bluuebunny/crossref_metadata_2025 huggingface dataset:
The age–chemical abundance structure of the Galaxy I: evidence for a late-accretion event in the outer disc at z ∼ 0.6
Authors: Lian Jianhui , Thomas Daniel , Maraston Claudia , Zamora Olga , Tayar Jamie , Pan Kaike , Tissera Patricia , Fernández-Trincado José G , Garcia-Hernandez D A
Published: March 2020

We investigate the age–chemical abundance structure of the outer Galactic disc at a galactocentric distance of r > 10 kpc as recently revealed by the SDSS/APOGEE survey. Two sequences are present in the [α/Fe]–[Fe/H] plane with systematically different stellar ages. Surprisingly, the young sequence is less metal rich, suggesting a recent dilution process by additional gas accretion. As the stars with the lowest iron abundance in the younger sequence also show an enhancement in α-element abundance, the gas accretion event must have involved a burst of star formation. In order to explain these observations, we construct a chemical evolution model. In this model, we include a relatively short episode of gas accretion at late times on top of an underlying secular accretion over long time-scales. Our model is successful at reproducing the observed distribution of stars in the three-dimensional space of [α/Fe]–[Fe/H]–age in the outer disc. We find that a late-time accretion with a delay of $8.2\,$Gyr and a time-scale of 0.7 Gyr best fits the observed data, in particular the presence of the young, metal-poor sequence. Our best-fitting model further implies that the amount of accreted gas in the late-time accretion event needs to be about three times the local gas reservoir in the outer disc at the time of accretion in order to sufficiently dilute the metal abundance. Given this large fraction, we interpret the late-time accretion event as a minor merger presumably with a gas-rich dwarf galaxy with a mass $M_*\lt 10^{9}\, \mathrm{ M}_{\odot }$ and a gas fraction of ∼75 per cent.
Diffusive photospheres in gamma-ray bursts
Authors: Vereshchagin G V , Siutsou I A
Published: March 2020

Photospheric emission may originate from relativistic outflows in two qualitatively different regimes: last scattering of photons inside the outflow at the photospheric radius or radiative diffusion to the boundary of the outflow. In this work, the measurement of temperature and flux of the thermal component in the early afterglows of several gamma-ray bursts along with the total flux in the prompt phase is used to determine initial radii of the outflow as well as its Lorentz factors. Results indicate that in some cases the outflow has relatively low Lorentz factors (Γ < 10), favouring cocoon interpretation, while in other cases Lorentz factors are larger (Γ > 10), indicating diffusive photospheric origin of the thermal component, associated with an ultrarelativistic outflow.
Cosmic magnetic fields with masclet: an application to galaxy clusters
Authors: Quilis Vicent , Martí José-María , Planelles Susana
Published: March 2020

We describe and test a new version of the adaptive mesh refinement cosmological code masclet. The new version of the code includes all the ingredients of its previous version plus a description of the evolution of the magnetic field under the approximation of the ideal magnetohydrodynamics (MHD). To preserve the divergence-free condition of MHD, the original divergence cleaning algorithm of Dedner et al. (2002) is implemented. We present a set of well-known 1D and 2D tests, such as several shock tube problems, the fast rotor, and the Orszag–Tang vortex. The performance of the code in all the tests is excellent with estimated median relative errors of ∇ · B in the 2D tests smaller than 5 × 10−5 for the fast rotor test, and 5 × 10−3 for the Orszag–Tang vortex. As an astrophysical application of the code, we present a simulation of a cosmological box of 40 comoving Mpc side length in which a primordial uniform comoving magnetic field of strength 0.1 nG is seeded. The simulation shows how the magnetic field is channelled along the filaments of gas and is concentrated and amplified within galaxy clusters. Comparison with the values expected from pure compression reveals an additional amplification of the magnetic field caused by turbulence in the central region of the cluster. Values of the order of ∼1µG are obtained in clusters at z ∼ 0 with median relative errors of ∇ · B below 0.4 per cent. The implications of a proper description of the dynamics of the magnetic field and their possible observational counterparts in future facilities are discussed.
Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond
Authors: Liu Ru-Juan , Long Tao , Li Hao , Zhao JingHua , Li Jing , Wang MingZhu , Palencia Andrés , Lin JinZhong , Cusack Stephen , Wang En-Duo
Published: March 2020

Human cytosolic leucyl-tRNA synthetase (hcLRS) is an essential and multifunctional enzyme. Its canonical function is to catalyze the covalent ligation of leucine to tRNALeu, and it may also hydrolyze mischarged tRNAs through an editing mechanism. Together with eight other aminoacyl-tRNA synthetases (AaRSs) and three auxiliary proteins, it forms a large multi-synthetase complex (MSC). Beyond its role in translation, hcLRS has an important moonlight function as a leucine sensor in the rapamycin complex 1 (mTORC1) pathway. Since this pathway is active in cancer development, hcLRS is a potential target for anti-tumor drug development. Moreover, LRS from pathogenic microbes are proven drug targets for developing antibiotics, which however should not inhibit hcLRS. Here we present the crystal structure of hcLRS at a 2.5 Å resolution, the first complete structure of a eukaryotic LRS, and analyze the binding of various compounds that target different sites of hcLRS. We also deduce the assembly mechanism of hcLRS into the MSC through reconstitution of the entire mega complex in vitro. Overall, our study provides the molecular basis for understanding both the multifaceted functions of hcLRS and for drug development targeting these functions.
PHF2 regulates homology-directed DNA repair by controlling the resection of DNA double strand breaks
Authors: Alonso-de Vega Ignacio , Paz-Cabrera Maria Cristina , Rother Magdalena B , Wiegant Wouter W , Checa-Rodríguez Cintia , Hernández-Fernaud Juan Ramón , Huertas Pablo , Freire Raimundo , van Attikum Haico , Smits Veronique A J
Published: March 2020

Post-translational histone modifications and chromatin remodelling play a critical role controlling the integrity of the genome. Here, we identify histone lysine demethylase PHF2 as a novel regulator of the DNA damage response by regulating DNA damage-induced focus formation of 53BP1 and BRCA1, critical factors in the pathway choice for DNA double strand break repair. PHF2 knockdown leads to impaired BRCA1 focus formation and delays the resolution of 53BP1 foci. Moreover, irradiation-induced RPA phosphorylation and focus formation, as well as localization of CtIP, required for DNA end resection, to sites of DNA lesions are affected by depletion of PHF2. These results are indicative of a defective resection of double strand breaks and thereby an impaired homologous recombination upon PHF2 depletion. In accordance with these data, Rad51 focus formation and homology-directed double strand break repair is inhibited in cells depleted for PHF2. Importantly, we demonstrate that PHF2 knockdown decreases CtIP and BRCA1 protein and mRNA levels, an effect that is dependent on the demethylase activity of PHF2. Furthermore, PHF2-depleted cells display genome instability and are mildly sensitive to the inhibition of PARP. Together these results demonstrate that PHF2 promotes DNA repair by homologous recombination by controlling CtIP-dependent resection of double strand breaks.
Systematic in vitro profiling of off-target affinity, cleavage and efficiency for CRISPR enzymes
Authors: Zhang Liyang , Rube H Tomas , Vakulskas Christopher A , Behlke Mark A , Bussemaker Harmen J , Pufall Miles A
Published: March 2020

CRISPR RNA-guided endonucleases (RGEs) cut or direct activities to specific genomic loci, yet each has off-target activities that are often unpredictable. We developed a pair of simple in vitro assays to systematically measure the DNA-binding specificity (Spec-seq), catalytic activity specificity (SEAM-seq) and cleavage efficiency of RGEs. By separately quantifying binding and cleavage specificity, Spec/SEAM-seq provides detailed mechanistic insight into off-target activity. Feature-based models generated from Spec/SEAM-seq data for SpCas9 were consistent with previous reports of its in vitro and in vivo specificity, validating the approach. Spec/SEAM-seq is also useful for profiling less-well characterized RGEs. Application to an engineered SpCas9, HiFi-SpCas9, indicated that its enhanced target discrimination can be attributed to cleavage rather than binding specificity. The ortholog ScCas9, on the other hand, derives specificity from binding to an extended PAM. The decreased off-target activity of AsCas12a (Cpf1) appears to be primarily driven by DNA-binding specificity. Finally, we performed the first characterization of CasX specificity, revealing an all-or-nothing mechanism where mismatches can be bound, but not cleaved. Together, these applications establish Spec/SEAM-seq as an accessible method to rapidly and reliably evaluate the specificity of RGEs, Cas::gRNA pairs, and gain insight into the mechanism and thermodynamics of target discrimination.
Hippocampal radiotherapy dose constraints for predicting long-term neurocognitive outcomes: mature data from a prospective trial in young patients with brain tumors
Authors: Goda Jayant S , Dutta Debnarayan , Krishna Uday , Goswami Savita , Kothavade Vikas , Kannan Sadhna , Maitre Madan , Bano Nazia , Gupta Tejpal , Jalali Rakesh
Published: March 2020

Background

Hippocampus is considered to be the seat for neurocognitive functions. Avoidance of hippocampus during radiotherapy to brain may serve to preserve various domains of neurocognition. We aimed to derive radiotherapy dose constraints to hippocampi for preserving neurocognition in young patients with brain tumors by measuring various neurocognitive parameters.

Methods

Forty-eight patients with residual/progressive benign or low-grade brain tumors treated with stereotactic conformal radiotherapy (SCRT) to a dose of 54 Gy in 30 fractions underwent prospective neuropsychological assessments at baseline before SCRT and at 6 months and 2, 3, 4, and 5 years. Hippocampi were drawn as per the Radiation Therapy Oncology Group atlas. Longitudinal change in intelligence quotient scores was correlated with hippocampal doses.

Results

Mean volume of bilateral hippocampi was 4.35 cc (range: 2.12–8.41 cc). Craniopharyngioma was the commonest histologic subtype. A drop of >10% in mean full-scale intelligence quotient (FSIQ) scores at 3 and 5 years post SCRT was observed in patients in whom left hippocampus received a mean dose of 30.7 Gy (P = 0.04) and 31 Gy (P = 0.04), respectively. Mean performance quotient (PQ) scores dropped > 10% at 5 years when the left hippocampus received a dose of > 32 Gy (P = 0.03). There was no significant correlation of radiotherapy doses with verbal quotient, or with doses received by the right hippocampus. Multivariate analysis revealed young age (<13 y) and left hippocampus dose predicted for clinically relevant decline in certain neurocognitive domains.

Conclusions

A mean dose of ≤30 Gy to the left hippocampus as a dose constraint for preserving intelligence quotient is suggested.

Key Points

1. Children and young adults with benign and low-grade gliomas survive long after therapy.

2. Higher dose to the hippocampi may result in long-term neurocognitive impairment.

3. Mean dose of <30 Gy to left hippocampus could be used as a pragmatic dose constraint to prevent long-term neurocognitive decline.
Rapid succession drives spring community dynamics of small protists at Helgoland Roads, North Sea
Authors: Käse Laura , Kraberg Alexandra C , Metfies Katja , Neuhaus Stefan , Sprong Pim A A , Fuchs Bernhard M , Boersma Maarten , Wiltshire Karen H
Published: March 2020

The dynamics of diatoms and dinoflagellates have been monitored for many decades at the Helgoland Roads Long-Term Ecological Research site and are relatively well understood. In contrast, small-sized eukaryotic microbes and their community changes are still much more elusive, mainly due to their small size and uniform morphology, which makes them difficult to identify microscopically. By using next-generation sequencing, we wanted to shed light on the Helgoland planktonic community dynamics, including nano- and picoplankton, during a spring bloom. We took samples from March to May 2016 and sequenced the V4 region of the 18S rDNA. Our results showed that mixotrophic and heterotrophic taxa were more abundant than autotrophic diatoms. Dinoflagellates dominated the sequence assemblage, and several small-sized eukaryotic microbes like Haptophyta, Choanoflagellata, Marine Stramenopiles and Syndiniales were identified. A diverse background community including taxa from all size classes was present during the whole sampling period. Five phases with several communities were distinguished. The fastest changes in community composition took place in phase 3, while the communities from phases 1 to 5 were more similar to each other despite contrasting environmental conditions. Synergy effects of next-generation sequencing and traditional methods may be exploited in future long-term observations.
Large enhancement of conductivity in a strongly layered type-II superconductor with an artificial pinning array
Authors: Tinh Bui Duc
Published: March 2020

We use the time-dependent Ginzburg–Landau equation to describe a type-II superconductor in a magnetic field in the presence of both strong thermal fluctuations and an artificial pinning array. Thermal fluctuations are represented by the Langevin white noise. The layered structure of the superconductor is taken into accounted with the Lawrence–Doniach model. The self-consistent Gaussian approximation is used to treat the nonlinear interaction term in the time-dependent Ginzburg–Landau equation. In the case of the $\delta $-function model for the pinning centers and the matching field, analytic expressions for the fluctuation electrical and thermoelectric conductivity are obtained. It is found that the fluctuations in electrical and thermoelectric conductivities increase with increasing pinning strength, and when the pinning strength comes near a critical value, the fluctuation conductivity is greatly enhanced. Our result shows that if a pinning array is added to a mixed state superconductor, the original properties of the superconductor are recovered. Physically, in the presence of thermal fluctuations, when the energy scale of the vortex lattice shear fluctuations becomes comparable to the pinning energy scale there is a large enhancement of the fluctuation conductivity in the presence of pinning.
Genetic regulation, biochemical properties and physiological importance of arginase from Sinorhizobium meliloti
Authors: Ide Alejandra Arteaga , Hernández Victor M. , Medina-Aparicio Liliana , Carcamo-Noriega Edson , Girard Lourdes , Hernández-Lucas Ismael , Dunn Michael F.
Published: March 2020

In bacteria,l-arginine is a precursor of various metabolites and can serve as a source of carbon and/or nitrogen. Arginine catabolism by arginase, which hydrolyzes arginine tol-ornithine and urea, is common in nature but has not been studied in symbiotic nitrogen-fixing rhizobia. The genome of the alfalfa microsymbiontSinorhizobium meliloti1021 has two genes annotated as arginases,argI1(smc03091) andargI2(sma1711). Biochemical assays with purified ArgI1 and ArgI2 (as 6His-Sumo-tagged proteins) showed that only ArgI1 had detectable arginase activity. A 1021argI1null mutant lacked arginase activity and grew at a drastically reduced rate with arginine as sole nitrogen source. Wild-type growth and arginase activity were restored in theargI1mutant genetically complemented with a genomically integratedargI1gene. In the wild-type, arginase activity andargI1transcription were induced several fold by exogenous arginine. ArgI1 purified as a 6His-Sumo-tagged protein had its highestin vitroenzymatic activity at pH 7.5 with Ni2+as cofactor. The enzyme was also active with Mn2+and Co2+, both of which gave the enzyme the highest activities at a more alkaline pH. The 6His-Sumo-ArgI1 comprised three identical subunits based on the migration of the urea-dissociated protein in a native polyacrylamide gel. A Lrp-like regulator (smc03092) divergently transcribed fromargI1was required for arginase induction by arginine or ornithine. This regulator was designated ArgIR. Electrophoretic mobility shift assays showed that purified ArgIR bound to theargI1promoter in a region preceding the predictedargI1transcriptional start. Our results indicate that ArgI1 is the sole arginase inS. meliloti, that it contributes substantially to arginine catabolismin vivoand thatargI1induction by arginine is dependent on ArgIR.
Scarce COVID-19 Testing Capabilities at Urgent Care Centers in States with Greatest Disease Burden
Authors: Hsiang Walter , Forman Howard , Jain Siddharth , Khunte Akshay , Jin Grace , Yousman Laurie , Najem Michael , Mosier-Mills Alison , Wiznia Daniel
Published: March 2020

As of March 22, 2020, the number of confirmed COVID-19 cases in the U.S. has reached nearly 30,000.1 While rapid and accessible diagnosis is paramount to monitoring and reducing the spread of disease, COVID-19 testing capabilities across the U.S. remain constrained. For many individuals, urgent care centers (UCCs) may offer the most accessible avenue to be tested. Using a phone survey, we describe the COVID-19 testing capabilities of UCCs in states with the greatest disease burden.
Is scaling-up COVID-19 testing cost-saving?
Authors: Sousa-Pinto Bernardo , Fonseca João Almeida , Costa-Pereira Altamiro , Rocha-Gonçalves Francisco Nuno
Published: March 2020

The World Health Organization currently recommends that governments scale up testing for COVID-19 infection. We performed health economic analyses projecting whether the additional costs from screening would be offset by the avoided costs with hospitalizations. We analysed Portuguese COVID-19 data up until the 22nd March 2020, and estimated the additional number of cases that would be detected if different testing rates and frequencies of positive results would have been observed. We projected that, in most scenarios, the costs with scaling up COVID-19 tests would be lower than savings with hospitalization costs, rendering large scale testing cost-saving.
Global transmission network of SARS-CoV-2: from outbreak to pandemic
Authors: Skums Pavel , Kirpich Alexander , Baykal Pelin Icer , Zelikovsky Alex , Chowell Gerardo
Published: March 2020

Background

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is straining health systems around the world. Although the Chinese government implemented a number of severe restrictions on people’s movement in an attempt to contain its local and international spread, the virus had already reached many areas of the world in part due to its potent transmissibility and the fact that a substantial fraction of infected individuals develop little or no symptoms at all. Following its emergence, the virus started to generate sustained transmission in neighboring countries in Asia, Western Europe, Australia, Canada and the United States, and finally in South America and Africa. As the virus continues its global spread, a clear and evidence-based understanding of properties and dynamics of the global transmission network of SARS-CoV-2 is essential to design and put in place efficient and globally coordinated interventions.

Methods

We employ molecular surveillance data of SARS-CoV-2 epidemics for inference and comprehensive analysis of its global transmission network before the pandemic declaration. Our goal was to characterize the spatial-temporal transmission pathways that led to the establishment of the pandemic. We exploited a network-based approach specifically tailored to emerging outbreak settings. Specifically, it traces the accumulation of mutations in viral genomic variants via mutation trees, which are then used to infer transmission networks, revealing an up-to-date picture of the spread of SARS-CoV-2 between and within countries and geographic regions.

Results and Conclusions

The analysis suggest multiple introductions of SARS-CoV-2 into the majority of world regions by means of heterogeneous transmission pathways. The transmission network is scale-free, with a few genomic variants responsible for the majority of possible transmissions. The network structure is in line with the available temporal information represented by sample collection times and suggest the expected sampling time difference of few days between potential transmission pairs. The inferred network structural properties, transmission clusters and pathways and virus introduction routes emphasize the extent of the global epidemiological linkage and demonstrate the importance of internationally coordinated public health measures.
Phylogenetic analyses suggest independent origins for trichromatic color vision in apes and Old World monkeys
Authors: Toloza-Villalobos Jessica , Opazo Juan C.
Published: March 2020

In catarrhine primates, trichromatic color vision is associated with the presence of three opsin genes that absorb light at three different wavelengths. The OPN1LW and OPN1MW genes are found on the X chromosome. Their proximity and similarity suggest that they originated from a duplication event in the catarrhine ancestor. In this study we use the primate genomes available in public databases to study the duplicative history of the OPN1LW and OPN1MW genes and characterize their spectral sensitivity. Our results reveal a phylogenetic tree that shows a clade containing all X-linked opsin paralogs found in Old World monkeys to be related to a clade containing all X-linked opsin paralogs identified in apes, suggesting that routine trichromacy originated independently in apes and Old World monkeys. Also, we found spectral variability in the X-linked opsin gene of primates. Our study presents a new perspective for the origin of trichromatic color vision in apes and Old World monkeys, not reported so far.
Structure-based modeling of SARS-CoV-2 peptide/HLA-A02 antigens
Authors: Nerli Santrupti , Sgourakis Nikolaos G.
Published: March 2020

As a first step toward the development of diagnostic and therapeutic tools to fight the Coronavirus disease (COVID-19), it is important to characterize CD8+ T cell epitopes in the SARS-CoV-2 peptidome that can trigger adaptive immune responses. Here, we use RosettaMHC, a comparative modeling approach which leverages existing high-resolution X-ray structures from peptide/MHC complexes available in the Protein Data Bank, to derive physically realistic 3D models for high-affinity SARS-CoV-2 epitopes. We outline an application of our method to model 439 9mer and 279 10mer predicted epitopes displayed by the common allele HLA-A*02:01, and we make our models publicly available through an online database (https://rosettamhc.chemistry.ucsc.edu). As more detailed studies on antigen-specific T cell recognition become available, RosettaMHC models of antigens from different strains and HLA alleles can be used as a basis to understand the link between peptide/HLA complex structure and surface chemistry with immunogenicity, in the context of SARS-CoV-2 infection.
Complex naturalistic stimuli are prioritized by attention when maintained in visual working memory
Authors: Rutkowska Natalia , Doradzińska Łucja , Bola Michał
Published: March 2020

Recent studies suggest that a stimulus actively maintained in working memory (WM) automatically captures visual attention when subsequently perceived. Such a WM-guidance effect has been consistently observed for stimuli defined by simple features, such as colour or orientation, but studies using more complex stimuli provide inconclusive results. Therefore, we investigated whether the WM-guidance effect occurs also for naturalistic stimuli, whose identity is defined by multiple features and relations among them, specifically for faces and houses. The experiment consisted of multiple blocks in which participants (N = 28) either memorized or merely saw (WM or exposure condition, respectively) a template stimulus and then performed several dot-probe trials, with pairs of stimuli (template and control) presented laterally as distractors and followed by a target-asterisk. Evidence for attentional prioritization of the memorized stimuli was found in the reaction-times (RT) analysis, but not in the analysis of the N2pc ERP component, which raises questions concerning the attentional mechanism involved. Further, in an exploratory ERP analysis we found evidence for a very early (100-200 ms post-stimulus) prioritization specific to the memorized faces, which is in line with the sensory recruitment theory of WM.
Analysis of adaptive immune cell populations and phenotypes in the patients infected by SARS-CoV-2
Authors: Yang Xiaofeng , Dai Tongxin , Zhou Xiaobo , Qian Hongbo , Guo Rui , Lei Lei , Zhang Xingzhe , Zhang Dan , Shi Lin , Cheng Yanbin , Hu Jinsong , Guo Yaling , Zhang Baojun
Published: March 2020

Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has rapidly spread to most of countries in the world, threatening the health and lives of many people. Unfortunately, information regarding the immunological characteristics in COVID-19 patients remains limited. Here we collected the blood samples from 18 healthy donors (HD) and 38 COVID-19 patients to analyze changes in the adaptive immune cell populations and phenotypes. In comparison to HD, the lymphocyte percentage was slightly decreased, the percentages of CD4 and CD8 T cells in lymphocytes are similar, whereas B cell percentage increased in COVID-19 patients. T cells, especially CD8 T cells, showed an enhanced expression of late activation marker CD25 and exhaustion marker PD-1. Importantly, SARS-CoV-2 induced an increased percentage of T follicular helpher (Tfh)- and germinal center B-like (GCB-like) cells in the blood. However, the parameters in COVD-19 patients remained unchanged across various age groups. Therefore, we demonstrated that the T and B cells can be activated normally and exhibit functional features. These data provide a clue that the adaptive immunity in most people could be primed to induce a significant immune response against SARS-CoV-2 infection upon receiving standard medical care.
Clinical Characteristics of Hospitalized Patients with SARS-CoV-2 and Hepatitis B virus Co-infection
Authors: Chen Xiaoping , Jiang Qunqun , Ma Zhiyong , Ling Jiaxin , Hu Wenjia , Cao Qian , Mo Pingzheng , Yang Rongrong , Gao Shicheng , Gui Xien , Xiong Yong , Li Jinlin , Zhang Yongxi
Published: March 2020

Background & Aims

The coronavirus disease 2019 (COIVD-19) caused by SARS-CoV-2 has been characterized as a pandemic, which causes a serious public health challenge in the world. A very large group of patients infected by HBV has been reported worldwide, especially in China. In order to answer whether specific treatment strategy on the patients coinfected with HBV and SARS-CoV-2, it requires profound understanding of the clinical characteristics on those patients. However, the impacts of SARS-CoV-2 infection on HBV patients remain largely unknown.

Approach & Results

In this retrospective investigation, we included 123 COVID-19 patients admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, from January 5 to March 7, 2020. All enrolled patients are the laboratory confirmed COVID-19 pneumonia cases according to the criteria reported previously. A total of 123 patients were analyzed for their Clinical records, laboratory results including the diagnosis of HBV infection and liver function. Among 123 confirmed COVID-19 patients, the mean age was 51 years old and 59.3% were females (73/123). Fifteen were previously HBV infected patients, 66.7% of them were males (10/15), patients with HBV infection appeared to have a higher incidence of liver cirrhosis and an increased level of total bilirubin. Seven (46.7%) patients with HBV infection were defined as severe cases, while the severity rate was 24.1% for the patients without HBV infection (26/108). The mortality of patients with HBV infection was 13.3% (2/15) compared to 2.8% (3/108) for the patients without HBV infection.

Conclusions

SARS-CoV-2 infection may cause Live function damage in COVID-19 cases and the patients with HBV infection are likely to have more severe disease outcome.
Core Outcome Set for Clinical Trials of COVID-19 based on Traditional Chinese and Western Medicine
Authors: Qiu Ruijin , Zhao Chen , Liang Tengxiao , Hao Xuezeng , Huang Ya , Zhang Xiaoyu , Chen Zhao , Wei Xuxu , Zhao Mengzhu , Zhong Changming , Hu Jiayuan , Li Min , Han Songjie , He Tianmai , Chen Jing , Shang Hongcai
Published: March 2020

Background

Development of a core outcome set (COS) for clinical trials for COVID-19 is urgent because of the pandemic wreaking havoc worldwide and the heterogeneity of outcomes in clinical trials.

Methods

A preliminary list of outcomes were developed after a systematic review of protocols of clinical trials for COVID-19. Then, two rounds of the Delphi survey were conducted. Stakeholders were traditional Chinese medicine (TCM) experts, Western medicine (WM) experts, nurses and the public. Patients with confirmed COVID-19 were also invited to participate in a questionnaire written in understandable language. Frontline clinicians, as well as nurse, methodologist, evidence based-medicine researcher, and staff from the Chinese Clinical Trials Registry participated by video conference to vote.

Results

Ninety-seven eligible study protocols were identified from 160 clinical trials. Seventy-six outcomes were identified from TCM clinical trials and 126 outcomes were identified from WM clinical trials. Finally, 145 outcomes were included in the first round of the Delphi survey. Then, a COS for clinical trials of TCM and WM was developed. The COS include clinical outcomes (recovery/improvement/progression/death), etiology (SARS-CoV-2 nucleic-acid tests, viral load), inflammatory factor (C-reactive protein), vital signs (temperature, respiration), blood and lymphatic-system parameters (lymphocytes, virus antibody), respiratory outcomes (Pulmonary imaging, blood oxygen saturation, PaO2/FiO2 ratio, arterial blood gas analysis, mechanical ventilation, oxygen intake, pneumonia severity index), clinical efficacy (prevalence of preventing patients with mild-to-moderate disease progressing to severe disease), symptoms (clinical symptom score). Outcomes were recommended according to different types of disease. Outcome measurement instrument/definition were also recommended.

Conclusion

A COS for COVID-19 may improve consistency of outcome reporting in clinical trials.
Spectral Clustering of Risk Score Trajectories Stratifies Sepsis Patients by Clinical Outcome and Interventions Received
Authors: Liu Ran , Greenstein Joseph L. , Fackler James C. , Bembea Melania M. , Winslow Raimond L.
Published: March 2020

Sepsis is not a monolithic disease, but a loose collection of symptoms with a diverse range of outcomes. The diverse patterns of sepsis make guideline-driven treatment difficult, as guidelines are based on the needs of the “average” patient. Thus, stratification and subtyping of sepsis patients is of interests, with the ultimate goal of identifying groups of patients who respond similarly to treatment. To do this, we examine the temporal evolution of patient state using our previously-published method for computing patient risk of transition into septic shock. The application of spectral clustering to risk score trajectories reveals that these trajectories diverge into four distinct clusters in the time window following early prediction of septic shock. Patients in these clusters stratify by outcome: the highest-risk group has a 76.5% prevalence of septic shock and 43% mortality, whereas the lowest-risk group has a 10.4% prevalence of septic shock and 18% mortality. These clusters differ also in treatments received, as well as median time to septic shock onset. Data analyses reveal the existence of a rapid (30-60 min) transition in risk at the time of threshold crossing. We hypothesize that this rapid transition occurs as a result of an abrupt failure of compensatory biological systems to cope with infection, resulting in a bifurcation of low to high risk. Such a collapse in compensation, we believe, represents the true onset of septic shock. Thus, what we previously referred to as the pre-shock state represents a potential new data-driven definition of septic shock.
A Social Network Model of the COVID-19 Pandemic
Authors: Zhao Pei Jun
Published: March 2020

In the COVID-19 coronavirus pandemic, currently vaccines and specific anti-viral treatment are not yet available. Thus, preventing viral transmission by case isolation, quarantine, and social distancing is essential to slowing its spread. Here we model social networks using weighted graphs, where vertices represent individuals and edges represent contact. As public health measures are implemented, connectivity in the graph decreases, resulting in lower effective reproductive numbers, and reduced viral transmission. For COVID-19, model parameters were derived from the coronavirus epidemic in China, validated by epidemic data in Italy, then applied to the United States. We calculate that, in the U.S., the public is able to contain viral transmission by limiting the average number of contacts per person to less than 7 unique individuals over each 5 day period. This increases the average social distance between individuals to 10 degrees of separation.
Population-Level Mortality Rates from Novel Coronavirus (COVID-19) in South Korea
Authors: Soneji Samir , Beltrán-Sánchez Hiram , Yang JaeWon , Mann Caroline
Published: March 2020

Background

South Korea was among the first countries to report a case of the novel coronavirus (COVID-19) outside of China. As of 22 March, 2020, South Korea reported 8897 confirmed cases of and 104 deaths from COVID-19.

Methods

We collected the number of laboratory-confirmed cases and deaths in South Korea from the World Health Organization (as of 21 March, 2020) and case distribution and fatality rates by age from the Korean Center for Disease Control and Prevention (as of 22 March, 2020). We estimated population-level mortality rates by fitting a negative binomial regression model with the number of deaths as the outcome and population by age as an offset. We then calculated the age-standardized death rate (ASDR) based on the current COVID-19 figures and for alternative scenarios of increased prevalence.

Findings

The COVID-19 population-level mortality rate (per 100,000 person-years) increased with age: from 0.1 deaths among 30-39 year olds to 9.5 deaths among ≥80 year olds. The ASDR (per 100,000 person-years) was 0.8 deaths. The ASDR would increase to 52.0 deaths at a 1% prevalence (becoming the third leading cause of death) and 155.9 deaths at 3% prevalence (becoming the leading cause of death).

Interpretation

Currently, the population-level mortality burden of COVID-19 in South Korea, as measured by the ASDR, was relatively low compared to other causes of death partly due to the low prevalence of COVID-19. If the prevalence increases from another outbreak, the mortality burden could increase substantially and surpass other leading causes.

Funding

Grant P2C-HD041022, California Center for Population Research, University of California, Los Angeles (US NIH).
Real-world structure facilitates the rapid emergence of scene category information in visual brain signals
Authors: Kaiser Daniel , Häberle Greta , Cichy Radoslaw M.
Published: March 2020

In everyday life, our visual surroundings are not arranged randomly, but structured in predictable ways. Although previous studies have shown that the visual system is sensitive to such structural regularities, it remains unclear whether the presence of an intact structure in a scene also facilitates the cortical analysis of the scene’s categorical content. To address this question, we conducted an EEG experiment during which participants viewed natural scene images that were either “intact” (with their quadrants arranged in typical positions) or “jumbled” (with their quadrants arranged into atypical positions). We then used multivariate pattern analysis to decode the scenes’ category from the EEG signals (e.g., whether the participant had seen a church or a supermarket). The category of intact scenes could be decoded rapidly within the first 100ms of visual processing. Critically, within 200ms of processing category decoding was more pronounced for the intact scenes compared to the jumbled scenes, suggesting that the presence of real-world structure facilitates the extraction of scene category information. No such effect was found when the scenes were presented upside-down, indicating that the facilitation of neural category information is indeed linked to a scene’s adherence to typical real-world structure, rather than to differences in visual features between intact and jumbled scenes. Our results demonstrate that early stages of categorical analysis in the visual system exhibit tuning to the structure of the world that may facilitate the rapid extraction of behaviorally relevant information from rich natural environments.
Topoisomerase III-ß is required for efficient replication of positive-sense RNA viruses
Authors: Prasanth K. Reddisiva , Hirano Minato , Fagg W. Samuel , McAnarney Eileen T. , Shan Chao , Xie Xuping , Hage Adam , Pietzsch Colette A. , Bukreyev Alexander , Rajsbaum Ricardo , Shi Pei-Yong , Bedford Mark T. , Bradrick Shelton S. , Menachery Vineet , Garcia-Blanco Mariano A.
Published: March 2020

Based on genome-scale loss-of-function screens we discovered that Topoisomerase III-ß (TOP3B), a human topoisomerase that acts on DNA and RNA, is required for yellow fever virus and dengue virus-2 replication. Remarkably, we found that TOP3B is required for efficient replication of all positive-sense-single stranded RNA viruses tested, including SARS-CoV-2. While there are no drugs that specifically inhibit this topoisomerase, we posit that TOP3B is an attractive anti-viral target.
Lactate dehydrogenase, a Risk Factor of Severe COVID-19 Patients: A Retrospective and Observational Study
Authors: Han Yi , Zhang Haidong , Mu Sucheng , Wei Wei , Jin Chaoyuan , Xue Yuan , Tong Chaoyang , Zha Yunfei , Song Zhenju , Gu Guorong
Published: March 2020

BACKGROUND

The World Health Organization (WHO) has recently declared coronavirus disease 2019 (COVID-19) a public health emergency of global concern. Updated analysis of cases might help identify the characteristic and risk factors of the illness severity.

METHODS

We extracted data regarding 47 patients with confirmed COVID-19 from Renmin Hospital of Wuhan University between February 1 and February 18, 2020. The degree of severity of COVID-19 patients (severe vs. non-severe) was defined at the time of admission according to American Thoracic Society (ATS) guidelines for community-acquired pneumonia (CAP).

RESULTS

The median age was 64.91 years, 26 cases (55.31%) were male of which, and 70.83% were severe cases. Severe patients had higher APACHE II (9.92 vs 4.74) and SOFA (3.0 vs 1.0) scores on admission, as well as the higher PSI (86.13 vs 61.39), Curb-65 (1.14 vs 0.48) and CT semiquantitative scores (5.0 vs 2.0) when compared with non-severe patients. Among all univariable parameters, APACHE II, SOFA, lymphocytes, CRP, LDH, AST, cTnI, BNP, et al were significantly independent risk factors of COVID-19 severity. Among which, LDH was most positively related both with APACHE II (R = 0.682) and SOFA (R = 0.790) scores, as well as PSI (R = 0.465) and CT (R = 0.837) scores. To assess the diagnostic value of these selected parameters, LDH (0.9727) had maximum sensitivity (100.00%) and specificity (86.67%), with the cutoff value of 283. As a protective factor, lymphocyte counts less than 1.045 ⨯ 109 /L showed a good accuracy for identification of severe patients with AUC = 0.9845 (95%CI 0.959-1.01), the maximum specificity (91.30%) and sensitivity (95.24%). In addition, LDH was positively correlated with CRP, AST, BNP and cTnI, while negatively correlated with lymphocyte cells and its subsets, including CD3+, CD4+ and CD8+ T cells (P < 0.01).

CONCLUSIONS

This study showed that LDH could be identified as a powerful predictive factor for early recognition of lung injury and severe COVID-19 cases. And importantly, lymphocyte counts, especially CD3+, CD4+, and CD8+ T cells in the peripheral blood of COVID-19 patients, which was relevant with serum LDH, were also dynamically correlated with the severity of the disease.

FUNDING

Key Project of Shanghai Municipal Health Bureau (2016ZB0202)
Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse
Authors: Kenney Patrick , Chan Benjamin K , Kortright Kaitlyn , Cintron Margaret , Havill Nancy , Russi Mark , Epright Jaqueline , Lee Lorraine , Balcezak Thomas , Martinello Richard
Published: March 2020

Abstract
Reprocessing of used N95 respirators may ameliorate supply chain constraints during the COVID-19 pandemic and provide a higher filtration crisis alternative. The FDA Medical Countermeasures Initiative previously funded a study of HP vapor decontamination of respirators using a Clarus C system (Bioquell, Horsham, PA) which normally is used to fumigate hospital rooms. The process preserved respirator function, but it is unknown if HP vapor would be virucidal since respirators have porous fabric that may harbor virus.

We evaluated the virucidal activity of HP vapor using a BQ-50 system (Bioquell, Horsham, PA) after inoculating 3M 1870 N95 respirators (3M, St. Paul, MN) with 3 aerosolized bacteriophage that are a reasonable proxy for SARS-CoV-2. Inoculation resulted in contamination of the respirator with 9.87e4 plaque forming units (PFU) of phage phi-6, 4.17e7 PFU of phage T7 and 1.35e7 PFU of phage T1. Respirators were reprocessed with BQ-50 with a long aeration phase to reduce HP vapors. Virucidal activity was measured by a standard plaquing assay prior to and after sterilization. A single HP vapor cycle resulted in complete eradication of phage from masks (limit of detection 10 PFU, lower than the infectious dose of the majority of respiratory viral pathogens). After 5 cycles, the respirators appeared similar to new with no deformity.

Use of a Bioquell machine can be scaled to permit simultaneous sterilization of a large number of used but otherwise intact respirators. HP vapor reprocessing may ease shortages and provide a higher filtration crisis alternative to non-NIOSH masks.
Anaesthetic managment and clinical outcomes of parturients with COVID-19: a multicentre, retrospective, propensity score matched cohort study
Authors: Zhang Yuan , Chen Rong , Wang Jie , Gong Yuan , Zhou Qin , Cheng Hui-hui , Xia Zhong-yuan , Chen Xiangdong , Meng Qing-tao , Ma Daqing
Published: March 2020

Objective

To analyse the clinical features of COVID-19 parturients, and to compare anaesthetic regimen and clinical outcomes in parturients with or without COVID-19 undergoing cesarean delivery.

Method

Data were extracted from the electronic medical record of 3 medical institutions in Hubei Province, China, from June 1, 2019 to March 20, 2020 according to inclusion and exclusion criteria. After propensity score matching with demographics, the clinical and laboratory characteristics of parturients with or without COVID-19 were analysed. The anaesthetic regimen and clinical outcomes of themselves and their infants were compared in these two groups of parturients.

Results

A total of 1,588 patients without SARS-CoV-2 infection undergoing cesarean delivery were retrospectively included. After achieving a balanced cohort through propensity score matching, 89 patients (COVID-19 group), who were diagnosed with COVID-19 by SARS-CoV-2 nucleic acid test and CT scan matched with 173 patients without COVID-19 (Control group). The SARS-CoV-2 infected parturients in the early stages of COVID-19 outbreak was much more than during the later stage. The main clinical characteristics of parturients with COVID-19 were fever (34.8%), cough (33.7%), an increased plasma CRP (52.8%) and a decreased lymphocyte counting (33.7%). A high rate of emergency and a high incidence of anaesthesia-related complications, such as pharyngalgia, multiple puncture, intraoperative hypotension, nausea, vomiting, vertigo and chills in the COVID-19 parturients. In addition, the parturients with COVID-19 had a long duration of operation and hospital stay, and an increased intraoperative oxytocin utilization and postoperative oxygen therapy. The newborns from the SARS-CoV-2 infected mothers, who received general anaesthesia, had a high risk of Apgar score ≤ 8 at 1 and 5 minutes after delivery and a higher rate of neonatal intensive care unit (NICU) admission.

Conclusions

Anaesthesia-related complications occur more frequently in the COVID-19 parturients and their newborns have a high risk of distress.
Mechanical Ventilator Milano (MVM): A Novel Mechanical Ventilator Designed for Mass Scale Production in Response to the COVID-19 Pandemics
Authors: Galbiati C. , Bonivento W. , Caravati M. , De Cecco S. , Dinon T. , Fiorillo G. , Franco D. , Gabriele F. , Kendziora C. L. , Kochanek I. , Ianni An. , McDonald A. , Tosatti L. Molinari , Malosio M. , Minuzzo D. , Pordes S. H. , Prini A. , Razeto A. , Razeti M. , Rescigno M. , Sablone D. , Scapparone E. , Testera G. , Tartaglia R. , Wang H. , Zardoni A.
Published: March 2020

We present here the design of the Mechanical Ventilator Milano (MVM), a novel mechanical ventilator designed for mass scale production in response to the COVID-19 pandemics, to compensate for the dramatic shortage of such ventilators in many countries. This ventilator is an electro-mechanical equivalent of the old, reliable Manley Ventilator. Our design is optimized to permit large sale production in short time and at a limited cost, relying on off-the-shelf components, readily available worldwide from hardware suppliers. Operation of the MVM requires only a source of compressed oxygen (or compressed medical air) and electrical power. The MVM control and monitoring unit can be connected and networked via WiFi so that no additional electrical connections are necessary other than the connection to the electrical power.

At this stage the MVM is not a certified medical device. Construction of the first prototypes is starting with a team of engineers, scientists and computing experts. The purpose of this paper is to disseminate the conceptual design of the MVM broadly and to solicit feed-back from the scientific and medical community to speed the process of review, improvement and possible implementation.