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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Role of anaesthesiologists during the coronavirus disease 2019 outbreak in China</title><author><name sortKey="Yang, Manping" sort="Yang, Manping" uniqKey="Yang M" first="Manping" last="Yang">Manping Yang</name></author><author><name sortKey="Dong, Hailong" sort="Dong, Hailong" uniqKey="Dong H" first="Hailong" last="Dong">Hailong Dong</name></author><author><name sortKey="Lu, Zhihong" sort="Lu, Zhihong" uniqKey="Lu Z" first="Zhihong" last="Lu">Zhihong Lu</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32307116</idno><idno type="pmc">7144667</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144667</idno><idno type="RBID">PMC:7144667</idno><idno type="doi">10.1016/j.bja.2020.03.022</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000340</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000340</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Role of anaesthesiologists during the coronavirus disease 2019 outbreak in China</title><author><name sortKey="Yang, Manping" sort="Yang, Manping" uniqKey="Yang M" first="Manping" last="Yang">Manping Yang</name></author><author><name sortKey="Dong, Hailong" sort="Dong, Hailong" uniqKey="Dong H" first="Hailong" last="Dong">Hailong Dong</name></author><author><name sortKey="Lu, Zhihong" sort="Lu, Zhihong" uniqKey="Lu Z" first="Zhihong" last="Lu">Zhihong Lu</name></author></analytic><series><title level="j">BJA: British Journal of Anaesthesia</title><idno type="ISSN">0007-0912</idno><idno type="eISSN">1471-6771</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y. 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Zhang</name></author><author><name sortKey="Zhou, X Y" uniqKey="Zhou X">X.Y. Zhou</name></author><author><name sortKey="Qiu, Y R" uniqKey="Qiu Y">Y.R. Qiu</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Fan, E" uniqKey="Fan E">E. Fan</name></author><author><name sortKey="Brodie, D" uniqKey="Brodie D">D. Brodie</name></author><author><name sortKey="Slutsky, A S" uniqKey="Slutsky A">A.S. Slutsky</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ahn, J H" uniqKey="Ahn J">J.H. Ahn</name></author><author><name sortKey="Kwon, E" uniqKey="Kwon E">E. Kwon</name></author><author><name sortKey="Lee, S Y" uniqKey="Lee S">S.Y. Lee</name></author><author><name sortKey="Hahm, T S" uniqKey="Hahm T">T.S. Hahm</name></author><author><name sortKey="Jeong, J S" uniqKey="Jeong J">J.S. Jeong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guan, W J" uniqKey="Guan W">W.J. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Br J Anaesth</journal-id><journal-id journal-id-type="iso-abbrev">Br J Anaesth</journal-id><journal-title-group><journal-title>BJA: British Journal of Anaesthesia</journal-title></journal-title-group><issn pub-type="ppub">0007-0912</issn><issn pub-type="epub">1471-6771</issn><publisher><publisher-name>British Journal of Anaesthesia. Published by Elsevier Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32307116</article-id><article-id pub-id-type="pmc">7144667</article-id><article-id pub-id-type="publisher-id">S0007-0912(20)30197-5</article-id><article-id pub-id-type="doi">10.1016/j.bja.2020.03.022</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Role of anaesthesiologists during the coronavirus disease 2019 outbreak in China</article-title></title-group><contrib-group><contrib contrib-type="author" id="au1"><name><surname>Yang</surname><given-names>Manping</given-names></name></contrib><contrib contrib-type="author" id="au2"><name><surname>Dong</surname><given-names>Hailong</given-names></name></contrib><contrib contrib-type="author" id="au3"><name><surname>Lu</surname><given-names>Zhihong</given-names></name><email>deerlu23@163.com</email><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1">Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an Shaanxi, China</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author. <email>deerlu23@163.com</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>9</day><month>4</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>9</day><month>4</month><year>2020</year></pub-date><history><date date-type="received"><day>10</day><month>3</month><year>2020</year></date><date date-type="rev-recd"><day>16</day><month>3</month><year>2020</year></date><date date-type="accepted"><day>17</day><month>3</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>British Journal of Anaesthesia</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><kwd-group id="kwrds0010"><title>Keywords</title><kwd>airway management</kwd><kwd>anaesthesiologist</kwd><kwd>China</kwd><kwd>critical care</kwd><kwd>coronavirus</kwd><kwd>COVID-19</kwd><kwd>infection control</kwd><kwd>rapid response team</kwd></kwd-group></article-meta><notes><p id="misc0010"><italic>Handling editor</italic><italic>:</italic></p></notes></front><body><p id="p0010">From December 2019, a respiratory disease caused by the novel coronavirus severe acute respiratory syndrome (SARS-CoV-2) was traced to Wuhan, China, and transmitted to more than 143 countries. On January 30, 2020, the WHO designated the novel coronavirus pneumonia outbreak as a global health emergency and named it coronavirus disease 2019 (COVID-19). As of March 15, 2020, a total of 81 048 confirmed COVID-19 cases had been reported in China.<xref rid="bib1" ref-type="bibr"><sup>1</sup></xref> Starting on January 24, 2020, the traditional Chinese New Year’s eve, more than 42 000 healthcare providers from all over China gathered in Wuhan to support the local healthcare system (data from National Health Commission of China). Among them, more than 1000 were anaesthesiologists (data from the Chinese Society of Anaesthesiology [CSA]). In the battle against COVID-19, Chinese anaesthesiologists explored new working models to improve patient outcomes and minimise the risk of contracting COVID-19.</p><sec id="sec1"><title>Airway management team</title><p id="p0015">COVID-19 has similarities and differences with SARS and Middle East respiratory syndrome (MERS) in terms of infectious period, transmissibility, clinical severity, and extent of community spread (<xref rid="tbl1" ref-type="table">Table 1</xref>). With the increasing knowledge of the clinical progress of COVID-19 cases, the timing of invasive ventilation changed. As indicated by CT results,<xref rid="bib9" ref-type="bibr"><sup>9</sup></xref> 5–8 days after onset of initial symptoms the infection rapidly aggravated and extended to a bilateral multi-lobar pulmonary effusion and consolidation. Although noninvasive ventilation temporarily improves oxygenation in COVID-19 patients, it may not necessarily change the natural course of acute respiratory distress syndrome (ARDS).<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref> On February 18, 2020, the state council of China issued ‘Question and answers of tracheal intubation for novel coronavirus pneumonia cases’, in which the criteria for tracheal intubation were defined as oxygenation index <150 mm Hg after at least 2 h of continuous positive airway pressure (CPAP) with 100% oxygen, and it was recommended that intubation be scheduled rather than emergent. According to the new criteria, patients would receive intubation and ventilation therapy earlier. As a result, more patients needed intubation. In many hospitals, airway management teams consisting of skilled anaesthesiologists were established to meet the need for intubation.<table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>Comparison of COVID–19, SARS and MERS. <sup>∗</sup>Data as of March 15, 2020. <sup>†</sup>Data up to 2003. <sup>‡</sup>Data up to November 2019. COVID, coronavirus disease; ARDS, acute respiratory syndrome; MERS, Middle East respiratory syndrome; GGO, ground-glass opacity; SARS, severe acute respiratory syndrome.</p></caption><alt-text id="alttext0010">Table 1</alt-text><table frame="hsides" rules="groups"><thead><tr><th>Characteristics</th><th>COVID-19</th><th>SARS</th><th>MERS</th></tr></thead><tbody><tr><td>Clinical symptoms</td><td>Presence or absence of cough, sore throat, shortness of breath, fever, myalgia</td><td>Cough, dyspnoea, fever, chill, malaise, headache, diarrhoea</td><td>Sore throat, dry cough, dyspnoea, fever, chill, rigors</td></tr><tr><td>Epidemiology</td><td>R<sub>0</sub>: 2.2–6.49, mean 3.28<sup>2</sup><break></break>Pre-symptomatic transmission exists</td><td>R<sub>0</sub>: 2–5<break></break>Peak viral shedding occurs after patients were already quite ill</td><td>R<sub>0</sub><1</td></tr><tr><td>Mortality</td><td>5735/15 3517 (3.7%)<sup>a1</sup></td><td>774/8096 (9.6%)<sup>†3</sup></td><td>858/2494 (34.4%)<sup>‡4</sup></td></tr><tr><td>CT results<xref rid="bib2" ref-type="bibr"><sup>2</sup></xref></td><td>Multifocal patchy GGOs with subpleural distribution, progresses into diffuse heterogeneous consolidation with GGO</td><td>Subpleural GGO and consolidation, prominent lower lobe involvement, interlobular septal and intralobular septal thickening</td><td>Bilateral, basilar and subpleural airspace, extensive GGO and occasional septal thickening and pleural effusions</td></tr><tr><td colspan="4">Pathology</td></tr><tr><td>Lung</td><td>Early phase<xref rid="bib5" ref-type="bibr"><sup>5</sup></xref>: lung oedema, proteinaceous exudate with globules, patchy inflammatory cellular infiltration<break></break>Late phase<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref>: pulmonary oedema with hyaline membrane formation, interstitial mononuclear inflammatory infiltrates, viral cytopathic-like changes in the intra-alveolar spaces</td><td>Bilateral lung extensive consolidation, localised haemorrhage and necrosis, desquamative pulmonary alveolitis and bronchitis, proliferation and desquamation of alveolar epithelial cells<break></break>Viral particles in lung tissue<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref></td><td>Necrotising pneumonia, pulmonary diffuse alveolar damage<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref></td></tr><tr><td>Other organs</td><td>Mild interstitial mononuclear inflammatory infiltrates in the heart<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref><break></break>Influence on other organs still not defined<xref rid="bib8" ref-type="bibr"><sup>8</sup></xref></td><td>Massive necrosis of splenic lymphoid tissue; systemic vasculitis; thrombosis in small veins; degeneration and necrosis of parenchyma cells in the lung, liver, kidney, heart, and adrenal gland<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref></td><td>Acute kidney injury, portal and lobular hepatitis and myositis with muscle atrophic changes. Brain and heart were histologically unremarkable<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref></td></tr></tbody></table></table-wrap></p><p id="p0020">Depending on the anaesthesiologists available, the airway management team size was 4–18 people. Airway management team members worked in rotation, with only one to two anaesthesiologists in the isolation ward at a time. The minimal size helps avoid unnecessary viral exposure. An intubation cart containing modular packs of medicines and materials was kept in the ward to minimise the traffic of people bringing materials into the room. Videolaryngoscopy with a replaceable blade was widely used to avoid placing the face of the anaesthesiologist close to the patient. Light wand, laryngeal mask airway (LMA), flexible bronchoscope, and cricothyroid puncture kit were also available in the cart in case of difficult intubation. Protocols for unanticipated difficult airway were followed, highlighting the role of an intubating LMA.<xref rid="bib11" ref-type="bibr"><sup>11</sup></xref></p><p id="p0025">Any known or suspected COVID-19 patient must be regarded as ultra-high risk. Tracheal intubation of these patients is a high-risk aerosol-generating airway procedure requiring standard grade 3 personal protective equipment (PPE)<xref rid="bib4" ref-type="bibr"><sup>4</sup></xref> including an N95 mask, goggles, face shield, double gown, double gloves, protective overshoes, and a powered respirator (powered air purifying respirators).</p><p id="p0030">The Airway Management group of the CSA issued ‘Expert Recommendations for Tracheal Intubation in Critically ill Patients with Novel Coronavirus Disease 2019’ on February 22, 2020.<xref rid="bib4" ref-type="bibr"><sup>4</sup></xref> According to these recommendations and current evidence, principles include minimising generation of aerosols (see Supplemental Digital Content 1 for guidance for tracheal intubation of COVID-19 cases).<sup>11 12</sup> Bag-mask ventilation before intubation, patient coughing during laryngoscopy or intubation, and inadequate sedation putting the patient at risk of agitation can generate aerosols. With adequate pre-oxygenation, bag-mask ventilation can ideally be avoided. CPAP with 100% oxygen for 5 min is recommended for pre-oxygenation. If available, high-flow nasal cannula (HFNC) delivery systems can be used for pre-oxygenation, although these can increase the risk of viral spread through aerosol generation.<xref rid="bib13" ref-type="bibr"><sup>13</sup></xref> To minimise this risk, the mouth and nose of the patient can be covered with normal saline saturated gauze during pre-oxygenation. To avoid agitation and cough, intubations are best done using a rapid sequence intubation technique.<sup>11 12</sup> Midazolam, propofol, and etomidate can be used depending on the patient’s condition. After sedation, at least 0.9 mg kg<sup>–1</sup> of rocuronium or 1 mg kg<sup>–1</sup> of succinylcholine should be used. A hydrophobic filter should be attached to the resuscitation bag, between the mask or tracheal tube (TT) and the bag. When difficult airway is anticipated, flexible bronchoscopic intubation can be performed using a videobronchoscope. Awake fibreoptic intubation should be avoided to decrease exposure to aerosols.<xref rid="bib12" ref-type="bibr"><sup>12</sup></xref> If unanticipated difficult airway occurs, an intubating LMA and surgical airway can be considered.</p><p id="p0035">Extubation with minimal agitation and coughing is important for both ICU patients and surgical patients. Careful suctioning with a closed sputum suction device before return of consciousness can be important.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref> A recent meta-analysis<xref rid="bib15" ref-type="bibr"><sup>15</sup></xref> reported that procedures (including dexmedetomidine, remifentanil, fentanyl, and lidocaine i.v., intracuff, tracheal, or topical) were all better than placebo in reducing moderate to severe emergence cough, with dexmedetomidine ranked as the most effective. Dexmedetomidine and lidocaine by various routes have been used in COVID-19 cases. Extubation before return of consciousness is recommended for patients without a difficult airway.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref> However, a device for reintubation should be available. Extubation without removal of the filter is important.<xref rid="bib11" ref-type="bibr"><sup>11</sup></xref></p></sec><sec id="sec2"><title>Intensive care</title><p id="p0040">Anaesthesiologists in surgical ICUs (SICU) and anaesthesia ICUs (AICU) contribute considerably to the management of COVID-19 cases. At Jinyintan Hospital in Wuhan,<xref rid="bib16" ref-type="bibr"><sup>16</sup></xref> of 17 patients who developed ARDS, 11 worsened within a short period. At Zhongnan Hospital in Wuhan,<xref rid="bib17" ref-type="bibr"><sup>17</sup></xref> 47.2% of patients in the ICU received invasive ventilation and four were switched to extracorporeal membrane oxygenation (ECMO). Preprint reports of deaths revealed that durations from initial symptoms to death were short (15 days; inter-quartile range, 11–20 days).<xref rid="bib18" ref-type="bibr"><sup>18</sup></xref> Autopsy results of COVID-19 cases indicated very sticky mucus in the small airways.<xref rid="bib19" ref-type="bibr"><sup>19</sup></xref> A high percentage of patients in the ICU require ‘active’ invasive airway intervention, and critically ill patients may benefit from ECMO, two fields that anaesthesiologists are expert in.</p><p id="p0045">During the outbreak, critical care services in China were confronted with a rapid increase in demand for resources. All hospitals and other organisations were involved in the care for COVID-19 cases. In many hospitals, airway team members took charge of ventilation management after tracheal intubation. Once intubated, classical ventilation strategies<sup>13 19</sup> have been effective in critically ill COVID-19 patients, including lung protective mechanical ventilation strategies and prone position ventilation. Lung protective mechanical ventilation strategies include low target tidal volume (6 ml kg<sup>–1</sup> predicted body weight), plateau pressure ≤30 cm H<sub>2</sub>O, target SaO<sub>2</sub> 88–95%, pH ≥7.25, and intermittent recruitment manoeuvres.<xref rid="bib20" ref-type="bibr"><sup>20</sup></xref></p><p id="p0050">Ultrasonography, another technique widely used in the field of anaesthesiology during the past decade in China, was very useful in the management of critically ill COVID-19 patients. Anaesthesiologists usually use ultrasound for nerve blocks, vascular puncture and emergency screening of the chest and abdomen. Given potential delay in obtaining examinations including chest radiography for patients under airborne isolation, portable ultrasonography is useful to quickly assist in the diagnosis of conditions such as pleural effusion and pneumothorax.<xref rid="bib13" ref-type="bibr"><sup>13</sup></xref> PPE, especially purifying respirators, can preclude procedures such as auscultation. Ultrasonography can also be used in airway evaluation and determination of TT depth.<xref rid="bib21" ref-type="bibr"><sup>21</sup></xref></p></sec><sec id="sec3"><title>Fast response resuscitation team</title><p id="p0055">Based on experience during the SARS outbreak,<xref rid="bib13" ref-type="bibr"><sup>13</sup></xref> fast response resuscitation teams made up mostly of anaesthesiologists were organised in some hospitals in Wuhan. Members of the resuscitation team stayed on call near the isolation area. During initial resuscitation efforts by the first responder, fast response resuscitation team members would don PPE and take charge of the resuscitation. Like the airway management cart, the resuscitation cart was equipped with modular medicine and equipment to avoid unnecessary traffic. The team size is typically minimised to four to avoid unnecessary viral exposure.</p></sec><sec id="sec4"><title>Clinical anaesthesia</title><p id="p0060">During the outbreak of COVID-19, the most important consideration for clinical anaesthesia is infection control. By February 10, 2020, most hospitals in China accepted emergency cases only. However, recently elective surgeries have increased rapidly. Besides Wuhan, many other areas could also have many infected people. Thus, anaesthesiologists play an essential and demanding role in the preoperative evaluation of COVID-19 infection risk (Supplemental Digital Content 2 shows a fast triage flowchart). At present, suspicion for infection with COVID-19 requires two symptoms with an epidemiological link, or three without epidemiological link.<xref rid="bib19" ref-type="bibr"><sup>19</sup></xref> Epidemiological links include travel within 14 days to affected areas, or close contact within 14 days of illness onset with a confirmed patient, or close contact with a person having fever and respiratory symptoms and travel to an affected area within 14 days of illness onset.<xref rid="bib19" ref-type="bibr"><sup>19</sup></xref> Fever may not be present in all patients. The absence of fever in COVID-19 is more frequent than in SARS and MERS, so appropriate infectious control precautions should be in place even in those without typical symptoms.<xref rid="bib22" ref-type="bibr"><sup>22</sup></xref> With the spread of the virus to more areas and countries, anaesthesiologists all over the world may face the challenge of weighing the risk of infection and the need for medical care of patients.</p></sec><sec id="sec5"><title>Role of academic anaesthesiology organisations in China</title><p id="p0065">Chinese academic anaesthesiology organisations immediately reacted to the COVID-19 outbreak, focusing on improving medical care and protecting anaesthesiologists.</p><p id="p0070">Psychological support for front-line anaesthesiologists. In the care of COVID-19 patients, anaesthesiologists are vulnerable to both infection and mental health problems. They may experience depression by the situation, fear of contagion, and fear of spreading the virus to their family and others. The heavy workload and discomfort of wearing PPE for long durations can worsen the depression. Healthcare workers in high-risk clinical settings such as SARS units had substantially more post-traumatic stress symptoms.<xref rid="bib23" ref-type="bibr"><sup>23</sup></xref> On February 13, 2020, the CSA established a platform to provide psychological support for healthcare providers, especially for front-line anaesthesiologists and their families. More than 20 psychologists provided consultations for anaesthesiologists who took care of COVID-19 patients.</p><p id="p0075">Continuous update of information on COVID-19. Clear communication with regular and accurate updates about the COVID-19 outbreak were provided to anaesthesiologists in order to improve quality of care and to address their sense of uncertainty and fear. The CSA and Chinese Association of Anaesthesiologists (CAA) issued and updated a series of practice recommendations and consensus guidelines, covering facility organisation and anaesthetic care during the outbreak of COVID-19 pneumonia. One of the most recent was expert recommendations for anaesthesia and infection control in elective surgeries during recovery after outbreak.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref> The CSA also established a platform for information on COVID-19 patient care.<xref rid="bib24" ref-type="bibr"><sup>24</sup></xref> The most frequently asked questions about COVID-19 are continuously collected and answered.</p><p id="p0080">Online discussion of anaesthesia care by experts and front-line anaesthesiologists. The CSA and CAA organised online discussions on various topics including airway management, infection control, and medical care of specific populations, such as parturients, during the outbreak of COVID-19. Experts with experiences in H1N1, SARS, and Ebola management and front-line anaesthesiologists were invited into the discussions.</p><p id="p0085">In conclusion, Chinese anaesthesiologists were essential to various critical aspects of the response to the outbreak of COVID-19. Earlier invasive ventilation, establishment of airway management teams and fast response resuscitation teams, and use of point-of-care ultrasonography were major contributions. With the change in epidemiologic characteristics of COVID-19 patients, anaesthesiologists took on the responsibility of infection control as well.</p></sec><sec id="sec6"><title>Authors’ contributions</title><p id="p0090">Conception: ZL, HD.</p><p id="p0095">Data collection: ZL, MY.</p><p id="p0100">Writing of the draft: MY.</p><p id="p0105">Revision of the manuscript: ZL, HD.</p><p id="p0110">All authors approved the final version of the manuscript.</p></sec><sec sec-type="COI-statement" id="sec7"><title>Declaration of interest</title><p id="p0115">The authors declare that they have no conflict of interest.</p></sec><sec id="sec8"><title>Funding</title><p id="p0120">National Science Foundation of China (No. 81871028) and Nature Science Foundation of Shaanxi Province (No. 2018-SF-277).</p></sec></body><back><ref-list id="cebib0010"><title>References</title><ref id="bib1"><label>1</label><mixed-citation publication-type="other" id="sref1">World Health Organization. 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