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LitCovid-sentences  

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Id Subject Object Predicate Lexical cue
T1 0-54 Sentence denotes Strategies and advances in combating COVID-19 in China
T2 56-64 Sentence denotes Abstract
T3 65-266 Sentence denotes Coronavirus disease 2019 (COVID-19)—the third in a series of coronavirus infections—has caused a global public health event in the 21st century, resulting in substantial global morbidity and mortality.
T4 267-588 Sentence denotes Building on its legacy of managing severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), China has played a key role in the scientific community by revealing the viral transmission routes and clinical characteristics of COVID-19 and developing novel therapeutic interventions and vaccines.
T5 589-840 Sentence denotes Despite these rapid scientific and technological advances, uncertainties remain in tracing the original sources of infection, determining the routes of transmission and pathogenesis, and addressing the lack of targeted clinical management of COVID-19.
T6 841-973 Sentence denotes Here, we summarize the major COVID-19 research advances in China in order to provide useful information for global pandemic control.
T7 975-990 Sentence denotes 1 Introduction
T8 991-1144 Sentence denotes Coronavirus disease 2019 (COVID-19), which emerged in December 2019, is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.
T9 1145-1300 Sentence denotes According to the World Health Organization (WHO), COVID-19 has resulted in 34 495 176 laboratory-confirmed cases and 1 025 729 deaths as of 3 October 2020.
T10 1301-1390 Sentence denotes SARS-CoV-2 shares at least 70% similarity of its genetic sequence with SARS-CoV [1], [2].
T11 1391-1662 Sentence denotes Coming after SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), the SARS-CoV-2 outbreak is the third in a series of coronavirus outbreaks that have elicited heterogeneous clinical manifestations, ranging from asymptomatic response to fatal illness [3].
T12 1663-1945 Sentence denotes Like other common respiratory viruses (i.e., influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinovirus), coronaviruses generally cause mild and self-limited upper respiratory tract infections with clinical manifestations of common cold or mild pneumonia [4].
T13 1946-2048 Sentence denotes Among all known coronavirus species, only six have been identified to cause human diseases as of 2019.
T14 2049-2177 Sentence denotes The 229E, OC43, NL63, and HKU1 coronaviruses are well documented and mostly result in mild-to-moderate respiratory diseases [5].
T15 2178-2474 Sentence denotes However, the substantial genetic diversity, frequent recombination, and cumulative mutations of their RNA genomes, along with the notable increase in human-to-wildlife activities, have collectively resulted in a greater likelihood of the emergence of more transmissible and/or virulent pathogens.
T16 2475-2726 Sentence denotes Since the prevalence of COVID-19, China has been confronted with various uncertainties, including the infectivity and routes of transmission, clinical manifestations and immune responses, and possible effective treatments against SARS-CoV-2 infection.
T17 2727-2996 Sentence denotes Determining how to best manage the surge of new cases, promptly triage patients based on the predicted disease development trajectory, and deploy practical management to improve the clinical outcomes has become the central task for the government and medical community.
T18 2997-3284 Sentence denotes During the battle against COVID-19, based on the “life supremacy” policy, China has enforced rapid non-pharmaceutical interventions and played a crucial role in unraveling the viral transmission and clinical characteristics, and in developing novel therapeutic interventions and vaccine.
T19 3285-3503 Sentence denotes Here, we summarize the strategies that have been used in China in different domains, which might help to increase our preparedness against future outbreaks and inform disease prevention and management across the globe.
T20 3505-3573 Sentence denotes 2 Overview of the strategies for battling against COVID-19 in China
T21 3574-3790 Sentence denotes Epidemiological surveillance systems, which have been well established since the 2003 SARS epidemic in China, underpinned China’s rapid identification of initial cases with a “pneumonia of unknown etiology” [6], [7].
T22 3791-4163 Sentence denotes Within only one month, the Chinese government had declared the epidemic an “extremely serious public health incident.” This familiar scenario, in which patchy shadows and ground-glass opacity on computed tomography (CT) images, even presenting with “white lung” in severe patients [8], surpassed the panic caused by the large-scale superspreading of SARS-CoV 17 years ago.
T23 4164-4371 Sentence denotes Defining the routes of transmission and sources of infection may inform the strategies for outbreak containment at a nationwide level, with the rapid deployment of non-pharmaceutical interventions [9], [10].
T24 4372-4484 Sentence denotes In Wuhan, most cases had a history of recent travel to or contact with the people in a seafood wholesale market.
T25 4485-4584 Sentence denotes Subsequent infections of medical staff and other sporadic cases showed no contact with this market.
T26 4585-4748 Sentence denotes In cases of close contact, the human-to-human transmission potential of the virus was soon released, and the public was warned via multiple social media platforms.
T27 4749-5097 Sentence denotes The declaration that Wuhan city—but not other regions—was the epicenter prompted the Chinese government to initiate an unprecedented and draconic measure: to lock down Wuhan and several other adjacent cities in Hubei province in order to rapidly curb the massive outflow of infected cases and enforce restrictions on movements to the epicenter [9].
T28 5098-5248 Sentence denotes To more rapidly achieve epidemic containment, non-governmental societies were soon mobilized to supervise and trace the paths of relevant individuals.
T29 5249-5560 Sentence denotes In order to more effectively manage the surge of mild-to-moderate cases, makeshift (Fangcang) hospitals with 13 000 beds were temporarily built in large-scale public venues to facilitate the isolation, treatment, and monitoring of confirmed cases, which would help to alleviate the shortage of medical supplies.
T30 5561-5802 Sentence denotes The establishment of these low-cost hospitals obviated within-household and community transmission; it also helped to release the pressure of patient admissions to designated hospitals and made it possible to triage severe patients promptly.
T31 5803-5992 Sentence denotes To minimize the risk of transmission, residents without symptoms and/or with a history of close contact yet a negative polymerase chain reaction (PCR) test were mandated to isolate at home.
T32 5993-6087 Sentence denotes These measures eventually proved to be highly effective in flattening the epidemiologic curve.
T33 6088-6316 Sentence denotes However, challenges in managing ongoing local outbreaks induced by imported cases remain due to the high risk of resurgence in regions such as Beijing, Xinjiang, Dalian, and Hong Kong, which have frequent population immigration.
T34 6318-6367 Sentence denotes 3 Possible mechanisms underlying viral infection
T35 6368-6558 Sentence denotes SARS-CoV-2 was initially identified and isolated from a cluster of patients with similar symptoms (fever, cough, and dyspnea) and radiologic findings of ground-glass opacity on chest CT [6].
T36 6559-6798 Sentence denotes Next-generation sequencing and real-time reverse transcription polymerase chain reaction (RT-PCR) targeting to a consensus RNA-dependent RNA polymerase (RdRp) region of panβ-CoV demonstrated the pathogen to be a novel beta coronavirus [7].
T37 6799-6944 Sentence denotes Electron microscopy revealed the solar appearance of virion particles, whose morphology was consistent with that of the Coronaviridae family [7].
T38 6945-7123 Sentence denotes SARS-CoV-2 most likely originated from bats due to its substantially high homology (96% nucleotide sequence identity) with SARS-like bat coronaviruses (BatCoV RaTG13) [11], [12].
T39 7124-7277 Sentence denotes A possible mechanism of the emergence of SARS-CoV-2 is that the accumulative mutations in its genome enabled the virus to cross the animal–human barrier.
T40 7278-7383 Sentence denotes However, animal-to-human transmission is unlikely to have been the main driver for the COVID-19 pandemic.
T41 7384-7483 Sentence denotes SARS-CoV-2 employs mechanisms similar to those of SARS-CoV for receptor recognition and cell entry.
T42 7484-7684 Sentence denotes The spike (S) protein on the virion surface facilitates the entry of the virus into the target cells by attachment to its cognate receptor, angiotensin-converting enzyme 2 (ACE2), on the cell surface.
T43 7685-7877 Sentence denotes Transmembrane serine proteases of the target cells, such as FURIN or transmembrane protease serine 2 (TMPRSS2), induce cleavage of the S protein before membrane fusion for cellular entry [13].
T44 7878-7979 Sentence denotes Therefore, cells that co-express ACE2 and serine protease could be the primary targets of SARS-CoV-2.
T45 7980-8322 Sentence denotes Single-cell RNA-sequencing studies have also confirmed the expression of ACE2 and TMPRSS2 in a vast array of cells, including lung alveolar epithelial type II cells, nasal goblet cells, cholangiocytes, colonocytes, esophageal keratinocytes, gastrointestinal epithelial cells, pancreatic β-cells, and renal proximal tubules and podocytes [14].
T46 8323-8449 Sentence denotes These observations have provided probable explanations for multiple-organ infection and injury via direct viral tissue damage.
T47 8450-8692 Sentence denotes Moreover, clinical observations have demonstrated extrapulmonary manifestations, ranging from hematologic, cardiovascular, renal, gastrointestinal and hepatobiliary, endocrinologic, neurologic, and ophthalmologic to dermatologic systems [14].
T48 8693-8892 Sentence denotes SARS-CoV-2 attacks the host through direct tissue damage, endothelial cell damage and thrombosis, dysregulation of the immune response, and disorders of the renin-angiotensin-aldosterone system [15].
T49 8893-9074 Sentence denotes COVID-19 infection is accompanied by an aggressive inflammatory response with the release of massive pro-inflammatory cytokines in an event known as the “cytokine storm” [16], [17].
T50 9075-9756 Sentence denotes Plasma collected from COVID-19 patients with pneumonia has shown markedly increased concentrations of pro-inflammatory cytokines (interleukin-1β (IL-1β), interleukin-1 receptor antagonist (IL-1RA), IL-7, IL-8, IL-9, IL-10, fibroblast growth factor, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), interferon-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1α), macrophage inflammatory protein-1 beta (MIP-1β), platelet-derived growth factor (PDGF), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF)) [18].
T51 9757-9944 Sentence denotes Critical illness in patients has also been associated with an elevated level of IL-2, IL-7, IL-10, G-CSF, IP10, MCP-1, MIP-1α, and TNF-α plasma concentrations as compared with mild cases.
T52 9945-10246 Sentence denotes These events drive the recruitment of immune cells such as macrophages, neutrophils, and T cells into the sites of infection, causing destabilization of endothelial cell to cell and the vascular barrier and diffusing alveolar damage, and ultimately leading to multi-organ failure and subsequent death.
T53 10247-10301 Sentence denotes ACE2 is the key determinant of viral transmissibility.
T54 10302-10582 Sentence denotes Recent studies have demonstrated that the receptor binding domain of the S protein from SARS-CoV-2 displays a 10- to 20-fold higher binding capacity with ACE2 compared with that of SARS-CoV [19], [20], which may partially explain the increased transmissibility of SARS-CoV-2 [21].
T55 10583-10800 Sentence denotes SARS-CoV-2 shows a gradient of reduced infectivity from the proximal to distal respiratory tract, which coincides with the finding of progressively decreased expression of ACE2 from the oropharynx to the alveoli [22].
T56 10801-10996 Sentence denotes SARS-CoV-2 infection might be initiated from the nasal passages, followed by the aspiration of virions seeding along the respiratory tract to the lungs, rather than causing direct lung infection.
T57 10997-11254 Sentence denotes A more possible process might involve high loads of virus shedding from the initially infected respiratory tract, along with the secretion of mucus accumulating at the oropharynx cavity, and finally arriving at the tracheobronchial tree via aspiration [23].
T58 11255-11456 Sentence denotes Molecular dynamics simulations suggest that SARS-CoV-2 has a distinct binding interface to ACE2, with higher affinities and a different network of residue-residue contacts than other coronaviruses [2].
T59 11457-11557 Sentence denotes SARS-CoV-2 has a larger contact area than SARS-CoV with more conserved residues for ACE2 attachment.
T60 11558-11815 Sentence denotes Unlike coronaviruses with low pathogenicity, SARS-CoV-2 exhibits enhancement of the nuclear localization signals in the nucleocapsid protein and distinct inserts in the spike glycoprotein, which appear to be associated with the high case-fatality rate [24].
T61 11816-11941 Sentence denotes SARS-CoV-2 could evolve into diverse lineages with different magnitudes of virulence and transmissibility via mutations [25].
T62 11942-12205 Sentence denotes Several studies have documented a SARS-CoV-2 variant, aspartic acid (D) with substitution of glycine (G) at codon 614 in the S protein [25], [26], [27], [28], which is located on a B-cell epitope with a highly immunodominant region on the receptor binding domain.
T63 12206-12324 Sentence denotes An in vitro study suggested that a D614G pseudotype variant was nine times more infectious than the D614 strains [29].
T64 12325-12534 Sentence denotes Strains carrying this mutation have become dominant since December 2019, and have been frequently observed in European countries (e.g., the Netherlands, Switzerland, and France) but not as frequently in China.
T65 12535-12671 Sentence denotes Strikingly, the variant S-D614G distinguishes the SARS-CoV-2 strains that may have caused fatal infections in European populations [27].
T66 12672-12994 Sentence denotes A study on the alignment of 10 022 SARS-CoV-2 genomes from infected persons in 68 countries identified 6294 samples carrying the D614G mutation; almost all of these genomes also had another co-mutation in the proteins responsible for replication (ORF1ab P4715L; RdRp P323L) that might affect the speed of replication [28].
T67 12995-13194 Sentence denotes D614G was predicted to fine-tune the spike conformation and result in a loss of immunogenicity for B-cell recognition, a dominated process to stimulate adaptive immunity against SARS-CoV-2 infection.
T68 13196-13218 Sentence denotes 4 Transmission routes
T69 13219-13359 Sentence denotes The major transmission route of SARS-CoV-2 is considered to be close contact with droplets containing exposed virus or contaminated fomites.
T70 13360-13607 Sentence denotes Further studies have revealed the presence of viral RNA in various bodily fluid samples, including bronchoalveolar lavage fluid, sputum, nasal swabs, pharyngeal swabs, feces, blood, and urine [30], which suggest alternative routes of transmission.
T71 13608-13695 Sentence denotes In fact, infectious SARS-CoV-2 virions have been isolated from fecal and urine samples.
T72 13696-13929 Sentence denotes In line with these reports, SARS-CoV-2 productively infects the human gut enterocytes [31], [32], [33], [34] and causes notable gastrointestinal symptoms, including abdominal pain and diarrhea in 20%–50% of patients [35], [36], [37].
T73 13930-14164 Sentence denotes Further investigations found that the viral load in feces was markedly higher than that in the respiratory tract between 17 and 28 d after symptom onset, and that RNA fragments—but not infectious virus—were detected in the feces [38].
T74 14165-14262 Sentence denotes During an episode of diarrhea, infectious virus could be more readily detected in the feces [37].
T75 14263-14327 Sentence denotes Moreover, infectious viruses have also been isolated from urine.
T76 14328-14419 Sentence denotes Given these findings, appropriate precautions should be taken to avoid fomite transmission.
T77 14421-14456 Sentence denotes 5 Advances in laboratory diagnosis
T78 14457-14631 Sentence denotes The development of rapid diagnosis is urgently needed during the early stages of an epidemic to enable community-based screening and consistent course development monitoring.
T79 14632-14733 Sentence denotes During the early stage of the COVID-19 epidemic, diagnosis was based on symptoms and chest radiology.
T80 14734-14851 Sentence denotes The majority of COVID-19 cases showed bilateral distribution of patchy shadows and ground-glass opacity on CT images.
T81 14852-14998 Sentence denotes However, 17.9% of non-critically ill patients and 2.9% patients with severe illnesses showed no radiologic abnormality on hospital admission [39].
T82 14999-15145 Sentence denotes RT-PCR has been extensively deployed for the detection of SARS-CoV-2 RNA fragments, and has been recommended for the diagnosis of acute infection.
T83 15146-15246 Sentence denotes However, false-negative results may be problematic, as they can jeopardize the whole community [40].
T84 15247-15505 Sentence denotes The fact that a patient who was RT-PCR negative developed clinical symptoms of COVID-19, suggesting that insufficient amounts of viral genome collection for amplification, or mutations in the NP and ORF of SARS-CoV-2, may lead to false-negative results [41].
T85 15506-15593 Sentence denotes Serological analysis is another typical method for COVID-19 diagnosis [42], [43], [44].
T86 15594-15754 Sentence denotes Accurate serological tests would enrich our understanding of the personal process of viral exposure, particularly in the monitoring of asymptomatic individuals.
T87 15755-15973 Sentence denotes Nucleocapsid (N)- and S-specific immunoglobulin M (IgM) and IgG could be used for the detection of SARS-CoV-2 infection because of the progressively elevated titers after symptom onset (typically peaking at Days 7–10).
T88 15974-16078 Sentence denotes The combined detection of N- and S-specific IgM and IgG may increase the detection rate at early stages.
T89 16079-16225 Sentence denotes In fact, the combination of N- and S-induced IgM and IgG could be detected in up to 75% of infections within the first week of symptom onset [45].
T90 16226-16346 Sentence denotes The sensitivity of combined detection of N-IgM and N-IgG, or N-IgG and S-IgG, reached 94.7% within the second week [45].
T91 16347-16465 Sentence denotes At Week 3, S-IgG titers were significantly higher in non-intensive care unit (ICU) patients than in ICU patients [45].
T92 16466-16616 Sentence denotes Moreover, the expression level of N-IgG was significantly higher in ICU patients, although S-IgG titers were higher in patients with moderate illness.
T93 16617-16676 Sentence denotes These findings provide hints for prognosis prediction [46].
T94 16677-16979 Sentence denotes To accelerate the clinical diagnostic testing of COVID-19 (particularly for population-based survey or point-of-care testing), a rapid, accurate, and portable detection method based on clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associate system (Cas) has been developed.
T95 16980-17112 Sentence denotes The CRISPR/Cas system is an adaptive immune system in archaea and bacteria that defends against foreign genetic elements [47], [48].
T96 17113-17264 Sentence denotes CRISPR allows a programmable protein to attach onto the target site assisted by a guide RNA for cleavage of the target sequence [47], [49], [50], [51].
T97 17265-17533 Sentence denotes CRISPR/Cas12a-based detection has been established together with SARS-CoV-2-specific CRISPR RNAs (crRNAs) targeting the orf1a, orf1b, N, and E genes, and a single-stranded DNA (ssDNA) reporter labeled with a quenched green fluorescent molecule has been developed [48].
T98 17534-17694 Sentence denotes The fluorescent molecule is cleaved in the presence of a trace amount of SARS-CoV-2 sequences; more importantly, the results can be determined by the naked eye.
T99 17695-17904 Sentence denotes This system also allows for simultaneous reverse transcription and isothermal amplification at a low temperature, independent of laboratory instruments, and thus could meet the urgent need for rapid diagnosis.
T100 17906-17945 Sentence denotes 6 Clinical characteristics of COVID-19
T101 17946-18188 Sentence denotes Given the lack of knowledge regarding the manifestations of COVID-19 and the unclear targets for its prevention, efforts have been expedited to extract the clinical data from the first 41 cases, who were unanimously recruited from Wuhan [52].
T102 18189-18362 Sentence denotes To depict the clinical characteristics at the national level, a study was performed to analyze 1099 laboratory-confirmed cases from 552 hospitals across mainland China [39].
T103 18363-18515 Sentence denotes The most common symptoms were fever and cough on admission, while gastrointestinal illnesses such as nausea, vomiting, and diarrhea were uncommon (<5%).
T104 18516-18574 Sentence denotes The median incubation period was 4 d (interquartile range:
T105 18575-18582 Sentence denotes 2–7 d).
T106 18583-18710 Sentence denotes The case-fatality rate was 1.4%, which was comparable to the national official statistics in China as of 16 February 2020 [39].
T107 18711-18830 Sentence denotes However, the case-fatality rate cannot be precisely calculated due to the unclear total number of infected individuals.
T108 18831-19018 Sentence denotes Importantly, fever was not present on admission in around half of the individuals, suggesting that fever cannot be the sole diagnostic standard for population-based screening of COVID-19.
T109 19019-19235 Sentence denotes The fact that lymphopenia was common and more prominent in patients with greater disease severity has inspired clinicians to perform clinical trials to validate the effectiveness of interventions against lymphopenia.
T110 19236-19396 Sentence denotes Furthermore, children are not immune to COVID-19 and most infected children have been found to have a history of recent infections in their families [53], [54].
T111 19397-19532 Sentence denotes Multiple comorbidities have been found to be associated with the severity of disease and progression in SARS and MERS [55], [56], [57].
T112 19533-19774 Sentence denotes Similarly, recent studies have shown that COVID-19 patients with diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular diseases (CVD), hypertension, malignancies, and other comorbidities had a markedly higher mortality rate.
T113 19775-19942 Sentence denotes Elevated levels of ACE2 that were proposed to be associated with an increased susceptibility have been observed in COVID-19 patients with diabetes, COPD, and CVD [58].
T114 19943-20117 Sentence denotes Persons suffering from hypertension may also have increased ACE2 levels induced by heavy dosages of ACE2 inhibitors and angiotensin receptor blockers (ARBs) during treatment.
T115 20118-20238 Sentence denotes However, there has been no evidence that ACE inhibitors or ARBs affects the severity of COVID-19 [59], [60], [61], [62].
T116 20239-20370 Sentence denotes Apart from hypertension, patients with cancer were found to be more susceptible due to their systemic immunosuppressive state [63].
T117 20371-20495 Sentence denotes Patients with cancer had a significantly higher risk of ICU admission, requiring invasive ventilation, and death [63], [64].
T118 20496-20702 Sentence denotes Therefore, patient triage should be based on the presence and spectrum of comorbidities, which would allow for more intensive monitoring among patients at higher risk of developing severe clinical outcomes.
T119 20703-20872 Sentence denotes Meanwhile, radiotherapy and chemotherapy may be postponed for cancer patients who are clinically stable in order to minimize the risk of acquiring nosocomial infections.
T120 20873-20953 Sentence denotes The presence of systemic symptoms varied considerably among different countries.
T121 20954-21156 Sentence denotes A recent meta-analysis of 29 studies, mainly from China, demonstrated that anorexia was present in 21%, nausea and/or vomiting in 7%, diarrhea in 9%, and abdominal pain in 3% of the cases, respectively.
T122 21157-21315 Sentence denotes However, in a study from the United States, the systemic symptoms of anorexia (34.8%), diarrhea (33.7%), and nausea (26.4%) were found to be more common [14].
T123 21316-21433 Sentence denotes It is noteworthy that a small proportion of patients remained asymptomatic throughout the course of the disease [65].
T124 21434-21571 Sentence denotes Because of the atypical manifestations, contact tracing of asymptomatic patients is necessary after a positive viral RNA test [66], [67].
T125 21572-21708 Sentence denotes The first report of an asymptomatic patient was anecdotal, based on a chest CT scan of an infected child in a familial cluster of cases.
T126 21709-21835 Sentence denotes Further studies demonstrated that the proportion of asymptomatic patients ranged from 20% to 78% of positive cases [66], [68].
T127 21836-21922 Sentence denotes Of the 166 new cases identified on 1 April 2020 in China, 130 (78%) were asymptomatic.
T128 21923-22140 Sentence denotes Unlike symptomatic patients, hyposmia and nasal congestion were frequent among asymptomatic patients—regardless of whether they had positive CT scan findings or not—but uninfected patients could be excluded by RT-PCR.
T129 22141-22350 Sentence denotes Asymptomatic patients remained contagious; viral shedding was found to be most prominent before symptom onset, and the duration of shedding might be extended in comparison with symptomatic patients [69], [70].
T130 22351-22562 Sentence denotes However, the population of asymptomatic individuals may be highly heterogeneous, as such individuals may be in the earlier stages of the disease or could remain asymptomatic throughout the course of the disease.
T131 22564-22610 Sentence denotes 7 Prognostic prediction of critical illnesses
T132 22611-22682 Sentence denotes COVID-19 is characterized by rapid progression in a number of patients.
T133 22683-22926 Sentence denotes The case-fatality rate ranged from 1.4% in the general population by the statistic of 1099 cases, [39] to 49% in patients with critical illness in summary of a report of 72 314 cases from Chinese Center for Disease Control and Prevention [71].
T134 22927-23100 Sentence denotes Early identification of patients at risk of developing critical illness would allow for early triage, timely clinical management, and optimization of medical resources [72].
T135 23101-23342 Sentence denotes The overall problem encountered in China during the first few months of the epidemic was the difficulty of identifying patients who were more likely to develop severe illness out of the thousands of daily confirmed cases as soon as possible.
T136 23343-23441 Sentence denotes However, no tool was available at the initial stage of the epidemic to inform clinicians in China.
T137 23442-23612 Sentence denotes To address this urgent issue, a predictive risk score estimating whether a hospitalized patient with COVID-19 would be inclined to develop critical illness was developed.
T138 23613-23739 Sentence denotes A retrospective cohort of 1590 patients with COVID-19 from 575 hospitals in 31 provincial administrative regions was included.
T139 23740-24312 Sentence denotes By using the least absolute shrinkage and selection operator model, 19 common clinical variables (clinical features and blood test results, chest X-ray (CXR) abnormality, age, exposure to Wuhan, first and highest body temperature, respiratory rate, systolic blood pressure, hemoptysis, dyspnea, skin rash, unconsciousness, number of comorbidities, COPD, cancer, oxygen saturation levels, neutrophils, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, direct bilirubin, and creatinine levels) remained to predict the likelihood of progressing to critical illness [72].
T140 24313-24566 Sentence denotes The deployment of an artificial intelligence (AI) system allowed a deep learning-based survival model to further establish an online calculation tool, which could differentiate patients with COVID-19 from those with other forms of common pneumonia [73].
T141 24567-24735 Sentence denotes A CT-based AI system could also assist in early diagnosis for triage, monitoring, and treatment, as well as in establishing a reference for longitudinal follow-up [74].
T142 24736-24980 Sentence denotes Since CT scanning provides more detailed information on pathology and gives a better quantitative measurement of the lesion’s size and the extent or severity of lung involvement, it may be a preferred tool, especially for point-of-care testing.
T143 24981-25252 Sentence denotes The rapid turnaround time of CT assessment, coupled with the application of an AI system, may help in the early triage of patients by significantly shortening the duration from clinical inspection to triage, especially when the healthcare system is overloaded [75], [76].
T144 25253-25459 Sentence denotes Dynamic changes in hematologic and immunologic biomarkers might also be valuable for informing clinicians of the severity of COVID-19 and enabling them to postulate the most probable clinical outcomes [77].
T145 25460-25568 Sentence denotes Peripheral blood lymphocyte, eosinophil, and platelet counts could serve as predictors for disease recovery.
T146 25569-25708 Sentence denotes Progressive increases in the numbers of neutrophils, basophils, and IL-6 levels have been found to be associated with a fatal outcome [18].
T147 25709-25873 Sentence denotes Regardless of the disease severity during the initial clinical visit, the absolute lymphocyte count remained substantially lower in non-survivors than in survivors.
T148 25874-26037 Sentence denotes In addition, higher levels of neutrophil count, IL-6, pro-calcitonin, D-dimer, amyloid A protein, and C-reactive protein have been identified in deceased patients.
T149 26038-26210 Sentence denotes Marked lymphopenia has also been associated with a fatal outcome; the platelet count was found to be significantly lower in severe patients and even lower in non-survivors.
T150 26211-26373 Sentence denotes These findings provide a scientific basis for implementing therapeutic interventions targeted at restoring the inflammatory cell count and inflammatory mediators.
T151 26375-26409 Sentence denotes 8 Advances in clinical management
T152 26410-26547 Sentence denotes Similar to the cases of SARS and MERS infection, no effective therapies with proven efficacy have been developed as yet against COVID-19.
T153 26548-26717 Sentence denotes Therefore, recommendations for therapeutic intervention (including supportive therapy) have been based on extrapolation of published guidelines or expert consensus [78].
T154 26718-26823 Sentence denotes Most pharmacological treatments were extrapolated from treatments used during the SARS or MERS outbreaks.
T155 26824-26925 Sentence denotes The main findings from the clinical trials of COVID-19 in mainland China were summarized in Table 1 .
T156 26926-27178 Sentence denotes However, at the initial stage of the COVID-19, few clinical trial findings were available to inform clinicians regarding which medications had the greatest efficacy in treating patients with COVID-19 and whether targeted therapies existed for COVID-19.
T157 27179-27271 Sentence denotes Table 1 Summary of the main findings from the clinical trials of COVID-19 in mainland China.
T158 27272-27373 Sentence denotes Treatment Target population Reduces viral loads Improvement in clinical outcomes Main adverse effects
T159 27374-27555 Sentence denotes Lopinavir–ritonavir Severe COVID-19 Probable No significant acceleration in the time to clinical improvement Gastrointestinal tract symptoms; impairment of liver and kidney function
T160 27556-27558 Sentence denotes 


T161 27559-27731 Sentence denotes Remdesivir Severe COVID-19 Probable No significant acceleration in the time to clinical improvement Gastrointestinal tract symptoms; impairment of liver and kidney function
T162 27732-27734 Sentence denotes 


T163 27735-27888 Sentence denotes Favipiravir Severe COVID-19 Yes Increase the rate of improvement of chest computed tomographic findings Diarrhea; impairment of liver and kidney function
T164 27889-27891 Sentence denotes 


T165 27892-28069 Sentence denotes Chloroquine Moderate-to-severe COVID-19 Yes No significant acceleration in the time to clinical improvement Prolongation of Qt intervals; impairment of liver and kidney function
T166 28070-28072 Sentence denotes 


T167 28073-28197 Sentence denotes Convalescent plasma Critical illness of COVID-19 Yes No significant acceleration in the time to clinical improvement Unknown
T168 28198-28200 Sentence denotes 


T169 28201-28360 Sentence denotes Lianhuaqingwen capsule Moderate COVID-19 No Accelerate symptom improvement and increase the rate of symptom improvement impairment of liver and kidney function
T170 28361-28363 Sentence denotes 


T171 28364-28556 Sentence denotes Granulocyte colony stimulating factor Lymphopenic patients with COVID-19 No Decrease the likelihood of disease progression and increase the rate of symptom improvement Leukocytosis; osteodynia
T172 28557-28559 Sentence denotes 


T173 28560-28687 Sentence denotes Hydrogen oxygen mixed gas inhalation Symptomatic patients with COVID-19 Unknown Rapidly ameliorate respiratory symptoms Unknown
T174 28688-28915 Sentence denotes The fact that viral infection (including viral sepsis) [79] remains the key driver of the pathogenesis of COVID-19 has fueled research exploring the efficacy of antiviral medications in patients with severe or critical illness.
T175 28916-29221 Sentence denotes Taking into account the findings from in vitro [80], [81] and in vivo studies [82], [83], [84], lopinavir/ritonavir, remdesivir, and chloroquine (previously intended for the treatment of Ebola virus or human immunodeficiency virus (HIV) infections) have been repurposed for combating SARS-CoV-2 infection.
T176 29222-29468 Sentence denotes In a randomized clinical trial conducted in the early stage of the epidemic in China, patients with severe COVID-19 were assigned to receive standard-of-care alone or in combination with a 14-day course of treatment with lopinavir/ritonavir [82].
T177 29469-29629 Sentence denotes Neither the duration from randomization to clinical improvement nor the mortality rate differed significantly between the treatment group and the control group.
T178 29630-29821 Sentence denotes Subsequently, in another double-blinded clinical trial, patients with severe COVID-19 were randomly allocated to receive standard-of-care alone or in combination with 10 d of remdesivir [81].
T179 29822-29946 Sentence denotes Again, there was no significant difference in the time to clinical improvement, which was the primary endpoint of the study.
T180 29947-30071 Sentence denotes Neither lopinavir/ritonavir nor remdesivir markedly reduced viral loads, as monitored dynamically throughout the two trials.
T181 30072-30137 Sentence denotes Several reasons could have accounted for these negative findings.
T182 30138-30325 Sentence denotes It was notable that patients entered the clinical trials after a median duration of 11–13 d, which could have diminished the efficacy as compared with earlier administration of the drugs.
T183 30326-30475 Sentence denotes In fact, early administration of lopinavir/ritonavir (within 10 d of symptom onset) has been associated with a shorter course of viral shedding [83].
T184 30476-30762 Sentence denotes Moreover, both of these trials might have been underpowered for statistical analysis due to the emergency of the outbreak and the premature cessation of patient recruitment (there was difficulty in recruiting sufficient patients once the epidemiologic curve has flattened within Wuhan).
T185 30763-30881 Sentence denotes Nevertheless, the results did not preclude the use of lopinavir/ritonavir and remdesivir for severe cases of COVID-19.
T186 30882-31198 Sentence denotes Both trials indicated a numerically faster time to clinical improvement in the treatment group [82], [85] and, in a more recent clinical trial, administration of remdesivir for 10 d was associated with a faster time to clinical improvement and a lower mortality rate by 14 d, as compared with the placebo group [86].
T187 31199-31386 Sentence denotes Furthermore, when administered in combination with IFN-β and ribavirin, lopinavir/ritonavir has been associated with a marked reduction in viral loads compared with usual care alone [87].
T188 31387-31505 Sentence denotes Therefore, combined antiviral medications might have a role in accelerating viral clearance in patients with COVID-19.
T189 31506-31598 Sentence denotes Several other candidate medications have also been tested in clinical settings for COVID-19.
T190 31599-31695 Sentence denotes The effects of chloroquine and hydroxychloroquine on patients with COVID-19 remain under debate.
T191 31696-32007 Sentence denotes While chloroquine effectively reduced viral loads and achieved negative conversion of viral assays in hospitalized patients [88], the administration of hydroxychloroquine failed to increase the probability of achieving negative conversion of viral assays by 28 d in patients with mild-to-moderate COVID-19 [84].
T192 32008-32251 Sentence denotes In a pilot open-label study, favipiravir was shown to markedly shorten the time to viral clearance and increase the rate of improvement in chest imaging compared with a combination treatment with lopinavir/ritonavir plus IFN-α inhalation [89].
T193 32252-32356 Sentence denotes This finding added to the scientific evidence on candidate medications with potent antiviral activities.
T194 32357-32539 Sentence denotes Apart from heightened inflammatory response and viral infections, the aberrant immune response has been the canonical pathophysiological change leading to the poor clinical outcomes.
T195 32540-32677 Sentence denotes Lymphopenia was identified in up to 80% of patients with COVID-19 and was significantly correlated with the risk of mortality [39], [90].
T196 32678-32913 Sentence denotes Mobilizing the trafficking of lymphocytes to the peripheral blood with recombinant human granulocyte colony stimulating factor (rhG-CSF) might represent an appealing therapeutic approach for patients with COVID-19 who have lymphopenia.
T197 32914-33289 Sentence denotes A recent randomized clinical trial revealed that, despite the failure to accelerate clinical improvement, rhG-CSF markedly increased CD8+ T cell and natural killer (NK) cell count while reducing the risk of progression to critical illness or death compared with the usual care alone [91], particularly in patients with a blood lymphocyte count below 400 per cubic milliliter.
T198 33290-33389 Sentence denotes Mechanistic studies unraveling the mode of actions of rhG-CSF in patients with COVID-19 are needed.
T199 33390-33569 Sentence denotes Corticosteroids confer powerful anti-inflammatory effects and hence may ameliorate inflammation-mediated lung injury, thus preventing progression to respiratory failure and death.
T200 33570-33779 Sentence denotes In an observational study, the use of methylprednisolone was found to be associated with a markedly lower risk of mortality in patients with COVID-19 who had developed acute respiratory distress syndrome [92].
T201 33780-34197 Sentence denotes In an echo of these findings, a recent clinical trial recruiting hospitalized patients with COVID-19 showed that the oral or intravenous administration of dexamethasone (6 mg·d–1) for up to 10 d resulted in a markedly lower 28-day mortality in comparison with the control group among patients receiving invasive mechanical ventilation at randomization or receiving oxygen without invasive mechanical ventilation [93].
T202 34198-34347 Sentence denotes The benefit was also clear in patients who were being treated more than 7 d after symptom onset, when inflammatory lung damage became more prominent.
T203 34348-34517 Sentence denotes However, no significant effects were observed among patients not receiving any respiratory support, which was in line with the findings from a recent meta-analysis [94].
T204 34518-34601 Sentence denotes Targeted therapy has been very limited among critically ill patients with COVID-19.
T205 34602-34771 Sentence denotes By extrapolating from experience in managing patients with SARS and MERS, efforts have been made to treat critically ill patients with COVID-19 with convalescent plasma.
T206 34772-34934 Sentence denotes In a pilot single-arm study with five patients, convalescent plasma with high-titers neutralizing antibodies appeared to improve the overall clinical status [95].
T207 34935-35119 Sentence denotes On the basis of usual care in a randomized clinical trial, convalescent plasma therapy did not confer additional benefits in terms of the time to clinical improvement within 28 d [69].
T208 35120-35469 Sentence denotes However, convalescent plasma did show clinical benefits in the subgroup of severe patients, albeit not in critically ill patients. [96] Nevertheless, the bona fide therapeutic benefits of convalescent plasma cannot be precluded, as the trial was underpowered for analysis due to the difficulty in recruiting patients at later stages of the outbreak.
T209 35470-35676 Sentence denotes Although there was no statistically significant difference, a possible clinical benefit was observed for patients with severe COVID-19 but not for patient subgroups with a life-threatening level of illness.
T210 35677-35794 Sentence denotes Several studies in China have observed disseminated intravascular coagulation (DIC) in most non-survivors [97], [98].
T211 35795-35978 Sentence denotes Significantly higher levels of D-dimer and fibrin degradation products, as well as a longer prothrombin time, suggested that coagulopathy might be associated with poor prognosis [99].
T212 35979-36075 Sentence denotes The dynamic changes in D-dimer levels correlated positively with the prognosis of COVID-19 [98].
T213 36076-36324 Sentence denotes Patients with a sepsis-induced coagulopathy score greater than or equal to 4, or a D-dimer level greater than six times the upper limit of normal, exhibited a lower mortality rate when receiving low molecular weight heparin for 7 d or longer [100].
T214 36325-36542 Sentence denotes When given anticoagulant treatment, attention should be paid to avoid the development of diffuse alveolar hemorrhage, which is a life-threatening complication that may occur after the administration of warfarin [101].
T215 36543-36634 Sentence denotes Non-pharmacological interventions might have a role in the clinical management of COVID-19.
T216 36635-36759 Sentence denotes Patients with COVID-19 have been characterized by increasingly laborious breathing as a result of greater airway resistance.
T217 36760-36947 Sentence denotes Due to smaller molecular weight, helium–oxygen mixed gas has been applied to ameliorate dyspnea in patients with respiratory failure [102] and chronic obstructive pulmonary disease [103].
T218 36948-37076 Sentence denotes However, due to the low cost-effectiveness ratio, helium–oxygen mixed gas has not been extensively adopted in clinical practice.
T219 37077-37265 Sentence denotes In contrast, hydrogen/oxygen mixed gas (H2–O2) could be generated via the direct electrolysis of water with the use of a commercialized instrument, and could be adopted for home use [104].
T220 37266-37385 Sentence denotes H2–O2 inhalation has recently been shown to markedly ameliorate dyspnea in patients with central airway stenosis [104].
T221 37386-37523 Sentence denotes It is essential to determine whether H2–O2 inhalation would result in a major clinical improvement in symptomatic patients with COVID-19.
T222 37524-37832 Sentence denotes In an open-label multicenter clinical trial, H2–O2 inhalation led to a marked and rapid amelioration of the key respiratory symptoms (including dyspnea, chest pain, and cough scale) and improved the resting oxygen saturation and disease severity in patients with COVID-19 who had dyspnea at enrollment [105].
T223 37833-38060 Sentence denotes Based on these findings, H2–O2 inhalation has been endorsed by the National Health Commission of the People’s Republic of China for COVID-19 patients with dyspnea or those in facilities without sufficient oxygen supplies [106].
T224 38061-38142 Sentence denotes Traditional Chinese medicine has been a treasure trove of complementary medicine.
T225 38143-38260 Sentence denotes Efforts have been made to explore the effects of a panel of herbal formulas for the management of SARS and influenza.
T226 38261-38376 Sentence denotes For example, Lianhuaqingwen (LH) capsule has been approved for the treatment of mild-to-moderate SARS [107], [108].
T227 38377-38601 Sentence denotes Therefore, priority could be given to the development of LH capsules, because off label marketing medications would help reduce the time for research and development (R&D) against other candidate medications in the pipeline.
T228 38602-38693 Sentence denotes In an in vitro study, LH capsule yielded potent antiviral effects against SARS-CoV-2 [109].
T229 38694-38870 Sentence denotes Based on these observations, a multicenter randomized clinical trial was undertaken to determine the effectiveness of LH capsule plus usual care, versus usual care alone [110].
T230 38871-39107 Sentence denotes At Day 14, treatment with LH capsule was associated with a significantly higher rate of symptom recovery and a markedly shortened time to symptom recovery, although no differences in the viral loads were observed between the two groups.
T231 39108-39357 Sentence denotes It is notable that these therapeutic effects might not be related to the antiviral effects because the serum concentrations of LH capsule were markedly lower than those reported in the in vitro study in which the antiviral effects were potent [109].
T232 39358-39518 Sentence denotes LH capsules also exhibited anti-inflammatory and anti-oxidative effects via suppressing cytokine release, according to the results from an in vitro study [110].
T233 39519-39703 Sentence denotes These findings have resulted in the endorsement of LH capsules by the National Health Commission of the People’s Republic of China for the treatment of mild-to-moderate COVID-19 [106].
T234 39704-39880 Sentence denotes Apart from LH capsules, other candidate herbal formulas such as Xuebijing injection and Liu Shen capsule have demonstrated antiviral activities against SARS-CoV-2 [111], [112].
T235 39881-40054 Sentence denotes Multicenter clinical trials to determine the efficacy of these herbal formulas (i.e., Xuebijing injection for severe or critically ill cases with COVID-19) are now underway.
T236 40056-40078 Sentence denotes 9 Vaccine development
T237 40079-40217 Sentence denotes Despite tremendous global efforts to contain the outbreak and rapid advances in therapeutics, few targeted approaches have been available.
T238 40218-40420 Sentence denotes Given the rapid transmission and the rapid decay of antibody titers [113], vaccines that can induce strong anti-SARS-CoV-2 immune responses are urgently needed to achieve global containment of COVID-19.
T239 40421-40524 Sentence denotes Vaccine development has benefited from the early release of the complete genome sequence of SARS-CoV-2.
T240 40525-40694 Sentence denotes As of 3 September 2020, according to the WHO, 33 vaccine candidates are at different stages of clinical development, six of which are at phase III clinical trials [114].
T241 40695-40804 Sentence denotes On 22 July 2020, China approved the use of two inactivated COVID-19 vaccines developed by Sinovac Biotech Co.
T242 40805-40816 Sentence denotes Ltd. [115].
T243 40817-40938 Sentence denotes Another adenovirus vector-based SARS-CoV-2 vaccine was approved by the administrative office of Russia on 10 August 2020.
T244 40939-41038 Sentence denotes U.S. authorities have recently announced the pending approval of a vaccine by the end of this year.
T245 41039-41243 Sentence denotes In public health emergencies, such as the COVID-19 pandemic, regulators are expected to act quickly to support accelerated vaccine development through the introduction of increased regulatory flexibility.
T246 41244-41494 Sentence denotes To guide the accelerated vaccine development and approval for COVID-19, the Chinese regulatory agencies and the National Medical Products Administration (NMPA) have issued seven guidelines since March 2020 to provide a roadmap and requirements [116].
T247 41495-41644 Sentence denotes Moreover, the Chinese NMPA has formulated a special scheme to synchronize the protocol reviewing process with the research and development processes.
T248 41645-41831 Sentence denotes Consequently, completion of the vaccine development and the review may take place simultaneously so that the vaccine development can proceed to clinical application without major delays.
T249 41832-41995 Sentence denotes For example, the NMPA completed the review process of the Sinopharm COVID-19 vaccine application within just 24 h, although such a review would normally take 60 d.
T250 41996-42230 Sentence denotes Thus far, there have been ten Chinese COVID-19 vaccine candidates in the pipeline of clinical trials [114], [117], [118], [119], [120], [121], [122], [123], in four of which international phase III clinical trials have been initiated.
T251 42231-42330 Sentence denotes Furthermore, more than 21 preclinical projects may have the potential to move into clinical trials.
T252 42331-42578 Sentence denotes Nearly all of the current human vaccines are based on two major platforms: the virus-based (inactivated/attenuated) vaccine platform and the recombinant protein-based (subunit/virus-like particle (VLP)) vaccine platform [120], [124], [125], [126].
T253 42579-42705 Sentence denotes Four “inactivated virus vaccines” are in post-phase II clinical trials, and two of these have been approved for emergency use.
T254 42706-42906 Sentence denotes This major achievement from the “inactivated virus vaccine platform” in China was made possible by the early development of the inactivated enterovirus 71 and inactivated poliovirus vaccines in China.
T255 42907-43188 Sentence denotes A replication-defective human adenovirus type-5-based COVD-19 vaccine encoding the full S protein of SARS-CoV-2 as a subunit-based vaccine was found to successfully elicit cellular immune responses via single-dose inoculation through the intramuscular or intranasal administration.
T256 43189-43298 Sentence denotes This vaccine could effectively prevent SARS-CoV-2 infection in the higher and lower respiratory tracts [127].
T257 43299-43460 Sentence denotes Moreover, mucosal vaccination might be more effective in preventing viral replication in the upper respiratory tract, as compared with intramuscular vaccination.
T258 43462-43473 Sentence denotes 10 Summary
T259 43474-43643 Sentence denotes The COVID-19 pandemic is an unprecedented global threat that has resulted in substantial morbidity and mortality and has dramatically disrupted socioeconomic activities.
T260 43644-43837 Sentence denotes Building on its experience in fighting against SARS and MERS, China has quickly adopted effective measures to curb the surge of cases and ultimately contain the epidemic (as shown in Table 2 ).
T261 43838-44022 Sentence denotes The principles of early detection, early isolation, early management, and early prevention are the key steps to achieve effective containment of this rapidly spreading global pandemic.
T262 44023-44128 Sentence denotes Table 2 Summary of the advances and interventions contributing to COVID-19 containment in mainland China.
T263 44129-44158 Sentence denotes Advance/intervention Measures
T264 44159-44247 Sentence denotes Non-pharmaceutical interventions Announcing the potential of human-to-human transmission
T265 44248-44309 Sentence denotes Lockdown of Wuhan and other adjacent cities in Hubei province
T266 44310-44356 Sentence denotes Imposing restrictions on all social activities
T267 44357-44413 Sentence denotes Enforcing national and international travel restrictions
T268 44414-44416 Sentence denotes 


T269 44417-44528 Sentence denotes Clinical characterization and epidemiologic advances Comprehensive characterization of the viral ultrastructure
T270 44529-44608 Sentence denotes Revealing the route for SARS-CoV-2 transmission (including fomite transmission)
T271 44609-44678 Sentence denotes Defining the clinical and epidemiological characteristics of COVID-19
T272 44679-44737 Sentence denotes Demonstration of the immune regulation network of COVID-19
T273 44738-44820 Sentence denotes AI prediction of the epidemics trend of COVID-19 under public health interventions
T274 44821-44823 Sentence denotes 


T275 44824-45052 Sentence denotes Therapeutic interventions Validation of the efficacy and safety of repurposed drugs, especially traditional Chinese medicines (Lianhuaqingwen capsule, Xuebijing injection, and Liu Shen capsule), for accelerating symptom recovery
T276 45053-45287 Sentence denotes Validation of the efficacy and safety of H2–O2 inhalation and endorsement by the National Health Commission of the People’s Republic of China for COVID-19 patients with dyspnea or those in facilities without sufficient oxygen supplies
T277 45288-45403 Sentence denotes Validation of the efficacy and safety of granulocyte colony stimulating factor for patients with marked lymphopenia
T278 45404-45406 Sentence denotes 


T279 45407-45478 Sentence denotes Diagnosis Development of PCR- and serology-based rapid detection method
T280 45479-45573 Sentence denotes Development of the portable, laboratory-instrument-independent CRISPR/Cas method for detection
T281 45574-45576 Sentence denotes 


T282 45577-45696 Sentence denotes Prognostic prediction Identification of hematologic and immunologic biomarkers that correlate with the disease severity
T283 45697-45784 Sentence denotes Establishment of AI model to predict the likelihood of developing into critical illness
T284 45786-45819 Sentence denotes Declaration of Competing Interest
T285 45820-45990 Sentence denotes The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
T286 45992-46008 Sentence denotes Acknowledgements
T287 46009-46154 Sentence denotes Special thanks are given to Tao Peng, Jin-Cun Zhao, Zi-Feng Yang, Jian Song, and Jun-Hou Zhou for manuscript revision and information collection.
T288 46155-46235 Sentence denotes Project supported by the National Natural Science Foundation of China (Grant No.
T289 46236-46323 Sentence denotes 81761128014 ) and the National Key Research and Development Program of China (Grant No.
T290 46324-46340 Sentence denotes 2020YFC0842400).
T291 46342-46375 Sentence denotes Compliance with ethics guidelines
T292 46376-46500 Sentence denotes Wei Liu, Wei-Jie Guan, and Nan-Shan Zhong declare that they have no conflict of interest or financial conflicts to disclose.