PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T18	0-12	Sentence	denotes	INTRODUCTION
T19	13-148	Sentence	denotes	Over the past 2 decades, coronaviruses (CoVs) have been associated with significant disease outbreaks in East Asia and the Middle East.
T20	149-289	Sentence	denotes	The severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) began to emerge in 2002 and 2012, respectively.
T21	290-557	Sentence	denotes	Recently, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), emerged in late 2019, and it has posed a global health threat, causing an ongoing pandemic in many countries and territories (1).
T22	558-788	Sentence	denotes	Health workers worldwide are currently making efforts to control further disease outbreaks caused by the novel CoV (originally named 2019-nCoV), which was first identified in Wuhan City, Hubei Province, China, on 12 December 2019.
T23	789-957	Sentence	denotes	On 11 February 2020, the World Health Organization (WHO) announced the official designation for the current CoV-associated disease to be COVID-19, caused by SARS-CoV-2.
T24	958-1072	Sentence	denotes	The primary cluster of patients was found to be connected with the Huanan South China Seafood Market in Wuhan (2).
T25	1073-1340	Sentence	denotes	CoVs belong to the family Coronaviridae (subfamily Coronavirinae), the members of which infect a broad range of hosts, producing symptoms and diseases ranging from the common cold to severe and ultimately fatal illnesses, such as SARS, MERS, and, presently, COVID-19.
T26	1341-1544	Sentence	denotes	SARS-CoV-2 is considered one of the seven members of the CoV family that infect humans (3), and it belongs to the same lineage of CoVs that causes SARS; however, this novel virus is genetically distinct.
T27	1545-1689	Sentence	denotes	Until 2020, six CoVs were known to infect humans, including human CoV 229E (HCoV-229E), HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, and MERS-CoV.
T28	1690-1842	Sentence	denotes	Although SARS-CoV and MERS-CoV have resulted in outbreaks with high mortality, others remain associated with mild upper-respiratory-tract illnesses (4).
T29	1843-1905	Sentence	denotes	Newly evolved CoVs pose a high threat to global public health.
T30	1906-2004	Sentence	denotes	The current emergence of COVID-19 is the third CoV outbreak in humans over the past 2 decades (5).
T31	2005-2150	Sentence	denotes	It is no coincidence that Fan et al. predicted potential SARS- or MERS-like CoV outbreaks in China following pathogen transmission from bats (6).
T32	2151-2257	Sentence	denotes	COVID-19 emerged in China and spread rapidly throughout the country and, subsequently, to other countries.
T33	2258-2486	Sentence	denotes	Due to the severity of this outbreak and the potential of spreading on an international scale, the WHO declared a global health emergency on 31 January 2020; subsequently, on 11 March 2020, they declared it a pandemic situation.
T34	2487-2670	Sentence	denotes	At present, we are not in a position to effectively treat COVID-19, since neither approved vaccines nor specific antiviral drugs for treating human CoV infections are available (7–9).
T35	2671-2829	Sentence	denotes	Most nations are currently making efforts to prevent the further spreading of this potentially deadly virus by implementing preventive and control strategies.
T36	2830-2936	Sentence	denotes	In domestic animals, infections with CoVs are associated with a broad spectrum of pathological conditions.
T37	2937-3098	Sentence	denotes	Apart from infectious bronchitis virus, canine respiratory CoV, and mouse hepatitis virus, CoVs are predominantly associated with gastrointestinal diseases (10).
T38	3099-3288	Sentence	denotes	The emergence of novel CoVs may have become possible because of multiple CoVs being maintained in their natural host, which could have favored the probability of genetic recombination (10).
T39	3289-3543	Sentence	denotes	High genetic diversity and the ability to infect multiple host species are a result of high-frequency mutations in CoVs, which occur due to the instability of RNA-dependent RNA polymerases along with higher rates of homologous RNA recombination (10, 11).
T40	3544-3733	Sentence	denotes	Identifying the origin of SARS-CoV-2 and the pathogen’s evolution will be helpful for disease surveillance (12), development of new targeted drugs, and prevention of further epidemics (13).
T41	3734-3859	Sentence	denotes	The most common symptoms associated with COVID-19 are fever, cough, dyspnea, expectoration, headache, and myalgia or fatigue.
T42	3860-3984	Sentence	denotes	In contrast, less common signs at the time of hospital admission include diarrhea, hemoptysis, and shortness of breath (14).
T43	3985-4181	Sentence	denotes	Recently, individuals with asymptomatic infections were also suspected of transmitting infections, which further adds to the complexity of disease transmission dynamics in COVID-19 infections (1).
T44	4182-4332	Sentence	denotes	Such efficient responses require in-depth knowledge regarding the virus, which currently is a novel agent; consequently, further studies are required.
T45	4333-4554	Sentence	denotes	Comparing the genome of SARS-CoV-2 with that of the closely related SARS/SARS-like CoV revealed that the sequence coding for the spike protein, with a total length of 1,273 amino acids, showed 27 amino acid substitutions.
T46	4555-4712	Sentence	denotes	Six of these substitutions are in the region of the receptor-binding domain (RBD), and another six substitutions are in the underpinning subdomain (SD) (16).
T47	4713-4901	Sentence	denotes	Phylogenetic analyses have revealed that SARS-CoV-2 is closely related (88% similarity) to two SARS-like CoVs derived from bat SARS-like CoVs (bat-SL-CoVZC45 and bat-SL-CoVZXC21) (Fig. 1).
T48	4902-5012	Sentence	denotes	Furthermore, SARS-CoV-2 is genetically distinct from SARS-CoV (79% similarity) and MERS-CoV (nearly 50%) (17).
T49	5013-5310	Sentence	denotes	COVID-19 is associated with afflictions of the lungs in all cases and generated characteristic chest computer tomography findings, such as the presence of multiple lesions in lung lobes that appear as dense, ground-glass opaque structures that occasionally coexist with consolidation shadows (18).
T50	5311-5345	Sentence	denotes	FIG 1 S-gene SplitsTree analysis.
T51	5346-5468	Sentence	denotes	Shown is the spike (S) glycoprotein gene-based phylogenetic analysis (SplitsTree 4.0) of SAR-CoV-2 isolates (39 isolates).
T52	5469-5684	Sentence	denotes	The SARS-CoV-2 isolates were analyzed with related CoVs from past human outbreaks and of animal origin, including MERS-CoV, bovine coronavirus, canine coronavirus, bat coronaviruses, bat-SL-SARS-CoV, and equine CoV.
T53	5685-5834	Sentence	denotes	The analysis includes all five defined subgenera of Betacoronaviruses, namely, Sarbecovirus, Embecovirus, Merbecovirus, Nobecovirus, and Hibecovirus.
T54	5835-5931	Sentence	denotes	The isolates in the gray area are from the current outbreak of SARS-CoV-2 from around the world.
T55	5932-6008	Sentence	denotes	The nearest neighbors of SARS-CoV-2 are the bat-SL-CoV, encircled in yellow.
T56	6009-6275	Sentence	denotes	Some therapeutic options for treating COVID-19 showed efficacy in in vitro studies; however, to date, these treatments have not undergone any randomized animal or human clinical trials, which limit their practical applicability in the current pandemic (7, 9, 19–21).
T57	6276-6468	Sentence	denotes	The present comprehensive review describes the various features of SARS-CoV-2/COVID-19 causing the current disease outbreaks and advances in diagnosis and developing vaccines and therapeutics.
T58	6469-6761	Sentence	denotes	It also provides a brief comparison with the earlier SARS and MERS CoVs, the veterinary perspective of CoVs and this emerging novel pathogen, and an evaluation of the zoonotic potential of similar CoVs to provide feasible One Health strategies for the management of this fatal virus (22–367).
T59	6763-6785	Sentence	denotes	THE VIRUS (SARS-CoV-2)
T60	6786-6927	Sentence	denotes	Coronaviruses are positive-sense RNA viruses having an extensive and promiscuous range of natural hosts and affect multiple systems (23, 24).
T61	6928-7082	Sentence	denotes	Coronaviruses can cause clinical diseases in humans that may extend from the common cold to more severe respiratory diseases like SARS and MERS (17, 279).
T62	7083-7349	Sentence	denotes	The recently emerging SARS-CoV-2 has wrought havoc in China and caused a pandemic situation in the worldwide population, leading to disease outbreaks that have not been controlled to date, although extensive efforts are being put in place to counter this virus (25).
T63	7350-7680	Sentence	denotes	This virus has been proposed to be designated/named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (ICTV), which determined the virus belongs to the Severe acute respiratory syndrome-related coronavirus category and found this virus is related to SARS-CoVs (26).
T64	7681-7908	Sentence	denotes	SARS-CoV-2 is a member of the order Nidovirales, family Coronaviridae, subfamily Orthocoronavirinae, which is subdivided into four genera, viz., Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (3, 27).
T65	7909-8084	Sentence	denotes	The genera Alphacoronavirus and Betacoronavirus originate from bats, while Gammacoronavirus and Deltacoronavirus have evolved from bird and swine gene pools (24, 28, 29, 275).
T66	8085-8229	Sentence	denotes	Coronaviruses possess an unsegmented, single-stranded, positive-sense RNA genome of around 30 kb, enclosed by a 5′-cap and 3′-poly(A) tail (30).
T67	8230-8305	Sentence	denotes	The genome of SARS-CoV-2 is 29,891 bp long, with a G+C content of 38% (31).
T68	8306-8381	Sentence	denotes	These viruses are encircled with an envelope containing viral nucleocapsid.
T69	8382-8514	Sentence	denotes	The nucleocapsids in CoVs are arranged in helical symmetry, which reflects an atypical attribute in positive-sense RNA viruses (30).
T70	8515-8760	Sentence	denotes	The electron micrographs of SARS-CoV-2 revealed a diverging spherical outline with some degree of pleomorphism, virion diameters varying from 60 to 140 nm, and distinct spikes of 9 to 12 nm, giving the virus the appearance of a solar corona (3).
T71	8761-8871	Sentence	denotes	The CoV genome is arranged linearly as 5′-leader-UTR-replicase-structural genes (S-E-M-N)-3′ UTR-poly(A) (32).
T72	8872-9009	Sentence	denotes	Accessory genes, such as 3a/b, 4a/b, and the hemagglutinin-esterase gene (HE), are also seen intermingled with the structural genes (30).
T73	9010-9187	Sentence	denotes	SARS-CoV-2 has also been found to be arranged similarly and encodes several accessory proteins, although it lacks the HE, which is characteristic of some betacoronaviruses (31).
T74	9188-9297	Sentence	denotes	The positive-sense genome of CoVs serves as the mRNA and is translated to polyprotein 1a/1ab (pp1a/1ab) (33).
T75	9298-9456	Sentence	denotes	A replication-transcription complex (RTC) is formed in double-membrane vesicles (DMVs) by nonstructural proteins (nsps), encoded by the polyprotein gene (34).
T76	9457-9569	Sentence	denotes	Subsequently, the RTC synthesizes a nested set of subgenomic RNAs (sgRNAs) via discontinuous transcription (35).
T77	9570-9697	Sentence	denotes	Based on molecular characterization, SARS-CoV-2 is considered a new Betacoronavirus belonging to the subgenus Sarbecovirus (3).
T78	9698-9801	Sentence	denotes	A few other critical zoonotic viruses (MERS-related CoV and SARS-related CoV) belong to the same genus.
T79	9802-9985	Sentence	denotes	However, SARS-CoV-2 was identified as a distinct virus based on the percent identity with other Betacoronavirus; conserved open reading frame 1a/b (ORF1a/b) is below 90% identity (3).
T80	9986-10162	Sentence	denotes	An overall 80% nucleotide identity was observed between SARS-CoV-2 and the original SARS-CoV, along with 89% identity with ZC45 and ZXC21 SARS-related CoVs of bats (2, 31, 36).
T81	10163-10284	Sentence	denotes	In addition, 82% identity has been observed between SARS-CoV-2 and human SARS-CoV Tor2 and human SARS-CoV BJ01 2003 (31).
T82	10285-10398	Sentence	denotes	A sequence identity of only 51.8% was observed between MERS-related CoV and the recently emerged SARS-CoV-2 (37).
T83	10399-10509	Sentence	denotes	Phylogenetic analysis of the structural genes also revealed that SARS-CoV-2 is closer to bat SARS-related CoV.
T84	10510-10657	Sentence	denotes	Therefore, SARS-CoV-2 might have originated from bats, while other amplifier hosts might have played a role in disease transmission to humans (31).
T85	10658-10770	Sentence	denotes	Of note, the other two zoonotic CoVs (MERS-related CoV and SARS-related CoV) also originated from bats (38, 39).
T86	10771-10872	Sentence	denotes	Nevertheless, for SARS and MERS, civet cat and camels, respectively, act as amplifier hosts (40, 41).
T87	10873-10929	Sentence	denotes	Coronavirus genomes and subgenomes encode six ORFs (31).
T88	10930-11004	Sentence	denotes	The majority of the 5′ end is occupied by ORF1a/b, which produces 16 nsps.
T89	11005-11127	Sentence	denotes	The two polyproteins, pp1a and pp1ab, are initially produced from ORF1a/b by a −1 frameshift between ORF1a and ORF1b (32).
T90	11128-11296	Sentence	denotes	The virus-encoded proteases cleave polyproteins into individual nsps (main protease [Mpro], chymotrypsin-like protease [3CLpro], and papain-like proteases [PLPs]) (42).
T91	11297-11388	Sentence	denotes	SARS-CoV-2 also encodes these nsps, and their functions have been elucidated recently (31).
T92	11389-11618	Sentence	denotes	Remarkably, a difference between SARS-CoV-2 and other CoVs is the identification of a novel short putative protein within the ORF3 band, a secreted protein with an alpha helix and beta-sheet with six strands encoded by ORF8 (31).
T93	11619-11777	Sentence	denotes	Coronaviruses encode four major structural proteins, namely, spike (S), membrane (M), envelope (E), and nucleocapsid (N), which are described in detail below.
T94	11779-11793	Sentence	denotes	S Glycoprotein
T95	11794-11880	Sentence	denotes	Coronavirus S protein is a large, multifunctional class I viral transmembrane protein.
T96	11881-12047	Sentence	denotes	The size of this abundant S protein varies from 1,160 amino acids (IBV, infectious bronchitis virus, in poultry) to 1,400 amino acids (FCoV, feline coronavirus) (43).
T97	12048-12143	Sentence	denotes	It lies in a trimer on the virion surface, giving the virion a corona or crown-like appearance.
T98	12144-12297	Sentence	denotes	Functionally it is required for the entry of the infectious virion particles into the cell through interaction with various host cellular receptors (44).
T99	12298-12400	Sentence	denotes	Furthermore, it acts as a critical factor for tissue tropism and the determination of host range (45).
T100	12401-12519	Sentence	denotes	Notably, S protein is one of the vital immunodominant proteins of CoVs capable of inducing host immune responses (45).
T101	12520-12636	Sentence	denotes	The ectodomains in all CoVs S proteins have similar domain organizations, divided into two subunits, S1 and S2 (43).
T102	12637-12734	Sentence	denotes	The first one, S1, helps in host receptor binding, while the second one, S2, accounts for fusion.
T103	12735-12855	Sentence	denotes	The former (S1) is further divided into two subdomains, namely, the N-terminal domain (NTD) and C-terminal domain (CTD).
T104	12856-12971	Sentence	denotes	Both of these subdomains act as receptor-binding domains, interacting efficiently with various host receptors (45).
T105	12972-13025	Sentence	denotes	The S1 CTD contains the receptor-binding motif (RBM).
T106	13026-13129	Sentence	denotes	In each coronavirus spike protein, the trimeric S1 locates itself on top of the trimeric S2 stalk (45).
T107	13130-13271	Sentence	denotes	Recently, structural analyses of the S proteins of COVID-19 have revealed 27 amino acid substitutions within a 1,273-amino-acid stretch (16).
T108	13272-13412	Sentence	denotes	Six substitutions are located in the RBD (amino acids 357 to 528), while four substitutions are in the RBM at the CTD of the S1 domain (16).
T109	13413-13560	Sentence	denotes	Of note, no amino acid change is seen in the RBM, which binds directly to the angiotensin-converting enzyme-2 (ACE2) receptor in SARS-CoV (16, 46).
T110	13561-13668	Sentence	denotes	At present, the main emphasis is knowing how many differences would be required to change the host tropism.
T111	13669-13799	Sentence	denotes	Sequence comparison revealed 17 nonsynonymous changes between the early sequence of SARS-CoV-2 and the later isolates of SARS-CoV.
T112	13800-13992	Sentence	denotes	The changes were found scattered over the genome of the virus, with nine substitutions in ORF1ab, ORF8 (4 substitutions), the spike gene (3 substitutions), and ORF7a (single substitution) (4).
T113	13993-14157	Sentence	denotes	Notably, the same nonsynonymous changes were found in a familial cluster, indicating that the viral evolution happened during person-to-person transmission (4, 47).
T114	14158-14290	Sentence	denotes	Such adaptive evolution events are frequent and constitute a constantly ongoing process once the virus spreads among new hosts (47).
T115	14291-14495	Sentence	denotes	Even though no functional changes occur in the virus associated with this adaptive evolution, close monitoring of the viral mutations that occur during subsequent human-to-human transmission is warranted.
T116	14497-14506	Sentence	denotes	M Protein
T117	14507-14639	Sentence	denotes	The M protein is the most abundant viral protein present in the virion particle, giving a definite shape to the viral envelope (48).
T118	14640-14730	Sentence	denotes	It binds to the nucleocapsid and acts as a central organizer of coronavirus assembly (49).
T119	14731-14868	Sentence	denotes	Coronavirus M proteins are highly diverse in amino acid contents but maintain overall structural similarity within different genera (50).
T120	14869-15020	Sentence	denotes	The M protein has three transmembrane domains, flanked by a short amino terminus outside the virion and a long carboxy terminus inside the virion (50).
T121	15021-15082	Sentence	denotes	Overall, the viral scaffold is maintained by M-M interaction.
T122	15083-15195	Sentence	denotes	Of note, the M protein of SARS-CoV-2 does not have an amino acid substitution compared to that of SARS-CoV (16).
T123	15197-15206	Sentence	denotes	E Protein
T124	15207-15306	Sentence	denotes	The coronavirus E protein is the most enigmatic and smallest of the major structural proteins (51).
T125	15307-15400	Sentence	denotes	It plays a multifunctional role in the pathogenesis, assembly, and release of the virus (52).
T126	15401-15489	Sentence	denotes	It is a small integral membrane polypeptide that acts as a viroporin (ion channel) (53).
T127	15490-15633	Sentence	denotes	The inactivation or absence of this protein is related to the altered virulence of coronaviruses due to changes in morphology and tropism (54).
T128	15634-15801	Sentence	denotes	The E protein consists of three domains, namely, a short hydrophilic amino terminal, a large hydrophobic transmembrane domain, and an efficient C-terminal domain (51).
T129	15802-15899	Sentence	denotes	The SARS-CoV-2 E protein reveals a similar amino acid constitution without any substitution (16).
T130	15901-15910	Sentence	denotes	N Protein
T131	15911-15956	Sentence	denotes	The N protein of coronavirus is multipurpose.
T132	15957-16171	Sentence	denotes	Among several functions, it plays a role in complex formation with the viral genome, facilitates M protein interaction needed during virion assembly, and enhances the transcription efficiency of the virus (55, 56).
T133	16172-16308	Sentence	denotes	It contains three highly conserved and distinct domains, namely, an NTD, an RNA-binding domain or a linker region (LKR), and a CTD (57).
T134	16309-16456	Sentence	denotes	The NTD binds with the 3′ end of the viral genome, perhaps via electrostatic interactions, and is highly diverged both in length and sequence (58).
T135	16457-16563	Sentence	denotes	The charged LKR is serine and arginine rich and is also known as the SR (serine and arginine) domain (59).
T136	16564-16682	Sentence	denotes	The LKR is capable of direct interaction with in vitro RNA interaction and is responsible for cell signaling (60, 61).
T137	16683-16811	Sentence	denotes	It also modulates the antiviral response of the host by working as an antagonist for interferon (IFN) and RNA interference (62).
T138	16812-17069	Sentence	denotes	Compared to that of SARS-CoV, the N protein of SARS-CoV-2 possess five amino acid mutations, where two are in the intrinsically dispersed region (IDR; positions 25 and 26), one each in the NTD (position 103), LKR (position 217), and CTD (position 334) (16).
T139	17071-17098	Sentence	denotes	nsps and Accessory Proteins
T140	17099-17286	Sentence	denotes	Besides the important structural proteins, the SARS-CoV-2 genome contains 15 nsps, nsp1 to nsp10 and nsp12 to nsp16, and 8 accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b, and ORF14) (16).
T141	17287-17353	Sentence	denotes	All these proteins play a specific role in viral replication (27).
T142	17354-17484	Sentence	denotes	Unlike the accessory proteins of SARS-CoV, SARS-CoV-2 does not contain 8a protein and has a longer 8b and shorter 3b protein (16).
T143	17485-17664	Sentence	denotes	The nsp7, nsp13, envelope, matrix, and p6 and 8b accessory proteins have not been detected with any amino acid substitutions compared to the sequences of other coronaviruses (16).
T144	17665-17721	Sentence	denotes	The virus structure of SARS-CoV-2 is depicted in Fig. 2.
T145	17722-17756	Sentence	denotes	FIG 2 SARS-CoV-2 virus structure.
T146	17758-17801	Sentence	denotes	SARS-CoV-2 Spike Glycoprotein Gene Analysis
T147	17803-17840	Sentence	denotes	Sequence percent similarity analysis.
T148	17841-18017	Sentence	denotes	We assessed the nucleotide percent similarity using the MegAlign software program, where the similarity between the novel SARS-CoV-2 isolates was in the range of 99.4% to 100%.
T149	18018-18205	Sentence	denotes	Among the other Serbecovirus CoV sequences, the novel SARS-CoV-2 sequences revealed the highest similarity to bat-SL-CoV, with nucleotide percent identity ranges between 88.12 and 89.65%.
T150	18206-18314	Sentence	denotes	Meanwhile, earlier reported SARS-CoVs showed 70.6 to 74.9% similarity to SARS-CoV-2 at the nucleotide level.
T151	18315-18527	Sentence	denotes	Further, the nucleotide percent similarity was 55.4%, 45.5% to 47.9%, 46.2% to 46.6%, and 45.0% to 46.3% to the other four subgenera, namely, Hibecovirus, Nobecovirus, Merbecovirus, and Embecovirus, respectively.
T152	18528-18688	Sentence	denotes	The percent similarity index of current outbreak isolates indicates a close relationship between SARS-CoV-2 isolates and bat-SL-CoV, indicating a common origin.
T153	18689-18979	Sentence	denotes	However, particular pieces of evidence based on further complete genomic analysis of current isolates are necessary to draw any conclusions, although it was ascertained that the current novel SARS-CoV-2 isolates belong to the subgenus Sarbecovirus in the diverse range of betacoronaviruses.
T154	18980-19130	Sentence	denotes	Their possible ancestor was hypothesized to be from bat CoV strains, wherein bats might have played a crucial role in harboring this class of viruses.
T155	19132-19162	Sentence	denotes	SplitsTree phylogeny analysis.
T156	19163-19324	Sentence	denotes	In the unrooted phylogenetic tree of different betacoronaviruses based on the S protein, virus sequences from different subgenera grouped into separate clusters.
T157	19325-19450	Sentence	denotes	SARS-CoV-2 sequences from Wuhan and other countries exhibited a close relationship and appeared in a single cluster (Fig. 1).
T158	19451-19632	Sentence	denotes	The CoVs from the subgenus Sarbecovirus appeared jointly in SplitsTree and divided into three subclusters, namely, SARS-CoV-2, bat-SARS-like-CoV (bat-SL-CoV), and SARS-CoV (Fig. 1).
T159	19633-19898	Sentence	denotes	In the case of other subgenera, like Merbecovirus, all of the sequences grouped in a single cluster, whereas in Embecovirus, different species, comprised of canine respiratory CoVs, bovine CoVs, equine CoVs, and human CoV strain (OC43), grouped in a common cluster.
T160	19899-20047	Sentence	denotes	Isolates in the subgenera Nobecovorus and Hibecovirus were found to be placed separately away from other reported SARS-CoVs but shared a bat origin.
T161	20049-20089	Sentence	denotes	CURRENT WORLDWIDE SCENARIO OF SARS-CoV-2
T162	20090-20279	Sentence	denotes	This novel virus, SARS-CoV-2, comes under the subgenus Sarbecovirus of the Orthocoronavirinae subfamily and is entirely different from the viruses responsible for MERS-CoV and SARS-CoV (3).
T163	20280-20339	Sentence	denotes	The newly emerged SARS-CoV-2 is a group 2B coronavirus (2).
T164	20340-20463	Sentence	denotes	The genome sequences of SARS-CoV-2 obtained from patients share 79.5% sequence similarity to the sequence of SARS-CoV (63).
T165	20464-20660	Sentence	denotes	As of 13 May 2020, a total of 4,170,424 confirmed cases of COVID-19 (with 287,399 deaths) have been reported in more than 210 affected countries worldwide (WHO Situation Report 114 [25]) (Fig. 3).
T166	20661-20721	Sentence	denotes	FIG 3 World map depicting the current scenario of COVID-19.
T167	20722-20829	Sentence	denotes	Shown are countries, territories, or regions with reported confirmed cases of SARS-CoV-2 as of 13 May 2020.
T168	20830-20937	Sentence	denotes	Different colors indicate different WHO designated geographical regions with the number of confirmed cases.
T169	20938-21028	Sentence	denotes	The WHO region-wise total number of confirmed cases is depicted in different color strips.
T170	21029-21156	Sentence	denotes	The leading information on the confirmed cases and deaths from all six WHO designated regions are depicted in circled balloons.
T171	21157-21793	Sentence	denotes	The numbers of COVID-19 cases and fatalities on three major cruise ships are also depicted. (Based on data from the WHO at https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200513-covid-19-sitrep-114.pdf?sfvrsn=17ebbbe_4; updated numbers of cases, deaths, and patients recovered can be found at https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6.) Initially, the epicenter of the SARS-CoV-2 pandemic was China, which reported a significant number of deaths associated with COVID-19, with 84,458 laboratory-confirmed cases and 4,644 deaths as of 13 May 2020 (Fig. 4).
T172	21794-21954	Sentence	denotes	As of 13 May 2020, SARS-CoV-2 confirmed cases have been reported in more than 210 countries apart from China (Fig. 3 and 4) (WHO Situation Report 114) (25, 64).
T173	21955-22018	Sentence	denotes	COVID-19 has been reported on all continents except Antarctica.
T174	22019-22247	Sentence	denotes	For many weeks, Italy was the focus of concerns regarding the large number of cases, with 221,216 cases and 30,911 deaths, but now, the United States is the country with the largest number of cases, 1,322,054, and 79,634 deaths.
T175	22248-22334	Sentence	denotes	Now, the United Kingdom has even more cases (226,4671) and deaths (32,692) than Italy.
T176	22335-22558	Sentence	denotes	A John Hopkins University web platform has provided daily updates on the basic epidemiology of the COVID-19 outbreak (https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6) (238).
T177	22559-22611	Sentence	denotes	FIG 4 Bar graph and pie chart for cases and deaths.
T178	22612-22977	Sentence	denotes	Shown are laboratory-confirmed cases and deaths in China and the rest of the world due to SARS-CoV-2. (A) SARS-CoV-2 confirmed cases in the top five affected countries from each WHO designated region, where maximum casualties were reported to WHO until 13 May 2020. (B) Total numbers of deaths and cases in China only. (C) Total number of cases worldwide by region.
T179	22978-23169	Sentence	denotes	COVID-19 has also been confirmed on a cruise ship, named Diamond Princess, quarantined in Japanese waters (Port of Yokohama), as well as on other cruise ships around the world (239) (Fig. 3).
T180	23170-23305	Sentence	denotes	The significant events of the SARS-CoV-2/COVID-19 virus outbreak occurring since 8 December 2019 are presented as a timeline in Fig. 5.
T181	23306-23415	Sentence	denotes	FIG 5 Timeline depicting the significant events that occurred during the SARS-CoV-2/COVID-19 virus outbreak.
T182	23416-23538	Sentence	denotes	The timeline describes the significant events during the current SARS-CoV-2 outbreak, from 8 December 2019 to 13 May 2020.
T183	23539-23840	Sentence	denotes	At the beginning, China experienced the majority of the burden associated with COVID-19 in the form of disease morbidity and mortality (65), but over time the COVID-19 menace moved to Europe, particularly Italy and Spain, and now the United States has the highest number of confirmed cases and deaths.
T184	23841-24090	Sentence	denotes	The COVID-19 outbreak has also been associated with severe economic impacts globally due to the sudden interruption of global trade and supply chains that forced multinational companies to make decisions that led to significant economic losses (66).
T185	24091-24316	Sentence	denotes	The recent increase in the number of confirmed critically ill patients with COVID-19 has already surpassed the intensive care supplies, limiting intensive care services to only a small portion of critically ill patients (67).
T186	24317-24420	Sentence	denotes	This might also have contributed to the increased case fatality rate observed in the COVID-19 outbreak.
T187	24422-24481	Sentence	denotes	Viewpoint on SARS-CoV-2 Transmission, Spread, and Emergence
T188	24482-24560	Sentence	denotes	The novel coronavirus was identified within 1 month (28 days) of the outbreak.
T189	24561-24697	Sentence	denotes	This is impressively fast compared to the time taken to identify SARS-CoV reported in Foshan, Guangdong Province, China (125 days) (68).
T190	24698-24956	Sentence	denotes	Immediately after the confirmation of viral etiology, the Chinese virologists rapidly released the genomic sequence of SARS-CoV-2, which played a crucial role in controlling the spread of this newly emerged novel coronavirus to other parts of the world (69).
T191	24957-25062	Sentence	denotes	The possible origin of SARS-CoV-2 and the first mode of disease transmission are not yet identified (70).
T192	25063-25235	Sentence	denotes	Analysis of the initial cluster of infections suggests that the infected individuals had a common exposure point, a seafood market in Wuhan, Hubei Province, China (Fig. 6).
T193	25236-25355	Sentence	denotes	The restaurants of this market are well-known for providing different types of wild animals for human consumption (71).
T194	25356-25467	Sentence	denotes	The Huanan South China Seafood Market also sells live animals, such as poultry, bats, snakes, and marmots (72).
T195	25468-25552	Sentence	denotes	This might be the point where zoonotic (animal-to-human) transmission occurred (71).
T196	25553-25819	Sentence	denotes	Although SARS-CoV-2 is alleged to have originated from an animal host (zoonotic origin) with further human-to-human transmission (Fig. 6), the likelihood of foodborne transmission should be ruled out with further investigations, since it is a latent possibility (1).
T197	25820-26054	Sentence	denotes	Additionally, other potential and expected routes would be associated with transmission, as in other respiratory viruses, by direct contact, such as shaking contaminated hands, or by direct contact with contaminated surfaces (Fig. 6).
T198	26055-26249	Sentence	denotes	Still, whether blood transfusion and organ transplantation (276), as well as transplacental and perinatal routes, are possible routes for SARS-CoV-2 transmission needs to be determined (Fig. 6).
T199	26250-26302	Sentence	denotes	FIG 6 Potential transmission routes for SARS-CoV-2.
T200	26303-26462	Sentence	denotes	From experience with several outbreaks associated with known emerging viruses, higher pathogenicity of a virus is often associated with lower transmissibility.
T201	26463-26627	Sentence	denotes	Compared to emerging viruses like Ebola virus, avian H7N9, SARS-CoV, and MERS-CoV, SARS-CoV-2 has relatively lower pathogenicity and moderate transmissibility (15).
T202	26628-26742	Sentence	denotes	The risk of death among individuals infected with COVID-19 was calculated using the infection fatality risk (IFR).
T203	26743-26889	Sentence	denotes	The IFR was found to be in the range of 0.3% to 0.6%, which is comparable to that of a previous Asian influenza pandemic (1957 to 1958) (73, 277).
T204	26890-27031	Sentence	denotes	Notably, the reanalysis of the COVID-19 pandemic curve from the initial cluster of cases pointed to considerable human-to-human transmission.
T205	27032-27305	Sentence	denotes	It is opined that the exposure history of SARS-CoV-2 at the Wuhan seafood market originated from human-to-human transmission rather than animal-to-human transmission (74); however, in light of the zoonotic spillover in COVID-19, is too early to fully endorse this idea (1).
T206	27306-27515	Sentence	denotes	Following the initial infection, human-to-human transmission has been observed with a preliminary reproduction number (R0) estimate of 1.4 to 2.5 (70, 75), and recently it is estimated to be 2.24 to 3.58 (76).
T207	27516-27679	Sentence	denotes	In another study, the average reproductive number of COVID-19 was found to be 3.28, which is significantly higher than the initial WHO estimate of 1.4 to 2.5 (77).
T208	27680-27788	Sentence	denotes	It is too early to obtain the exact R0 value, since there is a possibility of bias due to insufficient data.
T209	27789-27912	Sentence	denotes	The higher R0 value is indicative of the more significant potential of SARS-CoV-2 transmission in a susceptible population.
T210	27913-28051	Sentence	denotes	This is not the first time where the culinary practices of China have been blamed for the origin of novel coronavirus infection in humans.
T211	28052-28190	Sentence	denotes	Previously, the animals present in the live-animal market were identified to be the intermediate hosts of the SARS outbreak in China (78).
T212	28191-28321	Sentence	denotes	Several wildlife species were found to harbor potentially evolving coronavirus strains that can overcome the species barrier (79).
T213	28322-28441	Sentence	denotes	One of the main principles of Chinese food culture is that live-slaughtered animals are considered more nutritious (5).
T214	28442-28571	Sentence	denotes	After 4 months of struggle that lasted from December 2019 to March 2020, the COVID-19 situation now seems under control in China.
T215	28572-28877	Sentence	denotes	The wet animal markets have reopened, and people have started buying bats, dogs, cats, birds, scorpions, badgers, rabbits, pangolins (scaly anteaters), minks, soup from palm civet, ostriches, hamsters, snapping turtles, ducks, fish, Siamese crocodiles, and other animal meats without any fear of COVID-19.
T216	28878-28959	Sentence	denotes	The Chinese government is encouraging people to feel they can return to normalcy.
T217	28960-29150	Sentence	denotes	However, this could be a risk, as it has been mentioned in advisories that people should avoid contact with live-dead animals as much as possible, as SARS-CoV-2 has shown zoonotic spillover.
T218	29151-29317	Sentence	denotes	Additionally, we cannot rule out the possibility of new mutations in the same virus being closely related to contact with both animals and humans at the market (284).
T219	29318-29413	Sentence	denotes	In January 2020, China imposed a temporary ban on the sale of live-dead animals in wet markets.
T220	29414-29546	Sentence	denotes	However, now hundreds of such wet markets have been reopened without optimizing standard food safety and sanitation practices (286).
T221	29547-29750	Sentence	denotes	With China being the most populated country in the world and due to its domestic and international food exportation policies, the whole world is now facing the menace of COVID-19, including China itself.
T222	29751-29831	Sentence	denotes	Wet markets of live-dead animals do not maintain strict food hygienic practices.
T223	29832-30005	Sentence	denotes	Fresh blood splashes are present everywhere, on the floor and tabletops, and such food customs could encourage many pathogens to adapt, mutate, and jump the species barrier.
T224	30006-30138	Sentence	denotes	As a result, the whole world is suffering from novel SARS-CoV-2, with more than 4,170,424 cases and 287,399 deaths across the globe.
T225	30139-30356	Sentence	denotes	There is an urgent need for a rational international campaign against the unhealthy food practices of China to encourage the sellers to increase hygienic food practices or close the crude live-dead animal wet markets.
T226	30357-30575	Sentence	denotes	There is a need to modify food policies at national and international levels to avoid further life threats and economic consequences from any emerging or reemerging pandemic due to close animal-human interaction (285).
T227	30576-30748	Sentence	denotes	Even though individuals of all ages and sexes are susceptible to COVID-19, older people with an underlying chronic disease are more likely to become severely infected (80).
T228	30749-30879	Sentence	denotes	Recently, individuals with asymptomatic infection were also found to act as a source of infection to susceptible individuals (81).
T229	30880-31066	Sentence	denotes	Both the asymptomatic and symptomatic patients secrete similar viral loads, which indicates that the transmission capacity of asymptomatic or minimally symptomatic patients is very high.
T230	31067-31146	Sentence	denotes	Thus, SARS-CoV-2 transmission can happen early in the course of infection (82).
T231	31147-31264	Sentence	denotes	Atypical clinical manifestations have also been reported in COVID-19 in which the only reporting symptom was fatigue.
T232	31265-31345	Sentence	denotes	Such patients may lack respiratory signs, such as fever, cough, and sputum (83).
T233	31346-31501	Sentence	denotes	Hence, the clinicians must be on the look-out for the possible occurrence of atypical clinical manifestations to avoid the possibility of missed diagnosis.
T234	31502-31702	Sentence	denotes	The early transmission ability of SARS-CoV-2 was found to be similar to or slightly higher than that of SARS-CoV, reflecting that it could be controlled despite moderate to high transmissibility (84).
T235	31703-31855	Sentence	denotes	Increasing reports of SARS-CoV-2 in sewage and wastewater warrants the need for further investigation due to the possibility of fecal-oral transmission.
T236	31856-32010	Sentence	denotes	SARS-CoV-2 present in environmental compartments such as soil and water will finally end up in the wastewater and sewage sludge of treatment plants (328).
T237	32011-32191	Sentence	denotes	Therefore, we have to reevaluate the current wastewater and sewage sludge treatment procedures and introduce advanced techniques that are specific and effective against SARS-CoV-2.
T238	32192-32353	Sentence	denotes	Since there is active shedding of SARS-CoV-2 in the stool, the prevalence of infections in a large population can be studied using wastewater-based epidemiology.
T239	32354-32543	Sentence	denotes	Recently, reverse transcription-quantitative PCR (RT-qPCR) was used to enumerate the copies of SARS-CoV-2 RNA concentrated from wastewater collected from a wastewater treatment plant (327).
T240	32544-32627	Sentence	denotes	The calculated viral RNA copy numbers determine the number of infected individuals.
T241	32628-32857	Sentence	denotes	The increasing reports of virus shedding via the fecal route warrants the introduction of negative fecal viral nucleic acid test results as one of the additional discharge criteria in laboratory-confirmed cases of COVID-19 (326).
T242	32858-32989	Sentence	denotes	The COVID-19 pandemic does not have any novel factors, other than the genetically unique pathogen and a further possible reservoir.
T243	32990-33105	Sentence	denotes	The cause and the likely future outcome are just repetitions of our previous interactions with fatal coronaviruses.
T244	33106-33206	Sentence	denotes	The only difference is the time of occurrence and the genetic distinctness of the pathogen involved.
T245	33207-33354	Sentence	denotes	Mutations on the RBD of CoVs facilitated their capability of infecting newer hosts, thereby expanding their reach to all corners of the world (85).
T246	33355-33423	Sentence	denotes	This is a potential threat to the health of both animals and humans.
T247	33424-33618	Sentence	denotes	Advanced studies using Bayesian phylogeographic reconstruction identified the most probable origin of SARS-CoV-2 as the bat SARS-like coronavirus, circulating in the Rhinolophus bat family (86).
T248	33619-33830	Sentence	denotes	Phylogenetic analysis of 10 whole-genome sequences of SARS-CoV-2 showed that they are related to two CoVs of bat origin, namely, bat-SL-CoVZC45 and bat-SL-CoVZXC21, which were reported during 2018 in China (17).
T249	33831-33986	Sentence	denotes	It was reported that SARS-CoV-2 had been confirmed to use ACE2 as an entry receptor while exhibiting an RBD similar to that of SARS-CoV (17, 87, 254, 255).
T250	33987-34079	Sentence	denotes	Several countries have provided recommendations to their people traveling to China (88, 89).
T251	34080-34240	Sentence	denotes	Compared to the previous coronavirus outbreaks caused by SARS-CoV and MERS-CoV, the efficiency of SARS-CoV-2 human-to-human transmission was thought to be less.
T252	34241-34385	Sentence	denotes	This assumption was based on the finding that health workers were affected less than they were in previous outbreaks of fatal coronaviruses (2).
T253	34386-34497	Sentence	denotes	Superspreading events are considered the main culprit for the extensive transmission of SARS and MERS (90, 91).
T254	34498-34706	Sentence	denotes	Almost half of the MERS-CoV cases reported in Saudi Arabia are of secondary origin that occurred through contact with infected asymptomatic or symptomatic individuals through human-to-human transmission (92).
T255	34707-34827	Sentence	denotes	The occurrence of superspreading events in the COVID-19 outbreak cannot be ruled out until its possibility is evaluated.
T256	34828-34928	Sentence	denotes	Like SARS and MERS, COVID-19 can also infect the lower respiratory tract, with milder symptoms (27).
T257	34929-35100	Sentence	denotes	The basic reproduction number of COVID-19 has been found to be in the range of 2.8 to 3.3 based on real-time reports and 3.2 to 3.9 based on predicted infected cases (84).
T258	35102-35150	Sentence	denotes	Coronaviruses in Humans—SARS, MERS, and COVID-19
T259	35151-35357	Sentence	denotes	Coronavirus infection in humans is commonly associated with mild to severe respiratory diseases, with high fever, severe inflammation, cough, and internal organ dysfunction that can even lead to death (92).
T260	35358-35427	Sentence	denotes	Most of the identified coronaviruses cause the common cold in humans.
T261	35428-35542	Sentence	denotes	However, this changed when SARS-CoV was identified, paving the way for severe forms of the disease in humans (22).
T262	35543-35766	Sentence	denotes	Our previous experience with the outbreaks of other coronaviruses, like SARS and MERS, suggests that the mode of transmission in COVID-19 as mainly human-to-human transmission via direct contact, droplets, and fomites (25).
T263	35767-35988	Sentence	denotes	Recent studies have demonstrated that the virus could remain viable for hours in aerosols and up to days on surfaces; thus, aerosol and fomite contamination could play potent roles in the transmission of SARS-CoV-2 (257).
T264	35989-36078	Sentence	denotes	The immune response against coronavirus is vital to control and get rid of the infection.
T265	36079-36221	Sentence	denotes	However, maladjusted immune responses may contribute to the immunopathology of the disease, resulting in impairment of pulmonary gas exchange.
T266	36222-36391	Sentence	denotes	Understanding the interaction between CoVs and host innate immune systems could enlighten our understanding of the lung inflammation associated with this infection (24).
T267	36392-36612	Sentence	denotes	SARS is a viral respiratory disease caused by a formerly unrecognized animal CoV that originated from the wet markets in southern China after adapting to the human host, thereby enabling transmission between humans (90).
T268	36613-36716	Sentence	denotes	The SARS outbreak reported in 2002 to 2003 had 8,098 confirmed cases with 774 total deaths (9.6%) (93).
T269	36717-36804	Sentence	denotes	The outbreak severely affected the Asia Pacific region, especially mainland China (94).
T270	36805-37026	Sentence	denotes	Even though the case fatality rate (CFR) of SARS-CoV-2 (COVID-19) is lower than that of SARS-CoV, there exists a severe concern linked to this outbreak due to its epidemiological similarity to influenza viruses (95, 279).
T271	37027-37096	Sentence	denotes	This can fail the public health system, resulting in a pandemic (96).
T272	37097-37194	Sentence	denotes	MERS is another respiratory disease that was first reported in Saudi Arabia during the year 2012.
T273	37195-37250	Sentence	denotes	The disease was found to have a CFR of around 35% (97).
T274	37251-37389	Sentence	denotes	The analysis of available data sets suggests that the incubation period of SARS-CoV-2, SARS-CoV, and MERS-CoV is in almost the same range.
T275	37390-37453	Sentence	denotes	The longest predicted incubation time of SARS-CoV-2 is 14 days.
T276	37454-37549	Sentence	denotes	Hence, suspected individuals are isolated for 14 days to avoid the risk of further spread (98).
T277	37550-37820	Sentence	denotes	Even though a high similarity has been reported between the genome sequence of the new coronavirus (SARS-CoV-2) and SARS-like CoVs, the comparative analysis recognized a furin-like cleavage site in the SARS-CoV-2 S protein that is missing from other SARS-like CoVs (99).
T278	37821-37998	Sentence	denotes	The furin-like cleavage site is expected to play a role in the life cycle of the virus and disease pathogenicity and might even act as a therapeutic target for furin inhibitors.
T279	37999-38202	Sentence	denotes	The highly contagious nature of SARS-CoV-2 compared to that of its predecessors might be the result of a stabilizing mutation that occurred in the endosome-associated-protein-like domain of nsp2 protein.
T280	38203-38382	Sentence	denotes	Similarly, the destabilizing mutation near the phosphatase domain of nsp3 proteins in SARS-CoV-2 could indicate a potential mechanism that differentiates it from other CoVs (100).
T281	38383-38554	Sentence	denotes	Even though the CFR reported for COVID-19 is meager compared to those of the previous SARS and MERS outbreaks, it has caused more deaths than SARS and MERS combined (101).
T282	38555-38780	Sentence	denotes	Possibly related to the viral pathogenesis is the recent finding of an 832-nucleotide (nt) deletion in ORF8, which appears to reduce the replicative fitness of the virus and leads to attenuated phenotypes of SARS-CoV-2 (256).
T283	38781-38946	Sentence	denotes	Coronavirus is the most prominent example of a virus that has crossed the species barrier twice from wild animals to humans during SARS and MERS outbreaks (79, 102).
T284	38947-39075	Sentence	denotes	The possibility of crossing the species barrier for the third time has also been suspected in the case of SARS-CoV-2 (COVID-19).
T285	39076-39173	Sentence	denotes	Bats are recognized as a possible natural reservoir host of both SARS-CoV and MERS-CoV infection.
T286	39174-39302	Sentence	denotes	In contrast, the possible intermediary host is the palm civet for SARS-CoV and the dromedary camel for MERS-CoV infection (102).
T287	39303-39372	Sentence	denotes	Bats are considered the ancestral hosts for both SARS and MERS (103).
T288	39373-39475	Sentence	denotes	Bats are also considered the reservoir host of human coronaviruses like HCoV-229E and HCoV-NL63 (104).
T289	39476-39674	Sentence	denotes	In the case of COVID-19, there are two possibilities for primary transmission: it can be transmitted either through intermediate hosts, similar to that of SARS and MERS, or directly from bats (103).
T290	39675-39938	Sentence	denotes	The emergence paradigm put forward in the SARS outbreak suggests that SARS-CoV originated from bats (reservoir host) and later jumped to civets (intermediate host) and incorporated changes within the receptor-binding domain (RBD) to improve binding to civet ACE2.
T291	39939-40097	Sentence	denotes	This civet-adapted virus, during their subsequent exposure to humans at live markets, promoted further adaptations that resulted in the epidemic strain (104).
T292	40098-40193	Sentence	denotes	Transmission can also occur directly from the reservoir host to humans without RBD adaptations.
T293	40194-40384	Sentence	denotes	The bat coronavirus that is currently in circulation maintains specific “poised” spike proteins that facilitate human infection without the requirement of any mutations or adaptations (105).
T294	40385-40486	Sentence	denotes	Altogether, different species of bats carry a massive number of coronaviruses around the world (106).
T295	40487-40695	Sentence	denotes	The high plasticity in receptor usage, along with the feasibility of adaptive mutation and recombination, may result in frequent interspecies transmission of coronavirus from bats to animals and humans (106).
T296	40696-40809	Sentence	denotes	The pathogenesis of most bat coronaviruses is unknown, as most of these viruses are not isolated and studied (4).
T297	40810-40906	Sentence	denotes	Hedgehog coronavirus HKU31, a Betacoronavirus, has been identified from amur hedgehogs in China.
T298	40907-41018	Sentence	denotes	Studies show that hedgehogs are the reservoir of Betacoronavirus, and there is evidence of recombination (107).
T299	41019-41212	Sentence	denotes	The current scientific evidence available on MERS infection suggests that the significant reservoir host, as well as the animal source of MERS infection in humans, is the dromedary camels (97).
T300	41213-41398	Sentence	denotes	The infected dromedary camels may not show any visible signs of infection, making it challenging to identify animals actively excreting MERS-CoV that has the potential to infect humans.
T301	41399-41533	Sentence	denotes	However, they may shed MERS-CoV through milk, urine, feces, and nasal and eye discharge and can also be found in the raw organs (108).
T302	41534-41776	Sentence	denotes	In a study conducted to evaluate the susceptibility of animal species to MERS-CoV infection, llamas and pigs were found to be susceptible, indicating the possibility of MERS-CoV circulation in animal species other than dromedary camels (109).
T303	41777-41992	Sentence	denotes	Following the outbreak of SARS in China, SARS-CoV-like viruses were isolated from Himalayan palm civets (Paguma larvata) and raccoon dogs (Nyctereutes procyonoides) found in a live-animal market in Guangdong, China.
T304	41993-42140	Sentence	denotes	The animal isolates obtained from the live-animal market retained a 29-nucleotide sequence that was not present in most of the human isolates (78).
T305	42141-42242	Sentence	denotes	These findings were critical in identifying the possibility of interspecies transmission in SARS-CoV.
T306	42243-42390	Sentence	denotes	The higher diversity and prevalence of bat coronaviruses in this region compared to those in previous reports indicate a host/pathogen coevolution.
T307	42391-42511	Sentence	denotes	SARS-like coronaviruses also have been found circulating in the Chinese horseshoe bat (Rhinolophus sinicus) populations.
T308	42512-42738	Sentence	denotes	The in vitro and in vivo studies carried out on the isolated virus confirmed that there is a potential risk for the reemergence of SARS-CoV infection from the viruses that are currently circulating in the bat population (105).
T309	42740-42783	Sentence	denotes	CLINICAL PATHOLOGY OF SARS-CoV-2 (COVID-19)
T310	42784-42923	Sentence	denotes	The disease caused by SARS-CoV-2 is also named severe specific contagious pneumonia (SSCP), Wuhan pneumonia, and, recently, COVID-19 (110).
T311	42924-43098	Sentence	denotes	Compared to SARS-CoV, SARS-CoV-2 has less severe pathogenesis but has superior transmission capability, as evidenced by the rapidly increasing number of COVID-19 cases (111).
T312	43099-43190	Sentence	denotes	The incubation period of SARS-CoV-2 in familial clusters was found to be 3 to 6 days (112).
T313	43191-43292	Sentence	denotes	The mean incubation period of COVID-19 was found to be 6.4 days, ranging from 2.1 to 11.1 days (113).
T314	43293-43409	Sentence	denotes	Among an early affected group of 425 patients, 59 years was the median age, of which more males were affected (114).
T315	43410-43508	Sentence	denotes	Similar to SARS and MERS, the severity of this nCoV is high in age groups above 50 years (2, 115).
T316	43509-43638	Sentence	denotes	Symptoms of COVID-19 include fever, cough, myalgia or fatigue, and, less commonly, headache, hemoptysis, and diarrhea (116, 282).
T317	43639-43840	Sentence	denotes	Compared to the SARS-CoV-2-infected patients in Wuhan during the initial stages of the outbreak, only mild symptoms were noticed in those patients that are infected by human-to-human transmission (14).
T318	43841-43969	Sentence	denotes	The initial trends suggested that the mortality associated with COVID-19 was less than that of previous outbreaks of SARS (101).
T319	43970-44164	Sentence	denotes	The updates obtained from countries like China, Japan, Thailand, and South Korea indicated that the COVID-19 patients had relatively mild manifestations compared to those with SARS and MERS (4).
T320	44165-44367	Sentence	denotes	Regardless of the coronavirus type, immune cells, like mast cells, that are present in the submucosa of the respiratory tract and nasal cavity are considered the primary barrier against this virus (92).
T321	44368-44537	Sentence	denotes	Advanced in-depth analysis of the genome has identified 380 amino acid substitutions between the amino acid sequences of SARS-CoV-2 and the SARS/SARS-like coronaviruses.
T322	44538-44673	Sentence	denotes	These differences in the amino acid sequences might have contributed to the difference in the pathogenic divergence of SARS-CoV-2 (16).
T323	44674-44858	Sentence	denotes	Further research is required to evaluate the possible differences in tropism, pathogenesis, and transmission of this novel agent associated with this change in the amino acid sequence.
T324	44859-45052	Sentence	denotes	With the current outbreak of COVID-19, there is an expectancy of a significant increase in the number of published studies about this emerging coronavirus, as occurred with SARS and MERS (117).
T325	45053-45152	Sentence	denotes	SARS-CoV-2 invades the lung parenchyma, resulting in severe interstitial inflammation of the lungs.
T326	45153-45241	Sentence	denotes	This is evident on computed tomography (CT) images as ground-glass opacity in the lungs.
T327	45242-45334	Sentence	denotes	This lesion initially involves a single lobe but later expands to multiple lung lobes (118).
T328	45335-45609	Sentence	denotes	The histological assessment of lung biopsy samples obtained from COVID-19-infected patients revealed diffuse alveolar damage, cellular fibromyxoid exudates, hyaline membrane formation, and desquamation of pneumocytes, indicative of acute respiratory distress syndrome (119).
T329	45610-45733	Sentence	denotes	It was also found that the SARS-CoV-2-infected patients often have lymphocytopenia with or without leukocyte abnormalities.
T330	45734-45874	Sentence	denotes	The degree of lymphocytopenia gives an idea about disease prognosis, as it is found to be positively correlated with disease severity (118).
T331	45875-45959	Sentence	denotes	Pregnant women are considered to have a higher risk of getting infected by COVID-19.
T332	45960-46121	Sentence	denotes	The coronaviruses can cause adverse outcomes for the fetus, such as intrauterine growth restriction, spontaneous abortion, preterm delivery, and perinatal death.
T333	46122-46303	Sentence	denotes	Nevertheless, the possibility of intrauterine maternal-fetal transmission (vertical transmission) of CoVs is low and was not seen during either the SARS- or MERS-CoV outbreak (120).
T334	46304-46393	Sentence	denotes	However, there has been concern regarding the impact of SARS-CoV-2/COVID-19 on pregnancy.
T335	46394-46776	Sentence	denotes	Researchers have mentioned the probability of in utero transmission of novel SARS-CoV-2 from COVID-19-infected mothers to their neonates in China based upon the rise in IgM and IgG antibody levels and cytokine values in the blood obtained from newborn infants immediately postbirth; however, RT-PCR failed to confirm the presence of SARS-CoV-2 genetic material in the infants (283).
T336	46777-46894	Sentence	denotes	Recent studies show that at least in some cases, preterm delivery and its consequences are associated with the virus.
T337	46895-46992	Sentence	denotes	Nonetheless, some cases have raised doubts for the likelihood of vertical transmission (240–243).
T338	46993-47105	Sentence	denotes	COVID-19 infection was associated with pneumonia, and some developed acute respiratory distress syndrome (ARDS).
T339	47106-47315	Sentence	denotes	The blood biochemistry indexes, such as albumin, lactate dehydrogenase, C-reactive protein, lymphocytes (percent), and neutrophils (percent) give an idea about the disease severity in COVID-19 infection (121).
T340	47316-47554	Sentence	denotes	During COVID-19, patients may present leukocytosis, leukopenia with lymphopenia (244), hypoalbuminemia, and an increase of lactate dehydrogenase, aspartate transaminase, alanine aminotransferase, bilirubin, and, especially, D-dimer (244).
T341	47555-47758	Sentence	denotes	Middle-aged and elderly patients with primary chronic diseases, especially high blood pressure and diabetes, were found to be more susceptible to respiratory failure and, therefore, had poorer prognoses.
T342	47759-47866	Sentence	denotes	Providing respiratory support at early stages improved the disease prognosis and facilitated recovery (18).
T343	47867-48057	Sentence	denotes	The ARDS in COVID-19 is due to the occurrence of cytokine storms that results in exaggerated immune response, immune regulatory network imbalance, and, finally, multiple-organ failure (122).
T344	48058-48325	Sentence	denotes	In addition to the exaggerated inflammatory response seen in patients with COVID-19 pneumonia, the bile duct epithelial cell-derived hepatocytes upregulate ACE2 expression in liver tissue by compensatory proliferation that might result in hepatic tissue injury (123).
T345	48327-48388	Sentence	denotes	CORONAVIRUSES IN ANIMALS AND ZOONOTIC LINKS—A BRIEF VIEWPOINT
T346	48389-48491	Sentence	denotes	Coronavirus can cause disease in several species of domestic and wild animals, as well as humans (23).
T347	48492-48717	Sentence	denotes	The different animal species that are infected with CoV include horses, camels, cattle, swine, dogs, cats, rodents, birds, ferrets, minks, bats, rabbits, snakes, and various other wild animals (20, 30, 79, 93, 124, 125, 287).
T348	48718-48925	Sentence	denotes	Coronavirus infection is linked to different kinds of clinical manifestations, varying from enteritis in cows and pigs, upper respiratory disease in chickens, and fatal respiratory infections in humans (30).
T349	48926-49112	Sentence	denotes	Among the CoV genera, Alphacoronavirus and Betacoronavirus infect mammals, while Gammacoronavirus and Deltacoronavirus mainly infect birds, fishes, and, sometimes, mammals (27, 29, 106).
T350	49113-49466	Sentence	denotes	Several novel coronaviruses that come under the genus Deltacoronavirus have been discovered in the past from birds, like Wigeon coronavirus HKU20, Bulbul coronavirus HKU11, Munia coronavirus HKU13, white-eye coronavirus HKU16, night-heron coronavirus HKU19, and common moorhen coronavirus HKU21, as well as from pigs (porcine coronavirus HKU15) (6, 29).
T351	49467-49650	Sentence	denotes	Transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine hemagglutinating encephalomyelitis virus (PHEV) are some of the coronaviruses of swine.
T352	49651-49785	Sentence	denotes	Among them, TGEV and PEDV are responsible for causing severe gastroenteritis in young piglets with noteworthy morbidity and mortality.
T353	49786-49916	Sentence	denotes	Infection with PHEV also causes enteric infection but can cause encephalitis due to its ability to infect the nervous system (30).
T354	49917-50009	Sentence	denotes	Bovine coronaviruses (BoCoVs) are known to infect several domestic and wild ruminants (126).
T355	50010-50194	Sentence	denotes	BoCoV inflicts neonatal calf diarrhea in adult cattle, leading to bloody diarrhea (winter dysentery) and respiratory disease complex (shipping fever) in cattle of all age groups (126).
T356	50195-50289	Sentence	denotes	BoCoV-like viruses have been noted in humans, suggesting its zoonotic potential as well (127).
T357	50290-50531	Sentence	denotes	Feline enteric and feline infectious peritonitis (FIP) viruses are the two major feline CoVs (128), where feline CoVs can affect the gastrointestinal tract, abdominal cavity (peritonitis), respiratory tract, and central nervous system (128).
T358	50532-50779	Sentence	denotes	Canines are also affected by CoVs that fall under different genera, namely, canine enteric coronavirus in Alphacoronavirus and canine respiratory coronavirus in Betacoronavirus, affecting the enteric and respiratory tract, respectively (129, 130).
T359	50780-50932	Sentence	denotes	IBV, under Gammacoronavirus, causes diseases of respiratory, urinary, and reproductive systems, with substantial economic losses in chickens (131, 132).
T360	50933-51184	Sentence	denotes	In small laboratory animals, mouse hepatitis virus, rat sialodacryoadenitis coronavirus, and guinea pig and rabbit coronaviruses are the major CoVs associated with disease manifestations like enteritis, hepatitis, and respiratory infections (10, 133).
T361	51185-51351	Sentence	denotes	Swine acute diarrhea syndrome coronavirus (SADS-CoV) was first identified in suckling piglets having severe enteritis and belongs to the genus Alphacoronavirus (106).
T362	51352-51474	Sentence	denotes	The outbreak was associated with considerable scale mortality of piglets (24,693 deaths) across four farms in China (134).
T363	51475-51682	Sentence	denotes	The virus isolated from the piglets was almost identical to and had 95% genomic similarity with horseshoe bat (Rhinolophus species) coronavirus HKU2, suggesting a bat origin of the pig virus (106, 134, 135).
T364	51683-51823	Sentence	denotes	It is also imperative to note that the SADS-CoV outbreak started in Guangdong province, near the location of the SARS pandemic origin (134).
T365	51824-51911	Sentence	denotes	Before this outbreak, pigs were not known to be infected with bat-origin coronaviruses.
T366	51912-52005	Sentence	denotes	This indicates that the bat-origin coronavirus jumped to pig by breaking the species barrier.
T367	52006-52207	Sentence	denotes	The next step of this jump might not end well, since pigs are considered the mixing vessel for influenza A viruses due to their ability to be infected by both human and avian influenza A viruses (136).
T368	52208-52354	Sentence	denotes	Similarly, they may act as the mixing vessel for coronaviruses, since they are in frequent contact with both humans and multiple wildlife species.
T369	52355-52498	Sentence	denotes	Additionally, pigs are also found to be susceptible to infection with human SARS-CoV and MERS-CoV, making this scenario a nightmare (109, 137).
T370	52499-52633	Sentence	denotes	It is only a matter of time before another zoonotic coronavirus results in an epidemic by jumping the so-called species barrier (287).
T371	52634-52807	Sentence	denotes	The host spectrum of coronavirus increased when a novel coronavirus, namely, SW1, was recognized in the liver tissue of a captive beluga whale (Delphinapterus leucas) (138).
T372	52808-52901	Sentence	denotes	In recent decades, several novel coronaviruses were identified from different animal species.
T373	52902-53008	Sentence	denotes	Bats can harbor these viruses without manifesting any clinical disease but are persistently infected (30).
T374	53009-53144	Sentence	denotes	They are the only mammals with the capacity for self-powered flight, which enables them to migrate long distances, unlike land mammals.
T375	53145-53240	Sentence	denotes	Bats are distributed worldwide and also account for about a fifth of all mammalian species (6).
T376	53241-53378	Sentence	denotes	This makes them the ideal reservoir host for many viral agents and also the source of novel coronaviruses that have yet to be identified.
T377	53379-53543	Sentence	denotes	It has become a necessity to study the diversity of coronavirus in the bat population to prevent future outbreaks that could jeopardize livestock and public health.
T378	53544-53770	Sentence	denotes	The repeated outbreaks caused by bat-origin coronaviruses calls for the development of efficient molecular surveillance strategies for studying Betacoronavirus among animals (12), especially in the Rhinolophus bat family (86).
T379	53771-53870	Sentence	denotes	Chinese bats have high commercial value, since they are used in traditional Chinese medicine (TCM).
T380	53871-53995	Sentence	denotes	Therefore, the handling of bats for trading purposes poses a considerable risk of transmitting zoonotic CoV epidemics (139).
T381	53996-54229	Sentence	denotes	Due to the possible role played by farm and wild animals in SARS-CoV-2 infection, the WHO, in their novel coronavirus (COVID-19) situation report, recommended the avoidance of unprotected contact with both farm and wild animals (25).
T382	54230-54397	Sentence	denotes	The live-animal markets, like the one in Guangdong, China, provides a setting for animal coronaviruses to amplify and to be transmitted to new hosts, like humans (78).
T383	54398-54561	Sentence	denotes	Such markets can be considered a critical place for the origin of novel zoonotic diseases and have enormous public health significance in the event of an outbreak.
T384	54562-54681	Sentence	denotes	Bats are the reservoirs for several viruses; hence, the role of bats in the present outbreak cannot be ruled out (140).
T385	54682-55000	Sentence	denotes	In a qualitative study conducted for evaluating the zoonotic risk factors among rural communities of southern China, the frequent human-animal interactions along with the low levels of environmental biosecurity were identified as significant risks for the emergence of zoonotic disease in local communities (141, 142).
T386	55001-55189	Sentence	denotes	The comprehensive sequence analysis of the SARS-CoV-2 RNA genome identified that the CoV from Wuhan is a recombinant virus of the bat coronavirus and another coronavirus of unknown origin.
T387	55190-55315	Sentence	denotes	The recombination was found to have happened within the viral spike glycoprotein, which recognizes the cell surface receptor.
T388	55316-55447	Sentence	denotes	Further analysis of the genome based on codon usage identified the snake as the most probable animal reservoir of SARS-CoV-2 (143).
T389	55448-55613	Sentence	denotes	Contrary to these findings, another genome analysis proposed that the genome of SARS-CoV-2 is 96% identical to bat coronavirus, reflecting its origin from bats (63).
T390	55614-55707	Sentence	denotes	The involvement of bat-derived materials in causing the current outbreak cannot be ruled out.
T391	55708-55827	Sentence	denotes	High risk is involved in the production of bat-derived materials for TCM practices involving the handling of wild bats.
T392	55828-55961	Sentence	denotes	The use of bats for TCM practices will remain a severe risk for the occurrence of zoonotic coronavirus epidemics in the future (139).
T393	55962-56095	Sentence	denotes	Furthermore, the pangolins are an endangered species of animals that harbor a wide variety of viruses, including coronaviruses (144).
T394	56096-56269	Sentence	denotes	The coronavirus isolated from Malayan pangolins (Manis javanica) showed a very high amino acid identity with COVID-19 at E (100%), M (98.2%), N (96.7%), and S genes (90.4%).
T395	56270-56392	Sentence	denotes	The RBD of S protein in CoV isolated from pangolin was almost identical (one amino acid difference) to that of SARS-CoV-2.
T396	56393-56513	Sentence	denotes	A comparison of the genomes suggests recombination between pangolin-CoV-like viruses with the bat-CoV-RaTG13-like virus.
T397	56514-56611	Sentence	denotes	All this suggests the potential of pangolins to act as the intermediate host of SARS-CoV-2 (145).
T398	56612-56781	Sentence	denotes	Human-wildlife interactions, which are increasing in the context of climate change (142), are further considered high risk and responsible for the emergence of SARS-CoV.
T399	56782-56844	Sentence	denotes	COVID-19 is also suspected of having a similar mode of origin.
T400	56845-57205	Sentence	denotes	Hence, to prevent the occurrence of another zoonotic spillover (1), exhaustive coordinated efforts are needed to identify the high-risk pathogens harbored by wild animal populations, conducting surveillance among the people who are susceptible to zoonotic spillover events (12), and to improve the biosecurity measures associated with the wildlife trade (146).
T401	57206-57379	Sentence	denotes	The serological surveillance studies conducted in people living in proximity to bat caves had earlier identified the serological confirmation of SARS-related CoVs in humans.
T402	57380-57499	Sentence	denotes	People living at the wildlife-human interface, mainly in rural China, are regularly exposed to SARS-related CoVs (147).
T403	57500-57613	Sentence	denotes	These findings will not have any significance until a significant outbreak occurs due to a virus-like SARS-CoV-2.
T404	57614-57715	Sentence	denotes	There is a steady increase in the reports of COVID-19 in companion and wild animals around the world.
T405	57716-57926	Sentence	denotes	Further studies are required to evaluate the potential of animals (especially companion animals) to serve as an efficient reservoir host that can further alter the dynamics of human-to-human transmission (330).
T406	57927-58087	Sentence	denotes	To date, two pet dogs (Hong Kong) and four pet cats (one each from Belgium and Hong Kong, two from the United States) have tested positive for SARS-CoV-2 (335).
T407	58088-58239	Sentence	denotes	The World Organization for Animal Health (OIE) has confirmed the diagnosis of COVID-19 in both dogs and cats due to human-to-animal transmission (331).
T408	58240-58408	Sentence	denotes	The similarity observed in the gene sequence of SARS-CoV-2 from an infected pet owner and his dog further confirms the occurrence of human-to-animal transmission (333).
T409	58409-58531	Sentence	denotes	Even though asymptomatic, feline species should be considered a potential transmission route from animals to humans (326).
T410	58532-58629	Sentence	denotes	However, currently, there are no reports of SARS-CoV-2 transmission from felines to human beings.
T411	58630-58754	Sentence	denotes	Based on the current evidence, we can conclude that cats are susceptible to SARS-CoV-2 and can get infected by human beings.
T412	58755-58848	Sentence	denotes	However, evidence of cat-to-human transmission is lacking and requires further studies (332).
T413	58849-59068	Sentence	denotes	Rather than waiting for firmer evidence on animal-to-human transmission, necessary preventive measures are advised, as well as following social distancing practices among companion animals of different households (331).
T414	59069-59217	Sentence	denotes	One of the leading veterinary diagnostic companies, IDEXX, has conducted large-scale testing for COVID-19 in specimens collected from dogs and cats.
T415	59218-59277	Sentence	denotes	However, none of the tests turned out to be positive (334).
T416	59278-59501	Sentence	denotes	In a study conducted to investigate the potential of different animal species to act as the intermediate host of SARS-CoV-2, it was found that both ferrets and cats can be infected via experimental inoculation of the virus.
T417	59502-59585	Sentence	denotes	In addition, infected cats efficiently transmitted the disease to naive cats (329).
T418	59586-59716	Sentence	denotes	SARS-CoV-2 infection and subsequent transmission in ferrets were found to recapitulate the clinical aspects of COVID-19 in humans.
T419	59717-59912	Sentence	denotes	The infected ferrets also shed virus via multiple routes, such as saliva, nasal washes, feces, and urine, postinfection, making them an ideal animal model for studying disease transmission (337).
T420	59913-60108	Sentence	denotes	Experimental inoculation was also done in other animal species and found that the dogs have low susceptibility, while the chickens, ducks, and pigs are not at all susceptible to SARS-CoV-2 (329).
T421	60109-60282	Sentence	denotes	Similarly, the National Veterinary Services Laboratories of the USDA have reported COVID-19 in tigers and lions that exhibited respiratory signs like dry cough and wheezing.
T422	60283-60370	Sentence	denotes	The zoo animals are suspected to have been infected by an asymptomatic zookeeper (335).
T423	60371-60546	Sentence	denotes	The total number of COVID-19-positive cases in human beings is increasing at a high rate, thereby creating ideal conditions for viral spillover to other species, such as pigs.
T424	60547-60641	Sentence	denotes	The evidence obtained from SARS-CoV suggests that pigs can get infected with SARS-CoV-2 (336).
T425	60642-60720	Sentence	denotes	However, experimental inoculation with SARS-CoV-2 failed to infect pigs (329).
T426	60721-60895	Sentence	denotes	Further studies are required to identify the possible animal reservoirs of SARS-CoV-2 and the seasonal variation in the circulation of these viruses in the animal population.
T427	60896-61077	Sentence	denotes	Research collaboration between human and animal health sectors is becoming a necessity to evaluate and identify the possible risk factors of transmission between animals and humans.
T428	61078-61190	Sentence	denotes	Such cooperation will help to devise efficient strategies for the management of emerging zoonotic diseases (12).
T429	61192-61226	Sentence	denotes	DIAGNOSIS OF SARS-CoV-2 (COVID-19)
T430	61227-61367	Sentence	denotes	RNA tests can confirm the diagnosis of SARS-CoV-2 (COVID-19) cases with real-time RT-PCR or next-generation sequencing (148, 149, 245, 246).
T431	61368-61528	Sentence	denotes	At present, nucleic acid detection techniques, like RT-PCR, are considered an effective method for confirming the diagnosis in clinical cases of COVID-19 (148).
T432	61529-61663	Sentence	denotes	Several companies across the world are currently focusing on developing and marketing SARS-CoV-2-specific nucleic acid detection kits.
T433	61664-61732	Sentence	denotes	Multiple laboratories are also developing their own in-house RT-PCR.
T434	61733-61863	Sentence	denotes	One of them is the SARS-CoV-2 nucleic acid detection kit produced by Shuoshi Biotechnology (double fluorescence PCR method) (150).
T435	61864-61893	Sentence	denotes	Up to 30 March 2020, the U.S.
T436	61894-62162	Sentence	denotes	Food and Drug Administration (FDA) had granted 22 in vitro diagnostics Emergency Use Authorizations (EUAs), including for the RT-PCR diagnostic panel for the universal detection of SARS-like betacoronaviruses and specific detection of SARS-CoV-2, developed by the U.S.
T437	62163-62188	Sentence	denotes	CDC (Table 1) (258, 259).
T438	62189-62305	Sentence	denotes	TABLE 1 FDA-approved in vitro Emergency Use Authorization diagnostics available for SARS-CoV-2 as of 30 March 2020a
T439	62306-62336	Sentence	denotes	Developer Diagnostic platform
T440	62337-62434	Sentence	denotes	Centers for Disease Control and Prevention (CDC) CDC 2019-nCoV real-time RT-PCR diagnostic panel
T441	62435-62580	Sentence	denotes	Wadsworth Center, New York State Department of Public Health (CDC) New York SARS-CoV-2 real-time reverse transcriptase (RT)-PCR diagnostic panel
T442	62581-62634	Sentence	denotes	Roche Molecular Systems, Inc. (RMS) cobas SARS-CoV-2
T443	62635-62665	Sentence	denotes	Thermo Fisher Scientific, Inc.
T444	62667-62693	Sentence	denotes	TaqPath COVID-19 combo kit
T445	62694-62759	Sentence	denotes	Laboratory Corporation of America (LabCorp) COVID-19 RT-PCR test
T446	62760-62773	Sentence	denotes	Hologic, Inc.
T447	62775-62800	Sentence	denotes	Panther fusion SARS-CoV-2
T448	62801-62843	Sentence	denotes	Quest Diagnostics Infectious Disease, Inc.
T449	62845-62869	Sentence	denotes	Quest SARS-CoV-2 rRT-PCR
T450	62870-62911	Sentence	denotes	Quidel Corporation Lyra SARS-CoV-2 assay
T451	62912-62962	Sentence	denotes	Abbott Molecular Abbott RealTime SARS-CoV-2 assay
T452	62963-63011	Sentence	denotes	GenMark Diagnostics, Inc. ePlex SARS-CoV-2 test
T453	63012-63067	Sentence	denotes	DiaSorin Molecular, LLC Simplexa COVID-19 direct assay
T454	63068-63105	Sentence	denotes	Cepheid Xpert Xpress SARS-CoV-2 test
T455	63106-63124	Sentence	denotes	Primerdesign, Ltd.
T456	63126-63162	Sentence	denotes	COVID-19 Genesig real-time PCR assay
T457	63163-63181	Sentence	denotes	Mesa Biotech, Inc.
T458	63183-63205	Sentence	denotes	Accula SARS-Cov-2 test
T459	63206-63249	Sentence	denotes	BioFire Defense, LLC BioFire COVID-19 test
T460	63250-63267	Sentence	denotes	PerkinElmer, Inc.
T461	63269-63323	Sentence	denotes	PerkinElmer new coronavirus nucleic acid detection kit
T462	63324-63346	Sentence	denotes	Avellino Lab USA, Inc.
T463	63348-63365	Sentence	denotes	AvellinoCoV2 test
T464	63366-63383	Sentence	denotes	BGI Genomics, Co.
T465	63384-63388	Sentence	denotes	Ltd.
T466	63390-63451	Sentence	denotes	Real-time fluorescent RT-PCR kit for detecting SARS-2019-nCoV
T467	63452-63487	Sentence	denotes	Luminex Molecular Diagnostics, Inc.
T468	63489-63519	Sentence	denotes	NxTAG CoV extended panel assay
T469	63520-63556	Sentence	denotes	Abbott Diagnostics Scarborough, Inc.
T470	63558-63573	Sentence	denotes	ID Now COVID-19
T471	63574-63626	Sentence	denotes	Qiagen GmbH QIAstat-Dx respiratory SARS-CoV-2 panel
T472	63627-63650	Sentence	denotes	NeuMoDx Molecular, Inc.
T473	63652-63676	Sentence	denotes	NeuMoDx SARS-CoV-2 assay
T474	63677-63717	Sentence	denotes	a Data are from references 258 and 259.
T475	63718-63990	Sentence	denotes	Recently, 95 full-length genomic sequences of SARAS-CoV-2 strains available in the National Center for Biotechnology Information and GISAID databases were subjected to multiple-sequence alignment and phylogenetic analyses for studying variations in the viral genome (260).
T476	63991-64139	Sentence	denotes	All the viral strains revealed high homology of 99.99% (99.91% to 100%) at the nucleotide level and 99.99% (99.79% to 100%) at the amino acid level.
T477	64140-64267	Sentence	denotes	Overall variation was found to be low in ORF regions, with 13 variation sites recognized in 1a, 1b, S, 3a, M, 8, and N regions.
T478	64268-64397	Sentence	denotes	Mutation rates of 30.53% (29/95) and 29.47% (28/95) were observed at nt 28144 (ORF8) and nt 8782 (ORF1a) positions, respectively.
T479	64398-64528	Sentence	denotes	Owing to such selective mutations, a few specific regions of SARS-CoV-2 should not be considered for designing primers and probes.
T480	64529-64743	Sentence	denotes	The SARS-CoV-2 reference sequence could pave the way to study molecular biology and pathobiology, along with developing diagnostics and appropriate prevention and control strategies for countering SARS-CoV-2 (260).
T481	64744-65023	Sentence	denotes	Nucleic acids of SARS-CoV-2 can be detected from samples (64) such as bronchoalveolar lavage fluid, sputum, nasal swabs, fiber bronchoscope brush biopsy specimen, pharyngeal swabs, feces, blood, and urine, with different levels of diagnostic performance (Table 2) (80, 245, 246).
T482	65024-65189	Sentence	denotes	The viral loads of SARS-CoV-2 were measured using N-gene-specific quantitative RT-PCR in throat swab and sputum samples collected from COVID-19-infected individuals.
T483	65190-65357	Sentence	denotes	The results indicated that the viral load peaked at around 5 to 6 days following the onset of symptoms, and it ranged from 104 to 107 copies/ml during this time (151).
T484	65358-65504	Sentence	denotes	In another study, the viral load was found to be higher in the nasal swabs than the throat swabs obtained from COVID-19 symptomatic patients (82).
T485	65505-65677	Sentence	denotes	Although initially it was thought that viral load would be associated with poor outcomes, some case reports have shown asymptomatic individuals with high viral loads (247).
T486	65678-65891	Sentence	denotes	Recently, the viral load in nasal and throat swabs of 17 symptomatic patients was determined, and higher viral loads were recorded soon after the onset of symptoms, particularly in the nose compared to the throat.
T487	65892-66067	Sentence	denotes	The pattern of viral nucleic acid shedding of SARS-CoV-2-infected patients was similar to that of influenza patients but seemed to be different from that of SARS-CoV patients.
T488	66068-66300	Sentence	denotes	The viral load detected in asymptomatic patients resembled that of symptomatic patients as studied in China, which reflects the transmission perspective of asymptomatic or symptomatic patients having minimum signs and symptoms (82).
T489	66301-66509	Sentence	denotes	Another study, conducted in South Korea, related to SARS-CoV-2 viral load, opined that SARS-CoV-2 kinetics were significantly different from those of earlier reported CoV infections, including SARS-CoV (253).
T490	66510-66708	Sentence	denotes	SARS-CoV-2 transmission can occur early in the viral infection phase; thus, diagnosing cases and isolation attempts for this virus warrant different strategies than those needed to counter SARS-CoV.
T491	66709-66810	Sentence	denotes	Studies are required to establish any correlation between SARS-CoV-2 viral load and cultivable virus.
T492	66811-67074	Sentence	denotes	Recognizing patients with fewer or no symptoms, along with having modest detectable viral RNA in the oropharynx for 5 days, indicates the requirement of data for assessing SARS-CoV-2 transmission dynamics and updating the screening procedures in the clinics (82).
T493	67075-67130	Sentence	denotes	TABLE 2 Clinical specimens for detection of SARS CoV-2
T494	67131-67154	Sentence	denotes	Sample Recommendationa
T495	67155-67188	Sentence	denotes	Bronchoalveolar lavage fluid +++
T496	67189-67200	Sentence	denotes	Sputum +++
T497	67201-67217	Sentence	denotes	Nasal swabs +++
T498	67218-67252	Sentence	denotes	Fibrobronchoscope brush biopsy ++
T499	67253-67273	Sentence	denotes	Pharyngeal swabs ++
T500	67274-67282	Sentence	denotes	Feces +
T501	67283-67291	Sentence	denotes	Blood +
T502	67292-67300	Sentence	denotes	Urine +
T503	67301-67392	Sentence	denotes	a Recommendations are based on references 245 and 246. +++, strong; ++, moderate; +, weak.
T504	67393-67601	Sentence	denotes	The results of the studies related to SARS-CoV-2 viral loads reflect active replication of this virus in the upper respiratory tract and prolonged viral shedding after symptoms disappear, including via stool.
T505	67602-67767	Sentence	denotes	Thus, the current case definition needs to be updated along with a reassessment of the strategies to be adopted for restraining the SARS-CoV-2 outbreak spread (248).
T506	67768-67922	Sentence	denotes	In some cases, the viral load studies of SARS-CoV-2 have also been useful to recommend precautionary measures when handling specific samples, e.g., feces.
T507	67923-68146	Sentence	denotes	In a recent survey from 17 confirmed cases of SARS-CoV-2 infection with available data (representing days 0 to 13 after onset), stool samples from nine cases (53%; days 0 to 11 after onset) were positive on RT-PCR analysis.
T508	68147-68321	Sentence	denotes	Although the viral loads were lower than those of respiratory samples (range, 550 copies per ml to 1.21 × 105 copies per ml), this has essential biosafety implications (151).
T509	68322-68526	Sentence	denotes	The samples from 18 SARS-CoV-2-positive patients in Singapore who had traveled from Wuhan to Singapore showed the presence of viral RNA in stool and whole blood but not in urine by real-time RT-PCR (288).
T510	68527-68758	Sentence	denotes	Further, novel SARS-CoV-2 infections have been detected in a variety of clinical specimens, like bronchoalveolar lavage fluid, sputum, nasal swabs, fibrobronchoscope brush biopsy specimens, pharyngeal swabs, feces, and blood (246).
T511	68759-68842	Sentence	denotes	The presence of SARS-CoV-2 in fecal samples has posed grave public health concerns.
T512	68843-69085	Sentence	denotes	In addition to the direct transmission mainly occurring via droplets of sneezing and coughing, other routes, such as fecal excretion and environmental and fomite contamination, are contributing to SARS-CoV-2 transmission and spread (249–252).
T513	69086-69239	Sentence	denotes	Fecal excretion has also been documented for SARS-CoV and MERS-CoV, along with the potential to stay viable in situations aiding fecal-oral transmission.
T514	69240-69315	Sentence	denotes	Thus, SARS-CoV-2 has every possibility to be transmitted through this mode.
T515	69316-69505	Sentence	denotes	Fecal-oral transmission of SARS-CoV-2, particularly in regions having low standards of hygiene and poor sanitation, may have grave consequences with regard to the high spread of this virus.
T516	69506-69608	Sentence	denotes	Ethanol and disinfectants containing chlorine or bleach are effective against coronaviruses (249–252).
T517	69609-69725	Sentence	denotes	Appropriate precautions need to be followed strictly while handling the stools of patients infected with SARS-CoV-2.

T18

0-12

Sentence

denotes

INTRODUCTION

T19

13-148

Sentence

denotes

Over the past 2 decades, coronaviruses (CoVs) have been associated with significant disease outbreaks in East Asia and the Middle East.

T20

149-289

Sentence

denotes

The severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) began to emerge in 2002 and 2012, respectively.

T21

290-557

Sentence

denotes

Recently, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), emerged in late 2019, and it has posed a global health threat, causing an ongoing pandemic in many countries and territories (1).

T22

558-788

Sentence

denotes

Health workers worldwide are currently making efforts to control further disease outbreaks caused by the novel CoV (originally named 2019-nCoV), which was first identified in Wuhan City, Hubei Province, China, on 12 December 2019.

T23

789-957

Sentence

denotes

On 11 February 2020, the World Health Organization (WHO) announced the official designation for the current CoV-associated disease to be COVID-19, caused by SARS-CoV-2.

T24

958-1072

Sentence

denotes

The primary cluster of patients was found to be connected with the Huanan South China Seafood Market in Wuhan (2).

T25

1073-1340

Sentence

denotes

CoVs belong to the family Coronaviridae (subfamily Coronavirinae), the members of which infect a broad range of hosts, producing symptoms and diseases ranging from the common cold to severe and ultimately fatal illnesses, such as SARS, MERS, and, presently, COVID-19.

T26

1341-1544

Sentence

denotes

SARS-CoV-2 is considered one of the seven members of the CoV family that infect humans (3), and it belongs to the same lineage of CoVs that causes SARS; however, this novel virus is genetically distinct.

T27

1545-1689

Sentence

denotes

Until 2020, six CoVs were known to infect humans, including human CoV 229E (HCoV-229E), HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, and MERS-CoV.

T28

1690-1842

Sentence

denotes

Although SARS-CoV and MERS-CoV have resulted in outbreaks with high mortality, others remain associated with mild upper-respiratory-tract illnesses (4).

T29

1843-1905

Sentence

denotes

Newly evolved CoVs pose a high threat to global public health.

T30

1906-2004

Sentence

denotes

The current emergence of COVID-19 is the third CoV outbreak in humans over the past 2 decades (5).

T31

2005-2150

Sentence

denotes

It is no coincidence that Fan et al. predicted potential SARS- or MERS-like CoV outbreaks in China following pathogen transmission from bats (6).

T32

2151-2257

Sentence

denotes

COVID-19 emerged in China and spread rapidly throughout the country and, subsequently, to other countries.

T33

2258-2486

Sentence

denotes

Due to the severity of this outbreak and the potential of spreading on an international scale, the WHO declared a global health emergency on 31 January 2020; subsequently, on 11 March 2020, they declared it a pandemic situation.

T34

2487-2670

Sentence

denotes

At present, we are not in a position to effectively treat COVID-19, since neither approved vaccines nor specific antiviral drugs for treating human CoV infections are available (7–9).

T35

2671-2829

Sentence

denotes

Most nations are currently making efforts to prevent the further spreading of this potentially deadly virus by implementing preventive and control strategies.

T36

2830-2936

Sentence

denotes

In domestic animals, infections with CoVs are associated with a broad spectrum of pathological conditions.

T37

2937-3098

Sentence

denotes

Apart from infectious bronchitis virus, canine respiratory CoV, and mouse hepatitis virus, CoVs are predominantly associated with gastrointestinal diseases (10).

T38

3099-3288

Sentence

denotes

The emergence of novel CoVs may have become possible because of multiple CoVs being maintained in their natural host, which could have favored the probability of genetic recombination (10).

T39

3289-3543

Sentence

denotes

High genetic diversity and the ability to infect multiple host species are a result of high-frequency mutations in CoVs, which occur due to the instability of RNA-dependent RNA polymerases along with higher rates of homologous RNA recombination (10, 11).

T40

3544-3733

Sentence

denotes

Identifying the origin of SARS-CoV-2 and the pathogen’s evolution will be helpful for disease surveillance (12), development of new targeted drugs, and prevention of further epidemics (13).

T41

3734-3859

Sentence

denotes

The most common symptoms associated with COVID-19 are fever, cough, dyspnea, expectoration, headache, and myalgia or fatigue.

T42

3860-3984

Sentence

denotes

In contrast, less common signs at the time of hospital admission include diarrhea, hemoptysis, and shortness of breath (14).

T43

3985-4181

Sentence

denotes

Recently, individuals with asymptomatic infections were also suspected of transmitting infections, which further adds to the complexity of disease transmission dynamics in COVID-19 infections (1).

T44

4182-4332

Sentence

denotes

Such efficient responses require in-depth knowledge regarding the virus, which currently is a novel agent; consequently, further studies are required.

T45

4333-4554

Sentence

denotes

Comparing the genome of SARS-CoV-2 with that of the closely related SARS/SARS-like CoV revealed that the sequence coding for the spike protein, with a total length of 1,273 amino acids, showed 27 amino acid substitutions.

T46

4555-4712

Sentence

denotes

Six of these substitutions are in the region of the receptor-binding domain (RBD), and another six substitutions are in the underpinning subdomain (SD) (16).

T47

4713-4901

Sentence

denotes

Phylogenetic analyses have revealed that SARS-CoV-2 is closely related (88% similarity) to two SARS-like CoVs derived from bat SARS-like CoVs (bat-SL-CoVZC45 and bat-SL-CoVZXC21) (Fig. 1).

T48

4902-5012

Sentence

denotes

Furthermore, SARS-CoV-2 is genetically distinct from SARS-CoV (79% similarity) and MERS-CoV (nearly 50%) (17).

T49

5013-5310

Sentence

denotes

COVID-19 is associated with afflictions of the lungs in all cases and generated characteristic chest computer tomography findings, such as the presence of multiple lesions in lung lobes that appear as dense, ground-glass opaque structures that occasionally coexist with consolidation shadows (18).

T50

5311-5345

Sentence

denotes

FIG 1 S-gene SplitsTree analysis.

T51

5346-5468

Sentence

denotes

Shown is the spike (S) glycoprotein gene-based phylogenetic analysis (SplitsTree 4.0) of SAR-CoV-2 isolates (39 isolates).

T52

5469-5684

Sentence

denotes

The SARS-CoV-2 isolates were analyzed with related CoVs from past human outbreaks and of animal origin, including MERS-CoV, bovine coronavirus, canine coronavirus, bat coronaviruses, bat-SL-SARS-CoV, and equine CoV.

T53

5685-5834

Sentence

denotes

The analysis includes all five defined subgenera of Betacoronaviruses, namely, Sarbecovirus, Embecovirus, Merbecovirus, Nobecovirus, and Hibecovirus.

T54

5835-5931

Sentence

denotes

The isolates in the gray area are from the current outbreak of SARS-CoV-2 from around the world.

T55

5932-6008

Sentence

denotes

The nearest neighbors of SARS-CoV-2 are the bat-SL-CoV, encircled in yellow.

T56

6009-6275

Sentence

denotes

Some therapeutic options for treating COVID-19 showed efficacy in in vitro studies; however, to date, these treatments have not undergone any randomized animal or human clinical trials, which limit their practical applicability in the current pandemic (7, 9, 19–21).

T57

6276-6468

Sentence

denotes

The present comprehensive review describes the various features of SARS-CoV-2/COVID-19 causing the current disease outbreaks and advances in diagnosis and developing vaccines and therapeutics.

T58

6469-6761

Sentence

denotes

It also provides a brief comparison with the earlier SARS and MERS CoVs, the veterinary perspective of CoVs and this emerging novel pathogen, and an evaluation of the zoonotic potential of similar CoVs to provide feasible One Health strategies for the management of this fatal virus (22–367).

T59

6763-6785

Sentence

denotes

THE VIRUS (SARS-CoV-2)

T60

6786-6927

Sentence

denotes

Coronaviruses are positive-sense RNA viruses having an extensive and promiscuous range of natural hosts and affect multiple systems (23, 24).

T61

6928-7082

Sentence

denotes

Coronaviruses can cause clinical diseases in humans that may extend from the common cold to more severe respiratory diseases like SARS and MERS (17, 279).

T62

7083-7349

Sentence

denotes

The recently emerging SARS-CoV-2 has wrought havoc in China and caused a pandemic situation in the worldwide population, leading to disease outbreaks that have not been controlled to date, although extensive efforts are being put in place to counter this virus (25).

T63

7350-7680

Sentence

denotes

This virus has been proposed to be designated/named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (ICTV), which determined the virus belongs to the Severe acute respiratory syndrome-related coronavirus category and found this virus is related to SARS-CoVs (26).

T64

7681-7908

Sentence

denotes

SARS-CoV-2 is a member of the order Nidovirales, family Coronaviridae, subfamily Orthocoronavirinae, which is subdivided into four genera, viz., Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (3, 27).

T65

7909-8084

Sentence

denotes

The genera Alphacoronavirus and Betacoronavirus originate from bats, while Gammacoronavirus and Deltacoronavirus have evolved from bird and swine gene pools (24, 28, 29, 275).

T66

8085-8229

Sentence

denotes

Coronaviruses possess an unsegmented, single-stranded, positive-sense RNA genome of around 30 kb, enclosed by a 5′-cap and 3′-poly(A) tail (30).

T67

8230-8305

Sentence

denotes

The genome of SARS-CoV-2 is 29,891 bp long, with a G+C content of 38% (31).

T68

8306-8381

Sentence

denotes

These viruses are encircled with an envelope containing viral nucleocapsid.

T69

8382-8514

Sentence

denotes

The nucleocapsids in CoVs are arranged in helical symmetry, which reflects an atypical attribute in positive-sense RNA viruses (30).

T70

8515-8760

Sentence

denotes

The electron micrographs of SARS-CoV-2 revealed a diverging spherical outline with some degree of pleomorphism, virion diameters varying from 60 to 140 nm, and distinct spikes of 9 to 12 nm, giving the virus the appearance of a solar corona (3).

T71

8761-8871

Sentence

denotes

The CoV genome is arranged linearly as 5′-leader-UTR-replicase-structural genes (S-E-M-N)-3′ UTR-poly(A) (32).

T72

8872-9009

Sentence

denotes

Accessory genes, such as 3a/b, 4a/b, and the hemagglutinin-esterase gene (HE), are also seen intermingled with the structural genes (30).

T73

9010-9187

Sentence

denotes

SARS-CoV-2 has also been found to be arranged similarly and encodes several accessory proteins, although it lacks the HE, which is characteristic of some betacoronaviruses (31).

T74

9188-9297

Sentence

denotes

The positive-sense genome of CoVs serves as the mRNA and is translated to polyprotein 1a/1ab (pp1a/1ab) (33).

T75

9298-9456

Sentence

denotes

A replication-transcription complex (RTC) is formed in double-membrane vesicles (DMVs) by nonstructural proteins (nsps), encoded by the polyprotein gene (34).

T76

9457-9569

Sentence

denotes

Subsequently, the RTC synthesizes a nested set of subgenomic RNAs (sgRNAs) via discontinuous transcription (35).

T77

9570-9697

Sentence

denotes

Based on molecular characterization, SARS-CoV-2 is considered a new Betacoronavirus belonging to the subgenus Sarbecovirus (3).

T78

9698-9801

Sentence

denotes

A few other critical zoonotic viruses (MERS-related CoV and SARS-related CoV) belong to the same genus.

T79

9802-9985

Sentence

denotes

However, SARS-CoV-2 was identified as a distinct virus based on the percent identity with other Betacoronavirus; conserved open reading frame 1a/b (ORF1a/b) is below 90% identity (3).

T80

9986-10162

Sentence

denotes

An overall 80% nucleotide identity was observed between SARS-CoV-2 and the original SARS-CoV, along with 89% identity with ZC45 and ZXC21 SARS-related CoVs of bats (2, 31, 36).

T81

10163-10284

Sentence

denotes

In addition, 82% identity has been observed between SARS-CoV-2 and human SARS-CoV Tor2 and human SARS-CoV BJ01 2003 (31).

T82

10285-10398

Sentence

denotes

A sequence identity of only 51.8% was observed between MERS-related CoV and the recently emerged SARS-CoV-2 (37).

T83

10399-10509

Sentence

denotes

Phylogenetic analysis of the structural genes also revealed that SARS-CoV-2 is closer to bat SARS-related CoV.

T84

10510-10657

Sentence

denotes

Therefore, SARS-CoV-2 might have originated from bats, while other amplifier hosts might have played a role in disease transmission to humans (31).

T85

10658-10770

Sentence

denotes

Of note, the other two zoonotic CoVs (MERS-related CoV and SARS-related CoV) also originated from bats (38, 39).

T86

10771-10872

Sentence

denotes

Nevertheless, for SARS and MERS, civet cat and camels, respectively, act as amplifier hosts (40, 41).

T87

10873-10929

Sentence

denotes

Coronavirus genomes and subgenomes encode six ORFs (31).

T88

10930-11004

Sentence

denotes

The majority of the 5′ end is occupied by ORF1a/b, which produces 16 nsps.

T89

11005-11127

Sentence

denotes

The two polyproteins, pp1a and pp1ab, are initially produced from ORF1a/b by a −1 frameshift between ORF1a and ORF1b (32).

T90

11128-11296

Sentence

denotes

The virus-encoded proteases cleave polyproteins into individual nsps (main protease [Mpro], chymotrypsin-like protease [3CLpro], and papain-like proteases [PLPs]) (42).

T91

11297-11388

Sentence

denotes

SARS-CoV-2 also encodes these nsps, and their functions have been elucidated recently (31).

T92

11389-11618

Sentence

denotes

Remarkably, a difference between SARS-CoV-2 and other CoVs is the identification of a novel short putative protein within the ORF3 band, a secreted protein with an alpha helix and beta-sheet with six strands encoded by ORF8 (31).

T93

11619-11777

Sentence

denotes

Coronaviruses encode four major structural proteins, namely, spike (S), membrane (M), envelope (E), and nucleocapsid (N), which are described in detail below.

T94

11779-11793

Sentence

denotes

S Glycoprotein

T95

11794-11880

Sentence

denotes

Coronavirus S protein is a large, multifunctional class I viral transmembrane protein.

T96

11881-12047

Sentence

denotes

The size of this abundant S protein varies from 1,160 amino acids (IBV, infectious bronchitis virus, in poultry) to 1,400 amino acids (FCoV, feline coronavirus) (43).

T97

12048-12143

Sentence

denotes

It lies in a trimer on the virion surface, giving the virion a corona or crown-like appearance.

T98

12144-12297

Sentence

denotes

Functionally it is required for the entry of the infectious virion particles into the cell through interaction with various host cellular receptors (44).

T99

12298-12400

Sentence

denotes

Furthermore, it acts as a critical factor for tissue tropism and the determination of host range (45).

T100

12401-12519

Sentence

denotes

Notably, S protein is one of the vital immunodominant proteins of CoVs capable of inducing host immune responses (45).

T101

12520-12636

Sentence

denotes

The ectodomains in all CoVs S proteins have similar domain organizations, divided into two subunits, S1 and S2 (43).

T102

12637-12734

Sentence

denotes

The first one, S1, helps in host receptor binding, while the second one, S2, accounts for fusion.

T103

12735-12855

Sentence

denotes

The former (S1) is further divided into two subdomains, namely, the N-terminal domain (NTD) and C-terminal domain (CTD).

T104

12856-12971

Sentence

denotes

Both of these subdomains act as receptor-binding domains, interacting efficiently with various host receptors (45).

T105

12972-13025

Sentence

denotes

The S1 CTD contains the receptor-binding motif (RBM).

T106

13026-13129

Sentence

denotes

In each coronavirus spike protein, the trimeric S1 locates itself on top of the trimeric S2 stalk (45).

T107

13130-13271

Sentence

denotes

Recently, structural analyses of the S proteins of COVID-19 have revealed 27 amino acid substitutions within a 1,273-amino-acid stretch (16).

T108

13272-13412

Sentence

denotes

Six substitutions are located in the RBD (amino acids 357 to 528), while four substitutions are in the RBM at the CTD of the S1 domain (16).

T109

13413-13560

Sentence

denotes

Of note, no amino acid change is seen in the RBM, which binds directly to the angiotensin-converting enzyme-2 (ACE2) receptor in SARS-CoV (16, 46).

T110

13561-13668

Sentence

denotes

At present, the main emphasis is knowing how many differences would be required to change the host tropism.

T111

13669-13799

Sentence

denotes

Sequence comparison revealed 17 nonsynonymous changes between the early sequence of SARS-CoV-2 and the later isolates of SARS-CoV.

T112

13800-13992

Sentence

denotes

The changes were found scattered over the genome of the virus, with nine substitutions in ORF1ab, ORF8 (4 substitutions), the spike gene (3 substitutions), and ORF7a (single substitution) (4).

T113

13993-14157

Sentence

denotes

Notably, the same nonsynonymous changes were found in a familial cluster, indicating that the viral evolution happened during person-to-person transmission (4, 47).

T114

14158-14290

Sentence

denotes

Such adaptive evolution events are frequent and constitute a constantly ongoing process once the virus spreads among new hosts (47).

T115

14291-14495

Sentence

denotes

Even though no functional changes occur in the virus associated with this adaptive evolution, close monitoring of the viral mutations that occur during subsequent human-to-human transmission is warranted.

T116

14497-14506

Sentence

denotes

M Protein

T117

14507-14639

Sentence

denotes

The M protein is the most abundant viral protein present in the virion particle, giving a definite shape to the viral envelope (48).

T118

14640-14730

Sentence

denotes

It binds to the nucleocapsid and acts as a central organizer of coronavirus assembly (49).

T119

14731-14868

Sentence

denotes

Coronavirus M proteins are highly diverse in amino acid contents but maintain overall structural similarity within different genera (50).

T120

14869-15020

Sentence

denotes

The M protein has three transmembrane domains, flanked by a short amino terminus outside the virion and a long carboxy terminus inside the virion (50).

T121

15021-15082

Sentence

denotes

Overall, the viral scaffold is maintained by M-M interaction.

T122

15083-15195

Sentence

denotes

Of note, the M protein of SARS-CoV-2 does not have an amino acid substitution compared to that of SARS-CoV (16).

T123

15197-15206

Sentence

denotes

E Protein

T124

15207-15306

Sentence

denotes

The coronavirus E protein is the most enigmatic and smallest of the major structural proteins (51).

T125

15307-15400

Sentence

denotes

It plays a multifunctional role in the pathogenesis, assembly, and release of the virus (52).

T126

15401-15489

Sentence

denotes

It is a small integral membrane polypeptide that acts as a viroporin (ion channel) (53).

T127

15490-15633

Sentence

denotes

The inactivation or absence of this protein is related to the altered virulence of coronaviruses due to changes in morphology and tropism (54).

T128

15634-15801

Sentence

denotes

The E protein consists of three domains, namely, a short hydrophilic amino terminal, a large hydrophobic transmembrane domain, and an efficient C-terminal domain (51).

T129

15802-15899

Sentence

denotes

The SARS-CoV-2 E protein reveals a similar amino acid constitution without any substitution (16).

T130

15901-15910

Sentence

denotes

N Protein

T131

15911-15956

Sentence

denotes

The N protein of coronavirus is multipurpose.

T132

15957-16171

Sentence

denotes

Among several functions, it plays a role in complex formation with the viral genome, facilitates M protein interaction needed during virion assembly, and enhances the transcription efficiency of the virus (55, 56).

T133

16172-16308

Sentence

denotes

It contains three highly conserved and distinct domains, namely, an NTD, an RNA-binding domain or a linker region (LKR), and a CTD (57).

T134

16309-16456

Sentence

denotes

The NTD binds with the 3′ end of the viral genome, perhaps via electrostatic interactions, and is highly diverged both in length and sequence (58).

T135

16457-16563

Sentence

denotes

The charged LKR is serine and arginine rich and is also known as the SR (serine and arginine) domain (59).

T136

16564-16682

Sentence

denotes

The LKR is capable of direct interaction with in vitro RNA interaction and is responsible for cell signaling (60, 61).

T137

16683-16811

Sentence

denotes

It also modulates the antiviral response of the host by working as an antagonist for interferon (IFN) and RNA interference (62).

T138

16812-17069

Sentence

denotes

Compared to that of SARS-CoV, the N protein of SARS-CoV-2 possess five amino acid mutations, where two are in the intrinsically dispersed region (IDR; positions 25 and 26), one each in the NTD (position 103), LKR (position 217), and CTD (position 334) (16).

T139

17071-17098

Sentence

denotes

nsps and Accessory Proteins

T140

17099-17286

Sentence

denotes

Besides the important structural proteins, the SARS-CoV-2 genome contains 15 nsps, nsp1 to nsp10 and nsp12 to nsp16, and 8 accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b, and ORF14) (16).

T141

17287-17353

Sentence

denotes

All these proteins play a specific role in viral replication (27).

T142

17354-17484

Sentence

denotes

Unlike the accessory proteins of SARS-CoV, SARS-CoV-2 does not contain 8a protein and has a longer 8b and shorter 3b protein (16).

T143

17485-17664

Sentence

denotes

The nsp7, nsp13, envelope, matrix, and p6 and 8b accessory proteins have not been detected with any amino acid substitutions compared to the sequences of other coronaviruses (16).

T144

17665-17721

Sentence

denotes

The virus structure of SARS-CoV-2 is depicted in Fig. 2.

T145

17722-17756

Sentence

denotes

FIG 2 SARS-CoV-2 virus structure.

T146

17758-17801

Sentence

denotes

SARS-CoV-2 Spike Glycoprotein Gene Analysis

T147

17803-17840

Sentence

denotes

Sequence percent similarity analysis.

T148

17841-18017

Sentence

denotes

We assessed the nucleotide percent similarity using the MegAlign software program, where the similarity between the novel SARS-CoV-2 isolates was in the range of 99.4% to 100%.

T149

18018-18205

Sentence

denotes

Among the other Serbecovirus CoV sequences, the novel SARS-CoV-2 sequences revealed the highest similarity to bat-SL-CoV, with nucleotide percent identity ranges between 88.12 and 89.65%.

T150

18206-18314

Sentence

denotes

Meanwhile, earlier reported SARS-CoVs showed 70.6 to 74.9% similarity to SARS-CoV-2 at the nucleotide level.

T151

18315-18527

Sentence

denotes

Further, the nucleotide percent similarity was 55.4%, 45.5% to 47.9%, 46.2% to 46.6%, and 45.0% to 46.3% to the other four subgenera, namely, Hibecovirus, Nobecovirus, Merbecovirus, and Embecovirus, respectively.

T152

18528-18688

Sentence

denotes

The percent similarity index of current outbreak isolates indicates a close relationship between SARS-CoV-2 isolates and bat-SL-CoV, indicating a common origin.

T153

18689-18979

Sentence

denotes

However, particular pieces of evidence based on further complete genomic analysis of current isolates are necessary to draw any conclusions, although it was ascertained that the current novel SARS-CoV-2 isolates belong to the subgenus Sarbecovirus in the diverse range of betacoronaviruses.

T154

18980-19130

Sentence

denotes

Their possible ancestor was hypothesized to be from bat CoV strains, wherein bats might have played a crucial role in harboring this class of viruses.

T155

19132-19162

Sentence

denotes

SplitsTree phylogeny analysis.

T156

19163-19324

Sentence

denotes

In the unrooted phylogenetic tree of different betacoronaviruses based on the S protein, virus sequences from different subgenera grouped into separate clusters.

T157

19325-19450

Sentence

denotes

SARS-CoV-2 sequences from Wuhan and other countries exhibited a close relationship and appeared in a single cluster (Fig. 1).

T158

19451-19632

Sentence

denotes

The CoVs from the subgenus Sarbecovirus appeared jointly in SplitsTree and divided into three subclusters, namely, SARS-CoV-2, bat-SARS-like-CoV (bat-SL-CoV), and SARS-CoV (Fig. 1).

T159

19633-19898

Sentence

denotes

In the case of other subgenera, like Merbecovirus, all of the sequences grouped in a single cluster, whereas in Embecovirus, different species, comprised of canine respiratory CoVs, bovine CoVs, equine CoVs, and human CoV strain (OC43), grouped in a common cluster.

T160

19899-20047

Sentence

denotes

Isolates in the subgenera Nobecovorus and Hibecovirus were found to be placed separately away from other reported SARS-CoVs but shared a bat origin.

T161

20049-20089

Sentence

denotes

CURRENT WORLDWIDE SCENARIO OF SARS-CoV-2

T162

20090-20279

Sentence

denotes

This novel virus, SARS-CoV-2, comes under the subgenus Sarbecovirus of the Orthocoronavirinae subfamily and is entirely different from the viruses responsible for MERS-CoV and SARS-CoV (3).

T163

20280-20339

Sentence

denotes

The newly emerged SARS-CoV-2 is a group 2B coronavirus (2).

T164

20340-20463

Sentence

denotes

The genome sequences of SARS-CoV-2 obtained from patients share 79.5% sequence similarity to the sequence of SARS-CoV (63).

T165

20464-20660

Sentence

denotes

As of 13 May 2020, a total of 4,170,424 confirmed cases of COVID-19 (with 287,399 deaths) have been reported in more than 210 affected countries worldwide (WHO Situation Report 114 [25]) (Fig. 3).

T166

20661-20721

Sentence

denotes

FIG 3 World map depicting the current scenario of COVID-19.

T167

20722-20829

Sentence

denotes

Shown are countries, territories, or regions with reported confirmed cases of SARS-CoV-2 as of 13 May 2020.

T168

20830-20937

Sentence

denotes

Different colors indicate different WHO designated geographical regions with the number of confirmed cases.

T169

20938-21028

Sentence

denotes

The WHO region-wise total number of confirmed cases is depicted in different color strips.

T170

21029-21156

Sentence

denotes

The leading information on the confirmed cases and deaths from all six WHO designated regions are depicted in circled balloons.

T171

21157-21793

Sentence

denotes

The numbers of COVID-19 cases and fatalities on three major cruise ships are also depicted. (Based on data from the WHO at https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200513-covid-19-sitrep-114.pdf?sfvrsn=17ebbbe_4; updated numbers of cases, deaths, and patients recovered can be found at https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6.) Initially, the epicenter of the SARS-CoV-2 pandemic was China, which reported a significant number of deaths associated with COVID-19, with 84,458 laboratory-confirmed cases and 4,644 deaths as of 13 May 2020 (Fig. 4).

T172

21794-21954

Sentence

denotes

As of 13 May 2020, SARS-CoV-2 confirmed cases have been reported in more than 210 countries apart from China (Fig. 3 and 4) (WHO Situation Report 114) (25, 64).

T173

21955-22018

Sentence

denotes

COVID-19 has been reported on all continents except Antarctica.

T174

22019-22247

Sentence

denotes

For many weeks, Italy was the focus of concerns regarding the large number of cases, with 221,216 cases and 30,911 deaths, but now, the United States is the country with the largest number of cases, 1,322,054, and 79,634 deaths.

T175

22248-22334

Sentence

denotes

Now, the United Kingdom has even more cases (226,4671) and deaths (32,692) than Italy.

T176

22335-22558

Sentence

denotes

A John Hopkins University web platform has provided daily updates on the basic epidemiology of the COVID-19 outbreak (https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6) (238).

T177

22559-22611

Sentence

denotes

FIG 4 Bar graph and pie chart for cases and deaths.

T178

22612-22977

Sentence

denotes

Shown are laboratory-confirmed cases and deaths in China and the rest of the world due to SARS-CoV-2. (A) SARS-CoV-2 confirmed cases in the top five affected countries from each WHO designated region, where maximum casualties were reported to WHO until 13 May 2020. (B) Total numbers of deaths and cases in China only. (C) Total number of cases worldwide by region.

T179

22978-23169

Sentence

denotes

COVID-19 has also been confirmed on a cruise ship, named Diamond Princess, quarantined in Japanese waters (Port of Yokohama), as well as on other cruise ships around the world (239) (Fig. 3).

T180

23170-23305

Sentence

denotes

The significant events of the SARS-CoV-2/COVID-19 virus outbreak occurring since 8 December 2019 are presented as a timeline in Fig. 5.

T181

23306-23415

Sentence

denotes

FIG 5 Timeline depicting the significant events that occurred during the SARS-CoV-2/COVID-19 virus outbreak.

T182

23416-23538

Sentence

denotes

The timeline describes the significant events during the current SARS-CoV-2 outbreak, from 8 December 2019 to 13 May 2020.

T183

23539-23840

Sentence

denotes

At the beginning, China experienced the majority of the burden associated with COVID-19 in the form of disease morbidity and mortality (65), but over time the COVID-19 menace moved to Europe, particularly Italy and Spain, and now the United States has the highest number of confirmed cases and deaths.

T184

23841-24090

Sentence

denotes

The COVID-19 outbreak has also been associated with severe economic impacts globally due to the sudden interruption of global trade and supply chains that forced multinational companies to make decisions that led to significant economic losses (66).

T185

24091-24316

Sentence

denotes

The recent increase in the number of confirmed critically ill patients with COVID-19 has already surpassed the intensive care supplies, limiting intensive care services to only a small portion of critically ill patients (67).

T186

24317-24420

Sentence

denotes

This might also have contributed to the increased case fatality rate observed in the COVID-19 outbreak.

T187

24422-24481

Sentence

denotes

Viewpoint on SARS-CoV-2 Transmission, Spread, and Emergence

T188

24482-24560

Sentence

denotes

The novel coronavirus was identified within 1 month (28 days) of the outbreak.

T189

24561-24697

Sentence

denotes

This is impressively fast compared to the time taken to identify SARS-CoV reported in Foshan, Guangdong Province, China (125 days) (68).

T190

24698-24956

Sentence

denotes

Immediately after the confirmation of viral etiology, the Chinese virologists rapidly released the genomic sequence of SARS-CoV-2, which played a crucial role in controlling the spread of this newly emerged novel coronavirus to other parts of the world (69).

T191

24957-25062

Sentence

denotes

The possible origin of SARS-CoV-2 and the first mode of disease transmission are not yet identified (70).

T192

25063-25235

Sentence

denotes

Analysis of the initial cluster of infections suggests that the infected individuals had a common exposure point, a seafood market in Wuhan, Hubei Province, China (Fig. 6).

T193

25236-25355

Sentence

denotes

The restaurants of this market are well-known for providing different types of wild animals for human consumption (71).

T194

25356-25467

Sentence

denotes

The Huanan South China Seafood Market also sells live animals, such as poultry, bats, snakes, and marmots (72).

T195

25468-25552

Sentence

denotes

This might be the point where zoonotic (animal-to-human) transmission occurred (71).

T196

25553-25819

Sentence

denotes

Although SARS-CoV-2 is alleged to have originated from an animal host (zoonotic origin) with further human-to-human transmission (Fig. 6), the likelihood of foodborne transmission should be ruled out with further investigations, since it is a latent possibility (1).

T197

25820-26054

Sentence

denotes

Additionally, other potential and expected routes would be associated with transmission, as in other respiratory viruses, by direct contact, such as shaking contaminated hands, or by direct contact with contaminated surfaces (Fig. 6).

T198

26055-26249

Sentence

denotes

Still, whether blood transfusion and organ transplantation (276), as well as transplacental and perinatal routes, are possible routes for SARS-CoV-2 transmission needs to be determined (Fig. 6).

T199

26250-26302

Sentence

denotes

FIG 6 Potential transmission routes for SARS-CoV-2.

T200

26303-26462

Sentence

denotes

From experience with several outbreaks associated with known emerging viruses, higher pathogenicity of a virus is often associated with lower transmissibility.

T201

26463-26627

Sentence

denotes

Compared to emerging viruses like Ebola virus, avian H7N9, SARS-CoV, and MERS-CoV, SARS-CoV-2 has relatively lower pathogenicity and moderate transmissibility (15).

T202

26628-26742

Sentence

denotes

The risk of death among individuals infected with COVID-19 was calculated using the infection fatality risk (IFR).

T203

26743-26889

Sentence

denotes

The IFR was found to be in the range of 0.3% to 0.6%, which is comparable to that of a previous Asian influenza pandemic (1957 to 1958) (73, 277).

T204

26890-27031

Sentence

denotes

Notably, the reanalysis of the COVID-19 pandemic curve from the initial cluster of cases pointed to considerable human-to-human transmission.

T205

27032-27305

Sentence

denotes

It is opined that the exposure history of SARS-CoV-2 at the Wuhan seafood market originated from human-to-human transmission rather than animal-to-human transmission (74); however, in light of the zoonotic spillover in COVID-19, is too early to fully endorse this idea (1).

T206

27306-27515

Sentence

denotes

Following the initial infection, human-to-human transmission has been observed with a preliminary reproduction number (R0) estimate of 1.4 to 2.5 (70, 75), and recently it is estimated to be 2.24 to 3.58 (76).

T207

27516-27679

Sentence

denotes

In another study, the average reproductive number of COVID-19 was found to be 3.28, which is significantly higher than the initial WHO estimate of 1.4 to 2.5 (77).

T208

27680-27788

Sentence

denotes

It is too early to obtain the exact R0 value, since there is a possibility of bias due to insufficient data.

T209

27789-27912

Sentence

denotes

The higher R0 value is indicative of the more significant potential of SARS-CoV-2 transmission in a susceptible population.

T210

27913-28051

Sentence

denotes

This is not the first time where the culinary practices of China have been blamed for the origin of novel coronavirus infection in humans.

T211

28052-28190

Sentence

denotes

Previously, the animals present in the live-animal market were identified to be the intermediate hosts of the SARS outbreak in China (78).

T212

28191-28321

Sentence

denotes

Several wildlife species were found to harbor potentially evolving coronavirus strains that can overcome the species barrier (79).

T213

28322-28441

Sentence

denotes

One of the main principles of Chinese food culture is that live-slaughtered animals are considered more nutritious (5).

T214

28442-28571

Sentence

denotes

After 4 months of struggle that lasted from December 2019 to March 2020, the COVID-19 situation now seems under control in China.

T215

28572-28877

Sentence

denotes

The wet animal markets have reopened, and people have started buying bats, dogs, cats, birds, scorpions, badgers, rabbits, pangolins (scaly anteaters), minks, soup from palm civet, ostriches, hamsters, snapping turtles, ducks, fish, Siamese crocodiles, and other animal meats without any fear of COVID-19.

T216

28878-28959

Sentence

denotes

The Chinese government is encouraging people to feel they can return to normalcy.

T217

28960-29150

Sentence

denotes

However, this could be a risk, as it has been mentioned in advisories that people should avoid contact with live-dead animals as much as possible, as SARS-CoV-2 has shown zoonotic spillover.

T218

29151-29317

Sentence

denotes

Additionally, we cannot rule out the possibility of new mutations in the same virus being closely related to contact with both animals and humans at the market (284).

T219

29318-29413

Sentence

denotes

In January 2020, China imposed a temporary ban on the sale of live-dead animals in wet markets.

T220

29414-29546

Sentence

denotes

However, now hundreds of such wet markets have been reopened without optimizing standard food safety and sanitation practices (286).

T221

29547-29750

Sentence

denotes

With China being the most populated country in the world and due to its domestic and international food exportation policies, the whole world is now facing the menace of COVID-19, including China itself.

T222

29751-29831

Sentence

denotes

Wet markets of live-dead animals do not maintain strict food hygienic practices.

T223

29832-30005

Sentence

denotes

Fresh blood splashes are present everywhere, on the floor and tabletops, and such food customs could encourage many pathogens to adapt, mutate, and jump the species barrier.

T224

30006-30138

Sentence

denotes

As a result, the whole world is suffering from novel SARS-CoV-2, with more than 4,170,424 cases and 287,399 deaths across the globe.

T225

30139-30356

Sentence

denotes

There is an urgent need for a rational international campaign against the unhealthy food practices of China to encourage the sellers to increase hygienic food practices or close the crude live-dead animal wet markets.

T226

30357-30575

Sentence

denotes

There is a need to modify food policies at national and international levels to avoid further life threats and economic consequences from any emerging or reemerging pandemic due to close animal-human interaction (285).

T227

30576-30748

Sentence

denotes

Even though individuals of all ages and sexes are susceptible to COVID-19, older people with an underlying chronic disease are more likely to become severely infected (80).

T228

30749-30879

Sentence

denotes

Recently, individuals with asymptomatic infection were also found to act as a source of infection to susceptible individuals (81).

T229

30880-31066

Sentence

denotes

Both the asymptomatic and symptomatic patients secrete similar viral loads, which indicates that the transmission capacity of asymptomatic or minimally symptomatic patients is very high.

T230

31067-31146

Sentence

denotes

Thus, SARS-CoV-2 transmission can happen early in the course of infection (82).

T231

31147-31264

Sentence

denotes

Atypical clinical manifestations have also been reported in COVID-19 in which the only reporting symptom was fatigue.

T232

31265-31345

Sentence

denotes

Such patients may lack respiratory signs, such as fever, cough, and sputum (83).

T233

31346-31501

Sentence

denotes

Hence, the clinicians must be on the look-out for the possible occurrence of atypical clinical manifestations to avoid the possibility of missed diagnosis.

T234

31502-31702

Sentence

denotes

The early transmission ability of SARS-CoV-2 was found to be similar to or slightly higher than that of SARS-CoV, reflecting that it could be controlled despite moderate to high transmissibility (84).

T235

31703-31855

Sentence

denotes

Increasing reports of SARS-CoV-2 in sewage and wastewater warrants the need for further investigation due to the possibility of fecal-oral transmission.

T236

31856-32010

Sentence

denotes

SARS-CoV-2 present in environmental compartments such as soil and water will finally end up in the wastewater and sewage sludge of treatment plants (328).

T237

32011-32191

Sentence

denotes

Therefore, we have to reevaluate the current wastewater and sewage sludge treatment procedures and introduce advanced techniques that are specific and effective against SARS-CoV-2.

T238

32192-32353

Sentence

denotes

Since there is active shedding of SARS-CoV-2 in the stool, the prevalence of infections in a large population can be studied using wastewater-based epidemiology.

T239

32354-32543

Sentence

denotes

Recently, reverse transcription-quantitative PCR (RT-qPCR) was used to enumerate the copies of SARS-CoV-2 RNA concentrated from wastewater collected from a wastewater treatment plant (327).

T240

32544-32627

Sentence

denotes

The calculated viral RNA copy numbers determine the number of infected individuals.

T241

32628-32857

Sentence

denotes

The increasing reports of virus shedding via the fecal route warrants the introduction of negative fecal viral nucleic acid test results as one of the additional discharge criteria in laboratory-confirmed cases of COVID-19 (326).

T242

32858-32989

Sentence

denotes

The COVID-19 pandemic does not have any novel factors, other than the genetically unique pathogen and a further possible reservoir.

T243

32990-33105

Sentence

denotes

The cause and the likely future outcome are just repetitions of our previous interactions with fatal coronaviruses.

T244

33106-33206

Sentence

denotes

The only difference is the time of occurrence and the genetic distinctness of the pathogen involved.

T245

33207-33354

Sentence

denotes

Mutations on the RBD of CoVs facilitated their capability of infecting newer hosts, thereby expanding their reach to all corners of the world (85).

T246

33355-33423

Sentence

denotes

This is a potential threat to the health of both animals and humans.

T247

33424-33618

Sentence

denotes

Advanced studies using Bayesian phylogeographic reconstruction identified the most probable origin of SARS-CoV-2 as the bat SARS-like coronavirus, circulating in the Rhinolophus bat family (86).

T248

33619-33830

Sentence

denotes

Phylogenetic analysis of 10 whole-genome sequences of SARS-CoV-2 showed that they are related to two CoVs of bat origin, namely, bat-SL-CoVZC45 and bat-SL-CoVZXC21, which were reported during 2018 in China (17).

T249

33831-33986

Sentence

denotes

It was reported that SARS-CoV-2 had been confirmed to use ACE2 as an entry receptor while exhibiting an RBD similar to that of SARS-CoV (17, 87, 254, 255).

T250

33987-34079

Sentence

denotes

Several countries have provided recommendations to their people traveling to China (88, 89).

T251

34080-34240

Sentence

denotes

Compared to the previous coronavirus outbreaks caused by SARS-CoV and MERS-CoV, the efficiency of SARS-CoV-2 human-to-human transmission was thought to be less.

T252

34241-34385

Sentence

denotes

This assumption was based on the finding that health workers were affected less than they were in previous outbreaks of fatal coronaviruses (2).

T253

34386-34497

Sentence

denotes

Superspreading events are considered the main culprit for the extensive transmission of SARS and MERS (90, 91).

T254

34498-34706

Sentence

denotes

Almost half of the MERS-CoV cases reported in Saudi Arabia are of secondary origin that occurred through contact with infected asymptomatic or symptomatic individuals through human-to-human transmission (92).

T255

34707-34827

Sentence

denotes

The occurrence of superspreading events in the COVID-19 outbreak cannot be ruled out until its possibility is evaluated.

T256

34828-34928

Sentence

denotes

Like SARS and MERS, COVID-19 can also infect the lower respiratory tract, with milder symptoms (27).

T257

34929-35100

Sentence

denotes

The basic reproduction number of COVID-19 has been found to be in the range of 2.8 to 3.3 based on real-time reports and 3.2 to 3.9 based on predicted infected cases (84).

T258

35102-35150

Sentence

denotes

Coronaviruses in Humans—SARS, MERS, and COVID-19

T259

35151-35357

Sentence

denotes

Coronavirus infection in humans is commonly associated with mild to severe respiratory diseases, with high fever, severe inflammation, cough, and internal organ dysfunction that can even lead to death (92).

T260

35358-35427

Sentence

denotes

Most of the identified coronaviruses cause the common cold in humans.

T261

35428-35542

Sentence

denotes

However, this changed when SARS-CoV was identified, paving the way for severe forms of the disease in humans (22).

T262

35543-35766

Sentence

denotes

Our previous experience with the outbreaks of other coronaviruses, like SARS and MERS, suggests that the mode of transmission in COVID-19 as mainly human-to-human transmission via direct contact, droplets, and fomites (25).

T263

35767-35988

Sentence

denotes

Recent studies have demonstrated that the virus could remain viable for hours in aerosols and up to days on surfaces; thus, aerosol and fomite contamination could play potent roles in the transmission of SARS-CoV-2 (257).

T264

35989-36078

Sentence

denotes

The immune response against coronavirus is vital to control and get rid of the infection.

T265

36079-36221

Sentence

denotes

However, maladjusted immune responses may contribute to the immunopathology of the disease, resulting in impairment of pulmonary gas exchange.

T266

36222-36391

Sentence

denotes

Understanding the interaction between CoVs and host innate immune systems could enlighten our understanding of the lung inflammation associated with this infection (24).

T267

36392-36612

Sentence

denotes

SARS is a viral respiratory disease caused by a formerly unrecognized animal CoV that originated from the wet markets in southern China after adapting to the human host, thereby enabling transmission between humans (90).

T268

36613-36716

Sentence

denotes

The SARS outbreak reported in 2002 to 2003 had 8,098 confirmed cases with 774 total deaths (9.6%) (93).

T269

36717-36804

Sentence

denotes

The outbreak severely affected the Asia Pacific region, especially mainland China (94).

T270

36805-37026

Sentence

denotes

Even though the case fatality rate (CFR) of SARS-CoV-2 (COVID-19) is lower than that of SARS-CoV, there exists a severe concern linked to this outbreak due to its epidemiological similarity to influenza viruses (95, 279).

T271

37027-37096

Sentence

denotes

This can fail the public health system, resulting in a pandemic (96).

T272

37097-37194

Sentence

denotes

MERS is another respiratory disease that was first reported in Saudi Arabia during the year 2012.

T273

37195-37250

Sentence

denotes

The disease was found to have a CFR of around 35% (97).

T274

37251-37389

Sentence

denotes

The analysis of available data sets suggests that the incubation period of SARS-CoV-2, SARS-CoV, and MERS-CoV is in almost the same range.

T275

37390-37453

Sentence

denotes

The longest predicted incubation time of SARS-CoV-2 is 14 days.

T276

37454-37549

Sentence

denotes

Hence, suspected individuals are isolated for 14 days to avoid the risk of further spread (98).

T277

37550-37820

Sentence

denotes

Even though a high similarity has been reported between the genome sequence of the new coronavirus (SARS-CoV-2) and SARS-like CoVs, the comparative analysis recognized a furin-like cleavage site in the SARS-CoV-2 S protein that is missing from other SARS-like CoVs (99).

T278

37821-37998

Sentence

denotes

The furin-like cleavage site is expected to play a role in the life cycle of the virus and disease pathogenicity and might even act as a therapeutic target for furin inhibitors.

T279

37999-38202

Sentence

denotes

The highly contagious nature of SARS-CoV-2 compared to that of its predecessors might be the result of a stabilizing mutation that occurred in the endosome-associated-protein-like domain of nsp2 protein.

T280

38203-38382

Sentence

denotes

Similarly, the destabilizing mutation near the phosphatase domain of nsp3 proteins in SARS-CoV-2 could indicate a potential mechanism that differentiates it from other CoVs (100).

T281

38383-38554

Sentence

denotes

Even though the CFR reported for COVID-19 is meager compared to those of the previous SARS and MERS outbreaks, it has caused more deaths than SARS and MERS combined (101).

T282

38555-38780

Sentence

denotes

Possibly related to the viral pathogenesis is the recent finding of an 832-nucleotide (nt) deletion in ORF8, which appears to reduce the replicative fitness of the virus and leads to attenuated phenotypes of SARS-CoV-2 (256).

T283

38781-38946

Sentence

denotes

Coronavirus is the most prominent example of a virus that has crossed the species barrier twice from wild animals to humans during SARS and MERS outbreaks (79, 102).

T284

38947-39075

Sentence

denotes

The possibility of crossing the species barrier for the third time has also been suspected in the case of SARS-CoV-2 (COVID-19).

T285

39076-39173

Sentence

denotes

Bats are recognized as a possible natural reservoir host of both SARS-CoV and MERS-CoV infection.

T286

39174-39302

Sentence

denotes

In contrast, the possible intermediary host is the palm civet for SARS-CoV and the dromedary camel for MERS-CoV infection (102).

T287

39303-39372

Sentence

denotes

Bats are considered the ancestral hosts for both SARS and MERS (103).

T288

39373-39475

Sentence

denotes

Bats are also considered the reservoir host of human coronaviruses like HCoV-229E and HCoV-NL63 (104).

T289

39476-39674

Sentence

denotes

In the case of COVID-19, there are two possibilities for primary transmission: it can be transmitted either through intermediate hosts, similar to that of SARS and MERS, or directly from bats (103).

T290

39675-39938

Sentence

denotes

The emergence paradigm put forward in the SARS outbreak suggests that SARS-CoV originated from bats (reservoir host) and later jumped to civets (intermediate host) and incorporated changes within the receptor-binding domain (RBD) to improve binding to civet ACE2.

T291

39939-40097

Sentence

denotes

This civet-adapted virus, during their subsequent exposure to humans at live markets, promoted further adaptations that resulted in the epidemic strain (104).

T292

40098-40193

Sentence

denotes

Transmission can also occur directly from the reservoir host to humans without RBD adaptations.

T293

40194-40384

Sentence

denotes

The bat coronavirus that is currently in circulation maintains specific “poised” spike proteins that facilitate human infection without the requirement of any mutations or adaptations (105).

T294

40385-40486

Sentence

denotes

Altogether, different species of bats carry a massive number of coronaviruses around the world (106).

T295

40487-40695

Sentence

denotes

The high plasticity in receptor usage, along with the feasibility of adaptive mutation and recombination, may result in frequent interspecies transmission of coronavirus from bats to animals and humans (106).

T296

40696-40809

Sentence

denotes

The pathogenesis of most bat coronaviruses is unknown, as most of these viruses are not isolated and studied (4).

T297

40810-40906

Sentence

denotes

Hedgehog coronavirus HKU31, a Betacoronavirus, has been identified from amur hedgehogs in China.

T298

40907-41018

Sentence

denotes

Studies show that hedgehogs are the reservoir of Betacoronavirus, and there is evidence of recombination (107).

T299

41019-41212

Sentence

denotes

The current scientific evidence available on MERS infection suggests that the significant reservoir host, as well as the animal source of MERS infection in humans, is the dromedary camels (97).

T300

41213-41398

Sentence

denotes

The infected dromedary camels may not show any visible signs of infection, making it challenging to identify animals actively excreting MERS-CoV that has the potential to infect humans.

T301

41399-41533

Sentence

denotes

However, they may shed MERS-CoV through milk, urine, feces, and nasal and eye discharge and can also be found in the raw organs (108).

T302

41534-41776

Sentence

denotes

In a study conducted to evaluate the susceptibility of animal species to MERS-CoV infection, llamas and pigs were found to be susceptible, indicating the possibility of MERS-CoV circulation in animal species other than dromedary camels (109).

T303

41777-41992

Sentence

denotes

Following the outbreak of SARS in China, SARS-CoV-like viruses were isolated from Himalayan palm civets (Paguma larvata) and raccoon dogs (Nyctereutes procyonoides) found in a live-animal market in Guangdong, China.

T304

41993-42140

Sentence

denotes

The animal isolates obtained from the live-animal market retained a 29-nucleotide sequence that was not present in most of the human isolates (78).

T305

42141-42242

Sentence

denotes

These findings were critical in identifying the possibility of interspecies transmission in SARS-CoV.

T306

42243-42390

Sentence

denotes

The higher diversity and prevalence of bat coronaviruses in this region compared to those in previous reports indicate a host/pathogen coevolution.

T307

42391-42511

Sentence

denotes

SARS-like coronaviruses also have been found circulating in the Chinese horseshoe bat (Rhinolophus sinicus) populations.

T308

42512-42738

Sentence

denotes

The in vitro and in vivo studies carried out on the isolated virus confirmed that there is a potential risk for the reemergence of SARS-CoV infection from the viruses that are currently circulating in the bat population (105).

T309

42740-42783

Sentence

denotes

CLINICAL PATHOLOGY OF SARS-CoV-2 (COVID-19)

T310

42784-42923

Sentence

denotes

The disease caused by SARS-CoV-2 is also named severe specific contagious pneumonia (SSCP), Wuhan pneumonia, and, recently, COVID-19 (110).

T311

42924-43098

Sentence

denotes

Compared to SARS-CoV, SARS-CoV-2 has less severe pathogenesis but has superior transmission capability, as evidenced by the rapidly increasing number of COVID-19 cases (111).

T312

43099-43190

Sentence

denotes

The incubation period of SARS-CoV-2 in familial clusters was found to be 3 to 6 days (112).

T313

43191-43292

Sentence

denotes

The mean incubation period of COVID-19 was found to be 6.4 days, ranging from 2.1 to 11.1 days (113).

T314

43293-43409

Sentence

denotes

Among an early affected group of 425 patients, 59 years was the median age, of which more males were affected (114).

T315

43410-43508

Sentence

denotes

Similar to SARS and MERS, the severity of this nCoV is high in age groups above 50 years (2, 115).

T316

43509-43638

Sentence

denotes

Symptoms of COVID-19 include fever, cough, myalgia or fatigue, and, less commonly, headache, hemoptysis, and diarrhea (116, 282).

T317

43639-43840

Sentence

denotes

Compared to the SARS-CoV-2-infected patients in Wuhan during the initial stages of the outbreak, only mild symptoms were noticed in those patients that are infected by human-to-human transmission (14).

T318

43841-43969

Sentence

denotes

The initial trends suggested that the mortality associated with COVID-19 was less than that of previous outbreaks of SARS (101).

T319

43970-44164

Sentence

denotes

The updates obtained from countries like China, Japan, Thailand, and South Korea indicated that the COVID-19 patients had relatively mild manifestations compared to those with SARS and MERS (4).

T320

44165-44367

Sentence

denotes

Regardless of the coronavirus type, immune cells, like mast cells, that are present in the submucosa of the respiratory tract and nasal cavity are considered the primary barrier against this virus (92).

T321

44368-44537

Sentence

denotes

Advanced in-depth analysis of the genome has identified 380 amino acid substitutions between the amino acid sequences of SARS-CoV-2 and the SARS/SARS-like coronaviruses.

T322

44538-44673

Sentence

denotes

These differences in the amino acid sequences might have contributed to the difference in the pathogenic divergence of SARS-CoV-2 (16).

T323

44674-44858

Sentence

denotes

Further research is required to evaluate the possible differences in tropism, pathogenesis, and transmission of this novel agent associated with this change in the amino acid sequence.

T324

44859-45052

Sentence

denotes

With the current outbreak of COVID-19, there is an expectancy of a significant increase in the number of published studies about this emerging coronavirus, as occurred with SARS and MERS (117).

T325

45053-45152

Sentence

denotes

SARS-CoV-2 invades the lung parenchyma, resulting in severe interstitial inflammation of the lungs.

T326

45153-45241

Sentence

denotes

This is evident on computed tomography (CT) images as ground-glass opacity in the lungs.

T327

45242-45334

Sentence

denotes

This lesion initially involves a single lobe but later expands to multiple lung lobes (118).

T328

45335-45609

Sentence

denotes

The histological assessment of lung biopsy samples obtained from COVID-19-infected patients revealed diffuse alveolar damage, cellular fibromyxoid exudates, hyaline membrane formation, and desquamation of pneumocytes, indicative of acute respiratory distress syndrome (119).

T329

45610-45733

Sentence

denotes

It was also found that the SARS-CoV-2-infected patients often have lymphocytopenia with or without leukocyte abnormalities.

T330

45734-45874

Sentence

denotes

The degree of lymphocytopenia gives an idea about disease prognosis, as it is found to be positively correlated with disease severity (118).

T331

45875-45959

Sentence

denotes

Pregnant women are considered to have a higher risk of getting infected by COVID-19.

T332

45960-46121

Sentence

denotes

The coronaviruses can cause adverse outcomes for the fetus, such as intrauterine growth restriction, spontaneous abortion, preterm delivery, and perinatal death.

T333

46122-46303

Sentence

denotes

Nevertheless, the possibility of intrauterine maternal-fetal transmission (vertical transmission) of CoVs is low and was not seen during either the SARS- or MERS-CoV outbreak (120).

T334

46304-46393

Sentence

denotes

However, there has been concern regarding the impact of SARS-CoV-2/COVID-19 on pregnancy.

T335

46394-46776

Sentence

denotes

Researchers have mentioned the probability of in utero transmission of novel SARS-CoV-2 from COVID-19-infected mothers to their neonates in China based upon the rise in IgM and IgG antibody levels and cytokine values in the blood obtained from newborn infants immediately postbirth; however, RT-PCR failed to confirm the presence of SARS-CoV-2 genetic material in the infants (283).

T336

46777-46894

Sentence

denotes

Recent studies show that at least in some cases, preterm delivery and its consequences are associated with the virus.

T337

46895-46992

Sentence

denotes

Nonetheless, some cases have raised doubts for the likelihood of vertical transmission (240–243).

T338

46993-47105

Sentence

denotes

COVID-19 infection was associated with pneumonia, and some developed acute respiratory distress syndrome (ARDS).

T339

47106-47315

Sentence

denotes

The blood biochemistry indexes, such as albumin, lactate dehydrogenase, C-reactive protein, lymphocytes (percent), and neutrophils (percent) give an idea about the disease severity in COVID-19 infection (121).

T340

47316-47554

Sentence

denotes

During COVID-19, patients may present leukocytosis, leukopenia with lymphopenia (244), hypoalbuminemia, and an increase of lactate dehydrogenase, aspartate transaminase, alanine aminotransferase, bilirubin, and, especially, D-dimer (244).

T341

47555-47758

Sentence

denotes

Middle-aged and elderly patients with primary chronic diseases, especially high blood pressure and diabetes, were found to be more susceptible to respiratory failure and, therefore, had poorer prognoses.

T342

47759-47866

Sentence

denotes

Providing respiratory support at early stages improved the disease prognosis and facilitated recovery (18).

T343

47867-48057

Sentence

denotes

The ARDS in COVID-19 is due to the occurrence of cytokine storms that results in exaggerated immune response, immune regulatory network imbalance, and, finally, multiple-organ failure (122).

T344

48058-48325

Sentence

denotes

In addition to the exaggerated inflammatory response seen in patients with COVID-19 pneumonia, the bile duct epithelial cell-derived hepatocytes upregulate ACE2 expression in liver tissue by compensatory proliferation that might result in hepatic tissue injury (123).

T345

48327-48388

Sentence

denotes

CORONAVIRUSES IN ANIMALS AND ZOONOTIC LINKS—A BRIEF VIEWPOINT

T346

48389-48491

Sentence

denotes

Coronavirus can cause disease in several species of domestic and wild animals, as well as humans (23).

T347

48492-48717

Sentence

denotes

The different animal species that are infected with CoV include horses, camels, cattle, swine, dogs, cats, rodents, birds, ferrets, minks, bats, rabbits, snakes, and various other wild animals (20, 30, 79, 93, 124, 125, 287).

T348

48718-48925

Sentence

denotes

Coronavirus infection is linked to different kinds of clinical manifestations, varying from enteritis in cows and pigs, upper respiratory disease in chickens, and fatal respiratory infections in humans (30).

T349

48926-49112

Sentence

denotes

Among the CoV genera, Alphacoronavirus and Betacoronavirus infect mammals, while Gammacoronavirus and Deltacoronavirus mainly infect birds, fishes, and, sometimes, mammals (27, 29, 106).

T350

49113-49466

Sentence

denotes

Several novel coronaviruses that come under the genus Deltacoronavirus have been discovered in the past from birds, like Wigeon coronavirus HKU20, Bulbul coronavirus HKU11, Munia coronavirus HKU13, white-eye coronavirus HKU16, night-heron coronavirus HKU19, and common moorhen coronavirus HKU21, as well as from pigs (porcine coronavirus HKU15) (6, 29).

T351

49467-49650

Sentence

denotes

Transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine hemagglutinating encephalomyelitis virus (PHEV) are some of the coronaviruses of swine.

T352

49651-49785

Sentence

denotes

Among them, TGEV and PEDV are responsible for causing severe gastroenteritis in young piglets with noteworthy morbidity and mortality.

T353

49786-49916

Sentence

denotes

Infection with PHEV also causes enteric infection but can cause encephalitis due to its ability to infect the nervous system (30).

T354

49917-50009

Sentence

denotes

Bovine coronaviruses (BoCoVs) are known to infect several domestic and wild ruminants (126).

T355

50010-50194

Sentence

denotes

BoCoV inflicts neonatal calf diarrhea in adult cattle, leading to bloody diarrhea (winter dysentery) and respiratory disease complex (shipping fever) in cattle of all age groups (126).

T356

50195-50289

Sentence

denotes

BoCoV-like viruses have been noted in humans, suggesting its zoonotic potential as well (127).

T357

50290-50531

Sentence

denotes

Feline enteric and feline infectious peritonitis (FIP) viruses are the two major feline CoVs (128), where feline CoVs can affect the gastrointestinal tract, abdominal cavity (peritonitis), respiratory tract, and central nervous system (128).

T358

50532-50779

Sentence

denotes

Canines are also affected by CoVs that fall under different genera, namely, canine enteric coronavirus in Alphacoronavirus and canine respiratory coronavirus in Betacoronavirus, affecting the enteric and respiratory tract, respectively (129, 130).

T359

50780-50932

Sentence

denotes

IBV, under Gammacoronavirus, causes diseases of respiratory, urinary, and reproductive systems, with substantial economic losses in chickens (131, 132).

T360

50933-51184

Sentence

denotes

In small laboratory animals, mouse hepatitis virus, rat sialodacryoadenitis coronavirus, and guinea pig and rabbit coronaviruses are the major CoVs associated with disease manifestations like enteritis, hepatitis, and respiratory infections (10, 133).

T361

51185-51351

Sentence

denotes

Swine acute diarrhea syndrome coronavirus (SADS-CoV) was first identified in suckling piglets having severe enteritis and belongs to the genus Alphacoronavirus (106).

T362

51352-51474

Sentence

denotes

The outbreak was associated with considerable scale mortality of piglets (24,693 deaths) across four farms in China (134).

T363

51475-51682

Sentence

denotes

The virus isolated from the piglets was almost identical to and had 95% genomic similarity with horseshoe bat (Rhinolophus species) coronavirus HKU2, suggesting a bat origin of the pig virus (106, 134, 135).

T364

51683-51823

Sentence

denotes

It is also imperative to note that the SADS-CoV outbreak started in Guangdong province, near the location of the SARS pandemic origin (134).

T365

51824-51911

Sentence

denotes

Before this outbreak, pigs were not known to be infected with bat-origin coronaviruses.

T366

51912-52005

Sentence

denotes

This indicates that the bat-origin coronavirus jumped to pig by breaking the species barrier.

T367

52006-52207

Sentence

denotes

The next step of this jump might not end well, since pigs are considered the mixing vessel for influenza A viruses due to their ability to be infected by both human and avian influenza A viruses (136).

T368

52208-52354

Sentence

denotes

Similarly, they may act as the mixing vessel for coronaviruses, since they are in frequent contact with both humans and multiple wildlife species.

T369

52355-52498

Sentence

denotes

Additionally, pigs are also found to be susceptible to infection with human SARS-CoV and MERS-CoV, making this scenario a nightmare (109, 137).

T370

52499-52633

Sentence

denotes

It is only a matter of time before another zoonotic coronavirus results in an epidemic by jumping the so-called species barrier (287).

T371

52634-52807

Sentence

denotes

The host spectrum of coronavirus increased when a novel coronavirus, namely, SW1, was recognized in the liver tissue of a captive beluga whale (Delphinapterus leucas) (138).

T372

52808-52901

Sentence

denotes

In recent decades, several novel coronaviruses were identified from different animal species.

T373

52902-53008

Sentence

denotes

Bats can harbor these viruses without manifesting any clinical disease but are persistently infected (30).

T374

53009-53144

Sentence

denotes

They are the only mammals with the capacity for self-powered flight, which enables them to migrate long distances, unlike land mammals.

T375

53145-53240

Sentence

denotes

Bats are distributed worldwide and also account for about a fifth of all mammalian species (6).

T376

53241-53378

Sentence

denotes

This makes them the ideal reservoir host for many viral agents and also the source of novel coronaviruses that have yet to be identified.

T377

53379-53543

Sentence

denotes

It has become a necessity to study the diversity of coronavirus in the bat population to prevent future outbreaks that could jeopardize livestock and public health.

T378

53544-53770

Sentence

denotes

The repeated outbreaks caused by bat-origin coronaviruses calls for the development of efficient molecular surveillance strategies for studying Betacoronavirus among animals (12), especially in the Rhinolophus bat family (86).

T379

53771-53870

Sentence

denotes

Chinese bats have high commercial value, since they are used in traditional Chinese medicine (TCM).

T380

53871-53995

Sentence

denotes

Therefore, the handling of bats for trading purposes poses a considerable risk of transmitting zoonotic CoV epidemics (139).

T381

53996-54229

Sentence

denotes

Due to the possible role played by farm and wild animals in SARS-CoV-2 infection, the WHO, in their novel coronavirus (COVID-19) situation report, recommended the avoidance of unprotected contact with both farm and wild animals (25).

T382

54230-54397

Sentence

denotes

The live-animal markets, like the one in Guangdong, China, provides a setting for animal coronaviruses to amplify and to be transmitted to new hosts, like humans (78).

T383

54398-54561

Sentence

denotes

Such markets can be considered a critical place for the origin of novel zoonotic diseases and have enormous public health significance in the event of an outbreak.

T384

54562-54681

Sentence

denotes

Bats are the reservoirs for several viruses; hence, the role of bats in the present outbreak cannot be ruled out (140).

T385

54682-55000

Sentence

denotes

In a qualitative study conducted for evaluating the zoonotic risk factors among rural communities of southern China, the frequent human-animal interactions along with the low levels of environmental biosecurity were identified as significant risks for the emergence of zoonotic disease in local communities (141, 142).

T386

55001-55189

Sentence

denotes

The comprehensive sequence analysis of the SARS-CoV-2 RNA genome identified that the CoV from Wuhan is a recombinant virus of the bat coronavirus and another coronavirus of unknown origin.

T387

55190-55315

Sentence

denotes

The recombination was found to have happened within the viral spike glycoprotein, which recognizes the cell surface receptor.

T388

55316-55447

Sentence

denotes

Further analysis of the genome based on codon usage identified the snake as the most probable animal reservoir of SARS-CoV-2 (143).

T389

55448-55613

Sentence

denotes

Contrary to these findings, another genome analysis proposed that the genome of SARS-CoV-2 is 96% identical to bat coronavirus, reflecting its origin from bats (63).

T390

55614-55707

Sentence

denotes

The involvement of bat-derived materials in causing the current outbreak cannot be ruled out.

T391

55708-55827

Sentence

denotes

High risk is involved in the production of bat-derived materials for TCM practices involving the handling of wild bats.

T392

55828-55961

Sentence

denotes

The use of bats for TCM practices will remain a severe risk for the occurrence of zoonotic coronavirus epidemics in the future (139).

T393

55962-56095

Sentence

denotes

Furthermore, the pangolins are an endangered species of animals that harbor a wide variety of viruses, including coronaviruses (144).

T394

56096-56269

Sentence

denotes

The coronavirus isolated from Malayan pangolins (Manis javanica) showed a very high amino acid identity with COVID-19 at E (100%), M (98.2%), N (96.7%), and S genes (90.4%).

T395

56270-56392

Sentence

denotes

The RBD of S protein in CoV isolated from pangolin was almost identical (one amino acid difference) to that of SARS-CoV-2.

T396

56393-56513

Sentence

denotes

A comparison of the genomes suggests recombination between pangolin-CoV-like viruses with the bat-CoV-RaTG13-like virus.

T397

56514-56611

Sentence

denotes

All this suggests the potential of pangolins to act as the intermediate host of SARS-CoV-2 (145).

T398

56612-56781

Sentence

denotes

Human-wildlife interactions, which are increasing in the context of climate change (142), are further considered high risk and responsible for the emergence of SARS-CoV.

T399

56782-56844

Sentence

denotes

COVID-19 is also suspected of having a similar mode of origin.

T400

56845-57205

Sentence

denotes

Hence, to prevent the occurrence of another zoonotic spillover (1), exhaustive coordinated efforts are needed to identify the high-risk pathogens harbored by wild animal populations, conducting surveillance among the people who are susceptible to zoonotic spillover events (12), and to improve the biosecurity measures associated with the wildlife trade (146).

T401

57206-57379

Sentence

denotes

The serological surveillance studies conducted in people living in proximity to bat caves had earlier identified the serological confirmation of SARS-related CoVs in humans.

T402

57380-57499

Sentence

denotes

People living at the wildlife-human interface, mainly in rural China, are regularly exposed to SARS-related CoVs (147).

T403

57500-57613

Sentence

denotes

These findings will not have any significance until a significant outbreak occurs due to a virus-like SARS-CoV-2.

T404

57614-57715

Sentence

denotes

There is a steady increase in the reports of COVID-19 in companion and wild animals around the world.

T405

57716-57926

Sentence

denotes

Further studies are required to evaluate the potential of animals (especially companion animals) to serve as an efficient reservoir host that can further alter the dynamics of human-to-human transmission (330).

T406

57927-58087

Sentence

denotes

To date, two pet dogs (Hong Kong) and four pet cats (one each from Belgium and Hong Kong, two from the United States) have tested positive for SARS-CoV-2 (335).

T407

58088-58239

Sentence

denotes

The World Organization for Animal Health (OIE) has confirmed the diagnosis of COVID-19 in both dogs and cats due to human-to-animal transmission (331).

T408

58240-58408

Sentence

denotes

The similarity observed in the gene sequence of SARS-CoV-2 from an infected pet owner and his dog further confirms the occurrence of human-to-animal transmission (333).

T409

58409-58531

Sentence

denotes

Even though asymptomatic, feline species should be considered a potential transmission route from animals to humans (326).

T410

58532-58629

Sentence

denotes

However, currently, there are no reports of SARS-CoV-2 transmission from felines to human beings.

T411

58630-58754

Sentence

denotes

Based on the current evidence, we can conclude that cats are susceptible to SARS-CoV-2 and can get infected by human beings.

T412

58755-58848

Sentence

denotes

However, evidence of cat-to-human transmission is lacking and requires further studies (332).

T413

58849-59068

Sentence

denotes

Rather than waiting for firmer evidence on animal-to-human transmission, necessary preventive measures are advised, as well as following social distancing practices among companion animals of different households (331).

T414

59069-59217

Sentence

denotes

One of the leading veterinary diagnostic companies, IDEXX, has conducted large-scale testing for COVID-19 in specimens collected from dogs and cats.

T415

59218-59277

Sentence

denotes

However, none of the tests turned out to be positive (334).

T416

59278-59501

Sentence

denotes

In a study conducted to investigate the potential of different animal species to act as the intermediate host of SARS-CoV-2, it was found that both ferrets and cats can be infected via experimental inoculation of the virus.

T417

59502-59585

Sentence

denotes

In addition, infected cats efficiently transmitted the disease to naive cats (329).

T418

59586-59716

Sentence

denotes

SARS-CoV-2 infection and subsequent transmission in ferrets were found to recapitulate the clinical aspects of COVID-19 in humans.

T419

59717-59912

Sentence

denotes

The infected ferrets also shed virus via multiple routes, such as saliva, nasal washes, feces, and urine, postinfection, making them an ideal animal model for studying disease transmission (337).

T420

59913-60108

Sentence

denotes

Experimental inoculation was also done in other animal species and found that the dogs have low susceptibility, while the chickens, ducks, and pigs are not at all susceptible to SARS-CoV-2 (329).

T421

60109-60282

Sentence

denotes

Similarly, the National Veterinary Services Laboratories of the USDA have reported COVID-19 in tigers and lions that exhibited respiratory signs like dry cough and wheezing.

T422

60283-60370

Sentence

denotes

The zoo animals are suspected to have been infected by an asymptomatic zookeeper (335).

T423

60371-60546

Sentence

denotes

The total number of COVID-19-positive cases in human beings is increasing at a high rate, thereby creating ideal conditions for viral spillover to other species, such as pigs.

T424

60547-60641

Sentence

denotes

The evidence obtained from SARS-CoV suggests that pigs can get infected with SARS-CoV-2 (336).

T425

60642-60720

Sentence

denotes

However, experimental inoculation with SARS-CoV-2 failed to infect pigs (329).

T426

60721-60895

Sentence

denotes

Further studies are required to identify the possible animal reservoirs of SARS-CoV-2 and the seasonal variation in the circulation of these viruses in the animal population.

T427

60896-61077

Sentence

denotes

Research collaboration between human and animal health sectors is becoming a necessity to evaluate and identify the possible risk factors of transmission between animals and humans.

T428

61078-61190

Sentence

denotes

Such cooperation will help to devise efficient strategies for the management of emerging zoonotic diseases (12).

T429

61192-61226

Sentence

denotes

DIAGNOSIS OF SARS-CoV-2 (COVID-19)

T430

61227-61367

Sentence

denotes

RNA tests can confirm the diagnosis of SARS-CoV-2 (COVID-19) cases with real-time RT-PCR or next-generation sequencing (148, 149, 245, 246).

T431

61368-61528

Sentence

denotes

At present, nucleic acid detection techniques, like RT-PCR, are considered an effective method for confirming the diagnosis in clinical cases of COVID-19 (148).

T432

61529-61663

Sentence

denotes

Several companies across the world are currently focusing on developing and marketing SARS-CoV-2-specific nucleic acid detection kits.

T433

61664-61732

Sentence

denotes

Multiple laboratories are also developing their own in-house RT-PCR.

T434

61733-61863

Sentence

denotes

One of them is the SARS-CoV-2 nucleic acid detection kit produced by Shuoshi Biotechnology (double fluorescence PCR method) (150).

T435

61864-61893

Sentence

denotes

Up to 30 March 2020, the U.S.

T436

61894-62162

Sentence

denotes

Food and Drug Administration (FDA) had granted 22 in vitro diagnostics Emergency Use Authorizations (EUAs), including for the RT-PCR diagnostic panel for the universal detection of SARS-like betacoronaviruses and specific detection of SARS-CoV-2, developed by the U.S.

T437

62163-62188

Sentence

denotes

CDC (Table 1) (258, 259).

T438

62189-62305

Sentence

denotes

TABLE 1 FDA-approved in vitro Emergency Use Authorization diagnostics available for SARS-CoV-2 as of 30 March 2020a

T439

62306-62336

Sentence

denotes

Developer Diagnostic platform

T440

62337-62434

Sentence

denotes

Centers for Disease Control and Prevention (CDC) CDC 2019-nCoV real-time RT-PCR diagnostic panel

T441

62435-62580

Sentence

denotes

Wadsworth Center, New York State Department of Public Health (CDC) New York SARS-CoV-2 real-time reverse transcriptase (RT)-PCR diagnostic panel

T442

62581-62634

Sentence

denotes

Roche Molecular Systems, Inc. (RMS) cobas SARS-CoV-2

T443

62635-62665

Sentence

denotes

Thermo Fisher Scientific, Inc.

T444

62667-62693

Sentence

denotes

TaqPath COVID-19 combo kit

T445

62694-62759

Sentence

denotes

Laboratory Corporation of America (LabCorp) COVID-19 RT-PCR test

T446

62760-62773

Sentence

denotes

Hologic, Inc.

T447

62775-62800

Sentence

denotes

Panther fusion SARS-CoV-2

T448

62801-62843

Sentence

denotes

Quest Diagnostics Infectious Disease, Inc.

T449

62845-62869

Sentence

denotes

Quest SARS-CoV-2 rRT-PCR

T450

62870-62911

Sentence

denotes

Quidel Corporation Lyra SARS-CoV-2 assay

T451

62912-62962

Sentence

denotes

Abbott Molecular Abbott RealTime SARS-CoV-2 assay

T452

62963-63011

Sentence

denotes

GenMark Diagnostics, Inc. ePlex SARS-CoV-2 test

T453

63012-63067

Sentence

denotes

DiaSorin Molecular, LLC Simplexa COVID-19 direct assay

T454

63068-63105

Sentence

denotes

Cepheid Xpert Xpress SARS-CoV-2 test

T455

63106-63124

Sentence

denotes

Primerdesign, Ltd.

T456

63126-63162

Sentence

denotes

COVID-19 Genesig real-time PCR assay

T457

63163-63181

Sentence

denotes

Mesa Biotech, Inc.

T458

63183-63205

Sentence

denotes

Accula SARS-Cov-2 test

T459

63206-63249

Sentence

denotes

BioFire Defense, LLC BioFire COVID-19 test

T460

63250-63267

Sentence

denotes

PerkinElmer, Inc.

T461

63269-63323

Sentence

denotes

PerkinElmer new coronavirus nucleic acid detection kit

T462

63324-63346

Sentence

denotes

Avellino Lab USA, Inc.

T463

63348-63365

Sentence

denotes

AvellinoCoV2 test

T464

63366-63383

Sentence

denotes

BGI Genomics, Co.

T465

63384-63388

Sentence

denotes

Ltd.

T466

63390-63451

Sentence

denotes

Real-time fluorescent RT-PCR kit for detecting SARS-2019-nCoV

T467

63452-63487

Sentence

denotes

Luminex Molecular Diagnostics, Inc.

T468

63489-63519

Sentence

denotes

NxTAG CoV extended panel assay

T469

63520-63556

Sentence

denotes

Abbott Diagnostics Scarborough, Inc.

T470

63558-63573

Sentence

denotes

ID Now COVID-19

T471

63574-63626

Sentence

denotes

Qiagen GmbH QIAstat-Dx respiratory SARS-CoV-2 panel

T472

63627-63650

Sentence

denotes

NeuMoDx Molecular, Inc.

T473

63652-63676

Sentence

denotes

NeuMoDx SARS-CoV-2 assay

T474

63677-63717

Sentence

denotes

a Data are from references 258 and 259.

T475

63718-63990

Sentence

denotes

Recently, 95 full-length genomic sequences of SARAS-CoV-2 strains available in the National Center for Biotechnology Information and GISAID databases were subjected to multiple-sequence alignment and phylogenetic analyses for studying variations in the viral genome (260).

T476

63991-64139

Sentence

denotes

All the viral strains revealed high homology of 99.99% (99.91% to 100%) at the nucleotide level and 99.99% (99.79% to 100%) at the amino acid level.

T477

64140-64267

Sentence

denotes

Overall variation was found to be low in ORF regions, with 13 variation sites recognized in 1a, 1b, S, 3a, M, 8, and N regions.

T478

64268-64397

Sentence

denotes

Mutation rates of 30.53% (29/95) and 29.47% (28/95) were observed at nt 28144 (ORF8) and nt 8782 (ORF1a) positions, respectively.

T479

64398-64528

Sentence

denotes

Owing to such selective mutations, a few specific regions of SARS-CoV-2 should not be considered for designing primers and probes.

T480

64529-64743

Sentence

denotes

The SARS-CoV-2 reference sequence could pave the way to study molecular biology and pathobiology, along with developing diagnostics and appropriate prevention and control strategies for countering SARS-CoV-2 (260).

T481

64744-65023

Sentence

denotes

Nucleic acids of SARS-CoV-2 can be detected from samples (64) such as bronchoalveolar lavage fluid, sputum, nasal swabs, fiber bronchoscope brush biopsy specimen, pharyngeal swabs, feces, blood, and urine, with different levels of diagnostic performance (Table 2) (80, 245, 246).

T482

65024-65189

Sentence

denotes

The viral loads of SARS-CoV-2 were measured using N-gene-specific quantitative RT-PCR in throat swab and sputum samples collected from COVID-19-infected individuals.

T483

65190-65357

Sentence

denotes

The results indicated that the viral load peaked at around 5 to 6 days following the onset of symptoms, and it ranged from 104 to 107 copies/ml during this time (151).

T484

65358-65504

Sentence

denotes

In another study, the viral load was found to be higher in the nasal swabs than the throat swabs obtained from COVID-19 symptomatic patients (82).

T485

65505-65677

Sentence

denotes

Although initially it was thought that viral load would be associated with poor outcomes, some case reports have shown asymptomatic individuals with high viral loads (247).

T486

65678-65891

Sentence

denotes

Recently, the viral load in nasal and throat swabs of 17 symptomatic patients was determined, and higher viral loads were recorded soon after the onset of symptoms, particularly in the nose compared to the throat.

T487

65892-66067

Sentence

denotes

The pattern of viral nucleic acid shedding of SARS-CoV-2-infected patients was similar to that of influenza patients but seemed to be different from that of SARS-CoV patients.

T488

66068-66300

Sentence

denotes

The viral load detected in asymptomatic patients resembled that of symptomatic patients as studied in China, which reflects the transmission perspective of asymptomatic or symptomatic patients having minimum signs and symptoms (82).

T489

66301-66509

Sentence

denotes

Another study, conducted in South Korea, related to SARS-CoV-2 viral load, opined that SARS-CoV-2 kinetics were significantly different from those of earlier reported CoV infections, including SARS-CoV (253).

T490

66510-66708

Sentence

denotes

SARS-CoV-2 transmission can occur early in the viral infection phase; thus, diagnosing cases and isolation attempts for this virus warrant different strategies than those needed to counter SARS-CoV.

T491

66709-66810

Sentence

denotes

Studies are required to establish any correlation between SARS-CoV-2 viral load and cultivable virus.

T492

66811-67074

Sentence

denotes

Recognizing patients with fewer or no symptoms, along with having modest detectable viral RNA in the oropharynx for 5 days, indicates the requirement of data for assessing SARS-CoV-2 transmission dynamics and updating the screening procedures in the clinics (82).

T493

67075-67130

Sentence

denotes

TABLE 2 Clinical specimens for detection of SARS CoV-2

T494

67131-67154

Sentence

denotes

Sample Recommendationa

T495

67155-67188

Sentence

denotes

Bronchoalveolar lavage fluid +++

T496

67189-67200

Sentence

denotes

Sputum +++

T497

67201-67217

Sentence

denotes

Nasal swabs +++

T498

67218-67252

Sentence

denotes

Fibrobronchoscope brush biopsy ++

T499

67253-67273

Sentence

denotes

Pharyngeal swabs ++

T500

67274-67282

Sentence

denotes

Feces +

T501

67283-67291

Sentence

denotes

Blood +

T502

67292-67300

Sentence

denotes

Urine +

T503

67301-67392

Sentence

denotes

a Recommendations are based on references 245 and 246. +++, strong; ++, moderate; +, weak.

T504

67393-67601

Sentence

denotes

The results of the studies related to SARS-CoV-2 viral loads reflect active replication of this virus in the upper respiratory tract and prolonged viral shedding after symptoms disappear, including via stool.

T505

67602-67767

Sentence

denotes

Thus, the current case definition needs to be updated along with a reassessment of the strategies to be adopted for restraining the SARS-CoV-2 outbreak spread (248).

T506

67768-67922

Sentence

denotes

In some cases, the viral load studies of SARS-CoV-2 have also been useful to recommend precautionary measures when handling specific samples, e.g., feces.

T507

67923-68146

Sentence

denotes

In a recent survey from 17 confirmed cases of SARS-CoV-2 infection with available data (representing days 0 to 13 after onset), stool samples from nine cases (53%; days 0 to 11 after onset) were positive on RT-PCR analysis.

T508

68147-68321

Sentence

denotes

Although the viral loads were lower than those of respiratory samples (range, 550 copies per ml to 1.21 × 105 copies per ml), this has essential biosafety implications (151).

T509

68322-68526

Sentence

denotes

The samples from 18 SARS-CoV-2-positive patients in Singapore who had traveled from Wuhan to Singapore showed the presence of viral RNA in stool and whole blood but not in urine by real-time RT-PCR (288).

T510

68527-68758

Sentence

denotes

Further, novel SARS-CoV-2 infections have been detected in a variety of clinical specimens, like bronchoalveolar lavage fluid, sputum, nasal swabs, fibrobronchoscope brush biopsy specimens, pharyngeal swabs, feces, and blood (246).

T511

68759-68842

Sentence

denotes

The presence of SARS-CoV-2 in fecal samples has posed grave public health concerns.

T512

68843-69085

Sentence

denotes

In addition to the direct transmission mainly occurring via droplets of sneezing and coughing, other routes, such as fecal excretion and environmental and fomite contamination, are contributing to SARS-CoV-2 transmission and spread (249–252).

T513

69086-69239

Sentence

denotes

Fecal excretion has also been documented for SARS-CoV and MERS-CoV, along with the potential to stay viable in situations aiding fecal-oral transmission.

T514

69240-69315

Sentence

denotes

Thus, SARS-CoV-2 has every possibility to be transmitted through this mode.

T515

69316-69505

Sentence

denotes

Fecal-oral transmission of SARS-CoV-2, particularly in regions having low standards of hygiene and poor sanitation, may have grave consequences with regard to the high spread of this virus.

T516

69506-69608

Sentence

denotes

Ethanol and disinfectants containing chlorine or bleach are effective against coronaviruses (249–252).

T517

69609-69725

Sentence

denotes

Appropriate precautions need to be followed strictly while handling the stools of patients infected with SARS-CoV-2.

T518

69726-69837

Sentence

denotes

Biowaste materials and sewage from hospitals must be adequately disinfected, treated, and disposed of properly.

T519

69838-69955

Sentence

denotes

The significance of frequent and good hand hygiene and sanitation practices needs to be given due emphasis (249–252).

T520

69956-70238

Sentence

denotes

Future explorative research needs to be conducted with regard to the fecal-oral transmission of SARS-CoV-2, along with focusing on environmental investigations to find out if this virus could stay viable in situations and atmospheres facilitating such potent routes of transmission.

T521

70239-70530

Sentence

denotes

The correlation of fecal concentrations of viral RNA with disease severity needs to be determined, along with assessing the gastrointestinal symptoms and the possibility of fecal SARS-CoV-2 RNA detection during the COVID-19 incubation period or convalescence phases of the disease (249–252).

T522

70531-70763

Sentence

denotes

The lower respiratory tract sampling techniques, like bronchoalveolar lavage fluid aspirate, are considered the ideal clinical materials, rather than the throat swab, due to their higher positive rate on the nucleic acid test (148).

T523

70764-70900

Sentence

denotes

The diagnosis of COVID-19 can be made by using upper-respiratory-tract specimens collected using nasopharyngeal and oropharyngeal swabs.

T524

70901-71029

Sentence

denotes

However, these techniques are associated with unnecessary risks to health care workers due to close contact with patients (152).

T525

71030-71286

Sentence

denotes

Similarly, a single patient with a high viral load was reported to contaminate an entire endoscopy room by shedding the virus, which may remain viable for at least 3 days and is considered a great risk for uninfected patients and health care workers (289).

T526

71287-71412

Sentence

denotes

Recently, it was found that the anal swabs gave more positive results than oral swabs in the later stages of infection (153).

T527

71413-71590

Sentence

denotes

Hence, clinicians have to be cautious while discharging any COVID-19-infected patient based on negative oral swab test results due to the possibility of fecal-oral transmission.

T528

71591-71821

Sentence

denotes

Even though the viral loads in stool samples were found to be less than those of respiratory samples, strict precautionary measures have to be followed while handling stool samples of COVID-19 suspected or infected patients (151).

T529

71822-71935

Sentence

denotes

Children infected with SARS-CoV-2 experience only a mild form of illness and recover immediately after treatment.

T530

71936-72098

Sentence

denotes

It was recently found that stool samples of SARS-CoV-2-infected children that gave negative throat swab results were positive within ten days of negative results.

T531

72099-72203

Sentence

denotes

This could result in the fecal-oral transmission of SARS-CoV-2 infections, especially in children (290).

T532

72204-72386

Sentence

denotes

Hence, to prevent the fecal-oral transmission of SARS-CoV-2, infected COVID-19 patients should only be considered negative when they test negative for SARS-CoV-2 in the stool sample.

T533

72387-72664

Sentence

denotes

A suspected case of COVID-19 infection is said to be confirmed if the respiratory tract aspirate or blood samples test positive for SARS-CoV-2 nucleic acid using RT-PCR or by the identification of SARS-CoV-2 genetic sequence in respiratory tract aspirate or blood samples (80).

T534

72665-72761

Sentence

denotes

The patient will be confirmed as cured when two subsequent oral swab results are negative (153).

T535

72762-72864

Sentence

denotes

Recently, the live virus was detected in the self-collected saliva of patients infected with COVID-19.

T536

72865-73011

Sentence

denotes

These findings were confirmative of using saliva as a noninvasive specimen for the diagnosis of COVID-19 infection in suspected individuals (152).

T537

73012-73202

Sentence

denotes

It has also been observed that the initial screening of COVID-19 patients infected with RT-PCR may give negative results even if they have chest CT findings that are suggestive of infection.

T538

73203-73412

Sentence

denotes

Hence, for the accurate diagnosis of COVID-19, a combination of repeated swab tests using RT-PCR and CT scanning is required to prevent the possibility of false-negative results during disease screening (154).

T539

73413-73473

Sentence

denotes

RT-PCR is the most widely used test for diagnosing COVID-19.

T540

73474-73615

Sentence

denotes

However, it has some significant limitations from the clinical perspective, since it will not give any clarity regarding disease progression.

T541

73616-73747

Sentence

denotes

Droplet digital PCR (ddPCR) can be used for the quantification of viral load in the samples obtained from lower respiratory tracts.

T542

73748-73839

Sentence

denotes

Hence, based on the viral load, we can quickly evaluate the progression of infection (291).

T543

73840-74196

Sentence

denotes

In addition to all of the above findings, sequencing and phylogenetics are critical in the correct identification and confirmation of the causative viral agent and useful to establish relationships with previous isolates and sequences, as well as to know, especially during an epidemic, the nucleotide and amino acid mutations and the molecular divergence.

T544

74197-74422

Sentence

denotes

The rapid development and implementation of diagnostic tests against emerging novel diseases like COVID-19 pose significant challenges due to the lack of resources and logistical limitations associated with an outbreak (155).

T545

74423-74493

Sentence

denotes

SARS-CoV-2 infection can also be confirmed by isolation and culturing.

T546

74494-74586

Sentence

denotes

The human airway epithelial cell culture was found to be useful in isolating SARS-CoV-2 (3).

T547

74587-74670

Sentence

denotes

The efficient control of an outbreak depends on the rapid diagnosis of the disease.

T548

74671-74864

Sentence

denotes

Recently, in response to the COVID-19 outbreak, 1-step quantitative real-time reverse transcription-PCR assays were developed that detect the ORF1b and N regions of the SARS-CoV-2 genome (156).

T549

74865-74931

Sentence

denotes

That assay was found to achieve the rapid detection of SARS-CoV-2.

T550

74932-75097

Sentence

denotes

Nucleic acid-based assays offer high accuracy in the diagnosis of SARS-CoV-2, but the current rate of spread limits its use due to the lack of diagnostic assay kits.

T551

75098-75223

Sentence

denotes

This will further result in the extensive transmission of COVID-19, since only a portion of suspected cases can be diagnosed.

T552

75224-75429

Sentence

denotes

In such situations, conventional serological assays, like enzyme-linked immunosorbent assay (ELISA), that are specific to COVID-19 IgM and IgG antibodies can be used as a high-throughput alternative (149).

T553

75430-75523

Sentence

denotes

At present, there is no diagnostic kit available for detecting the SARS-CoV-2 antibody (150).

T554

75524-75735

Sentence

denotes

The specific antibody profiles of COVID-19 patients were analyzed, and it was found that the IgM level lasted more than 1 month, indicating a prolonged stage of virus replication in SARS-CoV-2-infected patients.

T555

75736-75814

Sentence

denotes

The IgG levels were found to increase only in the later stages of the disease.

T556

75815-75921

Sentence

denotes

These findings indicate that the specific antibody profiles of SARS-CoV-2 and SARS-CoV were similar (325).

T557

75922-76055

Sentence

denotes

These findings can be utilized for the development of specific diagnostic tests against COVID-19 and can be used for rapid screening.

T558

76056-76261

Sentence

denotes

Even though diagnostic test kits are already available that can detect the genetic sequences of SARS-CoV-2 (95), their availability is a concern, as the number of COVID-19 cases is skyrocketing (155, 157).

T559

76262-76435

Sentence

denotes

A major problem associated with this diagnostic kit is that it works only when the test subject has an active infection, limiting its use to the earlier stages of infection.

T560

76436-76556

Sentence

denotes

Several laboratories around the world are currently developing antibody-based diagnostic tests against SARS-CoV-2 (157).

T561

76557-76626

Sentence

denotes

Chest CT is an ideal diagnostic tool for identifying viral pneumonia.

T562

76627-76698

Sentence

denotes

The sensitivity of chest CT is far superior to that of X-ray screening.

T563

76699-76861

Sentence

denotes

The chest CT findings associated with COVID-19-infected patients include characteristic patchy infiltration that later progresses to ground-glass opacities (158).

T564

76862-76953

Sentence

denotes

Early manifestations of COVID-19 pneumonia might not be evident in X-ray chest radiography.

T565

76954-77080

Sentence

denotes

In such situations, a chest CT examination can be performed, as it is considered highly specific for COVID-19 pneumonia (118).

T566

77081-77199

Sentence

denotes

Those patients having COVID-19 pneumonia will exhibit the typical ground-glass opacity in their chest CT images (154).

T567

77200-77277

Sentence

denotes

The patients infected with COVID-19 had elevated plasma angiotensin 2 levels.

T568

77278-77431

Sentence

denotes

The level of angiotensin 2 was found to be linearly associated with viral load and lung injury, indicating its potential as a diagnostic biomarker (121).

T569

77432-77556

Sentence

denotes

The chest CT imaging abnormalities associated with COVID-19 pneumonia have also been observed even in asymptomatic patients.

T570

77557-77762

Sentence

denotes

These abnormalities progress from the initial focal unilateral to diffuse bilateral ground-glass opacities and will further progress to or coexist with lung consolidation changes within 1 to 3 weeks (159).

T571

77763-77837

Sentence

denotes

The role played by radiologists in the current scenario is very important.

T572

77838-77940

Sentence

denotes

Radiologists can help in the early diagnosis of lung abnormalities associated with COVID-19 pneumonia.

T573

77941-78123

Sentence

denotes

They can also help in the evaluation of disease severity, identifying its progression to acute respiratory distress syndrome and the presence of secondary bacterial infections (160).

T574

78124-78422

Sentence

denotes

Even though chest CT is considered an essential diagnostic tool for COVID-19, the extensive use of CT for screening purposes in the suspected individuals might be associated with a disproportionate risk-benefit ratio due to increased radiation exposure as well as increased risk of cross-infection.

T575

78423-78548

Sentence

denotes

Hence, the use of CT for early diagnosis of SARS-CoV-2 infection in high-risk groups should be done with great caution (292).

T576

78549-78676

Sentence

denotes

More recently, other advanced diagnostics have been designed and developed for the detection of SARS-CoV-2 (345, 347, 350–352).

T577

78677-78844

Sentence

denotes

A reverse transcriptional loop-mediated isothermal amplification (RT-LAMP), namely, iLACO, has been developed for rapid and colorimetric detection of this virus (354).

T578

78845-78985

Sentence

denotes

RT-LAMP serves as a simple, rapid, and sensitive diagnostic method that does not require sophisticated equipment or skilled personnel (349).

T579

78986-79089

Sentence

denotes

An interactive web-based dashboard for tracking SARS-CoV-2 in a real-time mode has been designed (238).

T580

79090-79242

Sentence

denotes

A smartphone-integrated home-based point-of-care testing (POCT) tool, a paper-based POCT combined with LAMP, is a useful point-of-care diagnostic (353).

T581

79243-79453

Sentence

denotes

An Abbott ID Now COVID-19 molecular POCT-based test, using isothermal nucleic acid amplification technology, has been designed as a point-of-care test for very rapid detection of SARS-CoV-2 in just 5 min (344).

T582

79454-79715

Sentence

denotes

A CRISPR-based SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) diagnostic for rapid detection of SARS-CoV-2 without the requirement of specialized instrumentation has been reported to be very useful in the clinical diagnosis of COVID-19 (360).

T583

79716-79820

Sentence

denotes

A CRISPR-Cas12-based lateral flow assay also has been developed for rapid detection of SARS-CoV-2 (346).

T584

79821-79987

Sentence

denotes

Artificial intelligence, by means of a three-dimensional deep-learning model, has been developed for sensitive and specific diagnosis of COVID-19 via CT images (332).

T585

79988-80408

Sentence

denotes

Tracking and mapping of the rising incidence rates, disease outbreaks, community spread, clustered transmission events, hot spots, and superspreader potential of SARS-CoV-2/COVID warrant full exploitation of real-time disease mapping by employing geographical information systems (GIS), such as the GIS software Kosmo 3.1, web-based real-time tools and dashboards, apps, and advances in information technology (356–359).

T586

80409-80933

Sentence

denotes

Researchers have also developed a few prediction tools/models, such as the prediction model risk of bias assessment tool (PROBAST) and critical appraisal and data extraction for systematic reviews of prediction modeling studies (CHARMS), which could aid in assessing the possibility of getting infection and estimating the prognosis in patients; however, such models may suffer from bias issues and, hence, cannot be considered completely trustworthy, which necessitates the development of new and reliable predictors (360).

T587

80935-80968

Sentence

denotes

VACCINES, THERAPEUTICS, AND DRUGS

T588

80969-81241

Sentence

denotes

Recently emerged viruses, such as Zika, Ebola, and Nipah viruses, and their grave threats to humans have begun a race in exploring the designing and developing of advanced vaccines, prophylactics, therapeutics, and drug regimens to counter emerging viruses (161–163, 280).

T589

81242-81367

Sentence

denotes

Several attempts are being made to design and develop vaccines for CoV infection, mostly by targeting the spike glycoprotein.

T590

81368-81561

Sentence

denotes

Nevertheless, owing to extensive diversity in antigenic variants, cross-protection rendered by the vaccines is significantly limited, even within the strains of a phylogenetic subcluster (104).

T591

81562-81785

Sentence

denotes

Due to the lack of effective antiviral therapy and vaccines in the present scenario, we need to depend solely on implementing effective infection control measures to lessen the risk of possible nosocomial transmission (68).

T592

81786-81968

Sentence

denotes

Recently, the receptor for SARS-CoV-2 was established as the human angiotensin-converting enzyme 2 (hACE2), and the virus was found to enter the host cell mainly through endocytosis.

T593

81969-82093

Sentence

denotes

It was also found that the major components that have a critical role in viral entry include PIKfyve, TPC2, and cathepsin L.

T594

82094-82243

Sentence

denotes

These findings are critical, since the components described above might act as candidates for vaccines or therapeutic drugs against SARS-CoV-2 (293).

T595

82244-82460

Sentence

denotes

The majority of the treatment options and strategies that are being evaluated for SARS-CoV-2 (COVID-19) have been taken from our previous experiences in treating SARS-CoV, MERS-CoV, and other emerging viral diseases.

T596

82461-82666

Sentence

denotes

Several therapeutic and preventive strategies, including vaccines, immunotherapeutics, and antiviral drugs, have been exploited against the previous CoV outbreaks (SARS-CoV and MERS-CoV) (8, 104, 164–167).

T597

82667-82901

Sentence

denotes

These valuable options have already been evaluated for their potency, efficacy, and safety, along with several other types of current research that will fuel our search for ideal therapeutic agents against COVID-19 (7, 9, 19, 21, 36).

T598

82902-83252

Sentence

denotes

The primary cause of the unavailability of approved and commercial vaccines, drugs, and therapeutics to counter the earlier SARS-CoV and MERS-CoV seems to owe to the lesser attention of the biomedicine and pharmaceutical companies, as these two CoVs did not cause much havoc, global threat, and panic like those posed by the SARS-CoV-2 pandemic (19).

T599

83253-83412

Sentence

denotes

Moreover, for such outbreak situations, the requirement for vaccines and therapeutics/drugs exists only for a limited period, until the outbreak is controlled.

T600

83413-83590

Sentence

denotes

The proportion of the human population infected with SARS-CoV and MERS-CoV was also much lower across the globe, failing to attract drug and vaccine manufacturers and producers.

T601

83591-83847

Sentence

denotes

Therefore, by the time an effective drug or vaccine is designed against such disease outbreaks, the virus would have been controlled by adopting appropriate and strict prevention and control measures, and patients for clinical trials will not be available.

T602

83848-83922

Sentence

denotes

The newly developed drugs cannot be marketed due to the lack of end users.

T603

83924-83932

Sentence

denotes

Vaccines

T604

83933-84102

Sentence

denotes

The S protein plays a significant role in the induction of protective immunity against SARS-CoV by mediating T-cell responses and neutralizing antibody production (168).

T605

84103-84251

Sentence

denotes

In the past few decades, we have seen several attempts to develop a vaccine against human coronaviruses by using S protein as the target (168, 169).

T606

84252-84393

Sentence

denotes

However, the developed vaccines have minimal application, even among closely related strains of the virus, due to a lack of cross-protection.

T607

84394-84511

Sentence

denotes

That is mainly because of the extensive diversity existing among the different antigenic variants of the virus (104).

T608

84512-84777

Sentence

denotes

The contributions of the structural proteins, like spike (S), matrix (M), small envelope (E), and nucleocapsid (N) proteins, of SARS-CoV to induce protective immunity has been evaluated by expressing them in a recombinant parainfluenza virus type 3 vector (BHPIV3).

T609

84778-85010

Sentence

denotes

Of note, the result was conclusive that the expression of M, E, or N proteins without the presence of S protein would not confer any noticeable protection, with the absence of detectable serum SARS-CoV-neutralizing antibodies (170).

T610

85011-85147

Sentence

denotes

Antigenic determinant sites present over S and N structural proteins of SARS-CoV-2 can be explored as suitable vaccine candidates (294).

T611

85148-85285

Sentence

denotes

In the Asian population, S, E, M, and N proteins of SARS-CoV-2 are being targeted for developing subunit vaccines against COVID-19 (295).

T612

85286-85450

Sentence

denotes

The identification of the immunodominant region among the subunits and domains of S protein is critical for developing an effective vaccine against the coronavirus.

T613

85451-85579

Sentence

denotes

The C-terminal domain of the S1 subunit is considered the immunodominant region of the porcine deltacoronavirus S protein (171).

T614

85580-85716

Sentence

denotes

Similarly, further investigations are needed to determine the immunodominant regions of SARS-CoV-2 for facilitating vaccine development.

T615

85717-85937

Sentence

denotes

However, our previous attempts to develop a universal vaccine that is effective for both SARS-CoV and MERS-CoV based on T-cell epitope similarity pointed out the possibility of cross-reactivity among coronaviruses (172).

T616

85938-86034

Sentence

denotes

That can be made possible by selected potential vaccine targets that are common to both viruses.

T617

86035-86109

Sentence

denotes

SARS-CoV-2 has been reported to be closely related to SARS-CoV (173, 174).

T618

86110-86271

Sentence

denotes

Hence, knowledge and understanding of S protein-based vaccine development in SARS-CoV will help to identify potential S protein vaccine candidates in SARS-CoV-2.

T619

86272-86469

Sentence

denotes

Therefore, vaccine strategies based on the whole S protein, S protein subunits, or specific potential epitopes of S protein appear to be the most promising vaccine candidates against coronaviruses.

T620

86470-86567

Sentence

denotes

The RBD of the S1 subunit of S protein has a superior capacity to induce neutralizing antibodies.

T621

86568-86748

Sentence

denotes

This property of the RBD can be utilized for designing potential SARS-CoV vaccines either by using RBD-containing recombinant proteins or recombinant vectors that encode RBD (175).

T622

86749-86949

Sentence

denotes

Hence, the superior genetic similarity existing between SARS-CoV-2 and SARS-CoV can be utilized to repurpose vaccines that have proven in vitro efficacy against SARS-CoV to be utilized for SARS-CoV-2.

T623

86950-87085

Sentence

denotes

The possibility of cross-protection in COVID-19 was evaluated by comparing the S protein sequences of SARS-CoV-2 with that of SARS-CoV.

T624

87086-87251

Sentence

denotes

The comparative analysis confirmed that the variable residues were found concentrated on the S1 subunit of S protein, an important vaccine target of the virus (150).

T625

87252-87374

Sentence

denotes

Hence, the possibility of SARS-CoV-specific neutralizing antibodies providing cross-protection to COVID-19 might be lower.

T626

87375-87557

Sentence

denotes

Further genetic analysis is required between SARS-CoV-2 and different strains of SARS-CoV and SARS-like (SL) CoVs to evaluate the possibility of repurposed vaccines against COVID-19.

T627

87558-87765

Sentence

denotes

This strategy will be helpful in the scenario of an outbreak, since much time can be saved, because preliminary evaluation, including in vitro studies, already would be completed for such vaccine candidates.

T628

87766-87884

Sentence

denotes

Multiepitope subunit vaccines can be considered a promising preventive strategy against the ongoing COVID-19 pandemic.

T629

87885-87984

Sentence

denotes

In silico and advanced immunoinformatic tools can be used to develop multiepitope subunit vaccines.

T630

87985-88161

Sentence

denotes

The vaccines that are engineered by this technique can be further evaluated using docking studies and, if found effective, then can be further evaluated in animal models (365).

T631

88162-88301

Sentence

denotes

Identifying epitopes that have the potential to become a vaccine candidate is critical to developing an effective vaccine against COVID-19.

T632

88302-88465

Sentence

denotes

The immunoinformatics approach has been used for recognizing essential epitopes of cytotoxic T lymphocytes and B cells from the surface glycoprotein of SARS-CoV-2.

T633

88466-88553

Sentence

denotes

Recently, a few epitopes have been recognized from the SARS-CoV-2 surface glycoprotein.

T634

88554-88725

Sentence

denotes

The selected epitopes explored targeting molecular dynamic simulations, evaluating their interaction with corresponding major histocompatibility complex class I molecules.

T635

88726-88773

Sentence

denotes

They potentially induce immune responses (176).

T636

88774-88859

Sentence

denotes

The recombinant vaccine can be designed by using rabies virus (RV) as a viral vector.

T637

88860-88976

Sentence

denotes

RV can be made to express MERS-CoV S1 protein on its surface so that an immune response is induced against MERS-CoV.

T638

88977-89181

Sentence

denotes

The RV vector-based vaccines against MERS-CoV can induce faster antibody response as well as higher degrees of cellular immunity than the Gram-positive enhancer matrix (GEM) particle vector-based vaccine.

T639

89182-89264

Sentence

denotes

However, the latter can induce a very high antibody response at lower doses (167).

T640

89265-89379

Sentence

denotes

Hence, the degree of humoral and cellular immune responses produced by such vaccines depends upon the vector used.

T641

89380-89434

Sentence

denotes

Dual vaccines have been getting more popular recently.

T642

89435-89561

Sentence

denotes

Among them, the rabies virus-based vectored vaccine platform is used to develop vaccines against emerging infectious diseases.

T643

89562-89750

Sentence

denotes

The dual vaccine developed from inactivated rabies virus particles that express the MERS-CoV S1 domain of S protein was found to induce immune responses for both MERS-CoV and rabies virus.

T644

89751-89844

Sentence

denotes

The vaccinated mice were found to be completely protected from challenge with MERS-CoV (169).

T645

89845-90138

Sentence

denotes

The intranasal administration of the recombinant adenovirus-based vaccine in BALB/c mice was found to induce long-lasting neutralizing immunity against MERS spike pseudotyped virus, characterized by the induction of systemic IgG, secretory IgA, and lung-resident memory T-cell responses (177).

T646

90139-90292

Sentence

denotes

Immunoinformatics methods have been employed for the genome-wide screening of potential vaccine targets among the different immunogens of MERS-CoV (178).

T647

90293-90479

Sentence

denotes

The N protein and the potential B-cell epitopes of MERS-CoV E protein have been suggested as immunoprotective targets inducing both T-cell and neutralizing antibody responses (178, 179).

T648

90480-90657

Sentence

denotes

The collaborative effort of the researchers of Rocky Mountain Laboratories and Oxford University is designing a chimpanzee adenovirus-vectored vaccine to counter COVID-19 (180).

T649

90658-90782

Sentence

denotes

The Coalition for Epidemic Preparedness Innovations (CEPI) has initiated three programs to design SARS-CoV-2 vaccines (181).

T650

90783-90906

Sentence

denotes

CEPI has a collaborative project with Inovio for designing a MERS-CoV DNA vaccine that could potentiate effective immunity.

T651

90907-91115

Sentence

denotes

CEPI and the University of Queensland are designing a molecular clamp vaccine platform for MERS-CoV and other pathogens, which could assist in the easier identification of antigens by the immune system (181).

T652

91116-91357

Sentence

denotes

CEPI has also funded Moderna to develop a vaccine for COVID-19 in partnership with the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) (182).

T653

91358-91529

Sentence

denotes

By employing mRNA vaccine platform technology, a vaccine candidate expressing SARS-CoV-2 spike protein is likely to go through clinical testing in the coming months (180).

T654

91530-91688

Sentence

denotes

On 16 March 2020, Jennifer Haller became the first person outside China to receive an experimental vaccine, developed by Moderna, against this pandemic virus.

T655

91689-91829

Sentence

denotes

Moderna, along with China’s CanSino Biologics, became the first research group to launch small clinical trials of vaccines against COVID-19.

T656

91830-91923

Sentence

denotes

Their study is evaluating the vaccine’s safety and ability to trigger immune responses (296).

T657

91924-92052

Sentence

denotes

Scientists from all over the world are trying hard to develop working vaccines with robust protective immunity against COVID-19.

T658

92053-92430

Sentence

denotes

Vaccine candidates, like mRNA-1273 SARS-CoV-2 vaccine, INO-4800 DNA coronavirus vaccine, and adenovirus type 5 vector vaccine candidate (Ad5-nCoV), are a few examples under phase I clinical trials, while self-amplifying RNA vaccine, oral recombinant COVID-19 vaccine, BNT162, plant-based COVID-19 vaccine, and Ii-Key peptide COVID-19 vaccine are under preclinical trials (297).

T659

92431-92562

Sentence

denotes

Similarly, the WHO, on its official website, has mentioned a detailed list of COVID-19 vaccine agents that are under consideration.

T660

92563-92856

Sentence

denotes

Different phases of trials are ongoing for live attenuated virus vaccines, formaldehyde alum inactivated vaccine, adenovirus type 5 vector vaccine, LNP-encapsulated mRNA vaccine, DNA plasmid vaccine, and S protein, S-trimer, and Ii-Key peptide as a subunit protein vaccine, among others (298).

T661

92857-93047

Sentence

denotes

The process of vaccine development usually takes approximately ten years, in the case of inactivated or live attenuated vaccines, since it involves the generation of long-term efficacy data.

T662

93048-93143

Sentence

denotes

However, this was brought down to 5 years during the Ebola emergency for viral vector vaccines.

T663

93144-93249

Sentence

denotes

In the urgency associated with the COVID-19 outbreaks, we expect a vaccine by the end of this year (343).

T664

93250-93499

Sentence

denotes

The development of an effective vaccine against COVID-19 with high speed and precision is the combined result of advancements in computational biology, gene synthesis, protein engineering, and the invention of advanced manufacturing platforms (342).

T665

93500-93648

Sentence

denotes

The recurring nature of the coronavirus outbreaks calls for the development of a pan-coronavirus vaccine that can produce cross-reactive antibodies.

T666

93649-93845

Sentence

denotes

However, the success of such a vaccine relies greatly on its ability to provide protection not only against present versions of the virus but also the ones that are likely to emerge in the future.

T667

93846-94029

Sentence

denotes

This can be achieved by identifying antibodies that can recognize relatively conserved epitopes that are maintained as such even after the occurrence of considerable variations (362).

T668

94030-94176

Sentence

denotes

Even though several vaccine clinical trials are being conducted around the world, pregnant women have been completely excluded from these studies.

T669

94177-94359

Sentence

denotes

Pregnant women are highly vulnerable to emerging diseases such as COVID-19 due to alterations in the immune system and other physiological systems that are associated with pregnancy.

T670

94360-94476

Sentence

denotes

Therefore, in the event of successful vaccine development, pregnant women will not get access to the vaccines (361).

T671

94477-94651

Sentence

denotes

Hence, it is recommended that pregnant women be included in the ongoing vaccine trials, since successful vaccination in pregnancy will protect the mother, fetus, and newborn.

T672

94652-94836

Sentence

denotes

The heterologous immune effects induced by Bacillus Calmette Guérin (BCG) vaccination is a promising strategy for controlling the COVID-19 pandemic and requires further investigations.

T673

94837-94908

Sentence

denotes

BCG is a widely used vaccine against tuberculosis in high-risk regions.

T674

94909-94976

Sentence

denotes

It is derived from a live attenuated strain of Mycobacterium bovis.

T675

94977-95112

Sentence

denotes

At present, three new clinical trials have been registered to evaluate the protective role of BCG vaccination against SARS-CoV-2 (363).

T676

95113-95237

Sentence

denotes

Recently, a cohort study was conducted to evaluate the impact of childhood BCG vaccination in COVID-19 PCR positivity rates.

T677

95238-95395

Sentence

denotes

However, childhood BCG vaccination was found to be associated with a rate of COVID-19-positive test results similar to that of the nonvaccinated group (364).

T678

95396-95533

Sentence

denotes

Further studies are required to analyze whether BCG vaccination in childhood can induce protective effects against COVID-19 in adulthood.

T679

95534-95665

Sentence

denotes

Population genetic studies conducted on 103 genomes identified that the SARS-CoV-2 virus has evolved into two major types, L and S.

T680

95666-95775

Sentence

denotes

Among the two types, L type is expected to be the most prevalent (∼70%), followed by the S type (∼30%) (366).

T681

95776-95937

Sentence

denotes

This finding has a significant impact on our race to develop an ideal vaccine, since the vaccine candidate has to target both strains to be considered effective.

T682

95938-96054

Sentence

denotes

At present, the genetic differences between the L and S types are very small and may not affect the immune response.

T683

96055-96178

Sentence

denotes

However, we can expect further genetic variations in the coming days that could lead to the emergence of new strains (367).

T684

96180-96202

Sentence

denotes

Therapeutics and Drugs

T685

96203-96414

Sentence

denotes

There is no currently licensed specific antiviral treatment for MERS- and SARS-CoV infections, and the main focus in clinical settings remains on lessening clinical signs and providing supportive care (183–186).

T686

96415-96693

Sentence

denotes

Effective drugs to manage COVID-19 patients include remdesivir, lopinavir/ritonavir alone or in a blend with interferon beta, convalescent plasma, and monoclonal antibodies (MAbs); however, efficacy and safety issues of these drugs require additional clinical trials (187, 281).

T687

96694-96851

Sentence

denotes

A controlled trial of ritonavir-boosted lopinavir and interferon alpha 2b treatment was performed on COVID-19 hospitalized patients (ChiCTR2000029308) (188).

T688

96852-97065

Sentence

denotes

In addition, the use of hydroxychloroquine and tocilizumab for their potential role in modulating inflammatory responses in the lungs and antiviral effect has been proposed and discussed in many research articles.

T689

97066-97148

Sentence

denotes

Still, no fool-proof clinical trials have been published (194, 196, 197, 261–272).

T690

97149-97313

Sentence

denotes

Recently, a clinical trial conducted on adult patients suffering from severe COVID-19 revealed no benefit of lopinavir-ritonavir treatment over standard care (273).

T691

97314-97545

Sentence

denotes

The efforts to control SARS-CoV-2 infection utilize defined strategies as followed against MERS and SARS, along with adopting and strengthening a few precautionary measures owing to the unknown nature of this novel virus (36, 189).

T692

97546-97762

Sentence

denotes

Presently, the main course of treatment for severely affected SARS-CoV-2 patients admitted to hospitals includes mechanical ventilation, intensive care unit (ICU) admittance, and symptomatic and supportive therapies.

T693

97763-98044

Sentence

denotes

Additionally, RNA synthesis inhibitors (lamivudine and tenofovir disoproxil fumarate), remdesivir, neuraminidase inhibitors, peptide (EK1), anti-inflammatory drugs, abidol, and Chinese traditional medicine (Lianhuaqingwen and ShuFengJieDu capsules) could aid in COVID-19 treatment.

T694

98045-98141

Sentence

denotes

However, further clinical trials are being carried out concerning their safety and efficacy (7).

T695

98142-98472

Sentence

denotes

It might require months to a year(s) to design and develop effective drugs, therapeutics, and vaccines against COVID-19, with adequate evaluation and approval from regulatory bodies and moving to the bulk production of many millions of doses at commercial levels to meet the timely demand of mass populations across the globe (9).

T696

98473-98661

Sentence

denotes

Continuous efforts are also warranted to identify and assess viable drugs and immunotherapeutic regimens that revealed proven potency in combating other viral agents similar to SARS-CoV-2.

T697

98662-98755

Sentence

denotes

COVID-19 patients showing severe signs are treated symptomatically along with oxygen therapy.

T698

98756-98905

Sentence

denotes

In such cases where the patients progress toward respiratory failure and become refractory to oxygen therapy, mechanical ventilation is necessitated.

T699

98906-99003

Sentence

denotes

The COVID-19-induced septic shock can be managed by providing adequate hemodynamic support (299).

T700

99004-99117

Sentence

denotes

Several classes of drugs are currently being evaluated for their potential therapeutic action against SARS-CoV-2.

T701

99118-99419

Sentence

denotes

Therapeutic agents that have anti-SARS-CoV-2 activity can be broadly classified into three categories: drugs that block virus entry into the host cell, drugs that block viral replication as well as its survival within the host cell, and drugs that attenuate the exaggerated host immune response (300).

T702

99420-99504

Sentence

denotes

An inflammatory cytokine storm is commonly seen in critically ill COVID-19 patients.

T703

99505-99580

Sentence

denotes

Hence, they may benefit from the use of timely anti-inflammation treatment.

T704

99581-99799

Sentence

denotes

Anti-inflammatory therapy using drugs like glucocorticoids, cytokine inhibitors, JAK inhibitors, and chloroquine/hydroxychloroquine should be done only after analyzing the risk/benefit ratio in COVID-19 patients (301).

T705

99800-99937

Sentence

denotes

There have not been any studies concerning the application of nonsteroidal anti-inflammatory drugs (NSAID) to COVID-19-infected patients.

T706

99938-100082

Sentence

denotes

However, reasonable pieces of evidence are available that link NSAID uses with the occurrence of respiratory and cardiovascular adverse effects.

T707

100083-100222

Sentence

denotes

Hence, as a cautionary approach, it is better to recommend the use of NSAIDs as the first-line option for managing COVID-19 symptoms (302).

T708

100223-100353

Sentence

denotes

The use of corticosteroids in COVID-19 patients is still a matter of controversy and requires further systematic clinical studies.

T709

100354-100517

Sentence

denotes

The guidelines that were put forward to manage critically ill adults suggest the use of systemic corticosteroids in mechanically ventilated adults with ARDS (303).

T710

100518-100679

Sentence

denotes

The generalized use of corticosteroids is not indicated in COVID-19, since there are some concerns associated with the use of corticosteroids in viral pneumonia.

T711

100680-100858

Sentence

denotes

Stem cell therapy using mesenchymal stem cells (MSCs) is another hopeful strategy that can be used in clinical cases of COVID-19 owing to its potential immunomodulatory capacity.

T712

100859-101008

Sentence

denotes

It may have a beneficial role in attenuating the cytokine storm that is observed in severe cases of SARS-CoV-2 infection, thereby reducing mortality.

T713

101009-101206

Sentence

denotes

Among the different types of MSCs, expanded umbilical cord MSCs can be considered a potential therapeutic agent that requires further validation for managing critically ill COVID-19 patients (304).

T714

101207-101347

Sentence

denotes

Repurposed broad-spectrum antiviral drugs having proven uses against other viral pathogens can be employed for SARS-CoV-2-infected patients.

T715

101348-101495

Sentence

denotes

These possess benefits of easy accessibility and recognized pharmacokinetic and pharmacodynamic activities, stability, doses, and side effects (9).

T716

101496-101643

Sentence

denotes

Repurposed drugs have been studied for treating CoV infections, like lopinavir/ritonavir, and interferon-1β revealed in vitro anti-MERS-CoV action.

T717

101644-101869

Sentence

denotes

The in vivo experiment carried out in the nonhuman primate model of common marmosets treated with lopinavir/ritonavir and interferon beta showed superior protective results in treated animals than in the untreated ones (190).

T718

101870-101964

Sentence

denotes

A combination of these drugs is being evaluated to treat MERS in humans (MIRACLE trial) (191).

T719

101965-102148

Sentence

denotes

These two protease inhibitors (lopinavir and ritonavir), in combination with ribavirin, gave encouraging clinical outcomes in SARS patients, suggesting their therapeutic values (165).

T720

102149-102436

Sentence

denotes

However, in the current scenario, due to the lack of specific therapeutic agents against SARS-CoV-2, hospitalized patients confirmed for the disease are given supportive care, like oxygen and fluid therapy, along with antibiotic therapy for managing secondary bacterial infections (192).

T721

102437-102686

Sentence

denotes

Patients with novel coronavirus or COVID-19 pneumonia who are mechanically ventilated often require sedatives, analgesics, and even muscle relaxation drugs to prevent ventilator-related lung injury associated with human-machine incoordination (122).

T722

102687-102959

Sentence

denotes

The result obtained from a clinical study of four patients infected with COVID-19 claimed that combination therapy using lopinavir/ritonavir, arbidol, and Shufeng Jiedu capsules (traditional Chinese medicine) was found to be effective in managing COVID-19 pneumonia (193).

T723

102960-103109

Sentence

denotes

It is difficult to evaluate the therapeutic potential of a drug or a combination of drugs for managing a disease based on such a limited sample size.

T724

103110-103277

Sentence

denotes

Before choosing the ideal therapeutic agent for the management of COVID-19, randomized clinical control studies should be performed with a sufficient study population.

T725

103279-103294

Sentence

denotes

Antiviral Drugs

T726

103295-103502

Sentence

denotes

Several classes of routinely used antiviral drugs, like oseltamivir (neuraminidase inhibitor), acyclovir, ganciclovir, and ribavirin, do not have any effect on COVID-19 and, hence, are not recommended (187).

T727

103503-103700

Sentence

denotes

Oseltamivir, a neuraminidase inhibitor, has been explored in Chinese hospitals for treating suspected COVID-19 cases, although proven efficacy against SARS-CoV-2 is still lacking for this drug (7).

T728

103701-104017

Sentence

denotes

The in vitro antiviral potential of FAD-approved drugs, viz., ribavirin, penciclovir, nitazoxanide, nafamostat, and chloroquine, tested in comparison to remdesivir and favipiravir (broad-spectrum antiviral drugs) revealed remdesivir and chloroquine to be highly effective against SARS-CoV-2 infection in vitro (194).

T729

104018-104235

Sentence

denotes

Ribavirin, penciclovir, and favipiravir might not possess noteworthy in vivo antiviral actions for SARS-CoV-2, since higher concentrations of these nucleoside analogs are needed in vitro to lessen the viral infection.

T730

104236-104410

Sentence

denotes

Both remdesivir and chloroquine are being used in humans to treat other diseases, and such safer drugs can be explored for assessing their effectiveness in COVID-19 patients.

T731

104411-104570

Sentence

denotes

Several therapeutic agents, such as lopinavir/ritonavir, chloroquine, and hydroxychloroquine, have been proposed for the clinical management of COVID-19 (299).

T732

104571-104903

Sentence

denotes

A molecular docking study, conducted in the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using different commercially available antipolymerase drugs, identified that drugs such as ribavirin, remdesivir, galidesivir, tenofovir, and sofosbuvir bind RdRp tightly, indicating their vast potential to be used against COVID-19 (305).

T733

104904-105132

Sentence

denotes

A broad-spectrum antiviral drug that was developed in the United States, tilorone dihydrochloride (tilorone), was previously found to possess potent antiviral activity against MERS, Marburg, Ebola, and Chikungunya viruses (306).

T734

105133-105217

Sentence

denotes

Even though it had broad-spectrum activity, it was neglected for an extended period.

T735

105218-105297

Sentence

denotes

Tilorone is another antiviral drug that might have activity against SARS-CoV-2.

T736

105298-105535

Sentence

denotes

Remdesivir, a novel nucleotide analog prodrug, was developed for treating Ebola virus disease (EVD), and it was also found to inhibit the replication of SARS-CoV and MERS-CoV in primary human airway epithelial cell culture systems (195).

T737

105536-105647

Sentence

denotes

Recently, in vitro study has proven that remdesivir has better antiviral activity than lopinavir and ritonavir.

T738

105648-105929

Sentence

denotes

Further, in vivo studies conducted in mice also identified that treatment with remdesivir improved pulmonary function and reduced viral loads and lung pathology both in prophylactic and therapeutic regimens compared to lopinavir/ritonavir-IFN-γ treatment in MERS-CoV infection (8).

T739

105930-106075

Sentence

denotes

Remdesivir also inhibits a diverse range of coronaviruses, including circulating human CoV, zoonotic bat CoV, and prepandemic zoonotic CoV (195).

T740

106076-106183

Sentence

denotes

Remdesivir is also considered the only therapeutic drug that significantly reduces pulmonary pathology (8).

T741

106184-106322

Sentence

denotes

All these findings indicate that remdesivir has to be further evaluated for its efficacy in the treatment of COVID-19 infection in humans.

T742

106323-106458

Sentence

denotes

The broad-spectrum activity exhibited by remdesivir will help control the spread of disease in the event of a new coronavirus outbreak.

T743

106459-106626

Sentence

denotes

Chloroquine is an antimalarial drug known to possess antiviral activity due to its ability to block virus-cell fusion by raising the endosomal pH necessary for fusion.

T744

106627-106772

Sentence

denotes

It also interferes with virus-receptor binding by interfering with the terminal glycosylation of SARS-CoV cellular receptors, such as ACE2 (196).

T745

106773-106980

Sentence

denotes

In a recent multicenter clinical trial that was conducted in China, chloroquine phosphate was found to exhibit both efficacy and safety in the therapeutic management of SARS-CoV-2-associated pneumonia (197).

T746

106981-107114

Sentence

denotes

This drug is already included in the treatment guidelines issued by the National Health Commission of the People’s Republic of China.

T747

107115-107225

Sentence

denotes

The preliminary clinical trials using hydroxychloroquine, another aminoquinoline drug, gave promising results.

T748

107226-107341

Sentence

denotes

The COVID-19 patients received 600 mg of hydroxychloroquine daily along with azithromycin as a single-arm protocol.

T749

107342-107425

Sentence

denotes

This protocol was found to be associated with a noteworthy reduction in viral load.

T750

107426-107582

Sentence

denotes

Finally, it resulted in a complete cure (271); however, the study comprised a small population and, hence, the possibility of misinterpretation could arise.

T751

107583-107791

Sentence

denotes

However, in another case study, the authors raised concerns over the efficacy of hydroxychloroquine-azithromycin in the treatment of COVID-19 patients, since no observable effect was seen when they were used.

T752

107792-107887

Sentence

denotes

In some cases, the treatment was discontinued due to the prolongation of the QT interval (307).

T753

107888-107973

Sentence

denotes

Hence, further randomized clinical trials are required before concluding this matter.

T754

107974-108086

Sentence

denotes

Recently, another FDA-approved drug, ivermectin, was reported to inhibit the in vitro replication of SARS-CoV-2.

T755

108087-108254

Sentence

denotes

The findings from this study indicate that a single treatment of this drug was able to induce an ∼5,000-fold reduction in the viral RNA at 48 h in cell culture. (308).

T756

108255-108370

Sentence

denotes

One of the main disadvantages that limit the clinical utility of ivermectin is its potential to cause cytotoxicity.

T757

108371-108563

Sentence

denotes

However, altering the vehicles used in the formulations, the pharmacokinetic properties can be modified, thereby having significant control over the systemic concentration of ivermectin (338).

T758

108564-108898

Sentence

denotes

Based on the pharmacokinetic simulation, it was also found that ivermectin may have limited therapeutic utility in managing COVID-19, since the inhibitory concentration that has to be achieved for effective anti-SARS-CoV-2 activity is far higher than the maximum plasma concentration achieved by administering the approved dose (340).

T759

108899-109040

Sentence

denotes

However, ivermectin, being a host-directed agent, exhibits antiviral activity by targeting a critical cellular process of the mammalian cell.

T760

109041-109151

Sentence

denotes

Therefore, the administration of ivermectin, even at lower doses, will reduce the viral load at a minor level.

T761

109152-109296

Sentence

denotes

This slight decrease will provide a great advantage to the immune system for mounting a large-scale antiviral response against SARS-CoV-2 (341).

T762

109297-109514

Sentence

denotes

Further, a combination of ivermectin and hydroxychloroquine might have a synergistic effect, since ivermectin reduces viral replication, while hydroxychloroquine inhibits the entry of the virus in the host cell (339).

T763

109515-109675

Sentence

denotes

Further, in vivo studies and randomized clinical control trials are required to understand the mechanism as well as the clinical utility of this promising drug.

T764

109676-109761

Sentence

denotes

Nafamostat is a potent inhibitor of MERS-CoV that acts by preventing membrane fusion.

T765

109762-109858

Sentence

denotes

Nevertheless, it does not have any sort of inhibitory action against SARS-CoV-2 infection (194).

T766

109859-110064

Sentence

denotes

Recently, several newly synthesized halogenated triazole compounds were evaluated, using fluorescence resonance energy transfer (FRET)-based helicase assays, for their ability to inhibit helicase activity.

T767

110065-110307

Sentence

denotes

Among the evaluated compounds, 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-iodophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol and 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-chlorophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol were found to be the most potent.

T768

110308-110457

Sentence

denotes

These compounds were used for in silico studies, and molecular docking was accomplished into the active binding site of MERS-CoV helicase nsp13 (21).

T769

110458-110604

Sentence

denotes

Further studies are required for evaluating the therapeutic potential of these newly identified compounds in the management of COVID-19 infection.

T770

110606-110647

Sentence

denotes

Passive Immunization/Antibody Therapy/MAb

T771

110648-110750

Sentence

denotes

Monoclonal antibodies (MAbs) may be helpful in the intervention of disease in CoV-exposed individuals.

T772

110751-110852

Sentence

denotes

Patients recovering from SARS showed robust neutralizing antibodies against this CoV infection (164).

T773

110853-111091

Sentence

denotes

A set of MAbs aimed at the MERS-CoV S protein-specific domains, comprising six specific epitope groups interacting with receptor-binding, membrane fusion, and sialic acid-binding sites, make up crucial entry tasks of S protein (198, 199).

T774

111092-111244

Sentence

denotes

Passive immunization employing weaker and strongly neutralizing antibodies provided considerable protection in mice against a MERS-CoV lethal challenge.

T775

111245-111415

Sentence

denotes

Such antibodies may play a crucial role in enhancing protective humoral responses against the emerging CoVs by aiming appropriate epitopes and functions of the S protein.

T776

111416-111778

Sentence

denotes

The cross-neutralization ability of SARS-CoV RBD-specific neutralizing MAbs considerably relies on the resemblance between their RBDs; therefore, SARS-CoV RBD-specific antibodies could cross-neutralized SL CoVs, i.e., bat-SL-CoV strain WIV1 (RBD with eight amino acid differences from SARS-CoV) but not bat-SL-CoV strain SHC014 (24 amino acid differences) (200).

T777

111779-112044

Sentence

denotes

Appropriate RBD-specific MAbs can be recognized by a relative analysis of RBD of SARS-CoV-2 to that of SARS-CoV, and cross-neutralizing SARS-CoV RBD-specific MAbs could be explored for their effectiveness against COVID-19 and further need to be assessed clinically.

T778

112045-112157

Sentence

denotes

The U.S. biotechnology company Regeneron is attempting to recognize potent and specific MAbs to combat COVID-19.

T779

112158-112308

Sentence

denotes

An ideal therapeutic option suggested for SARS-CoV-2 (COVID-19) is the combination therapy comprised of MAbs and the drug remdesivir (COVID-19) (201).

T780

112309-112464

Sentence

denotes

The SARS-CoV-specific human MAb CR3022 is found to bind with SARS-CoV-2 RBD, indicating its potential as a therapeutic agent in the management of COVID-19.

T781

112465-112600

Sentence

denotes

It can be used alone or in combination with other effective neutralizing antibodies for the treatment and prevention of COVID-19 (202).

T782

112601-112863

Sentence

denotes

Furthermore, SARS-CoV-specific neutralizing antibodies, like m396 and CR3014, failed to bind the S protein of SARS-CoV-2, indicating that a particular level of similarity is mandatory between the RBDs of SARS-CoV and SARS-CoV-2 for the cross-reactivity to occur.

T783

112864-112960

Sentence

denotes

Further assessment is necessary before confirming the effectiveness of such combination therapy.

T784

112961-113110

Sentence

denotes

In addition, to prevent further community and nosocomial spread of COVID-19, the postprocedure risk management program should not be neglected (309).

T785

113111-113321

Sentence

denotes

Development of broad-spectrum inhibitors against the human coronaviral pathogens will help to facilitate clinical trials on the effectiveness of such inhibitors against endemic and emerging coronaviruses (203).

T786

113322-113482

Sentence

denotes

A promising animal study revealed the protective effect of passive immunotherapy with immune serum from MERS-immune camels on mice infected with MERS-CoV (204).

T787

113483-113630

Sentence

denotes

Passive immunotherapy using convalescent plasma is another strategy that can be used for treating COVID-19-infected, critically ill patients (205).

T788

113631-113985

Sentence

denotes

The exploration of fully human antibodies (human single-chain antibodies; HuscFvs) or humanized nanobodies (single-domain antibodies; sdAb, VH/VHH) could aid in blocking virus replication, as these agents can traverse the virus-infected cell membranes (transbodies) and can interfere with the biological characteristics of the replicating virus proteins.

T789

113986-114099

Sentence

denotes

Such examples include transbodies to the influenza virus, hepatitis C virus, Ebola virus, and dengue virus (206).

T790

114100-114497

Sentence

denotes

Producing similar transbodies against intracellular proteins of coronaviruses, such as papain-like proteases (PLpro), cysteine-like protease (3CLpro), or other nsps, which are essential for replication and transcription of the virus, might formulate a practical move forward for a safer and potent passive immunization approach for virus-exposed persons and rendering therapy to infected patients.

T791

114498-114691

Sentence

denotes

In a case study on five grimly sick patients having symptoms of severe pneumonia due to COVID-19, convalescent plasma administration was found to be helpful in patients recovering successfully.

T792

114692-114995

Sentence

denotes

The convalescent plasma containing a SARS-CoV-2-specific ELISA (serum) antibody titer higher than 1:1,000 and neutralizing antibody titer more significant than 40 was collected from the recovered patients and used for plasma transfusion twice in a volume of 200 to 250 ml on the day of collection (310).

T793

114996-115113

Sentence

denotes

At present, treatment for sepsis and ARDS mainly involves antimicrobial therapy, source control, and supportive care.

T794

115114-115223

Sentence

denotes

Hence, the use of therapeutic plasma exchange can be considered an option in managing such severe conditions.

T795

115224-115300

Sentence

denotes

Further randomized trials can be designed to investigate its efficacy (311).

T796

115302-115330

Sentence

denotes

Potential Therapeutic Agents

T797

115331-115845

Sentence

denotes

Potent therapeutics to combat SARS-CoV-2 infection include virus binding molecules, molecules or inhibitors targeting particular enzymes implicated in replication and transcription process of the virus, helicase inhibitors, vital viral proteases and proteins, protease inhibitors of host cells, endocytosis inhibitors, short interfering RNA (siRNA), neutralizing antibodies, MAbs against the host receptor, MAbs interfering with the S1 RBD, antiviral peptide aimed at S2, and natural drugs/medicines (7, 166, 186).

T798

115846-116065

Sentence

denotes

The S protein acts as the critical target for developing CoV antivirals, like inhibitors of S protein and S cleavage, neutralizing antibodies, RBD-ACE2 blockers, siRNAs, blockers of the fusion core, and proteases (168).

T799

116066-116161

Sentence

denotes

All of these therapeutic approaches have revealed both in vitro and in vivo anti-CoV potential.

T800

116162-116311

Sentence

denotes

Although in vitro research carried out with these therapeutics showed efficacy, most need appropriate support from randomized animal or human trials.

T801

116312-116429

Sentence

denotes

Therefore, they might be of limited applicability and require trials against SARS-CoV-2 to gain practical usefulness.

T802

116430-116577

Sentence

denotes

The binding of SARS-CoV-2 with ACE2 leads to the exacerbation of pneumonia as a consequence of the imbalance in the renin-angiotensin system (RAS).

T803

116578-116736

Sentence

denotes

The virus-induced pulmonary inflammatory responses may be reduced by the administration of ACE inhibitors (ACEI) and angiotensin type-1 receptor (AT1R) (207).

T804

116737-116861

Sentence

denotes

Several investigations have suggested the use of small-molecule inhibitors for the potential control of SARS-CoV infections.

T805

116862-117064

Sentence

denotes

Drugs of the FDA-approved compound library were screened to identify four small-molecule inhibitors of MERS-CoV (chlorpromazine, chloroquine, loperamide, and lopinavir) that inhibited viral replication.

T806

117065-117123

Sentence

denotes

These compounds also hinder SARS-CoV and human CoVs (208).

T807

117124-117301

Sentence

denotes

Therapeutic strategies involving the use of specific antibodies or compounds that neutralize cytokines and their receptors will help to restrain the host inflammatory responses.

T808

117302-117431

Sentence

denotes

Such drugs acting specifically in the respiratory tract will help to reduce virus-triggered immune pathologies in COVID-19 (209).

T809

117432-117606

Sentence

denotes

The later stages of coronavirus-induced inflammatory cascades are characterized by the release of proinflammatory interleukin-1 (IL-1) family members, such as IL-1 and IL-33.

T810

117607-117785

Sentence

denotes

Hence, there exists a possibility that the inflammation associated with coronavirus can be inhibited by utilizing anti-inflammatory cytokines that belong to the IL-1 family (92).

T811

117786-117917

Sentence

denotes

It has also been suggested that the actin protein is the host factor that is involved in cell entry and pathogenesis of SARS-CoV-2.

T812

117918-118078

Sentence

denotes

Hence, those drugs that modulate the biological activity of this protein, like ibuprofen, might have some therapeutic application in managing the disease (174).

T813

118079-118217

Sentence

denotes

The plasma angiotensin 2 level was found to be markedly elevated in COVID-19 infection and was correlated with viral load and lung injury.

T814

118218-118321

Sentence

denotes

Hence, drugs that block angiotensin receptors may have potential for treating COVID-19 infection (121).

T815

118322-118509

Sentence

denotes

A scientist from Germany, named Rolf Hilgenfeld, has been working on the identification of drugs for the treatment of coronaviral infection since the time of the first SARS outbreak (19).

T816

118510-118626

Sentence

denotes

The SARS-CoV S2 subunit has a significant function in mediating virus fusion that provides entry into the host cell.

T817

118627-118805

Sentence

denotes

Heptad repeat 1 (HR1) and heptad repeat 2 (HR2) can interact and form a six-helix bundle that brings the viral and cellular membranes in close proximity, facilitating its fusion.

T818

118806-118942

Sentence

denotes

The sequence alignment study conducted between COVID-19 and SARS-CoV identified that the S2 subunits are highly conserved in these CoVs.

T819

118943-119026

Sentence

denotes

The HR1 and HR2 domains showed 92.6% and 100% overall identity, respectively (210).

T820

119027-119144

Sentence

denotes

From these findings, we can confirm the significance of COVID-19 HR1 and HR2 and their vital role in host cell entry.

T821

119145-119267

Sentence

denotes

Hence, fusion inhibitors target the HR1 domain of S protein, thereby preventing viral fusion and entry into the host cell.

T822

119268-119362

Sentence

denotes

This is another potential therapeutic strategy that can be used in the management of COVID-19.

T823

119363-119527

Sentence

denotes

Other than the specific therapy directed against COVID-19, general treatments play a vital role in the enhancement of host immune responses against the viral agent.

T824

119528-119644

Sentence

denotes

Inadequate nutrition is linked to the weakening of the host immune response, making the individual more susceptible.

T825

119645-119788

Sentence

denotes

The role played by nutrition in disease susceptibility should be measured by evaluating the nutritional status of patients with COVID-19 (205).

T826

119790-119821

Sentence

denotes

Animal Models and Cell Cultures

T827

119822-120045

Sentence

denotes

For evaluating the potential of vaccines and therapeutics against CoVs, including SARS-CoV, MERS-CoVs, and the presently emerging SARS-CoV-2, suitable animal models that can mimic the clinical disease are needed (211, 212).

T828

120046-120254

Sentence

denotes

Various animal models were assessed for SARS- and MERS-CoVs, such as mice, guinea pigs, golden Syrian hamsters, ferrets, rabbits, nonhuman primates like rhesus macaques and marmosets, and cats (185, 213–218).

T829

120255-120382

Sentence

denotes

The specificity of the virus to hACE2 (receptor of SARS-CoV) was found to be a significant barrier in developing animal models.

T830

120383-120506

Sentence

denotes

Consequently, a SARS-CoV transgenic mouse model has been developed by inserting the hACE2 gene into the mouse genome (219).

T831

120507-120640

Sentence

denotes

The inability of MERS-CoV to replicate in the respiratory tracts of animals (mice, hamsters, and ferrets) is another limiting factor.

T832

120641-120833

Sentence

denotes

However, with genetic engineering, a 288-330+/+ MERS-CoV genetically modified mouse model was developed and now is in use for the assessment of novel drugs and vaccines against MERS-CoV (220).

T833

120834-121098

Sentence

denotes

In the past, small animals (mice or hamsters) have been targeted for being closer to a humanized structure, such as mouse DPP4 altered with human DPP4 (hDPP4), hDPP4-transduced mice, and hDPP4-Tg mice (transgenic for expressing hDPP4) for MERS-CoV infection (221).

T834

121099-121242

Sentence

denotes

The CRISPR-Cas9 gene-editing tool has been used for inserting genomic alterations in mice, making them susceptible to MERS-CoV infection (222).

T835

121243-121619

Sentence

denotes

Efforts are under way to recognize suitable animal models for SARS-CoV2/COVID-19, identify the receptor affinity of this virus, study pathology in experimental animal models, and explore virus-specific immune responses and protection studies, which together would increase the pace of efforts being made for developing potent vaccines and drugs to counter this emerging virus.

T836

121620-121887

Sentence

denotes

Cell lines, such as monkey epithelial cell lines (LLC-MK2 and Vero-B4), goat lung cells, alpaca kidney cells, dromedary umbilical cord cells, and advanced ex vivo three-dimensional tracheobronchial tissue, have been explored to study human CoVs (MERS-CoV) (223, 224).

T837

121888-121982

Sentence

denotes

Vero and Huh-7 cells (human liver cancer cells) have been used for isolating SARS-CoV-2 (194).

T838

121983-122260

Sentence

denotes

Recently, an experimental study with rhesus monkeys as animal models revealed the absence of any viral loads in nasopharyngeal and anal swabs, and no viral replication was recorded in the primary tissues at a time interval of 5 days post-reinfection in reexposed monkeys (274).

T839

122261-122464

Sentence

denotes

The subsequent virological, radiological, and pathological observations indicated that the monkeys with reexposure had no recurrence of COVID-19, like the SARS-CoV-2-infected monkeys without rechallenge.

T840

122465-122714

Sentence

denotes

These findings suggest that primary infection with SARS-CoV-2 could protect from later exposures to the virus, which could help in defining disease prognosis and crucial inferences for designing and developing potent vaccines against COVID-19 (274).

T841

122716-122751

Sentence

denotes

PREVENTION, CONTROL, AND MANAGEMENT

T842

122752-122896

Sentence

denotes

In contrast to their response to the 2002 SARS outbreak, China has shown immense political openness in reporting the COVID-19 outbreak promptly.

T843

122897-123052

Sentence

denotes

They have also performed rapid sequencing of COVID-19 at multiple levels and shared the findings globally within days of identifying the novel virus (225).

T844

123053-123137

Sentence

denotes

The move made by China opened a new chapter in global health security and diplomacy.

T845

123138-123374

Sentence

denotes

Even though complete lockdown was declared following the COVID-19 outbreak in Wuhan, the large-scale movement of people has resulted in a radiating spread of infections in the surrounding provinces as well as to several other countries.

T846

123375-123456

Sentence

denotes

Large-scale screening programs might help us to control the spread of this virus.

T847

123457-123562

Sentence

denotes

However, this is both challenging as well as time-consuming due to the present extent of infection (226).

T848

123563-123728

Sentence

denotes

The current scenario demands effective implementation of vigorous prevention and control strategies owing to the prospect of COVID-19 for nosocomial infections (68).

T849

123729-123881

Sentence

denotes

Follow-ups of infected patients by telephone on day 7 and day 14 are advised to avoid any further unintentional spread or nosocomial transmission (312).

T850

123882-124065

Sentence

denotes

The availability of public data sets provided by independent analytical teams will act as robust evidence that would guide us in designing interventions against the COVID-19 outbreak.

T851

124066-124171

Sentence

denotes

Newspaper reports and social media can be used to analyze and reconstruct the progression of an outbreak.

T852

124172-124268

Sentence

denotes

They can help us to obtain detailed patient-level data in the early stages of an outbreak (227).

T853

124269-124423

Sentence

denotes

Immediate travel restrictions imposed by several countries might have contributed significantly to preventing the spread of SARS-CoV-2 globally (89, 228).

T854

124424-124606

Sentence

denotes

Following the outbreak, a temporary ban was imposed on the wildlife trade, keeping in mind the possible role played by wild animal species in the origin of SARS-CoV-2/COVID-19 (147).

T855

124607-124796

Sentence

denotes

Making a permanent and bold decision on the trade of wild animal species is necessary to prevent the possibility of virus spread and initiation of an outbreak due to zoonotic spillover (1).

T856

124797-124923

Sentence

denotes

Personal protective equipment (PPE), like face masks, will help to prevent the spread of respiratory infections like COVID-19.

T857

124924-125110

Sentence

denotes

Face masks not only protect from infectious aerosols but also prevent the transmission of disease to other susceptible individuals while traveling through public transport systems (313).

T858

125111-125229

Sentence

denotes

Another critical practice that can reduce the transmission of respiratory diseases is the maintenance of hand hygiene.

T859

125230-125390

Sentence

denotes

However, the efficacy of this practice in reducing the transmission of respiratory viruses like SARS-CoV-2 is much dependent upon the size of droplets produced.

T860

125391-125516

Sentence

denotes

Hand hygiene will reduce disease transmission only if the virus is transmitted through the formation of large droplets (314).

T861

125517-125742

Sentence

denotes

Hence, it is better not to overemphasize that hand hygiene will prevent the transmission of SARS-CoV-2, since it may produce a false sense of safety among the general public that further contributes to the spread of COVID-19.

T862

125743-125968

Sentence

denotes

Even though airborne spread has not been reported in SARS-CoV-2 infection, transmission can occur through droplets and fomites, especially when there is close, unprotected contact between infected and susceptible individuals.

T863

125969-126195

Sentence

denotes

Hence, hand hygiene is equally as important as the use of appropriate PPE, like face masks, to break the transmission cycle of the virus; both hand hygiene and face masks help to lessen the risk of COVID-19 transmission (315).

T864

126196-126285

Sentence

denotes

Medical staff are in the group of individuals most at risk of getting COVID-19 infection.

T865

126286-126349

Sentence

denotes

This is because they are exposed directly to infected patients.

T866

126350-126550

Sentence

denotes

Hence, proper training must be given to all hospital staff on methods of prevention and protection so that they become competent enough to protect themselves and others from this deadly disease (316).

T867

126551-126704

Sentence

denotes

As a preventive measure, health care workers caring for infected patients should take extreme precautions against both contact and airborne transmission.

T868

126705-126842

Sentence

denotes

They should use PPE such as face masks (N95 or FFP3), eye protection (goggles), gowns, and gloves to nullify the risk of infection (299).

T869

126843-126956

Sentence

denotes

The human-to-human transmission reported in SARS-CoV-2 infection occurs mainly through droplet or direct contact.

T870

126957-127126

Sentence

denotes

Due to this finding, frontline health care workers should follow stringent infection control and preventive measures, such as the use of PPE, to prevent infection (110).

T871

127127-127360

Sentence

denotes

The mental health of the medical/health workers who are involved in the COVID-19 outbreak is of great importance, because the strain on their mental well-being will affect their attention, concentration, and decision-making capacity.

T872

127361-127488

Sentence

denotes

Hence, for control of the COVID-19 outbreak, rapid steps should be taken to protect the mental health of medical workers (229).

T873

127489-127680

Sentence

denotes

Since the living mammals sold in the wet market are suspected to be the intermediate host of SARS-CoV-2, there is a need for strengthening the regulatory mechanism for wild animal trade (13).

T874

127681-127836

Sentence

denotes

The total number of COVID-19 confirmed cases is on a continuous rise and the cure rate is relatively low, making disease control very difficult to achieve.

T875

127837-127964

Sentence

denotes

The Chinese government is making continuous efforts to contain the disease by taking emergency control and prevention measures.

T876

127965-128148

Sentence

denotes

They have already built a hospital for patients affected by this virus and are currently building several more for accommodating the continuously increasing infected population (230).

T877

128149-128363

Sentence

denotes

The effective control of SARS-CoV-2/COVID-19 requires high-level interventions like intensive contact tracing, as well as the quarantine of people with suspected infection and the isolation of infected individuals.

T878

128364-128503

Sentence

denotes

The implementation of rigorous control and preventive measures together might control the R0 number and reduce the transmission risk (228).

T879

128504-128705

Sentence

denotes

Considering the zoonotic links associated with SARS-CoV-2, the One Health approach may play a vital role in the prevention and control measures being followed to restrain this pandemic virus (317–319).

T880

128706-128898

Sentence

denotes

The substantial importation of COVID-19 presymptomatic cases from Wuhan has resulted in independent, self-sustaining outbreaks across major cities both within the country and across the globe.

T881

128899-128983

Sentence

denotes

The majority of Chinese cities are now facing localized outbreaks of COVID-19 (231).

T882

128984-129091

Sentence

denotes

Hence, deploying efficient public health interventions might help to cut the spread of this virus globally.

T883

129092-129230

Sentence

denotes

The occurrence of COVID-19 infection on several cruise ships gave us a preliminary idea regarding the transmission pattern of the disease.

T884

129231-129353

Sentence

denotes

Cruise ships act as a closed environment and provide an ideal setting for the occurrence of respiratory disease outbreaks.

T885

129354-129516

Sentence

denotes

Such a situation poses a significant threat to travelers, since people from different countries are on board, which favors the introduction of the pathogen (320).

T886

129517-129764

Sentence

denotes

Although nearly 30 cruise ships from different countries have been found harboring COVID-19 infection, the major cruise ships that were involved in the COVID-19 outbreaks are the Diamond Princess, Grand Princess, Celebrity Apex, and Ruby Princess.

T887

129765-129836

Sentence

denotes

The number of confirmed COVID-19 cases around the world is on the rise.

T888

129837-129988

Sentence

denotes

The success of preventive measures put forward by every country is mainly dependent upon their ability to anticipate the approaching waves of patients.

T889

129989-130106

Sentence

denotes

This will help to properly prepare the health care workers and increase the intensive care unit (ICU) capacity (321).

T890

130107-130366

Sentence

denotes

Instead of entirely relying on lockdown protocols, countries should focus mainly on alternative intervention strategies, such as large-scale testing, contract tracing, and localized quarantine of suspected cases for limiting the spread of this pandemic virus.

T891

130367-130486

Sentence

denotes

Such intervention strategies will be useful either at the beginning of the pandemic or after lockdown relaxation (322).

T892

130487-130622

Sentence

denotes

Lockdown should be imposed only to slow down disease progression among the population so that the health care system is not overloaded.

T893

130623-130786

Sentence

denotes

The reproduction number (R0) of COVID-19 infection was earlier estimated to be in the range of 1.4 to 2.5 (70); recently, it was estimated to be 2.24 to 3.58 (76).

T894

130787-130956

Sentence

denotes

Compared to its coronavirus predecessors, COVID-19 has an R0 value that is greater than that of MERS (R0 < 1) (108) but less than that of SARS (R0 value of 2 to 5) (93).

T895

130957-131117

Sentence

denotes

Still, to prevent further spread of disease at mass gatherings, functions remain canceled in the affected cities, and persons are asked to work from home (232).

T896

131118-131350

Sentence

denotes

Hence, it is a relief that the current outbreak of COVID-19 infection can be brought under control with the adoption of strategic preventive and control measures along with the early isolation of subsequent cases in the coming days.

T897

131351-131592

Sentence

denotes

Studies also report that since air traffic between China and African countries increased many times over in the decade after the SARS outbreak, African countries need to be vigilant to prevent the spread of novel coronavirus in Africa (225).

T898

131593-131664

Sentence

denotes

Due to fear of virus spread, Wuhan City was completely shut down (233).

T899

131665-131893

Sentence

denotes

The immediate control of the ongoing COVID-19 outbreaks appears a mammoth task, especially for developing countries, due to their inability to allocate quarantine stations that could screen infected individuals’ movements (234).

T900

131894-132209

Sentence

denotes

Such underdeveloped countries should divert their resources and energy to enforcing the primary level of preventive measures, like controlling the entry of individuals from China or countries where the disease has flared up, isolating the infected individuals, and quarantining individuals with suspected infection.

T901

132210-132330

Sentence

denotes

Most of the sub-Saharan African countries have a fragile health system that can be crippled in the event of an outbreak.

T902

132331-132506

Sentence

denotes

Effective management of COVID-19 would be difficult for low-income countries due to their inability to respond rapidly due to the lack of an efficient health care system (65).

T903

132507-132651

Sentence

denotes

Controlling the imported cases is critical in preventing the spread of COVID-19 to other countries that have not reported the disease until now.

T904

132652-132774

Sentence

denotes

The possibility of an imported case of COVID-19 leading to sustained human-to-human transmission was estimated to be 0.41.

T905

132775-132971

Sentence

denotes

This can be reduced to a value of 0.012 by decreasing the mean time from the onset of symptoms to hospitalization and can only be made possible by using intense disease surveillance systems (235).

T906

132972-133158

Sentence

denotes

The silent importations of infected individuals (before the manifestation of clinical signs) also contributed significantly to the spread of disease across the major cities of the world.

T907

133159-133370

Sentence

denotes

Even though the travel ban was implemented in Wuhan (89), infected persons who traveled out of the city just before the imposition of the ban might have remained undetected and resulted in local outbreaks (236).

T908

133371-133519

Sentence

denotes

Emerging novel diseases like COVID-19 are difficult to contain within the country of origin, since globalization has led to a world without borders.

T909

133520-133644

Sentence

denotes

Hence, international collaboration plays a vital role in preventing the further spread of this virus across the globe (237).

T910

133645-133729

Sentence

denotes

We also predict the possibility of another outbreak, as predicted by Fan et al. (6).

T911

133730-133804

Sentence

denotes

Indeed, the present outbreak caused by SARS-CoV-2 (COVID-19) was expected.

T912

133805-133888

Sentence

denotes

Similar to previous outbreaks, the current outbreak also will be contained shortly.

T913

133889-134056

Sentence

denotes

However, the real issue is how we are planning to counter the next zoonotic CoV epidemic that is likely to occur within the next 5 to 10 years or even sooner (Fig. 7).

T914

134057-134084

Sentence

denotes

FIG 7 Coronavirus origins.

T915

134085-134233

Sentence

denotes

Coronavirus is the most prominent example of an emerging virus that has crossed the species barrier from wild animals to humans, like SARS and MERS.

T916

134234-134316

Sentence

denotes

The origin of SARS-CoV-2 is also suspected to be from an intermediate animal host.

T917

134317-134411

Sentence

denotes

The possibility of crossing the species barrier again for the fourth time cannot be ruled out.

T918

134413-134431

Sentence

denotes

CONCLUDING REMARKS

T919

134432-134675

Sentence

denotes

Several years after the global SARS epidemic, the current SARS-CoV-2/COVID-19 pandemic has served as a reminder of how novel pathogens can rapidly emerge and spread through the human population and eventually cause severe public health crises.

T920

134676-134833

Sentence

denotes

Further research should be conducted to establish animal models for SARS-CoV-2 to investigate replication, transmission dynamics, and pathogenesis in humans.

T921

134834-134933

Sentence

denotes

This may help develop and evaluate potential therapeutic strategies against zoonotic CoV epidemics.

T922

134934-135101

Sentence

denotes

Present trends suggest the occurrence of future outbreaks of CoVs due to changes in the climate, and ecological conditions may be associated with human-animal contact.

T923

135102-135473

Sentence

denotes

Live-animal markets, such as the Huanan South China Seafood Market, represent ideal conditions for interspecies contact of wildlife with domestic birds, pigs, and mammals, which substantially increases the probability of interspecies transmission of CoV infections and could result in high risks to humans due to adaptive genetic recombination in these viruses (323–325).

T924

135474-135573

Sentence

denotes

The COVID-19-associated symptoms are fever, cough, expectoration, headache, and myalgia or fatigue.

T925

135574-135738

Sentence

denotes

Individuals with asymptomatic and atypical clinical manifestations were also identified recently, further adding to the complexity of disease transmission dynamics.

T926

135739-135876

Sentence

denotes

Atypical clinical manifestations may only express symptoms such as fatigue instead of respiratory signs such as fever, cough, and sputum.

T927

135877-136049

Sentence

denotes

In such cases, the clinician must be vigilant for the possible occurrence of asymptomatic and atypical clinical manifestations to avoid the possibility of missed diagnoses.

T928

136050-136114

Sentence

denotes

The present outbreak caused by SARS-CoV-2 was, indeed, expected.

T929

136115-136198

Sentence

denotes

Similar to previous outbreaks, the current pandemic also will be contained shortly.

T930

136199-136364

Sentence

denotes

However, the real question is, how are we planning to counter the next zoonotic CoV epidemic that is likely to occur within the next 5 to 10 years or perhaps sooner?

T931

136365-136591

Sentence

denotes

Our knowledge of most of the bat CoVs is scarce, as these viruses have not been isolated and studied, and extensive studies on such viruses are typically only conducted when they are associated with specific disease outbreaks.

T932

136592-136809

Sentence

denotes

The next step following the control of the COVID-19 outbreak in China should be focused on screening, identification, isolation, and characterization of CoVs present in wildlife species of China, particularly in bats.

T933

136810-136936

Sentence

denotes

Both in vitro and in vivo studies (using suitable animal models) should be conducted to evaluate the risk of future epidemics.

T934

136937-137040

Sentence

denotes

Presently, licensed antiviral drugs or vaccines against SARS-CoV, MERS-CoV, and SARS-CoV-2 are lacking.

T935

137041-137220

Sentence

denotes

However, advances in designing antiviral drugs and vaccines against several other emerging diseases will help develop suitable therapeutic agents against COVID-19 in a short time.

T936

137221-137354

Sentence

denotes

Until then, we must rely exclusively on various control and prevention measures to prevent this new disease from becoming a pandemic.

PMC:7405836 / 2579-139933 JSON TXT 10 Projects

Annnotations TAB TSV DIC JSON TextAE

PMC:7405836 / 2579-139933 JSONTXT 10 Projects

Annnotations TAB TSV DIC JSON TextAE

PMC:7405836 / 2579-139933 JSON TXT 10 Projects