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middle east respiratory syndrome coronavirus (mers-cov): impact on saudi arabia, 2015.middle east respiratory syndrome is the acute respiratory syndrome caused by betacoronavirus mers-cov. the first case of this disease was reported from saudi arabia in 2012. this virus is lethal and is a close relative of a severe acute respiratory syndrome (sars), which is responsible for more than 3000 deaths in 2002-2003. according to ministry of health, saudi arabia. the number of new cases is 457 in 2015. riyadh has the highest number of reports in comparison to the other cities. according ...201830505188
neutralizing monoclonal antibodies as promising therapeutics against middle east respiratory syndrome coronavirus infection.since emerging in 2012, middle east respiratory syndrome coronavirus (mers-cov) has been a global public health threat with a high fatality rate and worldwide distribution. there are no approved vaccines or therapies for mers until now. passive immunotherapy with neutralizing monoclonal antibodies (mabs) is an effective prophylactic and therapeutic reagent against emerging viruses. in this article, we review current advances in neutralizing mabs against mers-cov. the receptor-binding domain (rbd ...201830513619
highly infectious diseases in the mediterranean sea area: inventory of isolation capabilities and recommendations for appropriate isolation.epidemics such as viral haemorrhagic fevers, severe acute respiratory syndrome, middle east respiratory syndrome coronavirus or yet unknown ones have few chances of disappearing. globalization, worldwide travel, climate change, social conflicts and wars, among others, are likely to favor the emergence of epidemics. preparedness of hospitals to prevent the spread of these outbreaks is among the prioritized political programmes of many countries. the euronhid network has in the past drawn a map of ...201830402245
prevalence of comorbidities in cases of middle east respiratory syndrome coronavirus: a retrospective study.the middle east respiratory syndrome coronavirus (mers-cov) is a life-threatening respiratory disease with a high case fatality rate; however, its risk factors remain unclear. we aimed to explore the influence of demographic factors, clinical manifestations and underlying comorbidities on mortality in mers-cov patients. retrospective chart reviews were performed to identify all laboratory-confirmed cases of mers-cov infection in saudi arabia that were reported to the ministry of health of saudi ...201830394248
significant spike-specific igg and neutralizing antibodies in mice induced by a novel chimeric virus-like particle vaccine candidate for middle east respiratory syndrome coronavirus. 201830374826
de novo design of α-helical lipopeptides targeting viral fusion proteins: a promising strategy for relatively broad-spectrum antiviral drug discovery.class i enveloped viruses share similarities in their apparent use of a hexameric coiled-coil assembly to drive the merging of virus and host cell membranes. inhibition of coiled coil-mediated interactions using bioactive peptides that replicate an α-helical chain from the viral fusion machinery has significant antiviral potential. here, we present the construction of a series of lipopeptides composed of a de novo heptad repeat sequence-based α-helical peptide plus a hydrocarbon tail. promisingl ...201830192544
screening for middle east respiratory syndrome coronavirus among febrile indonesian hajj pilgrims: a study on 28,197 returning pilgrims.there were 211,000 indonesian hajj pilgrims going to mecca through 11 main airports in 2015 who were at risk of contracting the middle east respiratory syndrome coronavirus (mers-cov). we aimed to find out whether there was any occurrence of mers-cov by performing screening on 28,197 returning pilgrims. those with a body temperature of > 38 °c and respiratory symptoms were sent to the airport clinic to have an oropharyngeal swab and a bacterial culture. fifteen pilgrims had fever (> 38 °c) accom ...201830159042
a screening campaign in sea urchin egg homogenate as a platform for discovering modulators of naadp-dependent ca2+ signaling in human cells.the ca2+ mobilizing second messenger nicotinic acid adenine dinucleotide phosphate (naadp) regulates intracellular trafficking events, including translocation of certain enveloped viruses through the endolysosomal system. targeting naadp-evoked ca2+ signaling may therefore be an effective strategy for discovering novel antivirals as well as therapeutics for other disorders. to aid discovery of novel scaffolds that modulate naadp-evoked ca2+ signaling in human cells, we have investigated the pote ...201830145428
a human dpp4-knockin mouse's susceptibility to infection by authentic and pseudotyped mers-cov.infection by the middle east respiratory syndrome coronavirus (mers-cov) causes respiratory illness and has a high mortality rate (~35%). the requirement for the virus to be manipulated in a biosafety level three (bsl-3) facility has impeded development of urgently-needed antiviral agents. here, we established anovel mouse model by inserting human dipeptidyl peptidase 4 (hdpp4) into the rosa26 locus using crispr/cas9, resulting in global expression of the transgene in a genetically stable mouse ...201830142928
naadp-dependent ca2+ signaling regulates middle east respiratory syndrome-coronavirus pseudovirus translocation through the endolysosomal system.middle east respiratory syndrome coronavirus (mers-cov) infections are associated with a significant mortality rate, and existing drugs show poor efficacy. identifying novel targets/pathways required for mers infectivity is therefore important for developing novel therapeutics. as an enveloped virus, translocation through the endolysosomal system provides one pathway for cellular entry of mers-cov. in this context, ca2+-permeable channels within the endolysosomal system regulate both the luminal ...201830121440
the endonucleolytic rna cleavage function of nsp1 of middle east respiratory syndrome coronavirus promotes the production of infectious virus particles in specific human cell lines.middle east respiratory syndrome coronavirus (mers-cov) nsp1 suppresses host gene expression in expressed cells by inhibiting translation and inducing endonucleolytic cleavage of host mrnas, the latter of which leads to mrna decay. we examined the biological functions of nsp1 in infected cells and its role in virus replication by using wild-type mers-cov and two mutant viruses with specific mutations in the nsp1; one mutant lacked both biological functions, while the other lacked the rna cleavag ...201830111568
mortality rate of icu patients with the middle east respiratory syndrome - coronavirus infection at king fahad hospital, jeddah, saudi arabia.the middle east respiratory syndrome coronavirus (mers-cov) is a novel coronavirus circulating in the arabian peninsula since september 2012. it leads to significant respiratory disease and among patients with co-morbidities is associated with high mortality. this research studied the mortality rate of mers-cov among intensive care unit (icu) patients and the correlation of mortality with different co-morbidities.201830102495
human β-defensin 2 plays a regulatory role in innate antiviral immunity and is capable of potentiating the induction of antigen-specific immunity.antimicrobial peptides (amps) are primarily known for their innate immune defense against invading microorganisms, including viruses. in addition, recent research has suggested their modulatory activity in immune induction. given that most subunit vaccines require an adjuvant to achieve effective immune induction through the activation of innate immunity, amps are plausible candidate molecules for stimulating not only innate immune but also adaptive immune responses.201830089512
middle east respiratory syndrome coronavirus (mers-cov) infection: epidemiology, pathogenesis and clinical characteristics.middle east respiratory syndrome coronavirus-(mers-cov) infection is an evolving worldwide health crisis. the early diagnosis and management of the disease remains a major challenge. this study designed to discuss the epidemiology, pathogenesis and clinical appearances of mers-cov infections.201830070331
inhibition of stress granule formation by middle east respiratory syndrome coronavirus 4a accessory protein facilitates viral translation, leading to efficient virus replication.stress granule (sg) formation is generally triggered as a result of stress-induced translation arrest. the impact of sg formation on virus replication varies among different viruses, and the significance of sgs in coronavirus (cov) replication is largely unknown. the present study examined the biological role of sgs in middle east respiratory syndrome (mers)-cov replication. the mers-cov 4a accessory protein is known to inhibit sg formation in cells in which it was expressed by binding to double ...201830068649
middle east respiratory syndrome coronavirus spike protein is not activated directly by cellular furin during viral entry into target cells.middle east respiratory syndrome coronavirus (mers-cov) utilizes host cellular proteases to enter cells. a previous report shows that furin, which is distributed mainly in the golgi apparatus and cycled to the cell surface and endosomes, proteolytically activates the mers-cov spike (s) protein following receptor binding to mediate fusion between the viral and cellular membranes. in this study, we reexamined furin usage by mers-cov using a real-time pcr-based virus cell entry assay after inhibiti ...201830021905
proficiency testing for the detection of middle east respiratory syndrome coronavirus demonstrates global capacity to detect middle east respiratory syndrome coronavirus.the first reported case of middle east respiratory syndrome coronavirus (mers-cov) infection was identified in saudi arabia in september 2012, since which time there have been over 2000 laboratory-confirmed cases, including 750 deaths in 27 countries. nucleic acid testing (nat) is the preferred method for the detection of mers-cov. a single round of a proficiency testing program (ptp) was used to assess the capability of laboratories globally to accurately detect the presence of mers-cov using n ...201830016543
clinical management of respiratory syndrome in patients hospitalized for suspected middle east respiratory syndrome coronavirus infection in the paris area from 2013 to 2016.patients with suspected middle east respiratory syndrome coronavirus (mers-cov) infection should be hospitalized in isolation wards to avoid transmission. this suspicion can also lead to medical confusion and inappropriate management of acute respiratory syndrome due to causes other than mers-cov.201830012113
structural definition of a unique neutralization epitope on the receptor-binding domain of mers-cov spike glycoprotein.the major mechanism of antibody-mediated neutralization of the middle east respiratory syndrome coronavirus (mers-cov) involves competition with the cellular receptor dipeptidyl peptidase 4 (dpp4) for binding to the receptor-binding domain (rbd) of the spike (s) glycoprotein. here, we report a unique epitope and unusual neutralizing mechanism of the isolated human antibody mers-4. structurally, mers-4 approached the rbd from the outside of the rbd-dpp4 binding interface. such binding resulted in ...201829996104
tmprss11a activates the influenza a virus hemagglutinin and the mers coronavirus spike protein and is insensitive against blockade by hai-1.the influenza virus hemagglutinin (ha) facilitates viral entry into target cells. cleavage of ha by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential targets for antiviral intervention. the type ii transmembrane serine protease (ttsp) tmprss2 has been identified as an ha activator in cell culture and in the infected host. however, it is less clear whether tmprss2-related enzymes can also activate ha for spread in target cells. moreover, the activit ...201829976755
structural and biochemical characterization of endoribonuclease nsp15 encoded by middle east respiratory syndrome coronavirus.nonstructural protein 15 (nsp15) encoded by coronavirus (cov) is a nidoviral uridylate-specific endoribonuclease (nendou) that plays an essential role in the life cycle of the virus. structural information on this crucial protein from the middle east respiratory syndrome cov (mers-cov), which is lethally pathogenic and has caused severe respiratory diseases worldwide, is lacking. here, we determined the crystal structure of mers-cov nsp15 at a 2.7-å resolution and performed the relevant biochemi ...201830135128
development of a diagnostic system for detection of specific antibodies and antigens against middle east respiratory syndrome coronavirus.middle east respiratory syndrome coronavirus (mers-cov) is a single-stranded rna virus that causes severe respiratory disease in humans with a high fatality rate. binding of the receptor binding domain (rbd) of the spike (s) glycoprotein to dipeptidyl peptidase 4 is the critical step in mers-cov infection of a host cell. no vaccines or clinically applicable treatments are currently available for mers-cov. therefore, rapid diagnosis is important for improving patient outcomes through prompt treat ...201830117617
current understanding of middle east respiratory syndrome coronavirus infection in human and animal models.middle east respiratory syndrome (mers) is a highly lethal respiratory disease caused by a novel betacoronavirus (mers coronavirus, mers-cov). since its first emergence in 2012, multiple transmission events of mers-cov (dromedary to human and human to human) have been reported, indicating that mers-cov has the potential to cause widespread outbreak. however, the epidemiology of mers as well as immune responses against the virus in animal models and patients are still not well understood, hinderi ...201830116605
lack of serological evidence of middle east respiratory syndrome coronavirus infection in virus exposed camel abattoir workers in nigeria, 2016.backgroundmiddle east respiratory syndrome coronavirus (mers-cov) is a zoonotic threat of global public health concern and dromedary camels are the source of zoonotic infection. although mers-cov is enzootic in dromedaries in africa as well as the middle east, zoonotic disease has not been reported in africa. methods: in an abattoir in kano, nigeria, we tested nasal swabs from camels and investigated 261 humans with repeated occupational exposure to camels, many of whom also reported drinking fr ...201830107872
reported direct and indirect contact with dromedary camels among laboratory-confirmed mers-cov cases.dromedary camels (camelus dromedarius) are now known to be the vertebrate animal reservoir that intermittently transmits the middle east respiratory syndrome coronavirus (mers-cov) to humans. yet, details as to the specific mechanism(s) of zoonotic transmission from dromedaries to humans remain unclear. the aim of this study was to describe direct and indirect contact with dromedaries among all cases, and then separately for primary, non-primary, and unclassified cases of laboratory-confirmed me ...201830104551
chimeric camel/human heavy-chain antibodies protect against mers-cov infection.middle east respiratory syndrome coronavirus (mers-cov) continues to cause outbreaks in humans as a result of spillover events from dromedaries. in contrast to humans, mers-cov-exposed dromedaries develop only very mild infections and exceptionally potent virus-neutralizing antibody responses. these strong antibody responses may be caused by affinity maturation as a result of repeated exposure to the virus or by the fact that dromedaries-apart from conventional antibodies-have relatively unique, ...201830101189
a novel nanobody targeting middle east respiratory syndrome coronavirus (mers-cov) receptor-binding domain has potent cross-neutralizing activity and protective efficacy against mers-cov.the newly emerged middle east respiratory syndrome coronavirus (mers-cov) continues to infect humans and camels, calling for efficient, cost-effective, and broad-spectrum strategies to control its spread. nanobodies (nbs) are single-domain antibodies derived from camelids and sharks and are potentially cost-effective antivirals with small size and great expression yield. in this study, we developed a novel neutralizing nb (nbms10) and its human-fc-fused version (nbms10-fc), both of which target ...201829950421
ultrapotent human neutralizing antibody repertoires against middle east respiratory syndrome coronavirus from a recovered patient.the middle east respiratory syndrome coronavirus (mers-cov) causes severe respiratory infection with a high (~35%) mortality rate. neutralizing antibodies targeting the spike of mers-cov have been shown to be a therapeutic option for treatment of lethal disease.201829846635
modeling the spread of middle east respiratory syndrome coronavirus in saudi arabia.middle east respiratory syndrome coronavirus has been persistent in the middle east region since 2012. abundant scientific evidence showed that dromedary camels are the primary host of the virus. majority of human cases (i.e., 75% or 88%) are due to human-to-human transmission, while the others are due to camel-to-human transmission. mathematical modeling of middle east respiratory syndrome coronavirus camel-to-camel transmission was lacking. using the plug-and-play likelihood-based inference fr ...201829846148
no molecular evidence of mers-cov circulation in jeddah, saudi arabia between 2010-2012: a single-center retrospective study.middle east respiratory syndrome coronavirus (mers-cov) is an emerging zoonotic viral pathogen and a serious public health concern. the virus was first reported in saudi arabia in 2012 and continues to be endemic in the region. most of the initial mers-cov cases in 2012 and early 2013 were sporadic, and it remains unclear whether mers-cov was circulating before 2012 or not. therefore, we tried here to find any molecular evidence of mers-cov circulation in humans before or during 2012 in the city ...201831865304
saracatinib inhibits middle east respiratory syndrome-coronavirus replication in vitro.the middle east respiratory syndrome-coronavirus (mers-cov), first identified in saudi arabia, is an emerging zoonotic pathogen that causes severe acute respiratory illness in humans with a high fatality rate. since its emergence, mers-cov continues to spread to countries outside of the arabian peninsula and gives rise to sporadic human infections following the entry of infected individuals to other countries, which can precipitate outbreaks similar to the one that occurred in south korea in 201 ...201829795047
effect of interferon alpha and cyclosporine treatment separately and in combination on middle east respiratory syndrome coronavirus (mers-cov) replication in a human in-vitro and ex-vivo culture model.middle east respiratory syndrome coronavirus (mers-cov) has emerged as a coronavirus infection of humans in the past 5 years. though confined to certain geographical regions of the world, infection has been associated with a case fatality rate of 35%, and this mortality may be higher in ventilated patients. as there are few readily available animal models that accurately mimic human disease, it has been a challenge to ethically determine what optimum treatment strategies can be used for this dis ...201829772254
heterologous prime-boost vaccination with adenoviral vector and protein nanoparticles induces both th1 and th2 responses against middle east respiratory syndrome coronavirus.the middle east respiratory syndrome coronavirus (mers-cov) is a highly pathogenic and zoonotic virus with a fatality rate in humans of over 35%. although several vaccine candidates have been developed, there is still no clinically available vaccine for mers-cov. in this study, we developed two types of mers-cov vaccines: a recombinant adenovirus serotype 5 encoding the mers-cov spike gene (ad5/mers) and spike protein nanoparticles formulated with aluminum (alum) adjuvant. next, we tested a hete ...201829739720
discovery of novel bat coronaviruses in south china that use the same receptor as middle east respiratory syndrome coronavirus.middle east respiratory syndrome coronavirus (mers-cov) has represented a human health threat since 2012. although several mers-related covs that belong to the same species as mers-cov have been identified from bats, they do not use the mers-cov receptor, dipeptidyl peptidase 4 (dpp4). here, we screened 1,059 bat samples from at least 30 bat species collected in different regions in south china and identified 89 strains of lineage c betacoronaviruses, including tylonycteris pachypus coronavirus ...201829669833
mers-cov pathogenesis and antiviral efficacy of licensed drugs in human monocyte-derived antigen-presenting cells.middle east respiratory syndrome coronavirus (mers-cov) presents an emerging threat to public health worldwide by causing severe respiratory disease in humans with high virulence and case fatality rate (about 35%) since 2012. little is known about the pathogenesis and innate antiviral response in primary human monocyte-derived macrophages (mdms) and dendritic cells (mddcs) upon mers-cov infection. in this study, we assessed mers-cov replication as well as induction of inflammatory cytokines and ...201829566060
the battle against sars and mers coronaviruses: reservoirs and animal models.in humans, infection with the coronavirus, especially the severe acute respiratory syndrome coronavirus (sars-cov) and the emerging middle east respiratory syndrome coronavirus (mers-cov), induces acute respiratory failure, resulting in high mortality. irregular coronavirus related epidemics indicate that the evolutionary origins of these two pathogens need to be identified urgently and there are still questions related to suitable laboratory animal models. thus, in this review we aim to highlig ...201830891557
genetic evidence of middle east respiratory syndrome coronavirus (mers-cov) and widespread seroprevalence among camels in kenya.we describe the first genome isolation of middle east respiratory syndrome coronavirus (mers-cov) in kenya. this fatal zoonotic pathogen was first described in the kingdom of saudi arabia in 2012. epidemiological and molecular evidence revealed zoonotic transmission from camels to humans and between humans. currently, mers-cov is classified by the who as having high pandemic potential requiring greater surveillance. previous studies of mers-cov in kenya mainly focused on site-specific and archiv ...201830570714
cd8+ t cells responding to the middle east respiratory syndrome coronavirus nucleocapsid protein delivered by vaccinia virus mva in mice.middle east respiratory syndrome coronavirus (mers-cov), a novel infectious agent causing severe respiratory disease and death in humans, was first described in 2012. antibodies directed against the mers-cov spike (s) protein are thought to play a major role in controlling mers-cov infection and in mediating vaccine-induced protective immunity. in contrast, relatively little is known about the role of t cell responses and the antigenic targets of mers-cov that are recognized by cd8+ t cells. in ...201830558354
the human sodium iodide symporter as a reporter gene for studying middle east respiratory syndrome coronavirus pathogenesis.single photon emission computed tomography (spect) is frequently used in oncology and cardiology to evaluate disease progression and/or treatment efficacy. such technology allows for real-time evaluation of disease progression and when applied to studying infectious diseases may provide insight into pathogenesis. insertion of a spect-compatible reporter gene into a virus may provide insight into mechanisms of pathogenesis and viral tropism. the human sodium iodide symporter (hnis), a spect and p ...201830541777
countrywide survey for mers-coronavirus antibodies in dromedaries and humans in pakistan.middle east respiratory syndrome coronavirus (mers-cov) is a zoonotic pathogen capable of causing severe respiratory disease in humans. although dromedary camels are considered as a major reservoir host, the mers-cov infection dynamics in camels are not fully understood. through surveillance in pakistan, nasal (n = 776) and serum (n = 1050) samples were collected from camels between november 2015 and february 2018. samples were collected from animal markets, free-roaming herds and abattoirs. an ...201830311100
overexpression of the nucleocapsid protein of middle east respiratory syndrome coronavirus up-regulates cxcl10.middle east respiratory syndrome coronavirus (mers-cov) causes respiratory diseases in humans and has a high mortality rate. during infection, mers-cov regulates several host cellular processes including antiviral response genes. in order to determine if the nucleocapsid protein of mers-cov (mers-n) plays a role in viral-host interactions, a murine monoclonal antibody was generated so as to allow detection of the protein in infected cells as well as in overexpression system. then, mers-n was sta ...201830242057
world health organization methodology to prioritize emerging infectious diseases in need of research and development.the world health organization r&d blueprint aims to accelerate the availability of medical technologies during epidemics by focusing on a list of prioritized emerging diseases for which medical countermeasures are insufficient or nonexistent. the prioritization process has 3 components: a delphi process to narrow down a list of potential priority diseases, a multicriteria decision analysis to rank the short list of diseases, and a final delphi round to arrive at a final list of 10 diseases. a gr ...201830124424
a spike-modified middle east respiratory syndrome coronavirus (mers-cov) infectious clone elicits mild respiratory disease in infected rhesus macaques.the recurrence of new human cases of middle east respiratory syndrome coronavirus (mers-cov) underscores the need for effective therapeutic countermeasures. nonhuman primate models are considered the gold standard for preclinical evaluation of therapeutic countermeasures. however, mers-cov-induced severe respiratory disease in humans is associated with high viral loads in the lower respiratory tract, which may be difficult to achieve in nonhuman primate models. considering this limitation, we wa ...201830013082
adaptive evolution of mers-cov to species variation in dpp4.middle east respiratory syndrome coronavirus (mers-cov) likely originated in bats and passed to humans through dromedary camels; however, the genetic mechanisms underlying cross-species adaptation remain poorly understood. variation in the host receptor, dipeptidyl peptidase 4 (dpp4), can block the interaction with the mers-cov spike protein and form a species barrier to infection. to better understand the species adaptability of mers-cov, we identified a suboptimal species-derived variant of dp ...201830110630
nsp3 of coronaviruses: structures and functions of a large multi-domain protein.the multi-domain non-structural protein 3 (nsp3) is the largest protein encoded by the coronavirus (cov) genome, with an average molecular mass of about 200 kd. nsp3 is an essential component of the replication/transcription complex. it comprises various domains, the organization of which differs between cov genera, due to duplication or absence of some domains. however, eight domains of nsp3 exist in all known covs: the ubiquitin-like domain 1 (ubl1), the glu-rich acidic domain (also called "hy ...201829128390
inactivation of middle east respiratory syndrome-coronavirus in human plasma using amotosalen and ultraviolet a light.middle east respiratory syndrome-coronavirus (mers-cov) is a novel zoonotic pathogen. although the potential for mers-cov transmission through blood transfusion is not clear, mers-cov was recognized as a pathogen of concern for the safety of the blood supply especially after its detection in whole blood, serum, and plasma of infected individuals. here we investigated the efficacy of amotosalen and ultraviolet a light (uva) to inactivate mers-cov in fresh-frozen plasma (ffp).201829239484
event based surveillance of middle east respiratory syndrome coronavirus (mers- cov) in bangladesh among pilgrims and travelers from the middle east: an update for the period 2013-2016.every year around 150,000 pilgrims from bangladesh perform umrah and hajj. emergence and continuous reporting of mers-cov infection in saudi arabia emphasize the need for surveillance of mers-cov in returning pilgrims or travelers from the middle east and capacity building of health care providers for disease containment. the institute of epidemiology, disease control & research (iedcr) under the bangladesh ministry of health and family welfare (mohfw), is responsible for mers-cov screening of p ...201829337997
[molecular epidemiological study of human coronavirus oc43 in shanghai from 2009-2016].objective:to understand the epidemiological characteristics of human coronavirus (hcov), the patterns of emergence and circulation, and the genotype distribution of human coronavirus oc43 (hcov-oc43) from november, 2009 to april, 2016 in shanghai.methods:a total of 6 059 respiratory specimens, including pharyngeal swab, sputum, nasopharyngeal aspirates and alveolar lavage fluid, as well as relative clinical data were collected from patients with acute respiratory infections from seven sentinel h ...201829334709
extracorporeal membrane oxygenation for severe middle east respiratory syndrome coronavirus.middle east respiratory syndrome (mers) is caused by a coronavirus (mers-cov) and is characterized by hypoxemic respiratory failure. the objective of this study is to compare the outcomes of mers-cov patients before and after the availability of extracorporeal membrane oxygenation (ecmo) as a rescue therapy in severely hypoxemic patients who failed conventional strategies.201829330690
safety and tolerability of a novel, polyclonal human anti-mers coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study.middle east respiratory syndrome (mers) is a severe respiratory illness with an overall mortality of 35%. there is no licensed or proven treatment. passive immunotherapy approaches are being developed to prevent and treat several human medical conditions where alternative therapeutic options are absent. we report the safety of a fully human polyclonal igg antibody (sab-301) produced from the hyperimmune plasma of transchromosomic cattle immunised with a mers coronavirus vaccine.201829329957
characterization of novel monoclonal antibodies against the mers-coronavirus spike protein and their application in species-independent antibody detection by competitive elisa.since discovering the middle east respiratory syndrome coronavirus (mers-cov) as a causative agent of severe respiratory illness in the middle east in 2012, serological testing has been conducted to assess antibody responses in patients and to investigate the zoonotic reservoir of the virus. although the virus neutralization test is the gold standard assay for mers diagnosis and for investigating the zoonotic reservoir, it uses live virus and so must be performed in high containment laboratories ...201828993122
host susceptibility to mers-cov infection, a retrospective cohort study of the 2015 korean mers outbreak.to evaluate host susceptibility factors to middle east respiratory syndrome coronavirus (mers-cov) infection, we conducted a retrospective cohort study from the single largest exposure event of the 2015 korean mers outbreak. a total of 175 patients were closely exposed to a super-spreader, 26 of which were infected (14.9%). in a multivariate analysis, history of autologous stem cell transplantation (hr, 31.151; 95% ci, 5.447-178.145; p < 0.001) and tachypnea at ed (hr, 4.392; 95% ci, 1.402-13.76 ...201829223614
investigation of nonlinear epidemiological models for analyzing and controlling the mers outbreak in korea.much concern has arisen regarding serious epidemics due to the middle east respiratory syndrome (mers) coronavirus. the first mers case of korea was reported on 20 may 2015, and since then, the mers outbreak in korea has resulted in hundreds of confirmed cases and tens of deaths. deadly infectious diseases such as mers have significant direct and indirect social impacts, which include disease-induced mortality and economic losses. also, a delayed response to the outbreak and underestimating its ...201829031518
development of middle east respiratory syndrome coronavirus vaccines - advances and challenges.middle east respiratory syndrome coronavirus (mers-cov) is an emerging pathogen with the potential to pose a threat to global public health. sporadic cases and outbreaks continue to be reported in the middle east, and case fatality rates remain high at approximately 36% globally. no specific preventive or therapeutic countermeasures currently exist. a safe and effective vaccine could play an important role in protecting against the threat from mers-cov. this review discusses human vaccine candid ...201829048984
the experience of korean nurses during the middle east respiratory syndrome outbreak.the authors in this article explore the experiences of eight south korean nurses during an outbreak of the middle east respiratory syndrome (mers), which took place in the fall of 2015. these nurses were mandated to remain in isolation in an intensive care unit (icu) dedicated to the treatment of the patients with the mers virus for 7 days. parse's humanbecoming theory was used to frame the discussion. three themes found in the nurse's stories are discussed: feeling hopeless and cut off, feeling ...201829235956
definitive diagnosis in suspected middle east respiratory syndrome coronavirus cases.we evaluated the microbiological diagnosis in 14 patients with epidemiological and clinical suspicion of middle east respiratory syndrome coronavirus (mers-cov) attended in a non-endemic area between june 2015 and january 2017. while no mers-cov was detected, other respiratory viruses were identified in 12 cases and mycoplasma pneumoniae in 1 case.201829232459
current treatment options and the role of peptides as potential therapeutic components for middle east respiratory syndrome (mers): a review.middle east respiratory syndrome coronavirus (mers-cov) is a highly pathogenic respiratory virus with mechanisms that may be driven by innate immune responses. despite the effort of scientific studies related to this virus, middle east respiratory syndrome (mers) is still a public health concern. mers-cov infection has a high mortality rate, and to date, no therapeutic or vaccine has been discovered, that is effective in treating or preventing the disease. in this review, we summarize our unders ...201828864360
clinical pearls in venovenous extracorporeal life support for adult respiratory failure.extracorporeal life support (ecls) has been widely utilized to treat neonatal respiratory failure for two decades. however, its uptake in the case of adult respiratory failure has been slow because of a paucity of quality evidence and a sluggish tempo of ecls-related technological advances. in recent years, interest in ecls has been piqued after encouraging results were reported from its use during the 2009 h1n1 influenza pandemic. in a world constantly under threat from another influenza epidem ...201828885377
inclusion of mers-spike protein elisa in algorithm to determine serologic evidence of mers-cov infection.the centers for disease control and prevention (cdc) algorithm for detecting presence of serum antibodies against middle east respiratory syndrome coronavirus (mers-cov) in subjects with potential infections with the virus has included screening by indirect elisa against recombinant nucleocapsid (n) protein and confirmation by immunofluorescent staining of infected monolayers and/or microneutralization titration. other international groups include indirect elisa assays using the spike (s) protei ...201828906003
middle east respiratory syndrome coronavirus transmission among health care workers: implication for infection control.many outbreaks of middle east respiratory syndrome coronavirus (mers-cov) have occurred in health care settings and involved health care workers (hcws). we describe the occurrence of an outbreak among hcws and attempt to characterize at-risk exposures to improve future infection control interventions.201828958446
nmr structure and localization of a large fragment of the sars-cov fusion protein: implications in viral cell fusion.the lethal coronaviruses (covs), severe acute respiratory syndrome-associated coronavirus (sars-cov) and most recently middle east respiratory syndrome coronavirus, (mers-cov) are serious human health hazard. a successful viral infection requires fusion between virus and host cells carried out by the surface spike glycoprotein or s protein of cov. current models propose that the s2 subunit of s protein assembled into a hexameric helical bundle exposing hydrophobic fusogenic peptides or fusion pe ...201828988778
a study of the probable transmission routes of mers-cov during the first hospital outbreak in the republic of korea.infections caused by the middle east respiratory syndrome coronavirus (mers-cov) are a serious health issue due to their prevalence and associated mortality. however, the transmission routes of the virus remain unclear, and thus, the current recommended control strategies are not evidence based. in this study, we investigated the transmission routes of mers-cov during the first nosocomial outbreak in the republic of korea in may 2015 using a multi-agent modeling framework. we identified seven hy ...201828960494
recent advances in aiv biosensors composed of nanobio hybrid material.since the beginning of the 2000s, globalization has accelerated because of the development of transportation systems that allow for human and material exchanges throughout the world. however, this globalization has brought with it the rise of various pathogenic viral agents, such as middle east respiratory syndrome coronavirus (mers-cov), severe acute respiratory syndrome coronavirus (sars-cov), zika virus, and dengue virus. in particular, avian influenza virus (aiv) is highly infectious and cau ...201830544883
multicenter evaluation of the biofire filmarray respiratory panel 2 for the detection of viruses and bacteria in nasopharyngeal swab samples.the filmarray® respiratory panel 2 (rp2) is a multiplexin vitrodiagnostic test for the simultaneous and rapid (∼45 minutes) detection of 22 pathogens directly from nasopharyngeal swab (nps) samples. it contains updated (and in some instances redesigned) assays that improve upon the filmarray® respiratory panel (rp; version 1.7), with a faster run time. the organisms identified are adenovirus, coronavirus 229e, coronavirus hku1, coronavirus nl63, coronavirus oc43, human metapneumovirus, human rhi ...201829593057
dynamics of interorganizational public health emergency management networks: following the 2015 mers response in south korea.we investigated public health emergency management networks during the recent outbreak of middle east respiratory syndrome coronavirus that affected more than 17 000 people in south korea.201829561166
coronavirus s protein-induced fusion is blocked prior to hemifusion by abl kinase inhibitors.enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. coronaviruses, including the severe acute respiratory syndrome coronavirus (sars-cov), middle east respiratory syndrome coronavirus (mers-cov) and infectious bronchitis virus (ibv), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. the virus spike (s) protein mediates fusion with the host cell ...201829557770
hosts and sources of endemic human coronaviruses.the four endemic human coronaviruses hcov-229e, -nl63, -oc43, and -hku1 contribute a considerable share of upper and lower respiratory tract infections in adults and children. while their clinical representation resembles that of many other agents of the common cold, their evolutionary histories, and host associations could provide important insights into the natural history of past human pandemics. for two of these viruses, we have strong evidence suggesting an origin in major livestock species ...201829551135
initial performance evaluation of a spotted array mobile analysis platform (map) for the detection of influenza a/b, rsv, and mers coronavirus.clinical samples were evaluated with the mobile analysis platform (map) to determine platform performance for detecting respiratory viruses in samples previously characterized using clinical reverse transcriptase polymerase chain reaction assays. the percent agreement between map and clinical results was 97% for influenza a (73/75), 100% (21/21) for influenza b, 100% (6/6) for respiratory syncytial virus (rsv), and 80% (4/5) for negative specimens. the approximate limit of detection of the map w ...201829550057
knowledge and attitude towards the middle east respiratory syndrome coronavirus among healthcare personnel in the southern region of saudi arabia.middle east respiratory syndrome coronavirus (mers-cov) belongs to the family coronaviridae, and is named for the crown-like spikes on its surface. the clinical presentation of mers-cov infection ranges from asymptomatic to very severe disease, and the classical presentation includes fever, cough chills, sore throat, myalgia, and arthralgia.201829525570
importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on mers-cov spike to avoid neutralization escape.middle east respiratory syndrome coronavirus (mers-cov) causes a highly lethal pulmonary infection with ∼35% mortality. the potential for a future pandemic originating from animal reservoirs or healthcare-associated events is a major public health concern. there are no vaccines or therapeutic agents currently available for mers-cov. using a probe-based single b cell-cloning strategy, we have identified and characterized multiple neutralizing mabs specifically binding to the receptor binding doma ...201829514901
rapid detection of mers coronavirus-like viruses in bats: pote1ntial for tracking mers coronavirus transmission and animal origin.recently, we developed a monoclonal antibody-based rapid nucleocapsid protein detection assay for diagnosis of mers coronavirus (mers-cov) in humans and dromedary camels. in this study, we examined the usefulness of this assay to detect other lineage c betacoronaviruses closely related to mers-cov in bats. the rapid mers-cov nucleocapsid protein detection assay was tested positive in 24 (88.9%) of 27 tylonycteris bat cov hku4 (ty-batcov-hku4) rna-positive alimentary samples of tylonycteris pachy ...201829511173
coronavirus susceptibility to the antiviral remdesivir (gs-5734) is mediated by the viral polymerase and the proofreading exoribonuclease.emerging coronaviruses (covs) cause severe disease in humans, but no approved therapeutics are available. the cov nsp14 exoribonuclease (exon) has complicated development of antiviral nucleosides due to its proofreading activity. we recently reported that the nucleoside analogue gs-5734 (remdesivir) potently inhibits human and zoonotic covsin vitroand in a severe acute respiratory syndrome coronavirus (sars-cov) mouse model. however, studies with gs-5734 have not reported resistance associated w ...201829511076
mers coronaviruses from camels in africa exhibit region-dependent genetic diversity.middle east respiratory syndrome coronavirus (mers-cov) causes a zoonotic respiratory disease of global public health concern, and dromedary camels are the only proven source of zoonotic infection. although mers-cov infection is ubiquitous in dromedaries across africa as well as in the arabian peninsula, zoonotic disease appears confined to the arabian peninsula. mers-covs from africa have hitherto been poorly studied. we genetically and phenotypically characterized mers-cov from dromedaries sam ...201829507189
mers-cov: understanding the latest human coronavirus threat.human coronaviruses cause both upper and lower respiratory tract infections in humans. in 2012, a sixth human coronavirus (hcov) was isolated from a patient presenting with severe respiratory illness. the 60-year-old man died as a result of renal and respiratory failure after admission to a hospital in jeddah, saudi arabia. the aetiological agent was eventually identified as a coronavirus and designated middle east respiratory syndrome coronavirus (mers-cov). mers-cov has now been reported in mo ...201829495250
pathogenicity and viral shedding of mers-cov in immunocompromised rhesus macaques.middle east respiratory syndrome coronavirus (mers-cov) has recently emerged in the middle east. since 2012, there have been approximately 2,100 confirmed cases, with a 35% case fatality rate. disease severity has been linked to patient health status, as people with chronic diseases or an immunocompromised status fare worse, although the mechanisms of disease have yet to be elucidated. we used the rhesus macaque model of mild mers to investigate whether the immune response plays a role in the pa ...201829483914
simple, rapid and sensitive portable molecular diagnosis of sfts virus using reverse transcriptional loop-mediated isothermal amplification (rt-lamp).recently, human infections caused by severe fever with thrombocytopenia syndrome virus (sftsv), which can lead to fatality, have dramatically increased in east asia. with the unavailability of vaccines or antiviral drugs to prevent and/or treat sftsv infection, early rapid diagnosis is critical for prevention and control of the disease. here, we report the development of a simple, rapid and sensitive portable detection method for sftsv infection applying reverse transcription-loop mediated isoth ...201830270605
a recombinant vsv-vectored mers-cov vaccine induces neutralizing antibody and t cell responses in rhesus monkeys after single dose immunization.middle east respiratory syndrome coronavirus (mers-cov) has been a highly threatening zoonotic pathogen since its outbreak in 2012. similar to sars-cov, mers-cov belongs to the coronavirus family and can induce severe respiratory symptoms in humans, with an average case fatality rate of 35% according to the world health organization. spike (s) protein of mers-cov is immunogenic and can induce neutralizing antibodies, thus is a potential major target for vaccine development. here we constructed a ...201829246504
receptor usage of a novel bat lineage c betacoronavirus reveals evolution of mers-related coronavirus spike proteins for human dpp4 binding.although bats are known to harbor mers-cov-related viruses, the role of bats in the evolutionary origin and pathway remains obscure. we identified a novel mers-cov-related betacoronavirus, hp-batcov hku25, from chinese pipistrelle bats. while being closely related to mers-cov in most genome regions, its spike protein occupies a phylogenetic position between that of ty-batcov hku4 and pi-batcov hku5. since ty-batcov hku4 but not pi-batcov hku5 can utilize mers-cov receptor, hdpp4, for cell entry, ...201829346682
mers-cov infection in humans is associated with a pro-inflammatory th1 and th17 cytokine profile.the middle east respiratory syndrome coronavirus (mers-cov) has been recognized as a highly pathogenic virus to humans that infects the respiratory tract and is associated with high morbidity and mortality. studies in animal models suggest that mers-cov infection induces a strong inflammatory response, which may be related to the severity of disease. data showing the cytokine profiles in humans during the acute phase of mers-cov infection are limited. in this study, we have analyzed the profile ...201829414327
the prevalence of middle east respiratory syndrome coronavirus (mers-cov) infection in livestock and temporal relation to locations and seasons.the middle east respiratory syndrome (mers) has been reported for the first time infecting a human being since 2012. the who was notified of 27 countries have reported cases of mers, the majority of these cases occur in the arabian peninsula, particularly in saudi arabia. dromedary camels are likely to be the main source of middle east respiratory syndrome virus (mers-cov) infection in humans.201829396257
mers-cov spillover at the camel-human interface.middle east respiratory syndrome coronavirus (mers-cov) is a zoonotic virus from camels causing significant mortality and morbidity in humans in the arabian peninsula. the epidemiology of the virus remains poorly understood, and while case-based and seroepidemiological studies have been employed extensively throughout the epidemic, viral sequence data have not been utilised to their full potential. here, we use existing mers-cov sequence data to explore its phylodynamics in two of its known majo ...201829336306
dpp4, the middle east respiratory syndrome coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients.middle east respiratory syndrome coronavirus (mers-cov) causes pneumonia with a relatively high case fatality rate in humans. smokers and chronic obstructive pulmonary disease (copd) patients have been reported to be more susceptible to mers-cov infection. here, we determined the expression of mers-cov receptor, dipeptidyl peptidase iv (dpp4), in lung tissues of smokers without airflow limitation and copd patients in comparison to nonsmoking individuals (never-smokers).201829020176
discovery of hydrocarbon-stapled short α-helical peptides as promising middle east respiratory syndrome coronavirus (mers-cov) fusion inhibitors.the hexameric α-helical coiled-coil formed between the c-terminal and n-terminal heptad repeat (chr and nhr) regions of class i viral fusion proteins plays an important role in mediating the fusion of the viral and cellular membranes and provides a clear starting point for molecular mimicry that drives viral fusion inhibitor design. unfortunately, such peptide mimicry of the short α-helical region in the chr of middle east respiratory syndrome coronavirus (mers-cov) spike protein has been thwart ...201829442512
mental health of nurses working at a government-designated hospital during a mers-cov outbreak: a cross-sectional study.during an epidemic of a novel infectious disease, many healthcare workers suffer from mental health problems.201829413067
detection of zika virus using reverse-transcription lamp coupled with reverse dot blot analysis in saliva.in recent years, there have been increasing numbers of infectious disease outbreaks that spread rapidly to population centers resulting from global travel, population vulnerabilities, environmental factors, and ecological disasters such as floods and earthquakes. some examples of the recent outbreaks are the ebola epidemic in west africa, middle east respiratory syndrome coronavirus (mers-co) in the middle east, and the zika outbreak through the americas. we have created a generic protocol for d ...201829401479
the calm before the storm: clinical observations of middle east respiratory syndrome (mers) patients.middle east respiratory syndrome coronavirus (mers-cov) infection emerged in 2012. the majority of cases occurred in the kingdom of saudi arabia and the disease carries a high case fatality rate.201829385908
treatment of middle east respiratory syndrome with a combination of lopinavir-ritonavir and interferon-β1b (miracle trial): study protocol for a randomized controlled trial.it had been more than 5 years since the first case of middle east respiratory syndrome coronavirus infection (mers-cov) was recorded, but no specific treatment has been investigated in randomized clinical trials. results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-β1b (ifn-β1b) may be effective against mers-cov. the aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant ifn-β1b ...201829382391
mers-cov 4b protein interferes with the nf-κb-dependent innate immune response during infection.middle east respiratory syndrome coronavirus (mers-cov) is a novel human coronavirus that emerged in 2012, causing severe pneumonia and acute respiratory distress syndrome (ards), with a case fatality rate of ~36%. when expressed in isolation, cov accessory proteins have been shown to interfere with innate antiviral signaling pathways. however, there is limited information on the specific contribution of mers-cov accessory protein 4b to the repression of the innate antiviral response in the cont ...201829370303
the hajj 2019 vaccine requirements and possible new challenges.each year millions of pilgrims perform the annual hajj from more than 180 countries around the world. this is one of the largest mass gathering events and may result in the occurrence and spread of infectious diseases. as such, there are mandatory vaccinations for the pilgrims such as meningococcal vaccines. the 2019 annual hajj will take place during august 8-13, 2019. thus, we review the recommended and mandated vaccinations for the 2019 hajj and umrah. the mandatory vaccines required to secur ...201931529930
precision mouse models with expanded tropism for human pathogens.a major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. however, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implan ...201931451733
design, synthesis, and anti-rna virus activity of 6'-fluorinated-aristeromycin analogues.the 6'-fluorinated aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral rna-dependent rna polymerase (rdrp) and the host cell s-adenosyl-l-homocysteine (sah) hydrolase, which would indirectly target capping of viral rna. the introduction of a fluorine at the 6'-position enhanced the inhibition of sah hydrolase and the activity against rna viruses. the adenosine and n6-methyladenosine analogues 2a-e showed potent inhibition against sah hydrolase, whil ...201931244113
probing the effects of pyrimidine functional group switches on acyclic fleximer analogues for antiviral activity.due to their ability to inhibit viral dna or rna replication, nucleoside analogues have been used for decades as potent antiviral therapeutics. however, one of the major limitations of nucleoside analogues is the development of antiviral resistance. in that regard, flexible nucleoside analogues known as "fleximers" have garnered attention over the years due to their ability to survey different amino acids in enzyme binding sites, thus overcoming the potential development of antiviral resistance. ...201931480658
identification of 6'-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication.we have reported on aristeromycin (1) and 6'-fluorinated-aristeromycin analogues (2), which are active against rna viruses such as middle east respiratory syndrome coronavirus (mers-cov), severe acute respiratory syndrome coronavirus (sars-cov), zika virus (zikv), and chikungunya virus (chikv). however, these exhibit substantial cytotoxicity. as this cytotoxicity may be attributed to 5'-phosphorylation, we designed and synthesized one-carbon homologated 6'-fluorinated-aristeromycin analogues. th ...201931841728
recombinant adenoviral vaccine encoding the spike 1 subunit of the middle east respiratory syndrome coronavirus elicits strong humoral and cellular immune responses in mice.middle east respiratory syndrome coronavirus (mers-cov) has rapidly spread throughout the middle east since its discovery in 2012. the virus poses a significant global public health threat with potentially devastating effects. in this study, a recombinant adenoviral-based vaccine encoding the spike 1 (s1) subunit of the mers-cov genome was constructed, and its humoral, and cellular immune responses were evaluated in mice.201931849416
the characteristics of hdpp4 transgenic mice subjected to aerosol mers coronavirus infection via an animal nose-only exposure device.middle east respiratory syndrome coronavirus (mers-cov), which is not fully understood in regard to certain transmission routes and pathogenesis and lacks specific therapeutics and vaccines, poses a global threat to public health.201931942559
blocking transmission of middle east respiratory syndrome coronavirus (mers-cov) in llamas by vaccination with a recombinant spike protein.the ongoing middle east respiratory syndrome coronavirus (mers-cov) outbreaks pose a worldwide public health threat. blocking mers-cov zoonotic transmission from dromedary camels, the animal reservoir, could potentially reduce the number of primary human cases. here we report mers-cov transmission from experimentally infected llamas to naïve animals. directly inoculated llamas shed virus for at least 6 days and could infect all in-contact naïve animals 4-5 days after exposure. with the aim to bl ...201931711379
cepi: driving progress toward epidemic preparedness and response.the coalition for epidemic preparedness innovations (cepi) was formed in the aftermath of the 2014-2015 ebola outbreak in west africa to support the development of vaccines that could improve the world's preparedness against outbreaks of epidemic infectious diseases. since its launch in 2017, cepi has mobilized more than us$750 million to support its mission to develop vaccines against agents such as lassa virus, middle east respiratory syndrome coronavirus, and nipah virus, as well as several r ...201931673694
the middle east respiratory syndrome (mers).the middle east respiratory syndrome (mers) is a novel lethal zoonotic disease of humans caused by the mers coronavirus (mers-cov). although mers is endemic to the middle east, travelers have exported mers-cov on return to their home countries. clinical manifestations range from mild to severe acute respiratory disease and death. the elderly, immunocompromised, and those with chronic comorbid liver, lung, and hepatic conditions have a high mortality rate. there is no specific treatment. person-t ...201931668197
from four-way linking to a one health platform in egypt: institutionalisation of a multidisciplinary and multisectoral one health system.the convergence of humans, animals and our shared environment results in a dynamic in which the health of each group is inextricably linked. taking into account the fact that the majority of emerging pathogens (e.g. highly pathogenic avian influenza [hpai], severe acute respiratory syndrome coronavirus, nipah virus, middle east respiratory syndrome coronavirus) are zoonotic diseases, egypt has established a national one health coordination mechanism. the primary purpose of this mechanism is to p ...201931564724
structural insights into coronavirus entry.coronaviruses (covs) have caused outbreaks of deadly pneumonia in humans since the beginning of the 21st century. the severe acute respiratory syndrome coronavirus (sars-cov) emerged in 2002 and was responsible for an epidemic that spread to five continents with a fatality rate of 10% before being contained in 2003 (with additional cases reported in 2004). the middle-east respiratory syndrome coronavirus (mers-cov) emerged in the arabian peninsula in 2012 and has caused recurrent outbreaks in hu ...201931522710
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