractHow cells control gene expression is a fundamental question. The relative contribution of protein-level and transcript-level regulation to this process remains unclear. Here we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate transcript and protein abundances of SCNA-containing genes, we provide insights into the rules of gene regulation. While gene compensation mainly occurs at the protein level across tumor types, genes gained or lost show surprisingly low protein compensation in lung and high RNA compensation in colon cancer. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong transcript-level regulation. Exceptions are plasma membrane protein complexes showing a very low protein-level regulation. Strikingly, we find a strong negative association between the degree of transcript-level and protein-level regulation across genes and pathways. Moreover, genes participating in the same pathway show similar degree of transcript- and protein-level regulation. Pathways including translation, splicing and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger transcript-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve a predominant mechanism of gene regulation, possibly due to energetic constraints.HighlightsProteogenomic analyses of cancer SCNAs reveal tissue specificity in gene compensation.Genes gained or lost show surprisingly low protein compensation in lung cancer and unexpected RNA compensation in colon cancer.We use DNA-RNA and RNA-protein correlations to infer the degree of RNA-level and protein-level regulation.Protein complex genes and non-complex genes show high protein-level and RNA-level regulation, respectively.Plasma membrane complexes are an exception showing more RNA-level than protein-level regulation than other complex genes.Genes participating in the same pathway show similar degree of RNA-level and protein-level regulation.There is a strong negative relationship between the RNA- and protein-level regulation among pathways, suggesting that they are regulated either at the protein or at the RNA level.Genes involved in RNA processing and protein synthesis are upregulated in highly aneuploid tumors, especially at the protein level.
RoPod, a customizable toolkit for non-invasive root imaging, reveals cell type-specific dynamics of plant autophagy
Authors: Guichard Marjorie , Holla Sanjana , Wernerová Daša , Grossmann Guido , Minina Elena A. 
Published: December 2021

AbstractArabidopsis root is a classic model system in plant cell and molecular biology. The sensitivity of plant roots to local environmental perturbation challenges data reproducibility and incentivizes further optimization of imaging and phenotyping tools.Here we present RoPod, an easy-to-use toolkit for low-stress live time-lapse imaging of Arabidopsis roots. RoPod comprises a dedicated protocol for plant cultivation and a customizable 3D-printed vessel with integrated microscopy-grade glass that serves simultaneously as a growth and imaging chamber. RoPod reduces impact of sample handling, preserves live samples for prolonged imaging sessions, and facilitates application of treatments during image acquisition.We describe a protocol for RoPods fabrication and provide illustrative application pipelines for monitoring root hair growth and autophagic activity. Furthermore, we showcase how the use of RoPods advanced our understanding of plant autophagy, a major catabolic pathway and a key player in plant fitness. Specifically, we obtained fine time resolution for autophagy response to commonly used chemical modulators of the pathway and revealed previously overlooked cell type-specific changes in the autophagy response. These results will aid a deeper understanding of the physiological role of autophagy and provide valuable guidelines for choosing sampling time during end-point assays currently employed in plant autophagy research.