bluuebunny/crossref_metadata_2025_split huggingface dataset:
COVID-19 infection and hospitalization according to the burden of chronic noncommunicable diseases in Brazil
Authors: Ferraz Fabiana R. , Conde Wolney L. , Venancio Isabela , Lopes Larrisa , Azeredo Catarina M. 
Published: May 2021

AbstractChronic diseases, worse socioeconomic conditions and old age can increase infection and hospitalization rate due to Coronavirus disease (COVID-19). We assessed the association between the burden of NCDs and the occurrence of infections and hospitalizations of COVID-19 in Brazil in a large COVID-19 national survey data. We analyzed only data collected between July and November 2020 (n= 1,071,782). The frequencies of positive COVID-19 diagnosis and NCD burden were estimated according to age, sex, socioeconomic strata and skin color categories. We estimated hazard ratios and 95% confidence intervals using Cox regression models. There is a non-linear dose-response inverse association betweenper capitaincome and the rates of infection and hospitalization due to COVID-19. The presence of NCDs was associated with a higher incidence of COVID-19 infection (HR1NCD= 1.34; 95% CI: 1.26; 1.43; HR2 or more NCD= 1.54 95% CI: 1.39; 1.71) and incidence of hospitalization (HR1NCD= 3.08 95% CI: 2.26; 4.19; HR2or more NCD= 6.81 95% CI: 4.88; 9.49).The difference between the risks of infection or hospitalization of COVID-19 attributable to the burden of NCDs is non-linearly associated with the income.
Impaired T-cell and antibody immunity after COVID-19 infection in chronically immunosuppressed transplant recipients
Authors: Ashokkumar Chethan , Rohan Vinayak , Kroemer Alexander H , Rao Sohail , Mazariegos George , Higgs Brandon W , Nadig Satish , Almeda Jose , Dhani Harmeet , Khan Khalid , Yazigi Nada , Ekong Udeme , Kaufman Stuart , Betancourt-Garcia Monica M , Mukund Kavitha , Sethi Pradeep , Mehrotra Shikhar , Soltys Kyle , Singh Manasi S , Bond Geoffrey , Khanna Ajai , Ningappa Mylarappa , Spishock Brianna , Sindhi Elizabeth , Atale Neha , Saunders Maggie , Baliga Prabhakar , Fishbein Thomas , Subramaniam Shankar , Sindhi Rakesh 
Published: May 2021

AbstractAssessment of T-cell immunity to the COVID-19 coronavirus requires reliable assays and is of great interest, given the uncertain longevity of the antibody response. Some recent reports have used immunodominant spike (S) antigenic peptides and anti-CD28 co-stimulation in varying combinations to assess T-cell immunity to SARS-CoV-2. These assays may cause T-cell hyperstimulation and could overestimate antiviral immunity in chronically immunosuppressed transplant recipients, who are predisposed to infections and vaccination failures. Here, we evaluate CD154-expressing T-cells induced by unselected S antigenic peptides in 204 subjects-103 COVID-19 patients and 101 healthy unexposed subjects. Subjects included 72 transplanted and 130 non-transplanted subjects. S-reactive CD154+T-cells co-express and can thus substitute for IFNγ (n=3). Assay reproducibility in a variety of conditions was acceptable with coefficient of variation of 2-10.6%. S-reactive CD154+T-cell frequencies were a) higher in 42 healthy unexposed transplant recipients who were sampled pre-pandemic, compared with 59 healthy non-transplanted subjects (p=0.02), b) lower in Tr COVID-19 patients compared with healthy transplant patients (p<0.0001), c) lower in Tr patients with severe COVID-19 (p<0.0001), or COVID-19 requiring hospitalization (p<0.05), compared with healthy Tr recipients. S-reactive T-cells were not significantly different between the various COVID-19 disease categories in NT recipients. Among transplant recipients with COVID-19, cytomegalovirus co-infection occurred in 34%; further, CMV-specific T-cells (p<0.001) and incidence of anti-receptor-binding-domain IgG (p=0.011) were lower compared with non-transplanted COVID-19 patients. Healthy unexposed transplant recipients exhibit pre-existing T-cell immunity to SARS-CoV-2. COVID-19 infection leads to impaired T-cell and antibody responses to SARS-CoV-2 and increased risk of CMV co-infection in transplant recipients.
Longitudinal Changes in COVID-19 Associated In-Hospital Mortality
Authors: Warner Frederick , Hitchings Matt D.T. , Cummings Derek A.T. , McPadden Jacob , Krumholz Harlan M. , Ko Albert I. , Schulz Wade L. 
Published: May 2021

AbstractObjectiveAs the COVID-19 pandemic has evolved, a key question for health care systems is whether in-hospital mortality has changed over time and if so, what factors contributed to these changes. Our goal was to leverage real-world data spanning two COVID-19 surges over the first year of the pandemic to determine the temporal trend of in-hospital mortality.DesignThis was an observational, retrospective study based on real-world data for patients admitted with COVID-19. Generalized additive models (GAM) were used to evaluate the association of covariates with the composite outcome over time.Setting and PopulationWe identified a retrospective cohort of all patients who were hospitalized within the Yale New Haven Health (YNHH) system with an admission diagnosis of COVID-19 between March 1, 2020 and February 28, 2021.Main outcomeThe primary outcome for the study was a composite endpoint of in-hospital mortality, defined as death during the index hospitalization or discharge to hospice.ResultsAmong 6,477 discharges over the study period, the mean age was 66.2 years (SD=17.6), 52.5% (n=3,401) were male and the overall composite mortality was 14.2% (n=920). Composite in-hospital mortality was significantly associated with increased age, comorbidity index, respiratory rate, and heart rate; decreased systolic blood pressure; male sex; and admission from a long-term care facility (LTCF). The significant temporal decrease in mortality that was observed for patients admitted from a location other than a LTCF was not seen in those admitted from a LTCF.ConclusionsWe found that the adjusted in-hospital mortality rate declined over the first year of the pandemic, despite a second surge in COVID-19-related hospitalizations. Importantly, the decrease in mortality appeared to be driven by declines in risk in those not admitted from a LTCF. The observed decrease in mortality over time suggests that improved outcomes may be due to progressive, incremental learning and continuous evolution in hospital practice and policy over the course of the pandemic.
Environmental Screening for Surface SARS-CoV-2 Contamination in Urban High-Touch Areas
Authors: Brazell Lauren Roppolo , Stetz Shawna , Hipp Adam , Taylor Samantha , Stark Nicholas , Jensen Katherine , Islam Juel Md Ariful , Deegan Patrick , Munir Mariya , Schlueter Jessica , Weller Jennifer , Gibas Cynthia 
Published: May 2021

AbstractThe novel human coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 outbreak, which reached pandemic-level infection rates in just a few short months after being identified in late 2019. Early transmission models focused on surface contamination, but current research provides evidence for person-to-person transmission via aerosolized viral particles. As such, the CDC’s guidance has recently been updated to increasingly redirect the focus of prevention methods to aerosol routes. Inhalation of SARS-CoV-2 particles presents the most significant threat of infection to individuals. A secondary route, from hand to mouth, eyes or nose, is likely after contact with a surface contaminated with particles that have settled out of aerosols or been deposited by contaminated hands. Using common molecular detection methods including endpoint and quantitative PCR, we investigated whether there is detectable contamination by SARS-CoV-2 on high-touch surfaces on public transit vehicles and on other high-touch surfaces on a college campus during normal use. Our results indicate that SARS-CoV-2 can be successfully recovered and detected on common high-touch surfaces, albeit in comparatively lower frequencies as public health guidance progressed and more rigorous sanitization procedures were implemented.Abstract FigureGraphical abstract created with permission from BioRender.com (2021).
Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis
Authors: Musiu Chiara , Caligola Simone , Fiore Alessandra , Lamolinara Alessia , Frusteri Cristina , Del Pizzo Francesco Domenico , De Sanctis Francesco , Canè Stefania , Adamo Annalisa , Hofer Francesca , Barouni Roza Maria , Grilli Andrea , Zilio Serena , Serafini Paolo , Tacconelli Evelina , Donadello Katia , Gottin Leonardo , Polati Enrico , Girelli Domenico , Polidoro Ildo , Iezzi Piera Amelia , Angelucci Domenico , Capece Andrea , Chen Ying , Shi Zheng-Li , Murray Peter J. , Chilosi Marco , Amit Ido , Bicciato Silvio , Iezzi Manuela , Bronte Vincenzo , Ugel Stefano 
Published: May 2021

AbstractInflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-Cov-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homologue in myeloid cells triggered a STAT3-linked, progressive and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.One sentence summaryFLIP-expressing myeloid cells are key drivers of CRS through aberrant overexpression of STAT3 pathway. STAT3-targeting is effective in mitigating CRS like severe COVID-19.
Clinically relevant shifts in endogenous and exogenous mutational processes proximate to metastasis support local consolidative treatment in EGFR-driven non-small cell lung cancer
Authors: Fisk J. Nicholas , Mahal Amandeep R. , Dornburg Alex , Gaffney Stephen G. , Aneja Sanjay , Contessa Joseph N. , Rimm David , Yu James B. , Townsend Jeffrey P. 
Published: May 2021

AbstractThe progression of cancer—including the acquisition of therapeutic resistance and the fatal metastatic spread of therapy-resistant cell populations—is an evolutionary process that is challenging to monitor between sampling timepoints. Here we apply mutational signature analysis to clinically correlated cancer chronograms to detect and describe the shifting mutational processes caused by both endogenous (e.g. mutator mutation) and exogenous (e.g. therapeutic) factors between tumor sampling timepoints. In one patient, we find that cisplatin therapy can introduce mutations that increase the likelihood of genetic adaptation to subsequent targeted therapeutics. In another patient, we trace the emergence of known driver mutation CTNNB1 S37C to specific detection of defective mismatch repair associated mutational signature SBS3. Metastatic lineages were found to emerge from a single ancestral lineage arising during therapy—a finding that argues for the consideration of local consolidative therapy over other therapeutic approaches in EGFR-positive non-small cell lung cancer. Broadly, these results demonstrate the utility of phylogenetic analysis that incorporates clinical time course and mutational signature detection to inform clinical decision making and retrospective assessment of disease etiology.
Modeling and Predicting Antibody Durability for mRNA-1273 Vaccine for SARS-CoV-2 Variants
Authors: Luo George , Hu Zhongbo , Letterio John J. 
Published: May 2021

AbstractRecently, the antibody titer levels have been followed in 33 adults who received the mRNA-1273 vaccine for 6 months. With single dose estimated effectiveness of 92.1%, we combine this knowledge with corresponding antibody levels to model and estimate the long-term durability of mRNA-1273 vaccine. Additionally, we integrate studies about differences in antibody neutralization to SARS-CoV-2 variants to understand how variants can affect the durability of the vaccine.The estimated days after first injection for binding antibodies to fall below levels of those from day 15 is 411 days. The estimated days after first injection to fall below the lower limit of detection of 20 GMTs is 327 days for pseudovirus neutralization and 461 days for live virus neutralization. Our model has pseudovirus neutralization against variant B.1.351 falling below 20 GMT on day 100; variant P.1 on day 202, variant B.1.429 on day 258; and variant B.1.1.7 on day 309.The data used contains many limitations including the small sample size with older age bias, sensitivity of the neutralization assays, and limited data on variants. Still, we believe mRNA-1273 two dose vaccine can provide over a year of protection against COVID-19 from the initial D614G variant. It is likely by the second year, protection against COVID-19 will fall below single dose efficacy. Therefore, there should be consideration for a booster shot a year after the first set of vaccines. If there is an observed increase in variants with higher resistance such as B.1.351 and P.1, a booster vaccine against the newer variants should be considered to increase protection against resistant variants.
Sex-biased response to and brain cell infection by SARS-CoV-2 in a highly susceptible human ACE2 transgenic model
Authors: Tsai Ching-Yen , Chen Chiung-Ya , Jan Jia-Tsrong , Chou Yu-Chi , Chang Mei-Ling , Lu Lu A , Huang Pau-Yi , Chu Mandy F.-C. , Hsu Tsan-Ting , Hsueh Yi-Ping 
Published: May 2021

SummaryThe COVID-19 pandemic is caused by SARS-CoV-2 infection. Human angiotensin-converting enzyme II (hACE2) has been identified as the receptor enabling SARS-CoV-2 host entry. To establish a mouse model for COVID-19, we generated transgenic mouse lines using the (HS4)2-pCAG-hACE2-HA-(HS4)2transgene cassette, which expresses HA-tagged hACE2 under control of the CAG promoter and is flanked by HS4 insulators. Expression levels of the hACE2 transgene are respectively higher in lung, brain and kidney of our CAG-hACE2 transgenic mice and relatively lower in duodenum, heart and liver. The CAG-hACE2 mice are highly susceptibility to SARS-CoV-2 infection, with 100 PFU of SARS-CoV-2 being sufficient to induce 87.5% mortality at 9 days post-infection and resulting in a sole (female) survivor. Mortality was 100% at the higher titer of 1000 PFU. At lower viral titers, we also found that female mice exposed to SARS-CoV-2 infection suffered much less weight loss than male mice, implying sex-biased responses to SARS-CoV-2 infection. We subjected neuronal cultures to SARS-CoV-2 pseudovirus infection to ascertain the susceptibilities of neurons and astrocytes. Moreover, we observed that expression of SARS-CoV-2 Spike protein alters the synaptic responses of cultured neurons. Our transgenic mice may serve as a model for severe COVID-19 and sex-biased responses to SARS-CoV-2 infection, aiding in the development of vaccines and therapeutic treatments for this disease.
Real-time HRMAS13C NMR of obligately anaerobic cells identifies new metabolic targets in the pathogenClostridioides difficile
Authors: Pavao Aidan , Girinathan Brintha , Peltier Johann , Silva Pamela Altamirano , Dupuy Bruno , Cheng Leo L. , Bry Lynn 
Published: May 2021

AbstractAnaerobic microbial metabolism drives critical aspects of host-microbiome interactions and supports many economically important industrial applications. Yet, the metabolic pathways of anaerobic bacteria and their associated constraints for maintaining energy and redox balance are often poorly described. We employ High-Resolution Magic Angle Spinning Carbon-13 (13C) Nuclear Magnetic Resonance spectroscopy with dynamic flux balance analysis to resolve real-time metabolism in living cells of the obligately anaerobic pathogenClostridioides difficile. Using13C-labeled carbon sources, we elaborate the time-dependent progression of reductive and oxidative anaerobic fermentation pathways. Analyses identified new integration points for redox and nitrogen coupling between carbohydrate and amino acid metabolism, particularly in the production of13C-alanine from13C-glucose to provide an ammonia sink from co-occurring amino acid fermentation. Analyses conducted in the presence or absence of selenium, a required co-factor for the proline Stickland reductase, demonstrate further capacity to modulate cellular metabolism and resulting metabolites. Findings informed a genome-scale metabolic model ofC. difficile, identifying alanine and associated electron carrier pools as critical metabolic integration points in energy flow and biomass expansion. We illustrate use of HRMAS NMR as a new analytical platform to resolve complex interactions in anaerobic metabolism and inform new metabolic targets to counterC. difficileinfections.
Histone marks are drivers of the splicing changes necessary for an epithelial-to-mesenchymal transition
Authors: Segelle A. , Núñez-Álvarez Y. , Oldfield A. J. , Webb K. M. , Voigt P. , Luco R. F. 
Published: May 2021

AbstractCell differentiation and reprogramming depend on coordinated changes in specific alternative splicing events. How these cell type-specific splicing patterns are dynamically modified in response to a stimulus remains elusive. Taking advantage of the epithelial-to-mesenchymal transition (EMT), a reversible cell reprogramming intimately involved in cancer cell invasiveness and metastasis, we found a strong correlation between changes in the alternative splicing of key exons for EMT, such as at theFgfr2andCnntd1loci, and changes in the enrichment levels of specific histone modifications, namely H3K27ac and H3K27me3. Localised CRISPR epigenome editing of these exon-specific histone marks was sufficient to induce changes in splicing capable of recapitulating important aspects of EMT, such as a motile and invasive cell phenotype. Whereas, impairment of the changes in H3K27 marks observed during EMT, using histone deacetylase inhibitors, repressed inclusion of the mesenchymal isoform despite an EMT induction, supporting a driving effect for H3K27 modifications in establishing the new cell type-specific splicing patterns necessary for EMT cell reprogramming. Finally, H3K27 marks were shown to impact splicing by modulating recruitment of the splicing factor PTB to its RNA binding sites, suggesting a direct link between chromatin modifications and the splicing machinery. Taken together, these results prove the causal role of H3K27 marks in driving the dynamic splicing changes necessary for induction of important aspects of EMT. They also prove that chromatin-mediated splicing changes are sufficient to impact the cell’s phenotype, which expands the cell’s toolkit to adapt and respond to diverse stimuli, such as EMT induction.
Functional architecture of neural circuits for leg proprioception inDrosophila
Authors: Chen Chenghao , Agrawal Sweta , Mark Brandon , Mamiya Akira , Sustar Anne , Phelps Jasper S , Lee Wei-Chung Allen , Dickson Barry J , Card Gwyneth M , Tuthill John C 
Published: May 2021

AbstractTo effectively control their bodies, animals rely on feedback from proprioceptive mechanosensory neurons. In theDrosophilaleg, different proprioceptor subtypes monitor joint position, movement direction, and vibration. Here, we investigate how these diverse sensory signals are integrated by central proprioceptive circuits. We find that signals for leg joint position and directional movement converge in second-order neurons, revealing pathways for local feedback control of leg posture. Distinct populations of second-order neurons integrate tibia vibration signals across pairs of legs, suggesting a role in detecting external substrate vibration. In each pathway, the flow of sensory information is dynamically gated and sculpted by inhibition. Overall, our results reveal parallel pathways for processing of internal and external mechanosensory signals, which we propose mediate feedback control of leg movement and vibration sensing, respectively. The existence of a functional connectivity map also provides a resource for interpreting connectomic reconstruction of neural circuits for leg proprioception.
The Immune landscape of pediatric solid tumors
Authors: Sherif Shimaa , Roelands Jessica , Mifsud William , Ahmed Eiman , Mifsud Borbala , Bedognetti Davide , Hendrickx Wouter 
Published: May 2021

AbstractBackgroundImmunotherapy is quickly coming to the forefront of cancer treatment; however, the implementation of immunotherapy in solid pediatric cancers, which classically display a low mutational load, is hindered by insufficient understanding of the determinants of cancer immune responsiveness in children. In order to better understand tumor-host interplay, we sought to characterize solid pediatric cancers based on immunological parameters using analytes extracted from gene expression data.MethodsWe used RNAseq data from the publicly available TARGET studies for five pediatric solid tumor types (408 patients): Wilms tumor (WT), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of previously identified immune signatures like the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response associated with favorable prognosis and responsiveness to immunotherapy. We also performed gene set enrichment analysis (ssGSEA) and clustering, using more than 100 immune signatures to define immune subtypes in pediatric tumors and compared the overall survival across subtypes. The expression of immune checkpoints and enrichment of oncogenic pathways were also assessed across the immune subtypes.ResultsThe five tumor types showed distinct ICR score distributions. A higher ICR score was associated with better survival in OS and NBL-HR-MYCN_NA, but with poorer survival in WT. The clustering of immune signatures revealed the same five principal modules observed in adult solid tumors: Wound Healing, TGF-B signaling, IFN-G signaling, Macrophages, and Lymphocytes. These modules clustered pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival and was characterized by low enrichment of the wound healing signature, high Th1, low Th2. Conversely, cluster S4 showed the worst survival and highest enrichment of wound healing signature, low Th1, and high Th2. Furthermore, the upregulation of the WNT/Beta-catenin pathway is associated with unfavorable outcomes and lack of T-cell infiltration in OS.ConclusionsWe demonstrated that extracranial solid pediatric tumors could be classified according to their immune disposition, unveiling similarity with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.