bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying treatment effects of hydroxychloroquine and azithromycin for COVID-19: a secondary analysis of an open label non-randomized clinical trial
Authors: Lover Andrew A.
Published: March 2020

Abstract

Human infections with a novel coronavirus (SARS-CoV-2) were first identified via syndromic surveillance in December of 2019 in Wuhan China. Since identification, infections (coronavirus disease-2019; COVID-19) caused by this novel pathogen have spread globally, with more than 250,000 confirmed cases as of March 21, 2020. An open-label clinical trial has just concluded, suggesting improved resolution of viremia with use of two existing therapies: hydroxychloroquine (HCQ) as monotherapy, and in combination with azithromycin (HCQ-AZ). [3, 4].

The results of this important trial have major implications for global policy in the rapid scale-up and response to this pandemic. The authors present results with p-values for differences in proportions between the study arms, but their analysis is not able to provide effect size estimates.

To address this gap, more modern analytical methods including survival models, have been applied to these data, and show modest to no impact of HCQ treatment, with more significant effects from the HCQ-AZ combination, potentially suggesting a role for co-infections in COVID-19 pathogenesis.

The trial of Gautret and colleagues, with consideration of the effect sizes, and p-values from multiple models, does not provide sufficient evidence to support wide-scale rollout of HCQ monotherapy for the treatment of COVID-19; larger randomized studies should be considered. These data also suggest further randomized-controlled studies of HCQ-AZ combination therapy should be undertaken.
Critical Care for Severe COVID-19: A Population-based Study from a Province with Low Case-fatality Rate in China
Authors: Liao Xuelian , Chen Hong , Wang Bo , Li Zhen , Zhang Zhongwei , Li Weimin , Liang Zongan , Tang Jin , Wang Jian , Shi Rui , Zhen Xiangde , Wang Maojuan , Lei Xianying , Gong Yu , Lv Sheng , Jia Chao , Chen Li , Shang Juan , Yang Min , Wei Hailong , Zhang Yuanjun , Yang Xiong , Shen Huaqiang , Xiao Xianhua , Yang Jie , Liu Chang , Wu Qin , Wang Wen , Yang Jin , Yin Wanhong , Xie Xiaoqi , Tian Yongming , Liu Huan , Shuai Bingxing , Zhang Wei , Song Xiangrong , Jin Xiaodong , Kang Yan
Published: March 2020

Background

Data regarding critical care for patients with severe COVID-19 are limited. We aimed to describe the clinical course, multi-strategy management, and respiratory support usage for the severe COVID-19 at the provincial level.

Methods

Using data from Sichuan Provincial Department of Health and the multicentre cohort study, all microbiologically confirmed COVID-19 patients in Sichuan who met the national severe criteria were included and followed-up from the day of inclusion (D1), until discharge, death, or the end of the study.

Findings

Out of 539 COVID-19 patients, 81 severe cases (15.0%) were identified. The median (IQR) age was 50 (39-65) years, 37% were female, and 53.1% had chronic comorbidities. All severe cases were identified before requiring mechanical ventilation and treated in the intensive care units (ICUs), among whom 51 (63.0%) were treated in provisional ICUs and 77 patients (95.1%) were admitted by D1. On D1, 76 (93.8%) were administered by respiratory support, including 55 (67.9%) by conventional oxygen therapy (COT), 8 (9.9%) by high-flow nasal cannula (HFNC) and 13 (16.0%) by non-invasive ventilation (NIV). By D28, 53 (65.4%) were discharged, three (3.7%) were deceased, and 25 (30.9%) were still hospitalized. COT, administered to 95.1% of the patients, was the most commonly used respiratory support and met 62.7% of the respiratory support needed, followed by HFNC (19.3%), NIV ventilation (9.4%) and IV 8.5%.

Interpretation

The multi-strategy management for severe COVID-19 patients including early identification and timely critical care may contribute to the low case-fatailty. Preparation of sufficient conventional oxygen equipment should be prioritized.

Trial registration number

ChiCTR2000029758.
The NKG2D ligand ULBP4 is not expressed by human monocytes
Authors: Lazarova Mariya , Kim Younghoon , Steinle Alexander
Published: March 2020

The C-type lectin-like receptor NKG2D contributes to the immunosurveillance of virally infected and malignant cells by cytotoxic lymphocytes. A peculiar and puzzling feature of the NKG2D-based immunorecognition system is the high number of ligands for this single immunoreceptor. In humans, there are a total of eight NKG2D ligands (NKG2DL) comprising two members of the MIC (MICA, MICB) and six members of the ULBP family of glycoproteins (ULBP1 to ULBP6). While MICA has been extensively studied with regard to its biochemistry, cellular expression and function, very little is known about the NKG2DL ULBP4. This is, at least in part, due to its rather restricted expression by very few cell lines and tissues. Recently, constitutive ULBP4 expression by human monocytes was reported, questioning the view of tissue-restricted ULBP4 expression. Here, we scrutinized ULBP4 expression by human peripheral blood mononuclear cells and monocytes by analyzing ULBP4 transcripts and ULBP4 surface expression. In contrast to MICA, there was no ULBP4 expression detectable, neither by freshly isolated monocytes nor by PAMP-activated monocytes. However, a commercial antibody erroneously indicated surface ULBP4 on monocytes due to a non-ULBP4-specific binding activity, emphasizing the critical importance of validated reagents for life sciences. Collectively, our data show that ULBP4 is not expressed by monocytes, and likely also not by other peripheral blood immune cells, and therefore exhibits an expression pattern rather distinct from other human NKG2DL.
Air Pollution Reduction and Mortality Benefit during the COVID-19 Outbreak in China
Authors: Chen Kai , Wang Meng , Huang Conghong , Kinney Patrick L. , Anastas Paul T.
Published: March 2020

To control the novel coronavirus disease (COVID-19) outbreak, China undertook stringent traffic restrictions and self-quarantine measures. We herein examine the change in air pollution levels and the potentially avoided cause-specific mortality during this massive population quarantine episode. We found that, due to the quarantine, NO2 dropped by 22.8 µg/m3 and 12.9 µg/m3 in Wuhan and China, respectively. PM2.5 dropped by 1.4 µg/m3 in Wuhan but decreased by 18.9 µg/m3 across 367 cities. Our findings show that interventions to contain the COVID-19 outbreak led to air quality improvements that brought health benefits which outnumbered the confirmed deaths due to COVID-19 in China
Anaesthesia and infection control in cesarean section of pregnant women with coronavirus disease 2019 (COVID-19)
Authors: Yue LinLi , Han Lefei , Li Qiannan , Zhong Min , Wang Jun , Wan Zhenzhen , Chu Caijuan , Zeng Yi , Peng Min , Yang Lin , Li Na
Published: March 2020

Background

The coronavirus disease 2019 (COVID-19) first emerged in Wuhan, China, and soon caused an ongoing pandemic globally. In this study we conducted a retrospective study to evaluate the safety and efficacy of combined spinal-epidural anaesthesia (CSEA) and infection control measures on perinatal care quality of 30 pregnant women with confirmed and suspected COVID-19.

Methods

Individual demographic data, clinical outcomes, laboratory investigations of pregnant women and their newborns were collected from electronic medical records of the Maternal and Children Health Hospital of Hubei Province, during January 24 to February 29, 2020. Anaesthesia and surgery results were compared between pregnant women with confirmed and suspected COVID-19 infection.

Results

Using CSEA in cesarean section was effective and safe for pregnant women with confirmed and suspected COVID-19 infection. Administration of dezocine and morphine was effective as postoperative analgesia, and well tolerated in COVID-19 patients. The assessment of surgery outcomes also showed similar results in both confirmed and suspected cases. No respiratory failure nor distress were found in the mothers with confirmed COVID-19 infection and their neonates. None of these patients experienced severe obstetric complications related to anaesthesia and surgeries. No COVID-19 infection was reported in the neonates born to the mothers with confirmed COVID-19 infection and healthcare workers in these operations.

Conclusions

In cesarean section for pregnant women with COVID-19 infection, CSEA was safe and efficient in achieving satisfactory obstetrical anaesthesia and postoperative analgesia. No cross-infection occurred in the HCWs working in these operations.
Modelling SARS-CoV-2 Dynamics: Implications for Therapy
Authors: Kim Kwang Su , Ejima Keisuke , Ito Yusuke , Iwanami Shoya , Ohashi Hirofumi , Koizumi Yoshiki , Asai Yusuke , Nakaoka Shinji , Watashi Koichi , Thompson Robin N , Iwami Shingo
Published: March 2020

The scientific community is focussed on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data collected from the same specimen (throat / nasal swabs or nasopharyngeal / sputum / tracheal aspirate), we compare within-host dynamics for patients infected in the current outbreak with analogous dynamics for MERS-CoV and SARS-CoV infections. Our quantitative analyses revealed that SARS-CoV-2 infection dynamics are more severe than those for mild cases of MERS-CoV, but are similar to severe cases, and that the viral dynamics of SARS-CoV infection are similar to those of MERS-CoV in mild cases but not in severe case. Consequently, SARS-CoV-2 generates infection dynamics that are more severe than SARS-CoV. Furthermore, we used our viral dynamics model to predict the effectiveness of unlicensed drugs that have different methods of action. The effectiveness was measured by AUC of viral load. Our results indicated that therapies that block de novo infections or virus production are most likely to be effective if initiated before the peak viral load (which occurs around three days after symptom onset on average), but therapies that promote cytotoxicity are likely to have only limited effects. Our unique mathematical approach provides insights into the pathogenesis of SARS-CoV-2 in humans, which are useful for development of antiviral therapies.
Containment measures limit environmental effects on COVID-19 early outbreak dynamics
Authors: Ficetola Gentile Francesco , Rubolini Diego
Published: March 2020

Environmental factors are well known to affect spatio-temporal patterns of infectious disease outbreaks, but whether the recent rapid spread of COVID-19 across the globe is related to local environmental conditions is highly debated. We assessed the impact of environmental factors (temperature, humidity and air pollution) on the global patterns of COVID-19 early outbreak dynamics during January-May 2020, controlling for several key socio-economic factors and airport connections. We showed that during the earliest phase of the global outbreak (January-March), COVID-19 growth rates were non-linearly related to climate, with fastest spread in regions with a mean temperature of ca. 5 degrees, and in the most polluted regions. However, environmental effects faded almost completely when considering later outbreaks, in keeping with the progressive enforcement of containment actions. Accordingly, COVID-19 growth rates consistently decreased with stringent containment actions during both early and late outbreaks. Our findings indicate that environmental drivers may have played a role in explaining the early variation among regions in disease spread. With limited policy interventions, seasonal patterns of disease spread might emerge, with temperate regions of both hemispheres being most at risk of severe outbreaks during colder months. Nevertheless, containment measures play a much stronger role and overwhelm impacts of environmental variation, highlighting the key role for policy interventions in curbing COVID-19 diffusion within a given region. If the disease will become seasonal in the next years, information on environmental drivers of COVID-19 can be integrated with epidemiological models to inform forecasting of future outbreak risks and improve management plans.
A demographic adjustment to improve measurement of COVID-19 severity at the developing stage of the pandemic
Authors: Bignami-Van Assche Simona , Ghio Daniela
Published: March 2020

The need for accurate statistics has never been felt so deeply as the novel COVID-19 pathogen spreads around the world and quantifying its severity is a primary clinical and public health issue. In Italy, the magnitude and increasing trend of the case-fatality risk (CFR) is fueling the already high levels of public alarm. In this paper, we highlight that the widely used crude CFR is an inaccurate measure of the disease severity since the pandemic is still unfolding. With the goal to improve its comparability over time and across countries at this stage, we then propose a demographic adjustment of the CFR that addresses the bias arising from differential case ascertainment by age. When applied to publicly released data for Italy, we show that until March 16 our adjusted CFR was similar to that of Wuhan – the most affected Chinese region, where COVID-19 has now been contained. This indicates that our adjusted CFR improves its comparability over time, making an important tool to chart the course of the COVID-19 pandemic across countries. Since March 16, the Italian COVID-19 outbreak has entered a new phase, with the northern and southern regions following different trajectories. As a result, our adjusted CFR has been increasing between March 16 and March 20. Data at the subnational level are needed to correctly assess the disease severity in the country at this stage.
Spatio-temporal propagation of COVID-19 pandemics
Authors: Gross Bnaya , Zheng Zhiguo , Liu Shiyan , Chen Xiaoqi , Sela Alon , Li Jianxin , Li Daqing , Havlin Shlomo
Published: March 2020

The new coronavirus known as COVID-19 is spread world-wide since December 2019. Without any vaccination or medicine, the means of controlling it are limited to quarantine and social distancing. Here we study the spatio-temporal propagation of the first wave of the COVID-19 virus in China and compare it to other global locations. We provide a comprehensive picture of the spatial propagation from Hubei to other provinces in China in terms of distance, population size, and human mobility and their scaling relations. Since strict quarantine has been usually applied between cities, more insight about the temporal evolution of the disease can be obtained by analyzing the epidemic within cities, especially the time evolution of the infection, death, and recovery rates which affected by policies. We study and compare the infection rate in different cities in China and provinces in Italy and find that the disease spread is characterized by a two-stages process. At early times, at order of few days, the infection rate is close to a constant probably due to the lack of means to detect infected individuals before infection symptoms are observed. Then at later times it decays approximately exponentially due to quarantines. The time evolution of the death and recovery rates also distinguish between these two stages and reflect the health system situation which could be overloaded.
Modeling COVID-19 epidemics in an Excel spreadsheet: Democratizing the access to first-hand accurate predictions of epidemic outbreaks
Authors: Alvarez Mario Moisés , González-González Everardo , Trujillo-de Santiago Grissel
Published: March 2020

COVID-19, the first pandemic of this decade and the second in less than 15 years, has harshly taught us that viral diseases do not recognize boundaries; however, they truly do discriminate between aggressive and mediocre containment responses.

We present a simple epidemiological model that is amenable to implementation in Excel spreadsheets and sufficiently accurate to reproduce observed data on the evolution of the COVID-19 pandemics in different regions (i.e., Italy, Spain, and New York City (NYC)). We also show that the model can be adapted to closely follow the evolution of COVID-19 in any large city by simply adjusting two parameters related to (a) population density and (b) aggressiveness of the response from a society/government to epidemics. Moreover, we show that this simple epidemiological simulator can be used to assess the efficacy of the response of a government/society to an outbreak.

The simplicity and accuracy of this model will greatly contribute to democratizing the availability of knowledge in societies regarding the extent of an epidemic event and the efficacy of a governmental response.
Multiple-Input Deep Convolutional Neural Network Model for COVID-19 Forecasting in China
Authors: Huang Chiou-Jye , Chen Yung-Hsiang , Ma Yuxuan , Kuo Ping-Huan
Published: March 2020

COVID-19 is spreading all across the globe. Up until March 23, 2020, the confirmed cases in 173 countries and regions of the globe had surpassed 346,000, and more than 14,700 deaths had resulted. The confirmed cases outside of China had also reached over 81,000, with over 3,200 deaths. In this study, a Convolutional Neural Network (CNN) was proposed to analyze and predict the number of confirmed cases. Several cities with the most confirmed cases in China were the focus of this study, and a COVID-19 forecasting model, based on the CNN deep neural network method, was proposed. To compare the overall efficacies of different algorithms, the indicators of mean absolute error and root mean square error were applied in the experiment of this study. The experiment results indicated that compared with other deep learning methods, the CNN model proposed in this study has the greatest prediction efficacy. The feasibility and practicality of the model in predicting the cumulative number of COVID-19 confirmed cases were also verified in this study.
Radiographic Findings and other Predictors in Adults with Covid-19
Authors: Li Kaiyan , Chen Dian , Chen Shenchong , Feng Yuchen , Chang Chenli , Wang Zi , Wang Nan , Zhen Guohua
Published: March 2020

As of March 20, 2020, there were 234,073 confirmed cases of coronavirus disease 2019 (Covid-19) and 9,840 deaths worldwide 1. Older age and elevated d-dimer are reported risk factors for Covid-19 2,3. However, whether early radiographic change is a predictor of fatality remains unknown. We retrospectively reviewed records of all laboratory-confirmed patients admitted to a quarantine unit at Tongji Hospital, a large regional hospital in Wuhan, China, between January 31 and March 5, 2020. The Tongji Hospital ethics committee approved this study.
Angular changes in implants placed in the anterior maxillae of adults: A cephalometric pilot study
Authors: Feher Balazs , Gruber Reinhard , Gahleitner Andre , Celar Ales , Necsea Philipp Luciano , Ulm Christian , Kuchler Ulrike
Published: March 2020

Objectives

Completion of adolescent growth represents the earliest time point for implant placement, yet craniofacial growth persists into adulthood and may affect implant position. We aimed to assess whether implants placed in the anterior maxillae of adults show angular changes.

Methods

We conducted a cephalometric pilot study in postpubertal patients with no growth disorders, skeletal malformations, or parafunctions. The patients received a single implant in the anterior maxilla and no orthodontic or orthognathic treatment afterwards. We measured angular changes on cephalograms taken immediately and at least 5 years postoperatively in a standardized setting.

Results

In a total of 21 patients (30.2 ± 11.5 years at surgery) after a mean follow-up time of 8.6 ± 1.3 years, 62% of implants showed counterclockwise rotations (1.8 ± 1.0 degrees) and 19% of implants showed clockwise rotations (2.4 ± 1.1 degrees). Angular changes were more frequent in males (100% vs. 58%) and patients under 30 at surgery (85% vs. 63%). Mean absolute differences were larger in males (1.8 ± 1.0 degrees vs. 1.3 ± 1.4 degrees) and patients under 30 at surgery (1.5 ± 1.4 degrees vs. 1.1 ± 1.4 degrees). Regression analysis did not identify explanatory factors for the observed changes.

Conclusions

Implants placed in the anterior maxillae of adults show modest angular changes over time.

Clinical relevance

Changes in implant angles have potential functional and esthetic consequences.
Haplotype networks of SARS-CoV-2 infections in the Diamond Princess cruise ship outbreak
Authors: Sekizuka Tsuyoshi , Itokawa Kentaro , Kageyama Tsutomu , Saito Shinji , Takayama Ikuyo , Asanuma Hideki , Nao Naganori , Tanaka Rina , Hashino Masanori , Takahashi Takuri , Kamiya Hajime , Yamagishi Takuya , Kakimoto Kensaku , Suzuki Motoi , Hasegawa Hideki , Wakita Takaji , Kuroda Makoto
Published: March 2020

The Diamond Princess (DP) cruise ship was put under quarantine offshore Yokohama, Japan, after a passenger who disembarked in Hong Kong was confirmed as a COVID-19 case. We performed whole genome sequencing of SARS-CoV-2 directly from PCR-positive clinical specimens and conducted a haplotype network analysis of the outbreak. All tested isolates exhibited a transversion at G11083T, suggesting that SARS-CoV-2 dissemination on the DP originated from a single introduction event before the quarantine started. Although further spreading might have been prevented by quarantine, some progeny clusters were linked to transmission through mass-gathering events in the recreational areas and direct transmission among passengers who shared cabins during the quarantine. This study demonstrates the usefulness of haplotype network analysis in identifying potential infection routes.

One Sentence Summary

Genome-based tracing of SARS-CoV-2 infections among passengers and crews in Diamond Princess cruise ship during the quarantine
Experimental erosion of microbial diversity decreases soil CH4consumption rates
Authors: Schnyder Elvira , Bodelier Paul L.E. , Hartmann Martin , Henneberger Ruth , Niklaus Pascal A.
Published: March 2020

Biodiversity-ecosystem functioning (BEF) experiments have predominantly focused on communities of higher organisms, in particular plants, with comparably little known to date about the relevance of biodiversity for microbially-driven biogeochemical processes. Methanotrophic bacteria play a key role in Earth’s methane (CH4) cycle by removing atmospheric CH4and reducing emissions from methanogenesis in wetlands and landfills. Here, we used a dilution-to-extinction approach to simulate diversity loss in a methanotrophic landfill cover soil community. Combining analyses of CH4flux and community structure, we found a linear decrease of CH4oxidation rates with the number of taxonomic units lost. This effect was independent of community size, consistent over the three-month study, and occurred in relatively diverse communities, challenging the notion of high functional redundancy mediating high resistance to diversity erosion in natural microbial systems. The effects we report resemble the ones for higher organisms, suggesting that BEF-relationships are universal across taxa and spatial scales.
Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein
Authors: Lupala Cecylia S. , Li Xuanxuan , Lei Jian , Chen Hong , Qi Jianxun , Liu Haiguang , Su Xiao-dong
Published: March 2020

A novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 pneumonia, an outbreak started near the end of 2019 in Wuhan, China. The SARS-CoV-2 was found to be closely related to the SARS-CoV, based on the genomic analysis. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2, initiated by the binding of the spike protein to the human ACE2. Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The predicted model is highly consistent with the experimentally determined complex structures. Besides the binding interface reported in the crystal structures, new plausible binding poses were revealed from all-atom MD simulations. The simulation data helped identify critical residues at the complex interface and provided more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Two mutants mimicking rat ACE2 were modeled to study the mutation effects on RBD binding to ACE2. The simulations showed that the N-terminal helix and the K353 are very important for the tight binding of the complex, the mutants were found to alter the binding modes of the CoV2-RBD to ACE2.
In-Silico evidence for two receptors based strategy of SARS-CoV-2
Authors: Milanetti Edoardo , Miotto Mattia , Rienzo Lorenzo Di , Monti Michele , Gosti Giorgio , Ruocco Giancarlo
Published: March 2020

We propose a novel numerical method able to determine efficiently and effectively the relationship of complementarity between portions of protein surfaces. This innovative and general procedure, based on the representation of the molecular iso-electron density surface in terms of 2D Zernike polynomials, allows the rapid and quantitative assessment of the geometrical shape complementarity between interacting proteins, that was unfeasible with previous methods. We first tested the method with a large dataset of known protein complexes obtaining an overall area under the ROC curve of 0.76 in the blind recognition of binding sites and then applied it to investigate the features of the interaction between the Spike protein of SARS-CoV-2 and human cellular receptors. Our results indicate that SARS-CoV-2 uses a dual strategy: its spike protein could also interact with sialic acid receptors of the cells in the upper airways, in addition to the known interaction with Angiotensin-converting enzyme 2.
A competency-based approach to pass/fail decisions in an objective structured clinical examination: An observational study
Authors: Alkhateeb Nazdar Ezzaddin , Al-Dabbagh Ali , Mohammed Yaseen Omar , Ibrahim Mohammed
Published: March 2020

Background

Any high-stakes assessment that leads to an important decision requires careful consideration in determining whether a student passes or fails. This observational study conducted in Erbil, Iraq, in June 2018 proposes a defensible pass/fail decision based on the number of failed competencies.

Methods

Results were obtained for 150 medical students on their final objective structured clinical examination. Cutoff scores and pass/fail decisions were calculated using the modified Angoff, borderline, borderline-regression and holistic methods. The results were compared with each other and with a new competency method using Cohen’s kappa. Rasch analysis was used to compare the consistency of competency data with Rasch model estimates.

Results

The competency method resulted in 40 (26.7%) students failing, compared with 76 (50.6%), 37 (24.6%), 35 (23.3%) and 13 (8%) for the modified Angoff, borderline, borderline regression and holistic methods, respectively. The competency method demonstrated a sufficient degree of fit to the Rasch model (mean outfit and infit statistics of 0.961 and 0.960, respectively).

Conclusions

the competency method was more stringent in determining pass/fail, compared with other standard-setting methods, except for the modified Angoff method. The fit of competency data to the Rasch model provides evidence for the validity and reliability of pass/fail decisions.
A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Authors: Zhou Ying , Yang Zhen , Guo Yanan , Geng Shuang , Gao Shan , Ye Shenglan , Hu Yi , Wang Yafei
Published: March 2020

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan, Hubei, China. This study sought to elucidate a novel predictor of disease severity in patients with coronavirus disease-19 (COVID-19) cased by SARS-CoV-2.

Methods

Patients enrolled in this study were all hospitalized with COVID-19 in the Central Hospital of Wuhan, China. Clinical features, chronic comorbidities, demographic data, and laboratory and radiological data were reviewed. The outcomes of patients with severe pneumonia and those with non-severe pneumonia were compared using the Statistical Package for the Social Sciences (IBM Corp., Armonk, NY, USA) to explore clinical characteristics and risk factors. The receiver operating characteristic curve was used to screen optimal predictors from the risk factors and the predictive power was verified by internal validation.

Results

A total of 377 patients diagnosed with COVID-19 were enrolled in this study, including 117 with severe pneumonia and 260 with non-severe pneumonia. The independent risk factors for severe pneumonia were age [odds ratio (OR): 1.059, 95% confidence interval (CI): 1.036–1.082; p < 0.001], N/L (OR: 1.322, 95% CI: 1.180–1.481; p < 0.001), CRP (OR: 1.231, 95% CI: 1.129–1.341; p = 0.002), and D-dimer (OR: 1.059, 95% CI: 1.013–1.107; p = 0.011). We identified a product of N/L*CRP*D-dimer as having an important predictive value for the severity of COVID-19. The cutoff value was 5.32. The negative predictive value of less than 5.32 for the N/L*CRP*D-dimer was 93.75%, while the positive predictive value was 46.03% in the test sets. The sensitivity and specificity were 89.47% and 67.42%. In the training sets, the negative and positive predictive values were 93.80% and 41.32%, respectively, with a specificity of 70.76% and a sensitivity of 89.87%.

Conclusions

A product of N/L*CRP*D-dimer may be an important predictor of disease severity in patients with COVID-19.
Structural Disconnection of the Tool Use Network After Left Hemisphere Stroke Predicts Limb Apraxia Severity
Authors: Garcea Frank E. , Greene Clint , Grafton Scott T. , Buxbaum Laurel J.
Published: March 2020

Producing a tool use gesture is a complex process drawing upon the integration of stored knowledge of tools and their associated actions with sensory-motor mechanisms supporting the planning and control of hand and arm actions. Understanding how sensory-motor systems in parietal cortex interface with semantic representations of actions and objects in the temporal lobe remains a critical issue, and is hypothesized to be a key determinant of the severity of limb apraxia, a deficit in producing skilled action after left hemisphere stroke. We used voxel-based and connectome-based lesion symptom mapping with data from 57 left hemisphere stroke participants to assess the lesion sites and structural disconnection patterns associated with poor tool use gesturing. We found that structural disconnection between the left inferior parietal lobule, lateral temporal lobe (left middle temporal gyrus) and ventral temporal cortex (left medial fusiform gyrus) predicted the severity of tool use gesturing performance. Control analyses demonstrated that reductions in right-hand grip strength were associated with motor system disconnection, bypassing regions supporting tool use gesturing. Our findings provide causal evidence that limb apraxia may arise, in part, from disconnection of conceptual representations in the temporal lobe from mechanisms enabling skilled action production in the inferior parietal lobule.
Precise replacement ofSaccharomyces cerevisiaeproteasome genes with human orthologs by an integrative targeting method
Authors: Yellman Christopher M.
Published: March 2020

Artificial induction of a chromosomal double-strand break inSaccharomyces cerevisiaeenhances the frequency of integration of homologous DNA fragments into the broken region by up to several orders of magnitude. The process of homologous repair can be exploited to integrate, in principle, any foreign DNA into a target site, provided the introduced DNA is flanked at both the 5’ and 3’ ends by sequences homologous to the region surrounding the double-strand break. We have developed a tool set that requires a minimum of steps to induce double-strand breaks at chromosomal target sites with the meganuclease I-SceI and select integration events at those sites. We demonstrate this method in two different applications. First, the introduction of site-specific single-nucleotide phosphorylation site mutations into theS. cerevisiaegeneSPO12. Second, the precise chromosomal replacement of elevenS. cerevisiaeproteasome genes with their human orthologs. Placing the human genes underS. cerevisiaetranscriptional control allowed us to update our of model of functional replacement. Our experience suggests that using native promoters may be a useful general strategy for the coordinated expression of foreign genes inS. cerevisiae. We provide an integrative targeting toolset that will facilitate a variety of precision genome engineering applications.
Dynamics of gaze control during prey capture in freely moving mice
Authors: Michaiel Angie M. , Abe Elliott T.T. , Niell Cristopher M.
Published: March 2020

Many studies of visual processing are conducted in unnatural conditions, such as head- and gaze-fixation. As this radically limits natural exploration of the visual environment, there is much less known about how animals actively use their sensory systems to acquire visual information in natural, goal-directed contexts. Recently, prey capture has emerged as an ethologically relevant behavior that mice perform without training, and that engages vision for accurate orienting and pursuit. However, it is unclear how mice target their gaze during such natural behaviors, particularly since, in contrast to many predatory species, mice have a narrow binocular field and lack foveate vision that would entail fixing their gaze on a specific point in the visual field. Here we measured head and bilateral eye movements in freely moving mice performing prey capture. We find that the majority of eye movements are compensatory for head movements, thereby acting to stabilize the visual scene. During head turns, however, these periods of stabilization are interspersed with non-compensatory saccades that abruptly shift gaze position. Analysis of eye movements relative to the cricket position shows that the saccades do not preferentially select a specific point in the visual scene. Rather, orienting movements are driven by the head, with the eyes following in coordination to sequentially stabilize and recenter the gaze. These findings help relate eye movements in the mouse to other species, and provide a foundation for studying active vision during ethological behaviors in the mouse.
Combining Information from Crosslinks and Monolinks in the Modelling of Protein Structures
Authors: Sinnott M. , Malhotra S. , Madhusudhan M.S. , Thalassinos K. , Topf M.
Published: March 2020

Monolinks are produced in a Chemical Crosslinking Mass Spectrometry experiment and are more abundant than crosslinks. They convey residue exposure information, but so far have not been used in the modelling of protein structures. Here we present the Monolink Depth Score (MoDS), for assessing structural models based on the depth of monolinked residues, corresponding to their distance to the nearest bulk water. Using simulated and reprocessed experimental data from the Proteomic Identification Database, we compare the performance of MoDS to MNXL - our previously-developed score for assessing models based on crosslinking data. Our results show that MoDS can be used to effectively score model structures based on monolinks, and that combining it with MNXL leads to overall higher scoring performance. The work strongly supports the use of monolink data in the context of integrative structure determination. We also present XLM-Tools, a programme to assist in this effort, available at:https://github.com/Topf-Lab/XLM-Tools.
Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis
Authors: Megremis Spyridon , Walker Thomas D. J. , He Xiaotong , O’Sullivan James , Ollier William E.R. , Chinoy Hector , Pendleton Neil , Payton Antony , Hampson Lynne , Hampson Ian , Lamb Janine A.
Published: March 2020

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. Increased microbial diversity was observed in dermatomyositis. Viruses were over-represented and species of the Poxviridae family were significantly enriched. The autoantibodies identified recognised a large portion of the human proteome, including interferon regulated proteins; these proteins were clustered in specific biological processes. Apart from TRIM33, autoantibodies against eleven further TRIM proteins, including TRIM21, were identified. Some of these TRIM proteins shared epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a significant role in the pathogenesis of dermatomyositis.
Anti-CD19 CAR T cells potently redirected to kill solid tumor cells
Authors: Ambrose Christine , Su Lihe , Wu Lan , Dufort Fay J. , Sanford Thomas , Birt Alyssa , Hackel Benjamin , Hombach Andreas , Abken Hinrich , Lobb Roy R. , Rennert Paul D.
Published: March 2020

Successful CAR T cell therapy for the treatment of solid tumors requires exemplary CAR T cell expansion, persistence and fitness, and the ability to target tumor antigens safely. Here we address this constellation of critical attributes for successful cellular therapy by using integrated technologies that simplify development and derisk clinical translation. We have developed a CAR-CD19 T cell that secretes a CD19-anti-Her2 bridging protein. This cell therapy strategy exploits the ability of CD19-targeting CAR T cells to interact with CD19 on normal B cells to drive expansion, persistence and fitness. The secreted bridging protein potently binds to Her2-positive tumor cells, mediating CAR-CD19 T cell cytotoxicityin vitroandin vivo. Because of its short half-life, the secreted bridging protein will selectively accumulate at the site of highest antigen expression, ie. at the tumor. Bridging proteins that bind to multiple different tumor antigens have been created. Therefore, antigen-bridging CAR-CD19 T cells incorporate critical attributes for successful solid tumor cell therapy. This platform can be exploited to attack tumor antigens on any cancer.
Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology
Authors: Bartell Eric , Fujimoto Masanobu , Khoury Jane C. , Khoury Philip R. , Vedantam Sailaja , Hirschhorn Joel , Dauber Andrew
Published: March 2020

The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 in 839 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels nearIGFBP3andIGFBP5genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, theIGFBP3signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); theIGFBP5signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated SNPs near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.
POMC neurons functional heterogeneity relies on mTORC1 signaling
Authors: Saucisse Nicolas , Mazier Wilfrid , Simon Vincent , Binder Elke , Catania Caterina , Bellocchio Luigi , Romanov Roman A. , Matias Isabelle , Zizzari Philippe , Leon Stephane , Quarta Carmelo , Cannich Astrid , Meece Kana , Gonzales Delphine , Clark Samantha , Becker Julia M. , Yeo Giles S.H. , Merkle Florian T. , Wardlaw Sharon L. , Harkany Tibor , Massa Federico , Marsicano Giovanni , Cota Daniela
Published: March 2020

Hypothalamic Pro-opiomelanocortin (POMC) neurons are classically known to trigger satiety. However, they encompass heterogeneous subpopulations whose functions are unknown. Here we show that POMC neurons releasing GABA, glutamate or both neurotransmitters possess distinct spatial distribution, molecular signatures and functions. Functional specificity of these subpopulations relies on the energy sensor mechanistic Target of Rapamycin Complex 1 (mTORC1), since pharmacological blockade of mTORC1, by mimicking a cellular negative energy state, simultaneously inhibited POMC/glutamatergic and activated POMC/GABAergic neurons. Chemogenetics and conditional deletion of mTORC1 then demonstrated that mTORC1 blockade in POMC neurons causes hyperphagia. This is due to decreased POMC-derived anorexigenicα-melanocyte-stimulating hormone and the recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Genetic inhibition of glutamate release from POMC neurons also produced hyperphagia, recapitulating the phenotype caused by mTORC1 blockade. Altogether, these findings pinpoint the molecular mechanisms engaged by POMC neurons to oppositely control feeding, thereby challenging conventional views about their functions.
Exploiting prior knowledge about biological macromolecules in cryo-EM structure determination
Authors: Kimanius Dari , Zickert Gustav , Nakane Takanori , Adler Jonas , Lunz Sebastian , Schönlieb Carola-Bibiane , Öktem Ozan , Scheres Sjors H.W.
Published: March 2020

Three-dimensional reconstruction of the electron scattering potential of biological macromolecules from electron cryo-microscopy (cryo-EM) projection images is an ill-posed problem. The most popular cryo-EM software solutions to date rely on a regularisation approach that is based on the prior assumption that the scattering potential varies smoothly over three-dimensional space. Although this approach has been hugely successful in recent years, the amount of prior knowledge it exploits compares unfavourably to the knowledge about biological structures that has been accumulated over decades of research in structural biology. Here, we present a regularisation framework for cryo-EM structure determination that exploits prior knowledge about biological structures through a convolutional neural network that is trained on known macromolecular structures. We insert this neural network into the iterative cryo-EM structure determination process through an approach that is inspired by Regularisation by Denoising. We show that the new regularisation approach yields better reconstructions than the current state-of-the-art for simulated data and discuss options to extend this work for application to experimental cryo-EM data.
Selection and suppression of visual information in the macaque prefrontal cortex
Authors: Di Bello F. , Ben Hadj Hassen S. , Astrand E. , Ben Hamed S.
Published: March 2020

In everyday life, we are continuously struggling at focusing on our current goals while at the same time avoiding distractions. Attention is the neuro-cognitive process devoted to the selection of behaviorally relevant sensory information while at the same time preventing distraction by irrelevant information. Visual selection can be implemented by both long-term (learning-based spatial prioritization) and short term (dynamic spatial attention) mechanisms. On the other hand, distraction can be prevented proactively, by strategically prioritizing task-relevant information at the expense of irrelevant information, or reactively, by actively suppressing the processing of distractors. The distinctive neuronal signature of each of these four processes is largely unknown. Likewise, how selection and suppression mechanisms interact to drive perception has never been explored neither at the behavioral nor at the neuronal level. Here, we apply machine-learning decoding methods to prefrontal cortical (PFC) activity to monitor dynamic spatial attention with an unprecedented spatial and temporal resolution. This leads to several novel observations. We first identify independent behavioral and neuronal signatures for learning-based attention prioritization and dynamic attentional selection. Second, we identify distinct behavioral and neuronal signatures for proactive and reactive suppression mechanisms. We find that while distracting task-relevant information is suppressed proactively, task-irrelevant information is suppressed reactively. Critically, we show that distractor suppression, whether proactive or reactive, strongly depends on both learning-based attention prioritization and dynamic attentional selection. Overall, we thus provide a unified neuro-cognitive framework describing how the prefrontal cortex implements spatial selection and distractor suppression in order to flexibly optimize behavior in dynamic environments.