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in category pathology

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1: Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans
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Posted 10 Apr 2020

Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans
90,051 downloads medRxiv pathology

Sharon E Fox, Aibek Akmatbekov, Jack L Harbert, Guang Li, J. Quincy Brown, Richard S. Vander Heide

SARS-CoV-2 has rapidly spread across the United States, causing extensive morbidity and mortality, though the histopathologic basis of severe disease cases has yet to be studied in detail. Over the past century, autopsy has contributed significantly to our understanding of numerous disease processes, but for several reasons, autopsy reports following deaths related to SARS- CoV-2 have thus far been limited across the globe. We report on the relevant cardiopulmonary findings in the first series of autopsies in the United States, with the cause of death being due to SARS-CoV-2 infection. These cases identify key pathologic states potentially contributing to severe disease and decompensation in these patients.

2: ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection
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Posted 09 May 2020

ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection
16,231 downloads bioRxiv pathology

Lingli Zhou, Zhenhua Xu, Gianni M. Castiglione, Uri S Soiberman, Charles G. Eberhart, Elia J Duh

Purpose: Conjunctival signs and symptoms are observed in a subset of patients with COVID-19, and SARS-CoV-2 has been detected in tears, raising concerns regarding the eye both as a portal of entry and carrier of the virus. The purpose of this study was to determine whether ocular surface cells possess the key factors required for cellular susceptibility to SARS-CoV-2 entry/infection. Methods: We analyzed human post-mortem eyes as well as surgical specimens for the expression of ACE2 (the receptor for SARS-CoV-2) and TMPRSS2, a cell surface-associated protease that facilitates viral entry following binding of the viral spike protein to ACE2. Results: Across all eye specimens, immunohistochemical analysis revealed expression of ACE2 in the conjunctiva, limbus, and cornea, with especially prominent staining in the superficial conjunctival and corneal epithelial surface. Surgical conjunctival specimens also showed expression of ACE2 in the conjunctival epithelium, especially prominent in the superficial epithelium, as well as the substantia propria. All eye and conjunctival specimens also expressed TMPRSS2. Finally, western blot analysis of protein lysates from human corneal epithelium obtained during refractive surgery confirmed expression of ACE2 and TMPRSS2. Conclusions: Together, these results indicate that ocular surface cells including conjunctiva are susceptible to infection by SARS-CoV-2, and could therefore serve as a portal of entry as well as a reservoir for person-to-person transmission of this virus. This highlights the importance of safety practices including face masks and ocular contact precautions in preventing the spread of COVID-19 disease. ### Competing Interest Statement The authors have declared no competing interest.

3: Molecular Architecture of Early Disseminationand Massive Second Wave of the SARS-CoV-2 Virus in a Major Metropolitan Area
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Posted 23 Sep 2020

Molecular Architecture of Early Disseminationand Massive Second Wave of the SARS-CoV-2 Virus in a Major Metropolitan Area
14,419 downloads medRxiv pathology

Scott Wesley Long, Randall J. Olsen, Paul A. Christensen, David W. Bernard, James J Davis, Maulik Shukla, Marcus Nguyen, Matthew Ojeda Saavedra, Prasanti Yerramilli, Layne Pruitt, Sishir Subedi, Hung-Che Kuo, Heather Hendrickson, Ghazaleh Eskandari, Hoang A.T. Nguyen, James Hunter Long, Muthiah Kumaraswami, Jule Goike, Daniel Boutz, Jimmy Gollihar, Jason S McLellan, Chia-Wei Chou, Kamyab Javanmardi, Ilya J. Finkelstein, James M. Musser

We sequenced the genomes of 5,085 SARS-CoV-2 strains causing two COVID-19 disease waves in metropolitan Houston, Texas, an ethnically diverse region with seven million residents. The genomes were from viruses recovered in the earliest recognized phase of the pandemic in Houston, and an ongoing massive second wave of infections. The virus was originally introduced into Houston many times independently. Virtually all strains in the second wave have a Gly614 amino acid replacement in the spike protein, a polymorphism that has been linked to increased transmission and infectivity. Patients infected with the Gly614 variant strains had significantly higher virus loads in the nasopharynx on initial diagnosis. We found little evidence of a significant relationship between virus genotypes and altered virulence, stressing the linkage between disease severity, underlying medical conditions, and host genetics. Some regions of the spike protein - the primary target of global vaccine efforts - are replete with amino acid replacements, perhaps indicating the action of selection. We exploited the genomic data to generate defined single amino acid replacements in the receptor binding domain of spike protein that, importantly, produced decreased recognition by the neutralizing monoclonal antibody CR30022. Our study is the first analysis of the molecular architecture of SARS-CoV-2 in two infection waves in a major metropolitan region. The findings will help us to understand the origin, composition, and trajectory of future infection waves, and the potential effect of the host immune response and therapeutic maneuvers on SARS-CoV-2 evolution.

4: Complete genome characterisation of a novel coronavirus associated with severe human respiratory disease in Wuhan, China
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Posted 25 Jan 2020

Complete genome characterisation of a novel coronavirus associated with severe human respiratory disease in Wuhan, China
13,756 downloads bioRxiv pathology

Fan Wu, Su Zhao, Bin Yu, Yan-Mei Chen, Wen Wang, Yi Hu, Zhi-Gang Song, Zhao-Wu Tao, Jun-Hua Tian, Yuan-Yuan Pei, Ming-Li Yuan, Yu-Ling Zhang, Fa-Hui Dai, Yi Liu, Qi-Min Wang, Jiao-Jiao Zheng, Lin Xu, Edward C Holmes, Yong-Zhen Zhang

Emerging and re-emerging infectious diseases, such as SARS, MERS, Zika and highly pathogenic influenza present a major threat to public health[1][1]–[3][2]. Despite intense research effort, how, when and where novel diseases appear are still the source of considerable uncertainly. A severe respiratory disease was recently reported in the city of Wuhan, Hubei province, China. At the time of writing, at least 62 suspected cases have been reported since the first patient was hospitalized on December 12nd 2019. Epidemiological investigation by the local Center for Disease Control and Prevention (CDC) suggested that the outbreak was associated with a sea food market in Wuhan. We studied seven patients who were workers at the market, and collected bronchoalveolar lavage fluid (BALF) from one patient who exhibited a severe respiratory syndrome including fever, dizziness and cough, and who was admitted to Wuhan Central Hospital on December 26th 2019. Next generation metagenomic RNA sequencing[4][3] identified a novel RNA virus from the family Coronaviridae designed WH-Human-1 coronavirus (WHCV). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that WHCV was most closely related (89.1% nucleotide similarity similarity) to a group of Severe Acute Respiratory Syndrome (SARS)-like coronaviruses (genus Betacoronavirus , subgenus Sarbecovirus ) previously sampled from bats in China and that have a history of genomic recombination. This outbreak highlights the ongoing capacity of viral spill-over from animals to cause severe disease in humans. [1]: #ref-1 [2]: #ref-3 [3]: #ref-4

5: Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience
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Posted 22 May 2020

Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience
12,508 downloads medRxiv pathology

Clare Bryce, Zachary Grimes, Elisabet Pujadas, Sadhna Ahuja, Mary Beth Beasley, Randy Albrecht, Tahyna Hernandez, Aryeh Stock, Zhen Zhao, Mohamed Al Rasheed, Joyce Chen, Li Li, Diane Wang, Adriana Corben, Kenneth Haines, William Westra, Melissa Umphlett, Ronald E Gordon, Jason Reidy, Bruce Petersen, Fadi Salem, MariaIsabel Fiel, Siraj M El Jamal, Nadejda M Tsankova, Jane Houldsworth, Zarmeen Mussa, Wen-Chun Liu, Brandon Veremis, Emilia M Sordillo, Melissa Gitman, Michael Nowak, Rachel Brody, Noam Harpaz, Miriam Merad, Sacha Gnjatic, Ryan Donnelly, Patricia Seigler, Calvin Keys, Jennifer Cameron, Isaiah Moultrie, Kae-Lynn Washington, Jacquelyn Treatman, Robert Sebra, Jeffrey Jhang, Adolfo Firpo, John Lednicky, Alberto Paniz-Mondolfi, Carlos Cordon-Cardo, Mary Fowkes

BACKGROUND Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease process is still lacking. METHODS Autopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays. RESULTS Laboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNF. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis and a secondary hemophagocytic lymphohistiocytosis-like syndrome in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples. CONCLUSIONS We report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome, with hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.

6: Plasma Metabolomic and Lipidomic Alterations Associated with COVID-19
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Posted 07 Apr 2020

Plasma Metabolomic and Lipidomic Alterations Associated with COVID-19
10,126 downloads medRxiv pathology

Di Wu, Ting Shu, Xiaobo Yang, Jian-Xin Song, Mingliang Zhang, Chengye Yao, Liu Wen, Muhan Huang, Yuan Yu, Qingyu Yang, Tingju Zhu, Jiqian Xu, Jingfang Mu, Yaxin Wang, Hong Wang, Tang Tang, Yujie Ren, Yongran Wu, Shu-Hai Lin, Yang Qiu, Ding-Yu Zhang, You Shang, Xi Zhou

The pandemic of the coronavirus disease 2019 (COVID-19) has become a global public health crisis. COVID-19 is marked by its rapid progression from mild to severe conditions, particularly in the absence of adequate medical care. However, the physiological changes associated with COVID-19 are barely understood. In this study, we performed untargeted metabolomic and lipidomic analyses of plasma from a cohort of COVID-19 patients who had experienced different symptoms. We found the metabolite and lipid alterations exhibit apparent correlation with the course of disease in these COVID-19 patients, indicating that the development of COVID-19 affected patient metabolism. Moreover, many of the metabolite and lipid alterations, particularly ones associated with hepatic functions, have been found to align with the progress and severity of COVID-19. This work provides valuable knowledge about blood biomarkers associated with COVID-19 and potential therapeutic targets, and presents important resource for further studies of COVID-19 pathogenesis.

7: High multiplex, digital spatial profiling of proteins and RNA in fixed tissue using genomic detection methods
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Posted 22 Feb 2019

High multiplex, digital spatial profiling of proteins and RNA in fixed tissue using genomic detection methods
7,779 downloads bioRxiv pathology

Christopher R. Merritt, Giang T Ong, Sarah Church, Kristi Barker, Gary Geiss, Margaret Hoang, Jaemyeong Jung, Yan Liang, Jill McKay-Fleisch, Karen Nguyen, Kristina Sorg, Isaac Sprague, Charles Warren, Sarah Warren, Zoey Zhou, Daniel R. Zollinger, Dwayne L. Dunaway, Gordon B. Mills, Joseph M. Beechem

We have developed Digital Spatial Profiling (DSP), a non-destructive method for high-plex spatial profiling of proteins and RNA, using oligonucleotide detection technologies with unlimited multiplexing capability. The key breakthroughs underlying DSP are threefold: (1) multiplexed readout of proteins/RNA using oligo-tags; (2) oligo-tags attached to affinity reagents (antibodies/RNA probes) through a photocleavable (PC) linker; (3) photocleaving light projected onto the tissue sample to release PC-oligos in any spatial pattern. Here we show precise analyte reproducibility, validation, and cellular resolution using DSP. We also demonstrate biological proof-of-concept using lymphoid, colorectal tumor, and autoimmune tissue as models to profile immune cell populations, stroma, and cancer cells to identify factors specific for the diseased microenvironment. DSP utilizes the unlimited multiplexing capability of modern genomic approaches, while simultaneously providing spatial context of protein and RNA to examine biological questions based on analyte location and distribution.

8: H&E-stained Whole Slide Image Deep Learning Predicts SPOP Mutation State in Prostate Cancer
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Posted 17 Jul 2016

H&E-stained Whole Slide Image Deep Learning Predicts SPOP Mutation State in Prostate Cancer
7,709 downloads bioRxiv pathology

Andrew J. Schaumberg, Mark A. Rubin, Thomas J. Fuchs

A quantitative model to genetically interpret the histology in whole microscopy slide images is desirable to guide downstream immunohistochemistry, genomics, and precision medicine. We constructed a statistical model that predicts whether or not SPOP is mutated in prostate cancer, given only the digital whole slide after standard hematoxylin and eosin [H&E] staining. Using a TCGA cohort of 177 prostate cancer patients where 20 had mutant SPOP, we trained multiple ensembles of residual networks, accurately distinguishing SPOP mutant from SPOP non-mutant patients (test AUROC=0.74, p=0.0007 Fisher's Exact Test). We further validated our full metaensemble classifier on an independent test cohort from MSK-IMPACT of 152 patients where 19 had mutant SPOP. Mutants and non-mutants were accurately distinguished despite TCGA slides being frozen sections and MSK-IMPACT slides being formalin-fixed paraffin-embedded sections (AUROC=0.86, p=0.0038). Moreover, we scanned an additional 36 MSK-IMPACT patient having mutant SPOP, trained on this expanded MSK-IMPACT cohort (test AUROC=0.75, p=0.0002), tested on the TCGA cohort (AUROC=0.64, p=0.0306), and again accurately distinguished mutants from non-mutants using the same pipeline. Importantly, our method demonstrates tractable deep learning in this "small data" setting of 20-55 positive examples and quantifies each prediction's uncertainty with confidence intervals. To our knowledge, this is the first statistical model to predict a genetic mutation in cancer directly from the patient's digitized H&E-stained whole microscopy slide. Moreover, this is the first time quantitative features learned from patient genetics and histology have been used for content-based image retrieval, finding similar patients for a given patient where the histology appears to share the same genetic driver of disease i.e. SPOP mutation (p=0.0241 Kost's Method), and finding similar patients for a given patient that does not have have that driver mutation (p=0.0170 Kost's Method).

9: Analytical Validation of a COVID-19 qRT-PCR Detection Assay Using a 384-well Format and Three Extraction Methods
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Posted 05 Apr 2020

Analytical Validation of a COVID-19 qRT-PCR Detection Assay Using a 384-well Format and Three Extraction Methods
6,650 downloads bioRxiv pathology

Andrew C. Nelson, Benjamin Auch, Matthew Schomaker, Daryl M. Gohl, Patrick Grady, Darrell Johnson, Robyn Kincaid, Kylene E Karnuth, Jerry Daniel, Jessica K Fiege, Elizabeth J Fay, Tyler Bold, Ryan A Langlois, Kenneth Beckman, Sophia Yohe

The COVID-19 global pandemic is an unprecedented health emergency. Insufficient access to testing has hampered effective public health interventions and patient care management in a number of countries. Furthermore, the availability of regulatory-cleared reagents has challenged widespread implementation of testing. We rapidly developed a qRT-PCR SARS-CoV-2 detection assay using a 384-well format and tested its analytic performance across multiple nucleic acid extraction kits. Our data shows robust analytic accuracy on residual clinical biospecimens. Limit of detection sensitivity and specificity was confirmed with currently available commercial reagents. Our methods and results provide valuable information for other high-complexity laboratories seeking to develop effective, local, laboratory-developed procedures with high-throughput capability to detect SARS-CoV-2.

10: Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections
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Posted 21 Apr 2020

Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections
6,495 downloads medRxiv pathology

Benjamin T. Bradley, Heather Maioli, Robert Johnston, Irfan Chaudhry, Susan L. Fink, Haodong Xu, Behzad Najafian, Desiree Marshall, J. Matthew Lacy, Timothy Williams, Nicole Yarid

Background SARS-CoV-2 is the cause of an ongoing pandemic with a projected 100,000 to 240,000 U.S. deaths. To date, documentation of histopathologic features in fatal cases of COVID-19 has been limited due to small sample size and incomplete organ sampling. Methods Post-mortem examinations were performed on 12 fatal COVID-19 cases in Washington State during February-March 2020. Clinical and laboratory data were reviewed. Tissue examination of all major organs was performed by light microscopy and electron microscopy. The presence of viral RNA in sampled tissues was tested by RT-PCR. Results All 12 patients were older with significant preexisting comorbidities. The major pulmonary finding was diffuse alveolar damage in the acute and/or organizing phases with virus identified in type I and II pneumocytes by electron microscopy. The kidney demonstrated viral particles in the tubular epithelium, endothelium, and podocytes without significant inflammation. Viral particles were also observed in the trachea and large intestines. SARS-CoV-2 RNA was detected in the cardiac tissue of a patient with lymphocytic myocarditis. RT-PCR also detected viral RNA in the subcarinal lymph nodes, liver, spleen, and large intestines. Conclusion SARS-CoV-2 represents the third novel coronavirus to cause widespread human disease since 2002. Similar to SARS and MERS, the primary pathology was diffuse alveolar damage with virus located in the pneumocytes. However, other major organs including the heart and kidneys may be susceptible to viral replication and damage leading to increased mortality in those with disseminated disease. Understanding the pathology of SARS-CoV-2 will be essential to design effective therapies.

11: Treatment of COVID-19 Patients with Convalescent Plasma in Houston, Texas
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Posted 13 May 2020

Treatment of COVID-19 Patients with Convalescent Plasma in Houston, Texas
6,120 downloads medRxiv pathology

Eric Salazar, Katherine K. Perez, Madiha Ashraf, Jian Chen, Brian Castillo, Paul A. Christensen, Taryn Eubank, David W. Bernard, Todd N Eagar, S. Wesley Long, Sishir Subedi, Randall J. Olsen, Christopher Leveque, Mary R. Schwartz, Monisha Dey, Cheryl Chavez-East, John Rogers, Ahmed Shehabeldin, David Joseph, Guy Williams, Karen Thomas, Faisal Masud, Christina Talley, Katharine G. Dlouhy, Bevin Valdez Lopez, Curt Hampton, Jason Lavinder, Jimmy D Gollihar, Andre C Maranhao, Gregory C Ippolito, Matthew Ojeda Saavedra, Concepcion C. Cantu, Prasanti Yerramilli, Layne Pruitt, James M. Musser

Background: COVID-19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally, and no proven treatments are available. Convalescent plasma therapy has been used with varying degrees of success to treat severe microbial infections for more than 100 years. Methods: Patients (n=25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28 to April 14, 2020. Patients were transfused with convalescent plasma obtained from donors with confirmed SARS-CoV-2 infection and had been symptom free for 14 days. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 post-transfusion. Clinical improvement was assessed based on a modified World Health Organization 6-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains. Results: At baseline, all patients were receiving supportive care, including anti-inflammatory and anti-viral treatments, and all patients were on oxygen support. At day 7 post-transfusion with convalescent plasma, nine patients had at least a 1-point improvement in clinical scale, and seven of those were discharged. By day 14 post-transfusion, 19 (76%) patients had at least a 1-point improvement in clinical status and 11 were discharged. No adverse events as a result of plasma transfusion were observed. The whole genome sequencing data did not identify a strain genotype-disease severity correlation. Conclusions: The data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease. Randomized, controlled trials are needed to determine its efficacy.

12: Diabetic Retinopathy detection through integration of Deep Learning classification framework
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Posted 27 Nov 2017

Diabetic Retinopathy detection through integration of Deep Learning classification framework
6,119 downloads bioRxiv pathology

Alexander Rakhlin

This document represents a brief account of ongoing project for Diabetic Retinopathy Detection (DRD) through integration of state-of the art Deep Learning methods. We make use of deep Convolutional Neural Networks (CNNs), which have proven revolutionary in multiple fields of computer vision including medical imaging, and we bring their power to the diagnosis of eye fundus images. For training our models we used publicly available Kaggle data set. For testing we used portion of Kaggle data withheld from training and Messidor-2 reference standard. Neither withheld Kaggle images, nor Messidor-2 were used for training. For Messidor-2 we achieved sensitivity 99%, specificity 71%, and AUC 0.97. These results close to recent state-of-the-art models trained on much larger data sets and surpass average results of diabetic retinopathy screening when performed by trained optometrists. With continuous development of our Deep Learning models we expect to further increase the accuracy of the method and expand it to cataract and glaucoma diagnostics.

13: Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19
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Posted 12 May 2020

Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19
5,980 downloads bioRxiv pathology

Liqun He, Maarja Andaloussi Mäe, Lars Muhl, Ying Sun, Riikka Pietilä, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Lei Zhang, Yuan Xie, Stefanos Leptidis, Giuseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsänen, Olivier Mirabeau, Emil Hansson, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, Taija Mäkinen, Xiao-Rong Peng, Thomas D. Arnold, Kari Alitalo, Lars I Eriksson, Urban Lendahl, Christer Betsholtz

Accumulating clinical observations implicate vascular inflammation as an underlying cause of coagulopathy in severely ill COVID-19 patients and it was recently suggested that SARS-CoV-2 virus particles infect endothelial cells. Here, we show that endothelial cells do not express angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 receptor. Instead, pericytes and microvascular smooth muscle cells express ACE2 in an organotypic manner. Pericyte deficiency leads to increased endothelial expression and release of Von Willebrand factor and intravascular platelet and fibrin aggregation, suggesting that pericytes limit endothelial pro-thrombotic responses. That pericytes and not endothelial cells express ACE2 may provide important clues to the pathology of COVID-19, as pericytes are normally shielded behind an endothelial barrier and may get infected only when this barrier is compromised by COVID-19 risk factors. ### Competing Interest Statement C.B. is a consultant for AstraZeneca BioPharmaceuticals R&D. X.-R. P. is an employee of AstraZeneca BioPharmaceuticals R&D.

14: Calcium channel blocker amlodipine besylate is associated with reduced case fatality rate of COVID-19 patients with hypertension
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Posted 14 Apr 2020

Calcium channel blocker amlodipine besylate is associated with reduced case fatality rate of COVID-19 patients with hypertension
5,976 downloads medRxiv pathology

Lei-Ke Zhang, Yuan Sun, Haolong Zeng, Yudong Peng, Xiaming Jiang, Wei-Juan Shang, Yan Wu, Shufen Li, Yu-Lan Zhang, Liu Yang, Hongbo Chen, Runming Jin, Wei Liu, Hao Li, Ke Peng, Gengfu Xiao

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread to more than 100 countries posing as a serious threat to the public health on a global scale. Patients with comorbidity such as hypertension suffer more severe infection with elevated case fatality rate. Development of effective anti-viral drug is in urgent need to treat COVID-19 patients. Here we report that calcium channel blockers (CCBs), a type of anti-hypertension drugs that are widely used in the clinics, can significantly inhibit the post-entry replication events of SARS-CoV-2 in vitro. Comparison with two other major types of anti-hypertension drugs, the angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), showed that only CCBs display significant anti-SARS-CoV-2 efficacy. Combined treatment with chloroquine and CCBs significantly enhanced the anti-SARS-CoV-2 efficacy. Retrospective clinical investigation of COVID-19 patients revealed that the CCB amlodipine besylate administration was associated with reduced case fatality rate of patients with hypertension. Results from this study suggest that CCB administration for COVID-19 patients with hypertension as the comorbidity might improve the disease outcome.

15: Are pangolins the intermediate host of the 2019 novel coronavirus (2019-nCoV) ?
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Posted 20 Feb 2020

Are pangolins the intermediate host of the 2019 novel coronavirus (2019-nCoV) ?
5,938 downloads bioRxiv pathology

Ping Liu, Jing-Zhe Jiang, Xiu-Feng Wan, Yan Hua, Xiaohu Wang, Fanghui Hou, Jing Chen, Jiejian Zou, Jinping Chen

The outbreak of 2019-nCoV pneumonia (COVID-19) in the city of Wuhan, China has resulted in more than 60,000 laboratory confirmed cases, and recent studies showed that 2019-nCoV (SARS-CoV-2) could be of bat origin but involve other potential intermediate hosts. In this study, we assembled the genomes of coronaviruses identified in sick pangolins. The molecular and phylogenetic analyses showed that pangolin Coronaviruses (pangolin-CoV) are genetically related to both the 2019-nCoV and bat Coronaviruses but do not support the 2019-nCoV arose directly from the pangolin-CoV. Our study also suggested that pangolin be natural host of Betacoronavirus, with a potential to infect humans. Large surveillance of coronaviruses in pangolins could improve our understanding of the spectrum of coronaviruses in pangolins. Conservation of wildlife and limits of the exposures of humans to wildlife will be important to minimize the spillover risks of coronaviruses from wild animals to humans.

16: Pangolin homology associated with 2019-nCoV
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Posted 20 Feb 2020

Pangolin homology associated with 2019-nCoV
5,747 downloads bioRxiv pathology

Tao Zhang, Qunfu Wu, Zhigang Zhang

To explore potential intermediate host of a novel coronavirus is vital to rapidly control continuous COVID-19 spread. We found genomic and evolutionary evidences of the occurrence of 2019-nCoV-like coronavirus (named as Pangolin-CoV) from dead Malayan Pangolins. Pangolin-CoV is 91.02% and 90.55% identical at the whole genome level to 2019-nCoV and BatCoV RaTG13, respectively. Pangolin-CoV is the lowest common ancestor of 2019-nCoV and RaTG13. The S1 protein of Pangolin-CoV is much more closely related to 2019-nCoV than RaTG13. Five key amino-acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and 2019-nCoV but four amino-acid mutations occur in RaTG13. It indicates Pangolin-CoV has similar pathogenic potential to 2019-nCoV, and would be helpful to trace the origin and probable intermediate host of 2019-nCoV.

17: Deep Convolutional Neural Networks for Breast Cancer Histology Image Analysis
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Posted 05 Feb 2018

Deep Convolutional Neural Networks for Breast Cancer Histology Image Analysis
4,890 downloads bioRxiv pathology

Alexander Rakhlin, Alexey A. Shvets, Vladimir I. Iglovikov, Alexandr A. Kalinin

Breast cancer is one of the main causes of cancer death worldwide. Early diagnostics significantly increases the chances of correct treatment and survival, but this process is tedious and often leads to a disagreement between pathologists. Computer-aided diagnosis systems showed potential for improving the diagnostic accuracy. In this work, we develop the computational approach based on deep convolution neural networks for breast cancer histology image classification. Hematoxylin and eosin stained breast histology microscopy image dataset is provided as a part of the ICIAR 2018 Grand Challenge on Breast Cancer Histology Images. Our approach utilizes several deep neural network architectures and gradient boosted trees classifier. For 4-class classification task, we report 87.2% accuracy. For 2-class classification task to detect carcinomas we report 93.8% accuracy, AUC 97.3%, and sensitivity/specificity 96.5/88.0% at the high-sensitivity operating point. To our knowledge, this approach outperforms other common methods in automated histopathological image classification. The source code for our approach is made publicly available at https://github.com/alexander-rakhlin/ICIAR2018.

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Posted 02 Nov 2019

4,111 downloads medRxiv pathology

Eric M. Reiman, Joseph F. Arboleda-Velasquez, Yakeel T. Quiroz, M.J. Huentelman, Thomas G Beach, Richard J Caselli, Yinghua Chen, Yi Su, Amanda J. Myers, John Hardy, Jean Paul Vonsattel, Steven G. Younkin, David A. Bennett, Phillip L. De Jager, Eric B Larson, Paul K. Crane, C. Dirk Keene, M. Ilyas Kamboh, Julia K. Kofler, Linda Duque, John R. Gilbert, Harry E. Gwirtsman, Joseph D. Buxbaum, Dennis W. Dickson, Matthew P Frosch, Bernardino Ghetti, Kathryn L. Lunetta, Li-San Wang, Bradley T Hyman, Walter A. Kukull, Tatiana Foroud, Jonathan L. Haines, Richard P. Mayeux, Margaret A. Pericak-Vance, Julie A Schneider, John Q Trojanowski, Lindsay A. Farrer, Gerard D. Schellenberg, Gary W Beecham, Thomas J. Montine, Gyungah R. Jun, for the Alzheimer’s Disease Genetics Consortium

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimers dementia, such that APOE4 homozygotes have a particularly high risk. While the APOE2 allele is associated with a lower risk of Alzheimers dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimers dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimers dementia cases and controls. APOE2/2 was associated with exceptionally low Alzheimers dementia odds ratios compared to APOE2/3, 3/3 and 4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimers disease could have a major impact on the understanding, treatment and prevention of this terrible disease.

19: Prognostic biomarkers in oral squamous cell carcinoma: a systematic review
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Posted 16 Jul 2017

Prognostic biomarkers in oral squamous cell carcinoma: a systematic review
3,822 downloads bioRxiv pathology

César Rivera, Ana Karina de Oliveira, Rute Alves Pereira e Costa, Tatiane De Rossi, Adriana Franco Paes Leme

Over the years, several tumor biomarkers have been suggested to foresee the prognosis of oral squamous cell carcinoma (OSCC) patients. Here, we present a systematic review to identify, evaluate and summarize the evidence for OSCC reported markers. Eligible studies were identified through a literature search of MEDLINE/PubMed until January 2016. We included primary articles reporting overall survival, disease-free survival and cause-specific survival as outcomes. Our findings were analysed using REporting recommendations for tumor MARKer prognostic studies (REMARK), QuickGo tool and SciCurve trends. We found 41 biomarkers, mostly proteins evaluated by immunohistochemistry. The selected studies are of good quality, although, any study referred to a sample size determination. Considering the lack of follow-up studies, the molecules are still potential biomarkers. Further research is required to validate these biomarkers in well designed clinical cohort-based studies.

20: Performance characteristics of the ID NOW COVID-19 assay: A regional health care system experience
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Posted 05 Jun 2020

Performance characteristics of the ID NOW COVID-19 assay: A regional health care system experience
3,477 downloads medRxiv pathology

Mohiedean Ghofrani, Mary T Casas, Robert K Pelz, Catherine Kroll, Natalie Blum, Scott D Foster

Objectives: We compared the Abbott ID NOW COVID-19 point-of-care test (POCT) with polymerase chain reaction (PCR)-based methods to assess the claimed sensitivity and specificity of POCT and to optimize test utilization in our regional health care system. Methods: Assuming PCR to be the gold standard, we used a convenience sampling of mostly symptomatic COVID-19 suspect hospital patients who had already been tested for internal validation and guideline development purposes by both PCR and POCT to calculate the sensitivity and specificity of POCT with Clopper-Pearson 95% confidence intervals (CI). Results: During the study period, 113 paired patient samples met eligibility criteria. The sensitivity of POCT in this population was calculated to be 94.1% [CI 71.31-99.85%] and the specificity was 99.0% [CI 94.33-99.97%]. Conclusions: Based on the lower sensitivity of POCT and the estimated prevalence of COVID-19 in our symptomatic and asymptomatic hospital patients, we recommend a two-pronged testing approach in which COVID-19 suspect patients are tested by the more sensitive PCR, while asymptomatic patients with a low pre-test probability of infection are tested with POCT supplemented by PCR confirmation of positive results. Furthermore, isolation decisions should not be based on POCT results alone.

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