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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991417</article-id><article-id pub-id-type=\"pmc\">PMC7523801</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08211</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022226</article-id><article-id pub-id-type=\"art-access-id\">22226</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3700</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Psychological effect of comprehensive nursing intervention in elderly patients with perforated peptic ulcer</article-title><subtitle>A protocol of systematic review</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Chen</surname><given-names>Bing</given-names></name><degrees>MB</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Xiu-Yu</given-names></name><degrees>MB</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Hong-Mei</given-names></name><degrees>MB</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Bai-Jun</given-names></name><degrees>MB</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0001-5042-2090</contrib-id><name><surname>Wang</surname><given-names>Ying-Ting</given-names></name><degrees>MB</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Gastroenterology, The Second Affiliated Hospital of Mudanjiang Medical University</aff><aff id=\"aff2\"><label>b</label>Department of Emergency, Mudanjiang Forestry Central Hospital</aff><aff id=\"aff3\"><label>c</label>Department of Geriatrics, The Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Ying-Ting Wang, Department of Geriatrics, The Second Affiliated Hospital of Mudanjiang Medical University, No. 15, Dongxiaoyun Street, Aimin District, Mudanjiang 157000, China (e-mail: <email>chaoben2166425@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22226</elocation-id><history><date date-type=\"received\"><day>17</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>19</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22226.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>This study aims to assess the psychological effect of comprehensive nursing intervention (CNI) in elderly patients with perforated peptic ulcer (PPU).</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>This protocol will search all potential studies from inception to the present in electronic database sources (Cochrane Library, PUBMED, EMBASE, PsycINFO, WANGFANG, CBM, and CNKI), and other sources (such as clinical trial registry, and conference proceedings). We will not apply limitations to language and publication status. Two independent authors will scan literature, extract data, and appraise study quality. A third author will be invited to solve any disagreements between 2 authors. We will utilize RevMan 5.3 software for statistical analysis. If necessary, we will also carry out subgroup group, sensitivity analysis, and reporting bias.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>This protocol will summarize high quality evidence to evaluate the psychological effect of CNI in elderly patients with PPU.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>The results of this study may provide evidence to determine whether CNI is effective or not on psychological effect in elderly patients with PPU.</p></sec><sec><title>Study registration:</title><p>INPLASY202080069.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>anxiety</kwd><kwd>comprehensive nursing intervention</kwd><kwd>depression</kwd><kwd>perforated peptic ulcer</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Mudanjiang Science and Technology Plan Project</funding-source><award-id>Z2018s052</award-id><principal-award-recipient>Not Applicable</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Peptic ulcer disease (PUD) is a very common gastrointestinal disease, which usually occurs in the stomach and proximal duodenum.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} It symptoms and signs mainly manifest as gnawing or burning pain in middle or upper stomach, bloating, heartburn, and nausea or vomiting.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Risk factors are responsible for such disorder, such as helicobacter pylori bacteria, frequent use of nonsteroidal anti-inflammatory drugs, and family history of PUD.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>&#x02013;<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} It is reported that its prevalence rate ranges from 5% to 12% worldwide.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>&#x02013;<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} If it cannot be treated timely and effectively, it may result in several complications, such as perforated peptic ulcer (PPU), gastrointestinal bleeding, gastric outlet obstruction, penetration, and even gastric cancer.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>&#x02013;<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} Of those, PPU accounts for about 2% to 10% of all patients with PUD.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} Thus, it is very important to detect and treat PPU at early stage. Surgery is the most effective management for PPU.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>,<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} However, most patients with PPU also suffer from psychological disorder (including depression and anxiety).^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} Previous studies have reported that comprehensive nursing intervention (CNI) can be utilized for the management of elderly patients with PPU.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>&#x02013;<xref rid=\"R28\" ref-type=\"bibr\">28</xref>]} However, there are inconsistent results, and no systematic review has investigated the effects of CNI on psychological disorder in elderly patients with PPU. Thus, this study will systematically and comprehensively assess the psychological effect of CNI in elderly patients with PPU.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Study registration</title><p>We have registered this study protocol on INPLASY202080069, and we report it according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol statement guidelines.^{[<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]}</p></sec><sec><label>2.2</label><title>Eligibility criteria</title><sec><label>2.2.1</label><title>Types of studies</title><p>This study will include randomized controlled trials of CNI on psychological effect in elderly patients with PPU. We will eliminate other studies, such as nonclinical trial, and uncontrolled trial.</p></sec><sec><label>2.2.2</label><title>Types of participants</title><p>Elderly patients (over 65 years old) with PPU who were also diagnosed as psychological disorder (including depression and anxiety) will be included, regardless gender, severity of psychological condition, and PPU.</p></sec><sec><label>2.2.3</label><title>Types of interventions</title><p>In the intervention group, all eligible patients administered CNI on psychological disorder.</p><p>In the control group, all patients underwent other managements will be included. However, we will exclude comparator involving any forms of CNI.</p></sec><sec><label>2.2.4</label><title>Type of outcome measurements</title><p>Primary outcome is psychological disorder. It comprises of depression and anxiety, as measured by Beck Depression Inventory and Hamilton Depression Rating Scale, or other relevant scales.</p><p>Secondary outcomes are health-related quality of life (as assessed by Global Quality of Life Scale), panic (as examined by Panic Disorder Severity Scale), and adverse events.</p></sec></sec><sec><label>2.3</label><title>Literature sources</title><sec><label>2.3.1</label><title>Electronic database sources</title><p>We will retrieve all potential studies from inception to the present in the Cochrane Library, PUBMED, EMBASE, PsycINFO, WANGFANG, CBM, and CNKI. No restrictions will be employed to the language and publication status. We summarize the sample of search strategy for PUBMED in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>. We will also modify similar search strategies for other electronic databases.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Detailed search strategy of PUBMED.</p></caption><graphic xlink:href=\"medi-99-e22226-g001\"/></table-wrap></sec><sec><label>2.3.2</label><title>Other sources</title><p>We will search other sources to avoid missing potential studies, such as clinical trial registry, conference proceedings, and reference list of included studies.</p></sec></sec><sec><label>2.4</label><title>Data collection and analysis</title><sec><label>2.4.1</label><title>Study selection</title><p>Two independent authors will scan titles/abstracts of all searched studies and all irrelevant literature will be eliminated. Then, full text of potential articles will be cautiously read in accordance with all inclusion criteria. All eligible studies will be included in this study, and all excluded studies will be recorded with reasons. Any disagreements will be solved by a third author through discussion. We will summarize the process of study selection in a flow diagram.</p></sec><sec><label>2.4.2</label><title>Data extraction</title><p>Two authors will independently extract data according to the previously designed data extraction form. It includes publication characteristics (such as title, first author, journal, and study design), patient characteristics (such as number of patients, age, gender, diagnosis criteria, and inclusion and exclusion criteria), study methods, details of CNI and controls, outcome indicators, results, conclusion, and follow-up information. Any divergences will be resolved by a third author via discussion.</p></sec><sec><label>2.4.3</label><title>Study quality assessment</title><p>Two authors will independently examine methodological quality of each included study using Cochrane Risk of Bias Tool. We will invite a third author to clear any confusion between 2 authors.</p></sec><sec><label>2.4.4</label><title>Dealing with missing data</title><p>If any insufficient or missing information occurs, we will contact original study authors to obtain it by email or fax. If it is not available, we will only analyze available data.</p></sec><sec><label>2.4.5</label><title>Data synthesis</title><p>We will use RevMan 5.3 software to conduct statistical analysis. For dichotomous data, we will calculate it as risk ratio and 95% confidence intervals. For continuous data,</p><p>We will estimate it as weighted mean difference or standardized mean difference and 95% confidence intervals.</p><p>Statistical heterogeneity will be identified by <italic>I</italic>² test. Values of <italic>I</italic>² illustrate as follows: <italic>I</italic>²&#x0200a;&#x02264;&#x0200a;50% means reasonable heterogeneity, and we will use a fixed-effects model to integrate outcome data. <italic>I</italic>²&#x0200a;&#x0003e;&#x0200a;50% signifies a substantial heterogeneity, and we will employ a random-effects model to combine outcome data. If the extracted data similar sufficiently on the same outcome measurement, we will synthesize those data and will carry out a meta-analysis. If there is remarkable heterogeneity across included studies, we will conduct a qualitative synthesis using narrative summary descriptions. In addition, we will undertake subgroup and sensitivity analysis to investigate the possible reasons of obvious heterogeneity.</p></sec><sec><label>2.4.6</label><title>Reporting bias</title><p>Any possible reporting bias will be checked using Funnel plot and Egger regression test when over 10 studies are eligible.^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]}</p></sec><sec><label>2.4.7</label><title>Subgroup analysis</title><p>We will conduct subgroup analysis to test the sources of significant heterogeneity based on characteristics of study, severity of psychological disorder or PPU, and details of CNI and controls.</p></sec><sec><label>2.4.8</label><title>Sensitivity analysis</title><p>We will perform sensitivity analysis to test robustness and stability of the present results by removing studies with low quality and small sample size.</p></sec></sec><sec><label>2.5</label><title>Dissemination and ethics</title><p>We plan to publish this study on a peer-reviewed journal. This study does not need ethical approval, because it will only extract data from the exist studies.</p></sec></sec><sec><label>3</label><title>Discussion</title><p>According to the best of our knowledge, this systematic review is the first one to examine the psychological effect of CNI in elderly patients with PPU. Although previous studies suggested utilizing CNI for the management of psychological disorder in elderly patients with PPU, their results were controversial up to now. In addition, there were no consensus and existing recommendations of CNI on psychological disorders in elderly patients with PPU specifically.</p><p>Therefore, considering this urgent demand, we will organize this systematic review through performing comprehensive literature search, and rigorous evidence synthesis. We also registered this protocol to make sure it is transparent. We will ensure that the findings of this study will provide rigorous evidence regarding whether CNI is effective or not on psychological disorder in elderly patients with PPU. It may also benefit both patients and clinicians.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Bing Chen, Xiu-Yu Liu, Hong-Mei Zhang, Bai-Jun Zhang.</p><p><bold>Data curation:</bold> Bing Chen, Xiu-Yu Liu, Ying-Ting Wang.</p><p><bold>Formal analysis:</bold> Bing Chen, Xiu-Yu Liu.</p><p><bold>Investigation:</bold> Ying-Ting Wang.</p><p><bold>Methodology:</bold> Bing Chen, Hong-Mei Zhang, Bai-Jun Zhang.</p><p><bold>Project administration:</bold> Ying-Ting Wang.</p><p><bold>Resources:</bold> Bing Chen, Xiu-Yu Liu, Hong-Mei Zhang, Bai-Jun Zhang.</p><p><bold>Software:</bold> Bing Chen, Xiu-Yu Liu, Hong-Mei Zhang, Bai-Jun Zhang.</p><p><bold>Supervision:</bold> Ying-Ting Wang.</p><p><bold>Validation:</bold> Bing Chen, Xiu-Yu Liu, Hong-Mei Zhang, Bai-Jun Zhang, Ying-Ting Wang.</p><p><bold>Visualization:</bold> Bing Chen, Bai-Jun Zhang, Ying-Ting Wang.</p><p><bold>Writing &#x02013; original draft:</bold> Bing Chen, Xiu-Yu Liu, Hong-Mei Zhang, Bai-Jun Zhang, Ying-Ting Wang.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Bing Chen, Bai-Jun Zhang, Ying-Ting Wang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CIs = confidence intervals, CNI = comprehensive nursing intervention, PPU = perforated peptic ulcer.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Chen B, Liu XY, Zhang HM, Zhang BJ, Wang YT. Psychological effect of comprehensive nursing intervention in elderly patients with perforated peptic ulcer: A protocol of systematic review. <italic>Medicine</italic>. 2020;99:39(e22226).</p></fn><fn fn-type=\"supported-by\"><p>This study is financially supported by Mudanjiang Science and Technology Plan Project (Z2018s052). 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991481</article-id><article-id pub-id-type=\"pmc\">PMC7523805</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-02309</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022450</article-id><article-id pub-id-type=\"art-access-id\">22450</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>6300</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Effects of tactile vibration feedback system on balance function and walking ability of a unilateral transtibial amputee with a prosthesis</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Shi-Qi</given-names></name><degrees>MM</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Gao</surname><given-names>Ya-Qian</given-names></name><degrees>MM</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Xu</surname><given-names>Ze-Hua</given-names></name><degrees>MM</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Xu</surname><given-names>Fang-Yuan</given-names></name><degrees>MSc</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0001-6718-8480</contrib-id><name><surname>Yuan</surname><given-names>Li</given-names></name><degrees>MM</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff>Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Fang-Yuan Xu, Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping road,Luzhou 646000, Sichuan, People's Republic of China. (e-mail: <email>x5144@163.com</email>); Li Yuan, Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping road,Luzhou 646000, Sichuan, People's Republic of China. (e-mail: <email>yuanli_swmu@163.com)</email></corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22450</elocation-id><history><date date-type=\"received\"><day>17</day><month>3</month><year>2020</year></date><date date-type=\"rev-recd\"><day>4</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>31</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22450.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>There is still a lack of case reports about tactile vibration feedback devices for the treatment of transtibial amputees so far. This case report aims to introduce a tactile vibration feedback device designed to improve the balance and walking function of the transtibial amputee.</p></sec><sec><title>Patient concerns:</title><p>The amputee was a 20-year-old man with right transtibial amputation in a car accident four years ago.</p></sec><sec><title>Diagnose:</title><p>The clinical diagnosis of him was &#x0201c;Right transtibial amputation,&#x0201d; and the rehabilitation diagnosis was &#x0201c;Motor dysfunction (Balance function abnormality and Gait abnormality).&#x0201d;</p></sec><sec><title>Interventions:</title><p>The patient was reminded to adjust their posture in time via the tactile vibration feedback device.</p></sec><sec><title>Outcomes:</title><p>The balance and walking function of the volunteer transtibial amputee was improved.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>The tactile vibration feedback device has the potential to improve the balance and walking function of the transtibial amputee after installation. Potential fields that can be recommended for future research include intelligent prosthetics, feedback training, motor function, prosthetic acceptance, compliance, social communication, and the quality of life.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>amputee</kwd><kwd>case report</kwd><kwd>feedback</kwd><kwd>vibration</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Sichuan science and technology program</funding-source><award-id>2019YFS0139</award-id><principal-award-recipient>Li Yuan</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Sensory feedback therapy is a research hotspot in the field of the prosthesis. Tactile feedback from the lower extremities is essential for maintaining balance, completing walking, and performing complex daily activities.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} In the case of transtibial amputation, amputees will lose part of his or her sensory and motor function.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Besides, most prosthetics are unable to correctly and comprehensively perceive and feedback the motor information of lower limbs, and can not effectively make up for the loss of sensation caused by the loss of the limb.</p><p>Previous literature has reported that using tactile vibration feedback to treat upper-limb amputees and achieved active results.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Husman M. A. has invented a wearable skin stretch haptic feedback device, which has been shown to have the potential to improve balance control in amputees.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} However, his device was only tested on normal people. We do not know the effect of the device on amputees.</p><p>At present, there is still a lack of case reports about tactile vibration feedback devices for the treatment of transtibial amputees so far. This case report introduced a tactile vibration feedback device designed by our team, aiming to improve the balance and walking ability of the transtibial amputee. Of note, written informed consent was obtained from the patient to publish the case report and accompanying images.</p></sec><sec><label>2</label><title>Case report</title><sec><label>2.1</label><title>Patient information</title><p>The tactile vibration feedback device was tested on a volunteer transtibial amputee. The amputee was a 20-year-old man with right transtibial amputation in a car accident 4 years ago. He weighed 62.5 kilograms (kg). The length from the medial tibial plateau to the stump was 18.2 centimeters (cm), and the prosthesis has been worn for 4 years. The amputee was in good health and had no history of hypertension or diabetes. The amputee did not receive formal rehabilitation training before participating in the test. When the amputee walked, his gait was significantly different from that of normal people. The clinical diagnosis of him was &#x0201c;Right transtibial amputation&#x0201d; and the rehabilitation diagnosis was &#x0201c;Motor dysfunction (Balance function abnormality and Gait abnormality)&#x0201d;. He signed the informed consent form and participated in the test after we introduce the purpose and method of the intervention for him. He was not allowed to use alcohol or painkillers a week before the test to ensure that the stump sensory was normal. The Clinical Trial Ethics Review Committee of the Affiliated Hospital of Southwest Medical University approved this study (number: KY2019160).</p></sec><sec><label>2.2</label><title>Therapeutic intervention</title><p>The tactile vibration feedback device consisted of a control motherboard, 5 gyroscope sensors, and 4 vibration motors (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). The sensors were located on both thighs and lower legs, as well as on the dorsum of the artificial foot. The vibration motors were located around the middle part of the thigh (front, back, inside, and outside). The whole device was powered by a portable mobile 10000mAh battery and was tied to the waist together with the control motherboard. Figure <xref ref-type=\"fig\" rid=\"F2\">2</xref> shows the location where each component is installed.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Composition of the tactile vibration feedback device. (A) Control motherboard. (B) Gyroscope sensor. (C) Vibration motor.</p></caption><graphic xlink:href=\"medi-99-e22450-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Schematic diagram of the device installation position. Prosthetic side: (a) A gyroscope sensor and 4 vibration motors around the middle part of the thigh. (b) A gyroscope sensor at the lower leg. (c) An artificial foot plane sensor. Healthy side: (d) A gyroscope sensor at the thigh. (e) A gyroscope sensor at the lower leg.</p></caption><graphic xlink:href=\"medi-99-e22450-g002\"/></fig><p>Five gyroscope sensors and four vibration motors were connected to the control motherboard via a silicone wire. The data (rotation angle) collected by the gyroscope sensor was transmitted to the CPU through five serial ports for processing. When the difference between the angles was greater than 5, the device would compare the motion of the prosthetic limb with that of the healthy limb, and then the corresponding part would be stimulated by the vibration motor. When the motion of the prosthetic side was large, the control motherboard guided the vibration motor to stimulate the front side of the corresponding limb. Oppositely, when the action motion was small, the vibration motor stimulated the posterior side. In this way, the amputee was reminded to adjust their posture in time.</p></sec><sec><label>2.3</label><title>Evaluation and outcome</title><p>Before using the device, the amputee was evaluated by Tinetti Performance Oriented Mobility Assessment (Tinetti POMA), indoor gait analysis, and outdoor 1000 m complex pavement test.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]}</p><p>The Tinetti POMA could be used to evaluate the gait and balance function of amputees. The total score is 28. The lower the score, the worse the balance. The amputee walked 3 times at a comfortable pace in the GAITRite gait analysis system (GAITRite Gold, CIR Systems, PA, USA) to record the gait-related parameters. The outdoor 1000 m complex pavement test used our hospital road as the test site, including flat road, grass, ramp, and staircase. The pedometer and stopwatch were used to record the steps, energy consumption, and the total time.</p><p>The amputee installed the device with a therapist help and was evaluated again after a three-hour familiarization process (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>). No adverse and unanticipated events occurred. The patient was very satisfied with the process of treatment and evaluation. Table <xref rid=\"T1\" ref-type=\"table\">1</xref> shows that the Tinetti POMA score increased before installation, especially the gait score. The parameters of indoor gait analysis were improved, and the number of steps, total time, and energy consumption in outdoor 1000 m complex road test decreased. The results suggested that the balance and walking function of the volunteer transtibial amputee could be improved.</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>The subject walked after installation.</p></caption><graphic xlink:href=\"medi-99-e22450-g003\"/></fig><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Evaluation results.</p></caption><graphic xlink:href=\"medi-99-e22450-g004\"/></table-wrap></sec></sec><sec><label>3</label><title>Discussion</title><p>After amputation, it is necessary to wear prosthetics and carry out the functional exercise as soon as possible to achieve the purpose of early rehabilitation. However, after wearing traditional prosthetics, there are still differences between the balance and walking function of amputees and normal people. The wrong balance and gait characteristics would affect the comfort of the stump, reducing the walking efficiency. The wrong posture may cause secondary physical damage to the amputee over time.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Therefore, the improvement of balance and walking function is vital to transtibial amputees with prostheses.</p><p>Duclos C vibrated the lateral neck or hip muscles of lower limb amputees and found that the muscle vibration in both positions solved the problem of posture asymmetry in more than half of amputees.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} This indicated that muscle vibration could maintain or cause directional changes in posture. Raveh E found that when visual feedback was disturbed, the increase of tactile vibration feedback in prosthesis users had a positive impact on the performance and accuracy of the prosthesis.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Although the subjects in this study were patients with upper limb amputation, it was undeniable that tactile vibration feedback has a positive effect on the improvement of amputee's movement and function. And our case report showed the tactile vibration feedback device has the potential to improve the balance and walking function of transtibial amputees after installation, which also shows a good development prospect.</p><p>Fan RE designed a pneumatic haptic feedback system, being able to provide sensory feedback to the lower extremities, but his device did not compare the data collected by the sensor with the healthy side in real-time.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} As for our device, CPU compared the data between the healthy limb and the prosthetic limb, and the data between the foot plane and the preset data, after collecting the data transmitted by the sensor. According to the results of the data comparison, the amputee was guided to change their posture by vibrating motor.</p><p>Our device had highly sensitive sensors. The sensors mainly used gyroscope acceleration sensor chip (type: MPU6050). The sensor weighed 1 gram (g), was 2.5&#x0200a;cm long and 1&#x0200a;cm wide. It was an integrated motion 6-axis motion processing component that could record the motion angles of the lower limbs in all directions and could reduce installation space. The control motherboard weighed 10&#x0200a;g, was 6.5&#x0200a;cm long and 3.4&#x0200a;cm wide. The CPU model used by the sensor and control motherboard is STM32F103RET6, with fast data processing capability. The vibration motor weighed 1.5&#x0200a;g, was 1.9&#x0200a;cm long and 1.3&#x0200a;cm wide. The total weight of the whole device is only 21&#x0200a;g.</p><p>In addition, the foot plane sensor was used to determine whether the amputee was making a turn. Even normal lower limbs could not fully coordinate the movements of the 2 limbs when making a turn. In order to avoid erroneous instructions, the vibrating motor suspended the stimulation to the patient when he was detected to make a turn. When the patients foot plane was inverted or everted, the sensor could detect the abnormal position of the artificial foot, and the vibration motor would stimulate the inside and outside of the thigh to remind the patient of the posture problem of the foot plane.</p><p>This simple technique can be mounted on the already used prosthesis with no change of prosthetic components. It is also expected to be directly integrated with prosthesis design in the future. Potential fields that can be recommended for future research include intelligent prosthetics, feedback training, motor function, prosthetic acceptance, compliance, social communication, and the quality of life.</p><p>There were some limitations in this case report. First, the battery life of the device was unstable. The power consumption of the whole device was about 25&#x0200a;mA and could last for more than 360&#x0200a;hours, but the more exercise of the amputee, the more power consumed. Users had to charge the device within half a month. Further consideration should be given to expanding the capacity of the portable mobile battery or changing to button batteries for easy replacement. Second, this device only tested on one amputee, and further high-quality clinical research was needed. In addition, the intervention time and follow-up time for the patient in this study were short, which could be appropriately extended in the future to observe the long-term effect of the device.</p></sec><sec><label>4</label><title>Conclusion</title><p>In summary, the tactile vibration feedback device has the potential to improve the balance and walking function of the transtibial amputee after installation. Potential fields that can be recommended for future research include intelligent prosthetics, feedback training, motor function, prosthetic acceptance, compliance, social communication, and the quality of life.</p></sec><sec><title>Author contributions</title><p><bold>Device and study design:</bold> Fang-Yuan Xu, Li Yuan.</p><p><bold>Investigation:</bold> Shi-Qi Wang, Ya-Qian Gao.</p><p><bold>Methodology:</bold> Shi-Qi Wang, Ya-Qian Gao, Ze-Hua Xu.</p><p><bold>Project administration:</bold> Fang-Yuan Xu, Li Yuan.</p><p><bold>Resources:</bold> Ze-Hua Xu.</p><p><bold>Writing &#x02013; original draft:</bold> Shi-Qi Wang.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> All authors.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: cm = centimeters, GC = gait cycle, kcal = kilocalorie, kg = kilograms, sec = second, Tinetti POMA = Tinetti Performance Oriented Mobility Assessment.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Wang SQ, Gao YQ, Xu ZH, Xu FY, Yuan L. Effects of tactile vibration feedback system on balance function and walking ability of a unilateral transtibial amputee with a prosthesis: a case report. <italic>Medicine</italic>. 2020;99:39(e22450).</p></fn><fn fn-type=\"other\"><p>FX and LY arecontributed to the work equally and should be regarded as co-senior authors.</p></fn><fn fn-type=\"supported-by\"><p>This work was supported by the grant of Sichuan science and technology program (grant number: 2019YFS0139).</p></fn><fn fn-type=\"COI-statement\"><p>The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991433</article-id><article-id pub-id-type=\"pmc\">PMC7523806</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-07854</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022294</article-id><article-id pub-id-type=\"art-access-id\">22294</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>7100</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Kirner's deformity of the fifth finger</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Tianxiao</surname><given-names>Ma</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Dongyue</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Song</surname><given-names>Lihua</given-names></name><degrees>MD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff>Department of Orthopaedic Surgery, The Orthopaedics Hospital of Xingtai City, Xingtai, Hebei, P.R. China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Lihua Song, Department of Orthopaedic Surgery, The Orthopaedics Hospital of Xingtai City, Xingtai, Hebei, P.R. China (e-mail: <email>songlh054000@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22294</elocation-id><history><date date-type=\"received\"><day>10</day><month>10</month><year>2019</year></date><date date-type=\"rev-recd\"><day>9</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>21</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22294.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Kirner's deformity is an uncommon deformity of finger, characterized by palmo-radial curvature of distal phalanx of the fifth finger. The specific mechanism remains unknown yet. This study aims to present a case report to add the knowledge on this type of deformity.</p></sec><sec><title>Patient concerns:</title><p>A 9-year-old girl presenting with deformity of her fifth finger since she was born was admitted to our hand surgery clinic. MRI findings showed widened epiphyseal plate, L-shaped physis, but normal flexor digitorum profundus tendon insertion, without any significantly enhanced soft issues.</p></sec><sec><title>Diagnosis:</title><p>Kirner's deformity of the fifth finger.</p></sec><sec><title>Interventions:</title><p>We presented 2 surgical choices for the patient: one was wedge osteotomy of the distal phalanx to correct the mechanical line of the distal phalanx and fixation with Kirschner wire and the other one was cut-off of deep flexor tendon insertion with brace immobilization, but her guardians refused either of them.</p></sec><sec><title>Outcomes:</title><p>Consecutive follow-up was performed for 19 months after the first visit, showing no any change in finger shape and function.</p></sec><sec><title>Lessons:</title><p>The L-shaped epiphyses may be the cause of Kirner's deformity and further attention should be paid on in the clinic. This case report provided a basis for the etiological diagnosis and future treatment of Kirner's deformity.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>child</kwd><kwd>hand</kwd><kwd>Kirner's deformity</kwd><kwd>MRI</kwd><kwd>osteotomy</kwd><kwd>radiography</kwd><kwd>skeletal deformity</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Kirner's deformity is a rare deformity of fingers, which was firstly reported by Kirner J in Germany in 1927.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} It was reported that the incidence rate of Kirner's deformity was extremely low, ranging from 0.15% to 0.25%.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} It is characterized by the palmo-radial curvature of the distal phalanx of the fifth finger.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>&#x02013;<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} Despite the symptom of being painless, the patients may have swelling of distal interphalangeal (DIP) joint and the development of watch-glass nail in the fingers involved.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Among most of the previously reported cases, the deformity usually affected the fifth finger only. However, some case reports also described involvement of other fingers.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} By now, no definite cause has been confirmed for this type of disease. One hypothesis is about abnormal insertion of flexor digitorum profundus tendon,^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} and the other is chronic inflammation and vascularization of soft issues.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} In another assumption, there is a cartilaginous extension of the physis in Kirner's deformity, which represented a &#x0201c;volar bracketed epiphysis&#x0201d; with an L-shaped physis.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} In this study, we reported a case of the Kirner's deformity in a 9-year-old girl, and systematically reviewed all the cases reported previously.</p></sec><sec><label>2</label><title>Case presentation</title><p>This study was approved by the ethics committee of the Orthopaedics Hospital of Xingtai City, and written informed consent had been obtained from the patient and her guardian, who permitted relevant data published in the journal.</p><p>A 9-year-old girl was admitted to our hospital with her parents for treatment of little finger deformity of her right hand. She complained about the curvature and deformity of distal phalanx of right fifth finger (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). One of her uncles suffered from the same deformity (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>). The patient had no history of fracture, burn, freezing injury or infectious disease. The clinical manifestations included the palmo-radial curvature of the distal phalanx of right little finger without significant tenderness. Radiograph showed volar-radial angular deformity of distal phalanges of her fifth finger, wider and thicker growth plate of distal phalanx in the form of L-physis (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>). Laboratory examinations showed no increase in leukocytes, erythrocyte sedimentation rate (ESR), and C-reactive protein, while MRI of fingers revealed slightly widened epiphyseal plate of the distal phalanx of the right little finger, L-shaped physis in epiphysis, and normally inserted flexor digitorum profundus tendon (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>). No abnormal or enhanced signal was spotted from soft issues even after higher dose was administered.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Photograph of the right hand shows volar-radial angular deformity of the distal phalanx of the fifth finger.</p></caption><graphic xlink:href=\"medi-99-e22294-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>The similar Kirner deformity of the distal fifth finger for the patient&#x02019; uncle.</p></caption><graphic xlink:href=\"medi-99-e22294-g002\"/></fig><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Radiograph shows fifth distal phalanges of the right hand with volar-radial angular deformity, Wider and thicker growth plate of distal phalanx in the form of L-physis (lateral projection).</p></caption><graphic xlink:href=\"medi-99-e22294-g003\"/></fig><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>MRI of the right fifth finger, Normal level of tendon insertion (A). Wider and thicker growth plate of distal phalanx in the form of L-physis, but without any enhanced soft tissue (B&#x02013;D).</p></caption><graphic xlink:href=\"medi-99-e22294-g004\"/></fig><p>According to the typical physical examination manifestations and imaging findings, we diagnosed it as Kirner's deformity of the fifth finger. We recommended that patients should be hospitalized for further operative treatment. We provided 2 operation choices, one was wedge osteotomy of the distal phalanx to correct the mechanical line of the distal phalanx and fixation with Kirschner wire, and the other one is cut-off of deep flexor tendon insertion with brace immobilization. However, the patient and her guardians refused our recommendation and were discharged home, because they thought this type of deformity did not affect the daily activities, similar as that her uncle experienced (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>).</p><p>In the subsequent visits, totally lasting 19 months since her first visit, we have not found any change in the finger shape, range of the deformed finger and the ability in daily activities.</p></sec><sec><label>3</label><title>Discussion and conclusions</title><p>As an uncommon deformity of finger, Kirner's deformity is characterized by the palmo-radial curvature of the distal phalanx of the fifth finger, and more often seen in women than men.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>&#x02013;<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} It may be present by heredity as autosomal dominant trait with incomplete penetrance. The homozygous state determines the manifestation of deformity of more than one finger and even in both hands. Based on this, Song et al and Koh et al proposed 2 ways of classification for this disease. The first one is regarding congenital anomaly that is mostly inherited in the family, which usually lasts for several months or years and then the deformity disappears after closure of epiphysis without affecting the function of the finger. The other is acquired, which is not found in other members of the family and usually attacks the patient for the first time at his or her 10 years old. Nevertheless, some researchers also found more complicated interplay between the hereditary susceptibility and clinical manifestations.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]}</p><p>Kirner's disease should be distinguished from other similar diseases, including camptodactyly, deformity of flexion at the PIP joint, and clinodactyly, radial deviation at the DIP joint. Literature review revealed that this deformity might be associated with Turner's syndrome, Cornelia de Lange syndrome, Down syndrome and Silver syndrome.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>,<xref rid=\"R15\" ref-type=\"bibr\">15</xref>&#x02013;<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]}</p><p>The pathogenesis of Kirner's deformity remains poorly understood. One of the assumptions is that Kirner's deformity may result from an unusually distal insertion of flexor digitorum profundus tendon along the palmar surface of nearly the entire distal phalanx. The flexor tendon may exert forces acting on the growing bone in the volar and radial direction, resulting in a flexion deformity prior to fusion of the physis.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} On the theoretical basis above, Benatar et al treated the disease by removing the stops of flexor digitorum profundus tendon, and reported anatomic variations during surgery as well as promising postoperative clinical efficacy.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} On the contrary, our case hereby is not consistent with the case described by Benatar et al, but similar as that depicted by Lee^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} where MRI revealed normal insertion site of flexor digitorum profundus tendon. Given the deduced deviation force of flexor digitorum profundus tendon from epiphysis, damage to the epiphysis of distal phalanx of the fifth finger during tendon detachment maybe the primary reason for improvement of affected finger after the surgery.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} As a result, the postsurgical performance cannot shed any light on the pathogenesis of Kirner's deformity.</p><p>Another assumption is bending of joints, and deformity of distal phalanx seems to result from a chronic inflammatory process that starts in the soft tissues of distal fingers.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Miller^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} pointed out in 2004 that there were 2 key problems with this assumption. Firstly, the diagnosis was wrong, because the Kirner's deformity could involve several fingers of both hands, as reported by Brune et al in 2003. Therefore, it is more appropriate that it should be diagnosed as Camptodactyly instead. Secondly, the &#x0201c;substantial&#x0201d; soft tissue enhancement as shown on the T1-W FSGad images may represent a commonly seen artifact when performing fat-saturation operation on the small curved area. By placing saline bags along the small parts or curved surfaces so as to provide increased magnetic field uniformity and remove the artifact, we got an outcome that was completely different from that of Brune et al. Our MRI indicated wider and thicker growth plate of distal phalanx in the form of L-physis, but without any enhanced soft tissue (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>).</p><p>According to the third assumption for Kirner's deformity, there is a cartilaginous extension representing a &#x0201c;volar bracketed epiphysis&#x0201d; with an L-shaped physis.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} This theory highlighted that cartilaginous extension of the physis indicated a &#x0201c;volar bracketed epiphysis&#x0201d; with an L-shaped rather than C-shaped physis. The morphological difference may be attributed to following several conditions. In the first place, as for clinodactyly, the bracket joins with the distal articular cartilage to complete the &#x0201c;C&#x0201d;, whereas as for Kirner's deformity the &#x0201c;C&#x0201d; is incomplete because the tip of the distal phalanx lacks articular cartilage, therefore developing as a result of intra-membranous rather than intra-cartilaginous ossification. Then, the L-shaped physis of Kirner's deformity appears to be limited distally by the FDP insertion. We believe this L-shaped physis may act as an anlage, restricting growth of the proximal volar metaphysis; and together with continued dorsal growth finally resulted in volar bowing of the distal phalanx. After reviewing all the previous reports concerning Kirner's deformity, the physical checking results, and the combined MRI and X-ray findings of our case, we believe this assumption is convincible (Figs. <xref ref-type=\"fig\" rid=\"F2\">2</xref> and <xref ref-type=\"fig\" rid=\"F3\">3</xref>).</p><p>The existing treatment choices for Kirner's deformity included early fixation with delayed continuous splinting before maturity,^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R14\" ref-type=\"bibr\">14</xref>,<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} removal of stops of flexor digitorum profundus tendon,^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} corrective osteotomy,^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} and excision of excessive epiphysis along palm to achieve bony alignment.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} As to early fixation with delayed continuous splinting before maturity, strict guardianship and follow-up are required for realizing effective prevention and correction of the deformity. For removal of stops of flexor digitorum profundus tendon, we think it sets to correct the deformity by reducing the deviation of flexor digitorum profundus tendon from epiphysis and damaging the epiphysis of distal phalanx. However, the natural retraction of flexor digitorum profundus tendon may cause a permanent loss of DIP joint. Corrective osteotomy has to be performed until the epiphysis becomes completely closed; otherwise, a relapse may occur. Furthermore, the primary goal of the surgery is to improve the morphology instead of function of the involved finger. As for excision of palmar excessive epiphysis, there remains lack of clinical data to support, though it is deemed as feasible.</p><p>Taken together, the pathogenesis of Kirner's deformity remains unclear. To our knowledge, we believe there is a cartilaginous extension of physis in this condition, which represents a &#x0201c;volar bracketed epiphysis&#x0201d;, with an L-shaped physis. We suggest the volar splint fixation transversely or resection procedure for treatment of such deformity to achieve bony alignment. Long-term follow-up results of this patients are warranted, despite she did not receive surgical treatment.</p></sec><sec><title>Acknowledgments</title><p>We are grateful to YQH and QBB of the Department of Orthopedics, and to QW and JBY of the Department of medical imaging for their kind assistance. All the authors declare that they have no conflict of interest.</p></sec><sec><title>Author contributions</title><p>LHS designed the study; LHS and TXM analysed the Imaging data; DYW and TXM seared the relevant literature. TXM wrote the manuscript and LHS approved the manuscript.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: DIP = distal interphalangeal, ESR = erythrocyte sedimentation rate, FDP = flexor digitorum profundus, PIP = proximal interphalangeal.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Tianxiao M, Wang D, Song L. Kirner's deformity of the fifth finger: A case report. <italic>Medicine</italic>. 2020;99:39(e22294).</p></fn><fn fn-type=\"other\"><p>The present case report was published as approved by the institutional review board of the orthopaedics hospital of Xingtai City. The patient guardian provided informed consent.</p></fn><fn fn-type=\"other\"><p>All authors read and approved the final manuscript. The patient guardian provided informed consent and permitted the relevant data published on this journal.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no funding and conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article [and its supplementary information files].</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Kirner</surname><given-names>J</given-names></name></person-group>\n<article-title>Doppelseitige Verkrummungen des Kleinfingerendgliedesals selbstfindigesKrankheitsbild</article-title>. <source>Fortschr Geb R&#x000f6;ntgenstr</source>\n<year>1927</year>;<volume>36</volume>:<fpage>804</fpage>&#x02013;<lpage>6</lpage>.</mixed-citation></ref><ref id=\"R2\"><label>[2]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Saitoh</surname><given-names>T</given-names></name></person-group>\n<article-title>A genetic study of the abnormal shortening of the finger (in Japanese)</article-title>. <source>Jpn J Hum Genet</source>\n<year>1963</year>;<volume>8</volume>:<fpage>177</fpage>&#x02013;<lpage>94</lpage>.</mixed-citation></ref><ref id=\"R3\"><label>[3]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Benatar</surname><given-names>N</given-names></name></person-group>\n<article-title>Kirner's deformity treated by distal detachment of the flexor digitorum profundus tendon</article-title>. <source>Handchir Mikrochir Plast Chir</source>\n<year>2004</year>;<volume>36</volume>:<fpage>166</fpage>&#x02013;<lpage>9</lpage>.<pub-id pub-id-type=\"pmid\">15162316</pub-id></mixed-citation></ref><ref id=\"R4\"><label>[4]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Fairbank</surname><given-names>SM</given-names></name><name><surname>Rozen</surname><given-names>WM</given-names></name><name><surname>Coombs</surname><given-names>CJ</given-names></name></person-group>\n<article-title>The pathogenesis of Kirner's deformity: a clinical, radiological and histological study</article-title>. <source>J Hand Surg Eur Vol</source>\n<year>2015</year>;<volume>40</volume>:<fpage>633</fpage>&#x02013;<lpage>7</lpage>.<pub-id pub-id-type=\"pmid\">25274771</pub-id></mixed-citation></ref><ref id=\"R5\"><label>[5]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Brune</surname><given-names>T</given-names></name><name><surname>Schiborr</surname><given-names>M</given-names></name><name><surname>Maintz</surname><given-names>D</given-names></name><etal/></person-group>\n<article-title>Kirner's deformity of all fingers in a 5-year-old girl: soft-tissue enhancement with normal bones on contrast-enhanced MRI</article-title>. <source>Pediatr Radiol</source>\n<year>2003</year>;<volume>33</volume>:<fpage>709</fpage>&#x02013;<lpage>11</lpage>.<pub-id pub-id-type=\"pmid\">12845503</pub-id></mixed-citation></ref><ref id=\"R6\"><label>[6]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Sugiura</surname><given-names>Y</given-names></name></person-group>\n<article-title>Polytopic dystelephalangy of the fingers</article-title>. <source>Pediatr Radiol</source>\n<year>1989</year>;<volume>19</volume>:<fpage>493</fpage>&#x02013;<lpage>5</lpage>.<pub-id pub-id-type=\"pmid\">2771501</pub-id></mixed-citation></ref><ref id=\"R7\"><label>[7]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Lee</surname><given-names>J</given-names></name><name><surname>Ahn</surname><given-names>JK</given-names></name><name><surname>Choi</surname><given-names>SH</given-names></name><etal/></person-group>\n<article-title>MRI findings in Kirner deformity: normal insertion of the flexor digitorum profundus tendon without soft tissue enhancement</article-title>. <source>Pediatr Radiol</source>\n<year>2010</year>;<volume>40</volume>:<fpage>1572</fpage>&#x02013;<lpage>5</lpage>.<pub-id pub-id-type=\"pmid\">20336287</pub-id></mixed-citation></ref><ref id=\"R8\"><label>[8]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Gouda</surname><given-names>A</given-names></name><name><surname>Davison</surname><given-names>IM</given-names></name></person-group>\n<article-title>Images for surgeons. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991488</article-id><article-id pub-id-type=\"pmc\">PMC7523807</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-01443</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022489</article-id><article-id pub-id-type=\"art-access-id\">22489</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>4100</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Sarcomatoid hepatocellular carcinoma mimicking hepatic abscess</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Yang</surname><given-names>Zheng</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Lv</surname><given-names>Kun</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-4938-9235</contrib-id><name><surname>Zhao</surname><given-names>Yanan</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Pan</surname><given-names>Minqiang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Chao</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wei</surname><given-names>Shumei</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Anesthesiology</aff><aff id=\"aff2\"><label>b</label>Department of Ultrasound</aff><aff id=\"aff3\"><label>c</label>Department of Pathology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Yanan Zhao, Department of Ultrasound, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China (e-mail: <email>2515193@zju.edu.cn</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22489</elocation-id><history><date date-type=\"received\"><day>18</day><month>2</month><year>2020</year></date><date date-type=\"rev-recd\"><day>30</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>1</day><month>9</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22489.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Primary sarcomatoid hepatocellular carcinoma (SHC) is a rare subtype of morphologic hepatocellular carcinoma reported on less than 1% of surgical pathology specimens. Herein, we report a rare case of SHC. The case in question was initially misdiagnosed as a liver abscess due to the clinical and radiological similarity between these 2 pathologies. Ultrasound(US)- and contrast-enhanced ultrasound (CEUS)- guided biopsies are helpful in making an accurate diagnosis under the appropriate biopsy area and angle of puncture.</p></sec><sec><title>Patient concerns:</title><p>A 56-year old male presented to our hospital with a 2-month history of dull, upper abdominal pain without radiation.</p></sec><sec><title>Diagnoses:</title><p>Upon initial investigation with computed tomography, a cystic mass was found in the hepatic V segment and an infectious etiology was presumed. Further diagnostic examination with CEUS and magnetic resonance imaging suggested a hepatic abscess. However, a diagnosis of atypical intrahepatic cholangiocarcinoma was not excluded. The patient received the standard antibiotic treatment without alleviation of his symptoms. Through 3 diagnostic US-and CEUS-guided biopsies over a 3-month period, the pathological diagnosis of SHC was finally confirmed.</p></sec><sec><title>Interventions:</title><p>The patient was diagnosed by 3 diagnostic US-and CEUS-guided biopsies, the pathological diagnosis of SHC was finally confirmed.</p></sec><sec><title>Outcomes:</title><p>Due to the delay in diagnosis, the patient was not a candidate for surgical resection, and showed dissemination of the lesion to the portal vein. Therefore, treatment with chemotherapy was initiated. After 4 courses of this regimen, tumor progression was found on enhanced magnetic resonance imaging. Therefore, the patient received immunotherapy and targeted therapy with limited response. The patient passed away 3 months later due to tumor progression.</p></sec><sec><title>Lessons:</title><p>A hepatic abscess should be considered as a malignant lesion when clinical symptoms do not resolve upon standard treatment. US- and CEUS- guided biopsies are helpful in making an accurate diagnosis under the appropriate biopsy area and angle of puncture.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>cholangiocarcinoma</kwd><kwd>hepatocellular carcinoma</kwd><kwd>liver abscess</kwd><kwd>sarcomatoid hepatocellular carcinoma</kwd><kwd>ultrasound</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Natural Science Foundation of Zhejiang Province</funding-source><award-id>Y16H180019</award-id><principal-award-recipient>Chao Zhang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Primary Sarcomatoid hepatocellular carcinoma (SHC) is a rare subtype of morphologic hepatocellular carcinoma (HCC) and is reported on less than 1% of surgical pathology specimens.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} As such, only a small number of cases have been reported in the literature.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} SHC is recognized as a clinically aggressive carcinoma with a poor prognosis and low 5-year survival rate. Primary presentation of malignancy often occurs as a liver abscess and is mainly described in patients with metastatic colorectal cancers, intrahepatic cholangiocarcinoma (ICC) or neuroendocrine tumors.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>&#x02013;<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} The accurate diagnosis of SHC is very difficult and without timely and reasonable surgical management, tumors could progress rapidly and miss the chance of surgery. To improve the understanding and guide diagnosis for SHC, this case report retrospectively analyzed the misdiagnosis factors of the rare case of SHC.</p></sec><sec><label>2</label><title>Case report</title><p>In February 2019, A 56-year old male presented to our hospital with a 2-month history of dull upper abdominal pain without abdominal distention, nausea or vomiting, and an absence of an inciting event prior to onset. Work-up with computed tomography (CT) in local hospital suggested an infectious hepatic lesion in the hepatic V segment. The pain was not alleviated following antibiotic therapy and the patient then presented to our hospital for further treatment. The patient was admitted to the inpatient ward with a space-occupying lesion of the liver. The patient has a medical history of Hepatitis B for 1 year, treated with Lamivudine, 1 tablet a day. The patient does not have a family history of SHC or HCC. Upon physical examination, abdominal tenderness was noted. The exam was negative for rebound tenderness, muscular tension, nausea, vomiting, or fever. There was no history of weight loss, cough, jaundice, pruritus, or any clinical feature of cholangitis. Laboratory studies showed a white blood cell (WBC) 10.1&#x02217;10³/&#x003bc;l with 74% neutrophils, ALT 61&#x0200a;U/L, AST 63&#x0200a;U/L, ALP 176&#x0200a;U/L, and a serum total bilirubin 18.2&#x0200a;&#x003bc;mol/L. Tumor markers were within normal limits with the exception of an SCCA of 1.8ng/mL. Urinary routine and microscopy examination were normal. Blood cultures were sterile. HBsAg and HBeAb were positive.</p><p>Ultrasound (US) in our hospital revealed a hypoechoic lesion of 5.1&#x0200a; by 4.0&#x0200a;cm in the hepatic V segment with a thick, irregular and shaggy margin. There was no evidence of intrahepatic biliary radical dilatation and the common bile duct appeared normal. Contrast-enhanced ultrasound (CEUS) detected an irregular, thick circular hyper-enhancement with no enhancement in the inner lesion during the arterial phase. Washout of the surrounding tissue around the lesion in early portal phase was observed with showed hypo-enhancement in the venous phase (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). The CEUS pattern revealed rapid wash in and wash out consistent with the diagnosis of a hepatic abscess. However, a diagnosis of atypical ICC was not excluded. Enhanced magnetic resonance imaging (MRI) showed a significant enhancement of the irregular margin with no enhancement of the central cystic necrosis. The portal venous phase revealed decreased enhancement consistent with a hepatic abscess, but not excluded atypical ICC (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>First contrast enhanced ultrasound. A, the hepatic V segment contained a hypoechoic lesion of size 5.1&#x0200a;cm ^&#x02217; 4.0&#x0200a;cm; B, arterial phase (16&#x0200a;seconds after SonoVue injection) showed an irregular, thick, circular hyper-enhancement with no enhancement in the inner lesion; C, portal venous phase (78&#x0200a;seconds) showed washout of the surrounding tissue around the lesion; D, venous phase (149&#x0200a;seconds) showed hypo-enhancement of the surrounding tissue around the lesion.</p></caption><graphic xlink:href=\"medi-99-e22489-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>magnetic resonance imaging images. A, the hepatic V segment showed a rim-like enhancement of the irregular margin with no enhancement of the central cystic necrosis; B, the portal venous phase revealed decreased enhancement of the irregular margin; C, the venous phase showed substantial enhancement of the surrounding tissue.</p></caption><graphic xlink:href=\"medi-99-e22489-g002\"/></fig><p>Therefore, the first diagnostic, US-guided biopsy was performed (2019.2.22) and revealed hepatic coagulative necrosis and pseudolobuli formation with lobular fibrous tissue hyperplasia and ductular proliferation. Lab values were as follows: WBC 12.3&#x02217;10³/&#x003bc;l with 79% neutrophils and a total serum bilirubin 23.2&#x0200a;&#x003bc;mol/L. The patient received Sulperazone 2&#x0200a;g twice a day in our hospital. In order to avoid a false negative result on the first biopsy, the second diagnostic biopsy was performed alongside a liver abscess drainage (2019.2.26). CEUS-guided biopsy from the enhanced wall of the lesion and drainage from the abscess cavity revealed a thick, purulent material. A culture of the abscess was sterile and cytology revealed abundant pus only. Pathology studies showed fibrous tissue proliferation with focal acute, and chronic inflammatory invasion with small ductular proliferation and a section of atypical tissue. Immunohistochemistry (IHC) expressed Vimentin with a population of fibroblasts. Based on these diagnostic findings, the patient was treated as a case of a hepatic abscess. After biopsy, the patient reported intermittent fever and was treated with Sulperazone for approximately 10 days. His temperature was normal with a WBC of 11.2&#x02217;103/&#x003bc;l after antibiotic and symptomatic therapy. He was discharged from the hospital (2019.3.1) and continued on oral moxifloxacin for about 20 days.</p><p>However, 20 days later, he presented to our hospital because of fevers up to 39.4&#x0200a;&#x000b0;C and severe abdominal pain (2019.3.20). Follow-up abdominal US and CEUS found a lesion of 6.7&#x0200a; by 4.7&#x0200a;cm in the hepatic V segment which was larger than on previous investigation. Enhancement was observed in the right portal vein without intra or extra-hepatic biliary extension (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>). Due to these findings, an etiology of ICC was considered and contrast-enhanced CT (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>) showed a solid, cystic mass of variable density, and no central enhancement due to necrosis. However, parenchymal tissue showed significant enhancement consistent with previous MRI. At this point, a third US-guided diagnostic biopsy was suggested (2019.3.28) and the following pathological diagnosis showed a poorly differentiated carcinoma with an IHC positive for cytokeratin (AE1/AE3) and vimentin (2019.4.17). With these findings, the diagnosis of SHC was finally confirmed (Figs. <xref ref-type=\"fig\" rid=\"F5\">5</xref> and <xref ref-type=\"fig\" rid=\"F6\">6</xref>).</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Third contrast enhanced ultrasound. A, the hepatic V segment showed a lesion of size 6.7&#x0200a;cm ^&#x02217; 4.7&#x0200a;cm, much larger than on initial imaging time; B, arterial phase (18&#x0200a;seconds after SonoVue injection) showed irregular, thick, circular hyper-enhancement with no enhancement area inner the lesion; C, portal venous phase (90&#x0200a;seconds) showed washout of the surrounding tissue around the lesion and enhancement of portal vein mass; D, venous phase (136&#x0200a;seconds) showed hypo-enhancement of the surrounding tissue around the lesion and portal vein mass.</p></caption><graphic xlink:href=\"medi-99-e22489-g003\"/></fig><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>CT images. A, the hepatic V segment showed mixed density and irregular margin enhancement with no enhancement of the central cystic necrosis in arterial phase; B, the portal phase revealed decreased enhancement of the parenchymal tissue; C, the venous phase showed substantial enhancement of the margin.</p></caption><graphic xlink:href=\"medi-99-e22489-g004\"/></fig><fig id=\"F5\" orientation=\"portrait\" position=\"float\"><label>Figure 5</label><caption><p>Pathological and immunohistochemical examination of a tumor sample. A, lesion tissue characterized by malignant spindle-shaped sarcomatoid hepatocellular carcinoma cells (HE&#x000d7;20); B, diffuse, weak positive signal for cytokeratin; C, diffuse strong positive signal for vimentin.</p></caption><graphic xlink:href=\"medi-99-e22489-g005\"/></fig><fig id=\"F6\" orientation=\"portrait\" position=\"float\"><label>Figure 6</label><caption><p>Ultrasound images of 3 performed biopsies. A, first time US-guided biopsy, the puncture needle was inserted alongside the margin of the lesion; B, second Contrast enhanced ultrasound-guided biopsy, the puncture needle was inserted at the enhancement wall of the lesion; C and D, third ultrasound-guided biopsy, the puncture was obtained from 2 different regions (hepatic VIII and V segments).</p></caption><graphic xlink:href=\"medi-99-e22489-g006\"/></fig><p>The patient was not a candidate for surgical resection due to the presence of metastasis. Therefore, treatment with chemotherapy was initiated. The chemotherapy regimen consisting of Albumin paclitaxel (105&#x0200a;mg/m2, 200&#x0200a;mg i.v. for 30&#x0200a;minutes) and gemcitabine (850&#x0200a;mg/m2, 1600&#x0200a;mg i.v. for 30&#x0200a;minutes). After 4 courses of this regimen, tumor progression was found on enhanced MRI (2019.6.14). Therefore, the patient received immunotherapy and targeted therapy that consisting of PD-1&#x0200a;(130&#x0200a;mg/m2, 240&#x0200a;mg i.v. for 30&#x0200a;minutes) on day 1 and Anlotinib (10&#x0200a;mg po) on day 1 to day 14. The patient dead 3 months later due to tumor progression (September 2019). The flowchart of the patient's treatment process is as followed (Fig. <xref ref-type=\"fig\" rid=\"F7\">7</xref>).</p><fig id=\"F7\" orientation=\"portrait\" position=\"float\"><label>Figure 7</label><caption><p>The flowchart of the treatment processes. CEUS&#x0200a;=&#x0200a;contrast enhanced ultrasound, CT&#x0200a;=&#x0200a;computed tomography, ICC&#x0200a;=&#x0200a;intrahepatic cholangiocarcinoma, MRI&#x0200a;=&#x0200a;magnetic resonance imaging.</p></caption><graphic xlink:href=\"medi-99-e22489-g007\"/></fig></sec><sec><label>3</label><title>Discussion</title><p>SHC is a relatively rare form of malignancy, characterized by features of epithelial and mesenchymal tumors. The fourth edition of WHO tumor classifications suggests that the sarcomatoid component represents a clonal evolution from a differentiated component from HCC or ICC.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} The etiology of SHC is not clear; some reports have suggested that HCC cases with sarcomatous changes after anticancer therapy such as transcatheter arterial chemoembolization, radiofrequency ablation, or percutaneous ethanol injection may cause the development of SHC, or accelerate the proliferation of sarcomatous cells.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Some reports suggest that this uncommon subtype of liver cancer is also associated with hepatitis B and hepatitis C infection.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Compared with HCC, the prognosis of SHC is much poorer due to frequent recurrence and metastasis. However, SHC is easily misdiagnosed as ICC and liver abscess, which delays the optimal treatment.</p><p>It is difficult to differentiate liver abscess from SHC not only in clinical practice but also on imaging examination. Clinically, shared features between the 2 pathologies include upper right quadrant abdominal pain, persistent fever with or without chills, rigor, nausea, vomiting, diarrhea, and weight loss. The nonspecific findings suggestive of a pyogenic liver abscess therefore delays the diagnosis of malignancy.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Laboratory tests usually indicate an inflammatory reaction with increased WBC, erythrocyte sedimentation rate, and C-reactive protein in the liver abscess, which is also present in malignancy with infection and necrosis. Secondary liver abscess formation by SHC may be driven by tumor necrosis and subsequent infection and transformation to an abscess.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} As far as imaging examination is concerned, peripheral enhancement, and central necrosis are the shared features between SHC and hepatic abscess, complicating the diagnosis of these lesions. Central necrosis and hemorrhage of SHC as the sarcomatoid component consists of rapidly proliferating, poorly differentiated cells that outgrow their vascular supply.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} The tissue surrounding of the core of necrosis consists of inflammatory cytokines increasing arterial perfusion of the affected area. Therefore, SHC usually presents as a large mass with peripheral enhancement and central necrosis, variable enhancement of the solid portion with or without tumor capsule, and intra- and extra-hepatic metastasis.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Alongside thrombosis of small portal and hepatic veins these mechanisms contribute to the observed increases in CEUS enhancement around the core of necrosis with a wash-out of the inflamed parenchyma.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} According to the findings presented herein, the most notable difference between a hepatic abscess and SHC is in the ring-enhancing part of the lesion, which is thicker in an abscess compared with SHC. Furthermore, hepatic abscesses usually demonstrate liquefactive necrosis in a honeycomb pattern without metastasis while SHC presents as diffuse liquefactive necrosis with metastasis or thrombosis of small portal and hepatic veins.</p><p>Additionally, it may be difficult to differentiate SHC from ICC by imaging without pathological confirmation. In most ICC cases, an irregular, rim-like hyper-enhancement is seen in the periphery of the lesion with a strip-like enhancement extending to the central portion in arterial phase. These findings are followed by a rapid washout in late arterial phase or early portal phase, and a marked washout in venous phase.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>&#x02013;<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} The boundary of the non-enhanced area in ICC contains abundant fibrous tissue in the core of the tumor. The border between fibrous tissue and peripheral tumor cells is obscured due to the infiltrative tumor growth of cholangiocytes. However, the presence of intratumor vasculature is a defining characteristic of ICC.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} Despite the sensitivity of this marker, clinical diagnosis in practice is difficult. However, some ancillary findings may serve to differentiate SHC from ICC. In most cases of ICC, capsular retraction, bile duct dilatation distal to the lesion, and vascular encasement are very common. Meanwhile, intra and extra-hepatic metastasis are relatively common in SHC. Additionally an elevated CA19 to 9 with increases of ALP is more common in ICC than SHC, but these values are non-specific to either disease.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]}</p><p>In this case-study, a normal level of CA19 to 9 was found. Initial CEUS and enhanced MRI suggested a liver abscess followed by the presence of inflammatory and necrotic cells on guided biopsy. Due to the diagnosis of a hepatic abscess, surgery was not elected for this patient. Upon his second presentation to our hospital due to a fever of 39.4&#x0200a;&#x000b0;C with severe abdominal pain, CEUS suggested an ICC due to the increased mass and portal vein thrombosis. Nevertheless, only the third US-guided biopsy confirmed the diagnosis of SHC according to IHC results, which was positive for both an epithelial marker CK (AE1/AE3) and mesenchymal marker (Vimentin). The potential causes of initial misdiagnosis may be due to the position of the puncture and tumor progression. The pathology of the first biopsy showed necrotic tissue, which is consistent with the necrotic core of the tumor. The second biopsy suggested fibrous proliferation and focal acute inflammatory invasion, consistent with the proliferating rim of the tumor. Aspiration from the abscess cavity revealed thick, purulent material suggesting an inflammatory reaction such as a hepatic abscess. However, the third puncture was obtained from 2 different regions, and revealed the presence of malignant cells.</p><p>The prognosis of SHC is poor with surgical excision being the best option for effective treatment. Currently, the 3-year survival rate is as low as 18.2% after liver resection.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Due to the presence of portal vein metastasis in this case, systemic treatment was the only viable option. However, had a definitive diagnosis been made earlier, surgical resection may have been possible.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} This case highlights the importance and difficulties in reaching an accurate and timely diagnosis of SHC.</p></sec><sec><label>4</label><title>Conclusion</title><p>In summary, this study reports a rare case of SHC and the resulting follow-up using CEUS, CT, and MRI. Eventually, SHC was confirmed through 3 diagnostic US-and CEUS-guided biopsies over a 3-month period. Due to the delay in diagnosis, the patient was not a candidate for surgical resection and showed dissemination of the lesion to the portal vein. Therefore, malignancy should always be considered when a hepatic abscess fails to resolve following the standard course of treatment. The specific patient population at risk would include an elderly patient presenting with persistent abdominal pain and intermittent fever with no response to multiple courses of antibiotics. Additionally, US-and CEUS-guided biopsies of multiple areas within the lesion are invaluable in making a timely and accurate diagnosis.</p></sec><sec><title>Acknowledgments</title><p>We would like to thank Kanlun Xu for his contribution to the review of all the drafts of the manuscript.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Zheng Yang, Yanan Zhao.</p><p><bold>Data curation:</bold> Zheng Yang, Kun Lv, Yanan Zhao.</p><p><bold>Formal analysis:</bold> Kun Lv, Minqiang Pan.</p><p><bold>Investigation:</bold> Zheng Yang, Chao Zhang.</p><p><bold>Methodology:</bold> Yanan Zhao, Shumei Wei</p><p><bold>Project administration:</bold> Yanan Zhao.</p><p><bold>Resources:</bold> Yanan Zhao.</p><p><bold>Supervision:</bold> Kun Lv.</p><p><bold>Validation:</bold> Zheng Yang, Chao Zhang.</p><p><bold>Visualization:</bold> Minqiang Pan, Chao Zhang, Shumei Wei.</p><p><bold>Writing &#x02013; original draft:</bold> Zheng Yang.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Zheng Yang, Yanan Zhao.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CEUS = contrast-enhanced ultrasound, CT = computed tomography, HCC = hepatocellular carcinoma, ICC = intrahepatic cholangiocarcinoma, IHC = immunohistochemistry, MRI = magnetic resonance imaging, SHC = sarcomatoid hepatocellular carcinoma, US = ultrasound, WBC = white blood cell.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Yang Z, Lv K, Zhao Y, Pan M, Zhang C, Wei S. Sarcomatoid hepatocellular carcinoma mimicking hepatic abscess: a case report. <italic>Medicine</italic>. 2020;99:39(e22489).</p></fn><fn fn-type=\"other\"><p>Patient's son provided informed consent for publication of the case. The written informed consent was obtained from the patient's son.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no funding and conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article [and its supplementary information files].</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Torbenson</surname><given-names>MS</given-names></name></person-group>\n<article-title>Morphologic subtypes of hepatocellular carcinoma</article-title>. <source>Gastroenterol Clin North Am</source>\n<year>2017</year>;<volume>46</volume>:<fpage>365</fpage>&#x02013;<lpage>91</lpage>.<pub-id pub-id-type=\"pmid\">28506370</pub-id></mixed-citation></ref><ref id=\"R2\"><label>[2]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Wang</surname><given-names>QB</given-names></name><name><surname>Cui</surname><given-names>BK</given-names></name><name><surname>Weng</surname><given-names>JM</given-names></name><etal/></person-group>\n<article-title>Clinicopathological characteristics and outcome of primary sarcomatoid carcinoma and carcinosarcoma of the liver</article-title>. <source>J Gastrointest Surg</source>\n<year>2012</year>;<volume>16</volume>:<fpage>1715</fpage>&#x02013;<lpage>26</lpage>.<pub-id pub-id-type=\"pmid\">22767081</pub-id></mixed-citation></ref><ref id=\"R3\"><label>[3]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Yu</surname><given-names>Y</given-names></name><name><surname>Zhong</surname><given-names>Y</given-names></name><name><surname>Wang</surname><given-names>J</given-names></name><etal/></person-group>\n<article-title>Sarcomatoid hepatocellular carcinoma (SHC): a case report</article-title>. <source>World J Surg Oncol</source>\n<year>2017</year>;<volume>15</volume>:<fpage>219</fpage>.<pub-id pub-id-type=\"pmid\">29233162</pub-id></mixed-citation></ref><ref id=\"R4\"><label>[4]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Shah</surname><given-names>V</given-names></name><name><surname>Arora</surname><given-names>A</given-names></name><name><surname>Tyagi</surname><given-names>P</given-names></name><etal/></person-group>\n<article-title>Intrahepatic cholangiocarcinoma masquerading as liver abscess</article-title>. <source>J Clin Exp Hepatol</source>\n<year>2015</year>;<volume>5</volume>:<fpage>89</fpage>&#x02013;<lpage>92</lpage>.<pub-id pub-id-type=\"pmid\">25941437</pub-id></mixed-citation></ref><ref id=\"R5\"><label>[5]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Giuliani</surname><given-names>A</given-names></name><name><surname>Caporale</surname><given-names>A</given-names></name><name><surname>Demoro</surname><given-names>M</given-names></name><etal/></person-group>\n<article-title>Silent colon carcinoma presenting as a hepatic abscess</article-title>. <source>Tumori</source>\n<year>2007</year>;<volume>93</volume>:<fpage>616</fpage>&#x02013;<lpage>8</lpage>.<pub-id pub-id-type=\"pmid\">18338500</pub-id></mixed-citation></ref><ref id=\"R6\"><label>[6]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Lee</surname><given-names>SH</given-names></name><name><surname>Kim</surname><given-names>KA</given-names></name><name><surname>Lee</surname><given-names>JS</given-names></name><etal/></person-group>\n<article-title>A case of primary neuroendocrine carcinoma of liver presenting with liver abscess</article-title>. <source>Korean J Gastroenterol</source>\n<year>2006</year>;<volume>48</volume>:<fpage>277</fpage>&#x02013;<lpage>80</lpage>.<pub-id pub-id-type=\"pmid\">17060722</pub-id></mixed-citation></ref><ref id=\"R7\"><label>[7]</label><mixed-citation publication-type=\"book\"><person-group person-group-type=\"author\"><name><surname>Miettinen</surname><given-names>M</given-names></name><name><surname>Fietcher</surname><given-names>CDM</given-names></name><name><surname>Kindblom</surname><given-names>LG</given-names></name></person-group>\n<person-group person-group-type=\"editor\"><name><surname>Bosman</surname><given-names>FT</given-names></name><name><surname>Carneiro</surname><given-names>F</given-names></name><name><surname>Hruban</surname><given-names>RH</given-names></name><etal/></person-group>\n<article-title>Mesenchymal tumours of the liver</article-title>. <source>WHO Classification of Tumours of the Digestive System</source>. <publisher-loc>Lyon</publisher-loc>: <publisher-name>IARC Press</publisher-name>; 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991400</article-id><article-id pub-id-type=\"pmc\">PMC7523808</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-03576</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000021780</article-id><article-id pub-id-type=\"art-access-id\">21780</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>6300</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Interventions to improve physical performances of older people with cancer before complex medico-surgical procedures</article-title><subtitle>Protocol for an umbrella review of systematic reviews and meta-analyses</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0001-7267-4723</contrib-id><name><surname>Falandry</surname><given-names>Claire</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Stefani</surname><given-names>Laetitia</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Andre</surname><given-names>Louise</given-names></name><degrees>BS</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Granger</surname><given-names>Marion</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Barbavara</surname><given-names>Claire</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Habchi</surname><given-names>Hocine</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff4\">^d</xref></contrib><contrib contrib-type=\"author\"><name><surname>Bourgeois</surname><given-names>Chrystelle</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Cure</surname><given-names>Herv&#x000e9;</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff5\">^e</xref></contrib><contrib contrib-type=\"author\"><name><surname>Passot</surname><given-names>Guillaume</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff6\">^f</xref></contrib><contrib contrib-type=\"author\"><name><surname>Gilbert</surname><given-names>Thomas</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff7\">^g</xref></contrib><on-behalf-of>For The PROADAPT working group</on-behalf-of></contrib-group><aff id=\"aff1\"><label>a</label>Geriatric Unit, Lyon-Sud Hospital</aff><aff id=\"aff2\"><label>b</label>CarMeN Laboratory, Inserm U1060, INRA U1397, Universit&#x000e9; Claude Bernard Lyon 1, INSA Lyon, Charles M&#x000e9;rieux Medical School, Lyon University, Oullins</aff><aff id=\"aff3\"><label>c</label>Oncology Department, Centre Hospitalier Annecy Genevois, Pringy</aff><aff id=\"aff4\"><label>d</label>Urology Department, University Hospital Jean Monnet, St. Etienne</aff><aff id=\"aff5\"><label>e</label>Department of Medical Oncology, CHU de Grenoble, La Tronche</aff><aff id=\"aff6\"><label>f</label>Department of Surgical Oncology, CHU Lyon Sud, Hospices Civils de Lyon, University of Lyon</aff><aff id=\"aff7\"><label>g</label>Health Services and Performance Research (HESPER EA7425), Lyon, France.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Claire Falandry, Hospices Civils de Lyon, Pierre-B&#x000e9;nite, Auvergne-Rh&#x000f4;ne-Alpes, France (e-mail: <email>claire.falandry@chu-lyon.fr</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e21780</elocation-id><history><date date-type=\"received\"><day>15</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>17</day><month>7</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e21780.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Current demographics lead increasing older cancer patients to undergo complex medico-surgical procedures, with substantial risk of decompensations and deconditioning. The Prehabilitation &#x00026; Rehabilitation in Oncology: Adaptation to Disease and Accompaniment of Patients&#x02019; Trajectories (PROADAPT) project is currently being developed with the aim of improving care, through standardized care pathways guided by existing evidence and implementation programs. A working group will specifically focus on improvement of physical performances before such procedures. These interventions may have been developed in different contexts: before surgery in large, before carcinologic surgery or complex medical interventions (chemotherapy, radiotherapy), or in primary care for elderly patients to prevent sarcopenia and frailty. Post-surgical interventions are out of the scope of this review. The objective of this review is to summarize the level of evidence to support physical reconditioning interventions and identify areas where further work is required.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>This umbrella review will include moderate to high quality systematic reviews, meta-analysis, and pre-existing umbrella or meta-reviews. Two reviewers will independently search the following databases: PubMed/MedLine, Cochrane Library, Embase, and CINAHL. Research strategy will use diverse keywords used to refer to the concepts of &#x0201c;prehabilitation,&#x0201d; &#x0201c;preoperative exercise,&#x0201d; or &#x0201c;preoperative rehabilitation,&#x0201d; with prespecified inclusion and exclusion criteria and only systematic reviews selection. The distinct types of interventions presented using PRISMA guidelines and a narrative reporting of results. A focus will be made on outcomes such as physical performances, quality of life, autonomy in everyday activities, or number of hospital bed days.</p></sec><sec><title>Ethics and dissemination:</title><p>Ethical approval is not required for such an umbrella review. Our review will be submitted for publication in a peer-reviewed international journal using open access option if available. It will be complementary to reviews focused on hospital discharge of older people.</p></sec><sec><title>PROSPERO registration number:</title><p>CRD42020100110.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>cancer</kwd><kwd>older people</kwd><kwd>prehabilitation</kwd><kwd>umbrella review</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Minist&#x000e8;re des Affaires Sociales et de la Sant&#x000e9;</funding-source><award-id>&#x000ab;Innovez en sant&#x000e9; pour le territoire Auvergne-Rhone-Alpes&#x000bb; 2016</award-id><principal-award-recipient>Claire FALANDRY</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>In 2016, cancer has become in Western Europe the first cause of death in patients over 65, a global trend due to the decrease in cardiovascular mortality and an increasing incidence of cancer with age.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Moreover, cancer itself and cancer treatments are a major cause of disability and physical deconditioning in the older population. Recent data from the Surveillance Epidemiology and End Results Program (SEER) demonstrated that, apart from direct surgical outcomes, usually evaluated using Clavien-Dindo classification of post-surgical adverse events, older people who underwent major carcinologic surgeries display a substantial risk of hospital admissions in the 30 days after surgery for geriatric events.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Consequently, treatment decisions may have a major impact, both medical and economical, both immediate on patients and the health system through patients&#x02019; care-courses and adverse events management, and in the long term on patients and their families through their long-term impact on functionality and quality of life. The health systems of developed countries face the dual issue of aging demographics and budget restriction, which push towards an increased turn-over of hospital beds and reduced length of stay. In this context, there is a need to develop intervention programs to decrease the risk of functional deconditioning in this high-risk population.</p><p>Prehabilitation has been for long conceptualized as an effective way to enhance functional capacity of the individual to enable him or her to withstand different stressors. Initially developed in the army as the association of physical training to improve strength and endurance, improved nutritional intake and general education, it was transposed to medicine and major surgery&#x02014;particularly elective cardiac and orthopedic surgery&#x02014;at the beginning of this century. The concept of cancer prehabilitation arose from that context as &#x0201c;a process on the cancer continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment and includes physical and psychological assessments that establish a baseline functional level, identify impairments, and provide interventions that promote physical and psychological health to reduce the incidence and/or severity of future impairments.&#x0201d;</p><p>Despite an increasing interest of medical community on prehabilitation and particularly cancer prehabilitation, the level of evidence for specific interventions is considered as too low to be implemented in common care. Among the major drawbacks of published data are the heterogeneity of the programs, sometimes a poor adherence of the patients and the fact that most studies were small pilot studies that were developed for fitter and younger patients than those expected to get the better benefit from prehabilitation. Another point to highlight is the fact that the majority of prehabilitation programs include only one intervention&#x02014;either a physical, nutritional, or psychological prehabilitation&#x02014;when multimodal interventions are frequently considered as more effective in older populations. Nevertheless, 71% of the surgeons interviewed would accept to prehabilitate their elderly patients 4 weeks before surgery, if such intervention is proven to be effective.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]}</p><p>Moreover, as the older population appears particularly vulnerable, with an increased risk of adverse outcomes and unplanned readmissions after discharge,^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} as his medico-social management is more complex and the risks are higher, the old patient is considered as a good target to demonstrate the medico-economic impact of such prehabilitation strategies. In the context of cancer care, older patients appear even more at risk, as the burden of the disease and treatments add up to the patient's underlying condition. Even the fittest older patients may be strongly affected by complex treatments such as chemotherapy, radiotherapy, or heavy surgical procedures, hence widening the scope of frailty.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]}</p><p>The PROADAPT project is currently being developed to address this concern, with the aim of improving outcomes of older patients undertaking complex medical and surgical treatments for cancer, through harmonized evidence-based pathways of care and procedures. In a holistic approach, various aspects of care and prevention will be covered by this program (nutritional status, pre/rehabilitation, standardization of procedures, medical reconciliation, patient education, and transition) (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>The global design of PROADAPT standardized multidomain geriatric intervention (dashed lines: contents included in the current meta-review on physical exercise prehabilitation; dotted lines: contents possibly associated to physical exercise interventions in the current meta-review). PROADAPT&#x0200a;=&#x0200a;prehabilitation &#x00026; rehabilitation in oncology: adaptation to disease and accompaniment of patients.</p></caption><graphic xlink:href=\"medi-99-e21780-g001\"/></fig></sec><sec><label>2</label><title>Objectives</title><p>The overarching aim of this review is to summarize and perform a grading of the level evidence in the literature on prehabilitation interventions (physical&#x0200a;&#x000b1;&#x0200a;nutritional&#x0200a;&#x000b1;&#x0200a;psychological) that may apply to older patients who will undergo complex medico-surgical procedures for cancer treatment. We will aim to answer the following questions:</p><list list-type=\"bullet\"><list-item><p>Which interventions are efficient?</p></list-item><list-item><p>For which patients/in which context?</p></list-item><list-item><p>For which outcomes?</p></list-item><list-item><p>And if possible, how are they best implemented?</p></list-item></list><p>Due to the paucity of published results in the specific field of the research topic, this umbrella review will aim at covering in large interventions designed for adult patients before surgery or complex medical interventions, either in the context of cancer or in other settings.</p></sec><sec><label>3</label><title>Methods and analysis</title><sec><label>3.1</label><title>Criteria for included studies</title><sec><label>3.1.1</label><title>Type of study</title><p>We will focus the literature search on existing high quality systematic reviews, meta-analysis and systematic mapping reviews. We will follow the PRISMA guidelines for conducting this review.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} The included reviews will need to:</p><list list-type=\"bullet\"><list-item><p>Clearly state the research question and the objectives of the study.</p></list-item><list-item><p>Include an explicit methods section with the eligibility criteria for included studies, a reproducible methodology with a systematic approach that attempts to identify all studies that would meet the eligibility criteria.</p></list-item><list-item><p>Show a predefined quality appraisal of included studies with validated methodology.</p></list-item><list-item><p>Describe a systematic method for data extraction, synthesis and presentation of findings.</p></list-item></list><p>Existing guidelines, expert consensus papers, randomized controlled trials performed and reported more recently than those reported in the included reviews, and existing qualitative studies focused on implementation of prehabilitation programs will not be included in the umbrella review, but might be considered as complementary information while analyzing the results.</p></sec><sec><label>3.1.2</label><title>Population and context</title><p>The overarching aim of this umbrella review is to gather evidence on prehabilitation of older patients planned to undergo complex treatments for cancer. However, programs designed towards broader age groups or in other contexts than cancer may still be relevant and possibly transposable to this specific purpose.</p><p>Therefore, we will include reviews of prehabilitation interventions designed for:</p><list list-type=\"bullet\"><list-item><p>Older patients (&#x0003e;65 years) planned to undergo major oncologic surgery and/or complex medical interventions as chemotherapy, radiotherapy.</p></list-item><list-item><p>Older patients (&#x0003e;65 years) planned to undergo non-oncologic major surgery (elective cardiac, orthopedic, digestive&#x02026;).</p></list-item><list-item><p>Older patients (&#x0003e;65 years) in primary care.</p></list-item><list-item><p>Patients (not specifically old) planned to undergo major oncologic surgery and/or complex medical interventions as chemotherapy, radiotherapy.</p></list-item><list-item><p>Patients (not specifically old) planned to undergo non-oncologic major surgery (elective cardiac, orthopedic, digestive&#x02026;).</p></list-item></list><p>Five meta-reviews are currently underway and identified in PROSPERO as &#x0201c;The effectiveness of prehabilitation for adults having elective surgery: a systematic review protocol,^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]}&#x0201d; &#x0201c;The effectiveness of prehabilitation on long term outcome measures for adults due to undergo treatment for cancer: a systematic review protocol,^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]}&#x0201d; &#x0201c;Prehabilitation programmes for newly diagnosed cancer patients,^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]}&#x0201d; &#x0201c;Multimodal prehabilitation programs as a bundle of care in gastrointestinal cancer surgery: systematic review^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]}&#x0201d; and &#x0201c;A systematic review and meta-analysis of nutrition prehabilitation with or without exercise^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]}&#x0201d; that will enrich our conclusions as soon as they are published before the end of data extraction. These works will be complementary to ours and we will take the results of this review into account according this umbrella review methodology rather than duplicating the review process.</p></sec><sec><label>3.1.3</label><title>Interventions and comparators</title><p>All interventions specifically designed to improve physical performance (strength and endurance)&#x0200a;&#x000b1;&#x0200a;nutrition&#x0200a;&#x000b1;&#x0200a;psychology and adherence will be considered (sometimes, these interventions will be associated within multi-modal programs but physical exercise is mandatory). This can include (not exclusively):</p><sec><label>3.1.3.1</label><title>Various types of exercises</title><list list-type=\"bullet\"><list-item><p>Aerobic (=endurance) training: cycling, walking, aquatic exercises&#x02026;</p></list-item><list-item><p>Resistance training (=strengthening).</p></list-item><list-item><p>Pulmonary exercises (=breathing): triflow,</p></list-item><list-item><p>Abdominal exercises,</p></list-item><list-item><p>Pelvic exercises (=continence training).</p></list-item></list></sec><sec><label>3.1.3.2</label><title>Various modalities of supervision</title><list list-type=\"bullet\"><list-item><p>Supervised exercise&#x0200a;&#x000b1;&#x0200a;biofeedback.</p></list-item><list-item><p>Unsupervised exercise.</p></list-item><list-item><p>Group activities.</p></list-item><list-item><p>Written instructions.</p></list-item><list-item><p>Verbal instructions.</p></list-item><list-item><p>Current guidelines prescription.</p></list-item></list><p>Various durations of the prehabilitation program.</p><p>Various duration of each training session.</p><p>Various frequencies of training sessions.</p><p>Various intensities and intensity scales, number of repetitions for strength exercises: steps, contractions&#x02026;</p></sec></sec><sec><label>3.1.4</label><title>Outcomes</title><p>The quality of prehabilitation can be evaluated on many different outcomes from the patient and the system's point of view (e.g., VO2 peak; functionality, urinary or rectum continence, mortality, postoperative complications, patient satisfaction, quality of life, length of stay, costs, ...). These outcomes will be listed and mapped during the review process.</p><p>For example, many interventions have been designed to decrease length of stay.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Even though such interventions may also have beneficial effects on patient-related outcomes, vulnerable older patients treated for cancer may still have an important risk of unplanned readmissions.</p><p>Another dimension to be highlighted in a specific population of older adults is the acceptability of the intervention program. Bruns recently highlighted in a systemic review that the compliance to preoperative exercise varied from 16% to 97% in elderly patients undergoing colorectal surgery.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} As this meta-review focuses on prehabilitation programs to be proposed to a heterogeneous population, eventually frail and psychologically distressed, a particular attention will be paid to compliance data.</p></sec><sec><label>3.1.5</label><title>Exclusion criteria</title><list list-type=\"bullet\"><list-item><p>Interventions in the paediatric context.</p></list-item><list-item><p>Interventions in the context of mental health care or psychiatry, except from delirium or dementia-orientated services.</p></list-item><list-item><p>Palliative support. Even if oncology patients may be likely to deteriorate, the aim of the PROADAPT program is to define methods for preventive interventions in actively treated patients rather than promoting palliative care, which is already well structured in this context.</p></list-item><list-item><p>Interventions not designed as prehabilitation exercise programs.</p></list-item><list-item><p>Reviews for which the full report is not available (e.g., published protocol with no final report available).</p></list-item><list-item><p>Reviews written in other languages than English or French (for pragmatic reasons), which will still be considered up to the English language version of the abstract during the selection process.</p></list-item><list-item><p>Reviews with insufficient quality based on the AMSTAR-2 check-list measurement tool to assess systematic reviews.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]}</p></list-item></list></sec></sec><sec><label>3.2</label><title>Study retrieval</title><sec><label>3.2.1</label><title>Sources</title><list list-type=\"bullet\"><list-item><p>Database searches: PubMed/MedLine, Cochrane Library, Embase, and CINAHL.</p></list-item><list-item><p>Ongoing studies: PROSPERO.</p></list-item><list-item><p>Grey literature: As this umbrella review will include systematic reviews of moderate to high quality, we will assume that they have sought grey literature and that they will have been published in indexed journals.</p></list-item></list><p>Limits: the initial search will be limited to the 2000 to 2020 period, as we will be searching for up-to-date information. However, this period might be extended if there are too few results to the search.</p></sec><sec><label>3.2.2</label><title>Timeline</title><p>The search will be conducted from January 2020 and repeated monthly up to December 2020. When possible, alerts will also be set in main databases such as PubMed.</p></sec><sec><label>3.2.3</label><title>Search strategy</title><p>In accordance with the scope of the research, three main concepts can be drawn out of the research question:</p><list list-type=\"bullet\"><list-item><p>Older patients</p></list-item><list-item><p>Physical prehabilitation</p></list-item><list-item><p>Cancer</p></list-item></list><p>The outline of the search strategy is pictured in Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>.</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Simplified outline of the search strategy.</p></caption><graphic xlink:href=\"medi-99-e21780-g002\"/></fig></sec><sec><label>3.2.4</label><title>Search terms</title><p>Searches will be developed and combined using broad search terms, key words and MeSH terms referring to each of the concepts pictured above (this is list is not comprehensive and subject to evolution):</p><list list-type=\"simple\"><list-item><label>-</label><p>Older adults (e.g., old&#x02217;, aged, aging, elder&#x02217;, senior&#x02217;, geriatric&#x02217;, frail, late-life, pensioner&#x02217;, veteran&#x02217;)</p></list-item><list-item><label>-</label><p>Prehabilitation, preoperative rehabilitation, preoperative exercise, etc.</p></list-item><list-item><label>-</label><p>Cancer, cancer treatment, neoplasms, tumour, surgical recovery</p></list-item><list-item><label>-</label><p>Review, Systematic review, meta-analysis, meta-review, mapping review</p></list-item></list></sec><sec><label>3.2.5</label><title>Detailed search strategy</title><p>The search strategies are presented in Table <xref rid=\"T1\" ref-type=\"table\">1</xref> according different databases.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Search strategies.</p></caption><graphic xlink:href=\"medi-99-e21780-g003\"/></table-wrap></sec><sec><label>3.2.6</label><title>Study selection</title><p>The number of results for each database search and with other sources will be noted and presented in a PRISMA flow-diagram, which will be updated and finalised in December 2020.</p><sec><label>3.2.6.1</label><title>Title and abstract selection</title><p>First, all the citations will be imported in Zotero and duplicates will be removed. After title screening, all potentially relevant citations will be exported to Microsoft Excel with full title, author, journal and year.</p><p>Two authors will then independently screen titles and abstracts for inclusion and exclusion criteria. Each decision to include or exclude a study will be marked by 1 or 0 by both reviewers to allow the evaluation of inter-rater agreement between reviewers. The inclusion scores between the two reviewers will be then be added up in Excel, and lead to three possible scores: 2 (selection for full-text review), 1 (need for discussion between authors), and 0 (exclusion). Two Excel files will initially be completed independently by two authors, and will then be merged into one and shared on a Google drive. Duplicates will be removed during the merging process.</p><p>All articles selected using this method will be considered for the full-text selection stage.</p><p>A Venn diagram will be constructed in order to evaluate the level of redoundancy between the different databases.</p></sec><sec><label>3.2.6.2</label><title>Full-text selection</title><p>After the initial title and abstract selection, the full-text articles will be obtained and screened independently for inclusion and exclusion criteria by 2 reviewers. This process will comprise the quality assessment of the reviews (see quality assessment).</p><p>Similarly to the previous step, each decision to include or exclude a study will be marked by 1 or 0 by both reviewers. This will allow the evaluation of inter-rater agreement between reviewers and unable to create a global score of 0 (exclusion), 1 (unclear, discussion), or 2 (inclusion).</p><p>At this stage, all exclusion decisions will be documented and recorded to allow the results of the screening to be reviewed. AMSTAR-2 scores will also be reported independently by both authors.</p></sec><sec><label>3.2.6.3</label><title>Follow-up of bibliography of key articles</title><p>After the full-text selection, the bibliography of all articles included by both authors will be screened in search for possible additional references, for which the process would be repeated from the title and abstract selection stage.</p></sec><sec><label>3.2.6.4</label><title>Critical appraisal</title><p>For the critical appraisal of the studies, we will apply the AMSTAR-2 checklist to select only the reviews of high to moderate quality, defined using the AMSTAR-2 check-list.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} In accordance with previous or ongoing studies using AMSTAR-2 for quality assessment of systematic reviews, the studies will be marked as of high quality if they present 0 to 1 non-critical weakness; of moderate quality if they have &#x0003e;1 non-critical weakness; of low quality if they present one critical flaw with or without non-critical weaknesses: of critically low quality if they have &#x0003e;1 critical flaw with or without non-critical weaknesses.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>&#x02013;<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]}</p></sec></sec></sec><sec><label>3.3</label><title>Data analysis plan</title><p>A &#x0201c;flow diagram&#x0201d; charting the number of references at each stage in the review process will be produced in line with the PRISMA statement.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} The quantity and quality of the literature will be summarized in both narrative commentary and summary tables, which may be adapted according to the results of the umbrella review.</p><p>The articles selected for full-text review will be screened according to a standard Data extraction form.</p><p>A full report will be developed, which will include a narrative overview with detailed description of the review methodology and findings.</p><p>The initial draft of manuscript will be circulated within the research team and coinvestigators among the PROADAPT group. Depending on the results of this review, we may be able to present a set of guidelines for good practice in accordance with the available evidence. For grading of recommendations, we will then use the GRADE guidance.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]}</p><p>The manuscript will be amended until a consensus is reached with regards to the recommendations which can be drawn out of the umbrella review.</p></sec></sec><sec><label>4</label><title>Ethics and dissemination</title><p>This review will aim to be as comprehensive as possible. In line with the concept of umbrella reviews or meta-reviews, sources of grey literature will not be sought directly. However, this umbrella review will include only systematic reviews, meta-analysis or meta-reviews of moderate to high quality, which should thus have considered grey literature. This should help to reduce the risk of publication bias. However, the exclusion of reviews in other languages than English or French may reduce the scope of the research.</p><p>This systematic umbrella review should help us to evaluate the acceptability and efficiency of different physical exercise programs with the level of evidence to support their implementation in the PROADAPT program. However, it is only focused on high quality systematic reviews and it is likely that it will leave many gaps due to insufficient quality evidence. The first steps of our analyse demonstrated that the manuscripts included in the different meta-analyses already published are not purely redundant, leading to potential misinterpretations. We expect that including the whole content of these systematic analyses will improve the interpretation. We are aware that some questions relevant to our work might be left unanswered. It may, thus, also be useful to widen the scope to reviews of lower quality evidence or expert consensus publications. Such sources could not be included in this review, which aims for high quality information in priority, but might be considered as complementary information while compiling the results of the review. Another conflicting point is located in the high heterogeneity of the interventions tested has been highlighted in many previous articles, leading to systematic reviews instead of real meta-analyses.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} The research team will also take into account existing guidelines from health authorities or expert groups. Nevertheless, this review will help to orientate future dedicated systematic reviews of randomised trials or new research projects on the topic, so that as much reliable information as possible can be gathered.</p><p>This study will focus specifically on older patients with cancer. We anticipate that this refined population may lead to few results. However, we felt that given the increasing numbers of older patients being treated for cancer, a systematic approach towards important level evidence would still be useful, even if this review only helps to draw out priorities for future (needed) research.</p><p>During the next step, while designing the implementation program as part of the PROADAPT project, we will use a Delphi method with a multi-professional group of stakeholders from different settings.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} This should help to address this concern. Our review may also provide a description of settings and implementation of the programs as reported in the included studies. Yet, a complementary review of qualitative studies with a realistic approach, may be deemed necessary to better understand the key elements and barriers for implementation of transition and patient education programs.</p></sec><sec><title>Acknowledgments</title><p>This review project is part of the PROADAPT initiative for improving care for older people with cancer. The authors wish to thank the professionals who participated to the group analyses: G. Albrand, D. Barnoud, D. Benayoun. B Billod, J. Bonhomme, A.-L. Bres, C. Brunengo, E. Castel-Kremer, D. Charlety, Y. Chauleur, G. Copaescu, A.-M. Dascalita, B. De La Vigerie, S. Ducoulombier, B. Galamand, E. Genest, M. Giroud, M. Haine, N. Jomard, C. Lecardonnel, B. Leroy, J.-A. Long, A. Marion, I. Morel-Soldner, E. Nony, A. Pelisset-Vanhersecke, A. Pirollet, C. Ravot, J.-E. Terrier, J. Trautmann, A.-C. Vincent.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Claire Falandry, Laetitia Stefani, Marion Granger, Claire Barbavara, Hocine Habchi, Chrystelle Bourgeois, Herv&#x000e9; Cure, Guillaume Passot, Thomas Gilbert.</p><p><bold>Data curation:</bold> Claire Falandry, Marion Granger, Claire Barbavara, Hocine Habchi, Chrystelle Bourgeois, Guillaume Passot, Thomas Gilbert.</p><p><bold>Formal analysis:</bold> Claire Falandry, Louise Andre.</p><p><bold>Funding acquisition:</bold> Claire Falandry.</p><p><bold>Investigation:</bold> Claire Falandry, Louise Andre.</p><p><bold>Methodology:</bold> Claire Falandry, Louise Andre.</p><p><bold>Project administration:</bold> Claire Falandry.</p><p><bold>Resources:</bold> Claire Falandry.</p><p><bold>Software:</bold> Claire Falandry.</p><p><bold>Supervision:</bold> Claire Falandry, Thomas Gilbert.</p><p><bold>Validation:</bold> Claire Falandry, Laetitia Stefani, Louise Andre, Marion Granger, Claire Barbavara, Hocine Habchi.</p><p><bold>Visualization:</bold> Claire Falandry, Laetitia Stefani, Louise Andre, Marion Granger, Claire Barbavara, Hocine Habchi, Chrystelle Bourgeois, Herv&#x000e9; Cure, Guillaume Passot, Thomas Gilbert.</p><p><bold>Writing &#x02013; original draft:</bold> Claire Falandry, Thomas Gilbert.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Claire Falandry, Laetitia Stefani, Louise Andre, Marion Granger, Claire Barbavara, Hocine Habchi, Chrystelle Bourgeois, Herv&#x000e9; Cure, Guillaume Passot, Thomas Gilbert.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: AMSTAR = A measurement tool for <italic>assessment of multiple systematic reviews</italic>, CINAHL = Cumulative Index to Nursing and Allied Health Literature, PROADAPT = Prehabilitation &#x00026; Rehabilitation in Oncology: Adaptation to Disease and Accompaniment of Patients&#x02019; Trajectories.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Falandry C, Stefani L, Andre L, Granger M, Barbavara C, Habchi H, Bourgeois C, Cure H, Passot G, Gilbert T. Interventions to improve physical performances of older people with cancer before complex medico-surgical procedures: Protocol for an umbrella review of systematic reviews and meta-analyses. <italic>Medicine</italic>. 2020;99:39(e21780).</p></fn><fn fn-type=\"other\"><p>Ethics approval and consent to participate: Not applicable.</p></fn><fn fn-type=\"other\"><p>Consent for publication: Not applicable.</p></fn><fn fn-type=\"other\"><p>Availability of data and material: Not applicable.</p></fn><fn fn-type=\"financial-disclosure\"><p>This study has received funding from the Auvergne-Rhone-Alpes region health agency (Agence Regionale de Sant&#x000e9;), FRANCE, which supports the PROADAPT project (Appel &#x000e0; Projets &#x000ab;Innovez en sant&#x000e9; pour le territoire Auvergne-Rhone-Alpes&#x000bb; 2016).</p></fn><fn fn-type=\"other\"><p>Sponsor: Hospices Civils de Lyon.</p></fn><fn fn-type=\"other\"><p>Role of sponsor in protocol development: none.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no competing interests to declare.</p></fn><fn fn-type=\"other\"><p>Patient and Public Involvement: It will not be appropriate or possible to involve patients or the public in the design or conduct of this work. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"research-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991480</article-id><article-id pub-id-type=\"pmc\">PMC7523812</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-03254</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022437</article-id><article-id pub-id-type=\"art-access-id\">22437</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3400</subject></subj-group><subj-group><subject>Research Article</subject><subject>Observational Study</subject></subj-group></article-categories><title-group><article-title>Higher hypertension prevalence, lower incidence, and aggressive treatment with decreasing mortality, cardiovascular, and cerebrovascular incidence in Taiwan from 2005 to 2010</article-title><subtitle>A 2 population-based cohorts study</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Liao</surname><given-names>Chia-Te</given-names></name><degrees>MD, MSc</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wu</surname><given-names>Pei-Chih</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref><xref ref-type=\"aff\" rid=\"aff4\">^d</xref></contrib><contrib contrib-type=\"author\"><name><surname>Shih</surname><given-names>Jung-Chang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff5\">^e</xref></contrib><contrib contrib-type=\"author\"><name><surname>Cheng</surname><given-names>Tain-Junn</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff6\">^f</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0003-4291-3388</contrib-id><name><surname>Wu</surname><given-names>Wen-Shiann</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff7\">^g</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Roever.</surname><given-names>Leonardo</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Division of Cardiovascular Medicine, Chi-Mei Medical Center</aff><aff id=\"aff2\"><label>b</label>Department of Public Health of Medicine, College of Medicine, National Cheng Kung University</aff><aff id=\"aff3\"><label>c</label>Department of Green Energy and Environmental Resources</aff><aff id=\"aff4\"><label>d</label>Department of Occupational Safety and Health, Chang Jung Christian University</aff><aff id=\"aff5\"><label>e</label>Division of Cardiovascular Medicine, Chiali branch of Chi-Mei Hospital</aff><aff id=\"aff6\"><label>f</label>Departments of Neurology and Occupational Medicine, Chi-Mei Medical Center</aff><aff id=\"aff7\"><label>g</label>Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Wen-Shiann Wu, Department of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan City, Taiwan No. 901, Chunghwa Rd., Yungkang Dist., Tainan City 710, Taiwan (e-mail: <email>850761wws@gmail.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22437</elocation-id><history><date date-type=\"received\"><day>18</day><month>4</month><year>2020</year></date><date date-type=\"rev-recd\"><day>16</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>22</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22437.pdf\"/><abstract><title>Abstract</title><p>Hypertension continues to be an important public health concern because of its associated morbidity, mortality, and economic impact on society. The aims of this study are to compare the secular changes in age-stratified hypertension prevalence, incidence, co-morbidity, and 3 years of cardiovascular outcome in Taiwan in the years 2005 and 2010.</p><p>We enrolled hypertensive individuals from the datasets of the Longitudinal Health Insurance Database (LHID) in 2005 and 2010 in Taiwan separately. We analyzed the hypertension prevalence, incidence, medication treatment, and associated morbidities. The risks of cardiovascular and cerebrovascular events and all-causes mortalities among the hypertensive individuals were evaluated in 3 years of follow-up.</p><p>There was an increased prevalence of hypertension but decreased incidence of hypertension in those over 65 from 2005 to 2010. Dyslipidemia was the highest rate of co-morbidity in 2005 and 2010. The most frequent categories of anti-hypertensive agents prescribed was 1 or 2 for both 2005 and 2010. Calcium channel blockers were the most common anti-hypertensive agents prescribed, followed by Angiotensin converting enzyme inhibitors/Angiotensin receptor blockers. After 3 years of follow-up, the risks of coronary artery disease (CAD), cerebrovascular diseases (CVD) as well as death were less in 2010 than in 2005 in Taiwan.</p><p>Our study showed that hypertension individuals had an increased prevalence, younger age, decreased incidence, increased medication treatment associated with decreased the CAD, CVD, and mortalities in 2010 compared to 2005 in Taiwan.</p></abstract><kwd-group><title>Keywords</title><kwd>cardiovascular risk</kwd><kwd>hypertension</kwd><kwd>incidence</kwd><kwd>mortality</kwd><kwd>National Health Insurance Research Database</kwd><kwd>prevalence</kwd><kwd>Taiwan</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Chi Mei Medical Center</funding-source><award-id>CMFHR10359</award-id><principal-award-recipient>Tain-Junn Cheng</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Pfizer</funding-source><award-id>WI209631 (2015-3)</award-id><principal-award-recipient>Tain-Junn Cheng</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>As a well-known risk factor for cardiovascular morbidity and mortality,^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} hypertension is a chronic disease with much world attention. It has been reported hypertension was present in 69% of patients who experienced their first heart attack, and 77% of those suffering from their first stroke.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>&#x02013;<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Prevalence estimates were significantly higher in the elderly (&#x02265;65 years old) compared with young adults (&#x0003c;65 years old).^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Previous research also reported the effective reduction of blood pressure is closely related to decreased cardiovascular disease and stroke.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} Additionally, antihypertensive therapy is directly associated with reduced blood pressure. A systematic review compiling 1479 related studies in these 40 years indicated the global prevalence of adult hypertension increased from 26.4% in 2000 to 31.1% in 2010, 28.5% in high-income countries such as the West and Asia Pacific area and 31.5% in low- and middle-income countries such as East Asia, Southeast Asia, South Asia, Oceania, and the South African region below the Sahara.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} An estimated 1.39 billion people had hypertension in 2010. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries but increased by 7.7% in low- and middle-income countries.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]}</p><p>A lot of research clearly shows the occurrence of high blood pressure increases the number of complications and even death, bringing a heavy financial burden to a country.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Therefore, monitoring blood pressure changes in epidemiological data, treatment type, and the quality of care must be ongoing. Early recognition and treatment of hypertension is important to improve morbidity and mortality, especially for cardiovascular and cerebrovascular diseases (CVD). Even in hemodialysis patients, blood pressure control was independently associated with all-cause mortality and cardiovascular events.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]}</p><p>Generally, the treatment of hypertension can be divided into 2 parts: lifestyle modification changes and drug treatment. The former includes salt and alcohol intake restrictions, weight loss, smoking cessation, diet control, and exercise.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} The latter would be various recommendation treatment guidelines in different countries and times, such as WHO/ISH; Prevention, Detection, Evaluation and Treatment of High Blood Pressure by the US Joint National Committee (JNC); the British Hypertension Society (BHS); and the European Society of hypertension / European Society of Cardiology (ESH / ESC), etc.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Taking JNC7 published in 2003 for instance, hypertensive patients in stage I (140/90 mm Hg) are recommended thiazide-type diuretics, as well as other drugs such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and others if complications existed. In addition, patients with different severity and treatment goals have corresponding recommendations for the number and type of medicine.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Two-drug combinations as a first step antihypertension treatment have been emphasized in recent years. An updated JNC8 with stronger evidence and revisions for treatment targets and medication choice was released after 10 years.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]}</p><p>The Taiwan Society of Cardiology also published 2 versions of guidelines for tackling high blood pressure in 2010 and 2015. These were more Asian-oriented, such as more emphasis on the importance of stroke when considering the cardiovascular prognosis.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} However, since following the guidelines is not compulsory in actual clinical practice, many studies focused on the prescription pattern of antihypertensive agents and factors affecting these patterns.</p><p>There have been several studies focused on the medication pattern for hypertension over the last few decades in Taiwan. In general, CCBs are the class of medication with the highest use frequency. Diuretics are uncommon on the other hand; and there has been a gradual trend for the replacement of ARBs to ACEIs.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} The most commonly used medication varies according to the country. For instance, ACEIs are the most frequently prescribed medications in Canada, the United Kingdom, and the United States; while BBs are popular in Finland, Iceland and Sweden; CCBs are often prescribed in Norway and Denmark.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} The factors leading to distinct prescription pattern involve the individual-level (such as sex, age, comorbidity) and environmental-level (such as physician specialty, institution level, healthcare insurance system, country). The findings of this study explore the real public health data of hypertension, confirm the health care achievements of NIH in Taiwan, and are anticipated to provide a reference not only for caregivers but also for the policy makers of national health insurance to achieve reasonable and cost-effective drug recommendations.</p></sec><sec><label>2</label><title>Methods</title><p>To evaluate secular changes in the prevalence and incidence of hypertension and the subsequent cardiovascular or CVD and mortality, we conducted a retrospective study cohort study by analyzing 2 independent datasets of the Longitudinal Health Insurance Database (LHID) 2005 and LHID 2010.</p><sec><label>2.1</label><title>Data source</title><p>The outpatient records dataset of the LHID 2005 and LHID 2010 were used in this study. Both LHID 2005 and LHID 2010 contain the entire original claim data of 1,000,000 beneficiaries randomly sampled from the corresponding year of the National Health Insurance Research Database (NHIRD). This corresponded to about 4% of all enrollees in the National Health Insurance program.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} The Health Insurance program is a nationwide healthcare system in Taiwan established in 1995, and its coverage rate exceeded 99% in 2007. There were no significant differences in the age and sex distribution between the selected sample and all enrollees.</p><p>The LHID contains information on each member, including an encrypted personal identification number, sex, date of birth, diagnostic codes using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), drug prescriptions, medical cost, medical care facilities, and specialty of care providers. All datasets are interlinked by the personal identification number of the patient.</p></sec><sec><label>2.2</label><title>Study population and study design</title><p>The study diagram is presented in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Study Diagram.</p></caption><graphic xlink:href=\"medi-99-e22437-g001\"/></fig><sec><label>2.2.1</label><title>Prevalence rate</title><p>Individuals whose records showed ICD-9-CM codes 401&#x02013;405 for 3 outpatient visits, or those prescribed an antihypertensive agent at any outpatient visit were diagnosed as hypertensive from January 1^st to December 31st for the year 2005 from the LHID 2005 dataset and 2010 from the LHID 2010 dataset, respectively, to evaluate the prevalence of hypertension by age group. The date of diagnosis of hypertension was the earlier date of either: the third outpatient visit, or the first outpatient visit with an antihypertensive prescription.</p></sec><sec><label>2.2.2</label><title>Incidence rate</title><p>Further, hypertensive individuals would be enrolled after excluding the hypertension history 1 year prior to the year of enrollment. The incidence of hypertension was calculated by age groups in the 2 different datasets.</p></sec><sec><label>2.2.3</label><title>Comorbidity evaluation</title><p>To compare the history of the concomitant conditions of patients between 2005 and 2010, outpatient records were traced for up to 1 year prior to the date of hypertension diagnosis for any diagnosis containing the following ICD-9-CM codes: 250 (diabetes mellitus), 272 (hyperlipidemia), 440&#x02013;459 (peripheral vascular disease), 140&#x02013;208 (cancer), 580&#x02013;589 (renal disease), 490&#x02013;496 (lung disease), 531&#x02013;534 (ulcer). Patients with records of any of the above-mentioned codes during that time were considered to have the corresponding comorbid conditions.</p><p>For evaluating CAD and CVD risk, hypertensive individuals with the ICD-9-CM code 410&#x02013;429 (heart disease), 430&#x02013;432 (hemorrhagic stroke), and 433&#x02013;438 (ischemic stroke) prior to the individuals were excluded.</p></sec><sec><label>2.2.4</label><title>Medication categories for hypertension treatment</title><p>Antihypertensive agents were categorized into 6 major categories, including alpha-blockers, BBs, CCBs, diuretics, ACEIs or ARBs, and others. This study examined the prescription of antihypertensive medication classes in hypertensive individuals on the date of diagnosis and the number of agent(s) prescribed. ACEIs and ARBs were treated as 1 class because of their similar treatment effects.</p></sec><sec><label>2.2.5</label><title>CAD and CVD risk and all-causes mortality in hypertensive individuals</title><p>Hypertensive individuals were followed up for 3 years. Individuals hospitalized for coronary artery disease (CAD) (ICD-9-CM 410&#x02013;414) including myocardial infarction and angina (ICD-9-CM 410&#x02013;414), and CVD ((ICD-9-CM 430&#x02013;438) were identified as outcome event. We also compared the events of all-cause deaths (withdrew from National Health Insurance after enrollment) for 3 years.</p></sec></sec><sec><label>2.3</label><title>Statistical analysis</title><p>For comparing 2005 and 2010, the Chi-Squared test was used for categorical variables and <italic>t</italic>-test for continuous variables. Subsequently, univariate and multivariate binary logistic regression was performed for the likelihood of prescribing any anti-hypertensive agents, as well as each type of agent. The different outcomes of 3-year cumulative incidences were analyzed by Cox proportional Hazard models. The univariate factors with <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05 were then entered into the multivariate model. <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05 was considered statistically significant. All the data processing and statistical analysis were performed using SAS statistical software (SAS Institute Inc., Version 9.4, Cary, NC). The study was approved by the Institutional Review Board at the Chi-Mei Medical Center.</p></sec></sec><sec><label>3</label><title>Results</title><sec><label>3.1</label><title>The prevalence, incidence, and characteristics of hypertension in 2005 and 2010</title><p>There were 97,187 (13% of sample population) 122,265 (15.71% of sample population) individuals meeting the criteria of hypertension in 2005 and 2010, respectively (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). There was increased prevalence of hypertension (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>a-c) but decreased incidence of hypertension in females and especially older age groups of 65 to 80 years old or more (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>, Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>d-f).</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Prevalence and incidence of hypertension in 2005 and 2010 at different age group. Prevalence of hypertension in total population. Prevalence of hypertension in male. Prevalence of hypertension in female. Incidence of hypertension in total population. Incidence of hypertension in male. Incidence of hypertension in female.</p></caption><graphic xlink:href=\"medi-99-e22437-g002\"/></fig><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Characteristics of patients with incident hypertension, co-morbidity and medication for hypertension in two groups from 2005 to 2010 in Taiwan.</p></caption><graphic xlink:href=\"medi-99-e22437-g003\"/></table-wrap><p>Characteristics of the hypertensive population are summarized in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>. The proportion of males was 54.9% in 2010, which was higher than 52.43% in 2005 (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.001) (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>b), and the age distribution of both cohorts was concentrated between 45 and 64 years old (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>). Among comorbidity in 2005 and 2010 during follow-up, dyslipidemia showed the highest rate of comorbidity in 2005 (25.86%) and 2010 (32.93%), and the rate increased in 2010 (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.001) (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>).</p><p>Of the types of anti-hypertensive agents prescribed (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>), the rankings in both cohorts are the same, which are CCBs, ACEIs/ARBs, beta-blockers, diuretics, alpha-blockers, and then others. CCBs, diuretics, and ACEIs or ARBs showed increased use while alpha-blockers, beta-blockers, and others decreased.</p><p>The most frequent number of anti-hypertensive agents prescribed was 1, 2 and none for both 2005 and 2010. For more details, more patients were not prescribed any agent (13.29%&#x02013;15.95% from 2005 to 2010); fewer patients were prescribed 1 agent (44.79%&#x02013;41.78% from 2005 to 2010). The trends for the proportions of patients with 2 agents were stable (29%). The mean numbers of antihypertensive drugs were about 1.3 in both the 2005 and 2010 cohorts (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>).</p></sec><sec><label>3.2</label><title>The 3- year-cardiovascular outcomes in 2005 and 2010</title><p>Patients were followed up for 3 years for the CAD, CVD and all-causes mortality. Cox proportional hazard models stratified by sex and adjusted for age and co-morbid condition were constructed to determine the development of cardiovascular, cerebrovascular endpoints as well as death. The Hazard Ratio (HR) revealed the cumulative incidence of CAD is 0.13 (in 2005) vs 0.10 (in 2010) (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.0001), the CVD is 0.07 (in 2005) vs 0.06 (in 2010) (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.0001) and the death is 0.04 (in 2005) vs 0.03 (in 2010) (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.0001) (Table <xref rid=\"T1\" ref-type=\"table\">1</xref> and Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>).</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Three years cumulative incidence of coronary artery diseases, CVD cerebrovascular diseases and mortality outcomes of hypertension individuals since 2005 and 2010.</p></caption><graphic xlink:href=\"medi-99-e22437-g004\"/></fig></sec></sec><sec><label>4</label><title>Discussion</title><p>To understand whether the model of antihypertension drugs is reliable for health insurance and medical source distribution, this study used Taiwan's National Health Insurance data base to analyze the hypertension prevalence, incidence, co-morbidity, drugs used, 3-year risk of vascular events, and all-cause mortality.</p><p>The study showed the overall prevalence of hypertension increased, but decreased in females and the elderly. The secular changes in the prevalence and incidence of hypertension were associated with the early recognition and treatment of hypertension and the improved treatment of cardiovascular and cerebrovascular disease attack and mortality prevention in Taiwan. In the Taiwan's National Health Insurance system, there was a relatively high awareness among health care professionals and the public as to the importance of hypertension in 2010 compared to 2005. Blood pressure is an important, modifiable, risk factor, and noteworthy for being easily measured by non-physician healthy providers. The major co-morbidity is dyslipidemia and this had increased in 2010. This was related to more obese patients and a higher cholesterol diet intake in Taiwan.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} In a prevalence study in Korea, a similar result was found.^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} Hypertension had the highest overall prevalence rates.</p><p>The prescribed anti-hypertension drugs showed more popular use of ACEIs /ARBs and CCBs. This was because of the target organ protective effect of ACEIs/ARBs being more emphasized by JNC8 and Taiwan Society of Cardiology guidelines^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} and the greater long-time potent effect of CCBs.</p><p>In our study, the mean numbers of antihypertensive drugs were about 1.3 in both 2005 and 2010. This information helps us modify the clinical practice that early combination therapy is better than monotherapy to achieve the target blood pressure.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>,<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]} Both the 2003 American and the 2007 and 2013 European Society of Cardiology/European Society of Hypertension guidelines advised initial use of 2 antihypertensive drugs in selected hypertensive groups of patients.^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>&#x02013;<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} For the American guidelines, an initial 2-drug combination was recommended when the baseline BP was at least 20/10&#x0200a;mm Hg (systolic/diastolic) above the target of &#x0003c;140/90&#x0200a;mm Hg.</p><p>The 3-year-outcome revealed less cumulative incidence of CAD, CVD, and deaths in 2010 than in 2005. This was partly due to more patients being included in the National Health Insurance and greater awareness of hypertension and its complications. More people received early treatment of hypertension and more potent end organ protective drugs were prescribed.</p><p>There are some limitations to our study. First, we were unable to obtain the blood pressure (BP) measurement data of the patients in the LHID 2010 and 2005. Blood pressure control, especially high systolic blood pressure and low diastolic blood pressure, is related to the clinical cardiovascular and cerebrovascular outcome.^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>&#x02013;<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} Owing to the limitations of real-world blood pressure information, we could not offer the BP management result that may be needed after full consideration of age and sex which can significantly influence health behaviors. Second, the LHID 2010 and 2005 did not include personal risk factors for hypertension, including smoking, body mass index, exercise, salt intake, and drinking. These risk factors may influence the prevalence of hypertension, but the confounding factor may be small because of this studys large sample size which is needed to evaluate the effects of many risk factors simultaneously. Future directions of the study should include the blood pressure data of the patients because the treatment rate and blood pressure level are related to the cardiovascular events.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R27\" ref-type=\"bibr\">27</xref>&#x02013;<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} The third limitation is we did not have LHID datasets earlier than 2005 or later than 2010 and these have helped in understanding these trends. This also aims our consideration for future study to collect more variables about the clinical patient data, including BMI, waist circumference, metabolic syndrome, lipids, exercise, smokers, liver steatosis, alcohol intake, lung disease&#x000b8; gout, atrial fibrillation, high-sensitivity C-reactive protein, Fasting glucose, depression, valve disorder, complete blood tests, family history of stroke, CAD, peripheral arterial disease, and stroke subtypes which may significantly affect clinical decisions.</p><p>In conclusion, in Taiwan, the hypertension incidence rates among those over 65 years old decreased in 2010 compared to 2005. CCB and ARB/ACEI were the top 2 most common categories prescribed for hypertension and more than 1 drug category used on average, suggesting more aggressive treatment as well as combination treatment as the first step in antihypertensive therapeutic intervention.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>,<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} Due to the convenience of the National Health Insurance System in Taiwan, more patients have access to affordable health care for hypertension and as a result the CAD, CVD, and mortalities in hypertensive individuals in Taiwan have improved.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Chia-Te Liao, Jung-Chang Shih, Tain-Junn Cheng, Wen-Shiann Wu.</p><p><bold>Data curation:</bold> Chia-Te Liao, Pei-Chih Wu, Jung-Chang Shih, Tain-Junn Cheng.</p><p><bold>Formal analysis:</bold> Chia-Te Liao.</p><p><bold>Funding acquisition:</bold> Tain-Junn Cheng.</p><p><bold>Investigation:</bold> Chia-Te Liao, Jung-Chang Shih, Tain-Junn Cheng.</p><p><bold>Methodology:</bold> Chia-Te Liao, Pei-Chih Wu, Tain-Junn Cheng, Wen-Shiann Wu.</p><p><bold>Project administration:</bold> Wen-Shiann Wu.</p><p><bold>Validation:</bold> Wen-Shiann Wu.</p><p><bold>Visualization:</bold> Wen-Shiann Wu.</p><p><bold>Writing &#x02013; original draft:</bold> Chia-Te Liao, Wen-Shiann Wu.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Wen-Shiann Wu.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: ACEIs/ARB = Angiotensin converting enzyme inhibitors/Angiotensin receptor blocker, CAD = coronary artery disease, CCBs = calcium channel Blocker, CVD = cerebrovascular diseases, LHID = Longitudinal Health Insurance Database.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Liao CT, Wu PC, Shih JC, Cheng TJ, Wu WS. Higher hypertension prevalence, lower incidence, and aggressive treatment with decreasing mortality, cardiovascular, and cerebrovascular incidence in Taiwan from 2005 to 2010: A 2 population-based cohorts study. <italic>Medicine</italic>. 2020;99:39(e22437).</p></fn><fn fn-type=\"equal\"><p>C-TL and P-CW contributed equally to this manuscript.</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by Chi Mei Medical Center (CMFHR10359) and Grant WI209631 (2015-3) from the Pfizer Inc. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.</p></fn><fn fn-type=\"COI-statement\"><p>All authors are free of any conflict of interest.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Kario</surname><given-names>K</given-names></name><name><surname>Chen</surname><given-names>C-H</given-names></name><name><surname>Park</surname><given-names>S</given-names></name><etal/></person-group>\n<article-title>Consensus document on improving hypertension management in Asian patients, taking into account Asian 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991441</article-id><article-id pub-id-type=\"pmc\">PMC7523813</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-01120</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022322</article-id><article-id pub-id-type=\"art-access-id\">22322</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>4100</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>First case of bronchiolar adenoma lined purely by mucinous luminal cells with molecular analysis</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Shuli</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Nan</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Xiao</surname><given-names>Mingming</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0003-4015-9385</contrib-id><name><surname>Wang</surname><given-names>Liang</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>En-Hua</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences, China Medical University</aff><aff id=\"aff2\"><label>b</label>Department of Pathology, the People's Hospital of Liaoning Province, Shenyang, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Liang Wang, Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang 110001, China (e-mail: <email>cmuwangliang@qq.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22322</elocation-id><history><date date-type=\"received\"><day>11</day><month>2</month><year>2020</year></date><date date-type=\"rev-recd\"><day>29</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>24</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22322.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Bronchiolar adenoma (BA) is a newly designated rare entity of the lung, including both the currently designated ciliated muconodular papillary tumor (CMPT) and so-called non-classic CMPT. The most prominent histological feature of BAs is the bilayered cell structures composed of the continuous basal cell layer and the luminal layer which consists of different proportion of mucinous cells, ciliated cells, Clara cells and/or type II pneumocytes. BA purely covered by mucinous cells without other components in the luminal layer has never been reported.</p></sec><sec><title>Patient concerns:</title><p>An 82-year-old female patient was detected a 0.8 cm ground glass nodule in the left lower lobe of the lung.</p></sec><sec><title>Diagnoses:</title><p>The serum levels of tumor markers were normal.</p></sec><sec><title>Interventions:</title><p>The patient underwent a segmentectomy of the left lower lobe.</p></sec><sec><title>Outcomes:</title><p>The postoperative pathological diagnosis was BA. Molecular analysis revealed that the tumor harbored ALK rearrangement and BRAF mutations simultaneously. There was no recurrence in 17 months of follow-up.</p></sec><sec><title>Lessons:</title><p>BA can be lined only by mucinous cells, without any cuboidal and/or ciliated cells in the surface layer. This sets a dangerous pitfall in differentiation diagnosis with invasive mucinous adenocarcinoma especially during intraoperative frozen pathological diagnosis.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>ALK</kwd><kwd>BRAF</kwd><kwd>bronchiolar adenoma</kwd><kwd>ciliated muconodular papillary tumor</kwd><kwd>immunohistochemistry</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Liaoning Technology Research Fund for Social Development and Industrialization</funding-source><award-id>2017225010</award-id><principal-award-recipient>Liang Wang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Bronchiolar adenoma (BA) is a newly designated entity of benign lung tumor which will be recognized in the upcoming World Health Organization classification in 2020. This entity encompass a spectrum of lesions including both the currently designated ciliated muconodular papillary tumor (CMPT) and so-called non-classic CMPT. The most prominent histological feature of BA is the bilayered cell structures composed of the continuous basal cell layer and the luminal cell layer which consists of different proportion of mucinous cells, ciliated cells, Clara cells and/or type II pneumocytes.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Based on the composition of surface cells, BA can be further divided into proximal-type BA and distal-type BAs. The proximal type is lined by ciliated and mucinous cells, in papillary or flat pattern. The distal type is generally flatted, covered by mucinous cells, cuboidal and/or ciliated cells. For this rare entity, the distal-type BA purely covered by mucinous cells has never been reported. This unique and extremely rare case can be easily misdiagnosed as invasive mucinous adenocarcinoma (IMA). Herein, we report this case with a focus of immunohistochemical features and driver gene mutations.</p></sec><sec><label>2</label><title>Case report</title><p>A 81-year-old female patient was initially detected a 0.6&#x0200a;cm ground glass nodule in the left lower lobe of the lung by computed tomography (CT) during healthy examination in June 2017. The nodule grew to 0.8&#x0200a;cm in August 2018, and no enlarged hilar and mediastinal lymph nodes were identified. The serum levels of tumor markers, including carcinoembryonic antigen, neuron-specific enolase, cytokeratin-19 fragment, etc. were normal. The patient underwent a segmentectomy of the left lower lobe, and macroscopical examination revealed a gray-white mucoid mass, measuring 1.0&#x0200a;&#x000d7;&#x0200a;0.6&#x0200a;cm. An intraoperative frozen pathological diagnosis favored benign mucinous tumor, and deferred to permanent sections to rule out IMA.</p><p>Postoperative pathological examination showed the well-circumscribed tumor is located in the lung parenchyma with a maximum diameter of 1.0&#x0200a;cm. The tumor cells grew along the alveolar walls, with a small number of papillary and adenoid structures (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>A). The luminal tumor cells were purely mild and tall columnar mucinous cells. No ciliated or cuboidal cells could be evident. The nuclei were located in the basal part, which seemed to be arranged in a single layer. However, in certain areas, the tumor was composed of bilayered cellular proliferation with a continuous basal cell layer (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>B).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>The tumor cells grew along the alveolar walls, with a small number of papillary and adenoid structures, with abundant extracellular mucin (A, 40&#x000d7;). The surface-layered tumor cells were purely tall columnar cells (B, 400&#x000d7;, black arrow) with areas showing bilayered structure (yellow arrowhead) with a continuous basal cell layer.</p></caption><graphic xlink:href=\"medi-99-e22322-g001\"/></fig><p>Immunohistochemically, the columnar luminal cells were strongly positive for CK7 (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>A), but negative for thyroid transcription factor-1 (TTF-1). Staining for CK5/6, p40, p63 and TTF-1 revealed an intact and continuous bottom layer of basal cells (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>B and 2C). The index of Ki-67 was less than 1%. The basal cells were negative for myoepithelial markers, such as S-100, smooth muscle antibody (SMA), and CD117. Alcian blue/periodic acid&#x02013;Schiff (AB-PAS) staining demonstrated abundant mucin in the cytoplasm of columnar cells and extracellular spaces (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>D). The final histological diagnosis was rendered as BA. A small panel of driver genes were examined using the ADx-ARMS Kit (Amoy Diagnostics, Xiamen, China). Rearrangement of <italic>ALK</italic> (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>A) and mutations of <italic>BRAF</italic> (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>B) were identified. The post-operative course was uneventful, and no recurrence was noted at 17 months&#x02019; follow-up.</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>The surface-layered tumor cells were positive for CK7 (A, 400&#x000d7;). The basal-layered tumor cells showed continuous positive staining for p63 (B, 400&#x000d7;, arrowhead) and CK5/6 (C, 400&#x000d7;, arrowhead). AB-PAS demonstrated abundant intracellular and extracellular mucin (D, 400&#x000d7;, asterisk).</p></caption><graphic xlink:href=\"medi-99-e22322-g002\"/></fig><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Quantitative reverse-transcript Polymerase chain reaction (qRT-PCR) revealed <italic>ALK</italic> rearrangement (A, arrow) and <italic>BRAF</italic> mutations (B, arrow) in the tumor cells.</p></caption><graphic xlink:href=\"medi-99-e22322-g003\"/></fig></sec><sec><label>3</label><title>Discussion</title><p>In 2002, Ishikawa^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} first, described and reported a rare tumor in the peripheral lung and named it as CMPT. CMPT is easily to be misdiagnosed as IMA, therefore it has been widely discussed and concerned in recent years.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>&#x02013;<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} With more and more observation and analysis of CMPT, it is found that the papillary structure, surface ciliated cells and mucinous cells are not absolutely necessary for the diagnosis. Some CMPT-like tumors may present flat growth pattern along the alveolar wall which were covered by Clara and/or alveolar cells on the surface. However, there was always a continuous basal cell layer at the bottom. Therefore, cases with papillary structures were named as classic CMPT, while those without papillary structures were proposed as non-classic CMPT.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} In order to solve this dilemma, Chang, et al carried a well-designed experimental observation, and found that the morphological change and immunophenotype of CMPT, both classic and non-classic types, are essentially consistent with the continuous spectrum of the components of mucous epithelial cells from the proximal to the distal bronchioles. So it is suggested to name these kinds of tumors as the diagnosis name of BA.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} This convincing work expanded the understanding of CMPT, and BA will be recognized in the upcoming World Health Organization classification in 2020.</p><p>Although the recognition of BA has made new progress, there are still some difficulties in its differential diagnosis. For example, the distal BA covered mainly by alveolar cells or Clara cells in the luminal layer needs to be differentiated from adenocarcinoma in situ. Vigorous proliferation of basal cells also needs to be discriminated from sclerosing pneumocytoma. The most challenging situation is the differentiation between BA rich in mucinous cells and IMA, especially in the rapid frozen pathological diagnosis, like the current case. Pathologists need to carefully look for cuboidal and/or ciliated cells to avoid the pitfall. If the luminal layer was purely lined by mucinous cells, pathologist must pay more effort to search areas showing bilayerd composition with the basal layer at the bottom. This is the key lesson we learned from the current case. Another 2 benign tumors, mucinous adenomas and mucinous cystadenomas, also need to be considered in differential diagnosis. These 2 tumors contain only a small number of myoepithelial cells at the bottom layer rather than a continuous basal cell layer, therefore, immunohistochemical staining of myoepithelial markers may contribute to the differential diagnosis.</p><p>Driver mutations have been observed in BAs.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>,<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} In the current study, we demonstrated that this special case harboring 2 different driver mutations simultaneously, which are rarely seen even in adenocarcinoma of the lung. It still needs further study to reveal whether coexistence of multiple driver-gene mutations may lead to worse prognosis.</p><p>In conclusion, this case expanded the understanding of BA that the luminal layer can be mucinouse cells alone without any other components, such as cilated cells, cuboid cells clara cells and/or alveolar cells.</p></sec><sec><title>Author contributions</title><p>SL, EHW and LW analyzed the data and wrote the manuscript. MX performed the immunochemical staining. NL performed genetic analysis. All authors have read and approved the final manuscript.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: AB-PAS = Alcian blue/periodic acid&#x02013;Schiff, AIS = adenocarcinoma in situ, BA = bronchiolar adenoma, CMPT = ciliated muconodular papillary tumor, IMA = invasive mucinous adenocarcinoma, SMA = smooth muscle antibody, TTF-1 = thyroid transcription factor-1.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Liu S, Liu N, Xiao M, Wang L, Wang EH. First case of bronchiolar adenoma lined purely by mucinous luminal cells with molecular analysis: a case report. <italic>Medicine</italic>. 2020;99:39(e22322).</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by grants from Liaoning Technology Research Fund for Social Development and Industrialization to Liang Wang (2017225010).</p></fn><fn fn-type=\"other\"><p>The datasets supporting the conclusions of this article are included within the article.</p></fn><fn fn-type=\"other\"><p>Ethical approval for this study was obtained from the institutional ethic review boards of the First Affiliated Hospital of China Medical University. Writing consent to participate was provided by the patients for the present research.</p></fn><fn fn-type=\"other\"><p>Informed consents were obtained from the patients for the publication of her case and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.</p></fn><fn fn-type=\"COI-statement\"><p>The authors declare that they have no competing interests.</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article [and its supplementary information files].</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Chang</surname><given-names>JC</given-names></name><name><surname>Montecalvo</surname><given-names>J</given-names></name><name><surname>Borsu</surname><given-names>L</given-names></name><etal/></person-group>\n<article-title>Bronchiolar adenoma: expansion of the concept of ciliated muconodular papillary tumors with proposal for revised terminology based on morphologic, immunophenotypic, and genomic analysis of 25 cases</article-title>. <source>Am J 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991448</article-id><article-id pub-id-type=\"pmc\">PMC7523814</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-09489</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022341</article-id><article-id pub-id-type=\"art-access-id\">22341</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>5200</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Goodpasture syndrome manifesting as nephrotic-range proteinuria with anti-glomerular basement membrane antibody seronegativity</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Zhong</surname><given-names>ZhengXia</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Tan</surname><given-names>JiaXing</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Tang</surname><given-names>Yi</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Li</surname><given-names>ZhengFu</given-names></name><degrees>BS</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Qin</surname><given-names>Wei</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Division of Nephrology, Department of Medicine, Affiliated Hospital of Zunyi Medical University, Guizhou</aff><aff id=\"aff2\"><label>b</label>Division of Nephrology, Department of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan</aff><aff id=\"aff3\"><label>c</label>Department of Respiration, Affiliated Hospital of Zunyi Medical University, Guizhou, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: ZhengFu Li, Department of Respiration, Affiliated Hospital of Zunyi Medical University, Guizhou, China (e-mail: <email>lzfzzx@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22341</elocation-id><history><date date-type=\"received\"><day>9</day><month>12</month><year>2019</year></date><date date-type=\"rev-recd\"><day>28</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>24</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22341.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>The Goodpasture syndrome is an extremely rare disease, with renal and pulmonary manifestations, and is mediated by anti-glomerular basement membrane (anti-GBM) antibodies. Renal pathological changes are mainly characterized by glomerular crescent formation and linear immunofluorescent staining for immunoglobulin G on the GBM. There are few reports on the atypical course of the syndrome involving serum-negative anti-GBM antibodies. Therefore, we present a case of Goodpasture syndrome that presented with nephrotic-range proteinuria and was seronegative for anti-GBM antibodies.</p></sec><sec><title>Patient concerns:</title><p>A 38-year-old Chinese man presented with a lung lesion that was discovered by physical examination a month prior to presentation. The chief concern was occasional hemoptysis without fever, cough, chest pain, and edema.</p></sec><sec><title>Diagnoses:</title><p>Laboratory testing revealed that the urinary protein level and urine erythrocyte count were 7.4&#x0200a;g/24&#x0200a;hours and 144/high-power field (HPF), respectively. Serological testing for anti-GBM antibodies was negative. Chest computed tomography revealed multiple exudative lesions in both lungs, indicating alveolar infiltration and hemorrhage. Electronic bronchoscopy and pathological examination of the alveolar lavage fluid indicated no abnormalities. However, kidney biopsy suggested cellular crescent formation and segmental necrosis of the globuli, with linear IgG and complement C3 deposition on the GBM. These findings were consistent with the diagnosis of anti-GBM antibody nephritis.</p></sec><sec><title>Interventions:</title><p>The patient underwent 7 sessions of double filtration plasmapheresis. He was also administered with intravenous methylprednisolone and cyclophosphamide. After renal function stabilization, he was discharged under an immunosuppressive regimen comprising of glucocorticoids and cyclophosphamides.</p></sec><sec><title>Outcomes:</title><p>Three months later, follow-up examination revealed that the 24-hour urine protein had increased to 13&#x0200a;g. Furthermore, the urine erythrocyte count was 243/HPF. After a 6-month follow-up, the patient achieved partial remission, with a proteinuria level of 3.9&#x0200a;g/24&#x0200a;hours and a urine erythrocyte count of 187/HPF.</p></sec><sec><title>Lessons:</title><p>This extremely rare case of Goodpasture syndrome manifested with seronegativity for anti-GBM antibodies and nephrotic-range proteinuria. Our findings emphasize the importance of renal biopsy for the clinical diagnosis of atypical cases. Furthermore, because renal involvement achieved only partial remission despite therapy, early detection and active treatment of the Goodpasture syndrome is necessary to improve the prognosis of patients.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>case report</kwd><kwd>goodpasture syndrome</kwd><kwd>negative anti-gbm antibody</kwd><kwd>nephrotic-range proteinuria</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>The Goodpasture syndrome is a rare autoimmune disease that is mediated by anti-glomerular basement membrane (anti-GBM) antibodies. Acute kidney failure and life-threatening pulmonary hemorrhage are typical clinical symptoms.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Associated renal pathological changes are characterized by glomerular crescent formation on the GBM and linear immunofluorescence staining positive for immunoglobulin G. The discovery of anti-GBM antibodies in 1967 verified the pathogenesis of the Goodpasture syndrome.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} However, only few studies have investigated the atypical course of the syndrome involving serum-negative anti-GBM antibodies. We present a case of Goodpasture syndrome with serology negative for anti-GBM antibodies and manifested as nephrotic-range proteinuria. The purpose of this report is to put forward new reflections for clinicians regarding this attractive case.</p></sec><sec><label>2</label><title>Case presentation</title><p>A 38-year-old Chinese man was admitted to our hospital for a lung lesion that was discovered upon physical examination a month prior to presentation. His clinical symptoms were mild. The chief complaint included occasional hemoptysis without fever, cough, chest pain, and edema. To determine the cause, he was admitted to our medical center on July 12, 2018. The patient had a history of chronic hepatitis B. No history of hypertension, diabetes, smoking, and exposure to special drugs and poisons was reported. A physical examination of the thoracic section did not reveal any remarkable findings, except for mild edema. A chest computed tomography (CT) scan indicated multiple exudative lesions in both lungs, indicating alveolar infiltration and hemorrhage (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>A). Electronic bronchoscopy and pathological examination of the alveolar lavage fluid revealed no abnormalities. Laboratory tests revealed that the hemoglobin level, serum creatinine level, estimated glomerular filtration rate (eGFR), serum albumin level, urinary protein level, and urine erythrocyte count were 104&#x0200a;g/L, 71&#x0200a;&#x003bc;mol/L, 113.0&#x0200a;ml/minute/1.73&#x0200a;mm², 40.7&#x0200a;g/L, 7.4&#x0200a;g/24&#x0200a;hours, and 144/HPF (shown Table <xref rid=\"T1\" ref-type=\"table\">1</xref>), respectively. Tests for hepatitis B virus (HBV) surface antigen and deoxyribonucleic acid (HBV DNA) were positive. Immunological tests for antinuclear antibodies, anti-double stranded DNA antibodies, anti-GBM antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA) were negative. The serum complement levels (C3 and C4) were normal. Ultrasonographic examination of the kidneys revealed an enhanced echo of the parenchyma in both kidneys. Renal biopsy indicated cellular crescent formation and segmental necrosis of the globuli with linear IgG and complement C3 deposition on the GBM (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>C and D). Electron microscopy indicated no electron-dense deposits. Therefore, he was diagnosed with the Goodpasture syndrome with crescentic glomerulonephritis and alveolar hemorrhage.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>(A) High resolution CT (HRCT) indicated multiple exudation lesions of both lungs before treatment, showing alveolar infiltration and hemorrhage. (B) HRCT indicated that the pulmonary lesion got improved significantly after treatment. (C) A cellular crescent was presented in the Light microscope (PAS &#x000d7;200). (D) Immunofluorescence findings showed there was linear staining along GBM with anti IgG antibody (&#x000d7;200).</p></caption><graphic xlink:href=\"medi-99-e22341-g001\"/></fig><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>The laboratory findings of the patient.</p></caption><graphic xlink:href=\"medi-99-e22341-g002\"/></table-wrap><p>Based on the renal pathology and laboratory findings, double filtration plasmapheresis (DFPP; once daily for 7 successive days), pulse methylprednisolone therapy (10&#x0200a;mg/kg daily for 3 consecutive days), and pulse cyclophosphamide treatment (1&#x0200a;g) were initiated. Simultaneously, entecavir was administrated to reduce HBV replication. Following DFPP, chest CT was repeated, which revealed that the pulmonary lesion had almost disappeared (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>B). Considering the stabilized renal function, he was discharged from the hospital under an immunosuppressive regimen including glucocorticoids (prednisone, 50&#x0200a;mg daily) and cyclophosphamide (50&#x0200a;mg, twice daily). The patient was followed up at the out-patient department every month. Three months later, the 24-hour urine protein level was observed to have increased to 13&#x0200a;g. Furthermore, the urine erythrocyte count, serum albumin, serum creatinine level, and eGFR were found to be 243/HPF, 33.8&#x0200a;g/L, 70&#x0200a;&#x003bc;mol/L, and 113.8&#x0200a;ml/minute/1.73&#x0200a;mm², respectively. Tests for anti-GBM antibodies, ANCA, and HBV-DNA remained negative. Thereafter, prednisone was tapered down to 30&#x0200a;mg daily. Cyclophosphamide was replaced with tacrolimus (1.5&#x0200a;mg, twice daily). At the last follow-up (6th month), the serum albumin, serum creatinine level, proteinuria level, urine erythrocyte count, and eGFR were 40&#x0200a;g/L, 77&#x0200a;&#x003bc;mol/L, 3.9&#x0200a;g/d, 187/HPF, and 108.7&#x0200a;ml/minute/1.73&#x0200a;mm², respectively. The patient provided informed consent for the inclusion of his data in the present report.</p></sec><sec><label>3</label><title>Discussion</title><p>The Goodpasture syndrome is an autoimmune disorder mediated by serum anti-GBM antibodies and is characterized by rapidly progressive crescent glomerulonephritis and pulmonary hemorrhage.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} It was first reported by Pasture in 1919.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]}</p><p>The disease is caused by anti-GBM antibodies targeted against the non-collagenous domain (NC1) of the alpha 3 chain (a3) of type IV collagen in the lungs and kidneys.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} The a3(IV) chain is mainly expressed in a few specialized basement membranes like the GBM. The anti-GBM antibody binds to the a3(IV) NC1 domain and deposits in the basement membranes of the kidneys and the lungs, subsequently activating the complement system that can result in tissue damage. Although the pathogenesis of the disease in the kidneys and the lungs is the same, the degree of damage is markedly different between them. It was reported that two-thirds of the patients with anti-GBM antibodies could progress to the Goodpasture syndrome, and one-third present with anti-GBM antibody nephritis without pulmonary manifestations.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Clinically, enzyme-linked immunosorbent assay (ELISA) is a common method for the detection of anti-GBM antibodies, especially if a kidney biopsy is not performed, and has high sensitivity (&#x0003e;95%) and specificity (&#x0003e;97%). However, as previously reported, certain cases of the Goodpasture syndrome are seronegative for anti-GBM antibodies, and the reasons for the same have not been elucidated.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]}</p><p>In our case, the patient was seronegative for ANCA and anti-GBM antibodies, and presented with the Goodpasture syndrome with nephrotic-range proteinuria and normal renal function. While this condition may clinically be misdiagnosed as membranous nephropathy and membranous proliferative glomerulonephritis, among others, renal pathology revealed crescent formation and necrotic changes, thereby enabling a confirmative diagnosis. Immunofluorescence staining also indicated a linear deposition of immunoglobulin G and complement C3 on the GBM. Considering that the impairment of the lungs was due to alveolar hemorrhage, the patient was diagnosed with atypical Goodpasture syndrome. There are 2 relatively rare aspects of our case. Usually, classical anti-GBM disease presents with rapidly progressive kidney failure;^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} however, one of the key characteristics of our report is the nephrotic-range proteinuria without renal dysfunction, which indicates a more severe degree of podocyte injury as compared to in the classic form. Nasr et al^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} recently reported 7 patients who presented with nephrotic syndromes presumed to be atypical GBM diseases; however, the presence or absence of serum anti-GBM antibodies was not described in these cases. Liang et al^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} also reviewed the clinical pathological features of antibody-negative anti-GBM disease, and observed that 7 out of 19 patients presented with nephrotic-range proteinuria; however, it is unclear whether the kidney function was impaired. Therefore, we believe that our report, which details a case seronegative for anti-GBM antibodies and presenting with nephrotic-range proteinuria without kidney failure, is fairly rare.</p><p>The mechanism behind undetectable circulating anti-GBM antibodies remains unclear; although there may be several explanations to this. Firstly, it is possible that the result was falsely negative due to the limitations of the test. Even though ELISA has a positive predictive value of 95%, antibody detection remains difficult in a small number of patients. It was reported the auto-antibody antigens included the &#x003b1;3NC1&#x02013;&#x003b1;5NC1 domains and the linear type IV collagen epitopes^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]}; this demonstrates that renal tissues may have different epitopes than those present in the native kidney. Secondly, the seronegativity for anti-GBM antibodies may be attributed to their shorter half-life in circulation than in the renal tissue; the antibodies may have disappeared from the circulation while collecting the blood during testing.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} Finally, antibodies with high affinity are removed from the patient's plasma by binding to the kidney and the alveolar basement membranes. Conversely, the circulating serum antibodies may have a lower affinity than those in the renal and lung tissues; therefore, these may have washed off more easily during the experimental rinsing step. Hence, it is rather important to perform a renal biopsy in highly suspicious patients that are seronegative for anti-GBM antibodies, even though the clinical manifestations are atypical.</p><p>The classical treatment regimens for the Goodpasture syndrome include plasma exchange, corticosteroids, and immunosuppressive therapy. Plasma exchange could eliminate the circulating antibodies. Corticosteroids and immunosuppressants could prevent the formation of anti-GBM antibodies. In our case, the patient received plasma exchange therapy, intravenous methylprednisolone (followed by oral prednisolone), and cyclophosphamide. These treatments relieved the lung lesion remarkably and ceased hemoptysis. However, only partial remission was achieved in case of renal involvement. The renal function was preserved and the proteinuria level was decreased by more than 50%. Considering that the Goodpasture syndrome could also lead to podocytopathy, tacrolimus was chosen for maintenance treatment. Our observations indicate that Goodpasture syndrome with nephrotic-range proteinuria may require a longer therapy and follow-up to determine prognosis.</p><p>In conclusion, we have reported the case of a patient who was diagnosed with antibody-negative Goodpasture syndrome accompanied by nephrotic-range proteinuria and normal kidney function. This presentation is different from that of classical cases. This report serves as a reminder for clinicians to maintain a high degree of awareness for identifying such uncommon cases.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Wei Qin.</p><p><bold>Data curation:</bold> ZhengXia Zhong, JiaXing Tan.</p><p><bold>Investigation:</bold> ZhengXia Zhong.</p><p><bold>Project administration:</bold> ZhengFu Li.</p><p><bold>Writing &#x02013; original draft:</bold> ZhengXia Zhong.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Yi Tang Wei Qin.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: ANA = antinuclear antibodies, ANCA = anti-neutrophil cytoplasmic antibodies, CT = computed tomography, DFPP = double filtration plasmapheresis therapy, dsDNA = anti-double-stranded DNA, eGFR = estimated glomerular filtration rate, ELISA = enzyme-linked immunosorbent assay, GBM = glomerular basement membrane, HBV DNA = hepatitis B virus deoxyribonucleic acid, HBVAg = hepatitis B surface antigen, HPF = high power field, NC1 = non-collagenous domain C1.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Zhong Z, Tan J, Tang Y, Li Z, Qin W. Goodpasture syndrome manifesting as nephrotic-range proteinuria with anti-glomerular basement membrane antibody seronegativity: A case report. <italic>Medicine</italic>. 2020;99:39(e22341).</p></fn><fn fn-type=\"other\"><p>Informed written consent was obtained from the patient for publication of this case report and accompanying images.</p></fn><fn fn-type=\"other\"><p>Ethical approval was obtained from the Ethics Committee of West China Hospital of Sichuan University, China, in compliance with the Declaration of Helsinki.</p></fn><fn fn-type=\"financial-disclosure\"><p>This study received no external funding.</p></fn><fn fn-type=\"other\"><p>The authors of this work have nothing to disclose.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991404</article-id><article-id pub-id-type=\"pmc\">PMC7523816</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-07327</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022012</article-id><article-id pub-id-type=\"art-access-id\">22012</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3900</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Effect of traditional Chinese medicine injections on severe pneumonia</article-title><subtitle>A protocol for systematic review and meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Luo</surname><given-names>Wei</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Ya</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Qiang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhong</surname><given-names>Huifang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff4\">^d</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-4690-0333</contrib-id><name><surname>Deng</surname><given-names>Jia</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Respiratory and Critical Care Medicine, Chongqing Jiangbei Hospital of Traditional Chinese Medicine</aff><aff id=\"aff2\"><label>b</label>Department of Dermatology, Chongqing Hospital of Traditional Chinese Medicine</aff><aff id=\"aff3\"><label>c</label>Department of Oncology, Army Medical Center of PLA</aff><aff id=\"aff4\"><label>d</label>Department of Personnel Office, Chongqing Jiangbei Hospital of Traditional Chinese Medicine, Chongoing, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Jia Deng, Department of Respiratory and Critical Care Medicine, Chongqing Jiangbei Hospital of Traditional Chinese Medicine, No. 35 Yi Cun, Jianxin Dong Lu, Jiangbei District, Chongqing 400020, China (e-mail: <email>D1123_456@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22012</elocation-id><history><date date-type=\"received\"><day>24</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>31</day><month>7</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22012.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Traditional Chinese medicine injections (TCMJ) used in the treatment of severe pneumonia have been widely implemented in clinical practice, but their overall efficacy and safety remain unclear. This paper aims to evaluate the efficacy and safety of TCMJ in the treatment of severe pneumonia.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WanFang, and the Chongqing VIP Chinese Science and Technology Periodical Database were all searched for randomized controlled trials focusing on the administration of TCMJ for severe pneumonia. Two researchers independently screened titles, abstracts, full texts, and extracted relevant data. The RevMan 5.3 software (The Cochrane Collaboration, Software Update, Oxford, UK) and Stata 14 software (STATA Corporation, College Station, TX) were used for statistical analysis.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>This study summarizes the related randomized controlled trials to assess the effect and safety of TCMJ in the treatment of severe pneumonia.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>This article provides theoretical support for the clinical application of TCMJ in the treatment of severe pneumonia.</p></sec><sec><title>PROSPERO Registration number:</title><p>CRD42020185072</p></sec></abstract><kwd-group><title>Keywords</title><kwd>meta-analysis</kwd><kwd>protocol</kwd><kwd>severe pneumonia</kwd><kwd>systematic review</kwd><kwd>traditional Chinese medicine injections</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Training program of talent innovation ability of Army Medical Center of PLA</funding-source><award-id>NO.2019CXHLC014</award-id><principal-award-recipient>Jia Deng</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Patients diagnosed with severe pneumonia, including those caused by the coronavirus disease 2019 have an increased mortality rate.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Severe pneumonia is a common acute and critical illness mostly encountered in the field of respiratory and critical medicine. It is basically a progressive pulmonary inflammation caused by infection with pathogenic microorganisms, which has the potential of developing acute and severe illness and worsen rapidly.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Symptoms such as cough, fever, and respiratory distress may occur in the early stage of the disease, and multiple organ dysfunction may arise in severe cases.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} In case the affected patient does not obtain prompt treatment, death is very likely to ensue. Modern medicine often adopts symptomatic treatment measures such as antimicrobial therapy, mechanical ventilation, and homeostatic interventions, but the virulence of various pathogen, together with pathogenic multiple drug resistance seriously affect the clinical efficacy of the treatment regimen, leading to a very uncertain prognosis.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]}</p><p>The role of traditional Chinese medicine injections (TCMJ) in critically ill patients has been gradually discovered since it has been shown to reduce the mortality, shorten the time of mechanical ventilation, and the length of stay in the intensive care unit.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>&#x02013;<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} Over the past couple of years, the efficacy of TCMJ in patients with severe pneumonia has been gradually confirmed by related studies.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>&#x02013;<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} However, the results reported by these clinical trials are still controversial and uncertain. The purpose of this meta-analysis was to evaluate the efficacy and safety of TCMJ in patients with severe pneumonia.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Protocol register</title><p>This study's protocol has been drafted under the guidance of the preferred reporting items for systematic reviews and meta-analyses protocols.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} Moreover, it has been registered on PROSPERO (Registration number: CRD42020185072).</p></sec><sec><label>2.2</label><title>Ethics</title><p>Ethical approval is not required because there is no patient recruitment or personal information collection, and the data included in our study were extracted from published literature.</p></sec><sec><label>2.3</label><title>Inclusion criteria for research programmes</title><sec><label>2.3.1</label><title>Type of studies</title><p>Randomized controlled trials (RCTs) of TCMJ application for treatment of severe pneumonia were included. Languages are English and Chinese only.</p></sec><sec><label>2.3.2</label><title>Study object</title><p>The study cohort was composed of patients diagnosed with severe pneumonia, regardless of gender, age, race, nationality, and other characteristics.</p></sec><sec><label>2.3.3</label><title>Intervention type</title><p>The control group adopted standard therapy such as antimicrobial therapy, fluid replacement, invasive mechanical ventilation etc. Meanwhile, the experimental group was treated with TCMJ and the type of TCMJ administered (including Xiyanping injection, Xuebijing injection, Reduning injection, Tanreqing injection, Xingnaojing injection, Shenfu injection, Shengmai injection, Shenmai injection) was not limited.</p></sec><sec><label>2.3.4</label><title>Outcome measurements</title><p>Primary outcome:</p><list list-type=\"simple\"><list-item><label>1)</label><p>clinical effective rate.</p></list-item></list><p>Secondary outcomes:</p><list list-type=\"simple\"><list-item><label>1)</label><p>28-day mortality;</p></list-item><list-item><label>2)</label><p>length of stay in the ICU;</p></list-item><list-item><label>3)</label><p>duration of mechanical ventilation;</p></list-item><list-item><label>4)</label><p>C-reactive protein;</p></list-item><list-item><label>5)</label><p>procalcitonin;</p></list-item><list-item><label>6)</label><p>leukocyte count;</p></list-item><list-item><label>7)</label><p>tumor necrosis factor-&#x003b1;;</p></list-item><list-item><label>8)</label><p>interleukin-6;</p></list-item><list-item><label>9)</label><p>D-dimer;</p></list-item><list-item><label>10)</label><p>adverse reactions.</p></list-item></list></sec></sec><sec><label>2.4</label><title>Exclusion criteria</title><list list-type=\"simple\"><list-item><label>(1)</label><p>The literature was published as abstract and conference, and the article's data could not be extracted by contacting the author;</p></list-item><list-item><label>(2)</label><p>Repeatedly published articles were eliminated and research projects with the most complete information were input;</p></list-item><list-item><label>(3)</label><p>Articles with either incomplete or erroneous original data were removed;</p></list-item><list-item><label>(4)</label><p>Articles with obvious randomization mistakes were also excluded.</p></list-item></list></sec><sec><label>2.5</label><title>Search strategy</title><p>Retrieval was conducted from PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WanFang and the Chongqing VIP Chinese Science and Technology Periodical Database, for RCTs of TCMJ administration for severe pneumonia cases. The retrieval words used were: traditional Chinese medicine, TCMJ, severe pneumonia etc. PubMed retrieval strategies are displayed in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>. We also adapted similar search strategies for other electronic databases.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>PubMed search strategy.</p></caption><graphic xlink:href=\"medi-99-e22012-g001\"/></table-wrap></sec><sec><label>2.6</label><title>Data extraction principle</title><p>Two investigators independently screened the articles. First, we eliminated duplicate pieces of literature. Second, we excluded literature that did not meet the inclusion criteria by reviewing the titles and abstracts. Third, we re-screened the literature's full text that may meet the inclusion criteria to determine whether it was finally included or not, and cross-checked them. Any disagreement was solved via dialogue or discussion with a third investigator when necessary. The 2 investigators independently extracted the data and cross-checked them. Excel 2019 literature information database was established to extract data including the author(s), year of publication, sample size, type of TCMJ, sex, age, intervention measures, course of treatment, outcome, etc. In case of disagreement, the issue was discussed and resolved with a third investigator. The literature selection process is illustrated in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flow diagram.</p></caption><graphic xlink:href=\"medi-99-e22012-g002\"/></fig></sec><sec><label>2.7</label><title>Literature quality evaluation</title><p>The 2 researchers independently assessed the risk of bias in the included literature by referring to the Cochrane system reviewer manual. The risk levels of literature quality bias were identified as high, unclear and low. In case of any disagreement, the decision was made after consultation with a third researcher.</p></sec><sec><label>2.8</label><title>Statistic analysis</title><sec><label>2.8.1</label><title>Data analysis and processing</title><p>The RevMan 5.3 software (The Cochrane Collaboration, Software Update, Oxford, UK) and Stata 14 software (STATA Corporation, College Station, TX) were used for statistical analysis. Regarding dichotomous variables, the relative risk was used for statistical analysis. For continuous variables, the Standardized Mean Difference was selected with different tools or units of measurement, and all the above were represented by effect value and 95% Confidence intervals. Heterogeneity test: the Q test was utilized to qualitatively determine inter-study heterogeneity. If <italic>P</italic>&#x02265;.1, there was no inter-study heterogeneity. Whereas if <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.1, it indicated inter-study heterogeneity. At the same time, the I² value was used to quantitatively evaluate the inter-study heterogeneity. If I²&#x02264;50%, the heterogeneity was considered to be adequate, and the fixed-effect model was adopted. If I²&#x0200a;&#x0003e;&#x0200a;50%, it was considered to have significant heterogeneity, the source of heterogeneity would be explored through either subgroup analysis or sensitivity analysis. If there was no obvious clinical or methodological heterogeneity detected, it would be regarded as having statistical heterogeneity, and the random-effect model would be used for analysis. Descriptive analysis was used if there was significant clinical heterogeneity between the 2 groups and subgroup analysis was not available.</p></sec><sec><label>2.8.2</label><title>Missing data processing</title><p>If data was reported missing or incomplete, we would contact the corresponding author to obtain the missing pieces of information. Otherwise, the concerned study would be be removed.</p></sec><sec><label>2.8.3</label><title>Subgroup analysis</title><p>In order to eliminate the clinical heterogeneity between studies, a subgroup analysis was conducted according to the types of TCMJ administered.</p></sec><sec><label>2.8.4</label><title>Sensitivity analysis</title><p>To test the stability of the meta-analysis results, a one-by-one elimination method was adopted for sensitivity analysis.</p></sec><sec><label>2.8.5</label><title>Reporting bias</title><p>If the included study was &#x02265;10, the funnel plot was used to qualitatively detect publication bias.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} Subsequently, Egger and Begg tests were used to quantitatively assess the potential publication bias.</p></sec></sec></sec><sec><label>3</label><title>Discussion</title><p>Severe pneumonia is an acute and critical disease of the respiratory system, which can further progress and worsened by increased inflammation of the lung tissue, causing multiple organ dysfunction, and can even be life-threatening.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} In addition to the common respiratory symptoms of pneumonia, severe pneumonia is characterized by insidious development, high mortality, and poor prognosis.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} In the treatment of severe pneumonia, antimicrobial therapy is the main means to reduce the mortality of patients.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} Nonetheless, in recent years, with the widespread use of antibiotics and the continuous increase of drug-resistant strains, conventional treatments such as antibiotics are generally unable to achieve an ideal therapeutic effect.^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} Consequently, the most important aspect of the treatment plan is to choose reasonable, effective and safe drugs to control the underlying infection.</p><p>TCMJ is the product of the modernization of traditional Chinese medicine dosage form, which has become a unique treatment option for clinical diseases and also plays an irreplaceable role.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>,<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]} At present, related studies have reported that integrated traditional Chinese and western medicine treatment modalities can safely and effectively reduce the clinical symptoms of patients, as well as lower the mortality and the conversion rate of critically ill patients.^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>,<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} As a result, traditional Chinese medicine is a potential treatment option for severe pneumonia. In a nutshell, this study systematically evaluates the efficacy and safety of TCMJ in the treatment of severe pneumonia based on the existing pieces of evidence. The presentation of these results provide better treatment alternatives and more convincing evidence for clinical therapy.</p><p>Withal, there were some limitations to our study: the included literature only consited of articles written in either Chinese or English, the included literatures are of low quality, allocation concealment and the blinding implementation process was not clear, and the follow-up period was short. The above factors could lead to biased results, so further investigation is still necessary, in order to determine the best way of exploring the safety and efficacy of TCMJ application in the treatment of severe pneumonia. In order to systematically verify the effectiveness and safety of TCMJ in patients with severe pneumonia, it is still imperative to design large sample size, high quality, multi-center RCTs.</p></sec><sec><title>Author contributions</title><p><bold>Data collection:</bold> Wei Luo, Jia Deng.</p><p><bold>Funding support:</bold> Qiang Zhang.</p><p><bold>Literature retrieval:</bold> Ya Liu.</p><p><bold>Software operating:</bold> Huifang Zhong.</p><p><bold>Supervision:</bold> Huifang Zhong.</p><p><bold>Writing &#x02013; original draft:</bold> Wei Luo, Ya Liu, Jia Deng.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Wei Luo, Huifang Zhong.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: RCTs = randomized controlled trials, TCMJ = traditional Chinese medicine injections.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Luo W, Liu Y, Zhang Q, Zhong H, Deng J. Effect of traditional Chinese medicine injections on severe pneumonia: A protocol for systematic review and meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22012).</p></fn><fn fn-type=\"equal\"><p>WL and YL contributed equally to this work and are the co-first authors.</p></fn><fn fn-type=\"supported-by\"><p>This work is supported by the training program of talent innovation ability of Army Medical Center of PLA (NO.2019CXHLC014).</p></fn><fn fn-type=\"other\"><p>The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not available. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991402</article-id><article-id pub-id-type=\"pmc\">PMC7523817</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-08058</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000021941</article-id><article-id pub-id-type=\"art-access-id\">21941</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>4800</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>A gene missense mutation in diffuse pulmonary lymphangiomatosis with thrombocytopenia</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Zheng</surname><given-names>Guixian</given-names></name><degrees>BS</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Tang</surname><given-names>Haijuan</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Su</surname><given-names>Rui</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Liang</surname><given-names>Yi</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>He</surname><given-names>Zhiyi</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Jianquan</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Deng</surname><given-names>Jingmin</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Bai</surname><given-names>Jing</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhong</surname><given-names>Xiaoning</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Respiratory Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning</aff><aff id=\"aff2\"><label>b</label>Department of Respiratory Medicine, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Jing Bai, Department of Respiratory Medicine, First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Qingxiu District, Nanning 530021, Guangxi, China (e-mail: <email>bj1312002@aliyun.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e21941</elocation-id><history><date date-type=\"received\"><day>4</day><month>11</month><year>2019</year></date><date date-type=\"rev-recd\"><day>17</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>28</day><month>7</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e21941.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"intro\"><title>Introduction:</title><p>Diffuse pulmonary lymphangiomatosis (DPL) is a rare condition. Most patients with DPL present dyspnea, cough, expectoration, and hemoptysis. There are few reports of DPL accompanied by thrombocytopenia, whose cause remains unknown.</p></sec><sec><title>Patient concerns:</title><p>An 18-year-old male patient presented with recurrent cough, expectoration, and dyspnea for 5 years, and thrombocytopenia was observed during a 2-month follow-up.</p></sec><sec><title>Diagnosis:</title><p>Chest computed tomography showed diffuse patchy shadows in both lungs, and pleural and pericardial effusions. Immunohistochemical lung tissue staining showed lymphatic and vascular endothelial cells positive for D2-40, CD31 and CD34. Routine blood test revealed platelets at 62&#x0200a;&#x000d7;&#x0200a;10⁹ cells/L during follow-up. Bone marrow biopsy was normal. Ultrasound revealed no hepatosplenomegaly. Finally, the patient was diagnosed with DPL accompanied by thrombocytopenia.</p></sec><sec><title>Interventions:</title><p>He was treated by subtotal pericardial resection, thoracocentesis, and anti-infective therapy. Oral prednisone was administered for 2 months.</p></sec><sec><title>Outcomes:</title><p>The symptoms of cough and shortness of breath were improved, but thrombocytopenia persisted. We investigated the cause of thrombocytopenia. Whole-exome sequencing identified a mutation in exon 3 of the <italic>TNFRSF13B</italic> gene in this patient.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>DPL may present with thrombocytopenia and DIC. Patients with thrombocytopenia but not DIC and splenomegaly should be screened for gene mutations.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>lung</kwd><kwd>lymphangioma</kwd><kwd>monoclonal antibody D2-40</kwd><kwd>gene</kwd><kwd>thrombocytopenia</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>The National Natural Science Foundation of China</funding-source><award-id>81560008</award-id><principal-award-recipient>Guixian Zheng</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>The Guangxi Municipal Natural Science Foundation</funding-source><award-id>2018GXNSFAA050056</award-id><principal-award-recipient>Guixian Zheng</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Lymphangiomatosis may occur in single or multiple organ sites. Diffuse pulmonary lymphangiomatosis (DPL) is a rare lung disease characterized by the proliferation of congenital lymphatic vessels, often accompanied by the involvement of lungs, pleura and mediastinal soft tissues. The main chest computed tomography (CT) findings in DPL are thickening of the pulmonary lobule septum, diffuse funicular shadows, reticular opacity, and patchy shadows. The major symptoms of DPL are dyspnea, cough, expectoration and hemoptysis, and seldom thrombocytopenia. To date, 8 cases of DPL have been reported with thrombocytopenia and DIC.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} In addition, only thrombocytopenia was observed in 1 patient^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>). Here, we present the case of a young male with DPL involving the mediastinum and pulmonary interstitium, accompanied by thrombocytopenia. He had no splenomegaly and disseminated intravascular coagulation (DIC). We investigated the cause of thrombocytopenia, and whole-exome sequencing was performed on the patient samples. The identified mutation could be an alternative explanation for DPL with thrombocytopenia.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Nine cases of lymphangiomatosis with thrombocytopenia.</p></caption><graphic xlink:href=\"medi-99-e21941-g001\"/></table-wrap></sec><sec><label>2</label><title>Case presentation</title><p>The study was approved by the local Ethics Review Board at First Affiliated Hospital of Guangxi Medical University, China (number 2019KY-E-079), and performed according to the Declaration of Helsinki. On February 19, 2013, a 12-year-old boy of Han nationality was referred to our hospital (Department of Pediatrics, the First Affiliated Hospital of Guangxi Medical University) for shortness of breath accompanied by cough and fever. He had been admitted to Liuzhou People's Hospital (a third-class A hospital) after diagnosis of chronic pericarditis and capillary hemangioma 11 months previously. Then, he presented with cough and shortness of breath; chest CT showed large amounts of pleural effusion in the right side of his chest (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>A), and echocardiography revealed large amounts of pericardial effusions. His condition was improved after subtotal pericardial resection, right chest clearing, and postoperative anti-infective treatment with flucloxacillin, cefoperazone sulbactam, and meropenem. Pericardial pathology reported chronic pericarditis and capillary hemangioma. Half a month ago, he experienced shortness of breath and cough with yellow-white sputum; body temperature raised to 38.5&#x000b0;C irregularly. After treatment with ceftriaxone, the temperature decreased to the normal level. Shortness of breath steadily progressed and was more serious in the lying position. The patient was the product of an uncomplicated pregnancy and delivery, and had experienced no developmental or growth problems. His medical history showed no abnormalities. No family history of lymphedema, bleeding tendency, or vascular malformations was present. The boy was referred to our hospital for further evaluation.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>(A) Chest computed tomography (CT) in April 2012 showing a massive right pleural effusion, as well as patchy, dense patches. (B) Chest CT in February 2013 showing the collapse of the right thorax and left lower lung, and thickening of the lobular septum. (C) Chest CT in September 2017 showing the collapse of the right thorax; the texture of both lungs was disordered, and glassy density of the right lung was observed in all layers.</p></caption><graphic xlink:href=\"medi-99-e21941-g002\"/></fig><p>On physical examination, he had a 12&#x0200a;cm old surgical scar on the front of the chest, and the right thoracic cage bulged slightly, whereas the intercostal space was widened. No cutaneous nevi or lymphangiomas was evident. There were right lung percussion, thick bilateral lung breathing, weak bilateral lower lung breathing, and medium and small vesicle sounds, with no pleural frictional sound. His cardiac sounds were normal and no murmurs were present. He had no abdominal masses, hepatomegaly, or splenomegaly. No peripheral edema was present, and neurological examination was normal.</p><p>Laboratory examination revealed normal routine blood test, erythrocyte sedimentation rate, tuberculosis antibodies, autoantibody profile, and rheumatoid factor. However, 150&#x0200a;mL of bloody fluid was aspirated by thoracocentesis, and its analysis showed chylous fluid without evidence of infection or malignancy. Pleural fluid cultures for bacteria, fungi, and acid-fast bacilli were negative. Echocardiography revealed minimal pericardial fluid. Chest ultrasound showed bilateral pleural effusion. Reviewed chest CT scan from the local hospital revealed large amounts of pericardial effusion, bilateral pleural effusion, and widening mediastinum. However, plain and enhanced chest CT scans showed no abnormalities in the mediastinum (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>B). A total of 9 pericardial pathologies were reviewed at Liuzhou People's Hospital (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>A and B), revealing a vascular tumor that included lymphangioma and hemangioma. Lymphangioma accounted for 50% to 80% of each section, and the morphology mainly reflected cavernous lymphangioma. Immunohistochemical staining showed that proliferating lymphatic endothelial cells expressed D2-40 and CD31. Vascular endothelial cells were positive for CD34. Peripheral lymphatic smooth muscle cells were positive for desmin and SMA. HMB45, Melan-A, and CD117 staining results were negative, ruling out angiomyolipoma and lymphangiomyoma. Histologic differentiation of lymphangiomatosis from hemangiomatosis is not always easy. Based on clinical findings, pathology, and immunohistochemical data, the overall picture favored the diagnosis of lymphangiomatosis.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} After right side thoracentesis, anti-infective treatment with ceftriaxone and clindamycin, and atomization for cough, no pericardial and pleural effusions were found in ultrasound examinations. His condition was improved and he was discharged on March 13, 2013.</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>(A) Nine pericardial pathologies showing that the lymphangiomatosis components accounted for 50% to 80% in each slice, with predominant cavernous lymphangiomatosis (original magnification &#x000d7;10). Lymphocytes were clustered into the bureaucratic cavity (arrowheads) and lined with monolayers and widely spaced endothelial cells. (B) Immunohistochemical detection of D2-40. (DAB, original magnification &#x000d7;10).</p></caption><graphic xlink:href=\"medi-99-e21941-g003\"/></fig><p>During follow-up, he was admitted to the hospital twice for recurrent episodes of cough, expectoration and shortness of breath in 2015. Routine blood parameters were within the normal limits. These symptoms were improved after anti-infection and thoracentesis. In September 2017, he was treated in Longtan Hospital of Guangxi (third-class hospital) twice for cough, accompanied by chest tightness, and shortness of breath which was more serious in the lying position. No fever, hemoptysis, rash, subcutaneous haemorrhage, and arthralgia were detected. Routine blood test revealed platelets at 62&#x0200a;&#x000d7;&#x0200a;10⁹ cells/L, whereas the total leucocyte number, types of white blood cells, and coagulation data were normal. Pleural effusion was bloody and milky, and bacterial culture was negative. Chest CT showed infiltration in the lungs, bilateral thickening of the pleura, minimal left pleural effusion, and multiple rib abnormalities with lytic areas in the first to fifth thoracic vertebras. After treatment with mezlocillin/sulbactam sodium and metronidazole in combination with left side thoracentesis, cough and shortness of breath remained. In November 2017, the patient presented again to the Department of Respiratory Medicine of the First Affiliated Hospital of Guangxi Medical University. Platelets were 61.40&#x0200a;&#x000d7;&#x0200a;10⁹ cells/L, and coagulation data were within the normal limits. He also tested negative for disseminated intravascular coagulation (DIC). The bone marrow was normal. Abdominal ultrasound revealed no hepatosplenomegaly. Plain and enhanced chest CT scans revealed lung infiltration and bilateral thickening of the pleura, as well as middle and lower lobe bronchial changes in right lung (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>C). However, DPL is rare, and we lacked related treatment experience. He was treated with systemic oral corticosteroids (30&#x0200a;mg/day for 2 months). The symptoms of cough and shortness of breath were improved, but thrombocytopenia persisted. He stopped taking the medication after 2 months because he worried about possible side effects after prolonged use. Because the patient was asymptomatic and thrombocytopenia had not worsened as assessed by blood tests, we observed him without specific treatment. He has been followed up for &#x0003e;1.5 years, and has not developed dyspnoea on exertion, lymphedema, or bleeding. Furthermore, chest roentgenographic features have remained stable. Persistent thrombocytopenia in this patient requires careful clinical follow-up.</p><p>We next investigated the cause(s) of lymphangiomatosis or thrombocytopenia. He is a unique son with no siblings. Whole-exome sequencing by second Generation Exome Sequencing (Beijing Kangxu Medical Laboratory) was performed on samples from his parents. The Review Board of the First Affiliated Hospital of Guangxi University has approved this research. A p.Ser144Leu mutation in TNFRSF13B was found by testing DNA from nucleated cells of the patient's blood, suggesting the possibility of thrombocytopenia (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>). This mutation was not found in his family members. Lymphatic malformation-related genes previously reported were not found in the current patient.</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Sanger sequencing of peripheral blood revealed the c.431C&#x0200a;&#x0003e;&#x0200a;T (p.Ser144Leu) mutation. Arrow indicates the heterozygous C&#x0200a;&#x0003e;&#x0200a;T mutation at exon 3 of the <italic>TNFRSF13B</italic> gene.</p></caption><graphic xlink:href=\"medi-99-e21941-g004\"/></fig></sec><sec><label>3</label><title>Discussion</title><p>Lymphangiomatosis is an abnormal proliferation of lymphatic endothelial cells. In 2014, the International Society for the Study of Vascular Anomalies (ISSVA) omitted the terms &#x0201c;lymphangioma&#x0201d; and &#x0201c;lymphangiomatosis&#x0201d; in favor of &#x0201c;generalized lymphatic anomaly&#x0201d;; the literature reflects a change in terminology. These signs commonly present in the head and neck in children. In a 25-year retrospective review of 186 children with lymphangiomas, only 19 patients (10%) had internal or visceral locations, such as the abdomen or thorax.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} It most frequently involves the liver, the spleen, the mediastinum, lungs, or soft tissues. To date, 49 cases of DPL have been reported. In a review of the literature, we observed that the clinical manifestation of DPL has no specificity. It mainly presents with dyspnea (34/49 [69%]), cough (24/49 [49%]), expectoration (12/49 [24%]), and hemoptysis (10/49 [20%]). Chest imaging in DPL cases also lacks specificity. Many patients (33/40 [83%]) show thickening of the interlobular septum and scattered streak, mesh, and patchy shadows on chest CT images. About 30%&#x0223c;60% patients present with pleural effusions, occupied mediastinal space, pleural thickening, or pericardial effusions. In the current patient, onset age was 12 years, and he has had DPL for 6 years. The main symptoms were cough, expectoration, and dyspnea. Chest CT mainly showed diffuse patchy shadows in both lungs, and pleural and pericardial effusions.</p><p>An important finding in the current patient was the presence of thrombocytopenia without associated splenic lymphangiomatosis. Literature review revealed that thrombocytopenia and DIC are found in a minority of DPL cases (9/49 [18%]). There are currently 9 cases of lymphangiomatosis accompanied by thrombocytopenia. Among them, 8 cases were DIC combined with thrombocytopenia, and 5 had spleen invasion. One case with associated splenic lymphangiomatosis only had thrombocytopenia but not DIC. DIC associated with or without splenic involvement complicates the clinical course. Coagulation abnormalities associated with lymphangiomatosis have been described in reports of thrombocytopenia and DIC. However, there are currently no studies evaluating the cause of thrombocytopenia. DPL with DIC is considered a coagulation abnormality associated with venous malformations; this so-called localized intravascular coagulation could develop into systemic DIC.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} However, this hypothesis lacks a pathological basis, and the actual etiology needs to be further studied. Two cases of DPL involving the spleen with thrombocytopenia and DIC showed improvement after partial splenic embolization and splenectomy; therefore, such cases may be related to lymphoma involving the spleen.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} For the patient in this report, the lesions involved the lungs, the pericardium, and the pleura, but the spleen was not involved; in addition, platelet counts were reduced. A mutation in the <italic>TNFRSF13B</italic> gene (c.431C&#x0200a;&#x0003e;&#x0200a;T, p.Ser144Leu) was found in the current patient by exome sequencing, and a gain-of-function mutation in TNFRSF13B was reported as a candidate for the predisposition to familial or sporadic immune thrombocytopenia.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Therefore, the disease etiology in these patients may be related to gene mutations.</p><p>From the literature review, it can be concluded that patients with lymphangioma presenting DIC and thrombocytopenia have high mortality. Among the 9 cases, 4 patients died, and 5 survived. Spleen involvement did not necessarily confer a bad prognosis, as 4 of the 5 patients with splenomegaly survived. Among the 5 surviving patients, 4 underwent surgery, including splenectomy^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} and splenic artery embolization,^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} and 1 received no specific treatment.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Bleeding in the 5 patients after surgery was significantly improved. One patient died after splenic artery embolization for intractable chylothorax and chylous ascites occurred, without DIC recurrence.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Systemic steroids, interferons, and radiation therapy exerted only palliative effects. Chemotherapy and tamoxifen, which are potentially effective treatment options, did not change the disease course. Medications (hormones and interferons) and chemotherapy or radiotherapy may play a role in mass reduction, but DIC and thrombocytopenia persisted.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Two of the 4 dead patients treated by medication alone had uncontrollable bleeding, and died from respiratory failure and DIC.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Like the present patient, 1 case with lymphangiomatosis had only thrombocytopenia without DIC and splenomegaly; she was not treated for thrombocytopenia and died from progressive respiratory failure.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} The current patient had thrombocytopenia during follow-up, but no DIC or spleen involvement; he had no bleeding symptoms or progressive respiratory failure, and received no therapy for thrombocytopenia. Fortunately, he showed no deterioration during follow-up. Moreover, a case was reported with DIC and thrombocytopenia, but no spleen invasion. The latter had no treatment for clinical symptoms, and was in good condition during follow-up.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} From the literature review, in case of related clinical symptoms, active treatment should be performed. Use of medication alone cannot control bleeding, but splenectomy or splenic embolization is effective for thrombocytopenia and DIC.</p><p>Overall, DPL may present with thrombocytopenia and DIC. A wider appreciation of this multisystem disease is warranted. Thrombocytopenia may be associated with mutated <italic>TNFRSF13B</italic> gene. Splenectomy or splenic embolization is effective for DPL combined with thrombocytopenia and DIC.</p></sec><sec><label>4</label><title>Consent for publication</title><p>Informed written consent was obtained from the patient and his parents for publication of this case report.</p></sec><sec><title>Acknowledgments</title><p>The authors thank Dr. Zili Lv for assistance with pathological diagnosis. The authors would also like to acknowledge the patient's contribution to this report.</p></sec><sec><title>Author contributions</title><p>XXXX.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CT = computed tomography, DIC = disseminated intravascular coagulation, DPL = diffuse pulmonary lymphangiomatosis, ISSVA = International Society for the Study of Vascular Anomalies.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Zheng G, Tang H, Su R, Liang Y, He Z, Zhang J, Deng J, Bai J, Zhong X. A gene missense mutation in diffuse pulmonary lymphangiomatosis with thrombocytopenia: A case report. <italic>Medicine</italic>. 2020;99:39(e21941).</p></fn><fn fn-type=\"equal\"><p>GZ and HT contributed equally to this work.</p></fn><fn fn-type=\"COI-statement\"><p>The authors report no conflicts of interest.</p></fn><fn fn-type=\"supported-by\"><p>Funding: This work was supported by the National Natural Science Foundation of China (Grant Number: 81560008) and the Guangxi Municipal Natural Science Foundation (Grant Number: 2018GXNSFAA050056).</p></fn><fn fn-type=\"other\"><p>Written informed consent was obtained from the patient and his parents for the publication of this report.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"research-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991458</article-id><article-id pub-id-type=\"pmc\">PMC7523819</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08074</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022381</article-id><article-id pub-id-type=\"art-access-id\">22381</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>5500</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Clinical Trial</subject></subj-group></article-categories><title-group><article-title>Long-term effects of a food pattern on cardiovascular risk factors and age-related changes of muscular and cognitive function</article-title></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0003-0868-3363</contrib-id><name><surname>Wernicke</surname><given-names>Charlotte</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Apostolopoulou</surname><given-names>Konstantina</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Hornemann</surname><given-names>Silke</given-names></name><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref ref-type=\"aff\" rid=\"aff3\">^c</xref><xref ref-type=\"aff\" rid=\"aff5\">^e</xref></contrib><contrib contrib-type=\"author\"><name><surname>Efthymiou</surname><given-names>Andriana</given-names></name><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Machann</surname><given-names>J&#x000fc;rgen</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff4\">^d</xref><xref ref-type=\"aff\" rid=\"aff5\">^e</xref><xref ref-type=\"aff\" rid=\"aff6\">^f</xref></contrib><contrib contrib-type=\"author\"><name><surname>Schmidt</surname><given-names>Sein</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff7\">^g</xref></contrib><contrib contrib-type=\"author\"><name><surname>Primessnig</surname><given-names>Uwe</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff8\">^h</xref><xref ref-type=\"aff\" rid=\"aff9\">ⁱ</xref></contrib><contrib contrib-type=\"author\"><name><surname>Bergmann</surname><given-names>Manuela M.</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Grune</surname><given-names>Tilman</given-names></name><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Gerbracht</surname><given-names>Christiana</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Herber</surname><given-names>Katharina</given-names></name><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Pohrt</surname><given-names>Anne</given-names></name><xref ref-type=\"aff\" rid=\"aff10\">^j</xref></contrib><contrib contrib-type=\"author\"><name><surname>Pfeiffer</surname><given-names>Andreas F.H.</given-names></name><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref ref-type=\"aff\" rid=\"aff3\">^c</xref><xref ref-type=\"aff\" rid=\"aff5\">^e</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-8900-4467</contrib-id><name><surname>Spranger</surname><given-names>Joachim</given-names></name><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref ref-type=\"aff\" rid=\"aff8\">^h</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Mai</surname><given-names>Knut</given-names></name><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref ref-type=\"aff\" rid=\"aff7\">^g</xref><xref ref-type=\"aff\" rid=\"aff8\">^h</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Charit&#x000e9; - Universit&#x000e4;tsmedizin Berlin, Corporate Member of Freie Universit&#x000e4;t Berlin, Humboldt-Universit&#x000e4;t zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin</aff><aff id=\"aff2\"><label>b</label>NutriAct-Competence Cluster Nutrition Research, Berlin-Potsdam</aff><aff id=\"aff3\"><label>c</label>Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal</aff><aff id=\"aff4\"><label>d</label>Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of T&#x000fc;bingen, T&#x000fc;bingen</aff><aff id=\"aff5\"><label>e</label>German Center for Diabetes Research, M&#x000fc;nchen-Neuherberg</aff><aff id=\"aff6\"><label>f</label>Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital T&#x000fc;bingen, T&#x000fc;bingen</aff><aff id=\"aff7\"><label>g</label>Charit&#x000e9; - Universit&#x000e4;tsmedizin Berlin, Corporate Member of Freie Universit&#x000e4;t Berlin, Humboldt-Universit&#x000e4;t zu Berlin, and Berlin Institute of Health, Clinical Research Unit, 10117 Berlin</aff><aff id=\"aff8\"><label>h</label>DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin</aff><aff id=\"aff9\"><label>i</label>Department of Internal Medicine and Cardiology, Charit&#x000e9; - Universit&#x000e4;tsmedizin Berlin, Campus Virchow-Klinikum, Berlin</aff><aff id=\"aff10\"><label>j</label>Charit&#x000e9; - Universit&#x000e4;tsmedizin Berlin, Corporate Member of Freie Universit&#x000e4;t Berlin, Humboldt-Universit&#x000e4;t zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Joachim Spranger, Department of Endocrinology &#x00026; Metabolism, Charite - Universit&#x000e4;tsmedizin, Chariteplatz 1, 10117 Berlin, Germany (e-mail: <email>joachim.spranger@charite.de</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22381</elocation-id><history><date date-type=\"received\"><day>24</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>26</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22381.pdf\"/><abstract abstract-type=\"toc\"><p>Supplemental Digital Content is available in the text</p></abstract><abstract><title>Abstract</title><sec sec-type=\"intro\"><title>Introduction:</title><p>The mean age of the German population increased over the last years, which resulted in a higher prevalence of cardiovascular diseases, type 2 diabetes, cognitive impairment, sarcopenia and bone fractures. Current evidence indicates a preservation of human wellbeing in the elderly by a healthy diet, although the recommended macronutrient composition and quality remains unclear and needs further long-term investigation. In this context we investigate the effect of a specific dietary pattern on age-related disorders in a randomized controlled multi-center trial (RCT).</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>We assess the effect of a specific dietary pattern (NutriAct) with a high proportion of unsaturated fat, plant proteins and fibres (fat 35%&#x02013;40% of total energy (%E) of which 15%E&#x02013;20%E monounsaturated fatty acids (MUFA) and 10%E&#x02013;15%E polyunsaturated fatty acids (PUFA), 15%E&#x02013;25%E proteins, &#x02265;30&#x0200a;g fibres per day and 35%E&#x02013;45%E carbohydrates) on age-related impairment of health within a 36-months RCT conducted in the region of Berlin and Potsdam. 502 eligible men (n&#x0200a;=&#x0200a;183) and women (n&#x0200a;=&#x0200a;319), aged 50 to 80 years, with an increased risk to develop age-related diseases were randomly assigned to either an intervention group focusing on NutriAct dietary pattern or a control group focusing on usual care and dietary recommendations in accordance to the German Nutrition Society (DGE). In the intervention group, 21 nutrition counsellings as well as supplementation of rapeseed oil, oil cake and specific designed foods are used to achieve the intended NutriAct dietary pattern.</p><p>The primary outcome is a composite endpoint of age-related disorders, including cardiovascular morbidity, decline of cognitive function as well as clinical features of sarcopenia. Secondary outcomes include diet-induced effects on quality of life, depression, frailty, cardiovascular function, bone density, fat distribution pattern, glucose, lipid and energy metabolism, as well as the identification of biomarkers linked with age-related disorders.</p></sec><sec sec-type=\"discussion\"><title>Discussion:</title><p>The findings of this trial will provide clinically relevant information regarding dietary effects on age-related impairment of health and will contribute to the definition of the optimal macronutrient composition in the context of healthy aging in the German population.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>cardiovascular function</kwd><kwd>cognition</kwd><kwd>diet</kwd><kwd>dietary fibre</kwd><kwd>dietary proteins</kwd><kwd>healthy aging</kwd><kwd>metabolism</kwd><kwd>sarcopenia</kwd><kwd>unsaturated fatty acids</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Bundesministerium f&#x000fc;r Bildung und Forschung</funding-source><award-id>01EA1408</award-id><principal-award-recipient>Not Applicable</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>The aging of the population is associated with a substantial rise of cardiovascular diseases (CVD), metabolic disorders like type 2 diabetes and non-alcoholic fatty liver disease, cancer, dementia and sarcopenia.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} The dietary pattern is thought to constitute a major contributing factor^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} and seemed to be causally linked to 17.9% of CVD-related deaths in Germany in 2016.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Vice versa, current evidence from predominantly epidemiological studies indicates the reduction of age-related diseases through a healthy diet.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Strongest evidence for the power of healthy nutrition to prevent cardiovascular endpoints has been shown for the Mediterranean diet,^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} which is particularly characterized by high intake of unsaturated fatty acids.</p><p>Over the last years, research has shifted from analysis of single macronutrients to the evaluation of dietary patterns, as numerous beneficial interactive effects are evident.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} However, a considerable uncertainty exists regarding the optimal macronutrient composition and quality for improving health status in the elderly. Exemplarily, the preferred amount of proteins (high protein vs low protein) is under debate.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} In middle-aged humans (&#x0003c;65 years), high protein intake was linked to an increased overall and cancer-related mortality, though this association was abolished or significantly reduced if the proteins were plant-derived.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} Accordingly, higher intake of plant protein seems to be associated with decreased cardiovascular, cancer-related and all-cause mortality compared to animal protein.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>&#x02013;<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} Especially in the elderly, high protein intake seems to be beneficial. High protein intake was even associated with a reduced all-cause and cancer-related mortality in people older than 65 years.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} Furthermore, high consumption of dietary protein did improve left ventricular function and remodeling in middle-aged patients with type 2 diabetes^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} as well as functional exercise capacity in heart failure in elderly patients &#x0003e;65 years.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} Moreover, observational studies also indicate a beneficial effect on maintenance of physical function^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} and prevention of frailty and sarcopenia in older adults.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]}</p><p>Modulation of fat intake might also improve age-related decline in health. While liver fat and serum cholesterol are elevated by saturated fatty acids (SFA), increase of mono- (MUFA) and polyunsaturated fatty acids (PUFA) seems to be beneficial for modulation of liver fat and lipid metabolism.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>&#x02013;<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]} Diets focusing on high MUFA and PUFA intake also improved insulin sensitivity,^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} risk of future type 2 diabetes^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} and cardiovascular outcome,^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} especially in a Mediterranean population. Nevertheless, the preventive role of PUFA in promoting cardiovascular health has been debated in recent meta-analyses showing little or no effect.^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>,<xref rid=\"R28\" ref-type=\"bibr\">28</xref>]} Apart from that, adherence to the Mediterranean diet with high content of unsaturated fatty acids was associated with decreased risk of age-related cognitive decline in predominantly observational studies.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]}</p><p>Furthermore, a low glycemic index diet has been shown to improve glycemic control particularly in type 2 diabetes.^{[<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} It might also reduce body weight, insulin resistance and low-density lipoprotein (LDL) cholesterol in obese subjects,^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} while increased fibre intake has been associated with reduction of cardiovascular risk and risk of type 2 diabetes.^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]}</p><p>Taken together, available data suggests that a dietary pattern based on high intake of plant protein, MUFA, PUFA and fibre may improve healthy aging, even if sufficiently powered RCTs with long-term follow-up are currently not available.</p></sec><sec><label>2</label><title>Objectives</title><p>We intend to assess the effect of a dietary approach focusing on high intake of unsaturated fat, plant proteins and fibre combined with a low glycemic index (NutriAct pattern) for healthy aging in middle-aged and elderly people with increased risk for age-related disorders. Therefore, we initiated a randomized controlled 36-months dietary intervention trial comparing the NutriAct dietary pattern and usual care including dietary advices for a healthy diet based on recommendations of the German Nutrition Society (DGE).^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]}</p></sec><sec><label>3</label><title>Methods: participants, intervention, and outcomes</title><sec><label>3.1</label><title>Study design</title><p>The aim of the here described randomized controlled multi-center parallel group trial named &#x0201c;NutriAct&#x0201d; is to compare long-term effects of 2 different dietary patterns in a German aging population. Therefore, 502 eligible persons were enrolled and randomly assigned to intervention or control group after initial characterization. The description of the study design follows the guidelines of the SPIRIT 2013 Statement using the Spirit checklist (see additional file).^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]} The study protocol was approved by the Institutional Review Board of the Charit&#x000e9; Medical School. The trial is conducted in accordance to the Declaration of Helsinki. All subjects gave written informed consent prior to inclusion in the study. The trial was registered at German Clinical Trials Register (DRKS00010049).</p></sec><sec><label>3.2</label><title>Study setting</title><p>The clinical trial is a multi-center study carried out at the Metabolic Research Unit of the Clinic of Endocrinology, Diabetes and Metabolism, Charit&#x000e9; - Universit&#x000e4;tsmedizin Berlin and the Human Study Center of the German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke.</p></sec><sec><label>3.3</label><title>Eligibility criteria</title><p>Potential participants of the study are men and women aged between 50 and 80 years with at least one risk factor for unhealthy aging as follows: elevated blood pressure (systolic blood pressure &#x02265;140&#x0200a;mm Hg or diastolic blood pressure &#x02265;90&#x0200a;mm Hg or medical history of hypertension or use of antihypertensive medication), known CVD (stroke, myocardial infarction, coronary heart disease (CHD), peripheral artery disease (PAD)), heart failure (defined by New York Heart Association (NYHA) &#x02265;II or NT-Pro-BNP &#x0003e;300 ng/l in absence of atrial fibrillation), cognitive impairment (Montreal Cognitive Assessment (MoCA) Score &#x0003c;26) or decreased physical function (Short Physical Performance Battery (SPPB) Score &#x0003c;10).</p><p>Exclusion criteria are the presence of acute severe CVD including unstable CVD, recent cardiovascular event or surgery &#x02264; 3 months, type 1 diabetes mellitus, type 2 diabetes mellitus under insulin therapy, uncontrolled hypertension (blood pressure values &#x0003e;180&#x0200a;mm Hg systolic and/or 110&#x0200a;mm Hg diastolic), life expectancy &#x0003c;1 year, prevalent cancer, severe hepatic or renal diseases (estimated GFR &#x0003c;50&#x0200a;ml/min/1.73 m²), severe gait disturbance diseases (e.g. Parkinson's disease, stroke with paresis), severe systemic infection, severe immune disease, severe food allergy, severe malabsorption disease, oral glucocorticoid treatment, untreated active endocrine disease, severe psychiatric disorder, severe drug and/or alcohol abuse, mental limitations or known eating disorder.</p></sec><sec><label>3.4</label><title>Intervention</title><p>Two different dietary patterns are compared within this RCT. The entire intervention period is 36 months. Within the intervention group a specific NutriAct dietary pattern is implemented. This pattern is defined by the composition of the macronutrients. It consists of 35% to 40% energy (%E) total fat with a high proportion of unsaturated fat, 15%E to 25%E protein emphasizing plant proteins, 35%E to 45%E carbohydrates focusing on low glycemic index and at least 30&#x0200a;g fibres per day. The exact composition of dietary fat is intended as follows: SFA &#x02264; 10%E, MUFA 15%E to 20%E und PUFA 10%E to 15%E. Therefore, SFA are replaced by MUFA and PUFA. Advice on diets and lifestyle as well as practical cookery courses are administered by professional dieticians within 21 group sessions over the entire trial (see Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref> and Supplemental Digital Content (Fig. S1)). This approach is supported by supplementation of rapeseed oil instead of butter and cream. Therefore, all participants in the intervention group receive one liter of rapeseed oil per month as well as 500&#x0200a;g of oil cake every 6 weeks at no cost. In addition, different specific designed NutriAct foods are supplemented in the intervention group on a regular basis to modify food intake according to the NutriAct pattern. Examples are protein and fibre enriched bread rolls and pasta as well as flakes with a high protein and a low carbohydrate content. Furthermore, a high intake of vegetables and nuts as well as moderate fruit intake is being encouraged.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>NutriAct study flowchart. The NutriAct pattern is implemented in the intervention group. The control group is a usual care group including dietary recommendations of the German Nutrition Society. Phenotyping is being performed at baseline (V0), at 3 m (V1), 6 m (V2), 12 m (V3), 24 m (V4) and 36 m (V5) after start of intervention. Sessions of nutrition counselling take place repeatedly between the visits as indicated. n = number, NS = nutrition session, m&#x0200a;=&#x0200a;months, V&#x0200a;=&#x0200a;visit.</p></caption><graphic xlink:href=\"medi-99-e22381-g001\"/></fig><p>The control group receives usual care in accordance to local standard care based on dietary recommendations of the DGE.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>,<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} This includes 5 sessions of nutrition counselling held by professional dieticians according to Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>. Thereby, we recommend a moderate total fat (30%E; SFA &#x02264; 10%E, MUFA &#x02265; 10%E, PUFA 7%E&#x02013;10%E), high carbohydrate (55%E) and moderate protein (15%E) intake.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>,<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} Participants of the control group intermittently receive high carbohydrate muesli, barley flakes and barley as an alternative to rice throughout the study period at no cost. Moreover, they receive small nonfood gifts to reinforce trial retention.</p><p>The dietary intervention started 4 to 6 weeks after the baseline phenotyping at visit (V) 0 (V0). All participants are asked to stabilize their individual body weight if possible. Further details of nutritional sessions as well as the dietary protocol of the intervention and control group are described in the Supplemental Digital Content (for used NutriAct foods in the intervention group see Supplemental Digital Content (Table S1)).</p><p>In addition, participants of both groups are regularly informed regarding their health status as well as crucial abnormal results of the phenotyping during the trial via telephone calls and written reports to further reinforce trial retention. Additional telephone assessments at month 18 and 30 are performed by the study staff to reflect the individual health status and to answer further questions of the participants.</p></sec><sec><label>3.5</label><title>Outcomes</title><p>In order to investigate the effect of the above-described nutritional strategy for healthy aging in middle-aged and elderly people, the primary outcome measure is defined as a composite endpoint of age-related disorders including cardiovascular morbidity and age-related impairment of cognitive function as well as lean body mass and muscular function.</p><p>In detail, this includes:</p><list list-type=\"simple\"><list-item><label>-</label><p>Cardiovascular morbidity</p><list list-type=\"simple\"><list-item><label>&#x02218;</label><p>Newly developed heart failure as defined by development of left ventricular (LV) ejection fraction &#x0003c;50% or hospitalization for heart failure</p></list-item><list-item><label>&#x02218;</label><p>Incidence of CHD, myocardial infarction, cardiovascular revascularization, stroke</p></list-item><list-item><label>&#x02218;</label><p>Increase of blood pressure by 10&#x0200a;mm Hg systolic or 10&#x0200a;mm Hg diastolic or more</p></list-item></list></list-item><list-item><label>-</label><p>Decrease of lean body mass (as a known estimate of muscle mass assessed by Dual-energy X-ray Absorbtiometry (DEXA)) by 3&#x0200a;kg or more</p></list-item><list-item><label>-</label><p>Muscular function</p><list list-type=\"simple\"><list-item><label>&#x02218;</label><p>Decrease of SPPB sum score by 1 point or more</p></list-item><list-item><label>&#x02218;</label><p>Decrease in hand grip strength by 3&#x0200a;kg or more</p></list-item></list></list-item><list-item><label>-</label><p>Cognitive function (impairment of at least one of the cognitive domains memory, processing speed or executive function)</p><list list-type=\"simple\"><list-item><label>&#x02218;</label><p>Memory: Decrease in forward digit span or backward digit span of one or more digits</p></list-item><list-item><label>&#x02218;</label><p>Processing speed: Increase in Stroop test time of 25&#x0200a;seconds or more</p></list-item><list-item><label>&#x02218;</label><p>Executive function: Increase in Trail Making Test A time of 15&#x0200a;seconds or more.</p></list-item></list></list-item></list><p>The study should provide evidence that the intervention supports healthy aging by decreasing the rate of the composite endpoint, implying that it mitigates at least one of the sub-endpoints over the 3 studied years.</p><p>The secondary outcome measures are: the distribution of intraabdominal, intrahepatic and intramuscular fat, change of insulin sensitivity, impairment of cardiac function, CHD, revascularization, myocardial infarction, stroke, increase of blood pressure or antihypertensive treatment, decline of muscle strength, lean body mass, frailty, physical activity, cognitive function, estimates of (health related) quality of life (QoL), inflammatory markers, cardiovascular and metabolic risk markers, biomarker responses to diet-induced changes, energy expenditure, depression, mRNA and protein expression in subcutaneous adipose tissue, gut microbiome, effects on individual dietary pattern as well as adherence to the diet. These analyses will also include gender specific aspects.</p></sec><sec><label>3.6</label><title>Recruitment strategy</title><p>Potential participants were recruited through advertisement in public media (intranet, newspaper) and brochures. The first participant was enrolled in June 2016 and recruitment was completed in July 2018.</p></sec><sec><label>3.7</label><title>Participant timeline</title><p>Phenotyping of all participants was performed at baseline (V0). Further phenotyping was performed 3 (V1), 6 (V2), 12 (V3), 24 (V4) and 36 (V5) months after start of dietary intervention. Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref> illustrates the study flowchart with time points of phenotyping and sessions of nutrition counselling within the trial for intervention and control group (for detailed time points of nutrition sessions see Supplemental Digital Content).</p></sec></sec><sec><label>4</label><title>Methods: assignment of interventions</title><sec><label>4.1</label><title>Allocation</title><p>After initial characterization, participants were randomized with a 1:1 allocation ratio into an intervention group or a control group. Randomization was performed using stratified randomization. The stratification criteria were: gender; known CVD (CHD, PAD, myocardial infarction, stroke); heart failure (NYHA &#x02265;2 or NT-proBNP &#x0003e;300 ng/l if no atrial fibrillation is present); arterial hypertension, known type 2 diabetes or newly diagnosed type 2 diabetes (based on results of oral glucose tolerance test at V0); cognitive impairment (MoCA test &#x0003c;26); SPPB score &#x0003c;10 (all yes or no). In case of inclusion of 2 subjects of the same family, the first family member was randomized according to the protocol and the second family member was allocated to the same group. An adaptive randomization was performed to balance for the above-mentioned stratification criteria. Allocation concealment was ensured, as the service did not release the randomisation code until the subject had been recruited into the trial, which took place after all baseline measurements had been completed. Due to the nature of the intervention, participants could not be blinded regarding group assignment.</p></sec></sec><sec><label>5</label><title>Methods: data collection, management, and analysis</title><sec><label>5.1</label><title>Data collection methods</title><p>All data are collected by means of electronic case report form (eCRF) using REDCap. All measurements are performed in accordance with standard operating procedures (SOPs) that were developed or adapted for this study and are conducted by trained and certified study staff. All intended phenotyping procedures and SOPs were harmonized between study centers. For quality assurance and standardized assessment of data, standardized study document sets are provided, including (web-based) data collection instruments, examination scheduling forms and standard sets with biosample storage material. All study nurses were trained by qualified staff in all phenotyping procedures performed within the trial. Data collection comprises medical history (including adverse events), drug history, alcohol consumption and smoking behaviour, family medical history, socio-demographic status and physical activity. All subjects undergo a comprehensive physical examination and data collection regarding cardiovascular, metabolic, muscular and cognitive function. All outcome measures for the assessment time points are presented in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>NutriAct schedule of enrollment and assessments.</p></caption><graphic xlink:href=\"medi-99-e22381-g002\"/></table-wrap><sec><label>5.1.1</label><title>Anthropometry</title><p>Following a 10-hour overnight fast, all subjects are examined at 8:00 <sc>am.</sc> Body weight (to the nearest of 0.1&#x0200a;kg) and height are measured with a digital column scale with integrated stadiometer (Charit&#x000e9;: Seca, Hamburg, Germany; DIfE: Soehnle, Nassau, Germany). The body mass index (BMI) is calculated (the weight in kilograms divided by the square of the height in meters). Waist and hip circumference are measured 2 times and the means are calculated.</p></sec><sec><label>5.1.2</label><title>Cardiovascular assessment</title><p>Blood pressure is measured 3 times at the left arm and one time at the right arm with the participants sitting for at least 5 minutes and always using the same sphygmomanometer. In detail, a digital sphygmomanometer is used at the study center of the Charit&#x000e9; (Carat professional, boso, Jungingen, Germany) and a manual sphygmomanometer at the study center of DIfE (boso, Jungingen, Germany). Means of measured values are calculated. A 12-channel-electrocardiogram is performed in all participants at each visit. Vascular status is being assessed by ankle-brachial index^{[<xref rid=\"R37\" ref-type=\"bibr\">37</xref>]} (ABI-system 100, boso, Jungingen, Germany). Here, one measurement is taken after a resting period of 5 minutes in lying position. Moreover, all subjects are examined at rest using an EPIQ 7 (Philips Healthcare, Germany) ultrasound machine for thransthoracic echocardiographic measurements. Chamber dimensions are evaluated using standard procedures, including LV mass index and left atrial volume index. The assessment of diastolic function includes pulsed-wave doppler measurements, tissue doppler measurements in 4-chamber view over at least 3 cardiac cycles and measurement of tricuspid regurgitant jet as recommended by the American society of echocardiography.^{[<xref rid=\"R38\" ref-type=\"bibr\">38</xref>,<xref rid=\"R39\" ref-type=\"bibr\">39</xref>]} Volume changes of the left ventricle are obtained by a 3-dimensional acquisition using full-volume assessment over 4 cardiac cycles. A Philips QLab software is used for post-acquisition volume analysis and measurement of LV end-diastolic volume, end-systolic volume, stroke volume, cardiac output and ejection fraction. The analysis of LV strain using 2D speckle-tracing echocardiography is determined as the average value of the longitudinal negative strain peak during LV contraction from all segments of the left ventricle in the apical 4-chamber, 3-chamber and 2-chamber views. LV strain measurements are performed at frame rates of 50 to 80 frames/s, averaging 3 measurements, and using the onset of the QRS as the referent point. The analysis is performed by 2 independent investigators who are blinded for all information and validation is proved in the Echocardiography Core Lab of the Department of Cardiology at the Charite Berlin, Campus Virchow Klinikum.</p></sec><sec><label>5.1.3</label><title>Metabolic phenotyping</title><p>Resting energy expenditure (REE) and whole body substrate utilization are being measured for 30&#x0200a;minutes by indirect calorimetry using a ventilatory hood (Charit&#x000e9;: Quark RMR, Cosmed, Sundern, Germany; DIfE: Vmax Encore Metabolic Cart, CareFusion, Yorba Linda, California, USA) after a 20&#x0200a;minute resting period.</p><p>Moreover, subjects undergo a fasting venous blood sample collection followed by an oral 75&#x0200a;g glucose tolerance test. Further blood samples are taken after 15, 30, 60, 90, 120 and 180&#x0200a;min.</p><p>Abdominal subcutaneous tissue biopsies (approximately 5.0&#x02013;10.0&#x0200a;g) are obtained in a subgroup in fasting state at baseline, after 1 and 3 years by needle biopsies from the periumbilical region using an aspiration through a 12 G needle with a side cutout and round end. After anesthetization of skin with 1% lidocaine without epinephrine, a skin incision (3&#x02013;4&#x0200a;mm) is made and adipose tissue biopsies are obtained. Samples are washed twice in 0.9% NaCl to separate adipose tissue from blood and immediately snap-frozen in liquid nitrogen and stored at &#x02212;80&#x0200a;&#x000b0;C until further laboratory analysis.</p></sec><sec><label>5.1.4</label><title>Self-administered questionnaires</title><p>Health related QoL is assessed by 36-item Short Form Health Survey (SF-36)^{[<xref rid=\"R40\" ref-type=\"bibr\">40</xref>]} and Patient-Reported Outcomes Measurement Information System (PROMIS-29) v2.0 Profile (<ext-link ext-link-type=\"uri\" xlink:href=\"http://www.healthmeasures.net/\">www.healthmeasures.net</ext-link>).^{[<xref rid=\"R41\" ref-type=\"bibr\">41</xref>,<xref rid=\"R42\" ref-type=\"bibr\">42</xref>]} Disease-specific QoL is assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ).^{[<xref rid=\"R43\" ref-type=\"bibr\">43</xref>]} The questionnaires Patient Health Questionnaire-9 (PHQ-9),^{[<xref rid=\"R44\" ref-type=\"bibr\">44</xref>]} Generalized Anxiety Disorder-7 (GAD-7),^{[<xref rid=\"R45\" ref-type=\"bibr\">45</xref>]} Self-Efficacy, Optimism and Pessimism (9 items; SWOP-K9)^{[<xref rid=\"R46\" ref-type=\"bibr\">46</xref>]} and Acceptance and Action Questionnaire-II (FAH-II)^{[<xref rid=\"R47\" ref-type=\"bibr\">47</xref>]} are used for evaluating depression or psychosomatic state, respectively. Physical activity is assessed by International Physical Activity Questionnaire (IPAQ; <ext-link ext-link-type=\"uri\" xlink:href=\"http://www.ipaq.ki.se/\">www.ipaq.ki.se</ext-link>).^{[<xref rid=\"R48\" ref-type=\"bibr\">48</xref>]} All questionnaires are usually completed electronically on mobile devices. A paper version or support for completing the questionnaires is provided if necessary.</p></sec><sec><label>5.1.5</label><title>Cognitive assessment</title><p>To characterize the cognitive status the German version of MoCA^{[<xref rid=\"R49\" ref-type=\"bibr\">49</xref>]} and Multiple-Choice Vocabulary Test (MWT-A)^{[<xref rid=\"R50\" ref-type=\"bibr\">50</xref>]} was performed for screening. Cognitive function is specifically assessed by a standardized neuropsychological test battery. This test battery comprises subtests of the extended version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery^{[<xref rid=\"R51\" ref-type=\"bibr\">51</xref>]} (CERAD-Plus test battery, Revised edition 2005, Memory Clinic Basel, Switzerland, <ext-link ext-link-type=\"uri\" xlink:href=\"http://www.memoryclinic.ch/\">www.memoryclinic.ch</ext-link>) as well as digit span forward and backward of the Wechsler Memory Scale (WMS) Revised^{[<xref rid=\"R52\" ref-type=\"bibr\">52</xref>]} and a Stroop color-word-interference test.^{[<xref rid=\"R53\" ref-type=\"bibr\">53</xref>]}</p></sec><sec><label>5.1.6</label><title>Evaluation of physical function</title><p>We perform SPPB to analyze physical function (including muscle strength) of the lower extremity, which consists of a balance test, gait speed test and 5-chair rise test.^{[<xref rid=\"R54\" ref-type=\"bibr\">54</xref>]} Grip strength is measured to assess muscle strength of the upper extremity using Jamar Plus Digital Hand Dynamometer (Sammons Preston, Bolingbrook, Illinois, USA). Further details for evaluation of motor function are described in the Supplemental Digital Content. The 6-minute walk test^{[<xref rid=\"R55\" ref-type=\"bibr\">55</xref>]} is being conducted to assess exercise capacity (in a subgroup of 252 participants). Frailty and physical activity are evaluated with The Frailty Phenotype Criteria according to Fried^{[<xref rid=\"R56\" ref-type=\"bibr\">56</xref>]} and with accelerometry (wGT3X-BT, ActiGraph, Pensacola, Florida, USA), respectively. Subjects are instructed to wear the accelerometer for 7 days on the right waist above or underneath clothing and to pursue daily activities as usual.</p></sec><sec><label>5.1.7</label><title>Imaging</title><p>Body composition, including lean body mass, and bone density are measured using DEXA (Charit&#x000e9;: QDR Discovery W, DIfE: QDR Explorer W; Hologic Canada ULC, Mississauga, Canada).</p><p>Magnetic resonance examinations are performed in every participant on a 1.5-T whole-body scanner (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany) for quantification of abdominal fat depots by axial magnetic resonance imaging (MRI) as well as quantification of intrahepatic lipids (IHL) and intramyocellular lipids (IMCL; in a subgroup) in tibialis anterior and soleus muscle by localized proton magnetic resonance spectroscopy (¹H-MRS). Analysis of MRI and ¹H-MRS data is carried out in cooperation with the Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of T&#x000fc;bingen. For quantification of abdominal fat depots, an axial T1-weighted fast spin echo technique is applied as described by Machann et al.^{[<xref rid=\"R57\" ref-type=\"bibr\">57</xref>]} Visceral adipose tissue is quantified from femoral head to thoracic diaphragm and nonvisceral abdominal adipose tissue integrating subcutaneous, intermuscular, and intrathoracic fat from femur to humerus - both in liters - by an automated segmentation algorithm based on fuzzy clustering.^{[<xref rid=\"R58\" ref-type=\"bibr\">58</xref>]} Additionally, adipose tissue on the level of femoral head and humerus are determined, which have shown to be representative for adipose tissue of the lower and upper extremities, respectively.^{[<xref rid=\"R59\" ref-type=\"bibr\">59</xref>]} IHLs are quantified by a single voxel stimulated echo acquisition mode (STEAM) technique with a voxel (volume of interest, VOI) size of 30 &#x000d7; 30 &#x000d7; 20 mm³ in the posterior part of segment 7^{[<xref rid=\"R60\" ref-type=\"bibr\">60</xref>]} and IHLs are given as ratio of fat (methylene&#x0200a;+&#x0200a;methyl resonances at 1.3 and 0.9&#x0200a;ppm, respectively) divided by the sum of water (at 4.7&#x0200a;ppm) and fat resonances, respectively. IMCL are determined from a VOI (11 &#x000d7; 11 &#x000d7; 20 mm³) placed in the most extended part of the right calf by a STEAM technique without and with water suppression. Regions with macroscopically visible fatty septa were carefully excluded from the VOI wherever possible. IMCL are quantified in arbitrary units by calculation of the methylene signal integral of IMCL at 1.3&#x0200a;ppm in the water suppressed spectrum in relation to the water signal at 4.7&#x0200a;ppm.^{[<xref rid=\"R61\" ref-type=\"bibr\">61</xref>]}</p></sec><sec><label>5.1.8</label><title>Collection of nutritional data</title><p>All participants complete open food records on 3 consecutive days, including one weekend day, 10-14 days before each visit (see Supplemental Digital Content (Fig. S1)). Therefore, participants are asked to possibly weigh or alternatively use a standard household measure (e.g. a tablespoon) as an estimate of consumed foods and beverages. These data are converted to intake of energy and nutrients through nutrient calculation software (Prodi 6.5 Expert; Nutri-Science GmbH, Freiburg, Germany). To strengthen adherence to the intended dietary pattern and to test different methods for dietary assessment, participants of both groups are additionally asked to fill out a modified web-based 24-hour food list^{[<xref rid=\"R62\" ref-type=\"bibr\">62</xref>]} on 21 random days during the whole study period (further details in the Supplemental Digital Content). However, only the open 3-day food records collected at each visit are used for dietary recommendations by the nutritionists. To monitor the intended stabilization of body weight, participants are also asked to record their body weight on the open food records.</p></sec><sec><label>5.1.9</label><title>Laboratory assessment</title><p>Capillary blood glucose is immediately measured by point-of-care method using the glucose oxidase method (Charit&#x000e9;: Dr. M&#x000fc;ller Super GL 2, Freital, Germany; DIfE: Biosen C-line, EKF-diagnostic GmbH, Barleben, Germany). Glucose is additionally measured in fluoride plasma (GlucoEXACT tubes; Sarstedt, Nuembrecht, Germany) performed on Cobas Mira (Roche Diagnostics, Mannheim, Germany). Preprocessing and intermediate storage of blood samples are being performed at both study centers. Blood samples are being centrifuged and frozen immediately at &#x02212;80&#x0200a;&#x000b0;C. Blood count and plasma NT-proBNP are measured immediately performed on Sysmex XN-9000 (Sysmex, Norderstedt, Germany) and cobas e602 module (Roche Diagnostics, Mannheim, Germany) using Roche Elecsys Immunoassay, respectively. Protein, transaminases, potassium, sodium, calcium, creatinine, urea, uric acid, triglycerides, cholesterol and high-density lipoprotein (HDL)-cholesterol are measured in serum using standard laboratory methods performed on ABX pentra 400 (HORIBA ABX SAS, Montpellier, France). LDL-cholesterol is calculated using the Friedewald formula. Glycated hemoglobin (HbA1c) is quantified in EDTA blood using spectrophotometry performed on ABX pentra 400 (HORIBA ABX SAS, Montpellier, France). Serum insulin and c-peptide are measured using enzyme-linked immunosorbent assays (ELISA; Mercodia, Uppsala, Sweden) (intra-assay CV 2.8%&#x02013;4.0% (insulin) and &#x0003c;4.8% (c-peptide), inter-assay CV 4%&#x02013;5% (insulin) and &#x0003c;6.8% (c-peptide)). Non-esterified fatty acids (NEFAs) are quantified in serum using a commercially available colorimetric assay (NEFA HR2, Wako, Neuss, Germany) (intra-assay CV &#x0003c;1.5%, inter-assay CV &#x0003c;5%). CRP is measured in serum using ABX Pentra CRP CP (Horiba ABX SAS, Montpellier, France) (intra-assay CV 0.74%&#x02013;4.1%, inter-assay CV 2.17%&#x02013;4.31%). Buffy coat samples are obtained from EDTA blood for further analysis. Isolation of peripheral blood mononuclear cells (PBMC) for further analysis is performed in a subsample using BD Vacutainer CPT tubes (BD Bectin Dickinson GmbH, Heidelberg, Germany). Isolation of RNA is performed using PAXgene blood RNA tubes (BD Bectin Dickinson GmbH, Heidelberg, Germany). First, these tubes are kept at room temperature for 2&#x0200a;hours. Then, after intermediate storage at &#x02212;20&#x0200a;&#x000b0;C for at least 24&#x0200a;hours, they are stored at &#x02212;80&#x0200a;&#x000b0;C for further analysis.</p><p>Stool samples are collected by the participants at home in faeces containers (Sarstedt, Nuembrecht, Germany), stored at participants&#x02019; home at &#x02212;20&#x0200a;&#x000b0;C and at the study center at &#x02212;80&#x0200a;&#x000b0;C until shipment to the laboratory for further analysis. 24-hour urine samples are obtained in containers (Sarstedt, Nuembrecht, Germany) and stored at &#x02212;80&#x0200a;&#x000b0;C.</p></sec><sec><label>5.1.10</label><title>Data management</title><p>All study relevant data are stored pseudonymized in digital form (eCRF). Electronic data is managed on protected servers with access restrictions. Participants&#x02019; files are stored in numerical order and at a secure place, only accessible to authorized persons (Principal Investigator, study physicians, study nurses), for a period of 15 years after completion of the study. Quality control is being ensured through regular data checks. For example, plausibility controls of the online data are being performed by frequency distribution checks of outcome measures on a regular base.</p></sec></sec><sec><label>5.2</label><title>Sample size</title><p>The sample size was planned based on previously reported data of a large RCT comparing different counselling strategies over 30 months.^{[<xref rid=\"R63\" ref-type=\"bibr\">63</xref>]} Sample size calculation for a log rank test was conducted in accordance with the primary endpoint. The sample size calculation was performed with nQuery Advisor V7.0. From the literature,^{[<xref rid=\"R64\" ref-type=\"bibr\">64</xref>&#x02013;<xref rid=\"R71\" ref-type=\"bibr\">71</xref>]} the cut-off values for the primary endpoint were selected such that in each component, an incidence of 10% to 15% is expected over 3 years. Depending on the correlation of the events, this may lead to a proportion of event-free patients of about 27% to 80% at the end of the observation period. We assume an improvement of around 10% to 13%, and therefore a reduction in events by the interventions. This difference will be considered realistic and clinically relevant. This corresponds to a hazard ratio of 1.42 to 2.11 which, at 80% power and a 2-sided alpha of 5%, results in sample sizes of 200 to 226 patients per group. Calculating a drop out of approximately 10% to 15%, 500 subjects should be at least included.</p></sec><sec><label>5.3</label><title>Statistical analysis</title><p>The primary outcome measure is defined as a composite endpoint including cardiovascular morbidity and age-related impairment of cognitive function as well as lean body mass and muscular function as described above. We aim to show that this intervention will decrease the rate of the composite endpoint, implying that it mitigates at least one of the sub-endpoints during the 3 studied years. The main analysis will be conducted with a log rank test for superiority of the intervention. A <italic>P</italic> value &#x0003c;.05 is considered statistically significant. Possible effect modifiers and confounders will be included in the cox regression analyses as needed to explain group differences. Kaplan-Meier curves are used to present the effects graphically. The analysis will be carried out in the intention-to-treat population. Missing values will be replaced by multiple imputation wherever necessary. Moreover, a per-protocol analyses will also be performed. Secondary endpoints will be analysed descriptively according to their presence and distribution using the usual statistical parameters. Both parametric and non-parametric tests will be used depending on the distribution of data. All <italic>P</italic> values from the secondary analyses will be considered exploratory and non-confirmatory.</p></sec></sec><sec><label>6</label><title>Methods: monitoring</title><sec><label>6.1</label><title>Data monitoring</title><p>A data monitoring committee is not established during the trial since this clinical trial does not include any prescription of new medication and usual care as well as previously prescribed medication is not affected during study participation. Therefore, the trial has a minimal risk for induction of serious adverse events.</p></sec><sec><label>6.2</label><title>Adverse events monitoring and reporting</title><p>A detailed monitoring plan is included as part of the protocol in each visit. These plans include documentation of any adverse event (AE) or serious adverse event (SAE) on case-report forms (eCRF) whether it is an unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease, whether or not it is considered related to the intervention. AEs and SAEs are documented throughout the complete follow-up period. SAEs with potential causal relationship with the intervention are reported to the Principal Investigators within 24&#x0200a;hours. In addition, participants are withdrawn from the study if it is medically indicated in the opinion of the Principal Investigator.</p></sec></sec><sec><label>7</label><title>Discussion</title><p>Age-related health decline such as the development of cardiovascular diseases, sarcopenia and cognitive decline is a growing challenge as the mean age of our population increases. Up to date, the optimal macronutrient composition to counteract age-related changes remains unclear, especially as large RCTs in non-mediterranean populations are still lacking and some data is controversial, for example, concerning the beneficial effect of PUFA on cardiovascular risk factors^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>,<xref rid=\"R28\" ref-type=\"bibr\">28</xref>]} or the recommendable amount of protein.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} Predominantly observational or non-randomized intervention studies indicate benefit of high protein (especially plant protein) intake and replacement of MUFA and PUFA instead of SFA on improvement of cardiovascular, muscular and cognitive endpoints in elderly.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>,<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} Together with a high fibre content and a low glycemic index, such a pattern may also lead to a lesser deterioration of age-related metabolic status, for example, a reduced risk for development of type 2 diabetes.^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} Given these data indicating a beneficial effect of specific nutritional components, we decided to analyze the effect of a complex dietary pattern including high intake of MUFA and PUFA, plant proteins, improved fibre content as well as a low glycemic index (the NutriAct pattern) within a long-term trial. To our best knowledge, this is the first long-term randomized controlled intervention study with large sample size in a middle-aged and elderly German population analyzing the effects of such a dietary pattern. Long-term modification of nutritional behavior is a well-known challenge. Therefore, the supplementation of specific designed food products in conjunction with regular nutritional sessions to support its implementation, acceptance and thus long-term adherence to this dietary pattern is a key component of the NutriAct approach. Given the high acceptance of rapeseed oil in the local population as well as the promising effects of short-term consumption of rapeseed oil on cardiovascular and metabolic risk markers,^{[<xref rid=\"R72\" ref-type=\"bibr\">72</xref>]} we focus on supplementation of rapeseed oil as a preferred source of dietary fat.</p><p>The NutriAct approach will be compared to usual care based on local standard care which also includes dietary recommendations of the DGE.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>,<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} As the NutriAct dietary pattern is substantially different from current local food consumption, a larger number of nutrition sessions is included compared to the control group.</p><p>The main objectives of this study are to analyze the long-term effect of NutriAct dietary pattern on healthy aging, particularly cardiovascular morbidity, cognition and sarcopenia. Further objectives are to investigate gender specific effects as well as effects on other age-related phenotypes such as bone density, quality of life or glucose metabolism. Therefore, a complex state of the art phenotyping is implemented in this study. These phenotyping procedures, which also include adipose tissue biopsies, DEXA and MRI/H-MRS scan, will allow a complex analysis of tissue specific metabolic responses. Associations between measured biomarkers at baseline as well as biomarker changes during the dietary intervention and concomitant alteration of metabolic, cognitive and cardiovascular status will further help to identify predictors of age-related health and potential mechanisms involved in those changes.</p><p>The findings of this RCT will contribute to define the optimal macronutrient composition in the context of healthy aging and to the implementation of a realizable healthy dietary pattern in a German population.</p></sec><sec><title>Acknowledgments</title><p>We thank S. J&#x000fc;rgens, N. Huckauf, C. Kalischke, A. Borchert, K. Ritter, S. Ernst, K. Warnke, P. Gro&#x000df;mann, T. Mikhailova, T. Brechlin and U. Redel for excellent technical assistance as well as F. Schwerin, R. Lifka, N. Stob&#x000e4;us, L. Napieralski, M. Hannemann, E. Wehrstedt, S. Schr&#x000f6;ter and D. Zschau for the excellent support regarding phenotyping. Furthermore, we thank E. Siebenh&#x000fc;hner, S. Sch&#x000f6;nfuss and C. Heerling for conducting nutrition counselling and U. Harttig, E. Kohlsdorf and K. Treu for support regarding the modified web-based 24h-food list. We also thank E. Kohlsdorf, M. Osterhoff, H. Piechot and A. Abel for contributing substantial support in data management as well as N. K&#x000fc;lzow and N. Stob&#x000e4;us for support concerning psychologic, cognitive and metabolic phenotyping. Our special thanks also go to the departments of radiology, Charit&#x000e9; Campus Virchow-Klinikum and Ernst von Bergmann Klinikum, Potsdam. Moreover, we thank D. Baier, S. Sevenich and U. Rzeha (NutriAct innovation office) for managing contacts and negotiations with the SMEs. We thank the following SMEs for development and delivery of specific food supplements in the intervention group: rapeseed oil (Br&#x000f6;kelmann &#x00026; Co - Oelm&#x000fc;hle GmbH &#x00026;Co, Hamm), oil cake and base mix for muesli (Kanow-M&#x000fc;hle Sagritz, Gol&#x000df;en), bread rolls (DewiBack Handels GmbH, Berlin; J. Rettenmaier &#x00026; S&#x000f6;hne GmBH&#x0200a;+&#x0200a;CoKG, Rosenberg), protein enriched pasta and flakes (IGV GmbH, Nuthetal). We thank Dieckmann GmbH&#x0200a;+&#x0200a;CoKG, Rinteln, and Zweiglein UG, Potsdam, for delivery of barley flakes and muesli, respectively, for use in the control group. Food supplements are also designed in cooperation with IGV GmbH and institute of food technology at TU Berlin.</p></sec><sec><title>Author contributions</title><p>KM, AFHP, SH and JS designed the study. KM, AFHP, TG, MB and JS designed and organized the study logistics. CW, KA, SH, AE, UP, SS, KH, JM and CG researched data. CW, KM, JS, UP, JM, KH, CG and AP wrote the manuscript. All authors critically read and edited several drafts before submission. All authors read and approved the submitted version. AFHP, CG, JS and KM designed the dietary intervention.</p></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD1\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e22381-s001.tif\" orientation=\"portrait\" id=\"d38e1208\" position=\"anchor\"/></supplementary-material></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD2\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e22381-s002.docx\" orientation=\"portrait\" id=\"d38e1216\" position=\"anchor\"/></supplementary-material></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD3\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e22381-s003.doc\" orientation=\"portrait\" id=\"d38e1225\" position=\"anchor\"/></supplementary-material></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: AE = adverse event, BMBF = German Ministry for Education and Research, BMI = body mass index, CERAD = Consortium to Establish a Registry for Alzheimer's Disease, CHD = coronary heart disease, CVD = cardiovascular disease, DEXA = dual-energy X-ray absorptiometry, DGE = German Nutrition Society, DIfE = Human Study Center of the German Institute of Human Nutrition, %E = percent of total energy, eCRF = electronic case report form, ELISA = enzyme-linked immunosorbent assay, FAH-II = Acceptance and Action Questionnaire-II, GAD-7 = Generalized Anxiety Disorder-7, HbA1c = glycated hemoglobin, ¹H-MRS = proton magnetic resonance spectroscopy, HDL = high-density lipoprotein, IDM = Institute for Diabetes Research and Metabolic Diseases, IHL = Intrahepatic lipids, IMCL = Intramyocellular lipids, IPAQ = International Physical Activity Questionnaire, LDL = low-density lipoprotein, LV = left ventricular, MLHFQ = Minnesota Living with Heart Failure Questionnaire, MoCA = Montreal Cognitive Assessment, MRI = magnetic resonance imaging, MUFA = monounsaturated fatty acids, MWT-A = Multiple-Choice Vocabulary Test, NEFAs = Non-esterified fatty acids, NYHA = New York Heart Association, PAD = peripheral artery disease, PBMC = peripheral blood mononuclear cells, PHQ-9 = Patient Health Questionnaire-9, PROMIS-29 = Patient-Reported Outcomes Measurement Information System, PUFA = polyunsaturated fatty acids, QoL = Quality of life, RCT = randomized controlled trial, REE = resting energy expenditure, SAE = serious adverse event, SFA = saturated fatty acids, SF-36 = 36-item Short Form Health Survey, SOP = standard operating procedure, SPPB = Short Physical Performance Battery, STEAM = stimulated echo acquisition mode, SWOP-K9 = Self-Efficacy, Optimism and Pessimism (9 items), V = visit, VOI = voxel of interest, vs = versus, WMS = Wechsler Memory Scale.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Wernicke C, Apostolopoulou K, Hornemann S, Efthymiou A, Machann J, Schmidt S, Primessnig U, Bergmann MM, Grune T, Gerbracht C, Herber K, Pohrt A, Pfeiffer AF, Spranger J, Mai K. Long-term effects of a food pattern on cardiovascular risk factors and age-related changes of muscular and cognitive function. <italic>Medicine</italic>. 2020;99:39(e22381).</p></fn><fn fn-type=\"supported-by\"><p>This work was supported by the Competence Cluster Nutrition Research Berlin-Potsdam, funded by the Federal Ministry of Education and Research (BMBF funding code 01EA1408). This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Sponsor: Charit&#x000e9; - Universit&#x000e4;tsmedizin Berlin, Charit&#x000e9;platz 1, 10117 Berlin.</p></fn><fn fn-type=\"other\"><p>Trial registration: German Clinical Trials Register: DRKS00010049, Registered 12.05.2016. Ethic proposal approved at 08.12.2015.</p></fn><fn fn-type=\"other\"><p>The trial is in the ongoing phase. The first participant was enrolled in June 2016. End of data collection is expected in July 2021.</p></fn><fn fn-type=\"other\"><p>Ethics applications were submitted to the Ethics Committee of Charit&#x000e9; - Universit&#x000e4;tsmedizin Berlin (leading ethics committee) and to the Ethics Committee of the Medical Association of Brandenburg. Ethic proposal approved at 08.12.2015 (EA1/315/15). Written informed detailed consent were obtained by the participants prior to study inclusion (concerning study background, objective, eligibility criteria, interventions, detailed description of outcome assessments and assessment timetable, risks, participants&#x02019; rights including withdrawal, confidentiality, analysis and storage of data as well as publication of data).</p></fn><fn fn-type=\"other\"><p>The study will provide high level evidence for a realizable healthier dietary pattern in Germany. It will support the development and analysis of tasty and attractive foods, which are compatible with middle European cultural habits and will facilitate the production of healthy foods for the German market. The development of such attractive foods, which are proofed to be associated with beneficial health effects, would represent a unique opportunity to improve diet induced modification of individual health. Causes for adherence to dietary advice and acceptance of new diet products will also be identified. The acceptance of products will be tested in real life and encourage food producers to invest in new products and advertisement campaigns. This will support the identification of effective strategies to implement the usage of such new foods into the German society. Data of the primary and secondary endpoints will be reported in scientific journals regardless of the magnitude or direction of effect. No publication restrictions exist.</p></fn><fn fn-type=\"COI-statement\"><p>The authors declare they have no competing interests.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the NutriAct consortia on reasonable request. All Principal Investigators will be given access to the cleaned data sets. Project Principal Investigators will have direct access to their own site's data sets, and will have access to other sites data by request. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991412</article-id><article-id pub-id-type=\"pmc\">PMC7523821</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08218</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022205</article-id><article-id pub-id-type=\"art-access-id\">22205</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3800</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Acupuncture and related techniques for restless legs syndrome</article-title><subtitle>A protocol for systematic review and meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Xiang</surname><given-names>Jie</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-7682-6525</contrib-id><name><surname>Li</surname><given-names>Honglian</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Xiong</surname><given-names>Jun</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Hua</surname><given-names>Fanghui</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Huang</surname><given-names>Shouqiang</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Jiang</surname><given-names>Yunfeng</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Qiang</surname><given-names>Hailiang</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Xie</surname><given-names>Fan</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Min</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Jiangxi University of Traditional Chinese Medicine</aff><aff id=\"aff2\"><label>b</label>Haiyang People's Hospital of Shandong Province, Haiyang</aff><aff id=\"aff3\"><label>c</label>Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Honglian Li, Haiyang People's Hospital of Shandong Province, No. 73 Haiyang Road, Haiyang City, Shandong PR China (e-mail: <email>978615812@qq.com</email>); Jun Xiong, the Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, No. 445 Bayi Avenue, Dongwu District, Nanchang City, Jiangxi, PR China (e-mail: <email>xiongjun196071@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22205</elocation-id><history><date date-type=\"received\"><day>17</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>18</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22205.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Restless legs syndrome (RLS) is a common sensory disorder of the nervous system, which often affects the sleep quality of patients. Acupuncture and related techniques are increasingly used to treat neurological diseases, but their efficacy and safety for RLS are yet to be established. The purpose of this study is to summarize the effectiveness and safety of acupuncture and related techniques for RLS.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>We will conduct a comprehensive data retrieval, and the electronic databases will include PubMed, Embase, Cochrane Library, WangFang Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Chinese Biomedical Literature Database, from establishment to October 2020. We will also manually search unpublished studies and references, and contact lead authors. Randomized clinical trials (RCTs) of acupuncture and related techniques for RLS will be included. The outcomes of interest include: The total effective rate and International Restless Leg Syndrome rating scale (IRLS), Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), adverse events, quality of life. To assess the methodological quality, we will use the Cochrane risk assessment tool. RevMan 5.3.5 software will be used to conduct data synthesis. The evidence quality of each outcome will be appraised according to Grades of Recommendation, Assessment, Development, and Evaluation (GRADE).</p></sec><sec sec-type=\"results\"><title>Results:</title><p>The results will be published in a peer-reviewed journal.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>This study will provide a high-quality evidence to evaluate the efficacy and adverse reactions of acupuncture and related techniques for RLS.</p></sec><sec><title>PROSPERO registration number:</title><p>CRD42020157957.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>acupuncture</kwd><kwd>protocol</kwd><kwd>restless legs syndrome</kwd><kwd>systematic review</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>iangxi university of traditional Chinese medicine 1050 youth talent project</funding-source><award-id>5141900101</award-id><principal-award-recipient>Jun Xiong</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Key Research and Development Project of Jiangxi Province</funding-source><award-id>20161BBG70109</award-id><principal-award-recipient>Jun Xiong</principal-award-recipient></award-group><award-group id=\"award3\" award-type=\"Fundref\"><funding-source>Foundation for Distinguished Young Talents in Higher Education of Guangdong</funding-source><award-id>20171BCB23093</award-id><principal-award-recipient>Jun Xiong</principal-award-recipient></award-group><award-group id=\"award4\" award-type=\"Fundref\"><funding-source>Natural Science Youth Foundation Key Projects of Jiangxi Province</funding-source><award-id>20192ACB21007</award-id><principal-award-recipient>Jun Xiong</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Restless legs syndrome (RLS, also called Willis-Ekbom disease), is a common sensory disorder of the nervous system, which is mainly manifested by patients desire for legs activity at night or at rest, accompanied by discomfort, and the symptoms are relieved after the activity. Diagnosis should be distinguished from certain diseases (such as muscle pain, varicose veins, arthritis, lower extremity edema).^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} There is currently no objectively available tests to diagnose RLS, mainly based on subjective symptom descriptions.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]}</p><p>In terms of prevalence, North America and Europe are the highest, estimated at between 5.5% and 11.6%, and relatively lower in Asia, estimated at between 1.0% and 7.5%.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Women over 35 years old are twice as likely to suffer from this disease as men, and the prevalence of children is 2%.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} The prevalence of RLS is mainly related to the following factors: genetics, iron deficiency, kidney disease, pregnancy, Parkinson, certain drugs (such as antidepressants, antipsychotics, histamine receptor blockers), smoking, drinking, caffeine, etc.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Previous studies have shown that family history of more than 60% of the patients with RLS.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Other studies have shown that the risk of RLS in patients with iron deficiency anemia is 5 to 6 times that of the general population, and the prevalence of patients with end-stage renal disease is 6.6% to 68%.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]}</p><p>The pathogenesis of RLS is still unclear. Existing studies indicate that it may be related to dopamine transport disorders, certain genes, neurotransmitter and neural pathway abnormalities, and neuroanatomical abnormalities.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>&#x02013;<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} A large number of studies have shown that the quality of life of RLS patients is affected, and 75% of patients have sleep disturbances, which can affect work in serious cases.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>&#x02013;<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} Long-term RLS may affect cardiovascular disease, diabetes, and cause autonomic disorders, which may be related to sympathetic nerve excitement.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>,<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} Psychological distress is also more common in patients with RLS.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} Studies on male patients with RLS suggest that RLS is associated with sexual dysfunction.^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]}</p><p>At present, &#x003b1;2&#x003b4; ligands and dopamine agonists are recommended as the first-line drugs for the treatment of RLS. Second-line drugs are opioids, benzodiazepines and iron.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} These drugs are selected according to the individuation of patients, which has been proved to be effective, but followed by some adverse consequences. According to the survey,^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]} 76% of patients using dopamine agonists developed augmentation (delayed exacerbation of symptoms) over time. Some drugs are dependent, causing dizziness, drowsiness, nausea, and so on.^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} Because the drugs are not applicable in some cases and the side effects can not be ignored, some non-pharmacologic treatments with less side effects may be the methods for the treatment of RLS.</p><p>Acupuncture is a kind of external treatment, is a traditional Chinese treatment.^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} It has been proven to be an effective and well-tolerated therapy for the treatment of neurological diseases.^{[<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} Studies have shown that its side effects are far less than dopamine agonists.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} Therefore, it is possible that acupuncture of RLS is effective and safe. Acupuncture and related techniques for the treatment of RLS include acupuncture, warming acupuncture, electroacupuncture, moxibustion and so on.</p><p>At present, there are 3 published systematic reviews of acupuncture of RLS.^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>&#x02013;<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} One of them included only 2 studies before 2007, and the conclusion was insufficient. The other 2 systematic reviews were published in Chinese. They did not conduct a comprehensive literature search, and the outcomes were few. The conclusions could not truly reflect the effectiveness and safety of acupuncture treatment for RLS. Therefore, we consider that it is necessary to re-conduct a systematic review. We will strictly abide by the method of systematic review in order to provide more reliable evidence for doctors and researchers, as well as more reasonable treatment for RLS patients.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Study registration</title><p>Our protocol has been registered in PROSPERO (CRD42020157957). This report will be conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Protocols (PRISMA-P).^{[<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} The changes will be described in our full review.</p></sec><sec><label>2.2</label><title>Inclusion criteria</title><sec><label>2.2.1</label><title>Type of studies</title><p>This study will include all relevant randomized clinical trials (RCTs) without language restrictions.</p></sec><sec><label>2.2.2</label><title>Type of participants</title><p>RLS patients who meet the diagnostic criteria will be included, regardless of age, gender, race.</p></sec><sec><label>2.2.3</label><title>Type of interventions</title><p>Acupuncture and related techniques will choose warming acupuncture, electroacupuncture, moxibustion, manual acupuncture, ear acupuncture, acupressure, etc. Combination with other conventional therapies (e.g., medication/drugs) will also be allowed.</p></sec><sec><label>2.2.4</label><title>Type of comparators</title><p>Conventional treatments, placebo, no treatment or sham acupuncture will be as comparators. However, the comparisons between acupuncture and related techniques will be excluded.</p></sec><sec><label>2.2.5</label><title>Types of outcome measures</title><sec><label>2.2.5.1</label><title>Primary outcomes</title><p>The total effective rate and international restless leg syndrome rating scale (IRLS).</p></sec><sec><label>2.2.5.2</label><title>Secondary outcomes</title><list list-type=\"simple\"><list-item><label>1.</label><p>Pittsburgh sleep quality index (PSQI).</p></list-item><list-item><label>2.</label><p>Hamilton anxiety scale (HAMA).</p></list-item><list-item><label>3.</label><p>Hamilton Depression Scale (HAMD).</p></list-item><list-item><label>4.</label><p>Adverse events.</p></list-item><list-item><label>5.</label><p>Quality of life.</p></list-item></list></sec></sec></sec><sec><label>2.3</label><title>Exclusion criteria</title><p>Studies that are repeatedly published and necessary information cannot be obtained in various ways will be excluded.</p></sec><sec><label>2.4</label><title>Search methods for identification of studies</title><p>We will conduct a comprehensive data retrieval, and the electronic databases will include PubMed, Embase, Cochrane Library, WangFang Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Chinese Biomedical Literature Database, from establishment to October 2020. We will also manually search unpublished studies and references. The specific search strategy of Pubmed is provided in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>The search strategy for PubMed.</p></caption><graphic xlink:href=\"medi-99-e22205-g001\"/></table-wrap></sec><sec><label>2.5</label><title>Studies selection</title><p>NoteExpress3.2.0 software will eliminate duplicate studies from all the obtained literatures. The unqualified studies in the remaining articles will be eliminated by 2 reviewers by reading the title and abstract. Then, 2 reviewers will read the full text to determine the final included studies. If the significant information of the article is incomplete, we will contact the author. In all the processes, the researchers will operate independently. When 2 reviewers have disagreements, the decision will be made by the third researcher. The above process is presented in the flowchart (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flowchart of literature selection.</p></caption><graphic xlink:href=\"medi-99-e22205-g002\"/></fig></sec><sec><label>2.6</label><title>Data extraction and management</title><p>We will establish a data extraction table, which will be used by 2 researchers to extract data from qualified literature. The specific contents will include: author, publication time, participant characteristics, intervention (s), comparison (s), outcome (s), adverse events and some relevant features. If the significant information of the article is incomplete, we will contact the author. In case of disagreements, the third researcher will be consulted.</p></sec><sec><label>2.7</label><title>Assessment of the methodological quality</title><p>The Cochrane risk assessment tool will be used by us to evaluate the methodological quality of qualified RCTs.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} It includes 7 items: random sequence generation, allocation concealment, blinding of participants and caregivers, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other bias. The evaluation result of each item will be &#x0201c;high risk&#x0201d;, &#x0201c;low risk&#x0201d;, or &#x0201c;unclear risk&#x0201d;. The assessment will be completed by 2 reviewers, and disagreements will be handed over to the third reviewer for the final decision.</p></sec><sec><label>2.8</label><title>Measures of treatment effect</title><p>Mean difference (MD) or standard mean difference (SMD) will be used for continuous outcomes with 95% confidence intervals (CIs). Dichotomous outcomes will be summarized by risk ratio (RR) with 95% CIs.</p></sec><sec><label>2.9</label><title>Dealing with missing data</title><p>We will contact the author by phone or email to obtain complete information. If we cannot obtain that missing data, the analysis will be performed according to the available data. Besides, we will consider the potential impact of missing data for our studies. Otherwise, we will rule out the study.</p></sec><sec><label>2.10</label><title>Assessment of heterogeneity</title><p>We will use chi-square test and <italic>I</italic>² value to verify heterogeneity. When <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.1, <italic>I</italic>²&#x0200a;&#x0003e;&#x0200a;50%, there is significant heterogeneity between studies; otherwise, heterogeneity is acceptable.</p></sec><sec><label>2.11</label><title>Data synthesis</title><p>Data synthesis will be completed using RevMan5.3.5 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). When <italic>I</italic>²&#x0200a;&#x0003c;&#x0200a;50%, we will choose the fixed effects model; Otherwise, the random effects model will be selected. The forest plots will present the results of the meta-analyses. We will conduct descriptive analysis, when the results are not suitable for consolidation. When more than 10 studies are included, we will use the funnel plot to assess publication bias.</p></sec><sec><label>2.12</label><title>Subgroup analysis</title><p>If necessary, subgroup analyses will be performed according to the different types of participant characteristics, treatment methods, treatment frequency, and so on.</p></sec><sec><label>2.13</label><title>Sensitivity analysis</title><p>When there is significant heterogeneity, we will conduct a sensitivity analysis. We will determine the robustness of the results by excluding low-quality studies.</p></sec><sec><label>2.14</label><title>Summary of evidence</title><p>We will evaluate the evidence quality of each outcome based on Grades of Recommendation, Assessment, Development, and Evaluation (GRADE).^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]} Two reviewers will conduct independent evaluation, and if there are disagreements, the third author will give the decision.</p></sec><sec><label>2.15</label><title>Ethics and dissemination</title><p>In this study, no individual data from participants will be involved, so ethics approval is not required. This systematic review will be published through peer-reviewed journal.</p></sec></sec><sec><label>3</label><title>Discussion</title><p>RLS is a disease that has a great influence on patients quality of life. At present, the internationally recommended treatment is pharmacotherapy, but if patients use drugs for a long time, the side effects cannot be ignored. RCTs have proved that acupuncture is effective in treating RLS with little side effects. Therefore, we hope that this study can provide a high level of evidence-based evidence for the effectiveness and safety of acupuncture and related techniques in the treatment of RLS, and guide clinical decision-making.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Jie Xiang, Jun Xiong.</p><p><bold>Data curation:</bold> Jie Xiang, Fanghui Hua, Shouqiang Huang.</p><p><bold>Formal analysis:</bold> Yunfeng Jiang, Hailiang Qiang, Min Wang.</p><p><bold>Investigation:</bold> Jie Xiang, Jun Xiong.</p><p><bold>Methodology:</bold> Honglian Li, Jun Xiong, Fanghui Hua, Shouqiang Huang.</p><p><bold>Software:</bold> Yunfeng Jiang, Hailiang Qiang, Min Wang.</p><p><bold>Supervision:</bold> Jun Xiong, Fan Xie.</p><p><bold>Writing &#x02013; original draft:</bold> Jie Xiang, Jun Xiong, Fanghui Hua, Shouqiang Huang.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Honglian Li, Yunfeng Jiang, Fan Xie, Min Wang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CI = confidence interval, GRADE = Grades of Recommendation, Assessment, Development, and Evaluation, HAMA = Hamilton anxiety scale, HAMD = Hamilton depression scale, IRLS = International Restless Leg Syndrome rating scale, MD = mean difference, PRISMA-P = Preferred reporting items for systematic reviews and meta-analysis protocols, PSQI = Pittsburgh Sleep Quality Index, RCT = randomized clinical trial, RLS = restless legs syndrome, RR = risk ratio, SMD = standard mean difference.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Xiang J, Li H, Xiong J, Hua F, Huang S, Jiang Y, Qiang H, Xie F, Wang M. Acupuncture and related techniques for restless legs syndrome: A protocol for systematic review and meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22205).</p></fn><fn fn-type=\"supported-by\"><p>This work was supported by Jiangxi university of traditional Chinese medicine 1050 youth talent project (Grant number: 5141900101), Key Research and Development Project of Jiangxi Province (Grant No. 20161BBG70109), Distinguished Young Talents Plan of Jiangxi Province (Grant No. 20171BCB23093), and Natural Science Youth Foundation Key Projects of Jiangxi Province (Grant No. 20192ACB21007).</p></fn><fn fn-type=\"other\"><p>The funders had no role in the design, execution, or writing of the study.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Allen</surname><given-names>RP</given-names></name><name><surname>Picchietti</surname><given-names>DL</given-names></name><name><surname>Garcia-Borreguero</surname><given-names>D</given-names></name><etal/></person-group>\n<article-title>Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria-history, rationale, description, and significance</article-title>. <source>Sleep Med</source>\n<year>2014</year>;<volume>15</volume>:<fpage>860</fpage>&#x02013;<lpage>73</lpage>.<pub-id pub-id-type=\"pmid\">25023924</pub-id></mixed-citation></ref><ref id=\"R2\"><label>[2]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Wijemanne</surname><given-names>S</given-names></name><name><surname>Ondo</surname><given-names>W</given-names></name></person-group>\n<article-title>Restless Legs Syndrome: clinical features, diagnosis and a practical approach to management</article-title>. <source>Pract Neurol</source>\n<year>2017</year>;<volume>17</volume>:<fpage>444</fpage>&#x02013;<lpage>52</lpage>.<pub-id pub-id-type=\"pmid\">29097554</pub-id></mixed-citation></ref><ref id=\"R3\"><label>[3]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Koo</surname><given-names>BB</given-names></name></person-group>\n<article-title>Restless leg syndrome across the globe: epidemiology of the restless legs Syndrome/Willis-Ekbom disease</article-title>. <source>Sleep Med Clin</source>\n<year>2015</year>;<volume>10</volume>:<fpage>189</fpage>&#x02013;<lpage>205</lpage>.<pub-id pub-id-type=\"pmid\">26329429</pub-id></mixed-citation></ref><ref id=\"R4\"><label>[4]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Manconi</surname><given-names>M</given-names></name><name><surname>Ulfberg</surname><given-names>J</given-names></name><name><surname>Berger</surname><given-names>K</given-names></name><etal/></person-group>\n<article-title>When gender matters: restless legs syndrome. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991427</article-id><article-id pub-id-type=\"pmc\">PMC7523822</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08144</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022274</article-id><article-id pub-id-type=\"art-access-id\">22274</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>5300</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Comparative efficacy and safety of traditional Chinese patent medicine for anxiety disorders in children or adolescence</article-title><subtitle>A protocol for systematic review and network meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0001-8702-2955</contrib-id><name><surname>Jiang</surname><given-names>Zhenyuan</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Jiahao</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yu</surname><given-names>Xiaowen</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Li</surname><given-names>Chuancheng</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Shao</surname><given-names>Yuze</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Zhonglin</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine</aff><aff id=\"aff2\"><label>b</label>Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Zhonglin Wang, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369, Jingshi Road, Jinan City, Shandong Province, China (e-mail: <email>J15562437830@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22274</elocation-id><history><date date-type=\"received\"><day>18</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>20</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22274.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Anxiety is the most common mental illness among adolescents and children, and its incidence is increasing year by year, which has a serious adverse effect on the academic and growth of adolescents and children. Conventional treatment methods such as oral administration of western medicine and psycho-behavioral therapy have obvious limitations. Chinese patent medicines play an irreplaceable role in the treatment of this disease. At present, there is no comparison of the safety and effectiveness of various Chinese patent medicines curing anxiety in adolescents. So we take advantage of the method of network meta-analysis to systematically compare the efficacy of various Chinese patent medicines curing this disease.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>We will systematically and comprehensively search the following databases, including PubMed, Web of Science, EMBASE, The Cochrane Library, China BioMedical Literature (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang database. We will include all RCT trials that meet the inclusion criteria, starting from the establishment of the database until August 2020. Two researchers will independently screen the literature based on inclusion criteria. While extracting data, we also assess the risk of bias in the included studies. All the data and evidence obtained will be evaluated by the method of Bayesian network meta-analysis. STATA and WinBUGS software will be used.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>This study will evaluate the effectiveness and safety of various TCPMs for anxiety disorders in children or adolescence.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>The results of this study will provide valuable references for the clinical application of Traditional Chinese patent medicines, and assist clinicians in formulating more reasonable diagnosis and treatment strategies.</p></sec><sec><title>Ethics and dissemination:</title><p>This study does not require ethical approval.</p></sec><sec><title>INPLASY registration number:</title><p>INPLASY202080048.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>anxiety disorders in childhood or adolescence</kwd><kwd>network meta-analysis</kwd><kwd>protocol</kwd><kwd>traditional Chinese patent medicine (TCPM)</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Chinese Medicine Technology Development Project of Shandong Province, China.</funding-source><award-id>2019-0108</award-id><principal-award-recipient>zhenyuan jiang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Anxiety is the appearance of inner fear and restlessness for no obvious reason, often accompanied by autonomic dysfunction, and the clinical symptoms are persistent mental stress or episodic panic.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} Adolescents and children are in a special period of physical and mental development. Due to their young age and poor mental endurance, they are vulnerable to adverse life events,^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Therefore, Anxiety symptoms are very common especially in adolescents and children. Relevant research shows that about 5% to 20% of children and adolescents worldwide have anxiety disorders.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} A Norwegian survey on the stability, changes, and incidence of anxiety symptom clusters among 13 to 16-year-olds found that the incidence of high-level anxiety was 8.2%.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Children suffering from anxiety disorders are vulnerable to other mental problems and related physical symptoms in the later growth process than other children.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>&#x02013;<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]}</p><p>The cause of this disease is very complex and closely related to genetic factors,^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} researches have confirmed that if 1 parent suffering from anxiety disorder, the risk of their children suffering from an anxiety disorder is significantly increasing; When both parents suffer from anxiety and other similar mental illnesses, the risk of children suffering from this illness is particularly high.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} Inappropriate parental education methods, such as excessive protection or excessive restraint, can increase the risk of social phobia in their children; Parents indifference and tyranny towards their children increase the risk of almost all diseases, but it is more closely related to anxiety and other mental disorders. Childrens excessive attachment to their parents is also a significant cause of this disease.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} Also, excessive study pressure, campus bullying, and strained relationships with classmates are also risk factors for this disease. This disease has a significant impact on the mental and social life of adolescents, severely affects learning efficiency, reduces social skills, and makes it hard to integrate into social life as an adult.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} In addition, due to the invisibility of the disease, it brings a great economic burden to patients and the medical system. According to estimates by Chisholm et al, anxiety and depression cost the world US$925 billion in productivity losses each year.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]}</p><p>Although a lot of research has been conducted, the pathogenesis of anxiety disorder is still not very clear, involving the regulation of multiple system functions. Neurotransmitters distributed in the limbic system, hippocampus, raphe nucleus and nucleus septum, such as serotonin (5-HT), dopamine (DA), and norepinephrine (NE), are closely related to the regulation of emotions. A large number of basic experiments have shown that changes in its concentration can cause mental disorders,^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>&#x02013;<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} and anxiety is one of the most common. Changes in the quantity and sensitivity of NMDA receptors in the brain can also cause anxiety symptoms.^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} Immune dysfunction is another important mechanism that causes anxiety symptoms; Studies have shown that the dysfunction of microglia and CD4⁺ cells can significantly increase the anxiety behavior of experimental animals. In addition, oxidative stress and endocrine disorders in the brain are also critical mechanisms for anxiety disorders.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} According to the symptoms and severity of the disease, there are many treatments for anxiety disorders in adolescents and children. The drugs currently used to treat anxiety disorders mainly include weak tranquilizers (anxiolytics) and antidepressants. Benzodiazepines are widely used anti-anxiety agents, but their effects are short-lived, and they have side effects such as drowsiness, ataxia, and respiratory depression, so they are not suitable for long-term use. Commonly used antidepressants such as paroxetine and escitalopram have the dual effects of anti-anxiety and anti-depression, but their consequences are relatively slow and require long-term use. However, the nervous system of adolescents has not fully developed and matured. Animal experiments have shown that the results of SSRIs on adult and adolescent neurons are different. Exposure to psychiatric drugs during brain development may cause unpredictable short-term and long-lasting neuronal outcomes. Such medicine should be used with caution.^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>&#x02013;<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} Cognitive-behavioral-therapy (CBT) is currently the recommended first-line evidence-based treatment for anxiety disorders in children and adolescents.^{[<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} Comparing the CBT treatment group with no treatment group, the remission rate is about 60%. This result indicates that 40% of adolescents suffering from anxiety disorders still have no effect on CBT treatment.^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} Chinese patent medicine (TCPM) is a powerful weapon of traditional Chinese medicine to cure diseases. It plays a significant role in relieving clinical symptoms, improving disease prognosis, and preventing recurrence. After long-term use and clinical observation, traditional Chinese patent medicine have the advantages of small side effects, high safety, and reliable efficacy. Many clinical trials and systematic reviews have confirmed the clinical efficacy of TCPM in the treatment of anxiety. Traditional Chinese patent medicines which are wildly used for treating anxiety include Xiaoyao Pills, Wuling Capsules, Shugan Jieyu Capsules, and Xuefu Zhuyu Oral Liquid. Basic research has shown that Xiaoyao Pill can reduce the expression of NSF and PICK1 protein by increasing GluR2/3 in the brain, inhibiting neuroinflammation induced by lipopolysaccharide, and alleviating anxiety symptoms.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} Xuefu Zhuyu Oral Liquid can improve the mental symptoms of model rats by increasing the content of monoamine neurotransmitter 5-HT and BDNF.^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]} Network meta-analysis can compare the advantages and disadvantages of 3 or more treatment methods, making full use of clinical data than traditional meta-analysis. Therefore, we use it to compare the effectiveness and safety of each traditional Chinese patent medicine in treating anxiety disorders in adolescents and children</p></sec><sec><label>2</label><title>Methods</title><p>We will use Bayesian NMA. Then we compliant PRISMA-P guidelines to conduct this study.</p><sec><label>2.1</label><title>Study registration</title><p>This NMA has been registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) and the registration number is INPLASY202080048 (URL = <ext-link ext-link-type=\"uri\" xlink:href=\"https://inplasy.com/inplasy-2020-8-0048/\">https://inplasy.com/inplasy-2020-8-0048/</ext-link>).</p></sec><sec><label>2.2</label><title>Inclusion criteria</title><sec><label>2.2.1</label><title>Type of study</title><p>We will include all RCTs using TCPM for the treatment of anxiety in adolescents and children, as well as related clinical trials, such as I/II early stage, stage III trials, prospective and retrospective observational studies. The language is limited to Chinese and English.</p></sec><sec><label>2.2.2</label><title>Participants</title><p>Adolescents and children diagnosed with anxiety disorders will be included. The diagnosis of anxiety will follow the Hamilton Anxiety Scale (HAMA) and Anxiety Self-Rating Scale (SAS).</p></sec><sec><label>2.2.3</label><title>Interventions</title><p>The experimental group was treated with traditional Chinese patent medicines combined with conventional Western medicine. Chinese patent medicines included Xiaoyao Pills, Wuling Capsules, Shugan Jieyu Capsules, and Xuefu Zhuyu Oral Liquid. The control group received Western medicine treatment, including oral medication or mental behavior therapy. RCTs that use 2 or more proprietary Chinese medicines or combined acupuncture, moxibustion, and other traditional Chinese medicine methods are excluded.</p></sec><sec><label>2.2.4</label><title>Outcomes</title><p>According to the Hamilton Anxiety Scale, a 5-point scale of 0&#x02013;is adopted. The main indicators are: total clinical effective rate, improvement of anxiety mood, insomnia remission rate, improvement of cognitive function; secondary indicators including relapse rate, plant Nervous system symptoms and the rate of improvement in behavior when talking to people. The included literature must cover 1 or more main indicators.</p></sec></sec><sec><label>2.3</label><title>Database and search strategy</title><p>We will search the Cochrane Library, PubMed, Embase, Clinical Trials, CNKI Database, VIP, Wanfang Database, and China Biomedical Database. The search strategy will be constructed in the form of Medical Subject Headings (MeSH) combine with keywords, including &#x0201c;Traditional Chinese patent medicine, TCPM, Anxiety disorders in children or adolescence, Adolescent generalized anxiety, Panic Disorder in childhood or adolescence, social phobia in children or adolescence, Randomized controlled,&#x0201d; etc. The search time limit is from the establishment of each database to August 2020. (The retrieval scheme of the PubMed database is listed in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>.)</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Detailed search strategy for PubMed.</p></caption><graphic xlink:href=\"medi-99-e22274-g001\"/></table-wrap></sec><sec><label>2.4</label><title>Study selection and data extraction</title><p>The literature will be screened by 2 independent researchers according to the inclusion and exclusion criteria, and cross-checked them. In case of disagreement, they will discuss and negotiate with the third investigator. The extracted data include: &#x02460; the fundamental information of the included study (research title, first author, sample size, age, year, course of disease, treatment period); &#x02461; baseline characteristics and intervention measures of the research object; &#x02462; key elements of bias risk evaluation; &#x02463; outcome indicators.</p></sec><sec><label>2.5</label><title>Risk of bias assessment</title><p>The quality of each trial will be assessed by 2 researchers independently based on the Cochrane Risk of Bias Risk Assessment Tool recommended by Cochrane Handbook version 5.1.0. Use the decision words &#x0201c;high risk&#x0201d;, &#x0201c;low risk&#x0201d;, and &#x0201c;unclear risk&#x0201d; to evaluate the quality of the input article in 7 aspects, including: whether the random sequence is sufficient; whether there is hidden allocation; whether blinding is used; whether the result data is complete; whether there is selective reporting; whether there is publication bias; others.</p></sec><sec><label>2.6</label><title>Statistical analysis</title><p>We will use Stata 14.0 software and Markov chain-Monte Carlo (MCMC) method to conduct Bayesian meta-analysis. Three Markov chains will be used for simulation, and the number of iterations will be set at 50,000 (the first 20,000 are used for annealing to eliminate the effect of the initial value, and the last 30,000 are used for sampling).</p><p>The reticular diagram will be drawn by Stata 15.0 software to show the direct and indirect comparison between different interventions. The relative odds ratio (RoR) and its 95% confidence interval (CI) are calculated to evaluate the consistency of each closed loop. The lower limit of 95% CI is equal to 1, indicating good consistency. If RoR is close to 1, direct evidence and indirect evidence are consistent, and the fixed effect model is adopted for analysis. Otherwise, the closed-loop is considered to have obvious inconsistencies, and the random effect model is used for analysis. Dichotomous data will be represented by odds ratio (OR) and 95% CI, and <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05 was considered statistically significant. WinBUGS 1.4.3 will be used to rank the efficacy of different interventions and the area under the curve will be recorded (the area under the curve will be expressed as a percentage, the larger the value, the better the effect).</p></sec><sec><label>2.7</label><title>Assessment of heterogeneity</title><p>If (<italic>P</italic>&#x0200a;&#x0003e;&#x0200a;.10 and <italic>I</italic>²&#x0200a;&#x0003c;&#x0200a;50%), we will use the fixed-effect model. Otherwise, we will further explore the source of heterogeneity, and if the source cannot be found, the random-effects model will be used for analysis.</p></sec><sec><label>2.8</label><title>Subgroup analysis and sensitivity analysis</title><p>Subgroup analysis will be considered if sufficient data is available. Sensitivity analysis will be conducted with symptom improvement rate to evaluate clinical similarity and methodology of included studies to determine the reliability of the results of this study.</p></sec><sec><label>2.9</label><title>Evaluation of publication bias</title><p>Total effective rate, anxiety after treatment, degree of nervousness after treatment, and sleep status after treatment will be taken as indicators, and the inverted funnel plot will be drawn with each effect amount as the horizontal coordinate and the standard error of effect amount as the vertical coordinate. If the inverted funnel plot is symmetric, it suggests that there is a small sample effect or a slight possibility of publication bias in this study.</p></sec><sec><label>2.10</label><title>Grading the quality of evidence</title><p>We will use GRADE to evaluate the quality of evidence from the following 5 aspects: risk of bias, indirectness, inconsistency, imprecision, and publication bias.^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]}</p></sec></sec><sec><label>3</label><title>Discussion</title><p>Teenagers are not fully mature mentally and are vulnerable to adverse life events. Mental health problems are common among children and adolescents, and anxiety disorder is the most common mental illness. Failure to receive timely and effective treatment will result in childrens academic frustration, substance abuse, and poor social function, which will seriously affect personal development. Whether it is cognitive-behavioral-therapy (CBT) or oral psychiatric drugs, there are obvious limitations. Traditional Chinese patent medicine are under the strict supervision of relevant national departments, according to traditional Chinese medicine theories, the prescriptions are selected with rigorous compatibility, and have been effective after long-term clinical application. The Chinese medicine decoction pieces are processed through scientific preparation techniques to produce pills, tablets, capsules, granules, and other different dosage forms are convenient to take, widely used, and have good therapeutic effects. At present, there is no comparison of the advantages and disadvantages of various Chinese patent medicines for the treatment of anxiety in adolescents, so it is necessary to use the method of network meta-analysis to study this topic. In this study, we will introduce the network meta-analysis on the basis of the existing RCT to evaluate the advantages and disadvantages of various Chinese patent medicines, so as to provide clinicians with more complete diagnosis and treatment plans.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Zhenyuan Jiang, Zhonglin Wang.</p><p><bold>Data curation:</bold> Zhenyuan Jiang, Xiaowen Yu.</p><p><bold>Formal analysis:</bold> Zhenyuan Jiang, Yuze Shao, Zhonglin Wang.</p><p><bold>Funding acquisition:</bold> Zhonglin Wang.</p><p><bold>Investigation:</bold> Zhenyuan Jiang.</p><p><bold>Methodology:</bold> Zhenyuan Jiang, Jiahao Wang, Chuancheng Li.</p><p><bold>Project administration:</bold> Zhenyuan Jiang.</p><p><bold>Resources:</bold> Zhenyuan Jiang.</p><p><bold>Software:</bold> Zhenyuan Jiang, Jiahao Wang, Xiaowen Yu.</p><p><bold>Validation:</bold> Zhenyuan Jiang.</p><p><bold>Visualization:</bold> Zhenyuan Jiang.</p><p><bold>Writing &#x02013; original draft:</bold> Zhenyuan Jiang, Jiahao Wang.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Zhenyuan Jiang, Zhonglin Wang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CBM = Chinese biomedical literature database, CI = confidence interval, CNKI = Chinese national knowledge infrastructure, MD = mean difference, NMA = network meta-analysis, OR = odds ratio, RCT = randomized controlled trial, SE = standard error, SMD = standardized mean difference, TCPM = traditional Chinese patent medicine.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Jiang Z, Wang J, Yu X, Li C, Shao Y, Wang Z. Comparative efficacy and safety of traditional Chinese patent medicine for anxiety disorders in children or adolescence: A protocol for systematic review and network meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22274).</p></fn><fn fn-type=\"supported-by\"><p>This study is supported by Chinese Medicine Technology Development Project of Shandong Province, China. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991442</article-id><article-id pub-id-type=\"pmc\">PMC7523823</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-02303</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022324</article-id><article-id pub-id-type=\"art-access-id\">22324</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>7000</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Fractured coracoid process with acromioclavicular joint dislocation</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Wei</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Huang</surname><given-names>Bingzhe</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Yang</surname><given-names>Jingjing</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Xue</surname><given-names>Pan</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Xiaoning</given-names></name><degrees>MD, PhD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff>Orthopaedic Medical Center, the Second Hospital of Jilin University, Changchun, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Xiaoning Liu, Orthopaedic Medical Center, the Second Hospital of Jilin University, Changchun, China 130041 (e-mail: <email>jluliuxiaoning@gmail.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22324</elocation-id><history><date date-type=\"received\"><day>13</day><month>3</month><year>2020</year></date><date date-type=\"rev-recd\"><day>30</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>24</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22324.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Coracoid processes (CPs) fracture with acromioclavicular (AC) joint dislocation are extremely rare. This combined injury has brought many challenges to surgeons, and the mechanism underlying the injury is still not fully understood. There is no clear consensus on its treatment.</p></sec><sec><title>Patient concerns:</title><p>Here, we describe a CP fracture with AC joint dislocation in a middle-aged manual worker.</p></sec><sec><title>Diagnosis:</title><p>Radiographs showed a fracture of the base of the CP and a third-degree AC joint separation.</p></sec><sec><title>Interventions:</title><p>The patient was treated surgically with open reduction and internal fixation of the AC joint by LCP clavicle hook plate, and the CP was fixed with a 3.5&#x0200a;mm diameter cannulated screw.</p></sec><sec><title>Outcomes:</title><p>Three months after the operation, shoulder function was completely restored, and the affected shoulder had full mobility with no tenderness. Plain film radiography showed anatomical indications of the healing of these combined injuries.</p></sec><sec><title>Lessons:</title><p>Although AC joint dislocation with CP fractures is extremely rare in adults, it is important to remind and remember that this possibility exists. In unclear cases, special radiographic films and CT are necessary. Surgical treatment of AC joint dislocation with CP fractures can provide solid stability and restore normal shoulder function with an excellent prognosis.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>acromioclavicular dislocation</kwd><kwd>coracoid processes</kwd><kwd>fracture</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Science and Technology Project of the 13th Five-Year Plan of Jilin Provincial Department of Education</funding-source><award-id>JJKH20190057KJ</award-id><principal-award-recipient>Xiaoning Liu</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Special Foundation for Science and Technology Innovation of Jilin Province</funding-source><award-id>No. 20200201566JC</award-id><principal-award-recipient>Xiaoning Liu</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>The incidence of scapular fractures is not high, accounting for only 1% of all fractures, and fractures of the coracoid processes (CPs) are also relatively rare, accounting for 3% to 13% of scapular fractures.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} CP fractures with acromioclavicular (AC) joint dislocation are even rarer. There are only a few cases reported in the literature.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>&#x02013;<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} This combined injury has brought many challenges to surgeons, and the mechanism underlying the injury is still not fully understood. There is no clear consensus on its treatment.</p><p>In the present case, we describe a CP fracture with AC joint dislocation in a middle-aged manual worker. Patients and their families have provided written consent to publish the case report, and the institutional review board of the Second Hospital of Jilin University approved the study.</p></sec><sec><label>2</label><title>Case report</title><p>A 55-year-old worker suffered from trauma to his right shoulder after he fell from a bicycle due to a car accident and landed on the right side of his body. He had a major injury and fractured multiple ribs. Physical examination showed a prominent distal clavicle and tenderness over the AC joint and the CP. The range of motion of the right shoulder was decreased due to pain. The results of the neurovascular examination were essentially normal. Radiographs showed a fracture of the base of the CP and a third-degree AC joint separation (Figs. <xref ref-type=\"fig\" rid=\"F1\">1</xref> and <xref ref-type=\"fig\" rid=\"F2\">2</xref>).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Preoperative anteroposterior X-ray showed CP fracture and a third-degree AC joint separation.</p></caption><graphic xlink:href=\"medi-99-e22324-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Preoperative 3D-CT showed a displaced fracture of the coracoid process base.</p></caption><graphic xlink:href=\"medi-99-e22324-g002\"/></fig><p>He was treated surgically with open reduction and internal fixation of the AC joint by LCP clavicle hook plate (Synthes Inc, PA, US). The CP was fixed with a 3.5&#x0200a;mm diameter cannulated screw (Synthes Cannulated Screw System, Synthes Inc., PA) (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>). The positions of the CP and the screw were confirmed with intraoperative radiographic screening. The patient had an uneventful postoperative course and was discharged on the fifth day with an arm sling.</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>AC joint was fixed by LCP clavicle hook plate; the CP was fixed with a 3.5&#x0200a;mm diameter cannulated screw. Immediate postoperative anteroposterior X-ray view (A), immediate postoperative outlet X-ray view (B).</p></caption><graphic xlink:href=\"medi-99-e22324-g003\"/></fig><p>The patient's shoulder was placed in a sling after surgery, and the pendulum movement began immediately after surgery. The patient was advised not to engage in elbow flexion or place any weight on that arm for 6 weeks after surgery. The range of motion of the shoulder was limited to 45&#x000b0; abduction and 90&#x000b0; forward flexion. After 6 weeks, the patient was permitted to begin progressive active activities. Muscle exercises began at 8 weeks.</p><p>Three months after the operation, shoulder function was completely restored, and the affected shoulder had full mobility with no tenderness. Plain film radiography showed anatomical indications of the healing of these combined injuries.</p></sec><sec><label>3</label><title>Discussion</title><p>CP fractures with AC joint dislocations rarely occur in adults, and there is still disagreement about the underlying mechanisms.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} A direct blow with cephalad-to-caudad violence and alternatively a strong contraction of the short head of the biceps and pectoralis minor muscles are both plausible mechanisms. The sudden pull of the combined tendon and pectoralis minor could cause the CP to break. Whether the coracoclavicular ligament remains intact depends on the ligament's component residual force. In AC dislocations with CP fractures but intact coracoclavicular ligaments, as in our patient, CP fractures are often associated with type 3 AC dislocations.</p><p>In such cases of combined injuries, if only conventional radiography is used, AC joint dislocation is often pronounced, which draws considerable attention, and the CP fracture may be ignored. At this time, computed tomography (CT) is necessary to clearly show the images of CP fractures and AC joint dislocations to avoid misdiagnosis. For this reason, we recommend that, for patients with AC joint dissection and shoulder injuries, the anterior and posterior view of the shoulder joint, oblique position, axillary view is necessary.</p><p>Previously published case reports include both surgical and conservative treatment for this combined injury.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Overall, more cases have been treated with surgery than with conservative treatment. As this type of combined injury is extremely rare, it is difficult to compare the advantages and disadvantages of the 2 treatments without a large cohort. According to the current literature, in these concomitant injuries, there are no differences in the long-term outcomes of patients treated conservatively and surgically.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} However, some earlier reports mentioned that AC joint pain and cosmetic symptoms persist after conservative treatment.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} This may be related to AC joint capsule entrapment and fibrocartilage disc rupture. For this combined injury, several surgical methods have been reported in the literature. Some people choose to only address the AC joint, while others have found that AC can be reduced indirectly after CP reduction by surgery.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} In this regard, we believe that in cases of patients who perform manual labor or heavy-duty work, it is more logical that both injuries (AC dislocation and CP fracture) should be fixed. For patients with lower functional requirements, it is feasible to deal with only 1 injury. Obtaining reliable stability for CP fractures and AC joint dislocations can help patients recover early. Considering that this case is a manual laborer and the double structure injury of the shoulder joint complex, we chose surgical treatment to obtain rigid fixation. In addition to the tension screws used for CP fractures, we also used the traditional method for fixing isolated AC joint dislocations, using a hook plate to fix the AC joint. This double fixation method can reduce the tensile force of the CC ligament on the CP, so that the 2 injuries can be healed early and function can be exercised early as well. At week 8 after surgery, the shoulder joint was painless, active, and strong.</p></sec><sec><label>4</label><title>Conclusion</title><p>Although AC joint dislocation with CP fractures is extremely rare in adults, it is important to remind and remember that this possibility exists. In unclear cases, special radiographic films and CT are necessary. Surgical treatment of AC joint dislocation with CP fractures can provide solid stability and restore normal shoulder function with an excellent prognosis.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Wei Zhang, Xiaoning Liu.</p><p><bold>Formal analysis:</bold> Jingjing Yang.</p><p><bold>Funding acquisition:</bold> Xiaoning Liu.</p><p><bold>Investigation:</bold> Bingzhe Huang.</p><p><bold>Methodology:</bold> Bingzhe Huang, Pan Xue.</p><p><bold>Writing &#x02013; original draft:</bold> Wei Zhang, Bingzhe Huang, Pan Xue, Xiaoning Liu.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Jingjing Yang, Xiaoning Liu.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: AC = acromioclavicular, CP = coracoid processes, CT = computed tomography.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Zhang W, Huang B, Yang J, Xue P, Liu X. Fractured coracoid process with acromioclavicular joint dislocation: A case report. <italic>Medicine</italic>. 2020;99:39(e22324).</p></fn><fn fn-type=\"equal\"><p>WZ and BH contributed equally to this paper.</p></fn><fn fn-type=\"COI-statement\"><p>The authors report no conflicts of interest</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by grants from the Science and Technology Project of the 13th Five-Year Plan of Jilin Provincial Department of Education (JJKH20190057KJ) and Special Foundation for Science and Technology Innovation of Jilin Province (No. 20200201566JC).</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article [and its supplementary information files].</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991482</article-id><article-id pub-id-type=\"pmc\">PMC7523825</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-00041</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022451</article-id><article-id pub-id-type=\"art-access-id\">22451</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>5300</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Acute basilar artery occlusion with recurrent shivering</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Lee</surname><given-names>Chan-Hyuk</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Jeon</surname><given-names>Seung-Ho</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Kim</surname><given-names>Sang Yeon</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Shin</surname><given-names>Byoung-Soo</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0001-5443-3635</contrib-id><name><surname>Kang</surname><given-names>Hyun Goo</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Neurology and Research, Institute of Clinical Medicine of Jeonbuk National University</aff><aff id=\"aff2\"><label>b</label>Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju, South Korea.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Hyun Goo Kang, Department of Neurology and Research Institute of Clinical Medicine, Jeonbuk National University School of Medicine and Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju-si, Jeonbuk-do 54907, South Korea. (e-mail: <email>hgkang@jbnu.ac.kr</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22451</elocation-id><history><date date-type=\"received\"><day>2</day><month>1</month><year>2020</year></date><date date-type=\"rev-recd\"><day>22</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>31</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22451.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Shivering is an important physiological response of the body that causes muscle tremors to maintain temperature homeostasis. Traumatic brain injuries that affect the hypothalamus cause hypothermia, and physical removal of suprasellar tumors causes thermoregulation imbalance. However, no study has reported shivering due to ischemic stroke.</p></sec><sec><title>Patient concerns:</title><p>A 58-year-old male patient was admitted to our emergency department to evaluate severe stenosis of the basilar artery. While waiting for further examination, he exhibited coarse shivering and severe dysarthria.</p></sec><sec><title>Diagnosis:</title><p>Brain computed tomography angiography revealed occlusion of the entire basilar artery, and cerebral hypoperfusion was diagnosed in that area.</p></sec><sec><title>Interventions:</title><p>Transfemoral cerebral angiography (TFCA) was immediately performed, followed by thrombectomy of the basilar artery.</p></sec><sec><title>Outcomes:</title><p>Neurological deficits, including shivering, were rapidly reversed. The same symptom reoccurred 5&#x0200a;hours later, and TFCA was performed for thrombectomy and stenting, and neurological symptoms immediately reversed. The patient's neurological symptoms did not worsen during hospitalization.</p></sec><sec><title>Lessons:</title><p>Patients with acute basilar artery occlusion need prompt management because they have a higher mortality rate than those with other intracranial artery occlusions. When a patient exhibits neurological deficits accompanied by abrupt shivering for no specific reason, basilar artery occlusion must be considered.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>basilar artery</kwd><kwd>hypothalamus</kwd><kwd>ischemic stroke</kwd><kwd>shivering</kwd><kwd>thermoregulation</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>National Research Foundation of Korea</funding-source><award-id>NRF-2017R1C1B5017293</award-id><principal-award-recipient>Hyun Goo Kang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>The basilar artery is an important major cerebral artery that supplies blood to key structures of the limbic system, including the brainstem, thalamus, and hypothalamus. These structures have centers that control essential functions for maintenance of life. Basilar artery stenosis or occlusion causes severe neurological deficits, and the prognosis is generally poor.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Therefore, it is critical to recognize when neurological deficits in a patient are caused by disintegration of the basilar artery. A traumatic injury^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} involving the hypothalamus causes hypothermia, and physical removal of suprasellar tumors causes an imbalance in thermoregulation.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} However, an association between shivering and acute ischemic stroke has not been reported. We report the case of a patient who recurrently experienced reversible shivering caused by basilar artery occlusion.</p></sec><sec><label>2</label><title>Case report</title><p>A 58-year-old male patient visited our emergency department with acutely worsened non-whirling type dizziness, which first occurred 7 days prior. It lasted approximately 30&#x0200a;minutes and disappeared. Previously, he was diagnosed with vertebrobasilar insufficiency (VBI) due to severe basilar artery stenosis confirmed during brain magnetic resonance imaging (MRI) and angiography, which were performed at a local hospital 7 days prior. He was diagnosed as having hypertension and hypothyroidism and was on medication. He had been taking aspirin 100&#x0200a;mg and atorvastatin 20&#x0200a;mg daily. Results of neurological examinations, which included cranial nerve and cerebellar function tests, were unremarkable.</p><p>Results of routine laboratory examinations, blood chemistry, and coagulation test were normal, but triglyceride levels increased to 350&#x0200a;mg/dL. Thyroid function test showed that thyroid-stimulating hormone level decreased to 0.151&#x0200a;&#x003bc;IU/mL and free T4 level increased to 24.07&#x0200a;pmol/L. Electrocardiogram showed a normal sinus rhythm. Cardiac output was 58% on transthoracic echocardiography. In addition, there was no cardiomegaly or regional wall motion abnormality. The patient experienced dizziness for 7 days, which suddenly worsened on the day of visit. Therefore, computed tomography (CT) perfusion was planned to obtain additional information to confirm VBI. However, while waiting for the test, he exhibited shivering accompanied by sudden chilling sensation. Neurological examination revealed drowsiness, severe dysarthria, and clumsiness and numbness in both forearms. His blood pressure was 150/100&#x0200a;mm Hg, body temperature was 37.2&#x000b0;C, and blood glucose level was 137&#x0200a;mg/dL. Brain CT perfusion with angiography showed basilar artery occlusion and decreased perfusion in the affected area (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>A). He was diagnosed with acute ischemic stroke due to basilar artery occlusion. Intravenous tissue plasminogen activator was administered, and endovascular intervention was performed. Stent insertion was challenging due to the high tortuosity of the basilar artery. Therefore, only aspiration thrombectomy was performed using the penumbra system (Penumbra, CA). The vessel was fully recanalized (Thrombolysis in cerebral infarction scale 3), and his symptoms resolved completely.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Images from a 58-year-old male patient with basilar artery occlusion. (A) This is a conventional angiography image acquired immediately after acute ischemic stroke. Severe stenosis with filling defects were seen in the mid-basilar artery on basilar artery angiography (A-1, arrow head). Post-thrombectomy angiography showing recanalization of the basilar artery (A-2, arrow head). (B) This is a conventional angiography image acquired after the second ischemic attack. Reocclusion of the mid-basilar artery was confirmed (B-1, arrow), and the endovascular stent was placed after mechanical thrombectomy. Post-stenting conventional angiography showing successful recanalization of the basilar artery (B-2, arrow). (C) Brain magnetic resonance (MR) images taken after stent insertion. Diffusion-weighted image showing diffusion restriction in both superior cerebellar artery and left posterior cerebral artery territory, but the brainstem remains intact. (D) In MR perfusion imaging, the time to maximum map showing delayed perfusion in the basilar artery region, including the hypothalamus and left occipital area.</p></caption><graphic xlink:href=\"medi-99-e22451-g001\"/></fig><p>He was under observation in the neurology intensive care unit for 5&#x0200a;hours. Shivering with chilling reoccurred, and his consciousness worsened to a deep drowsy state. Spontaneous downbeat nystagmus and severe dysarthria were confirmed in a cranial nerve examination. Left-sided muscle power was reduced to medical research council grade 4+. Brain CT angiography showed basilar artery reocclusion. Therefore, intra-arterial thrombectomy was performed again, followed by endovascular stent placement (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>B), resulting in a diagnosis of vertigo, right homonymous hemianopsia, and left sensorineural hearing impairment. However, shivering, dysarthria, and mental deterioration disappeared immediately after the procedure.</p><p>He underwent brain diffusion-weighted MRI, which confirmed acute ischemic stroke in the superior cerebellar artery region of the cerebellum and posterior cerebral artery region of the right occipital lobe (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>C). The MR perfusion image showed hypoperfusion in the hypothalamus and left occipital areas (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>D). Finally, he was diagnosed with multifocal infarction in the basilar artery region due to basilar artery occlusion. He received aspirin 100&#x0200a;mg, clopidogrel 75&#x0200a;mg, and atorvastatin 40&#x0200a;mg once a day.</p></sec><sec><label>3</label><title>Discussion</title><p>We report the case of a patient who visited our hospital for dizziness caused by basilar artery stenosis. His neurological symptoms, possibly induced by basilar artery occlusion, aggravated in the emergency room. He was also shivering. When the occluded basilar artery was recanalized using intra-arterial thrombectomy, his shivering improved. His neurological symptoms accompanied by shivering worsened again due to basilar artery reocclusion. His symptoms improved after basilar artery recanalization and stent placement.</p><p>Shivering induces muscle tremor in response to low body temperature. It is an important physiological response to maintain constant body temperature.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} The hypothalamus regulates body temperature by collecting and integrating information about temperature from various organs and responding appropriately. The hypothalamus is a collection of nuclei responsible for maintaining body homeostasis and largely comprises anterior, tuberal, and posterior regions.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Preoptic and anterior hypothalamic nuclei in the anterior region and the posterior nucleus in the posterior region are associated with body temperature regulation.</p><p>Thermal receptors present on the skin and some internal organs detect coldness and warmness, and electrical signals are transmitted along the lateral spinal tract or trigeminal nerve. Heat and cold-sensitive neurons are distributed in the preoptic nucleus, and the response of the posterior nucleus is determined by its relative signal intensity.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Because the posterior nucleus contains temperature-insensitive interneurons, it functions like a thermostat. Thus, posterior nucleus has an independent set-point for body temperature, which it compares to the signal transmitted from the preoptic nucleus.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} When the transmitted signal is higher than the set-point, it activates mechanisms for lowering body temperature (e.g., vasodilation and sweating), whereas when the signal is lower than the set-point, it activates mechanisms for increasing body temperature (e.g., shivering and vasoconstriction). The thermal set-point varies depending on various internal and external conditions. Physiologically, body temperature fluctuates diurnally and is the lowest during sleep or early in the morning. However, it is approximately 1&#x000b0;C higher in the evening.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Body temperature of women varies during the menstrual cycle and is approximately 1&#x000b0;C higher than the usual temperature in the luteal phase. The set-point can also be changed by external conditions. Pyrogens, such as endotoxins, increase the set-point by lowering the activity of heat-sensitive neurons. Although the mechanism is poorly understood, the set-point might increase in the presence of a space-occupying lesion or during dehydration.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]}</p><p>Arterial blood is mainly supplied to the anterior region, including the preoptic nucleus, by the anterior communicating artery (anterior circulation) and perforating branch of the anterior cerebral artery. The posterior nucleus is supplied by branches of the thalamoperforating artery that originates from the site immediately after the basilar artery branches to the posterior cerebral artery.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} Therefore, if basilar artery stenosis progresses further in these patients, the posterior hypothalamus, supplied by the basilar artery, is likely to be in a hypoperfusion state.</p><p>Two possible mechanisms can cause shivering due to hypoperfusion of the posterior hypothalamus. One mechanism is dysfunction of the anterior nucleus fibers. These fibers pass through the posterior hypothalamic nuclei. Therefore, if posterior nuclei are damaged, fibers of the adjacent anterior nucleus may also be damaged. Specifically, if heat-sensitive neurons are mainly damaged, signals from the cold-sensitive neurons become relatively more prevalent. As a result, posterior nuclei activate mechanisms for increasing body temperature, thereby causing shivering (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>A). Normally, there are 4 times more heat-sensitive neurons than cold-sensitive neurons, implying that heat-sensitive neurons are more likely to be damaged when exposed to an ischemic event.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} The other possible mechanism is posterior nuclei dysfunction. When hypoperfusion of posterior nuclei occurs due to basilar artery occlusion, they may lose their thermostat function or become unstable, which can cause fluctuations in the set-point, leading to shivering (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>B).</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Mechanism of shivering due to hypoperfusion of the posterior hypothalamus. (A) First hypothesis. (B) Second hypothesis.</p></caption><graphic xlink:href=\"medi-99-e22451-g002\"/></fig><p>Previously, associations between hypothalamic damage and body temperature regulation have been reported. In a study involving 8 patients who underwent suprasellar resection, sympathetic nerve response to elevated body temperature was reduced compared with that in normal subjects.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} In another study, patients with traumatic brain injuries involving the hypothalamus exhibited periodic hypothermia.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} In these studies, patients did not shiver. However, in our study, the patient shivered as a result of ischemia. We suspect that shivering was not observed in the previous studies because functions of the hypothalamus, including the set-point function, were completely lost due to trauma or resection.</p><p>In a study on body temperature and stroke, hypothermia in patients with ischemic stroke had a slightly lower threshold for vasoconstriction and shivering than that in normal subjects.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} However, to our knowledge, no study has reported shivering associated with hypoperfusion in the basilar artery region. It is possible that shivering was ignored because many cases of basilar artery-related stroke exhibited severe neurological deficits including decreased consciousness. In our case, the entire basilar artery was occluded, and shivering occurred as soon as neurologic symptoms worsened. In addition, the symptoms immediately disappeared after intra-arterial thrombectomy, suggesting a causal relationship between hypoperfusion in the basilar artery region and shivering.</p><p>Basilar artery occlusion damages the brain area essential for survival. Therefore, the mortality rate is higher for basilar artery occlusion than for occlusion in other parts of the brain, and survivors are more likely to have severe complications. Therefore, rapid management is required. When a patient admitted to an emergency department suddenly shows neurological deficits accompanied by shivering, ischemia in the basilar artery region should be considered.</p></sec><sec><title>Author contributions</title><p>CHL, SHJ, and HGK participated the design of this research. SHJ, SYK, and BSS collected and analyzed the raw clinical data. CHL, SHJ, BSS, and HGK carried out computational studies and wrote the manuscript. All authors have read and approved the final manuscript.</p><p><bold>Conceptualization:</bold> Chan-Hyuk Lee, Sang Yeon Kim, Byoung-Soo Shin, Hyun Goo Kang.</p><p><bold>Data curation:</bold> Chan-Hyuk Lee, Seung-Ho Jeon.</p><p><bold>Formal analysis:</bold> Seung-Ho Jeon, Byoung-Soo Shin.</p><p><bold>Funding acquisition:</bold> Hyun Goo Kang.</p><p><bold>Investigation:</bold> Chan-Hyuk Lee.</p><p><bold>Methodology:</bold> Chan-Hyuk Lee, Seung-Ho Jeon, Sang Yeon Kim, Hyun Goo Kang.</p><p><bold>Supervision:</bold> Sang Yeon Kim, Byoung-Soo Shin, Hyun Goo Kang.</p><p><bold>Validation:</bold> Byoung-Soo Shin.</p><p><bold>Visualization:</bold> Hyun Goo Kang.</p><p><bold>Writing &#x02013; original draft:</bold> Chan-Hyuk Lee, Seung-Ho Jeon.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Hyun Goo Kang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CT = computed tomography, MRI = magnetic resonance imaging, TFCA = transfemoral cerebral angiography, VBI = vertebrobasilar insufficiency.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Lee CH, Jeon SH, Kim SY, Shin BS, Kang HG. Acute basilar artery occlusion with recurrent shivering: A case report. <italic>Medicine</italic>. 2020;99:39(e22451).</p></fn><fn fn-type=\"equal\"><p>CH Lee and SH Jeon contributed equally to this manuscript.</p></fn><fn fn-type=\"supported-by\"><p>This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, NRF-2017R1C1B5017293).</p></fn><fn fn-type=\"other\"><p>A written informed consent was obtained from our patient for publication of this case report and any accompanying images. Our patient was able to converse with others. At the moment, we obtained the informed consent. A copy of the written consent is available for review by the editor of this journal.</p></fn><fn fn-type=\"COI-statement\"><p>The authors report no conflicts of interest</p></fn><fn fn-type=\"other\"><p>The authors of this work have nothing to disclose.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Mattle</surname><given-names>HP</given-names></name><name><surname>Arnold</surname><given-names>M</given-names></name><name><surname>Lindsberg</surname><given-names>PJ</given-names></name><etal/></person-group>\n<article-title>Basilar artery occlusion</article-title>. <source>Lancet Neurol</source>\n<year>2011</year>;<volume>10</volume>:<fpage>1002</fpage>&#x02013;<lpage>14</lpage>.<pub-id pub-id-type=\"pmid\">22014435</pub-id></mixed-citation></ref><ref id=\"R2\"><label>[2]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>De Tanti</surname><given-names>A</given-names></name><name><surname>Gasperini</surname><given-names>G</given-names></name><name><surname>Rossini</surname><given-names>M</given-names></name></person-group>\n<article-title>Paroxysmal episodic hypothalamic instability with hypothermia after traumatic brain injury</article-title>. <source>Brain Inj</source>\n<year>2005</year>;<volume>19</volume>:<fpage>1277</fpage>&#x02013;<lpage>83</lpage>.<pub-id pub-id-type=\"pmid\">16286344</pub-id></mixed-citation></ref><ref id=\"R3\"><label>[3]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Ratcliffe</surname><given-names>PJ</given-names></name><name><surname>Bell</surname><given-names>JI</given-names></name><name><surname>Collins</surname><given-names>KJ</given-names></name><etal/></person-group>\n<article-title>Late onset post-traumatic hypothalamic hypothermia</article-title>. <source>J Neurol Neurosurg Psychiatry</source>\n<year>1983</year>;<volume>46</volume>:<fpage>72</fpage>&#x02013;<lpage>4</lpage>.<pub-id pub-id-type=\"pmid\">6405012</pub-id></mixed-citation></ref><ref id=\"R4\"><label>[4]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Watanabe</surname><given-names>T</given-names></name><name><surname>Iwase</surname><given-names>S</given-names></name><name><surname>Saito</surname><given-names>K</given-names></name><etal/></person-group>\n<article-title>Altered sympathetic thermoregulation in patients with hypothalamic dysfunction following resection of suprasellar tumors</article-title>. <source>Auton Neurosci</source>\n<year>2004</year>;<volume>112</volume>:<fpage>80</fpage>&#x02013;<lpage>7</lpage>.<pub-id pub-id-type=\"pmid\">15233933</pub-id></mixed-citation></ref><ref id=\"R5\"><label>[5]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Sessler</surname><given-names>DI</given-names></name></person-group>\n<article-title>Thermoregulatory defense mechanisms</article-title>. <source>Crit Care Med</source>\n<year>2009</year>;<volume>37</volume>: <issue>7 suppl</issue>: <fpage>S203</fpage>&#x02013;<lpage>10</lpage>.<pub-id pub-id-type=\"pmid\">19535948</pub-id></mixed-citation></ref><ref id=\"R6\"><label>[6]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Rudelli</surname><given-names>R</given-names></name><name><surname>Deck</surname><given-names>JH</given-names></name></person-group>\n<article-title>Selective traumatic infarction of the human anterior hypothalamus. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991435</article-id><article-id pub-id-type=\"pmc\">PMC7523830</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-09970</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022299</article-id><article-id pub-id-type=\"art-access-id\">22299</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>4800</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Acquired hemophagocytic lymphohistiocytosis as initial manifestation of multiple myeloma</article-title><subtitle>A case report and literature review</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Mendes</surname><given-names>Fernanda Rodrigues</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Sobral</surname><given-names>Karine Marques</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Culler</surname><given-names>Hebert Fabricio</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Couto</surname><given-names>Samuel Campanelli Freitas</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Pereira</surname><given-names>Juliana</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Rocha</surname><given-names>Vanderson</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Martinez</surname><given-names>Gracia Aparecida</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Lage</surname><given-names>Lu&#x000ed;s Alberto de P&#x000e1;dua Covas</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Hematology, Hemotherapy and Cell Therapy, Medicine School, Sao Paulo University (FMUSP)</aff><aff id=\"aff2\"><label>b</label>Funda&#x000e7;&#x000e3;o Pr&#x000f3;-Sangue &#x02013; Hemocentro de S&#x000e3;o Paulo, S&#x000e3;o Paulo, Brazil</aff><aff id=\"aff3\"><label>c</label>Hematology &#x00026; Hemotherapy, Churchill Hospital, Oxford University, Oxford, UK.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Lu&#x000ed;s Alberto de P&#x000e1;dua Covas Lage, Laboratory of Imunopathology, Department of Hematology, Hemotherapy &#x00026; Cell Therapy, University os S&#x000e3;o Paulo, Av. Dr. En&#x000e9;as de Carvalho Aguiar, 155, room 61, Zip code: 01246-000, Sao Paulo, Brazil (e-mail: <email>luisalberto_lage@yahoo.com.br</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22299</elocation-id><history><date date-type=\"received\"><day>10</day><month>1</month><year>2020</year></date><date date-type=\"rev-recd\"><day>30</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>21</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22299.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"intro\"><title>Introduction:</title><p>Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by a hyperinflammatory state and persistent macrophage activation, resulting in reactive phagocytosis of the hematopoietic elements. In children, it is usually a hereditary disorder, while in adults it is usually acquired secondary to viral infections, collagenoses, or tumors. Although accounting for 10% of hematologic malignancies, HLH is rarely associated with multiple myeloma (MM) and other plasmacytic dyscrasias.</p></sec><sec><title>Patient concerns:</title><p>A 64-year-old Brazilian man seeked medical care with a 3-month history of intermittent fever, weight loss, night sweats, and progressive anemic symptoms.</p></sec><sec><title>Diagnosis:</title><p>Total blood count showed severe bicytopenia (normocytic-normochromic anemia and thrombocytopenia), biochemical exams showed elevation of creatinine, as well as monoclonal peak in serum protein electrophoresis, high IgA dosage, and serum immunofixation with IgA kappa paraprotein. Bone marrow biopsy showed 30% of monoclonal and phenotypically anomalous plasmocytes, confirming the diagnosis of MM. Diagnosis of HLH was established by the presence of clinical and laboratory criteria: fever, splenomegaly, cytopenias, hypofibrinogenemia, hyperferritinemia, elevation of triglycerides, and several figures of erythrophagocytosis in bone marrow aspirate.</p></sec><sec><title>Interventions:</title><p>The patient experienced pulse therapy with methylprednisolone for hemophagocytic lymphohistiocytosis, followed by initial therapy for multiple myeloma with cyclophosphamide and dexamethasone.</p></sec><sec><title>Outcomes:</title><p>Once the diagnosis of MM and secondary hemophagocytic syndrome was established, the patient had a rapid clinical deterioration despite the established therapeutic measures, evolving with cardiovascular failure, acute liver failure, acute disseminated intravascular coagulation, worsening renal dysfunction requiring dialysis support, respiratory dysfunction, and lowering of consciousness, characterizing rapid multiple organ dysfunction, ultimately leading to the death of the patient.</p></sec><sec><title>Innovation:</title><p>Here, we aimed to describe the sixth reported case of HLH associated with MM, according to cases cataloged in the PubMed database, and the first case evaluated by 18-fluordeoxyglucose positron emission tomography (18-FDG-PETCT).</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>Our case report seeks to provide support for a better clinical and laboratory characterization of this rare paraneoplastic entity associated with MM, and aims to call the attention of hematologists and intensivists to this condition that falls within the scope of the differential diagnosis of rapid onset multiple organ failure in patients with plasmacytic neoplasms.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>acute liver failure</kwd><kwd>hemophagocytic lymphohistiocytosis</kwd><kwd>multiple myeloma</kwd><kwd>prognosis</kwd><kwd>treatment</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome (HPS) is a potentially life-threatening condition characterized by reactive phagocytosis of the hematopoietic elements.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} It is marked by persistent activation of CD8&#x0200a;+&#x0200a;cytotoxic T lymphocytes and natural killer (NK) cells, leading to increased secretion of inflammatory cytokines and macrophage activation.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Macrophages and cytotoxic T cells, via tumor necrosis factor alpha (TNF-alpha) and interferon-gamma stimulation invade the reticuloendothelial system and trigger a cytokine storm.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} As a hyperinflammatory state, HLH causes signs and symptoms that may progress to multiorgan dysfunction and death.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]}</p><p>HLH was initially recognized as a hereditary disease that preferentially affected children until the early 1980s, when it was observed that acquired factors could also trigger this phenomenon. Therefore, 2 main forms are recognized, the primary one, that is usually found in children and associated with autosomal recessive mutations in perforin receptor 1 gene (PFR-1)/perforin, protein unc-13 homolog D (UNC13D), or syntaxin 11 gene (STX11) genes. On the other hand, the secondary or acquired HLH occurs in adolescents and adults and is associated with immune dysfunction and malignancies, viral infections such as Epstein-Barr virus and cytomegalovirus, as well bacterial, fungi, or parasitic infection, autoimmune diseases like as systemic lupus erythematosus and rheumatoid arthritis, pregnancy, transplantation, and cytotoxic therapy.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]}</p><p>Malignancies, particularly hematological tumors, account for 45% to 50% of HLH in adults, and result from immune activation by neoplastic cells or loss of inhibitory cell functions mediated by tumor.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>,<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} In a recent review article, Vick et al^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} reported 822 cases of cancer-induced HLH. The most common neoplastic cause was aggressive lymphomas (80%) and 46% of them was related to T-cell lymphoma, 28% with B-cell lymphoma, and 6% with Hodgkin lymphoma. Ninety-seven per cent were associated with hematologic neoplasms and 3% of cases were caused by solid tumors.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]}</p><p>Although plasma cell dyscrasias correspond to 10% of hematologic malignancies, representing 1.8% of all new cancer cases in the United States in 2019 according to Surveillance, Epidemiology and End Results Program (SEER),^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} malignancy-induced HLH were associated with plasma cell neoplasms in only 0.36% of cases.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Moreover, there is scarce data in the medical literature regarding this entity associated with multiple myeloma and only a few cases have been reported.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R10\" ref-type=\"bibr\">10</xref>,<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]}</p><p>Hence, here we describe a case of HLH as initial manifestation of multiple myeloma in a Brazilian man who had rapid clinical deterioration with liver, cardio-respiratory, and renal dysfunction associated with coagulopathy and rapidly evolution to death. This report may contribute to a better clinical and laboratory characterization of this rare paraneoplastic manifestation in patients with multiple myeloma.</p></sec><sec><label>2</label><title>Case report</title><p>A 64-year-old Brazilian man was admitted to the emergency department of our institution in April 2019 claiming fatigue, malaise, intermittent fever, and weight loss. In the first physical exam he presented hypotension and mental confusion. Three months before he began with progressive prostration, unintentional weight loss of 15&#x0200a;kg, intermittent fever, and night sweats. He was evaluated at an external hematology clinic 2 weeks before to come at our service and was diagnosed with multiple myeloma based on laboratory tests and bone marrow biopsy.</p><p>At initial physical examination, he had a temperature of 36.3&#x0200a;&#x000b0;C, a pulse of 81 beats per minute, a respiratory rate of 16 incursions per minute, a peripheral oxygen saturation of 94% in ambient air, a blood pressure of 86/51&#x0200a;mmHg, and a slower peripheral perfusion (4&#x0200a;seconds). He had significant skin-mucous pallor, jaundice 2+/4+, lowered level of consciousness (Glasgow 14), mental confusion, and flapping in the upper extremities. The rest of the physical examination showed no other significant changes.</p><p>Initial laboratory evaluation revealed: hemoglobin (Hb) 9.7&#x0200a;g/L, hematocrit (Ht) 28.2%, mean corpuscular volume (MCV) 82.7 fl, white blood count (WBC) 3.02&#x0200a;&#x000d7;&#x0200a;10⁹/L, neutrophils: 2.3&#x0200a;&#x000d7;&#x0200a;10⁹/L, lymphocytes: 0.5&#x0200a;&#x000d7;&#x0200a;10⁹/L, platelets: 39&#x0200a;&#x000d7;&#x0200a;10⁹/L, Na++ 127&#x0200a;mEq/L, K+ 4.3&#x0200a;mEq/L, total Ca++ 9.3&#x0200a;mg/L, P 3.1&#x0200a;mg/L, creatinine 1.84&#x0200a;mg/dL, BUN 122&#x0200a;mg/dL, lactate dehydrogenase (LDH) 648&#x0200a;U/L, and C-protein reactive (CPR) 58.1&#x0200a;mg/L. Hepatic profile showed alanine aminotransferase (ALT) 258&#x0200a;U/L, aspartate aminotransferase (AST) 213&#x0200a;U/L, alkaline phosphatase 386&#x0200a;U/L, gamma GT 473&#x0200a;U/L, total bilirubin: 2.95&#x0200a;mg dL (direct bilirubin [DB]: 2.29&#x0200a;/indirect bilirubin [IB]: 0.66), albumin 2.4&#x0200a;g/dL, prothrombin time/international normalized ratio (PT/INR): 1.27, and activated partial thromboplastin time (aPTT) ratio&#x0200a;=&#x0200a;1.23. Laboratory evolution throughout hospitalization is summarized in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Laboratory evolution during hospitalization.</p></caption><graphic xlink:href=\"medi-99-e22299-g001\"/></table-wrap><p>In the emergency department, peripheral blood and urine cultures were collected and intravenous saline fluid and ceftriaxone was administered for treatment of supposed infectious etiologies. After initial measurements, blood pressure was normalized and the patient was stabilized. In his previous medical history, he had systemic arterial hypertension, congestive heart failure, and chronic renal failure caused by recurrent nephrolithiasis. He used carvedilol 25&#x0200a;mg twice daily, spironolactone 25&#x0200a;mg once daily, ivabradine 5&#x0200a;mg twice daily, AAS 100&#x0200a;mg daily, and rosuvastatin 10&#x0200a;mg daily.</p><p>The patient had external laboratory tests showing 0.8&#x0200a;g/dL of monoclonal protein, IgA kappa paraprotein at serum immunofixation, serum IgA of 1038&#x0200a;mg/dL (70&#x02013;400&#x0200a;mg/dL), and &#x003b2;2 microglobulin of 20.61&#x0200a;mg/L (0.8&#x02013;2.2&#x0200a;mg/L). Bone marrow biopsy was hypercellular with monoclonal plasma cell proliferation CD56 (+), kappa light chain restriction, representing 30% of the total nucleated cells. A diagnosis of multiple myeloma (MM) Durie Salmon IIIA, ISS III was established in this moment.</p><p>Chest, abdomen, and pelvic computerized tomography (CT) revealed multiple lymphadenopathies up to 5.0&#x0200a;cm and splenomegaly. Positron emission CT with 18-fluoro deoxyglucose (18-FDG-PETCT) showed multiple lymphadenopathies in the neck, chest, abdomen, and pelvis with SUVmax 12.0, liver FDG uptake 15.8 (SUVmax), and 16.4&#x0200a;cm splenomegaly with 15.8 spleen FDG uptake (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). Echocardiography was negative for endocarditis.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Enhanced 18-FDG uptake in cervical, retroperitoneal lymph nodes, spleen, and liver (SUV max 15.8 in spleen /liver). 18-FDG&#x0200a;=&#x0200a;18-fluordeoxyglucose; SUV&#x0200a;=&#x0200a;standardized uptake value.</p></caption><graphic xlink:href=\"medi-99-e22299-g002\"/></fig><p>There was negativity for viral hepatitis B and C serology as well as for HIV, HTLV1, chickenpox, toxoplasmosis, herpes, cytomegalovirus, adenovirus, Epstein-Barr virus, parvovirus B19, enterovirus, paraecovirus, and <italic>Mycobacterium tuberculosis.</italic> Blood cultures were negative. As the patient persisted with fever, ceftriaxone introduced at admission was replaced by Piperacillin/Tazobactam and Teicoplanin. However, the patient evolved quickly with multiorgan dysfunction characterized by liver and renal failure, LDH increase, and coagulopathy characterized by prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen, and factor V reduction keeping factor VIII level between the normal range values (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>).</p><p>As the clinician suspected of concurrent HLH further tests showed serum ferritin level of 47.502&#x0200a;ng/mL (30&#x02013;400&#x0200a;ng/mL) and slight elevation of triglycerides. A new bone marrow aspiration confirmed the presence of 21.6% of aberrant plasma cells with significant macrophage activity with several haemophagocytosis pictures (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>). Immunophenotyping demonstrated 4.9% of anomalous and monoclonal plasma cells expressing CD45^dim, CD19^partial, CD38^bright, CD138^bright, CD56^dim, CD117^dim, and kappa light chain restriction in cytoplasm. Thereafter, the patient was immediately transferred to the intensive care unit and pulse therapy with methylprednisolone 1&#x0200a;g/d for 3 days was administered to control HLH. Afterwards the patient received cyclophosphamide at dose of 500&#x0200a;mg once weekly and dexamethasone 20&#x0200a;mg once daily D1&#x02013;D4 as anti-multiple myeloma treatment. We were not able to investigate lymphadenopathy because the patient became soon hemodynamically unstable, requiring mechanical ventilation support and renal replacement therapy with hemodialysis. Unfortunately, the patient died 15 days after hospitalization.</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Bone marrow aspirate (40&#x000d7; optic microscopy)&#x02014;anomalous plasma cell proliferation is observed, with the presence of bi- and trinucleated forms and intense macrophage activity with eritrophagocytosis pictures.</p></caption><graphic xlink:href=\"medi-99-e22299-g003\"/></fig></sec><sec><label>3</label><title>Discussion</title><p>Herein we report an uncommon clinical case of MM that present an early and unusual complication characterized by hemophagocytic lymphohistiocytosis. Until now only 6 cases have been described at literature.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R10\" ref-type=\"bibr\">10</xref>,<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} In our service among 1206 MM cases that we have seem in the last 25 years only this case presented HLH as initial manifestation. The patient's relatives provided an informed consent for publication, because he died rapidly after the hospitalization in our service.</p><p>In fact, in the clinical practice the HLH diagnosis is usually a challenge because it clinical findings may overcome with a lot of differential diagnoses, as well its laboratory features are far from unspecific. Although secondary HLH has become a medical concern in recent decades, its diagnostic criteria is still based on pediatric studies. However, the HLH 2004 trial included patients above and below aged of 18-year-old seeking for appropriate therapeutic approaches. The HLH was established based in both molecular data and clinical-laboratory features. For HLH diagnosis at least 5 of 8 signals and symptoms must be presented by patients: fever, splenomegaly, cytopenias at least 2 lineages in peripheral blood (Hb&#x0200a;&#x0003c;&#x0200a;10.0&#x0200a;g/dL, neutrophils&#x0200a;&#x0003c;&#x0200a;1.0&#x0200a;&#x000d7;&#x0200a;10⁹/L, and/or platelets&#x0200a;&#x0003c;&#x0200a;100&#x0200a;&#x000d7;&#x0200a;10⁹/L), hypertriglyceridemia (&#x0003e;3.0&#x0200a;mmol/L) or hypofibrinogenemia (&#x0003c;1.5&#x0200a;g/L), hemophagocytosis pictures in bone marrow, spleen or lymph node, lacking or low NK-cell activity, hyperferritinemia (&#x0003e;500&#x0200a;mg/L), and soluble CD25 (soluble IL-2 receptor) &#x0003e;2400&#x0200a;U/mL.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} Regardless of differences in pathophysiology, etiology, and prevalence of signals and symptoms, the diagnostic criteria proposed in this study are used for diagnosis of HLH in adults and for secondary HLH. Additionally, demonstration of low/lack NK-cell activity and soluble CD25 levels represent a barrier to the diagnosis of HLH and do not add important information in daily clinical practice. In addition, these tests are usually reserved in the setting of research and are not widely available.</p><p>Thereafter, on the other hand, it is important to emphasize the differences between HLH manifestations in children and adults. Nikiforow and Berliner^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} has reported that in adults the most prevalent signals are not included in the most used diagnostic criteria for HLH such as the elevation of transaminases that occur in 84% of patients, as well hypoalbuminemia in 92%, high level of LDH in 93%, and acute renal failure in 52%. Fulminant hepatitis followed by acute liver failure like that presented by our patient may be part of this syndrome and has been also reported for other authors.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>&#x02013;<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]}</p><p>Nikiforow and Berliner^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} also highlight the poor correlation between reduced/lack of NK function and secondary HLH, as well as the lack of specificity of ferritin level above 10,000&#x0200a;ng/mL in adults with HLH (60% for adults VS 86&#x02013;96% for children). Similarly, Schram et al^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} retrospectively identified 113 adults with ferritin levels above 50,000&#x0200a;ng/mL in which only 19% met diagnostic criteria for HLH. They concluded that hyperferritinemia was not able to predict HLH diagnosis in this population.</p><p>In our case, the patient met at least 6 of 8 HLH criteria according to 2004 HLH trial. However, we were not able measure the NK cell activity neither the level of soluble CD25. In addition, the patient also showed increment of serum transaminases and LDH, hypoalbuminemia, and acute renal failure suggesting the relevance of other laboratory abnormalities for the diagnosis of this life-threatening syndrome.</p><p>Regarding malignancy-associated HLH therapy, there is no standard approach in the medical literature and only rare cases have been prospectively analyzed. Thus, management in this scenario is considered an extrapolation of experience from pediatric patients. In our patient, in addition to antibiotics and clinical support, the patient received corticosteroids to control the hyperinflammatory state and cytokine storm. Unfortunately, he was not exposed to other HLH-targeted therapies as he showed rapid clinical deterioration and progressed to multiple organ dysfunction.</p><p>Previous case reports of HLH associated with multiple myeloma are quite rare in the literature and difficult to interpret given their heterogeneity and the presence of other concomitant illness. The patients described so far have different MM status such as at diagnosis period, after autologous hematopoietic stem cell transplantation and in the setting of relapsed/refractory disease. Thereafter, different triggers for HLH have been considered related to MM activity or with ASCT. In addition, various therapies for HLH have been used such as steroids alone, steroids plus immunoglobulin, cyclosporine, etoposide, and multidrug therapy for myeloma, including DRV-PACE regimen (dexamethasone, bortezomib, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide) and DVP-PACE (dexamethasone, bortezomibe, pomalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide).^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R10\" ref-type=\"bibr\">10</xref>,<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]}</p><p>Unlike other cases that have been reported until now, we performed 18-FDG-PET-CT in our patient, and we found FDG uptake in enlarged lymph nodes, spleen, and liver. Unfortunately, we could not perform lymph node biopsy for histopathological analysis due to the patient's rapid clinical deterioration as described above. However, we have supposed that 18-FDG-PET-CT findings may be explained by the macrophage hyperactivation seemed in the reticuloendothelial system organ. Yuan et al^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} conducted a retrospective study in patients with secondary HLH aiming to evaluate the accuracy of 18-FDG-PET-CT to identify the HLH etiology. The authors have concluded that 18-FDG-PET-CT alone are not enough to discriminate the differential diagnosis between infection and neoplastic cause of HLH. Kim et al^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} also demonstrated that hypermetabolic activity in the spleen, bone marrow, and multiple lymph nodes may also occur in non-neoplastic HLH probably because the FDG should have been up taken by activated immune cells such as macrophages, histiocytes, and T lymphocytes. The only study with a positive correlation between SUV level and underlying cause of secondary HLH was performed by Wang et al.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} They showed that lymphoma-associated HLH had higher SUVmax in the spleen, liver, lymph nodes, and bone marrow. Nevertheless, the authors did not include other kind of malignancies in this study.</p></sec><sec><label>4</label><title>Conclusion</title><p>In conclusion, HLH should be considered in a context of malignancy including multiple myeloma, particularly in patients with significant pro-inflammatory status and rapid clinical worsening concomitant at multiorgan dysfunction. The suspicion and the diagnosis of HLH must be done early and a specific therapy should be promptly started to control the malignancy disease and to interrupting the patient's evolution into a fatal outcome.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Juliana Pereira, Lu&#x000ed;s Alberto de P&#x000e1;dua Covas Lage.</p><p><bold>Data curation:</bold> Fernanda Rodrigues Mendes, Karine Marques Sobral.</p><p><bold>Formal analysis:</bold> Hebert Fabricio Culler, Samuel Campanelli Freitas Couto, Gracia Aparecida Martinez.</p><p><bold>Funding acquisition:</bold> Juliana Pereira, Lu&#x000ed;s Alberto de P&#x000e1;dua Covas Lage.</p><p><bold>Investigation:</bold> Fernanda Rodrigues Mendes, Karine Marques Sobral.</p><p><bold>Methodology:</bold> Gracia Aparecida Martinez, Juliana Pereira, Lu&#x000ed;s Alberto de P&#x000e1;dua Covas Lage.</p><p><bold>Project administration:</bold> Vanderson Rocha, Juliana Pereira, Lu&#x000ed;s Alberto de P&#x000e1;dua Covas Lage.</p><p><bold>Resources:</bold> Fernanda Rodrigues Mendes, Karine Marques Sobral.</p><p><bold>Supervision:</bold> Gracia Aparecida Martinez, Juliana Pereira, Lu&#x000ed;s Alberto de P&#x000e1;dua Covas Lage.</p><p><bold>Validation:</bold> Vanderson Rocha, Juliana Pereira, Lu&#x000ed;s Alberto de P&#x000e1;dua Covas Lage.</p><p><bold>Writing &#x02013; original draft:</bold> Fernanda Rodrigues Mendes, Karine Marques Sobral.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Gracia Aparecida Martinez, Vanderson Rocha, Juliana Pereira, Lu&#x000ed;s Alberto de P&#x000e1;dua Covas Lage.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: 18-FDG-PETCT = 18-fluordeoxyglucose positron emission tomography, ALT = alanine aminotransferase, aPTT = activated partial thromboplastin time, ASCT = autologous stem cell transplantation, AST = aspartate aminotransferase, CPR = C-protein reactive, CT = computerized tomography, DB = direct bilirubin, DRV-PACE = dexamethasone, bortezomib, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide, DVP-PACE = dexamethasone, bortezomibe, pomalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide, Hb = hemoglobin, HIV = human immunodeficiency virus, HLH = hemophagocytic lymphohistiocytosis, HPS = hemophagocytic syndrome, Ht = hematocrit, HTLV-1 = human T-cell lymphotropic virus type 1, IB = indirect bilirubin, INR = international normalized ratio, LDH = lactate dehydrogenase, MCV = mean corpuscular volume, MM = multiple myeloma, NK = natural killer, PFR-1 = perforin receptor 1 gene, PT = prothrombin time, SEER = Surveillance, Epidemiology and End Results Program, STX11 = syntaxin 11 gene, SUV = standardized uptake value, TNF-alpha = tumor necrosis factor alpha, UNC13D = protein unc-13 homolog D, WBC = white blood count.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Mendes FR, Sobral K, Culler HF, Couto SC, Pereira J, Rocha V, Martinez GA, Lage LA. Acquired hemophagocytic lymphohistiocytosis as initial manifestation of multiple myeloma: A case report and literature review. <italic>Medicine</italic>. 2020;99:39(e22299).</p></fn><fn fn-type=\"financial-disclosure\"><p>Funding: Not applicable.</p></fn><fn fn-type=\"other\"><p>The patient's relatives provided an informed consent to publish this case because the patient died rapidly after hospitalization in our service.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article [and its supplementary information files].</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991455</article-id><article-id pub-id-type=\"pmc\">PMC7523831</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-00446</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022365</article-id><article-id pub-id-type=\"art-access-id\">22365</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>4600</subject></subj-group><subj-group><subject>Research Article</subject><subject>Systematic Review and Meta-Analysis</subject></subj-group></article-categories><title-group><article-title>Acupuncture for mild cognitive impairment in elderly people</article-title><subtitle>Systematic review and meta-analyses</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0003-3267-3085</contrib-id><name><surname>Li</surname><given-names>Weitong</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Qing</given-names></name><degrees>MS, RN</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Du</surname><given-names>Shizheng</given-names></name><degrees>RN</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Pu</surname><given-names>Yalou</given-names></name><degrees>MS, RN</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Xu</surname><given-names>Guihua</given-names></name><degrees>MD, RN</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Roever.</surname><given-names>Leonardo</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>School of Nursing, Nanjing University of Chinese Medicine</aff><aff id=\"aff2\"><label>b</label>Nursing Department, Jiangsu Cancer Hospital, Nanjing, Jiangsu, PR China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Guihua Xu, School of Nursing, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia District, Nanjing, Jiangsu Province, China (e-mail: <email>xgh_88@126.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22365</elocation-id><history><date date-type=\"received\"><day>16</day><month>1</month><year>2020</year></date><date date-type=\"rev-recd\"><day>6</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>25</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22365.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Acupuncture has an unique role in preventing and managing mild cognitive impairment (MCI) in nonpharmaceutical therapies because of its small wound, mild pain, and high security for many years. However, there is no systematic review evaluating safety and efficacy of acupuncture for MCI in elderly people. Therefore, this study will provide a protocol to explore the effectiveness and safety of acupuncture for MCI in the elderly.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>Retrieval from 8 electronic databases was conducted to determine eligible trials published until May, 2019. Homogeneity qualified studies were included for data were extracted such as study country location, demographic characteristics, and measure outcomes, and were analyzed by a random effect model and sensitivity analyses to identify heterogeneity. Review Manager (Revman Version 5.3) software will be used for data synthesis, sensitivity analysis, meta regression, subgroup analysis, and risk of bias assessment. A funnel plot will be developed to evaluate reporting bias.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>A total of 15 randomized control trials involving 1051 subjects were included. The results were as follows: Compared with the control group, the clinical efficacy rates of acupuncture was better, odds ratio&#x0200a;=&#x0200a;2.52, 95% confidence interval (CI) (1.86, 3.42), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, mini-mental state examination scores (mean difference [MD]&#x0200a;=&#x0200a;1.53, 95% CI [1.04, 2.01], <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001), Montreal cognitive assessment scores (MD&#x0200a;=&#x0200a;2.05, 95% CI [1.17, 1.92], <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001), activity of daily living scale (MD&#x0200a;=&#x0200a;1.71, 95% CI [&#x02013;1.38, 4.79], <italic>P</italic>&#x0200a;&#x0003e;&#x0200a;.05), and clock drawing task scores (MD&#x0200a;=&#x0200a;1.91, 95% CI [1.74, 2.08], <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001).</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>This study shows that acupuncture is beneficial for improving aspects of cognitive function in elderly people with MCI, which suggests that acupuncture may be an effective alternative and complementary approach to existing therapies for elderly people. More rigorous experimental studies and longer follow-up studies should be conducted in the future.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>acupuncture</kwd><kwd>meta-analysis</kwd><kwd>mild cognitive impairment</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>National Natural Science Foundation of China</funding-source><award-id>71573140</award-id><principal-award-recipient>Guihua Xu</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Postgraduate Research &#x00026;amp; Practice Innovation Program of Jiangsu Province</funding-source><award-id>KYCX19_1216</award-id><principal-award-recipient>Weitong Li</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Mild cognitive impairment (MCI) is an intermediary state between normal aging and clinical Alzheimer disease (AD). The elderly people with MCI are at increased risk for conversion to clinical AD.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} People with MCI have significant impairment in all 5 cognitive domains, namely, speed/attention, memory and learning, visual spatial function, language and executive function.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} Approximately 5% to 10% of the cases with MCI will evolve into dementia per year.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>&#x02013;<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} A Canadian study demonstrated that almost half of people with MCI will progress to fulfill the diagnostic criteria of dementia in 5 years.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Early intervention and treatment in the MCI state can reduce the incidence of AD and delay or prevent the development of the disease.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} Once MCI develops into AD, severe cognitive decline will have a huge impact on people&#x02019; daily lives and their family.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} No approaches have been developed specifically to prevent and treat MCI. There are ongoing randomized control trial (RCT) studies but acetilcholinesterasis inhibitors are not approved for MCI. Long-term use of drugs may cause nausea, vomiting, bradycardia, increased gastric acid secretion, and even worsen cognitive impairment and adverse reactions. More and more other effective measures have been given attention.</p><p>In recent years, the &#x0201c;Chinese guidelines for the diagnosis and treatment of dementia and Cognitive Disorder 2015&#x0201d;^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} suggested a strategy for the prevention and treatment of MCI involving reducing the conversion rate from MCI to AD. A number of basic and clinical studies have provided evidence that acupuncture is beneficial for the treatment of dementia or MCI.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>&#x02013;<xref rid=\"R19\" ref-type=\"bibr\">19</xref>,<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} The forms of acupuncture include simple acupuncture,^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>&#x02013;<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} acupuncture combined with western medicine,^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} acupuncture combined with cognitive function training,^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>&#x02013;<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} acupuncture combined with moxibustion,^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} acupoint embedding, auricular compression combined with herbs^{[<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} and acupoint stimulation.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} Acupuncture has an unique role in preventing and managing MCI in nonpharmaceutical therapies because of its small wound, mild pain, and high security for many years. Several systematic reviews and meta-analyses have been published to discuss the role of acupuncture in treating MCI.^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>&#x02013;<xref rid=\"R37\" ref-type=\"bibr\">37</xref>]} However, in the existing meta-analyses, there was no systematic review or meta-analyses has been performed to evaluate the effectiveness of acupuncture specifically for elderly people, most samples in the RCTs included people under 60 years of age. These previous studies were typically meta-analyzed at final time points, paying no attention to all time points of repeated measures. The original study of systematic evaluation had a relatively large age range and was not analyzed and compared specifically for the elderly. Compared with previous systematic reviews, this study has added the literature that has been updated in recent years. Therefore, this study planned to conduct a systematic review and meta-analyses to evaluate the evidence from all available RCTs that evaluate acupuncture on MCI in elderly people, which could provide constructive guidance for clinical medical staff.</p><p>The structure of the whole article consisted of 5 parts, including Introduction, Methods, Results, Discussion, and Conclusion. In the results section, this study analyzed the efficacy of acupuncture in the 5 major aspects of Clinical efficacy rates, mini-mental state examination (MMSE) scale score, Montreal cognitive assessment (MoCA) test score, activity of daily living scale (ADL) scale score and clock drawing task (CDT), and conducted subgroup analysis based on different course of treatment. This study summarized results and innovations in the discussion and conclusion section.</p></sec><sec><label>2</label><title>Methods</title><p>This systematic review and meta-analysis has been reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. The trial registration number is as follows: PROSPERO registration no. CRD42019120033. All analyses were based on previous published studies, thus no ethical approval and patient consent are required.</p><sec><label>2.1</label><title>Selection strategy</title><p>This study searched the following electronic databases to identify eligible trials published from inception to May 1, 2019: including PubMed, Web of science, Cochrane Library, EMBASE, CBM, Chinese National Knowledge Infrastructure Database, VIP Database, and Wanfang Database. This study used the following medical subject heading terms and text words when searching: (acupuncture OR meridian OR acupuncture treatment OR acupuncture therapy OR acupuncture points OR electroacupuncture OR ear acupuncture OR fire needle OR bee needle) AND (mild cognitive impairment OR MCI OR cognitive dissonance OR delirium OR dementia OR amnestic OR cognitive disorders) AND (elderly OR old people OR older people OR aged OR old population) AND (randomized controlled trial OR &#x0201c;random^&#x02217;&#x0201d; OR &#x0201c;alloc^&#x02217;&#x0201d; OR &#x0201c;assign^&#x02217;&#x0201d;). Accordingly, this was the search strategy used in the 8 databases.</p></sec><sec><label>2.2</label><title>Study selection</title><p>The inclusion criteria were as follows:</p><p>This study included MCI elderly people who were clearly diagnosed by domestically and internationally recognized criteria, diagnostic criteria included:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>Diagnostic criteria for MCI in the American Psychiatric Manual of Psychiatry and Statistics, 4th Edition (DSM-IV)^{[<xref rid=\"R38\" ref-type=\"bibr\">38</xref>]};</p></list-item><list-item><label>(2)</label><p>MCI Clinical Diagnostic Standards revised by Petersen et al 2001^{[<xref rid=\"R39\" ref-type=\"bibr\">39</xref>]};</p></list-item><list-item><label>(3)</label><p>MCI Clinical Diagnostic Standards revised by Petersen et al 1999^{[<xref rid=\"R40\" ref-type=\"bibr\">40</xref>]};</p></list-item><list-item><label>(4)</label><p>The Reference Standard of Deficiency Syndrome Differentiation in traditional Chinese Medicine^{[<xref rid=\"R41\" ref-type=\"bibr\">41</xref>]};</p></list-item><list-item><label>(5)</label><p>The 2006 Chinese expert consensus on cognitive dysfunction^{[<xref rid=\"R42\" ref-type=\"bibr\">42</xref>]};</p></list-item></list><p>Furthermore, these studies should meet the following inclusion criteria (PICO format).</p><p><bold>P</bold> (population): Studies that examined elderly people suffering from MCI which caused by nonorganic diseases. This study included the studies that focused on elderly participants. According to the World Health Organization, the elderly population is referred to as 60+ years old (World Health Organization).</p><p><bold>I</bold> (intervention): People in the treatment group must have received acupuncture therapy, either is used alone or in combination with other therapies. In acupuncture therapy, acupoints can be head points, ear points, experience points or points outside the meridian; Acupuncture methods can be traditional acupuncture needle or electroacupuncture. However, acupuncture therapy does not include other acupuncture methods, such as finger massage acupoints, laser acupuncture, magnetic pole acupuncture, and acupoint injection. The specifications of needle and electroacupuncture instruments are not limited to manufacturers because there is no international standard at present. Moreover, acupuncture can be combined with other therapies (such as basic treatment, medication, and cognitive training therapy), and acupuncture techniques and points do not distinguish. Acupuncture can be combined with the same basic therapy as that of the control group simultaneously.</p><p><bold>C</bold> (comparison): The control group needed to have received drug therapy (Donepezil/Nimodipine/Yinao capsule/Duxil/Oxiracetam Injection) and psychological intervention (cognitive training).</p><p><bold>O</bold> (outcome): The outcome measurements needed to include at least 1 authority scale of cognitive assessment such as the MoCA, MMSE, CDT, ADL, considering the heterogeneity of outcomes, 15 RCTs used different outcome indicators to analyze the validity of acupuncture, this study excluded the literature of self-designed outcome indicators. Finally, this study chose 5 indicators as the main outcome indicators which included the clinical efficacy rates, the MoCA, MMSE, CDT, ADL. This study also included grey literature in the evaluation in the form of 3 degree papers.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>&#x02013;<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]} There are no restrictions on the language or type of publication.</p><p>The exclusion criteria are as follows:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>no control group or multiple control groups;</p></list-item><list-item><label>(2)</label><p>nonclinical trials (reviews, case and repeated reports, expert experience reports, meeting notices, and nonrelated contributions to research);</p></list-item><list-item><label>(3)</label><p>animal experiments;</p></list-item><list-item><label>(4)</label><p>literature on treatment mechanisms;</p></list-item><list-item><label>(5)</label><p>literature on acupuncture was also included in the basic treatment of the control group;</p></list-item><list-item><label>(6)</label><p>self-control trials;</p></list-item><list-item><label>(7)</label><p>self-designed curative effect index;</p></list-item><list-item><label>(8)</label><p>documents in which articles or data were published repeatedly.</p></list-item></list></sec><sec><label>2.3</label><title>Data extraction</title><p>The details of included trials were extracted independently by 2 authors (LWT and WQ) using a standard data extraction form, which included the following items:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>the basic characteristics of the included trials: title, authors, publication year, literature sources, country where the trial was conducted, publication language, sample size, diagnosis standard, study design, interventions, controls, treatment duration, and adverse events; and</p></list-item><list-item><label>(2)</label><p>the basic characteristics of the included subjects: age, gender, intervention, course of treatment, diagnostic criteria, inclusion criteria, exclusion criteria, outcome measures.</p></list-item></list><p>During this process, any disagreements between the 2 reviewers were resolved through consensus, and the discrepancy was resolved by discussion or judged by the third author (DSZ).</p></sec><sec><label>2.4</label><title>Quality assessment</title><p>The quality of the selected studies was assessed using the RCT-quality criteria recommended in the Cochran intervention system Review Manual, 5.1.0 (Higgins and Green 2011).^{[<xref rid=\"R43\" ref-type=\"bibr\">43</xref>]} These criteria include 6 items on sequence generation, allocation concealment, blind, incomplete data results, selective result reporting, and other biases (baseline imbalances, early discontinuities, and sources of funding). Each project was rated as a &#x0201c;low deviation risk,&#x0201d; &#x0201c;unclear deviation risk&#x0201d; or &#x0201c;high deviation risk&#x0201d; and treated as level &#x0201c;A, B, and C.&#x0201d;^{[<xref rid=\"R43\" ref-type=\"bibr\">43</xref>]} Because acupuncture treatment is unlikely to be double blind, this study concluded that single-blind outcome evaluators were &#x0201c;consistent&#x0201d; with blinding. In general, this study considered randomization, distributive concealment, blind, incomplete data results, selective outcome reporting, and trials of other potential sources of bias. If the content of the study is insufficient to determine the risk of bias, the author of the study should be contacted for further information.</p></sec><sec><label>2.5</label><title>Data synthesis and statistical analysis</title><p>RevManV.5.3 (Cochrane Collaboration) was the tool of statistical analysis. The effect estimates for the dichotomous data were presented as odds ratios (ORs) with their 95% confidence intervals (CIs), and the continuous data were presented as the mean differences (MDs) and their 95% CIs. In each meta-analyses, the standard <italic>&#x003c7;</italic>² statistics and <italic>I</italic>² test were used to measure the statistical heterogeneity (Higgins and Green, 2011).^{[<xref rid=\"R44\" ref-type=\"bibr\">44</xref>]} A fixed-effect model was adopted if no significant heterogeneity existed (<italic>I</italic>²&#x0200a;&#x0003c;&#x0200a;50%); a random-effect model was adopted if significant heterogeneity existed. Publication bias was assessed through funnel plots. Subgroup analysis were performed if the primary outcome demonstrated statistically significant differences between the 2 groups.</p></sec></sec><sec><label>3</label><title>Results</title><sec><label>3.1</label><title>Search process</title><p>The results of the search process are shown in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>. A total of 1184 articles of potential relevance were retrieved from 8 databases, of which 615 were duplicates. After a preliminary screening of the titles and abstracts, 441 studies were excluded for the following reasons: 289 were unrelated articles, 73 were reviews, 10 were case studies, 48 were animal experiments, 4 were mechanism studies, 6 were meta-analyses, 9 were conference papers and 2 were patents. Overall, 128 RCTs were obtained for a full-text assessment. These retrieved articles were subsequently evaluated by deep reading. Finally, 15 studies^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>&#x02013;<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} were ultimately included in the qualitative synthesis and meta-analyses.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flow chart of trial selection process.</p></caption><graphic xlink:href=\"medi-99-e22365-g001\"/></fig></sec><sec><label>3.2</label><title>Methodological quality assessment</title><p>The risk of bias assessment of each included trial is summarized in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>, the risk of bias graph is shown in Figure <xref ref-type=\"fig\" rid=\"F2\">2</xref>, and the risk of bias summary is shown in Figure <xref ref-type=\"fig\" rid=\"F3\">3</xref>. Based on the Cochrane manual, the quality is divided. RCT was divided into 3 levels (A, B, and C). &#x0201c;A&#x0201d; means that all or most of the 6 criteria were met, which represents a low risk bias. For candidate RCTs, if 1 or more criteria partially meet the B rating, it represents an unclear risk bias. However, if 1 or more criteria are insufficient, &#x0201c;C&#x0201d; is the high risk of bias level. The outcomes of methodological quality of all included studies are listed in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Quality scores of trials included in this review.</p></caption><graphic xlink:href=\"medi-99-e22365-g002\"/></table-wrap><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Risk of bias graph of included trials.</p></caption><graphic xlink:href=\"medi-99-e22365-g003\"/></fig><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Risk of bias summary of included trials.</p></caption><graphic xlink:href=\"medi-99-e22365-g004\"/></fig><p>Fifteen RCTs^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>&#x02013;<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} were considered to be eligible for analysis. The information concerning their characteristics is summarized in Table <xref rid=\"T2\" ref-type=\"table\">2</xref>. Because the concept of MCI was put forward later, and its connotation has been revised,^{[<xref rid=\"R45\" ref-type=\"bibr\">45</xref>]} there are relatively few studies on MCI, and its diagnosis has not yet arrived at a standard. Thus, this study excluded the studies that have developed their own criteria for inclusion and exclusion and studies in which the diagnostic criteria met the 6 criteria mentioned in the first half of this article. Generally, the 15 included RCTs were published between 2009 and 2016. The total number of MCI elderly participants was 1051, with 530 people allocated to the acupuncture group (experimental group) and 521 people allocated to receive a conventional treatment (control group), which included western medicine alone (eg, 1 trial^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]} directly compared acupuncture with Nimodipine, 3 trials^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>&#x02013;<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} compared acupuncture with Donepezil). Eight trials examined the role of acupuncture as an adjunct to Nimodipine,^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} Duxil,^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} Oxiracetam Injection,^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} and the traditional Chinese medicine Yinao capsule alone,^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} where the people in both groups received medical therapy and were randomized to receive additional acupuncture or not. Two trials^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} set cognitive training as a control group, while the experimental group was a combination of acupuncture and cognitive training. The number of participants in each experimental group of study varied from 9 to 80. In these 15 studies, the course of treatment time ranged from 30 days to 3 months, this study categorized these durations as short-term (up to 1 month), medium-term (2 months) or long-term (3 months); each treatment session lasted 30&#x0200a;minutes. Overall, 15 RCTs treated GV 20, EX-HN 1, ST 2, GB 20, GB12, BL 10, HT 7, PC 6, GV 26, SP 6, LR 3, ST 40 as the main acupoints. The outcome measures included the clinical efficacy rate, MoCA, MMSE, CDT, ADL, gobal deterioration scale, clinical dementia rating scale, clinical memory scale, event-related potential-P300, revised Hasegawa dementia scale, modified Barthel and scale for the differentiation of syndromes in vascular dementia and memory quotient. The clinical efficacy rate of all studies was consistent.</p><table-wrap id=\"T2\" orientation=\"portrait\" position=\"float\"><label>Table 2</label><caption><p>Characteristics of the included studies.</p></caption><graphic xlink:href=\"medi-99-e22365-g005\"/></table-wrap></sec><sec><label>3.3</label><title>Clinical efficacy rates</title><p>This analysis included 12 articles, which included the outcome indicators of the clinical efficacy rates. According to different forms of acupuncture (acupuncture + pharmacotherapy, acupuncture + training therapy, acupuncture), this study made a subgroup analysis. According to Figure <xref ref-type=\"fig\" rid=\"F4\">4</xref>, the clinical efficacy rates was significantly improved in the treatment group (OR&#x0200a;=&#x0200a;2.52, 95% CI [1.86, 3.42], <italic>Z</italic>&#x0200a;=&#x0200a;5.96, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.0001), competed with the control group of 12 studies (n&#x0200a;=&#x0200a;256) with low heterogeneity (<italic>I</italic>²&#x0200a;=&#x0200a;0%). The result showed that acupuncture combined with pharmacotherapy or acupuncture treatment alone have better efficacy on elderly people with MCI, but the effect of acupuncture combined with training therapy is not significant (OR&#x0200a;=&#x0200a;1.98, 95% CI [0.90, 4.35]), <italic>Z</italic>&#x0200a;=&#x0200a;1.69, <italic>P</italic>&#x0200a;=&#x0200a;.09). This not only showed that acupuncture has a therapeutic effect on MCI in elderly people, but also acupuncture can better promote the absorption of drugs, making the curative effect more significant.</p><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>Forest plot of comparisons by different forms of acupuncture versus routine treatment for the outcome of the clinical efficacy rates.</p></caption><graphic xlink:href=\"medi-99-e22365-g006\"/></fig></sec><sec><label>3.4</label><title>MMSE scale score</title><p>Eight studies involving 281 participants in the treatment group and 279 in the control group assessed the MMSE scale score. According to Figure <xref ref-type=\"fig\" rid=\"F5\">5</xref>, the data heterogeneity test <italic>I</italic>²&#x0200a;=&#x0200a;63%, when <italic>I</italic>²&#x0200a;&#x0003e;&#x0200a;25% and 50% showed moderate heterogeneity, and <italic>I</italic>²&#x0200a;&#x02264;&#x0200a;70% could still be used for the meta-analyses; thus, this study did the sensitivity analysis, the forest plot showed that the <italic>I</italic>² dropped from 63% to 0%, and the article that this study removed in the sensitivity analysis had repeated interventions compared with the other RCTs, this study could not eliminate this article in the end, so the random effects model was used. The results of the meta-analyses showed that acupuncture therapy could improved the MMSE scores compared with the control group (MD&#x0200a;=&#x0200a;1.53, 95% CI [1.04, 2.01], <italic>Z</italic>&#x0200a;=&#x0200a;6.14, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.0001).</p><fig id=\"F5\" orientation=\"portrait\" position=\"float\"><label>Figure 5</label><caption><p>Forest plot of comparison of acupuncture versus routine treatment for the outcome of the MMSE scale score. MMSE = mini-mental state examination.</p></caption><graphic xlink:href=\"medi-99-e22365-g007\"/></fig></sec><sec><label>3.5</label><title>MoCA test score</title><p>The MoCA test score was almost the same in the treatment group (MD&#x0200a;=&#x0200a;1.96, 95% CI [0.94, 2.97], <italic>P</italic>&#x0200a;=&#x0200a;.0002), compared with people who did not have the acupuncture therapy of 7 studies (n&#x0200a;=&#x0200a;415) with high heterogeneity (<italic>I</italic>²&#x0200a;=&#x0200a;69%). When this study used a fixed-effect model, heterogeneity (<italic>I</italic>²&#x0200a;=&#x0200a;69%). Given <italic>I</italic>²&#x0200a;&#x0003e;&#x0200a;50%, this study employed the randomized-effect model and the <italic>I</italic>² still was 69%, the result showed that compared with the control group, the MoCA test score was significantly higher in the acupuncture group (Fig. <xref ref-type=\"fig\" rid=\"F6\">6</xref>). Forms of acupuncture of eligible RCTs included acupuncture combined with western medicine or cognitive training, only 1 study used acupuncture alone as a treatment. The durations of treatment and intervention methods were different, which is the reason for the heterogeneity.</p><fig id=\"F6\" orientation=\"portrait\" position=\"float\"><label>Figure 6</label><caption><p>Forest plot of comparison of acupuncture versus routine treatment for the outcome of the MoCA test score. MoCA = Montreal cognitive assessment.</p></caption><graphic xlink:href=\"medi-99-e22365-g008\"/></fig></sec><sec><label>3.6</label><title>ADL scale score</title><p>Two studies involving 70 participants in the treatment group and 70 in the control group assessed the ADL scale score (MD&#x0200a;=&#x0200a;1.71, 95% CI [&#x02013;1.38, 4.79], <italic>P</italic>&#x0200a;&#x0003e;&#x0200a;.05). The data heterogeneity test <italic>I</italic>²&#x0200a;=&#x0200a;92%, <italic>I</italic>²&#x0200a;&#x0003e;&#x0200a;70% could not be used for the meta-analyses, so the result showed that the treatment group was combined with acupuncture therapy would not have the improvement in ADL scale score (Fig. <xref ref-type=\"fig\" rid=\"F7\">7</xref>).</p><fig id=\"F7\" orientation=\"portrait\" position=\"float\"><label>Figure 7</label><caption><p>Forest plot of comparison of acupuncture versus routine treatment for the outcome of the ADL scale score. ADL = activity of daily living scale.</p></caption><graphic xlink:href=\"medi-99-e22365-g009\"/></fig></sec><sec><label>3.7</label><title>CDT</title><p>Two studies using CDT score showed that the treatment group had the obvious effects in MCI elderly people with no heterogeneity (<italic>I</italic>²&#x0200a;=&#x0200a;0%) (MD&#x0200a;=&#x0200a;1.91, 95% CI [1.74, 2.08], <italic>Z</italic>&#x0200a;=&#x0200a;21.83, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.0001), which illustrated that in the future treatment of MCI in the elderly, CDT could be used to detect and exercise the cognitive level of the elderly, while instructing the elderly to carry out the task of clock painting, medical staff could purposefully exercise the memory of the elderly (Fig. <xref ref-type=\"fig\" rid=\"F8\">8</xref>).</p><fig id=\"F8\" orientation=\"portrait\" position=\"float\"><label>Figure 8</label><caption><p>Forest plot of comparison of acupuncture versus routine treatment for the outcome of the CDT score. CDT = clock drawing task.</p></caption><graphic xlink:href=\"medi-99-e22365-g010\"/></fig></sec><sec><label>3.8</label><title>Course of treatment</title><p>This study did the meta-analyses with different subgroups including 1 months, 2 months, and 3 months (Fig. <xref ref-type=\"fig\" rid=\"F9\">9</xref>). This analysis included 12 studies with 453 participants (treatment group) and 440 elderly people (control group). The heterogeneity of the 1 month was greater (<italic>I</italic>²&#x0200a;=&#x0200a;30%) and the reliability of the results was lower. The review demonstrated that 2 months (<italic>I</italic>²&#x0200a;=&#x0200a;0%, MD&#x0200a;=&#x0200a;2.39, 95% CI [1.59, 3.58]) and 3 months (<italic>I</italic>²&#x0200a;=&#x0200a;0%, MD&#x0200a;=&#x0200a;2.19, 95% CI [1.19, 4.01]) of acupuncture treatment could have better efficacy in clinical efficacy rates, so longer treatment should be implemented in the future to facilitate a better comparison.</p><fig id=\"F9\" orientation=\"portrait\" position=\"float\"><label>Figure 9</label><caption><p>Forest plot of comparisons by different duration for the outcome of the clinical efficacy rates.</p></caption><graphic xlink:href=\"medi-99-e22365-g011\"/></fig></sec><sec><label>3.9</label><title>Bias analysis</title><p>This study performed the funnel diagram to test whether there was a published bias in this study (Fig. <xref ref-type=\"fig\" rid=\"F10\">10</xref>). With the combined OR value (the dashed line in the diagram) as the center, the scattered points of the 12 RCTs were well distributed, and the results of the small sample study were roughly distributed around the global effect (dashed line) or large sample study. Based on the shape of an funnel diagram and basic symmetry, the results showed that the bias of the 12 study samples was not significant.</p><fig id=\"F10\" orientation=\"portrait\" position=\"float\"><label>Figure 10</label><caption><p>Funnel diagram of the treatment in elderly people with MCI. MCI = mild cognitive impairment.</p></caption><graphic xlink:href=\"medi-99-e22365-g012\"/></fig></sec><sec><label>3.10</label><title>Adverse events</title><p>Eight trials showed that they did not have the exfoliated specimen, and only 1 trial did not mention the standard of the exfoliated specimen, the other remaining 7 articles, 3 trials mentioned that the reason for exfoliating was that the participants could not endure acupuncture pain. One RCT mentioned the specific safety tests that included the general examination items of body temperature, blood pressure, pulse, breathing, blood routine, urine routine, and stool routine. One RCT mentioned the examination before and after the administration of medicine and the following steps:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>a neurological examination and general physical examination;</p></list-item><list-item><label>(2)</label><p>a laboratory examination to check routine blood, urine, stool, liver and kidney function, blood glucose, blood lipids, and so on;</p></list-item><list-item><label>(3)</label><p>an electrocardiogram.</p></list-item></list></sec></sec><sec><label>4</label><title>Discussion</title><sec><label>4.1</label><title>Summary of evidence</title><p>This systematic review and meta-analyses illustrated that acupuncture and its combined therapy were more effective than conventional therapy alone for MCI in older people in effectiveness, as indicated specifically by increases in the living ability state and mental cognitive state of the elderly, especially the MMSE scale score (MD&#x0200a;=&#x0200a;1.53), MoCA test score (MD&#x0200a;=&#x0200a;1.96), ADL scale score (MD&#x0200a;=&#x0200a;1.71), and CDT (MD&#x0200a;=&#x0200a;1.91). In the subgroup analysis, the review demonstrated that 2 months of acupuncture treatment could have better efficacy in clinical efficacy rates. Sensitivity analysis showed that the results of this meta-analyses were robust.</p><p>Several previous systematic reviews and meta-analyses have been published to explore the role of acupuncture interventions for MCI in middle-aged people. These articles were somewhat constant with each other with the conclusion that acupuncture is an effective and safe method for the treatment of MCI, but the clinical efficacy is not better than the routine treatment of western medicine.^{[<xref rid=\"R36\" ref-type=\"bibr\">36</xref>,<xref rid=\"R37\" ref-type=\"bibr\">37</xref>,<xref rid=\"R46\" ref-type=\"bibr\">46</xref>,<xref rid=\"R47\" ref-type=\"bibr\">47</xref>,<xref rid=\"R48\" ref-type=\"bibr\">48</xref>,<xref rid=\"R49\" ref-type=\"bibr\">49</xref>]} The results of this study show that acupuncture can effectively improve the MMSE and ADL scores of the elderly with MCI, which is similar to studies results of YT Yao and SZ Mao.^{[<xref rid=\"R46\" ref-type=\"bibr\">46</xref>,<xref rid=\"R47\" ref-type=\"bibr\">47</xref>]} However, this study analyzed data from 15 RCTs involving 1051 individuals older than 60 years of age to summarize and evaluate the available evidence on the efficacy and safety of acupuncture therapy for MCI, the largest subgroup analyzed different courses of treatment improved clinical efficacy rates in elderly people, this study further found that acupuncture can also improve the ADL and CDT scores of MCI elderly people. Moreover, the clinical efficacy rates in acupuncture group may be the most significant at 2 months of treatment, the interventional time is becoming more and more important, through this approach that giving us a more concrete picture on the role of acupuncture in improving the quality of life and mental state of the elderly than before.</p><p>This study also undertook subgroup analyses of different forms of acupuncture, including acupuncture and pharmacotherapy, acupuncture and training therapy, acupuncture. The result showed that acupuncture combined with pharmacotherapy or acupuncture treatment alone have better efficacy on elderly people with MCI, this not only showed that acupuncture has a therapeutic effect on MCI in elderly people, but also acupuncture can better promote the absorption of drugs, making the curative effect more significant. Acupuncture treatment has certain effects on various aspects of Clinical efficacy rates, MMSE scale score, MoCA test score, and CDT. Specifically, acupuncture is effective in the treatment of MCI in elderly people, and the acupuncture group had statistically significant better outcomes than the control group.</p><p>In order to avoid methodological weaknesses, the sample size should be expanded as much as possible, a small sample size can distort the results of meta-analyses, by over estimating treatment effects. 10 RCTs were considered to be at low risk of bias, 5 RCTs (33%) were at an unknown risk of bias. Additionally, with regard to the risk of bias, its major responsibility was the lack of proper blinding and allocation concealment. The estimate of the intervention effect can be exaggerated when there is inadequate allocation concealment or lack of blinding in trials where a subjective outcome is analyzed. These methodological weaknesses may lead to an overestimation of treatment effects.</p><p>The innovation of this paper is that this study conducted a systematic review and meta-analyses of the elderly people with MCI who received acupuncture treatment. With slighter heterogeneity of intervention among trials and people this study included in the RCTs were all elderly people, the conclusion and result may be more reliable to generalize and simplify. This study performed a subgroup analysis and a sensitivity analysis when this study encountered inconsistent conditions, all of which might have helped to decrease clinical heterogeneity to some extent. At the same time, this study chose 5 indicators as the main outcome indicators, the clinical efficacy rates and the MoCA, MMSE, CDT, and ADL scores; these 5 indicators are closely related to cognition. Accordingly, this study can explain the influence and significance of cognitive impairment for the elderly through an analysis of these indicators. This review shows that acupuncture treatment can significantly improve the various cognitive function indicators of elderly people. After implementing the acupuncture therapy strategy, in order to improve the treatment effect of the disease and reduce the adverse reactions of elderly MCI people, the acupuncture therapy should be popularized. The most important direction of future research is to carry out more diversified methods and measures for acupuncture in elderly people with MCI, to cultivate the ability and technology of medical staff in the acupuncture of elderly people with MCI and strengthen clinical education and improve the career quality of clinical physician of Chinese medicine.</p></sec><sec><label>4.2</label><title>Limitations</title><p>There are some limitations of this review. First, this study considered the commonness of acupuncture stimulation and assumed that all treatments were similar; thus, this study did not distinguish all acupuncture methods such as common acupuncture from electroacupuncture and body acupuncture from other acupuncture methods. Second, it was difficult to find out the influence of contingency factors. The operation technique used in acupuncture, the choice of acupoint, and the depth of acupuncture are not discussed in this paper. The quality of clinical trials should be considered. Third, despite the utilization of a range of outcome measures, the impact based on the smallest clinically important difference for each metric may not be reflected.</p><p>Acupuncture as a safety and economical method which has also been shown to be effective in the treatment of MCI, but this study have to take into account that the subjects of the study are people over the age of 60. Future studies could take into account the following points. First, In the future, this study hope systematic review can be updated based on more rigorous and powerful evidence. Second, optimal acupoint selection, session duration, and application frequency have not been established. As clinical health care workers, this study should use humanized treatment methods to care for the elderly. This study need to pay more attention to the mental health of the elderly, and it is more important to provide them with continuous and effective psychological care and counseling than treatment and at the same time strengthen health education for MCI in older people.</p></sec></sec><sec><label>5</label><title>Conclusions</title><p>Preliminary evidence indicated that as a relatively safe and reliable intervention, acupuncture therapy has a significant positive effective on cognitive and memory function in elderly people with MCI, and improved the MMSE, MoCA, ADL, and CDT scores. However, the methodological quality of some trials included in this review were of low quality. Despite the apparently positive findings, it is premature to conclude the effectiveness of acupuncture for the treatment of MCI in elderly people due to the heterogeneity of the included trials and the generally low methodological quality of the included trials. Multi-center, double-blinded, and placebo-controlled RCTs are required to provide stronger evidence.</p></sec><sec><title>Acknowledgment</title><p>The authors wish to thank Professor Shi-Zheng Du, School of Nursing, Nanjing University of Chinese Medicine, for giving advice on writing this manuscript.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Li Weitong.</p><p><bold>Data curation:</bold> Li Weitong, Wang Qing, Pu Yalou.</p><p><bold>Methodology:</bold> Du Shizheng.</p><p><bold>Project administration:</bold> Xu Guihua.</p><p><bold>Software:</bold> Li Weitong.</p><p><bold>Writing &#x02013; original draft:</bold> Li Weitong. Wang Qing, Xu Guihua.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Li Weitong, Pu Yalou.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: AD = Alzheimer disease, ADL = activity of daily living scale, CDT = clock drawing task, CI = confidence interval, MCI = mild cognitive impairment, MD = mean difference, MMSE = mini-mental state examination, MoCA = Montreal cognitive assessment, RCTs = randomized control trials.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Li W, Wang Q, Du S, Pu Y, Xu G. Acupuncture for mild cognitive impairment in elderly people: systematic review and meta-analyses. <italic>Medicine</italic>. 2020;99:39(e22365).</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article [and its supplementary information files];</p></fn><fn fn-type=\"supported-by\"><p>The study was supported by the National Natural Science Foundation of China (No.71673149).</p></fn><fn fn-type=\"financial-disclosure\"><p>Funding was provided by the National Natural Science Foundation of China: The Research of Grading Care Model For the Elderly Under the Guidings of the Theory of Health Management, Grant/Award Number: 71573140; Postgraduate Research &#x00026; Practice Innovation Program of Jiangsu Province: Research on Comprehensive Evaluation Model of Elderly Care Needs Based on Elderly Ability Assessment and InterRAI, Grant/Award Number: KYCX19_1216.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991431</article-id><article-id pub-id-type=\"pmc\">PMC7523832</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-00337</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022286</article-id><article-id pub-id-type=\"art-access-id\">22286</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>4300</subject></subj-group><subj-group><subject>Research Article</subject><subject>Systematic Review and Meta-Analysis</subject></subj-group></article-categories><title-group><article-title>Moxibustion for the treatment of diabetic peripheral neuropathy</article-title><subtitle>A systematic review and meta-analysis following PRISMA guidelines</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Tan</surname><given-names>Yumeng</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Hu</surname><given-names>Jun</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Pang</surname><given-names>Bing</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Du</surname><given-names>Lijuan</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yang</surname><given-names>Yanan</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Pang</surname><given-names>Qing</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Meizhen</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wu</surname><given-names>Qian</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Yi</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Ni</surname><given-names>Qing</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Tarantino.</surname><given-names>Giovanni</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Endocrinology</aff><aff id=\"aff2\"><label>b</label>Department of Cardiovascular, Guang&#x02019;an Men Hospital, China Academy of Chinese Medical Sciences</aff><aff id=\"aff3\"><label>c</label>Beijing University of Chinese Medicine, Beijing, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Qing Ni, Department of Endocrinology, Guang&#x02019;an Men Hospital, China Academy of Chinese Medical Sciences, No 5 Beixiange, Xicheng District, Beijing 100053, China (e-mail: <email>niqing669@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22286</elocation-id><history><date date-type=\"received\"><day>15</day><month>1</month><year>2020</year></date><date date-type=\"rev-recd\"><day>8</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>19</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22286.pdf\"/><abstract abstract-type=\"toc\"><p>Supplemental Digital Content is available in the text</p></abstract><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>At present, the effect of western-medicine (WM) therapy to treat diabetic peripheral neuropathy (DPN) is limited. Moxibustion is a representative external treatment in traditional Chinese medicine that has been beneficial to DPN. We aim to systematically assess the efficacy and safety of moxibustion in treating DPN, following PRISMA guidelines.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>Eight electronic databases were searched to acquire information on eligible trials published from inception to June 1, 2019. We included randomized controlled trials (RCTs) applying moxibustion therapy with a minimum of 14-days treatment duration for DPN patients compared with placebo, no intervention, or conventional WM interventions. The primary outcomes in our study include the sensory-nerve conduction velocity (SNCV) and motor-nerve conduction velocity (MNCV). We used the Cochrane Collaboration Risk of Bias tool to assess the methodological quality of eligible RCTs. Statistical analyses were conducted using Review Manager 5.3. Risk ratios (RR) and mean differences (MD) were calculated with a 95% confidence interval (CI). The <italic>&#x003c7;</italic>² test was applied to assess the heterogeneity.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>In total, 11 RCTs were included that involved 927 DPN patients. Compared with the control group, there was an increase in median MNCV (MD&#x0200a;=&#x0200a;6.26, 95% CI 2.64&#x02013;9.89, Z&#x0200a;=&#x0200a;3.39, <italic>P</italic>&#x0200a;=&#x0200a;.0007) and peroneal MNCV (MD&#x0200a;=&#x0200a;6.45, 95% CI 5.30&#x02013;7.61, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001). There was also an increase in median SNCV (MD&#x0200a;=&#x0200a;6.64, 95% CI 3.25&#x02013;10.03, <italic>P</italic>&#x0200a;=&#x0200a;.0001) and peroneal SNCV (MD&#x0200a;=&#x0200a;3. 57, 95% CI 2.06&#x02013;5.09, Z&#x0200a;=&#x0200a;4.63, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001) in the treatment groups. The treatment groups receiving moxibustion therapy indicated a more significant improvement in total effectiveness rate (RR&#x0200a;=&#x0200a;0.25, 95% CI 0.18&#x02013;0.37, Z&#x0200a;=&#x0200a;7.16, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001). Toronto Clinical Scoring System indicated a significant decrease in the treatment groups (MD&#x0200a;=&#x0200a;&#x02212;2.12, 95% CI &#x02212;2.82 to 1.43, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001). Only 1 study reported that treatment groups experienced no adverse reactions. The other 10 studies did not mention adverse events.</p></sec><sec sec-type=\"conclusion\"><title>Conclusions:</title><p>Moxibustion therapy may be an effective and safe option for DPN patients but needs to be verified in further rigorous studies.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>diabetic peripheral neuropathy</kwd><kwd>meta-analysis</kwd><kwd>moxibustion</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>the capital health research and development of special</funding-source><award-id>2016-1-4151</award-id><principal-award-recipient>Yumeng Tan</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Natural Science Foundation of Beijing Municipality</funding-source><award-id>7182143</award-id><principal-award-recipient>Yumeng Tan</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>A recent rapid increase in the number of diabetic patients has made diabetes a serious public-health concern. The latest edition of IDF Diabetes Atlas states that 463 million adults are currently living with diabetes worldwide and estimates that there will be 578 million adults with diabetes by 2030.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Peripheral neuropathy is one of the common chronic complications of diabetes mellitus, with the incidence increasing with the escalating number of diabetics. The prevalence of neuropathy in patients with diabetes is approximately 30% with up to 50% eventually developing neuropathy during their disease.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} The most common presentation of diabetic peripheral neuropathy (DPN) is distal symmetric polyneuropathy that is characterized by pain, numbness, abnormal sensation, and weakness that affect the nerves in distal extremities^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} that can easily lead to conditions such as diabetic foot, foot ulcer, and amputation, adding further burden to the public healthcare. Controlling glycemia and cardiovascular risks are now considered to be vital in the management of DPN patients.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} There are several measures available for addressing the painful symptoms including mecobalamin, tricyclic compounds, antioxidant alpha-lipoic acid, anticonvulsants, opiates, etc. However, few therapies are available for the improvement of painless symptoms. Moreover, the efficacy of western-medicine (WM) is poor and limited. For example, a study by Su et al^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} pointed out that a simple application of mecobalamin could not improve the ischemia and anoxemia status of nervous tissues.</p><p>For this reason, many physicians have started to explore what the traditional Chinese medicine (TCM) could offer to DPN therapy. TCM prevents and cures diseases based on its guidance that includes many therapeutic options (e.g., herbal medicine, Chinese patent medicine, acupuncture, moxibustion, manipulation, etc.). External therapies of TCM are widely used in clinical practice; in particular, acupuncture has been proven to be clinically effective and is being widely applied to treat DPN.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Besides acupuncture, moxibustion is also a representative external treatment in TCM that can regulate and harmonize qi and blood, warm meridians, and activate blood circulation, and thus that treats and prevents diseases. The clinical effectiveness of moxibustion in treating DPN has been widely recognized. Recent studies showed that moxibustion can increase serum superoxide dismutase concentration,^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} reduce free-radical production, prevent impairments of nerve tissues resulting from free-radical accumulation, and alleviate neuro-inflammation possibly by inhibiting NF-&#x003ba;B and activating Nrf2.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} The efficacy of moxibustion therapy has been claimed by many studies but there is still a lack of objective evaluation of its benefits in treating DPN. Therefore, the effectiveness of moxibustion therapy in DPN remains controversial and its application is limited.</p><p>We conducted this meta-analysis to assess the strength of the current evidence to support the efficacy and safety of moxibustion for the treatment of DPN that might be a novel treatment strategy for DPN.</p></sec><sec><label>2</label><title>Methods</title><p>Our systematic review was registered with PROSPERO in June 2019 (registration number CRD 42019138266). The methods of this meta-analysis were performed following the PRISMA guideline.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]}</p><sec><label>2.1</label><title>Search strategy</title><p>To identify eligible studies, the main search was conducted in the following 8 electronic databases: Cochrane Library, PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure database (CNKI), Chinese Biomedical Database (CBM), Chinese Science and Technique Journal Database (VIP), and Wan Fang Database up to June 1, 2019. The search was performed using various combinations of Medical Subject Headings (MeSH) and non-MeSH terms. The search terms used included diabetic neuropathy, diabetic peripheral neuropathy, diabetic neuropathies, DPN, moxibustion, moxa, moxa-moxibustion, warm-moxibustion, mild-moxibustion, indirect-moxibustion, randomized controlled trial, controlled clinical trial, randomized, placebo and randomly for searching Cochrane Library, PubMed, EMBASE, and Web of Science. Corresponding Chinese terms were used when searching for VIP, CBM, Wan Fang, and CNKI databases. A complete search strategy used for PubMed is shown in Supplementary Material File1.</p></sec><sec><label>2.2</label><title>Study design</title><sec><label>2.2.1</label><title>Inclusion criteria</title><list list-type=\"simple\"><list-item><label>1.</label><p>Study types: randomized controlled trials (RCTs) in English or Chinese were included.</p></list-item><list-item><label>2.</label><p>Participants: age&#x02265;18 years, with nationally or internationally recognized diagnostic criteria of DPN by organizations such as the WHO, American Diabetes Association, 2009 Chinese Medical Doctor Association Guidelines for diagnosis and treatment of diabetic peripheral neuropathy being met by all participants.</p></list-item><list-item><label>3.</label><p>Interventions: Moxibustion without restrictions on the types of moxibustion, equipment, materials, points, or frequency. The control interventions were no intervention, placebo, or WM therapy. Besides, routine hypoglycemic therapy should be used in both groups.</p></list-item><list-item><label>4.</label><p>Outcomes: Primary: the sensory-nerve conduction velocity (SNCV) and motor-nerve conduction velocity (MNCV). Secondary: the total effectiveness rate, Toronto Clinical Scoring System (TCSS),^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} glucose indices (e.g., FBG, 2hPG, and HbA1c), and adverse events.</p></list-item></list></sec><sec><label>2.2.2</label><title>Exclusion criteria</title><p>Study types: randomized controlled animal study. Diagnosis: participants with peripheral neuropathy not caused by diabetes. Interventions: moxibustion combined with other TCM treatments (e.g., acupuncture, foot bath, herbal medicine, etc.)</p></sec></sec><sec><label>2.3</label><title>Data extraction</title><p>Two reviewers extracted the following data: study ID, sample size, average age, gender, duration of diabetes, diabetes types, TCM-syndrome types, DPN diagnostic criteria, interventions (Types and dosage of WM, a dose of moxibustion therapy), treatment duration, moxibustion treatment times, and outcome measures. Discrepancies were resolved through discussions with a third party (QN).</p></sec><sec><label>2.4</label><title>Risk-of-bias assessment</title><p>Based on the Cochrane Risk of Bias Tool,^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} 2 reviewers independently evaluated the methodological quality of the included studies. The following 7 elements were assessed: random-sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete-outcome data, selective reporting, and other bias. Any discrepancies were resolved by consensus.</p></sec><sec><label>2.5</label><title>Data analysis</title><p>Statistical analyses were performed using the RevMan 5.3 software. Dichotomous data were expressed as the risk ratio (RR), and continuous outcomes between groups as mean difference (MD), both with a 95% confidence interval (CI).</p><p>We accessed heterogeneity by the <italic>&#x003c7;</italic>² test. When there was substantial heterogeneity (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.10, I²&#x0003e;50%), we used the random effects model to analyze the data. Otherwise, a fixed-effect model was applied (i.e., when <italic>P</italic>&#x0200a;&#x0003e;&#x0200a;.1 or I²&#x0200a;&#x0003c;&#x0200a;50%).^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} The sensitivity analysis and subgroup analysis would be performed to explore the possible sources of heterogeneity. Furthermore, publication bias was assessed using a funnel plot.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]}</p></sec></sec><sec><label>3</label><title>Results</title><sec><label>3.1</label><title>Searching result</title><p>As displayed in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>, our search strategy initially identified a total of 144 records. After removing 73 duplicates, further 40 irrelevant records were excluded by screening the titles and abstracts. A full-text analysis of 31 potentially relevant articles excluded an additional 20 articles because other TCM therapies were used in treatment and control (n&#x0200a;=&#x0200a;16), republications (n&#x0200a;=&#x0200a;1), outcomes not meet criteria (n&#x0200a;=&#x0200a;1), treatment course not meet criteria (n&#x0200a;=&#x0200a;2), respectively. Finally, 11 RCTs met our eligibility criteria and were selected for the meta-analysis.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>&#x02013;<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]}</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flow chart of the literature screen.</p></caption><graphic xlink:href=\"medi-99-e22286-g001\"/></fig></sec><sec><label>3.2</label><title>Description of selected studies</title><p>All 11 included RCTs were conducted in China, 1 was published in English.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} The characteristics of the 11 studies are presented in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>. The sample size of individual studies varied from 39 to 132 participants. In 5 studies, enrolled patients suffered from type-2 diabetes,^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>,<xref rid=\"R19\" ref-type=\"bibr\">19</xref>,<xref rid=\"R20\" ref-type=\"bibr\">20</xref>,<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]} and the other studies enrolled patients with no restriction to the type of diabetes. All included patients met the diagnostic criteria for DPN. Additionally, 4 trials reported the TCM syndromes of their participants.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>,<xref rid=\"R20\" ref-type=\"bibr\">20</xref>,<xref rid=\"R22\" ref-type=\"bibr\">22</xref>,<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]}</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Characteristics of the included studies.</p></caption><graphic xlink:href=\"medi-99-e22286-g002\"/></table-wrap><p>Participants in both groups received hypoglycemic therapy. All treatment groups received a combination of moxibustion plus WM therapies, and control groups received only WM interventions. Six trials used mild moxibustion (i.e., the lighted Moxa sticks were pointed to the acupoint for several minutes until flush and hot feelings were detected).^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R18\" ref-type=\"bibr\">18</xref>,<xref rid=\"R20\" ref-type=\"bibr\">20</xref>,<xref rid=\"R22\" ref-type=\"bibr\">22</xref>&#x02013;<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} In 1 trial,^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} electronic moxibustion was used. One trial^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} did not provide a clear description of the moxibustion equipment. Other trials^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>,<xref rid=\"R19\" ref-type=\"bibr\">19</xref>,<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} were performed with moxibustion equipment (i.e., moxibustion-massage apparatus). WM treatments in most of the included trials used mecobalamin (8/11), other trials used vitamin B1, vitamin B12, vitamin B6, or &#x003b1;-lipoic acid. The studies&#x02019; treatment duration ranged from 14 days to 3 months. The moxibustion treatment was administered from 14 to 90 times. All the specific moxibustion acupoints adopted in 11 studies are shown in Table <xref rid=\"T2\" ref-type=\"table\">2</xref>.</p><table-wrap id=\"T2\" orientation=\"portrait\" position=\"float\"><label>Table 2</label><caption><p>The specific moxibustion acupoints adopted in all 11 studies.</p></caption><graphic xlink:href=\"medi-99-e22286-g003\"/></table-wrap><p>Seven trials reported SNCV and MNCV outcomes.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>&#x02013;<xref rid=\"R18\" ref-type=\"bibr\">18</xref>,<xref rid=\"R21\" ref-type=\"bibr\">21</xref>&#x02013;<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} Eight trials reported the total effectiveness rate that consisted of 2 parts: the subjective part (the symptoms and physical signs disappeared, improved, or alleviated) and the objective part (improvements of nerve-conduction velocity, tendon reflex, and deep sense). Finally, 2 trials reported the TCSS and only 1 trial reported glucose indices.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>,<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]}</p></sec><sec><label>3.3</label><title>Methodological quality within studies</title><p>The results of the bias-risk assessment are shown in Figures <xref ref-type=\"fig\" rid=\"F2\">2</xref> and <xref ref-type=\"fig\" rid=\"F3\">3</xref>. Of the 11 studies, 4 RCTs adopted strict randomization and reported their methods of random-number-sequence generation in detail. Two studies were assessed as a &#x0201c;high risk&#x0201d; for the random-number-sequence generation.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} Since insufficient information was available on the allocation concealment, blinding of participants and personnel, blinding of outcome assessment, and other bias in all 11 trials, the above items were judged to be &#x0201c;unclear.&#x0201d; There was no attrition bias in the 11 studies since the outcome data were complete. None of the 11 studies was found to have reporting bias.</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Risk of bias graph of included studies.</p></caption><graphic xlink:href=\"medi-99-e22286-g004\"/></fig><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Risk of bias summary of included studies.</p></caption><graphic xlink:href=\"medi-99-e22286-g005\"/></fig></sec><sec><label>3.4</label><title>Meta-analysis results</title><sec><label>3.4.1</label><title>Nerve-conduction velocity (NCV)</title><p>Seven trials reported outcomes of NCV and those that did, examined different nerves. Seven trials provided the MNCV and SNCV of the median nerve, 6 trials provided the MNCV and SNCV of the peroneal nerve.</p><sec><label>3.4.1.1</label><title>Median MNCV</title><p>Seven trials assessed the changes of median MNCV with high heterogeneity between trials (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;331.78, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, I²&#x0200a;=&#x0200a;98%); a random-effect model was used for statistical analysis. Compared with control groups, treatment groups improved median MNCV significantly (MD&#x0200a;=&#x0200a;6.26, 95% CI 2.64&#x02013;9.89, Z&#x0200a;=&#x0200a;3.39, <italic>P</italic>&#x0200a;=&#x0200a;.0007) (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>).</p><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>Forest plots of moxibustion effects on median MNCV. MNCV = motor nerve conduction velocity.</p></caption><graphic xlink:href=\"medi-99-e22286-g006\"/></fig><p>Anticipating that different moxibustion-treatment times may affect the results, subgroup analysis was performed. We divided studies into 2 subgroups according to different moxibustion-treatment times. Two studies with &#x02265;60 moxibustion treatments reported median MNCV as an outcome (MD&#x0200a;=&#x0200a;7.12, 95% CI: &#x02212;0.11 to 14.35, Z&#x0200a;=&#x0200a;1.93, <italic>P</italic>&#x0200a;=&#x0200a;.05); high heterogeneity between trials was observed (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;12.76, <italic>P</italic>&#x0200a;=&#x0200a;.0004, I²&#x0200a;=&#x0200a;92%). The treatment groups from 5 studies with &#x0003c;60 moxibustion treatments were superior to control groups in terms of median MNCV (MD&#x0200a;=&#x0200a;5.95, 95% CI: 1.54&#x02013;10.36, Z&#x0200a;=&#x0200a;2.64, <italic>P</italic>&#x0200a;=&#x0200a;.008). These 5 studies also showed significant heterogeneity of the trial results (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;317.67, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, I²&#x0200a;=&#x0200a;99%).</p></sec><sec><label>3.4.1.2</label><title>Peroneal MNCV</title><p>As shown in Figure <xref ref-type=\"fig\" rid=\"F5\">5</xref>, 6 trials reported the changes in peroneal MNCV (MD&#x0200a;=&#x0200a;6.45, 95% CI 5.30&#x02013;7.61, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001). We used the random-effect model because of the significant heterogeneity between trials (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;13.41, <italic>P</italic>&#x0200a;=&#x0200a;.02, I²&#x0200a;=&#x0200a;63%).</p><fig id=\"F5\" orientation=\"portrait\" position=\"float\"><label>Figure 5</label><caption><p>Forest plots of moxibustion effects on peroneal MNCV. MNCV = motor nerve conduction velocity.</p></caption><graphic xlink:href=\"medi-99-e22286-g007\"/></fig><p>Two studies with moxibustion treatment times &#x02265;60 compared the peroneal MNCV between treatment groups and control groups (MD&#x0200a;=&#x0200a;5.48, 95% CI 3.37&#x02013;7.28, Z&#x0200a;=&#x0200a;5.95, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001) without heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;0.53, <italic>P</italic>&#x0200a;=&#x0200a;.47, I²&#x0200a;=&#x0200a;0%). The other 4 trials used less than 60 moxibustion treatments and compared the peroneal MNCV between treatment groups and control groups (MD&#x0200a;=&#x0200a;6.78, 95% CI 5.34&#x02013;8.22, Z&#x0200a;=&#x0200a;9.25, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001) with high heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;11.24, <italic>P</italic>&#x0200a;=&#x0200a;.01, I²&#x0200a;=&#x0200a;73%). Sensitivity analysis showed that heterogeneity decreased after studies Han et al and Liu and Zhang were removed from the &#x0003c;60 moxibustion-treatments subgroup (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;0.41, <italic>P</italic>&#x0200a;=&#x0200a;.36, I²&#x0200a;=&#x0200a;0%). Therefore, we speculate that the possible sources of heterogeneity may be related to the type of moxibustion used and the degree of peripheral neuropathy.</p></sec><sec><label>3.4.1.3</label><title>Median SNCV</title><p>Seven studies that involved 531 patients reported changes in median SNCV. Significant heterogeneity between trials was observed (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;223.08, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, I²&#x0200a;=&#x0200a;97%), a random-effect model was applied for statistical analysis. There was a significant increase in the median SNCV compared with the control group (MD&#x0200a;=&#x0200a;6.64, 95% CI 3.25&#x02013;10.03, <italic>P</italic>&#x0200a;=&#x0200a;.0001) (Fig. <xref ref-type=\"fig\" rid=\"F6\">6</xref>).</p><fig id=\"F6\" orientation=\"portrait\" position=\"float\"><label>Figure 6</label><caption><p>Forest plots of moxibustion effects on median SNCV. SNCV = sensory nerve conduction velocity.</p></caption><graphic xlink:href=\"medi-99-e22286-g008\"/></fig><p>Two studies with &#x02265;60 moxibustion treatments compared the median SNCV between treatment groups and control groups (MD&#x0200a;=&#x0200a;9. 50, 95% CI 7.75&#x02013;11.26, Z&#x0200a;=&#x0200a;10.61, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001) without heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;0.46, <italic>P</italic>&#x0200a;=&#x0200a;.5, I²&#x0200a;=&#x0200a;0%). The other 5 trials that had less than 60 moxibustion treatments compared the median SNCV between treatment groups and control groups (MD&#x0200a;=&#x0200a;5.45, 95% CI 1.34&#x02013;9.57, Z&#x0200a;=&#x0200a;2.60, <italic>P</italic>&#x0200a;=&#x0200a;.0009) with high heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;203.36, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, I²&#x0200a;=&#x0200a;98%). Heterogeneity was reduced after studies by Han et al and Zheng et al were removed from the moxibustion-treatment times &#x0003c;60 subgroup (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;0.38, <italic>P</italic>&#x0200a;=&#x0200a;.83, I²&#x0200a;=&#x0200a;0%). The heterogeneity may have been caused by the moxibustion type used; the Han et al study used electronic moxibustion and the Zheng et al study did not describe in enough detail the type of moxibustion that was employed.</p></sec><sec><label>3.4.1.4</label><title>Peroneal SNCV</title><p>Six studies involving 461patients reported peroneal SNCV data (MD&#x0200a;=&#x0200a;3. 57, 95% CI 2.06&#x02013;5.09, Z&#x0200a;=&#x0200a;4.63, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001) (Fig. <xref ref-type=\"fig\" rid=\"F7\">7</xref>); a random-effect model was used because of the high heterogeneity between studies (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;46.57, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, I²&#x0200a;=&#x0200a;89%).</p><fig id=\"F7\" orientation=\"portrait\" position=\"float\"><label>Figure 7</label><caption><p>Forest plots of moxibustion effects on peroneal SNCV. SNCV = sensory nerve conduction velocity.</p></caption><graphic xlink:href=\"medi-99-e22286-g009\"/></fig><p>Two studies with &#x02265;60 moxibustion treatments compared the peroneal SNCV between the treatment and control groups (MD&#x0200a;=&#x0200a;1. 41, 95% CI &#x02212;0.22 to 3.04, Z&#x0200a;=&#x0200a;1.70, <italic>P</italic>&#x0200a;=&#x0200a;.09) without heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;0.21, <italic>P</italic>&#x0200a;=&#x0200a;.65, I²&#x0200a;=&#x0200a;0%). The other 4 trials that used less than 60 moxibustion treatments compared the peroneal SNCV between the treatment and control groups (MD&#x0200a;=&#x0200a;4.35, 95% CI 2.59 to 6.11, Z&#x0200a;=&#x0200a;4.84, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001) with high heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;38.69, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, I²&#x0200a;=&#x0200a;92%). Heterogeneity was reduced after the Zheng et al study was removed from the &#x0003c;60 moxibustion treatments subgroup (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;0.27, <italic>P</italic>&#x0200a;=&#x0200a;.87, I²&#x0200a;=&#x0200a;0%). The lack of specific details about the instrument and the type of moxibustion treatment used in the Zheng et al study may be the reason for the observed heterogeneity.</p></sec></sec><sec><label>3.4.2</label><title>Total effectiveness rate</title><p>Eight studies involving 678 participants reported the total-effectiveness-rate outcome. Due to the low heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;9.71, <italic>P</italic>&#x0200a;=&#x0200a;.21, I²&#x0200a;=&#x0200a;28%) (Fig. <xref ref-type=\"fig\" rid=\"F8\">8</xref>), we used a fixed-effect model for the combined analysis. The treatment groups indicated a better total-effectiveness rate than the control groups (RR&#x0200a;=&#x0200a;0.25, 95% CI 0.18&#x02013;0.37, Z&#x0200a;=&#x0200a;7.16, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001).</p><fig id=\"F8\" orientation=\"portrait\" position=\"float\"><label>Figure 8</label><caption><p>Forest plots of moxibustion effects on total effectiveness rate.</p></caption><graphic xlink:href=\"medi-99-e22286-g010\"/></fig><p>In subgroup analysis, the total effective rate of the treatment group was higher than that of the control group, with the &#x02265;60 moxibustion-treatment group showing high heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;3.54, <italic>P</italic>&#x0200a;=&#x0200a;.06, I²&#x0200a;=&#x0200a;72%; RR&#x0200a;=&#x0200a;0.21, 95% CI 0.11&#x02013;0.39, Z&#x0200a;=&#x0200a;4.95, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001) and the &#x0003c;60 moxibustion-treatment group showing low heterogeneity (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;5.55, <italic>P</italic>&#x0200a;=&#x0200a;.35, I²&#x0200a;=&#x0200a;10%; RR&#x0200a;=&#x0200a;0.29, 95% CI 0.18&#x02013;0.46, Z&#x0200a;=&#x0200a;5.18, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001).</p></sec><sec><label>3.4.3</label><title>Toronto clinical scoring system (TCSS)</title><p>As shown in Figure <xref ref-type=\"fig\" rid=\"F9\">9</xref>, 2 studies investigated TCSS. Based on the low heterogeneity, the meta-analysis was performed using a fixed-effect model (<italic>&#x003c7;</italic>²&#x0200a;=&#x0200a;0.17, <italic>P</italic>&#x0200a;=&#x0200a;.68, I²&#x0200a;=&#x0200a;0%). Compared with the control groups, TCSS indicated a significant decrease in the treatment groups (MD&#x0200a;=&#x0200a;&#x02212;2.12, 95% CI &#x02212;2.82 to 1.43, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001).</p><fig id=\"F9\" orientation=\"portrait\" position=\"float\"><label>Figure 9</label><caption><p>Forest plots of moxibustion effects on TCSS. TCSS = Toronto Clinical Scoring System.</p></caption><graphic xlink:href=\"medi-99-e22286-g011\"/></fig></sec><sec><label>3.4.4</label><title>Adverse events</title><p>Only 1 study mentioned adverse events,^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} however, there were no serious side effects reported for the treatment period in the treatment and control groups. The other 10 studies did not mention adverse events.</p></sec></sec><sec><label>3.5</label><title>Publication bias</title><p>The outcomes of the total-effectiveness rate involving 8 studies were tested for publication bias. As indicated in Figure <xref ref-type=\"fig\" rid=\"F10\">10</xref>, the funnel-graph shape was visually imperfectly symmetrical indicating a potential publication bias.</p><fig id=\"F10\" orientation=\"portrait\" position=\"float\"><label>Figure 10</label><caption><p>Funnel plot for assessing publication bias.</p></caption><graphic xlink:href=\"medi-99-e22286-g012\"/></fig></sec></sec><sec><label>4</label><title>Discussion</title><p>DPN is the most common complication of diabetes that may lead to the occurrence of diabetic foot ulcers and even to foot or limb amputations. At present, the main important strategy to prevent and treat DPN is to control hyperglycemia and keep the blood-glucose level stable. Other therapeutic approaches to control DPN including those evaluated in clinical trials have shown limited efficacy especially on painless symptoms.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]}</p><p>According to the theory of TCM, DPN belongs to the &#x0201c;bi syndrome&#x0201d; of TCM and is related to the blockage of meridians. Moxibustion can warm Yang, eliminate cold, and dredge meridians, and is a representative external treatment in TCM. Based on meridians and acupoints, it can intervene in various diseases utilizing heat, light radiation, and drug effects.^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} Clinical effectiveness of moxibustion in DPN has been widely recognized. A study demonstrated that moxibustion could improve DPN-related neuroinflammation by restoring the balance between NF-&#x003ba;B and Nrf2 in rats and may thus be complementary to the current treatment of DPN.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Our study evaluated the efficacy and safety of moxibustion in treating DPN.</p><p>The study conducted a meta-analysis of 11 studies involving 927 patients. The data suggested that the efficacy of moxibustion in treating DPN was significantly better than that of the control groups. NCV is considered to be the most objective and reliable method in the diagnosis of DPN having 40% sensitivity and 100% specificity ^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>]} and was the primary outcome criterion in our analysis; however, only 7 studies reported NCV results and the nerves examined by NCV were not identical. Therefore, it was necessary to standardize NCV evaluation to improve the reliability of data analysis. Moreover, we speculated that many factors would influence the results performed by subgroup and sensitivity analyses such as moxibustion type, the times of moxibustion treatment, the degree of peripheral neuropathy, and so on. Such factors will need to be controlled in future clinical trials involving moxibustion applied to DPN treatment. Only 2 studies reported outcomes based on the assessment of TCSS symptoms. TCSS is a relatively simple, comprehensive, and effective screening method that includes symptoms and signs. The examination is relatively objective, consistent with clinical examinations, and highly reliable.^{[<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} Accordingly, it is essential to standardize the assessment of symptoms.</p><p>Only 1 study reported changes in blood-glucose level,^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} hence we could not evaluate the effect of moxibustion treatment on this parameter. Consequently, it remains unclear whether the improvement of outcomes such as NVC is related to an improvement of blood-glucose levels. Two studies have shown that moxibustion can improve hemorheological indexes^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]}; this effect may also be related to improvements in neurological function. More pharmacological and clinical studies are still required to verify the mechanism of moxibustion in treating DPN.</p><p>All the 11 trials reported specific acupoints applied in their treatment; this data might provide a reference for acupoints selection in clinical practice. The 5 most frequently used acupoints were Zusanli (ST36), Sanyinjiao (SP6), Yanglingquan (GB34), Hegu (LI4), and Quchi (LI11). We also found that most of the acupoints used in the 11 trials are located on limbs, with some being located at the abdomen (e.g., Zhongwan (RN12), Xiawan (RN10), Qihai (RN6), etc.) and back (e.g., Pishu (BL20), Weishu (BL21), Shenshu (BL23), etc.) (Fig. <xref ref-type=\"fig\" rid=\"F11\">11</xref>). Acupoints have not only local effects but also systemic effects based on their meridian route.</p><fig id=\"F11\" orientation=\"portrait\" position=\"float\"><label>Figure 11</label><caption><p>Acupoints used in the included trials.</p></caption><graphic xlink:href=\"medi-99-e22286-g013\"/></fig><p>This meta-analysis has several limitations. All the clinical studies included in our analysis were performed in China; this may suggest that the reported positive results might have a likelihood of publication bias possibly resulting from high heterogeneity, an insufficient number of trials, and a small sample size. Further, no follow-up study and long-term effects of moxibustion on DPN were reported. Additionally, the use of different therapeutic acupoints, treatment frequency, and moxibustion equipment would likely affect the result; we were not able to assess this due to the lack of such data in the included studies.</p><p>Although the conclusion of our meta-analysis is limited, it may still provide some inspiration. For any follow-up study, establishing methodological quality is critical. For example, the studies we analyzed generally failed to ensure patient blinding; suitable devices for sham moxibustion treatment will be necessary for future studies. Moreover, attention must be paid to adverse events because moxibustion is not free of risks and generates heat, smoke, and tar that may present a risk of adverse events. The availability of a large amount of safety data will be necessary to standardize the moxibustion therapy.</p></sec><sec><label>5</label><title>Conclusions</title><p>Moxibustion therapy has been shown to have better clinical effects compared with control treatments and to be an effective and safe alternative for treating DPN patients. However, due to the poor methodological quality of the included trials, more rigorous RCTs are required to evaluate the efficacy and safety of moxibustion before definitive recommendations for the use of the procedure to treat DPN patients can be made.</p></sec><sec><title>Author contributions</title><p><bold>Investigation:</bold> Qian Wu, Yi Zhang, Qing Pang, Meizhen Zhang, Yanan Yang</p><p><bold>Methodology:</bold> Bing Pang, Lijuan Du, Qing Ni</p><p><bold>Writing &#x02013; original draft:</bold> Yumeng Tan, Jun Hu</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Yumeng Tan</p></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD1\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e22286-s001.pdf\" orientation=\"portrait\" id=\"d38e1235\" position=\"anchor\"/></supplementary-material></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CI = confidence interval, DPN = diabetic peripheral neuropathy, MD = mean differences, MNCV = motor nerve conduction velocity, RCT = randomized controlled trial, RR = risk ratios, SNCV = sensory nerve conduction velocity, TCM = traditional Chinese medicine, TCSS = Toronto Clinical Scoring System, WM = western medicine.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Tan Y, Hu J, Pang B, Du L, Yang Y, Pang Q, Zhang M, Wu Q, Zhang Y, Ni Q. Moxibustion for the treatment of diabetic peripheral neuropathy: A systematic review and meta-analysis following PRISMA guidelines. <italic>Medicine</italic>. 2020;99:39(e22286).</p></fn><fn fn-type=\"other\"><p>YT and JH contributed to the work equally and should be regarded as co-first authors.</p></fn><fn fn-type=\"other\"><p>Because all of the data used in this meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process Trial.</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by the capital health research and development of special (no: 2016-1-4151), Beijing Natural Science Foundation (no: 7182143).</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during the study are available and included in this published article.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"book\"><comment>International Diabetes Federation. IDF Diabetes Atlas, 9th edition. Brussels, Belgium: International Diabetes Federation, 2019. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991449</article-id><article-id pub-id-type=\"pmc\">PMC7523835</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08282</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022344</article-id><article-id pub-id-type=\"art-access-id\">22344</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>6500</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Psychotherapy for depression in college students</article-title><subtitle>A protocol for systematic review and network meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Xiu</given-names></name><degrees>MN</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Niu</surname><given-names>Ming-Ming</given-names></name><degrees>MN</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Ma</surname><given-names>Pei-Fen</given-names></name><degrees>MN</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref><xref ref-type=\"aff\" rid=\"aff4\">^d</xref></contrib><contrib contrib-type=\"author\"><name><surname>Du</surname><given-names>Li</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff5\">^e</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0003-0150-9063</contrib-id><name><surname>Wan</surname><given-names>Lin</given-names></name><degrees>MN</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Orthopedics, Second Hospital of Lanzhou University</aff><aff id=\"aff2\"><label>b</label>Evidence-Based Nursing Center, School of Nursing, Lanzhou University</aff><aff id=\"aff3\"><label>c</label>Department of Nursing, Second Hospital of Lanzhou University</aff><aff id=\"aff4\"><label>d</label>School of Nursing, Lanzhou University</aff><aff id=\"aff5\"><label>e</label>The Third People's Hospital of Lanzhou city, Lanzhou, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Lin Wan, Department of Orthopedics, Second Hospital of Lanzhou University, No. 82, Cuiyingmen, Chengguan District, Lanzhou City, Gansu Province, China (e-mail: <email>390052783@qq.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22344</elocation-id><history><date date-type=\"received\"><day>20</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>26</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22344.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Depression is a disease with a high incidence and easy to relapse. It not only affects the work and life of patients, but also brings a heavy economic burden. University is the peak of depression, and the prevalence of depression among college students is much higher than that of ordinary people. The purpose of this research is to evaluate depression symptoms, life satisfaction, self-confidence, substance use, social adjustment, and dropout rates of the use of psychological intervention for college students.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>We will identify relevant trials from systematic searches in the following electronic databases: PubMed, Embase, Web of Science and The Cochrane Library. We will also search Clinical Trials.gov, the WHO International Clinical Trials Registry Platform for unpublished data. Additional relevant studies will be searched through search engines (such as Google), and references included in the literature will be tracked. All relevant randomized controlled trials (RCTs) will be included. There are no date restrictions. Use Cochrane Collaboration's Risk of bias tool to conduct risk of bias analysis. Use the Grades of Recommendation, Assessment, Development, and Evaluation to assess the quality of evidence. All statistical analysis will be performed using Stata (V.15.0.) and Review Manager (V.5.2.0).</p></sec><sec sec-type=\"results\"><title>Results:</title><p>A total of 6238 records were obtained by searching the database and 27 records were obtained by other sources. After removing duplicate records, there are 4225 records remaining. We excluded 3945 records through abstract and title, leaving 280 full-text articles.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>This will be the first study to compare the effects of different psychological treatments on depression in college students. We hope that this study will guide clinical decision-making of psychotherapy to better treat depression in college students.</p></sec><sec><title>Protocol Registration:</title><p>INPLASY202070134.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>college students</kwd><kwd>depression</kwd><kwd>network meta-analysis</kwd><kwd>psychotherapy</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Gansu Province Health Industry Scientific Research Project</funding-source><award-id>No. GSWSKY-2019-102</award-id><principal-award-recipient>Xiu Zhang</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Lanzhou University Second Hospital Cuiying Technology Project</funding-source><award-id>No. CY2018-HL18</award-id><principal-award-recipient>Xiu Zhang</principal-award-recipient></award-group><award-group id=\"award3\" award-type=\"Fundref\"><funding-source>Development and promotion of mental health tracking and intervention database for pediatric medical staff in Gansu Province</funding-source><award-id>No. 2018-RC-52</award-id><principal-award-recipient>Li Du</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Depression is a common mental health disorder, which is mainly manifested by significant and lasting depression, slow thinking, sleep disturbance, loss of appetite, etc. In severe cases, suicide attempts or behaviors may occur.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Each episode of depression lasts at least two weeks. In severe cases, it may last for several years. This has a serious impact on work and life, and has caused a heavy financial burden. According to the World Health Organization, more than 350 million people worldwide suffer from depression.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} The current incidence of depression in China is 6.1%.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} By 2020, depression may become the second largest disease after heart disease.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} And depression has become the main reason for people's loss of social function and ranks third in the global burden of disease.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Studies have shown that in the United States alone, the annual cost exceeds $43.7 billion.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} College students are faced with the pressure from interpersonal communication, arduous learning tasks and adaptation to the new environment and lifestyle, which makes them prone to produce strong psychological conflicts and lead to depression.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Therefore, compared with their peers, college students have a higher risk of depression.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]}</p><p>At present, the treatment of depression is mainly divided into medication and psychotherapy. Drug therapy mainly includes selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs), etc.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} Psychotherapy is to establish a relationship with the patient through a structured and purposeful connection and use a series of specific techniques to improve the patient's mental state.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} It plays an important role in the treatment of depression. At present, the common psychotherapy in clinical treatment methods include cognitive behavior therapy, group psychotherapy, interpersonal behavior therapy, mindfulness therapy, etc. Previous studies showed that there are few systematic reviews and meta-analysis of depression in college students. However, the relevant evidence for the effectiveness of psychotherapy is still unclear, and there is no evidence to directly compare different psychological interventions. Therefore, this field urgently needs a Bayesian network meta-analysis (NMA) method that combines direct evidence with indirect evidence from multiple treatment comparisons to estimate the correlation between all treatments.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} In this study, we will conduct a systematic review and NMA to evaluate depression symptoms, life satisfaction, self-confidence, substance use, social adjustment, and dropout rates of the use of psychotherapy for college students.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Eligibility criteria</title><sec><label>2.1.1</label><title>Type of study</title><p>We will include all relevant randomized controlled trials (RCTs) including crossover trials. There are no language restrictions.</p></sec><sec><label>2.1.2</label><title>Type of patient</title><p>The patients we will include are college students diagnosed with depression according to any diagnostic criteria, such as Diagnostic and Statistical Manual of Mental Disorders (DSM)-III,^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} DSM-IV,^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} and International Classification of Diseases, 10th Revision (ICD-10).^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} Studies in which participants have a diagnosis of bipolar disorder, psychotic depression will be excluded. In addition, studies where participants are not clearly diagnosed with depression will also be excluded.</p></sec><sec><label>2.1.3</label><title>Type of interventions</title><p>We will include RCTs comparing one psychological intervention with another control conditions for depression in college students. For psychotherapy, mindfulness therapy, cognitive-behavioral therapy (CBT), meditation therapy, comprehensive self-control training (CSCT),^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} acceptance and commitment therapy (ACT), ^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} and behavioral activation (BA) will be included. There will be no limit to the treatment session. In terms of control conditions, waiting-list control (WLC),^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} non-treatment control, physical exercise, bibliotherapy,^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} treatment as usual (TAU) will be included.</p></sec><sec><label>2.1.4</label><title>Type of outcomes</title><p>Primary outcome</p><p>Depression symptoms that mean the change in severity of depression from baseline to end point which is measured by the depression scale, such as Beck Depression Inventory (BDI),^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} The Center for Epidemiologic Studies Depression Scale (CESD-R),^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} Hamilton Rating Scale for Depression (HRSD).^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]}</p><p>Second outcomes</p><list list-type=\"simple\"><list-item><label>1.</label><p>self-confidence, life satisfaction was assessed using visual rating scale</p></list-item><list-item><label>2.</label><p>social adjustment was assessed using the Social Adaptation Self Evaluation Scale (SASS) ^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]} and the Social Adjustment Scale-Self Report for Youth.^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]}</p></list-item><list-item><label>3.</label><p>substance use was measured with 10 items to assess the use of eight substances, quantity per drinking and smoking day.^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]}</p></list-item><list-item><label>4.</label><p>Dropout rates from the beginning of the study to the end of the intervention.</p></list-item></list></sec></sec><sec><label>2.2</label><title>Data source</title><p>We will identify relevant trials from systematic searches in the following electronic databases: PubMed, Embase, Web of Science and The Cochrane Library. We will also search Clinical Trials.gov, the WHO International Clinical Trials Registry Platform for unpublished data. The search terms will include &#x0201c;depression&#x0201d;, &#x0201c;depressive disorder&#x0201d;, &#x0201c;students&#x0201d;, &#x0201c;university student&#x0201d;, &#x0201c;college student&#x0201d;. Additional relevant studies will be searched through search engines (such as Google), and references included in the literature will be tracked. There is no date restriction. Detail of search strategy of PubMed is shown in Table <xref rid=\"T1\" ref-type=\"table\">1</xref> as well as detail of search strategy of Embase is shown in Table <xref rid=\"T2\" ref-type=\"table\">2</xref>.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Searching strategy in PubMed.</p></caption><graphic xlink:href=\"medi-99-e22344-g001\"/></table-wrap><table-wrap id=\"T2\" orientation=\"portrait\" position=\"float\"><label>Table 2</label><caption><p>Searching strategy in Embase.</p></caption><graphic xlink:href=\"medi-99-e22344-g002\"/></table-wrap></sec><sec><label>2.3</label><title>Study selection</title><p>All records identified in the databases will be collected in the reference management software EndNote X8 for data screening. Two (MMN and PFM) reviewers will use data extraction tables to extract data from the original report independently, including research characteristics (such author information, publication year, journal and country), patient characteristics, intervention and outcome. Any disagreements will be resolved by the third member of our review team.</p></sec><sec><label>2.4</label><title>Risk of bias analysis</title><p>According to Cochrane Collaboration's Risk of bias tool, we will assess risk of bias as &#x02018;low risk&#x02019;, &#x02018;unclear risk&#x02019; or &#x02018;high risk&#x02019;.^{[<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} The following items will be evaluated: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data and selective outcome reporting and other sources of bias.^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} The evaluation will be conducted by two independent raters (PFM and LD). Any disagreements will be resolved by a third review author.</p></sec><sec><label>2.5</label><title>Statistical analysis</title><sec><label>2.5.1</label><title>Pairwise meta-analysis</title><p>We will use Review Manager (V.5.2.0) to perform traditional pairwise meta-analysis. Dichotomous data will be expressed as relative risk (RR) with 95% confidence interval (CI), and continuous outcomes will be expressed as standard mean difference (SMD) with 95% CI.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>]}</p></sec><sec><label>2.5.2</label><title>Network meta-analysis</title><p>To simultaneously assess the comparative effects of more than 2 psychotherapy, an NMA will be performed. An NMA synthesizes direct and indirect comparisons over an entire network of psychotherapy, allowing for all available evidence to be considered in one analysis. Based on the network development process as outlined above, the outcome variable for the NMA is the standardized mean change in the DSST (measured using Hedge's G) from baseline to end of study. The standardization is based on the pooled (across treatment arms within study) estimate of the SDs. The NMA will be carried out using a frequentist's approach, and a 2-way ANOVA model is used. As the residual variances between treatment groups are known, it is possible for random effect estimates to be produced, which account for the between-trial heterogeneity. The model is used to perform ordinary pairwise meta-analysis comparing the different psychotherapy based on direct evidence from the clinical studies. Ranking probabilities will be calculated based on the joint distribution of the estimates of relative efficacy.^{[<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]}</p><p>Consistency will be addressed through the principle of node splitting by using a network meta-regression model. The purpose of node-splitting is to investigate if the relative effect of 2 psychotherapy based on direct comparisons is comparable with the same effect based on indirect comparisons. Statistically, the model is an extension of the NMA, which allows for a different relative effect between the 2 psychotherapy that are being split in head-to-head trials compared with all other trials. NMA will be implemented by the mvmeta software package in Stata (15.0; Stata Corporation, College Station, TX, USA Stata),^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]} If <italic>P</italic> value &#x0003c;.1 and I² &#x0003e; 50%, it is considered that there is heterogeneity in the study, and sensitivity analysis or subgroup analysis will be performed to detect the source of heterogeneity. Funnel plot and Egger linear regression analysis will be used to assess publication bias. Using Review Manager (V.5.2.0) to analyze the risk of bias in the included studies, where the green, yellow, and red in the image represent low, unclear, and high risks, respectively.^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]}</p></sec><sec><label>2.5.3</label><title>Subgroup analysis</title><p>If statistical heterogeneity is evident, we will analyze the causes of heterogeneity, if there is enough data (such as differences between sexes, comparison between different countries, studies sponsored versus not sponsored by companies).</p></sec><sec><label>2.5.4</label><title>Sensitivity analysis</title><p>We will use the exclusion method to conduct sensitivity analysis:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>exclude low-quality studies;</p></list-item><list-item><label>(2)</label><p>exclude studies with comorbid physical or mental illnesses;</p></list-item><list-item><label>(3)</label><p>exclude trials with missing data.</p></list-item></list></sec></sec><sec><label>2.6</label><title>Quality of evidence</title><p>We will use Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess the quality of evidence for the primary outcomes.^{[<xref rid=\"R33\" ref-type=\"bibr\">33</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} The quality of evidence is assessed as &#x02018;high&#x02019;, &#x02018;moderate&#x02019;, &#x02018;low&#x02019; or &#x02018;very low&#x02019;. The following item will be evaluated: limitations, inconsistency, imprecision, indirectness, and publication bias.^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]}</p></sec><sec><label>2.7</label><title>Summary of findings</title><p>A &#x0201c;summary of finding&#x0201d; table will be created for the major outcome. We will also add absolute and relative percentage changes to the &#x0201c;summary of finding&#x0201d;. For detailed information, see Table <xref rid=\"T3\" ref-type=\"table\">3</xref>; we have listed partial summary of findings for the main comparison.</p><table-wrap id=\"T3\" orientation=\"portrait\" position=\"float\"><label>Table 3</label><caption><p>Summary of findings for the main comparison.</p></caption><graphic xlink:href=\"medi-99-e22344-g003\"/></table-wrap></sec></sec><sec><label>3</label><title>Result</title><sec><label>3.1</label><title>Results of the search</title><p>A total of 6238 records were obtained by searching the database and 27 records were obtained by other means. After removing duplicate records, there are 4225 records remaining. We excluded 3945 records through abstract and title, leaving 280 full-text articles. The document screening flowchart is shown in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>The flowchart of the screening process.</p></caption><graphic xlink:href=\"medi-99-e22344-g004\"/></fig></sec><sec><label>3.2</label><title>Characteristic of included studies</title><p>In a preliminary trial, we included 8 studies. The average age of patients was 18 to 26, with a maximum sample size of 181 and a minimum sample size of 32. The research period ranges from one month to 12 months. For more detailed information, see Table <xref rid=\"T4\" ref-type=\"table\">4</xref>.</p><table-wrap id=\"T4\" orientation=\"portrait\" position=\"float\"><label>Table 4</label><caption><p>Basic characteristics of some of the included studies.</p></caption><graphic xlink:href=\"medi-99-e22344-g005\"/></table-wrap></sec></sec><sec><label>4</label><title>Discussion</title><p>At present, although some studies have evaluated the intervention effects of psychotherapy, there is no NMA to compare the therapeutic effects of different psychological interventions for college students. Therefore, this systematic review and NMA will summarize the direct comparison and indirect comparison evidence to evaluate different psychological interventions. We hope that this study will help guide clinical decision-making for psychotherapy to better treat depression in college students.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Xiu Zhang, Lin Wan.</p><p><bold>Data curation:</bold> Xiu Zhang, Ming-Ming Niu, Pei-Fen Ma, Li Du, Lin Wan.</p><p><bold>Methodology:</bold> Xiu Zhang, Lin Wan.</p><p><bold>Software:</bold> Xiu Zhang, Ming-Ming Niu, Pei-Fen Ma, Li Du.</p><p><bold>Writing &#x02013; original draft:</bold> Xiu Zhang, Ming-Ming Niu, Lin Wan.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Xiu Zhang, Lin Wan.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: ACT = acceptance and commitment therapy, BA = behavioral activation, BDI = beck depression inventory, CBT = cognitive-behavioral therapy, CESD-R = center for epidemiologic studies depression scale revised, CSCT = comprehensive self-control training, DSM = diagnostic and statistical manual of mental disorders, HRSD = Hamilton Rating Scale for depression, ICD = International Classification of Diseases, NMA = network meta-analysis, RCTs = randomized controlled trials, SASS = social adaptation self-evaluation scale, SMD = standard mean difference, SNRIs = serotonin norepinephrine reuptake inhibitors, SSRIs = selective serotonin reuptake inhibitors, SUCRA = surface under the cumulative ranking area, TAU = treatment as usual, TCAs = tricyclic antidepressants, WLC = waiting-list control.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Zhang X, Niu MM, Ma PF, Du L, Wan L. Psychotherapy for depression in college students: a protocol for systematic review and network meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22344).</p></fn><fn fn-type=\"equal\"><p>XZ and M-MN contributed equally to this work.</p></fn><fn fn-type=\"other\"><p>This study is based on a network meta-analysis of published studies, so ethical approval and patient consent are not required. And this systematic review and network meta-analysis will be published in a peer-reviewed journal.</p></fn><fn fn-type=\"supported-by\"><p>This study is supported by Gansu Province Health Industry Scientific Research Project (No. GSWSKY-2019-102), Lanzhou University Second Hospital Cuiying Technology Project (No. CY2018-HL18) and Development and promotion of mental health tracking and intervention database for pediatric medical staff in Gansu Province (No. 2018-RC-52).</p></fn><fn fn-type=\"COI-statement\"><p>There are no potential conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"book\"><collab>American Psychiatric Association</collab>. <article-title>Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991485</article-id><article-id pub-id-type=\"pmc\">PMC7523836</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-10047</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022471</article-id><article-id pub-id-type=\"art-access-id\">22471</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3900</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Clinical warning signs of life-threatening hematochezia in neurosurgical patients with long-term bed rest</article-title><subtitle>Three cases report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Jung</surname><given-names>Ji-Ho</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Cho</surname><given-names>Yong-Hwan</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Park</surname><given-names>Man-Seok</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Joo</surname><given-names>Sung-Pil</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Neurosurgery</aff><aff id=\"aff2\"><label>b</label>Department of Neurology, Chonnam National University Hospital and Medical School, Gwangju, Republic of Korea.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Sung-Pil Joo, Department of Neurosurgery, Chonnam National University Hospital, 42 Jebong-Ro Dong-Gu, Gwangju, 501-757 Republic of Korea (e-mail: <email>nsjsp@jnu.ac.kr, nsjsp@hanmail.net</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22471</elocation-id><history><date date-type=\"received\"><day>18</day><month>12</month><year>2019</year></date><date date-type=\"rev-recd\"><day>17</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>31</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22471.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Patients with long term bed rest in intensive care unit after neurosurgery could experience splanchnic hypoperfusion. These patients have several other medical conditions that exacerbate splanchnic hypoperfusion during treatment and the splanchnic hypoperfusion could result in &#x0201c;stress-induced intestinal necrosis&#x0201d;, which could cause massive hematochezia. We report here the experience of life-threatening hematochezia in 3 patients who underwent brain surgery in our institution.</p></sec><sec sec-type=\"subjects\"><title>Patients concerns:</title><p>One female patient (72-year-old) and 2 male patients (58- and 35-year-old) were admitted to our institution because of traumatic intracerebral hemorrhage, subarachnoid hemorrhage due to a ruptured anterior communicating artery, and subarachnoid hemorrhage with unknown cause respectively. All patients underwent emergency brain surgery for diagnosis and treatment. After surgery, they all experienced long-term bed rest in intensive care unit. Hematochezia occurred on postoperative day 15, 17, and 49, respectively.</p></sec><sec><title>Diagnoses:</title><p>All of the patients were assessed by abdomen/pelvis computed tomography and underwent a colonoscopy.</p></sec><sec><title>Interventions:</title><p>The female patient underwent embolization through pelvic arteriography and epinephrine injection through colonoscopy, but a total colectomy and ileostomy was performed due to refractory hematochezia. 58-year-old male patient had a laparoscopic ileostomy for the bowel rest. The other patient underwent nil per os and conservative treatment for 2 weeks.</p></sec><sec><title>Outcomes:</title><p>The female patient was discharged without further treatment plan, 58-year-old male patient survived after laparoscopic ileostomy, while the other patient survived after 2 weeks of nil per os.</p></sec><sec><title>Lesson:</title><p>Abdominal symptoms, such as hematochezia, should be actively managed in neurosurgical patients who are undergoing long-term bed rest in an intensive care unit under physiologically stressful medical conditions.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>hematochezia</kwd><kwd>intensive care unit</kwd><kwd>neurosurgery</kwd><kwd>stress</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Chonnam National University Hospital Biomedical Research Institute</funding-source><award-id>CRI16040-21</award-id><principal-award-recipient>Sung-Pil Joo</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Patients who undergo brain surgery often need prolonged intensive care unit (ICU) management. The patients treated in ICU may suffer from a number of different symptoms during their treatment. In particular, gastrointestinal (GI) tract dysfunction is quite common. Many GI tract complications, such as diarrhea, constipation, stool impaction, infection, and hematochezia, can occur during long-term hospitalization. According to Reintam A et al, 59% of patients experience at least 1 GI symptom during their ICU stay.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} However, neurosurgeons tend to overlook GI tract symptoms, since their focus is on patients&#x02019; neurological changes and ICU patients are frequently unable to adequately communicate their symptoms. Additionally, there are currently no validated markers for assessing gut function,^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} with some authors describing GI bleeding as the only credible symptom of GI track failure.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Critical illness that needs brain surgery can cause splanchnic hypoperfusion, resulting in mesenteric ischemic necrosis, which in turn can manifest as hematochezia.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} We report here the experience of life-threatening hematochezia in 3 patients who underwent brain surgery in our institution between January 1, 2016 and December 31, 2017. By analyzing these events, we aim to evaluate the importance of abdominal symptoms, such as hematochezia, in the management of ICU patients in the neurosurgery department.</p></sec><sec><label>2</label><title>Case presentation</title><p>We reviewed the medical records of 1965 patients who underwent brain surgery between January 1, 2016 and December 30, 2017. Three patients who experienced massive hematochezia and were diagnosed with chronic ulcer by colonoscopy and biopsy findings were identified and selected for further analysis. One of the patients was discharged without further management plan, while 2 patients survived and recovered (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>). For these 3 cases, we made the diagnosis of &#x0201c;stress-induced bowel ischemia manifesting as hematochezia&#x0201d; after detailed consideration.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Summary of the reported cases.</p></caption><graphic xlink:href=\"medi-99-e22471-g001\"/></table-wrap><sec><label>2.1</label><title>Illustrative cases</title><p>A 72-year-old woman who had no past medical history was admitted to the emergency center in mental stupor after a fall. At the emergency room, Glasgow coma scale score of 10 was determined. Initial computed tomography (CT) revealed traumatic intracerebral haemorrhage in the left temporal lobe, frontal subdural hemorrhage, traumatic subarachnoid hemorrhage (SAH), and multiple hemorrhagic contusions. Emergency craniotomy and removal of the hematoma were performed. Following the procedure, the patient was admitted to the ICU, where she was treated with antibiotics for concomitant pneumonia and continuous renal replacement therapy (CRRT) for acute renal injury. She was on a mechanical ventilator and a vasopressor was administered due to the general condition, followed by sedative therapy for brain swelling. On the 15th day of the ICU treatment, massive hematochezia occurred. Abdomen/pelvis CT (APCT) revealed contrast media extravasation in the rectum, as well as proctocolitis and enteritis involving the pelvic small bowel loop. To treat the extravasation in the rectum, pelvic arteriography and embolization were performed. Bleeding recurred at postoperative day (POD) 27, requiring colonoscopy and administration of epinephrine. Despite these procedures, refractory hematochezia continued. The patient underwent total colectomy and ileostomy, after which she experienced sepsis due to peritonitis. The patient was discharged with no further treatment plan (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Case 1. A: Patient underwent craniotomy and removal of a hematoma due to traumatic intracerebral hemorrhage in the left temporal lobe. B: APCT revealed media extravasation at rectum (black arrow). C. Pre-angioembolization angiography shows extravasation of right middle rectal artery (white arrow). D: Extravasation of contrast media stopped following embolization with histoacryl and lipiodol. E: Following a recurrence of bleeding, colonoscopy reveled multiple ulcerative lesions with suspected exposed vessel. F: Total colectomy and end-ileostomy was performed for management of refractory hematochezia. APCT&#x0200a;=&#x0200a;abdomen/pelvis computed tomography.</p></caption><graphic xlink:href=\"medi-99-e22471-g002\"/></fig><p>A 35-year-old man positive for human immunodeficiency virus infection was admitted to our hospital with sudden paraparesis (grade III) with rigidity. A brain CT revealed SAH of unknown origin and spinal magnetic resonance imaging demonstrated intradural extramedullary mass on thoracic 11 to 12 level. The patient underwent cerebral angiography, which detected no aneurysm. There were no abnormal signs of somatosensory evoked potential, and results of nerve conduction study and electromyography were normal. Extra-ventricular drainage was performed to identify human immunodeficiency virus encephalitis, but ribonucleic acid polymerase chain reaction was negative in the analysis of the cerebrospinal fluid. At POD 49, hematochezia occurred. APCT showed proctocolitis, while colonoscopy revealed ulcerative lesions. The patient recovered after laparoscopic ileostomy for bowel rest. Chronic ulcer was confirmed by pathologic exam (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>).</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Case 2. A: SAH with no aneurysm sac. B: APCT revealed edematous wall thickening in distal sigmoid colon and rectum, suggesting proctocolitis (white arrow). C and D: Colonoscopy showed diffuse ulcerative lesions with mucosal friability. APCT&#x0200a;=&#x0200a;abdomen/pelvis computed tomography, SAH&#x0200a;=&#x0200a;subarachnoid haemorrhage.</p></caption><graphic xlink:href=\"medi-99-e22471-g003\"/></fig><p>A 58-year-old man with ruptured anterior choroidal artery aneurysm underwent clipping. Ten days later, coil embolization was performed because of aneurysm recurrence, followed by administration of dual antiplatelet agents. In ICU, the patient was treated for sepsis with antibiotics and a vasopressor. Hematochezia was observed at POD 17. Colonoscopy showed multiple erosion. After 2 weeks of nil per os management and discontinuation of the antiplatelet agents, the patient recovered (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>).</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Case 3. A: APCT showed rectum and sigmoid colon wall thickening and enhancement suggestive of proctocolitis involving rectum and sigmoid colon (white arrows). B, C, and D: serial colonoscopy images. Multiple ulcerative lesions improved following NPO. APCT&#x0200a;=&#x0200a;abdomen/pelvis computed tomography, NPO&#x0200a;=&#x0200a;nil per os.</p></caption><graphic xlink:href=\"medi-99-e22471-g004\"/></fig></sec></sec><sec><label>3</label><title>Discussion</title><p>Delayed massive hematochezia occurred in 3 patients undergoing long-term ICU care following brain surgery. Two of the 3 patients underwent surgical treatment and 1 underwent 2 weeks of intense conservative treatment. One of the patients who underwent surgical treatment was discharged with no treatment plan, while the remaining surgically treated patient and the conservatively treated patient recovered fully. All of the studied patients exhibited the following common characteristics:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>experience of brain surgery;</p></list-item><list-item><label>(2)</label><p>long-term bed rest in ICU;</p></list-item><list-item><label>(3)</label><p>concomitant medical issue, such as infection or vasopressor usage;</p></list-item><list-item><label>(4)</label><p>severe constipation and abdominal distension without early abdominal tenderness;</p></list-item><list-item><label>(5)</label><p>proctocolitis finding in APCT;</p></list-item><list-item><label>(6)</label><p>multiple ulcerative lesions on colonoscopy; and</p></list-item><list-item><label>(7)</label><p>pathological examination suggesting the presence of a chronic ulcer.</p></list-item></list><p>The mucosal and submucosal layers of GI tract is vulnerable to ischemic changes because seventy percent of the mesenteric blood flow perfuses these layers.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} The extent of intestinal damage due to ischemia varies, ranging from mucosal lesions due to reversible ischemia to necrosis and perforation with transmural injury.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Stress conditions, such as ICU care following brain surgery, can result in splanchnic hypoperfusion, which was shown to be linked with mesenteric ischemic necrosis.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} If intestinal necrosis or ulceration exposes the bowel lumen vessels and there is damage present on the exposed vessels, it can lead to massive hematochezia. Stress situations induce sympathetic nervous system excitation and vagal inactivation. Sympathetic excitation causes intestinal vasoconstriction and results in mucosal hypoxia, while vagal inactivation inhibits anti-inflammatory pathways, leading to intestinal injury.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R6\" ref-type=\"bibr\">6</xref>&#x02013;<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Approximately 3% to 4% of stress-induced mucosal damage was reported to result in clinically significant GI bleeding.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} The 3 patients in our study underwent long periods of ICU care following brain surgery, as well as concomitant medical conditions. Their bodies were subjected to a constant stress led to intestinal necrosis.</p><p>A number of other concomitant medical conditions experienced by neurosurgical ICU patients, such as the use of vasopressors, sepsis, hemodialysis, and utilization of mechanical ventilators, can exacerbate splanchnic hypoperfusion. Vasopressors are commonly used to maintain cerebral perfusion during delayed vasospasm in subarachnoid hemorrhage caused by aneurismal rupture, septic shock, and neurogenic shock.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>,<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} Because vasopressors centralize the blood volume and increase blood supply to vital organs such as the brain and heart, they cause splanchnic hypoperfusion, which can exacerbate mesenteric ischemia.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} In patients with multiple trauma in neurosurgical ICU, acute kidney injury due to rhabdomyolysis, acute kidney injury due to use of mannitol to control intracranial pressure, refractory metabolic acidosis, and acute kidney injury in septic conditions may occur. In these situations, renal replacement such as conventional hemodialysis and CRRT cause hypovolemia and myocardial depression, leading to a decrease in splanchnic perfusion.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>,<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} Use of a mechanical ventilator was shown to cause splanchnic hypoperfusion (resulting from positive end-expiratory pressure [PEEP]), decrease cardiac output, activate the sympathetic system, and cause a systemic inflammatory response that results in GI tract damage (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>).^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]}</p><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>Overview of the development of stress-induced intestinal necrosis and hematochezia following neurosurgery in critically ill patients in ICU care with multiple concomitant medical conditions. ICU = intensive care unit.</p></caption><graphic xlink:href=\"medi-99-e22471-g005\"/></fig><p>Intestinal necrosis, which occurs in neurosurgical patients, may be detected late for the following reasons:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>neurosurgeons tend not to pay much attention to the patient's GI symptoms,</p></list-item><list-item><label>(2)</label><p>chronic intestinal necrosis manifests as non-specific GI symptoms in the early phase,</p></list-item><list-item><label>(3)</label><p>there are no specific laboratory tests for detecting mesenteric ischemia, and</p></list-item><list-item><label>(4)</label><p>mentally impaired patients do not provide adequate descriptions of GI symptoms (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>).</p></list-item></list><p>In advanced intestinal necrosis, at the point at which neurosurgeons become aware of the severity of the GI symptoms, the patient can experience massive hematochezia and intestinal necrosis may have already progressed too far to treat easily. Gong et al reported 3 cases of stress-induced intestinal necrosis.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} Stress-induced intestinal necrosis is a process that progresses slowly and does not accompany abdominal pain in early stages. Accordingly, the 3 patients in this study exhibited signs of hematochezia on POD 15, 17, or 49, but did not complain of acute abdominal pain. Routine laboratory tests such as the measurements of lactate, lactate dehydrogenase, amylase, D-dimer, pH, and base excess have low specificity for diagnosing mesenteric ischemia.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} Recently, meta-analysis evaluating the use of serum intestinal fatty acid-binding protein for the diagnosis of acute intestinal ischemia reported a sensitivity of 0.80 and specificity of 0.85.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} However, the use of serum intestinal fatty acid-binding protein as a biomarker is still under study and clinical use is not common.</p><p>GI tract bleeding is associated with significantly higher mortality^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} and the prognosis in patients with mesenteric ischemia is poor, with a lethal outcome found in up to 60% of patients.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>,<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} GI complications requiring surgical treatment, such as GI bleeding and perforation, were reported in 6.8% of neurosurgical patients, with 2.1%, patients dying of GI complications.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} In our study, 1 of the patients was discharged with no further treatment planned, 1 survived after laparoscopic ileostomy, and 1 survived after 2 weeks of Nil per os. Based on our observations, a number of recommendations can be made. First, if a patient is affected by concomitant medical conditions, he/she should be considered to be at risk of stress-induced intestinal necrosis. All 3 cases in our report presented with concomitant medical conditions, notably infection. Two of the 3 cases needed vasopressors. The patient who was discharged with no curative plan underwent treatment with CRRT, mechanical ventilator, vasopressor, and antibiotics due to septic shock. Second, non-essential use of vasoconstrictors should be prohibited. Third, normal intestinal environment should be maintained by adjusting the patient's bowel habits. Patients undergoing long-term bed rest tend to experience abdominal distension due to GI tract hypomotility. Worsening GI distension leads to a disruption in the blood supply, resulting in injury to the GI wall and thereby causing bacterial translocation, leading to peritoneal infection and septic conditions.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Stress-induced intestinal necrosis is a relatively slow process, so it is difficult to predict the occurrence of GI failure in advance. Therefore, neurosurgeons should regularly check the GI symptoms of patients who are affected by physiological stress conditions.</p></sec><sec><label>4</label><title>Conclusion</title><p>Regeneration of the GI tract is inhibited in the conditions of physiological stress, and worsening of the situation can lead to severe colitis and ulceration. Patients with severe cerebral lesions undergo prolonged state of absolute bed rest in ICU care, tend to experience septic conditions with prolonged use of antibiotics and vasopressor agents, and are often kept on mechanical ventilation. In these situations, the patients with cerebral lesions are exposed to prolonged physiological stress. There are multiple factors that can delay the diagnosis of GI problems, including the focus of the treating physician on neurological changes, the inability of ICU patients to report symptoms, and the lack of validated markers for gut function. It is essential for physicians to pay close attention to the GI symptoms in critically ill patients following neurosurgery, particularly in patients with multiple concomitant medical conditions, and to actively cope with GI issues.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Sung-Pil Joo</p><p><bold>Data curation:</bold> Ji-Ho Jung, Yong-Hwan Cho</p><p><bold>Supervisions:</bold> Man-Seok Park, Sung-Pil Joo</p><p><bold>Writing:</bold> Ji-Ho Jung</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: APCT = abdomen/pelvis computed tomography, CRRT = continuous renal replacement therapy, CT = computed tomography, GI = gastrointestinal, ICU = intensive care unit, POD = postoperative day.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Jung JH, Cho YH, Park MS, Joo SP. Clinical warning signs of life-threatening hematochezia in neurosurgical patients with long-term bed rest: three cases report. <italic>Medicine</italic>. 2020;99:39(e22471).</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by a grant (CRI16040-21) from the Chonnam National University Hospital Biomedical Research Institute.</p></fn><fn fn-type=\"other\"><p>Written informed consent was obtained from the patient for publication of this case report and accompanying images.</p></fn><fn fn-type=\"other\"><p>The authors have no personal, financial, or institutional interests in any of the drugs, materials, or devices described in this article.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991451</article-id><article-id pub-id-type=\"pmc\">PMC7523838</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08473</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022357</article-id><article-id pub-id-type=\"art-access-id\">22357</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3800</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Efficacy and safety of Kanglaite injection combined with chemotherapy for colorectal cancer</article-title><subtitle>A protocol for systematic review and meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0001-5000-5895</contrib-id><name><surname>Mao</surname><given-names>Weili</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Fan</surname><given-names>Yihua</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Cheng</surname><given-names>Chao</given-names></name><degrees>MB</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yuan</surname><given-names>Xingyu</given-names></name><degrees>MB</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Lan</surname><given-names>Tian</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Mao</surname><given-names>Kaili</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Jun</given-names></name><degrees>MB</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>People's Hospital of QuZhou, Quzhou, Zhejiang province</aff><aff id=\"aff2\"><label>b</label>First Teaching Hospital of Tianjin University of Traditional Chinese Medicine</aff><aff id=\"aff3\"><label>c</label>Tianjin University of Traditional Chinese Medicine, Tianjin, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Jun Wang, People's Hospital of QuZhou, No.2 Zhongloudi Road, Kecheng District, Quzhou 324000, Zhejiang province, China (e-mail: <email>wangjun1983hy@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22357</elocation-id><history><date date-type=\"received\"><day>25</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>26</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22357.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>The incidence and mortality of colorectal cancer are high. Chemotherapy is currently the commonly used therapeutic scheme, but there are drug resistance and toxic and side effects. Kanglaite (KLT) injection is a broad-spectrum anticancer drug extracted from <italic>Semen Coicis (Yi Yi Ren)</italic>, which has been widely used in the treatment of colorectal cancer. Clinical practice shows that KLT injection combined with chemotherapy has certain therapeutic advantages, but there is a lacking of evidence of evidence-based medicine. The purpose of this study is to systematically investigate the efficacy and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>Randomized controlled trials of KLT injection combined with chemotherapy in the treatment of colorectal cancer were retrieved from English databases (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese databases (China National Knowledge Infrastructure, Wanfang, Chongqing VIP Chinese Science and Technology Periodical Database, Chinese Biological and Medical database), as well as searching Baidu academic and Google academic manually, and the retrieval time was from their establishment to August 2020. Two researchers independently conducted data extraction and literature quality evaluation on the quality of the included literatures, and meta-analysis was conducted on the included literatures using RevMan 5.3 (developed by the UK's International Cochrane Collaboration).</p></sec><sec sec-type=\"results\"><title>Results:</title><p>This study assessed the efficacy and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer by effective rate, Karnofsky Performance Status, Carcinoemybryonic Angtigen remission rate, pain remission rate, and incidence of adverse reactions etc.</p></sec><sec sec-type=\"conclusion\"><title>Conclusions:</title><p>This study will provide reliable evidence-based evidence for the clinical application of KLT injection combined with chemotherapy in the treatment of colorectal cancer.</p></sec><sec><title>Ethics and dissemination:</title><p>The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.</p></sec><sec><title>OSF Registration number:</title><p>DOI 10.17605/OSF.IO/EKVAF</p></sec></abstract><kwd-group><title>Keywords</title><kwd>chemotherapy</kwd><kwd>colorectal cancer</kwd><kwd>Kanglaite injection</kwd><kwd>protocol</kwd><kwd>systematic review</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>the Natural Science Foundation of Zhejiang Province</funding-source><award-id>NO.LYQ20H300001</award-id><principal-award-recipient>weili mao</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Colorectal cancer refers to a cancer occurring in the colon or rectum, which may occur in any part of the colorectal, but the rectum and sigmoid are the most common, it is a common and malignant tumor in the gastrointestinal tract. And it has high morbidity which is the third and mortality rate which is the second^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} among common and malignant tumors in the gastrointestinal tract globally, while its morbidity is the fourth in China.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} Globally, there are 800,000 new cases of colorectal cancer every year, accounting for about 10% of global malignant tumors.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} The incidence of colorectal cancer is increasing year by year. Some studies have reported that the number of colorectal cancer patients will increase by more than 60% by 2030.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Its pathogenesis has not been fully confirmed, but it is generally believed to be related to genetic factors, gene mutation and high-fat diet.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} The early symptoms of colorectal cancer are not obvious, but with the increase of cancers&#x02019; size, the symptoms such as hematochezia, diarrhea, change of bowel habits, local abdominal pain, anemia, and so on appear. The early symptoms of most patients are not easily detected. In the past 20 years, about 20% of patients had reached the advanced stage when clinical diagnosed and lost the best opportunity for treatment.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} At present, the treatment of advanced colorectal cancer is mainly based on chemotherapy, which can improve the survival rate and prolong the survival period of patients to a certain extent.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} However, patients&#x0201d; immune function will be affected to different extent in the long term chemotherapy, and there are short-term or long-term toxic and side effects.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} Therefore, it is necessary to seek alternative therapies with high efficacy and low side effects.</p><p>Chinese medicine is being widely used in the treatment of colorectal cancer.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Clinical evidence shows that Chinese medicine has multi-targets, can be applied to multiple stages of colorectal cancer, and has reliable anti-inflammatory effects.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} KLT injection is a Chinese materia medical injection with anti-tumor activity.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} In 1997, KLT injection was officially approved by the Ministry of Public Health in China for the treatment of liver cancer, lung cancer, and gastric cancer.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>,<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} KLT has showed good efficacy in the USA and its clinical trial smoothly completed in Russia, where it has been registered as a new drug and can be marketed legally.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} At present, KLT injection is widely used in the treatment of cancers such as lung cancer, liver cancer, pancreatic cancer, gastric cancer, and colorectal cancer, with reliable clinical efficacy.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>&#x02013;<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]}</p><p>Although a number of randomized controlled trials (RCTs) have shown that KLT injection combined with chemotherapy has the characteristics of enhancing the efficacy of chemotherapy and reducing the toxic and side effects in the treatment of colorectal cancer,^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>&#x02013;<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} there are differences in research protocols and efficacy among various clinical trials, which have affected the promotion of this therapy to some degree. Therefore, this study plans to systematically evaluate the effectiveness and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer, so as to provide reliable evidence-based proof for the clinical application of KLT injection in the treatment of colorectal cancer.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Protocol register</title><p>This protocol of systematic review and meta-analysis has been drafted under the guidance of the preferred reporting items for systematic reviews and meta-analyses protocols. Moreover, it has been registered on open science framework (OSF) on August 25, 2020. (Registration number: DOI 10.17605/OSF.IO/EKVAF).</p></sec><sec><label>2.2</label><title>Ethics</title><p>Since this is a protocol with no patient recruitment and personal information collection, the approval of the ethics committee is not required.</p></sec><sec><label>2.3</label><title>Eligibility criteria</title><sec><label>2.3.1</label><title>Types of studies</title><p>We will collected all available RCTs on KLT injection combined with chemotherapy for colorectal cancer, regardless of blinding, publication status, region, but language will be restricted to Chinese and English.</p></sec><sec><label>2.3.2</label><title>Research objects</title><p>Patients with colorectal cancer who were definitely diagnosed, regardless of nationality, race, age, gender, or course of disease. Patients with other malignancies and non-primary colorectal cancer were excluded.</p></sec><sec><label>2.3.3</label><title>Intervention measures</title><p>The treatment group was treated with KLT injection combined with chemotherapy. The control group was treated with the same chemotherapy regimen. (There is no limit on the dose and course of KLT injection, nor on the dose, frequency and course of chemotherapy.)</p></sec><sec><label>2.3.4</label><title>Outcome indicators</title><list list-type=\"simple\"><list-item><label>(1)</label><p>Primary outcome: &#x02460; the overall effective rate; &#x02461; Karnofsky Performance Status</p></list-item><list-item><label>(2)</label><p>Secondary outcomes: &#x02460; Carcinoemybryonic Angtigen remission rate; &#x02461; pain remission rate; &#x02462; incidence of adverse reactions.</p></list-item></list></sec></sec><sec><label>2.4</label><title>Exclusion criteria</title><list list-type=\"simple\"><list-item><label>(1)</label><p>Literatures published repeatedly;</p></list-item><list-item><label>(2)</label><p>Literatures which are abstracts or have incomplete data and whose data cannot be obtained after contacting the author;</p></list-item><list-item><label>(3)</label><p>Literatures with obvious data errors;</p></list-item><list-item><label>(4)</label><p>Literature with high bias risk by randomization or allocation concealment assessment^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>]};</p></list-item><list-item><label>(5)</label><p>Literatures in which the intervention measures are inconsistent with the literatures;</p></list-item><list-item><label>(6)</label><p>Literatures with no relevant outcome indicators.</p></list-item></list></sec><sec><label>2.5</label><title>Search strategy</title><p>&#x0201c;Kang Lai Te (Kanglaite)&#x0201d;, &#x0201c;Jie Zhi Chang Ai (colorectal cancer)&#x0201d;, &#x0201c;Jie Zhi Chang Ai Zhong (colorectal neoplasm)&#x0201d;, &#x0201c;Zhi Chang Ai (rectal cancer)&#x0201d; and &#x0201c;Da Chang Ai (colorectal cancer)&#x0201d; were searched in Chinese databases, including China National Knowledge Infrastructure, Wanfang, Chongqing VIP Chinese Science, Technology Periodical Database and Chinese Biological and Medical database; &#x0201c;Kanglaite&#x0201d;, &#x0201c;KLT&#x0201d;, &#x0201c;Colorectal Neoplasm&#x0201d; and &#x0201c;Colorectal Carcinoma&#x0201d; etc were retrieved in English database, including PubMed, EMBASE, Web of Science, the Cochrane Library. In addition, manually searched on Baidu academic and Google academic. The retrieval time was from establishment of the databases to August 2020, and all domestic and foreign literatures on KLT injection combined with chemotherapy for colorectal cancer were collected. Take PubMed as an example, and the search strategy is shown in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Search strategy in PubMed database.</p></caption><graphic xlink:href=\"medi-99-e22357-g001\"/></table-wrap></sec><sec><label>2.6</label><title>Data screening and extraction</title><p>Referring to the method of research selection in version 5.0 of the Cochrane collaboration Network system Evaluator Manual, according to the the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart, the 2 researchers used the EndNote X9 document management software to independently screen and check the literature according to the above inclusion and exclusion criteria, and check each other, if there were different opinions, negotiate with a third party to resolve the differences. At the same time, Excel 2013 was used to extract relevant information, including: &#x02460; Clinical study (title, first author, date of publication, sample size, sex ratio, average age, average course of disease, tumor stage, and type); &#x02461; Intervention measures (dose, frequency and course of KLT injection in the treatment group; chemotherapy regimen, intensity, frequency and course of treatment for treatment group, and control group); &#x02462; Risk bias assessment elements in RCTs; &#x02463; Observation targets. The selection process of literature is shown in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flow diagram.</p></caption><graphic xlink:href=\"medi-99-e22357-g002\"/></fig></sec><sec><label>2.7</label><title>Literature quality assessment</title><p>Use the Cochrane collaboration's tool for assessing risk of bias to do the risk of bias assessment of included studies. According to the performance of the included literatures in the above evaluation items, 2 researchers will give judgments like low risk, unclear, or high risk judgments one by one, and cross-check after completion respectively. In case of any disagreement, discussion will be carried out. If no agreement can be reached between the 2, discussion will be made with the researchers in the third party.</p></sec><sec><label>2.8</label><title>Statistical analysis</title><sec><label>2.8.1</label><title>Data analysis and processing</title><p>The RevMan 5.3 software (developed by the UK's International Cochrane Collaboration) provided by the Cochrane Collaboration will be used for statistical analysis. &#x02460; Relative risk is selected as the statistic for the dichotomous variable. For continuous variables, Weighted Mean Difference is selected when the tools and units of measurement indicators are the same, Standardized Mean Difference is selected with different tools or units of measurement, and all the above are represented by effect value and 95% Confidence interval. &#x02461; Heterogeneity test: Q test is used to qualitatively determine inter-study heterogeneity. If <italic>P</italic>&#x02265;.1, there is no inter-study heterogeneity; If <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.1, it indicate inter-study heterogeneity. At the same time, I² value is used to quantitatively evaluate the inter-study heterogeneity. If I²&#x02264;50%, the heterogeneity is considered to be good, and the fixed-effect model is adopted. If I²&#x0200a;&#x0003e;&#x0200a;50%, it is considered to be significant heterogeneity, the source of heterogeneity will be explored through subgroup analysis or sensitivity analysis. If there is no obvious clinical or methodological heterogeneity, it will be considered as statistical heterogeneity, and the random-effect model will be used for analysis. Descriptive analysis will be used if there is significant clinical heterogeneity between the 2 groups and subgroup analysis is not available.</p></sec><sec><label>2.8.2</label><title>Dealing with missing data</title><p>If there is missing data in the article, contact the author via email for additional information. If the author cannot be contacted, or the author has lost relevant data, descriptive analysis will be conducted instead of meta-analysis.</p></sec><sec><label>2.8.3</label><title>Subgroup analysis</title><p>According to the age, patients were divided into young and old for subgroup analysis. Subgroup analysis was performed according to the stages of disease course. Subgroup analysis was performed according to the course of treatment. Subgroup analysis was performed according to different chemotherapy regimens.</p></sec><sec><label>2.8.4</label><title>Sensitivity analysis</title><p>In order to test the stability of meta-analysis results of indicators, a one-by-one elimination method will be adopted for sensitivity analysis.</p></sec><sec><label>2.8.5</label><title>Assessment of publication bias</title><p>Funnel plots were used to assess publication bias if no fewer than 10 studies were included in an outcome measure. Moreover, Egger and Begg test were used for the evaluation of potential publication bias.</p></sec><sec><label>2.8.6</label><title>Evidence quality evaluation</title><p>The Grading of Recommendations Assessment, Development, and Evaluation will be used to assess the quality of evidence. It contains 5 domains (bias risk, consistency, directness, precision, and publication bias). And the quality of evidence will be rated as high, moderate, low, and very low.</p></sec></sec></sec><sec><label>3</label><title>Discussion</title><p>Colorectal cancer belongs to the category of diseases like &#x0201c;abdominal mass (Zheng Jia)&#x0201d;, &#x0201c;amassment and accumulation (Ji Ju)&#x0201d; and &#x0201c;intestinal wind (Chang Feng)&#x0201d;etc in traditional Chinese medicine.^{[<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} High incidence, poor prognosis and high mortality of colorectal cancer seriously harm people's health.^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]} At present, the treatment schemes include surgical treatment, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medical treatment, etc. Due to the hidden of early symptoms, it is already in the middle and advanced stage when diagnosed, and mainly uses chemotherapy to treat. But chemotherapy often fails because of drug resistance and the intolerance of toxic and side effects of chemotherapy.</p><p>Kanglaite (KLT) injection is extracted from <italic>Semen Coicis (Yi Yi Ren)</italic>, and <italic>Semen Coicis (Yi Yi Ren)</italic> has anti-tumor and immunomodulatory effects confirmed by modern pharmacology,^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} KLT principally blocks cell cycle at G2/M phase to reduce cellular mitotic division and inhibit proliferation of tumour cells. KLT can also activate pro-apoptotic factors and lead cells to apoptosis.^{[<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} It has been clinically verified that KLT injection can effectively reverse multidrug resistance of tumor cells and improve the sensitivity of tumor cells to chemotherapy.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>,<xref rid=\"R22\" ref-type=\"bibr\">22</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} In recent years, KLT injection has been widely used in the treatment of colorectal cancer, with significant efficacy.^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]} Yet the evidence from the RCTs is inconsistent. With the increasing number of clinical trials, it is urgent to systematically evaluate the efficacy of KLT injection in the treatment of colorectal cancer. In this study, we will summarize the latest evidence on the efficacy of KLT injection combined with chemotherapy for colorectal cancer. This work also provides useful evidence to determine whether KLT injection is effective and safe to patients with colorectal cancer, which is beneficial to both clinical practice and health-related decision-makers.</p><p>However, this systematic review has some limitations. The types and doses of chemotherapy regiments used in the included studies were different, which may cause some clinical heterogeneity. There are differences in course of the diseases of patients that may influence the outcome. In addition, due to the limitation of language ability, we only search literatures in English and Chinese, and may ignore research or reports in other languages.</p></sec><sec><title>Author contributions</title><p><bold>Data curation:</bold> Weili Mao, Yihua Fan.</p><p><bold>Formal analysis:</bold> Weili Mao, Yihua Fan.</p><p><bold>Funding acquisition:</bold> Jun Wang.</p><p><bold>Funding support:</bold> Jun Wang.</p><p><bold>Literature retrieval:</bold> Chao Cheng and Xingyu Yuan.</p><p><bold>Resources:</bold> Chao Cheng, Xingyu Xingyu Yuan.</p><p><bold>Software operating:</bold> Tian Lan and Kaili Mao.</p><p><bold>Software:</bold> Chao Cheng, Tian Lan, Kaili Mao.</p><p><bold>Supervision:</bold> Jun Wang.</p><p><bold>Writing &#x02013; original draft:</bold> Weili Mao, Yihua Fan.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Weili Mao and Jun Wang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: KLT = Kanglaite, RCTs = randomized controlled trials.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Mao W, Fan Y, Cheng C, Yuan X, Lan T, Mao K, Wang J. Efficacy and safety of Kanglaite injection combined with chemotherapy for colorectal cancer: A protocol for systematic review and meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22357).</p></fn><fn fn-type=\"supported-by\"><p>This work is supported by the Natural Science Foundation of Zhejiang Province (NO.LYQ20H300001).</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Ferlay</surname><given-names>J</given-names></name><name><surname>Soerjomataram</surname><given-names>I</given-names></name><name><surname>Dikshit</surname><given-names>R</given-names></name><etal/></person-group>\n<article-title>Cancer 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"research-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991477</article-id><article-id pub-id-type=\"pmc\">PMC7523840</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-05208</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022425</article-id><article-id pub-id-type=\"art-access-id\">22425</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>5300</subject></subj-group><subj-group><subject>Research Article</subject><subject>Observational Study</subject></subj-group></article-categories><title-group><article-title>Effects of visual feedback balance training with the Pro-kin system on walking and self-care abilities in stroke patients</article-title></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-9786-8564</contrib-id><name><surname>Zhang</surname><given-names>Min</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-4658-8511</contrib-id><name><surname>You</surname><given-names>Hong</given-names></name><degrees>MD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Hongxia</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Zhao</surname><given-names>Weijing</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Han</surname><given-names>Tingting</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Jia</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Jiang</surname><given-names>Shangrong</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Feng</surname><given-names>Xianhui</given-names></name><degrees>MD</degrees></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Tu.</surname><given-names>Wen-Jun</given-names></name></contrib></contrib-group><aff>Sino-French Department of Neurological Rehabilitation, Gansu Provincial Hospital, Lanzhou, Gansu, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Hong You, Sino-French Department of Neurological Rehabilitation, Gansu Provincial Hospital, 204 Donggang West Road, Lanzhou, Gansu 730000, China (e-mail: <email>lzyouhonginedin@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22425</elocation-id><history><date date-type=\"received\"><day>31</day><month>5</month><year>2020</year></date><date date-type=\"rev-recd\"><day>18</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>25</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22425.pdf\"/><abstract><title>Abstract</title><p>Some scholars&#x02019; studies have demonstrated that Pro-kin balance system training is able to promote the recovery of the balance function in stroke patients. The present study has expanded on those studies, and was not merely limited to studying balance, but also encompassed walking and self-care abilities of the patients; furthermore, the association among balance and walking and self-care abilities was also explored.</p><p>A total of 40 stroke patients were randomly and equally divided into 2 groups: the control group (n&#x0200a;=&#x0200a;20) and the treatment group (n&#x0200a;=&#x0200a;20). Both groups underwent conventional balance training, although the treatment group also underwent visual feedback balance training with the Pro-kin system. The balance function was assessed using the Berg Balance Scale (BBS), the Timed &#x0201c;Up &#x00026; Go&#x0201d; (TUG) test, and Pro-kin system parameters. The Pro-kin system parameters included the perimeter and ellipse area, which were both tested once with eyes open (EO) and eyes closed (EC). Walking ability was assessed using the Holden Walking Ability Scale, according to the Functional Ambulation Classification (FAC). The self-care abilities were assessed with the Barthel Index (BI). The tests were conducted prior to training, and 3 weeks after the end of the training programme.</p><p>No significant differences were noted among the groups before the training. After 3 weeks of training, for both the groups, significant improvements in balance and the walking and self-care abilities were noted: The BBS value was significantly increased (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05), whereas the TUG, perimeter, and ellipse area with EO and EC measurements were significantly decreased after treatment (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05). The FAC and BI readings were significantly increased after treatment (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;0.05), and the treatment group outperformed the control group (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05). Furthermore, the balance function was shown to be strongly correlated with the walking and self-care abilities (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01).</p><p>The present study has demonstrated that the use of the Pro-kin visual feedback balance training system in combination with conventional training is a viable method for improving walking and self-care abilities of stroke patients.</p></abstract><kwd-group><title>Keywords</title><kwd>balance training</kwd><kwd>Pro-kin system</kwd><kwd>self-care abilities</kwd><kwd>stroke</kwd><kwd>visual feedback</kwd><kwd>walking</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Gansu Provincial Science and Tech. Department</funding-source><award-id>145RJZA069</award-id><principal-award-recipient>Hong You</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Gansu Provincial Hospital</funding-source><award-id>18GSSY4-31</award-id><principal-award-recipient>Hong You</principal-award-recipient></award-group><award-group id=\"award3\" award-type=\"Fundref\"><funding-source>Gansu Provincial Hospital</funding-source><award-id>20GSSY4-52</award-id><principal-award-recipient>Min Zhang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Stroke is one of the most common causes of human death and disability.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Balance problems are a common dysfunction that arises after stroke, and they have been implicated in poor recovery of both standing and walking ability of the patients, as well as an increased risk of falls.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>&#x02013;<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} How to improve the balance function in stroke patients has become a hot topic in neurological rehabilitation research. Various therapeutic methods, including core-strength exercises,^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} visual feedback training,^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} and task-related training,^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} have been used to improve balance. Among the therapeutic methods used for this purpose, visual feedback training has been shown to be especially effective.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>&#x02013;<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Previous studies^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>&#x02013;<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} have highlighted the Pro-kin system (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>), a new type of commercially available computerized balance assessment and training system that provides the user with accurate visual feedback information about the position of the center of pressure (CoP). Liu^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} demonstrated that Pro-kin balance instrument training can promote the recovery of the balance function of stroke patients; furthermore, Li et al^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} reported that treatment with the Pro-kin balance system improved balance ability in stroke patients with hemiplegia.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Pro-kin system.</p></caption><graphic xlink:href=\"medi-99-e22425-g001\"/></fig><p>The present study has expanded on those previous studies, not merely being limited to a study of the balance, but also encompassing walking and self-care abilities. Therefore, the present study has investigated the effects of visual feedback balance training with the Pro-kin system on walking and self-care abilities of stroke patients; furthermore, the associations among balance and the walking and self-care abilities in stroke patients were also explored.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Study participants</title><p>The study group included 40 participants (the minimum sample size that can satisfy the test efficiency is determined by using the sample size calculation formula of the superiority test) with a radiological diagnosis of stroke, who were patients at Gansu Provincial Hospital between November 2018 and December 2019. All the participants were between 50 and 80 years of age, and had no history of leg injuries or other diseases associated with balance impairments; they also scored &#x0003c;56 on the Berg Balance Scale (BBS) and &#x0003e;22 on the Mini-Mental State Examination (MMSE). Individuals were referred if they had experienced a stroke within the last 3 months, could stand unassisted for 1&#x0200a;minute, and needed balance training, according to the judgement of the senior physical therapist. Candidates were excluded if: they had recurrent strokes; they had bilateral hemispheric, cerebellar, or brain stem lesions; they experienced severe spasticity or cognitive deficits; they had orthopedic problems; they experienced peripheral neuropathy, significant visual-field or hemineglect problems; they had impairments of the cardiovascular or respiratory system; or other accompanying ailments were present. Individuals who participated in &#x0003c;80% of the exercise program, and those who were unable to perform follow-up tests, were also excluded from the final analyses.</p><p>The pool of participants was randomly and equally divided into a treatment group (n&#x0200a;=&#x0200a;20) and a control group (n&#x0200a;=&#x0200a;20) according to a random number distribution table. The present study was approved by the Ethics Committee of Gansu Provincial Hospital, and all the participants provided written informed consent. All methods were performed in accordance with the relevant guidelines and regulations.</p></sec><sec><label>2.2</label><title>Data collection</title><p>Balance function was calculated by using the BBS^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} and Timed &#x0201c;Up &#x00026; Go&#x0201d; (TUG)^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} tests. The BBS, a clinical functional measurement of balance impairment, consists of 14 items of increasing difficulty, which is scored on a 5-point ordinal scale (0 to 4). The maximum possible score is 56, and higher scores indicate an improved balance. In the present study, the TUG was also performed to assess the subjects&#x02019; balance; this test records the time (in sec) required for subjects to stand up from a chair, walk 3 m, turn around, return to the chair, and sit down again. Shorter times indicate better balance. Self-care ability performance was assessed using the Barthel Index (BI),^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} which includes eating, washing, dressing, defecating, and transferring between a bed and a chair, among other activities. Each item has a minimum score of 0 and a maximum score of up to 15 points, for a total score of 100 points, where higher scores indicate improved self-care ability. The Functional Ambulation Classification (FAC), as previously described,^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} was used to evaluate walking ability; this scale is divided into 5 grades, where higher grades indicate an improved walking ability. Four tests were repeated twice, and the mean scores were recorded as the results.</p><p>The present study also used the Pro-kin system (PK254, TenoBody s.r.l. Bergamo, Italy) to assess balance. This system utilizes a force-sensitive platform to assess postural sway from movements of the CoP. Subjects stood comfortably in a standardized position on the platform; they were instructed to look at a screen surface positioned straight ahead and to keep their arms at their sides while standing in a normal forward-facing position, with their eyes focused on a stationary target. Each participant performed 2 standing tests lasting 30&#x0200a;seconds each: One test with eyes open (EO), and one with eyes closed (EC). In each of these conditions, the perimeter (in&#x0200a;mm) and ellipse area (in&#x0200a;mm²) were measured, for a total of 4 different outcome variables. The test was performed twice, and the mean score was recorded.</p></sec><sec><label>2.3</label><title>Procedures</title><p>All participants received conventional balance training, which consisted of 5 practice sessions lasting 20&#x0200a;minutes each, conducted 5 times a week for 3 weeks. The exercises were as follows: standing on 1 leg for 5&#x0200a;seconds; standing in front of the mirror and being pushed by the therapists from different directions; shifting one's weight forward, backward, sideward, and diagonally with EO and EC; passing balls to the therapist that had been arranged in a circle, and throwing and catching a ball; and walking in a straight line.</p><p>All the subjects in the treatment group performed balance training using the Pro-kin system in addition to the conventional training; the subjects used the Pro-kin system for 20&#x0200a;minutes per session, 5 times a week, for 3 weeks. Using visual feedback sensitive to the displacement of the CoP, patients were required to move their CoP past the specified area in various directions, including forward, backward, sideward, and in a circular motion (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>). The patients also played 2 games of their choice, selected from 3 options: a table-tennis game, a light display, and a skiing simulator (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>).</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Modes of training using the Pro-kin system. (A) Forward and backward, (B) sideward, and (C) circular motion.</p></caption><graphic xlink:href=\"medi-99-e22425-g002\"/></fig><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Game training. (A) Table tennis, (B) light, and (C) skiing.</p></caption><graphic xlink:href=\"medi-99-e22425-g003\"/></fig></sec><sec><label>2.4</label><title>Statistical analysis</title><p>All statistical tests were performed with SPSS version 17.0 (SPSS, Inc). Values were compared between groups using the independent <italic>t</italic> test, and values from before and after treatment were compared using the paired <italic>t</italic> test. Differences in categorical variables were analyzed using the chi-squared test. Correlations of balance function with walking and self-care abilities were determined by calculating Pearson correlation coefficient. For all tests, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05 was considered to indicate a statistically significant value.</p></sec></sec><sec><label>3</label><title>Results</title><p>The general characteristics of the participants, including age, sex, height, weight, and lesion location, are described in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>. No significant differences were identified among the groups (<italic>P</italic>&#x0200a;&#x0003e;&#x0200a;.05). The BBS, TUG, FAC, and BI scores before and after training, along with the changes in those scores, are shown in Tables <xref rid=\"T2\" ref-type=\"table\">2</xref> and <xref rid=\"T3\" ref-type=\"table\">3</xref>. The results of testing with the Pro-kin system before and after training, and the changes in those outcomes, are shown in Table <xref rid=\"T4\" ref-type=\"table\">4</xref>. No significant differences were identified among groups before training; however, regarding the results before and after training in each group, the BBS, FAC, and BI values were significantly increased (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05), whereas the TUG, perimeter with EO, ellipse area with EO, perimeter with EC, and ellipse area with EC values were significantly decreased after training (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05), especially with the treatment group. The BBS, TUG, FAC, BI, and Pro-kin system results were significantly improved after training in the treatment group compared with the control group (<italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05).</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Characteristics of the participants.</p></caption><graphic xlink:href=\"medi-99-e22425-g004\"/></table-wrap><table-wrap id=\"T2\" orientation=\"portrait\" position=\"float\"><label>Table 2</label><caption><p>Comparison of BBS, TUG scores before and after training between the 2 groups.</p></caption><graphic xlink:href=\"medi-99-e22425-g005\"/></table-wrap><table-wrap id=\"T3\" orientation=\"portrait\" position=\"float\"><label>Table 3</label><caption><p>Comparison of FAC and BI scores before and after training between the 2 groups.</p></caption><graphic xlink:href=\"medi-99-e22425-g006\"/></table-wrap><table-wrap id=\"T4\" orientation=\"portrait\" position=\"float\"><label>Table 4</label><caption><p>Comparison of perimeter and ellipse area before and after training between the 2 groups with eyes open and closed.</p></caption><graphic xlink:href=\"medi-99-e22425-g007\"/></table-wrap><p>The correlations of balance function with walking and self-care abilities in the treatment group are shown in Table <xref rid=\"T5\" ref-type=\"table\">5</xref>. The BBS and TUG values before training were significantly correlated with FAC (r&#x0200a;=&#x0200a;0.934, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01; and r&#x0200a;=&#x0200a;&#x02212;0.943, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01 for BBS and TUG, respectively) and BI (r&#x0200a;=&#x0200a;0.973, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01; and r&#x0200a;=&#x0200a;&#x02212;0.976, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01 for BBS and TUG, respectively) before training. The BBS and TUG values before training were also significantly correlated with FAC (r&#x0200a;=&#x0200a;0.914, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01; and r&#x0200a;=&#x0200a;&#x02212;0.918, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01 for BBS and TUG, respectively) and BI (r&#x0200a;=&#x0200a;0.954, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01; and r&#x0200a;=&#x0200a;&#x02212;0.972, <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.01 for BBS and TUG, respectively) after training. In order to evaluate the findings in the 2 groups further, the changes in all outcomes from baseline to posttraining were calculated; this demonstrated that there were clear changes in the treatment group for all outcomes.</p><table-wrap id=\"T5\" orientation=\"portrait\" position=\"float\"><label>Table 5</label><caption><p>Correlation of balance function with walking and self-care ability (Treatment group).</p></caption><graphic xlink:href=\"medi-99-e22425-g008\"/></table-wrap></sec><sec><label>4</label><title>Discussion</title><p>Stroke is often accompanied by deterioration or loss of balance function to varying degrees, and balance dysfunction is an important cause of stroke patients&#x02019; motor dysfunction. Therefore, training to recover balance function is crucial in the rehabilitation training of stroke patients.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>&#x02013;<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]}</p><p>Previous studies have demonstrated that the balance function of the human body is controlled by the central nervous system through a variety of reflexes, adjustments based on peripheral proprioceptive and visual inputs, and the coordination of contractions among muscle groups, which comprise a series of complex processes.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>,<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} The proprioceptive hypofunction or vestibular paresthesia of stroke hemiplegic patients requires visual compensation for walking, flexion, and extension movements of affected limbs. Visual feedback associated with weight distribution and the position of the center of gravity was considered to improve the symmetrical posture of stroke patients, and this hypothesis has now been proven.^{[<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} For a long time, the Bobath technique and Brunnstrom method have been used as the main treatments for the balance function of stroke hemiplegic patients, with an emphasis placed on standing balance training and lower limb motion control training.^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>,<xref rid=\"R28\" ref-type=\"bibr\">28</xref>]} However, these training methods are boring for the patients, their enthusiasm is restrained, and only modest improvements in balance are generally obtained. In recent years, visual feedback balance training with the Pro-kin system has gradually become an important treatment method. Through visual dynamic feedback with the Pro-kin system, patients are able to effectively control the movement of the body center of gravity and correct abnormal posture in time, thus improving the ability of patients to move the body center of gravity within the stable limit, and also improving their balance control function.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>,<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]}</p><p>The present study has amply shown that combined balance training using both conventional treatment and the Pro-kin system with visual feedback elicited significant improvements, outperforming conventional balance training alone in enhancing the balance function, walking and self-care abilities of our stroke patients. In a comparison of the results from before and after training, the BBS and the TUG outcomes were more dramatically changed after 3 weeks of training in both groups. Compared with the control group, the group that received conventional balance training and Pro-kin training also showed a significantly improved balance function. Pro-kin system test results were also significantly improved after 3 weeks of balance training. During the training process, whenever a patient's weight or posture shifts, the position and movement tracks of the center of gravity can be monitored; this information is presented through visual feedback, enabling a patient to adopt appropriate strategies to keep his or her posture as steady as possible,^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} thus improving their balance ability. Our results are consistent with those of previous studies that have used the Pro-kin system in stroke patients,^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>,<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]} providing supporting evidence that using visual feedback from the force-sensitive platform is effective in reducing balance dysfunction in stroke patients. Moreover, in the present study, the perimeter and ellipse areas with EO were lower than with EC, since visual information can compensate for the loss of vestibular and proprioceptive function and facilitate the motor programs in the human brain, thus increasing the effectiveness of treatment.^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>&#x02013;<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]}</p><p>The walking and self-care abilities were also improved significantly for patients in the treatment group compared with those in the control group. It is important to note that balance ability is closely associated with the recovery of walking ability and the probability of falling down in stroke patients.^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]} Furthermore, Liston and Brouwer^{[<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} reported that good postural control in balance may be closely correlated with the outcome of functional task performance during the activities of daily living. Confirming those findings, the stroke patients in our treatment group showed improvements in balance, as well as walking and self-care ability, after 3 weeks&#x02019; training. Furthermore, the BBS and TUG values before training were significantly correlated with FAC and BI, these results demonstrated that balance training via visual feedback of the Pro-kin system could strengthen the associations of walking and self-care abilities with balance. Therefore, we propose that the loss of balance function may be the main reason underlying poor walking and slower self-care abilities among stroke patients.</p><p>The fact that the improvements in balance, walking, and self-care abilities in stroke patients resulting from using the Pro-kin visual feedback system were superior to those of conventional training methods may be attributed to the distinctive properties of the Pro-kin system. The Pro-kin system, which is similar to the Biodex Balance Master^{[<xref rid=\"R37\" ref-type=\"bibr\">37</xref>]} but is based on a force platform with a regular, flat surface fixed to 4 force-transduction systems, is a comprehensive training system for human balance using visual feedback. Patients use their own sense of balance, as well as dynamic feedback on postural sway from the Pro-kin system. A variety of deep and superficial sensations and complex sensory stimuli are provided to the brain to adjust the patients&#x02019; control of their center of gravity, to enhance the function of nerve synapses, to induce cortical reorganization of nerve motor pathways,^{[<xref rid=\"R38\" ref-type=\"bibr\">38</xref>]} and also to promote the recovery of the balance and coordination functions and improve gait stability. At the same time, the system enhances the patients&#x02019; initiative, interest, and enthusiasm toward the training, thereby hastening the improvement in their balance function.</p><p>Although the present study has demonstrated the usefulness of the Pro-kin system, there were a few limitations in the study design, including a small sample size and the short duration of the training period (only 3 weeks). In addition, patients with cognitive or visual disorders, or other conditions that might affect their understanding of the task, were excluded from the selection process; therefore, further study is required to evaluate the effectiveness of the Pro-kin system in treating patients with these disorders.</p></sec><sec><label>5</label><title>Conclusions</title><p>In conclusion, these results have demonstrated that visual feedback balance training with the Pro-kin system is of significant benefit for patients after stroke, and that the use of the Pro-kin system in combination with conventional training is a viable training method for improving walking and self-care abilities of stroke patients.</p></sec><sec><title>Acknowledgments</title><p>The authors thank all of the study participants, and the Spandidos Publications English Language Editing Service which provided the professional language editing service.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Min Zhang, Hong You.</p><p><bold>Data curation:</bold> Min Zhang, Hongxia Zhang, Weijing Zhao, Tingting Han.</p><p><bold>Formal analysis:</bold> Min Zhang, Hong You.</p><p><bold>Funding acquisition:</bold> Min Zhang, Hong You.</p><p><bold>Investigation:</bold> Min Zhang, Shangrong Jiang, Jia Liu.</p><p><bold>Methodology:</bold> Min Zhang, Hongxia Zhang, Weijing Zhao.</p><p><bold>Project administration:</bold> Min Zhang, Hongxia Zhang, Jia Liu.</p><p><bold>Resources:</bold> Min Zhang, Tingting Han, Shangrong Jiang.</p><p><bold>Software:</bold> Min Zhang, Hongxia Zhang, Weijing Zhao, Tingting Han, Jia Liu, Xianhui Feng.</p><p><bold>Supervision:</bold> Min Zhang, Hong You, Tingting Han.</p><p><bold>Validation:</bold> Min Zhang, Hong You, Hongxia Zhang, Weijing Zhao.</p><p><bold>Visualization:</bold> Min Zhang, Xianhui Feng.</p><p><bold>Writing &#x02013; original draft:</bold> Min Zhang.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Min Zhang, Hong You, Hongxia Zhang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: BBS = Berg Balance Scale, BI = Barthel Index, CoP = center of pressure, EC = eyes closed, EO = eyes open, FAC = Functional Ambulation Classification, MMSE = mini-mental state examination, TUG = Timed &#x0201c;UP &#x00026; GO.&#x0201d;.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Zhang M, You H, Zhang H, Zhao W, Han T, Liu J, Jiang S, Feng X. Effects of visual feedback balance training with the Pro-kin system on walking and self-care abilities in stroke patients. <italic>Medicine</italic>. 2020;99:39(e22425).</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by grant from the Gansu Provincial Science and Tech. Department (No. 145RJZA069) and the Gansu Provincial Hospital (No. 18GSSY4-31, No. 20GSSY4-52) in China.</p></fn><fn fn-type=\"other\"><p>This study was approved by the ethics committee of Gansu Provincial Hospital and all participants provided written informed consent.</p></fn><fn fn-type=\"other\"><p>All authors have approved the manuscript for publication.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991438</article-id><article-id pub-id-type=\"pmc\">PMC7523841</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-07014</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022316</article-id><article-id pub-id-type=\"art-access-id\">22316</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3800</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>External treatment of traditional Chinese medicine for COVID-19</article-title><subtitle>A protocol for systematic review and meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Wu</surname><given-names>Liu</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yuan</surname><given-names>Qiang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Kuang</surname><given-names>Yongbing</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Chen</surname><given-names>Yong</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Li</surname><given-names>Jin</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Feng</surname><given-names>Yinhao</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Luo</surname><given-names>Jian</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Tuina, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, P. R. China</aff><aff id=\"aff2\"><label>b</label>Emergency Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, P. R. China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Jian Luo, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, P. R. China (e-mail: <email>Lj6176@126.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22316</elocation-id><history><date date-type=\"received\"><day>19</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>20</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22316.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>There is a worldwide outbreak of COVID-19, as the number of patients increases. External treatment of traditional Chinese medicine includes acupuncture, massage, fire needle, cupping, and other alternative therapies. Currently, there are no relevant articles for systematic review.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>We will search the randomized controlled trials related to the external treatment of traditional Chinese medicine (such as, acupuncture, massage, etc) and COVID-19 from inception to June 2020. The following database is our focus area: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wan-Fang Database. All published randomized controlled trials in English or Chinese related to massage for COVID-19 will be included. Primary outcomes include the influence of external treatment of traditional Chinese medicine on the patients with COVID-19. Secondary outcomes include accompanying symptoms (such as myalgia, expectoration, stuffiness, runny nose, pharyngalgia, anhelation, chest distress, dyspnea, crackles, headache, nausea, vomiting, anorexia, diarrhea) disappear rate, negative COVID-19 results rate on 2 consecutive occasions (not on the same day), average hospitalization time, Clinical curative effect, and improved quality of life.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>The results will provide a high-quality synthesis of current evidence for researchers in this subject area.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>The conclusion of our study will provide evidence to judge whether external treatment of traditional Chinese medicine is an effective intervention on the patients with COVID-19.</p></sec><sec><title>PROSPERO registration number:</title><p>CRD42020181336</p></sec></abstract><kwd-group><title>Keywords</title><kwd>COVID-19</kwd><kwd>systematic review</kwd><kwd>traditional Chinese medicine</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Chengdu Science and Technology Bureau (CN)</funding-source><award-id>2015-HM01- 00432-SF</award-id><principal-award-recipient>Jian Luo</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>At the end of 2019, a series of pneumonia cases of unknown cause emerged in Wuhan (Hubei, China).^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} A few weeks later, in January 2020, deep sequencing analysis from lower respiratory tract samples identified a novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a causative agent for that observed pneumonia cluster.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} On February 11th, 2020, the World Health Organization (WHO) Director-General, Dr. Tedros Adhanom Ghebreyesus, named the disease caused by the SARS-CoV-2 as &#x0201c;COVID-19,&#x0201d; and by May 6th, 2020 when the number of countries involved was 211 with more than 3,700,000 cases and over 260,000 deaths, the WHO declared the pandemic status.</p><p>Through the analysis of sequence, this unidentified pneumonia was considered to be caused by a novel coronavirus (CoV) named 2019-nCoV.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Subsequently, the WHO announced a standard format of Coronavirus Disease-2019 (COVID-19), according to its nomenclature, for this novel coronavirus pneumonia on February 11, 2020.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} On the same day, the International Committee on Taxonomy of Viruses (ICTV) named this novel coronavirus as SARS-CoV-2.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} So far, the SARS-CoV-2 infection is still spreading, and this virus poses a serious threat to public health, though joint prevention and quarantine mechanisms in almost all provinces of mainland China have been confirmed to be enacted. Due to a lack of specific antiviral treatments and pressure of clinical treatment, thousands of severe cases have died every day worldwide.</p><p>The patients also displayed various clinical symptoms, such as fever (83%), cough (82%), shortness of breath (31%), muscle ache (11%), confusion (9%), headache (8%), sore throat (5%), rhinorrhea (4%), chest pain (2%), diarrhea (2%), and nausea and vomiting (1%) (see Fig. 5B). Approximately 90% of the patients were observed to have more than one of the symptoms, whereas 15% experienced fever, cough, and shortness of breath simultaneously.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]}</p><p>The outbreak of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China has been brought to global attention and declared a pandemic by the WHO on March 11, 2020. Initial epidemiological investigation suggested that a majority of suspected cases were associated with their presence (exposure) in a local Huanan seafood market. However, such a decisive conclusion was disputed because the earliest case had had no reported link connection to the mentioned market.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} In addition, it was found that at least 2 different strains of SARS-CoV-2 had occurred a few months earlier before COVID-19 was officially reported.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} A recently phyloepidemiologic analysis suggests that SARS-CoV-2 at the Huanan Seafood Market could have been imported from other places.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]}</p><p>Currently, COVID-19 patients are the main source of infection, and severe patients are considered to be more contagious than mild ones. Asymptomatically infected persons or patients in incubation who show no signs or symptoms of respiratory infection proven to shed infectious virus, may also be potential sources of infection.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} In addition, samples taken from patients recovered from COVID-19 continuously show a positive RT-PCR test,^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} which has never been seen in the history of human infectious diseases. In other words, asymptomatically infected persons and patients in incubation or recovered from COVID-19 may pose serious challenges for disease prevention and control.</p><p>External treatment of traditional Chinese medicine does not refer to a special treatment, but refers to acupuncture, moxibustion, massage and a series of external treatment. The acupuncture and moxibustion have been practiced in China for more than 3000 years and was spread to Europe and American from the sixteenth to the nineteenth century.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} The history of acupuncture research was initiated in the eighteenth century and developed rapidly since then. Accumulated evidences that acupuncture and moxibustion are beneficial in various conditions significantly enhanced our understanding the mechanisms of acupuncture treatment.</p><p>Acupuncture is a component of External treatment of traditional Chinese medicine. According to the literature, acupuncture can enhance the immune system function of patients and thus play a role In the treatment of respiratory diseases.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} According to a number of clinical practices, acupuncture therapy has a considerable effect, has a high technical content, can inhibit allergic reactions, activate its defense system function, and the patient's bronchial smooth muscle tone is reduced, and finally eliminate a part of respiratory symptoms.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} COVID-19 is a respiratory disease, so acupuncture may be effective in the treatment of COVID-19, especially in the improvement of some related symptoms.</p><p>Massage is also a kind of external treatment of traditional Chinese medicine; it is a preventive and restorative therapy involving the systematic application of pressure to the skin, muscle, and connective tissue with the aim of improving blood and lymph circulation.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} With the outbreak of the epidemic, COVID-19 is not only harmful for our body but also for the mental health, especially the people who have recovered from covid-19. Massage has been shown to relieve psychological problems such as anxiety, insomnia, depression aggression, frustration, and hysteria.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]}</p><p>Currently, there is still a lack of evidence-based medical evidence for the external treatment of traditional Chinese medicine for COVID-19. Therefore, it is necessary to review it and provide evidence for clinicians.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Study registration</title><p>The systematic review protocol has been registered in PROSPERO. The registration number: CRD42020181336, the consent of this protocol report is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMAP) statement guidelines.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]}</p></sec><sec><label>2.2</label><title>Inclusion criteria for study selection</title><sec><label>2.2.1</label><title>Type of study</title><p>We will include articles related to the external treatment of traditional Chinese medicine (such as, acupuncture, massage, etc) of patients with COVID-19. Due to language restrictions, we will search for articles in English and Chinese in order to get a more objective and true evaluation; all articles included are randomized controlled trial (RCT) type articles.</p></sec><sec><label>2.2.2</label><title>Type of participant</title><p>All patients with COVID-19 will be included regardless of sex, age, race, education, and economic status. Pregnant women, postoperative infections, psychopaths, and patients with severe cardiovascular and liver and kidney diseases will not be included.</p></sec><sec><label>2.2.3</label><title>Type of intervention</title><p>The external treatment of traditional Chinese medicine (such as, acupuncture, massage, etc) while other traditional Chinese therapies will be excluded. We will compare the following interventions: treatments other than the external treatment of traditional Chinese medicine (eg, usual or standard care, placebo, wait-list controls).</p></sec><sec><label>2.2.4</label><title>Type of outcome measure</title><p>Primary outcomes include the influence of the external treatment of traditional Chinese medicine on patients with COVID-19. Secondary outcomes include accompanying symptoms (such as myalgia, expectoration, stuffiness, runny nose, pharyngalgia, anhelation, chest distress, dyspnea, crackles, headache, nausea, vomiting, anorexia, diarrhea) disappear rate, average hospitalization time, occurrence rate of common type to severe form, clinical cure rate, and mortality.</p></sec></sec><sec><label>2.3</label><title>Data sources</title><p>The following electronic databases will be searched from inception to May 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wan-Fang Database. About other sources, we also plan to manually search for the unpublished conference articles and the bibliography of established publications.</p></sec><sec><label>2.4</label><title>Search strategy</title><p>The search terms on PubMed are as follows: massage (eg, &#x0201c;acupoints&#x0201d; or &#x0201c;tuina&#x0201d; or &#x0201c;manipulation&#x0201d;); acupuncture (eg, &#x0201c;acupuncture&#x0201d; or &#x0201c;acupuncture therapy&#x0201d; or &#x0201c;body acupuncture&#x0201d; or &#x0201c;manual acupuncture&#x0201d; or &#x0201c;electroacupuncture&#x0201d; or &#x0201c;fire needling&#x0201d; or &#x0201c;plum blossom needling&#x0201d;); COVID-19 (eg, &#x0201c;Corona Virus Disease 2019&#x0201d; or &#x0201c;Corona Virus&#x0201d;); RCT (eg, &#x0201c;randomized&#x0201d; or &#x0201c;randomly&#x0201d; or &#x0201c;clinical trial&#x0201d;). Combinations of Medical Subject Headings (MeSH) and text words will be used. The same search term is used in electronic databases in China. These search terms are summarized in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Search strategy for the PubMed database.</p></caption><graphic xlink:href=\"medi-99-e22316-g001\"/></table-wrap></sec><sec><label>2.5</label><title>Data collection and analysis</title><sec><label>2.5.1</label><title>Selection of studies</title><p>We chose the PRISMA flow chart to show the process of selecting literature for the entire study (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). Before searching the literature, all reviewers will discuss and determine the screening criteria. After the screening requirements are clearly defined, the 2 reviewers will independently review and screen the literature. They screened the titles and abstracts of the literature, in order to get qualified studies, and then excluded some duplicate studies or studies with incomplete information. We will also try to obtain the full text, and the obtained literature will be managed by using EndNote software, V.X8 (United States). In case of disagreement between the 2 reviewers, discussions will be held with the third author for arbitration.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flow chart of the study.</p></caption><graphic xlink:href=\"medi-99-e22316-g002\"/></fig></sec><sec><label>2.5.2</label><title>Data extraction and management</title><p>The authors will strictly follow the inclusion criteria and select RCT articles related to the topic. Through the analysis of the article, we know participants&#x02019; characteristics (height, weight, sex), interventions, outcomes, the study characteristics (press, nationality, journals, research design), adverse reactions, etc. If there is any disagreement between the 2 authors in the literature data extraction, a third article participant will discuss the decision together. If there is a lack of data in the literature, we will contact the author or publisher as much as possible.</p></sec><sec><label>2.5.3</label><title>Assessment of risk of bias in included studies</title><p>We will use the Cochrane collaborative tool to independently assess the risk of bias in the included studies. We will evaluate the following aspects of the article: sequence generation, assignment sequence hiding, blindness of participants and staff, outcome evaluators, incomplete result data, selective result reporting, and other sources of bias. The risk of bias is evaluated at 3 levels, namely, low risk, high risk, and ambiguity. If the information is vague, we will try to contact the author of the article.</p></sec><sec><label>2.5.4</label><title>Measures of treatment effect</title><p>In this protocol, we will use 95% confidence interval (95% CI) risk ratio (RR) to rigorously analyze the dichotomous data. And for the continuous data, mean difference (MD) or standard MD (SMD) is used to measure the efficacy of 95% CI.</p></sec><sec><label>2.5.5</label><title>Unit of analysis issues</title><p>We will include data from parallel group design studies for meta-analysis. In these trials, we will collect and analyze individual measurements of each outcome for each participant.</p></sec><sec><label>2.5.6</label><title>Management of missing data</title><p>We will try our best to ensure the integrity of the data. If the included RCT data is not complete, we will try every means to contact the corresponding author of the article, including sending emails or making a phone call. If the corresponding author cannot be contacted, we will remove the experiment with incomplete data. After data integrity is assured, intention analysis therapy and sensitivity analysis will be performed.</p></sec><sec><label>2.5.7</label><title>Assessment of heterogeneity</title><p>For the detection of heterogeneity, the <italic>I</italic>² test will be used to detect the heterogeneity among trials. When the <italic>I</italic>² test value is &#x0003c;50% and <italic>P</italic>&#x0200a;&#x0003e;&#x0200a;1, we think there is no heterogeneity between these trials, and when the <italic>I</italic>² test value is &#x0003e;50% and the <italic>P</italic> value is &#x0003c;1, there is significant heterogeneity between these included trials. If significant differences are detected, we will analyze the possible causes of heterogeneity, and then we can use the random effects model.</p></sec><sec><label>2.5.8</label><title>Assessment of reporting biases</title><p>In this analysis, once &#x0003e;10 trials are included, funnel plots could be used to test for reporting bias.</p></sec><sec><label>2.5.9</label><title>Data synthesis</title><p>We will use Review Manager Software (RevMan) V.5.3 (Copenhagen, Denmark) for data analysis and quantitative data synthesis. If there is no finding of statistical heterogeneity, the fixed-effect model is used for data synthesis. If there is significant statistical heterogeneity, we will use the random effect model, and all participants will explore the possible causes from a clinical and methodological perspective and provide a descriptive or subgroup analysis.</p></sec><sec><label>2.5.10</label><title>Subgroup analysis</title><p>Subgroup analysis will be performed to explain heterogeneity if possible. Factors such as different types of control interventions and different outcomes will be considered.</p></sec><sec><label>2.5.11</label><title>Sensitivity analysis</title><p>On the basis of sample size, study design, heterogeneous quality, methodological quality, and statistical model, sensitivity analysis will be performed to exclude trials with quality defects and ensure the stability of the analysis results.</p></sec><sec><label>2.5.12</label><title>Grading the quality of evidence</title><p>This paper will use the evidence quality rating method to evaluate the results obtained from this analysis. GRADE is generally applied to a large amount of evidence. It has 4 evaluation levels, namely, high, medium, low, and very low. GRADE was used to evaluate the bias, inconsistencies, discontinuities, and inaccuracies of test results. In the context of the system review, quality reflects our confidence in the effectiveness of assessment.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]}</p></sec><sec><label>2.5.13</label><title>Ethical review and informed consent of patients</title><p>The content of this article does not involve moral approval or ethical review and will be presented in print or at relevant conferences.</p></sec></sec></sec><sec><label>3</label><title>Discussion</title><p>This review is divided into 4 parts: identification, literature inclusion, data extraction, and data synthesis. It will systematically review the RCT literature; this review will evaluate the effectiveness of the external treatment of traditional Chinese medicine in treating COVID-19. There are also limitations in our research and the language bias here is that we only search for Chinese and English documents. Our study may provide a basis for clinicians to choose replacement therapy for further study in the future.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Liu Wu, Qiang Yuan.</p><p><bold>Data curation:</bold> Qiang Yuan, Liu Wu, Yongbing Kuang.</p><p><bold>Formal analysis:</bold> Yinhao Feng, Qiang Yuan, Jin Li, Yong Chen.</p><p><bold>Funding acquisition:</bold> Jian Luo.</p><p><bold>Investigation:</bold> Liu Wu, Yongbing Kuang.</p><p><bold>Methodology:</bold> Liu Wu, Yongbing Kuang.</p><p><bold>Project administration:</bold> Yong Chen.</p><p><bold>Resources:</bold> Liu Wu, Jian Luo.</p><p><bold>Software:</bold> Liu Wu.</p><p><bold>Supervision:</bold> Yongbing Kuang, Jin Li.</p><p><bold>Validation:</bold> Jin Li.</p><p><bold>Visualization:</bold> Yinhao Feng.</p><p><bold>Writing &#x02013; original draft:</bold> Qiang Yuan, Liu Wu.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Qiang Yuan, Liu Wu, Yongbing Kuang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CIs = confidence intervals, COVID-19 = Corona Virus Disease 2019, PRISMA-P = the preferred reporting items for systematic reviews and meta-analyses protocols, RevMan = Review Manager Software.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Wu L, Yuan Q, Kuang Y, Chen Y, Li J, Feng Y, Luo J. External treatment of traditional Chinese medicine for COVID-19: A protocol for systematic review and meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22316).</p></fn><fn fn-type=\"equal\"><p>LW, QY, and YBK contributed equally to this work and should be considered cofirst authors.</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by Chengdu Science and Technology Bureau (NO.2015-HM01- 00432-SF).</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to declare.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are publicly available.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991487</article-id><article-id pub-id-type=\"pmc\">PMC7523843</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-00833</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022480</article-id><article-id pub-id-type=\"art-access-id\">22480</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>6800</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Imaging features of periostitis as a manifestation of IgA vasculitis</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Noh</surname><given-names>Ji Hoon</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0003-2687-7014</contrib-id><name><surname>Chung</surname><given-names>Bo Mi</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Kim</surname><given-names>Wan Tae</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Radiology, Veterans Health Service Medical Center, 53, Jinhwangdo-ro 61-gil, Gangdong-gu</aff><aff id=\"aff2\"><label>b</label>Departement of Radiology, Graduate School of Chung-Ang University, Seoul, Republic of Korea.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Bo Mi Chung, Department of Radiology, Veterans Health Service Medical Center, 53, Jinhwangdo-ro 61-gil, Gangdong-gu, Seoul, 05368, Republic of Korea (e-mail: <email>chungbm1086@gmail.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22480</elocation-id><history><date date-type=\"received\"><day>2</day><month>2</month><year>2020</year></date><date date-type=\"rev-recd\"><day>1</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>1</day><month>9</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22480.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"intro\"><title>Introduction:</title><p>Periostitis in systemic vasculitis is very rare with only a few previously reported cases. The reported cases were seen in polyarteritis nodosa or Takayasu arteritis. We report the first case of periostitis associated with IgA vasculitis with demonstration of computed tomography (CT), magnetic resonance imaging (MRI) features, and serial changes of radiographs.</p></sec><sec><title>Patient concerns:</title><p>A 74-year-old man visited an orthopedic outpatient clinic for pain in both lower legs and left ankle pain. He underwent a total ankle arthroplasty of the left ankle 3 years ago. His medical history disclosed IgA vasculitis/nephropathy caused by cephalosporin antibiotic class 5 months earlier. Plain radiography, MRI of the right lower leg, CT scan of the left ankle showed single lamellar to spiculated periosteal reactions at both tibia, fibula and left calcaneus. There was no evidence of bone or soft tissue mass lesions or cortical destruction.</p></sec><sec><title>Diagnosis:</title><p>We concluded that this was a case of periosteal reactions associated with IgA vasculitis for the following reasons: (1) periosteal biopsy was negative for tumor. (2) there was no pulmonary lesion on chest radiography and CT, no history of trauma, inflammatory arthritis, metabolic disease, or genetic disease that could cause periostitis at multiple bones, (3) the initial MRI showed predominant signal changes around the tibial and fibular shafts, possibly explaining subsequent periosteal reactions, and (4) symptoms subsided with conservative treatment and follow-up radiographs showed remodeling of periosteal reactions.</p></sec><sec><title>Interventions:</title><p>The patient took conservative management.</p></sec><sec><title>Outcomes:</title><p>His calf pain improved, and a radiograph 7 months later showed remodeling to the solid or single lamellar periosteal reaction along the both tibia and left fibula.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>Awareness of this uncommon manifestation would help differential diagnosis of periostitis and could help decrease the patient's anxiety. It should also be noted that periosteal reactions by benign entities could cause aggressive-looking periosteal reactions in post-operative regions.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>IgA vasculitis</kwd><kwd>periosteal reaction</kwd><kwd>periostitis</kwd><kwd>systemic vasculitis</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Periosteal reactions at multiple bones are nonspecific pathologies with many causes, including tumors, infections, trauma, metabolic diseases, inflammatory diseases, and rarely, vascular causes.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Periosteal reactions as manifestations of systemic vasculitis are uncommon, with only a few case reports in the English literature.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>&#x02013;<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Polyarteritis nodosa (PAN) was the most common type of vasculitis presenting periostitis, followed by Takayasu arteritis (TA).^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>&#x02013;<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Here, we report the first case of periostitis associated with IgA vasculitis with demonstration of computed tomography (CT), magnetic resonance imaging (MRI) features, and serial changes of radiographs in a 74-year-old man who presented with pain in both lower legs. When multifocal periosteal reactions are encountered, considering systemic vasculitis as a potential cause could help with differential diagnosis.</p></sec><sec><label>2</label><title>Case report</title><p>A 74-year-old man visited an orthopedic outpatient clinic for pain in both lower legs and left ankle pain. Physical examination at this presentation revealed mild swelling around the left ankle. No heating sensation, redness, or tenderness was noted in either lower leg or ankle. He was afebrile and his vitals were a pulse rate of 85 beats per minute and blood pressure of 71/119 mm Hg. Laboratory examinations were only notable for erythrocyte sedimentation rate of 36&#x0200a;mm/h, creatinine of 1.7&#x0200a;mg/dL, and blood urea nitrogen of 23&#x0200a;mg/dL. He had a history of a total ankle arthroplasty of the left ankle 3 years ago.</p><p>His medical history disclosed IgA vasculitis. He had been admitted to our institution 5 months previously, presenting with pain, swelling, and petechia in both legs. He took cephalosporin antibiotic class for the impression of cellulitis 3 days before. Laboratory examinations revealed an elevated white blood cell count of 13390/mm³, C-reactive protein of 173.3&#x0200a;mg/L, and erythrocyte sedimentation rate of 120&#x0200a;mm/h. Serological studies were positive for IgA (516&#x0200a;mg/dL). Biopsy from the skin lesions showed features of vasculitis with predominant IgA deposits at the small vessel walls. Urinalysis revealed hematuria and proteinuria. Renal biopsy showed severe interstitial fibrosis and global sclerosis. The diagnosis of IgA vasculitis/nephropathy caused by cephalosporin antibiotic class was made based on clinical features and biopsy findings. He was given an oral corticosteroid with follow-up visits in the outpatient nephrology clinic after discharge at the time of presentation.</p><p>Plain radiography showed a single lamellar periosteal reaction in the right tibial shaft (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>A). There were spiculated or thick irregular periosteal reactions at the left distal tibia and fibula (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>B). An MRI of the right lower leg revealed a single lamellar periosteal reaction in the tibial shaft (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>A). A CT scan of the left ankle showed spiculated periosteal reactions at the distal tibia, fibula, and calcaneus (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>B). There was no evidence of bone or soft tissue mass lesions or cortical destruction.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>(A) Frontal radiograph of the right lower leg demonstrates a single lamellar periosteal reaction at the tibial shaft (arrowheads). A focal irregular periosteal reaction is also noted (arrow). (B) Frontal radiograph of the left lower leg shows spiculated and thick irregular periosteal reactions at the distal tibia and fibula. Note total ankle arthroplasty state at the left ankle (arrowheads).</p></caption><graphic xlink:href=\"medi-99-e22480-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>(A) Axial fat-suppressed T2-weighted image of the right lower leg demonstrates a periosteal thickening with mineralization at the anterior aspect of the tibia, suggesting a single lamellar periosteal reaction (arrowheads). (B) CT of the left ankle demonstrates spiculated periosteal reactions at the distal tibia and fibula (arrowheads). No bone or soft tissue mass lesions or cortical destruction were noted.</p></caption><graphic xlink:href=\"medi-99-e22480-g002\"/></fig><p>We reviewed previous imaging studies performed 5 months ago, when the patient presented with pain, swelling, and petechia in both legs. Radiography of both lower legs revealed soft tissue swelling in both of the lower legs, a single lamellar periosteal reaction in the right tibial shaft, and normal left tibial and fibular shafts (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>). MRI of the right lower leg revealed a single lamellar periosteal reaction at the anterior aspect of the tibial shaft (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>A). MRI of both lower legs showed multifocal patchy signal changes in the muscles of both lower legs, especially prominent around the tibia and fibula, and intermuscular septa, findings which were initially interpreted as muscle involvement of systemic vasculitis (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>A and B).</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Frontal radiographs of the right (A) and left (B) lower leg 5 months earlier. There is a single lamellar periosteal reaction at the medial border of the right tibial shaft (arrowheads), which is thinner than the plain radiography in Figure 1. No bony abnormalities, except post-operative changes of the left ankle, were noted in the left lower leg. Note soft tissue swelling in both lower legs.</p></caption><graphic xlink:href=\"medi-99-e22480-g003\"/></fig><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>Axial fat-suppressed T2-weighted images of the right (A) and left (B) lower leg 5 months earlier. The right lower leg MRI shows periosteal elevation with mineralization at the tibial shaft (arrowheads). No periosteal reactions were noted in the left tibia or fibula. There are multifocal patchy edema in both lower leg muscles, especially prominent around both tibia, left fibula, and both intermuscular septa. Note diffuse swelling of the subcutaneous layers in both legs.</p></caption><graphic xlink:href=\"medi-99-e22480-g004\"/></fig><p>A periosteal biopsy was performed to exclude unusual tumor of periosteal origin because periosteal reaction at left distal tibia seemed aggressive. The histopathological examination revealed bone fragments and some inflammatory cells and was negative for tumor. There was no pulmonary lesion on chest radiography and CT. He had no history of trauma, inflammatory arthritis, metabolic disease, or genetic disease that could cause periostitis at multiple bones. We concluded these lesions as periostitis associated with IgA vasculitis. His calf pain improved after conservative management and a radiograph 7 months later showed remodeling to the solid or single lamellar periosteal reaction along the both tibia and left fibula (Fig. <xref ref-type=\"fig\" rid=\"F5\">5</xref>).</p><fig id=\"F5\" orientation=\"portrait\" position=\"float\"><label>Figure 5</label><caption><p>Follow-up frontal radiographs of the right (A) and left (B) lower legs taken 7 months later show thick single lamellar or solid periosteal reactions in both tibias and in the left fibula.</p></caption><graphic xlink:href=\"medi-99-e22480-g005\"/></fig><p>This study received institutional review board approval and written informed consent was obtained from the patient for publication of this article.</p></sec><sec><label>3</label><title>Discussion</title><p>IgA vasculitis, formerly known as Henoch-Schonlein purpura, is an immune complex-mediated, small vessel vasculitis with predominant IgA deposits in the vessel wall.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} IgA vasculitis is the most common vasculitis in childhood. It is less common in adults, with an annual incidence of 0.1 to 1.8 per 1,00,000 individuals.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} IgA vasculitis is characterized clinically by palpable purpura, gastrointestinal, renal, or joint involvement.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} Although arthritis or arthralgia is known as a musculoskeletal manifestation, there is no case of periostitis associated with IgA vasculitis. We concluded that this was a case of periosteal reactions associated with IgA vasculitis for the following reasons: (1) periosteal biopsy was negative for tumor. (2) there was no pulmonary lesion on chest radiography and CT, no history of trauma, inflammatory arthritis, metabolic disease, or genetic disease that could cause periostitis at multiple bones, (3) the initial MRI showed predominant signal changes around the tibial and fibular shafts, possibly explaining subsequent periosteal reactions, and (4) symptoms subsided with conservative treatment and follow-up radiographs showed remodeling of periosteal reactions.</p><p>Periosteal reactions as manifestations of systemic vasculitis are uncommon, with a small number of case reports in the English literature.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>&#x02013;<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} PAN was the most common type of vasculitis presenting periostitis, followed by TA.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>&#x02013;<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Although the mechanism of periosteal reactions in systemic vasculitis is uncertain, researchers have suggested several hypotheses. McConachie et al^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} stated that arterial insufficiency appeared to be the main mechanism, a theory questioned by Kim et al^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} proposed that periosteal reactions may occur as an inflammatory process independent of direct vessel involvement or hypoxia, because periosteal reactions occurred in normoxic regions in their patient. Bogaert et al^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} suggested a common inflammatory process of both vessels and periosteal bone as a mechanism of periosteal reactions based on their MRI findings that revealed edema at intermuscular regions and near intermuscular vessels. In a case report of PAN presenting as periostitis, the MRI showed high SI and enhancement around the periosteum of tibia and intermuscular septum.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Similar to previous cases,^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} the initial MRI in our case showed predominant signal changes around the periosteum and intermuscular septum, which were thought to reflect inflammation of the periosteum and soft tissues around the small vessels that led to periosteal reactions. Small vessel vasculitis at and around the periosteum would have resulted in vascular damage and caused tissue hypoxia and local production of bone growth factors.</p><p>Periosteal reactions by benign causes generally show solid or single lamellar patterns.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Spiculated patterns are usually associated with the worst prognosis, as they occur in aggressive and fast-growing diseases.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Our case showed spiculated periosteal reactions at the left lower leg, a finding which led to a periosteal biopsy. We speculated that the previous total ankle arthroplasty would have altered structures and vascularity of the periosteum around the ankle, causing more active reactions to inflammation or hypoxia of the periosteum. Similarly, in a report by Cheon et al, a 10-year-old boy with TA presented periosteal reactions with thick, fluffy margins, because the periosteum is more active in children.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]}</p><p>In conclusion, this is the first case report of periostitis associated with IgA vasculitis in an adult. Awareness of this uncommon manifestation would help differential diagnosis of periostitis and could help decrease the patient's anxiety. It should also be noted that periosteal reactions by benign entities could cause aggressive-looking periosteal reactions in post-operative regions.</p></sec><sec><title>Author contributions</title><p><bold>Data collection:</bold> Ji Hoon Noh.</p><p><bold>Case analysis:</bold> Bo Mi Chung.</p><p><bold>Writing_original draft:</bold> Ji Hoon Noh, Bo Mi Chung.</p><p><bold>Writing_review, editing:</bold> Bo Mi Chung.</p><p><bold>Supervision:</bold> Wan Tae Kim.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CT = computed tomography, MRI = magnetic resonance imaging, PAN = polyarteritis nodosa, TA = Takayasu arteritis.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Noh JH, Chung BM, Kim WT. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991425</article-id><article-id pub-id-type=\"pmc\">PMC7523845</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08285</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022264</article-id><article-id pub-id-type=\"art-access-id\">22264</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>6900</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Traditional therapies of Zhuang medicine improve pain and joint dysfunction of patients in rheumatoid arthritis</article-title><subtitle>A protocol for systematic review and meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Luo</surname><given-names>Yehao</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Xu</surname><given-names>Donghan</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Cao</surname><given-names>Zhiyong</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Chen</surname><given-names>Qiuxia</given-names></name><degrees>MS</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Lizhen</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff4\">^d</xref></contrib><contrib contrib-type=\"author\"><name><surname>Fang</surname><given-names>Gang</given-names></name><xref ref-type=\"aff\" rid=\"aff5\">^e</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0003-4410-5050</contrib-id><name><surname>Pang</surname><given-names>Yuzhou</given-names></name><xref ref-type=\"aff\" rid=\"aff5\">^e</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi Province</aff><aff id=\"aff2\"><label>b</label>Macau University of Science and Technology, Macau</aff><aff id=\"aff3\"><label>c</label>Hubei Minzu University, Wuhan</aff><aff id=\"aff4\"><label>d</label>Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province</aff><aff id=\"aff5\"><label>e</label>Guangxi Zhuang Yao Medicine Center of Engineering and Technology, Guangxi University of Chinese Medicine, Nanning, Guangxi Province, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Gang Fang, Guangxi University of Traditional Chinese Medicine, Nanning 530200, Guangxi Province, P.R. China (e-mail: <email>fglzyznn@sina.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22264</elocation-id><history><date date-type=\"received\"><day>19</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>20</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22264.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease, which can lead to joint destruction, dysfunction, finally deformity. Currently, Western medicine treats it with disease-modifying antireheumatic drugs, NSAIDs, glucocorticoid, biological agents, etc, which can induce adverse drug reactions. And now, as an important mean of treating RA, Zhuang medicine has been widely used in clinics, and has achieved significant efficacy.</p></sec><sec sec-type=\"methods\"><title>Methods and analysis:</title><p>The following databases will be searched for relevant information before July 2020: PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure. Major results: levels of C-reactive protein, erythrocyte sedimentation rate, Rheumatoid factor. Secondary results: morning stiffness time, range of motion, arthralgia, joint tenderness index, joint swelling index, total effective rate, adverse event. Data will be collected independently by 2 researchers, and the risk of bias in meta analysis will be evaluated according to &#x0201c;Cochrane Handbook for Systematic Reviews of Interventions&#x0201d;. All data analysis will be conducted using Review Manager V.5.3. and Stata V.12.0.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>The curative effect and safety of traditional therapies of Zhuang Medicine treatment for RA patients will be evaluated systematically.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>The systematic review of this study will summarize the currently published evidence of traditional therapies of Zhuang Medicine treatment for RA to further guide its promotion and application.</p><p>Open Science Framework (OSF) registration number: <ext-link ext-link-type=\"uri\" xlink:href=\"https://osf.io/c4xv3/\">https://osf.io/c4xv3/</ext-link>.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>joint dysfunction</kwd><kwd>pain</kwd><kwd>protocol</kwd><kwd>rheumatoid arthritis</kwd><kwd>systematic review</kwd><kwd>Zhuang medicine</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>National Natural Science Foundation of China</funding-source><award-id>No.81973976</award-id><principal-award-recipient>yuzhou pang</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>The National Key Research and Development Program of China</funding-source><award-id>No.2017YFC1704004</award-id><principal-award-recipient>yuzhou pang</principal-award-recipient></award-group><award-group id=\"award3\" award-type=\"Fundref\"><funding-source>Open Project for Guangxi First-class Discipline Construction of Guangxi University of Chinese Medicine</funding-source><award-id>No.2019XK036</award-id><principal-award-recipient>yuzhou pang</principal-award-recipient></award-group><award-group id=\"award4\" award-type=\"Fundref\"><funding-source>Development Program of High-level Talent Team under Qihuang Project of Guangxi University of Chinese Medicine</funding-source><award-id>No.2018005</award-id><principal-award-recipient>yuzhou pang</principal-award-recipient></award-group><award-group id=\"award5\" award-type=\"Fundref\"><funding-source>Guangxi Talent Highland for Zhuang and Yao Medicine and Combination of Medical Care and Elderly Care</funding-source><award-id>NoTing Fa[2017]44</award-id><principal-award-recipient>yuzhou pang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Rheumatoid arthritis (RA),as known to all, is a long-lasting disease that primarily affects the joints.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Also, it is characterized by an aggressive inflammatory reaction of the small joints of the hand and foot, often accompanied by a positive serum rheumatoid factor, which can lead to joint deformity and dysfunction.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} However, the cause of RA is unclear, but genetic and environmental factors are involved.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} It is reported that the immune system affected by certain conditions could attack the joints. To the patients, RA has a significant negative impact on the ability to perform daily activities, including work and household tasks, and health-related quality of life, even it increases mortality. Globally, RA affects about 0.5 to 1 percent of adults in the developed countries, and it is more occupied in women at the middle age.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} Therefore, it is necessary to relieve the symptoms of RA, even cure. Modern Western Medicine mainly treats RA with traditional disease-modifying antireheumatic drugs (DMARDs), biologic agents, tofacitinib, glucocorticoids and treat-to-target approach.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} But partial patients unfortunately have to suffer from gastrointestinal adverse reactions which are induced by DMARDs, and a high price of the treatments that could add up the burden on the family.</p><p>Unexpectedly, we found that the treatment of traditional Chinese Medicine has a great impact on RA, not only relieve the pain and joints dysfunction but also raise the health-life quality. Have to commit, Zhuang medicine is one kind of treatments of traditional Chinese medicine. According to Zhuang medicine, RA belongs to range of &#x0201c;Fungcaep&#x0201d; (a unique term used in Zhuang medicine).^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} The guideline for the treatments of RA is based on the theory of Zhuang medicine, moreover, the use of medicated thread moxibustion, cupping therapy with Zhuang medicine, exsanguainate therapy and other treatments with Zhuang medicine have been applied in clinics, which obtain an outstanding clinical efficiency.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} However, there is a lack of evidence of results of traditional therapies of Zhuang Medicine in treating RA. Therefore, the paper will evaluate the effectiveness and safety of traditional therapies of Zhuang medicine treatment for RA. This review will be the first evaluation of the impact of traditional therapies of Zhuang medicine treatment.</p></sec><sec><label>2</label><title>Objectives</title><p>In a randomized controlled trial (RCT), the efficacy and side effects of traditional therapies of Zhuang medicine in treating RA have been evaluated systematically. We expect to provide reference for RA treatment in the field of traditional Chinese medicine.</p></sec><sec><label>3</label><title>Methods</title><sec><label>3.1</label><title>Study registration</title><p>The protocol of the systematic review has been registered.</p><p>Registration: OSF Preregisration.2020, Aug.19. osf.io/c4xv3/. This systematic review protocol will be conducted and reported strictly according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} statement guidelines, and the important protocol amendments will be documented in the full review.</p></sec><sec><label>3.2</label><title>Inclusion and exclusion criteria for study selection</title><sec><label>3.2.1</label><title>Inclusion criteria</title><p>Inclusion criteria are all RCTs, which main treatment of RA is traditional therapies of Zhuang medicine. The language of the trials to be included only Chinese or English.</p></sec><sec><label>3.2.2</label><title>exclusion criteria. Following studies will be excluded</title><list list-type=\"simple\"><list-item><label>1.</label><p>Repeated publications</p></list-item><list-item><label>2.</label><p>Review of literature and cases</p></list-item><list-item><label>3.</label><p>Animal studies</p></list-item><list-item><label>4.</label><p>Incomplete literature</p></list-item><list-item><label>5.</label><p>Non-RCT</p></list-item></list></sec></sec><sec><label>3.3</label><title>Types of participants</title><p>We will include RCTs of participants of 18 years or older, of any sex, race/ethnicity, and the patients are in accordance with diagnostic criteria of RA established by the American College of Rheumatology (ACR) in 1987 or the European alliance against Rheumatism (EULAR)/ACR in 2009 or the Chinese institute of Rheumatology in 2010 or the World Health Organization (WHO)in 2008. We will exclude advanced stage patients, severe joint deformities, and grade IV joint function; patients who are also participating in clinical trials for other drugs or treatments; patients with mental or legal disabilities should not be treated with this therapy; overlap other rheumatic diseases, such as systemic lupus erythematosus, Sjogren syndrome, severe knee osteoarthritis, etc; pregnant or lactating women, mental patients, etc; patients with severe diseases of the heart, brain, liver, kidney, or hematopoietic system.</p></sec><sec><label>3.4</label><title>Interventions and controls</title><p>Interventions included treatment with traditional therapies of Zhuang medicine. The control group only received conventional western medicine treatment. The routine treatment of each RCT may not be identical, but the use of traditional therapies of Zhuang medicine is the only difference between intervention and control.</p></sec><sec><label>3.5</label><title>Type of outcome measures</title><sec><label>3.5.1</label><title>Main outcomes</title><list list-type=\"simple\"><list-item><label>1.</label><p>C-reactive protein;</p></list-item><list-item><label>2.</label><p>erythrocyte sedimentation rate;</p></list-item><list-item><label>3.</label><p>rheumatoid factor</p></list-item></list></sec><sec><label>3.5.2</label><title>Additional outcomes</title><list list-type=\"simple\"><list-item><label>1.</label><p>morning stiffness time;</p></list-item><list-item><label>2.</label><p>range of motion;</p></list-item><list-item><label>3.</label><p>arthralgia;</p></list-item><list-item><label>4.</label><p>joint tenderness index;</p></list-item><list-item><label>5.</label><p>joint swelling index;</p></list-item><list-item><label>6.</label><p>total effective rate;</p></list-item><list-item><label>7.</label><p>adverse events.</p></list-item></list></sec></sec><sec><label>3.6</label><title>Search methods</title><sec><label>3.6.1</label><title>Search resources</title><p>This review will include the following electronic databases from their inception to July 2020: Electronic database includes PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure. (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>) The research flowchart.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>The research flowchart. This figure shows the identification, screening, eligibility and included when we searching articles.</p></caption><graphic xlink:href=\"medi-99-e22264-g001\"/></fig></sec><sec><label>3.6.2</label><title>Search strategies</title><p>The following MeSH terms and their combinations will be searched:</p><list list-type=\"simple\"><list-item><label>1.</label><p>RA;</p></list-item><list-item><label>2.</label><p>RCT OR RCTs;</p></list-item><list-item><label>3.</label><p>Zhuang medicine thread moxibustion or Zhuang medicine bamboo cupping therapy or Zhuang medicine fire needle or Zhuang medicine needle pricking therapy or Zhuang medicine hot-sensitive point-probing acupuncture therapy. The search strategy for PubMed is shown in (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>). Other electronic data bases will be used the same strategy.</p></list-item></list><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Search strategy in PubMed database.</p></caption><graphic xlink:href=\"medi-99-e22264-g002\"/></table-wrap></sec></sec><sec><label>3.7</label><title>Data collection and analysis</title><sec><label>3.7.1</label><title>Studies selection</title><p>There will be 2 researchers (YL and DX) carry out the selection of research literature independently using endnote x9 software. We will first make the preliminary selection by screening titles and abstracts. Secondly, we will download full text of the relevant studies for further selection according to the inclusion criteria. If there is any different opinion, 2 researchers will discuss and reach an agreement. If a consensus could not be reached, there will be a third researcher (GF) who make the final decision. The details of selection process will be displayed in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart.</p></sec><sec><label>3.7.2</label><title>Assessment of risk of bias</title><p>The assessment of risk of bias will be carried out by 2 independent reviewers (YL and WLQ), using the Cochrane Collaboration's &#x0201c;Risk of bias&#x0201d; tool. Study bias will be conducted as either: &#x0201c;unclear,&#x0201d; &#x0201c;low,&#x0201d; or &#x0201c;high&#x0201d; risk for the following criteria: random sequence generation, alloca-tion concealment, blinding, incomplete data, selective outcome reporting, and other bias. The assessment of the bias has caused controversy, there is a need for discussion with a third reviewer (PYZ). The graphic representations of potential bias within and across studies using Rev Man V.5.3.5.</p></sec><sec><label>3.7.3</label><title>Measures of treatment effect</title><p>Statistical analyses will be conducted using the risk ratio with 95% confidence intervals. Odds ratio and relative risk are commonly used for dichotomous outcomes data. For continuous outcomes, the weighted mean difference or the standard mean difference (SMD) will be analyzed.</p></sec><sec><label>3.7.4</label><title>Unit of analysis issues</title><p>The unit of analysis will be the individual participant.</p></sec><sec><label>3.7.5</label><title>Dealing with missing data</title><p>Among the results of several studies with insufficient data or missing data, the corresponding author will be contacted to complement the contents. If the corresponding author cannot be contacted, the data alone will be conducted.</p></sec><sec><label>3.7.6</label><title>Assessment of heterogeneity</title><p>The assessment of heterogeneity will be conducted by Review Manager (V.5.3.5). Chi-squared test and I2value of the forest, plot will be calculated to assess heterogeneity, according to the Cochrane Handbook. The I2value is classified into 4 levels: little or no heterogeneity (0%&#x02013;40%), moderate heterogeneity (30%&#x02013;60%), substantial heterogeneity (50%&#x02013;90%), and considerable heterogeneity (75%&#x02013;100%).</p></sec><sec><label>3.7.7</label><title>Assessment of reporting biases</title><p>If the numbers of available studies are sufficient, funnel plots will be assessed reporting biases.</p></sec><sec><label>3.7.8</label><title>Data synthesis</title><p>Review Manager (V.5.3.5) will be used to analyze. The test indicated little or no heterogeneity; a fixed effect model will be used for data. The random effect model will be adopted when there is considerable heterogeneity (I2&#x02265;50%). If there is considerable variation in results (I2&#x02265;75%), the meta-analysis will not be performed. The narrative and qualitative summary will be available.</p></sec><sec><label>3.7.9</label><title>Subgroup analysis and investigation of heterogeneity</title><p>Subgroup analysis will be conducted to assess heterogeneity. The different types of auricular acupuncture (embedding therapy on-ear point, auricular point seeds pressure, bloodletting at auricular points, auricular point on auto chemotherapy) may be affected heterogeneity.</p></sec><sec><label>3.7.10</label><title>Sensitivity analysis</title><p>Sensitivity analysis will be used to assess the robustness of the results. It is possible to determine according to methodological quality, sample size, and analysis-related issues. The studies that follow a sequence will be removed from all the inclusion reviews. The Chi-squared test and I2 value will be used to quantify statistical heterogeneity.</p></sec><sec><label>3.7.11</label><title>Summary of evidence</title><p>The assessment of evidence for all outcomes will be summarized using the Grading of Recommendations Assessment, Development and Evaluation approach. The quality of evidence will be rated as high, moderate, low, and very low quality.</p></sec></sec></sec><sec><label>4</label><title>Discussion</title><p>Globally, treatments of RA is a difficult but important problem in the medical field. In Western medicine, treatments of RA emphasize on &#x0201c;target therapy&#x0201d;, with a preference to relieve symptoms. Most patients are treated with non-steroidal anti-inflammatory drugs, DMARDs and biological agents, however, these drugs have serious side effects such as hepatorenal toxicity and immunosuppression, and biological agents are costly so that it could be a financial burden on family.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} Zhuang medicine, as a part of traditional Chinese medicine, has a complete theoretical system and abundant clinical experience. Moreover, various treatments have a remarkable curative effects in RA. According to the theory of Zhuang medicine, there is a unique understanding of RA, which belongs to the category of Fungcaep (a special term used in Zhuang medicine).^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} According to the theory of Zhuang medicine, it is mostly caused by pathogenic toxin, physical weakness, emotional disorder and so on. In fact, the essence of pathogeny is &#x0201c;Shi Du&#x0201d; (dampness toxin). Up to now, the therapies of Zhuang medicine are various, which mainly contains of Zhuang medicine thread moxibustion, Zhuang medicine bamboo cupping therapy, Zhuang medicine fire needle, Zhuang medicine needle pricking therapy, Zhuang medicine hot-sensitive point-probing acupuncture therapy and so on.</p><p>The treatment of Zhuang medicine in RA has been widely applied in clinics, which obtains a great effect. It is reported that, for instance, Zhuang medicine cupping combined with pricking blood therapy can improve the clinical symptoms of arthralgia disease patients significantly (Zeng et al 2008).^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} Besides, Zhuang medicine thread Moxibustion can obviously reduce the levels of serum tumor necrosis factor-&#x003b1; (TNF-&#x003b1;) and interleukin-1&#x003b2; (IL-1&#x003b2;) (Xu et al 2014).^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Through many clinical samples, it is fully realized that Zhuang medicine has its advantages in treating RA, even in curative effects, it is greater than Western medicine, with fewer adverse reactions.</p><p>However, the mechanism and standards of treating RA using traditional therapies of Zhuang Medicine are not expounded systematically. In short, this systematic review and meta-analysis can help identify the potential value of Zhuang Medicine in treating RA and improving pain, joint dysfunction and life quality. This study can provide a foundation for the release of RA treatment guidelines and treatment options of RA patients, and thus benefit more patients.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Yehao Luo, Donghan Xu.</p><p><bold>Data curation:</bold> Donghan Xu, Qiuxia Chen, Fang Gang.</p><p><bold>Data curation:</bold> Yehao Luo.</p><p><bold>Formal analysis:</bold> Yehao Luo, Zhiyong Cao, Lizhen Wang, Donghan Xu.</p><p><bold>Funding acquisition:</bold> Yuzhou Pang, Fang Gang.</p><p><bold>Investigation:</bold> Qiuxia Chen, Lizhen Wang, Donghan Xu.</p><p><bold>Methodology:</bold> Zhiyong Cao.</p><p><bold>Project administration:</bold> Gang Fang, yuzhou pang.</p><p><bold>Quality assessment:</bold> Fang Gang, Yehao Luo.</p><p><bold>Resources:</bold> Donghan Xu, Lizhen Wang.</p><p><bold>Software:</bold> Qiuxia Chen, Donghan Xu, Lizhen Wang, Zhiyong Cao.</p><p><bold>Supervision:</bold> Yehao Luo.</p><p><bold>Validation:</bold> Yehao Luo, Lizhen Wang.</p><p><bold>Writing &#x02013; original draft:</bold> Yehao Luo, Donghan Xu, Zhiyong Cao, Gang Fang.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Donghan Xu, Fang Gang, Yuzhou Pang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: DMARDs = disease-modifying antireheumatic drugs, RA = rheumatoid arthritis, RCT = randomized controlled trial.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Luo Y, Xu D, Cao Z, Chen Q, Wang L, Fang G, Pang Y. Traditional therapies of Zhuang medicine improve pain and joint dysfunction of patients in rheumatoid arthritis: A protocol for systematic review and meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22264).</p></fn><fn fn-type=\"equal\"><p>YL and DX contributed equally to this work and are the co-first authors.</p></fn><fn fn-type=\"other\"><p>This project is funded by National Natural Science Foundation of China (No.81973976); The National Key Research and Development Program of China (No.2017YFC1704004); Open Project for Guangxi First-class Discipline Construction of Guangxi University of Chinese Medicine (No.2019XK036); Development Program of High-level Talent Team under Qihuang Project of Guangxi University of Chinese Medicine (No.2018005); Guangxi Talent Highland for Zhuang and Yao Medicine and Combination of Medical Care and Elderly Care (NoTing Fa[2017]44). The sponsors are not involved in design, execution, or whiting the study.</p></fn><fn fn-type=\"other\"><p>If amendments are needed, the authors will update their protocol to include any changes in the whole process of research.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Bergot</surname><given-names>AS</given-names></name><name><surname>Giri</surname><given-names>R</given-names></name><name><surname>Thomas</surname><given-names>R</given-names></name></person-group>\n<article-title>The microbiome and rheumatoid arthritis</article-title>. <source>Best Pract Res Clin Rheumatol</source>\n<year>2019</year>;<volume>33</volume>:<fpage>101497</fpage>.<pub-id pub-id-type=\"pmid\">32199713</pub-id></mixed-citation></ref><ref id=\"R2\"><label>[2]</label><mixed-citation publication-type=\"book\"><comment>Handout on health: rheumatoid arthritis. national institute of arthritis and musculoskeletal and skin diseases. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"research-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991479</article-id><article-id pub-id-type=\"pmc\">PMC7523846</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-04374</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022428</article-id><article-id pub-id-type=\"art-access-id\">22428</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>5700</subject></subj-group><subj-group><subject>Research Article</subject><subject>Observational Study</subject></subj-group></article-categories><title-group><article-title>Risk of primary liver cancer associated with gallstones and cholecystectomy</article-title><subtitle>A competing risks analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Tong</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Siyin</surname><given-names>Sarah Tan</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yao</surname><given-names>Nan</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Xu</surname><given-names>Guoshuai</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Chen</surname><given-names>Yi-Tsun</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Duan</surname><given-names>Ning</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Li</surname><given-names>Wenqiang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-9738-2038</contrib-id><name><surname>Qu</surname><given-names>Jun</given-names></name><degrees>PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Siqing</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff4\">^d</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Gao.</surname><given-names>Chun</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of General Surgery, Aerospace Center Hospital</aff><aff id=\"aff2\"><label>b</label>Department of General Surgery, Beijing Children's Hospital, National Center for Children's Health</aff><aff id=\"aff3\"><label>c</label>Department of Clinic Medicine, Peking University Health Science Center, Beijing</aff><aff id=\"aff4\"><label>d</label>Department of Hepatobiliary Surgery, Kailuan General Hospital, Tangshan, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Jun Qu, Department of General Surgery, Aerospace Center Hospital, Yuquan Road 13, Haidian District, Beijing 100089, China (e-mail: <email>qujunchief@163.com</email>); Siqing Liu, Department of Hepatobiliary Surgery, Kailuan General Hospital, Xinhua Road 57, Lubei district, Tangshan 063000, China (e-mail: <email>siqingliu@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22428</elocation-id><history><date date-type=\"received\"><day>13</day><month>5</month><year>2020</year></date><date date-type=\"rev-recd\"><day>15</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>25</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22428.pdf\"/><abstract><title>Abstract</title><p>Previous research has revealed a positive relationship between GSD, cholecystectomy and primary liver cancer (PLC). However, previous studies had several limitations including the retrospective design, narrow assessment of potential confounders and lack of competing risk models in time-to-event analyses. We conducted a large prospective cohort study to explore the relationship between GSD, cholecystectomy and PLC. A total of 95,021 participants who had not been diagnosed with PLC previously were enrolled from the Kailuan Cohort study. Demographic characteristics and biochemical parameters were recorded at baseline for all participants. We used Cox regression models and competing risk regression models to evaluate the association of GSD and cholecystectomy with the risk PLC. A total of 306 incidental PLC cases were identified during a median follow-up of 9.05 (8.75&#x02013;9.22) years per participant. Compared with the normal group, the multivariable HRs (95%CI) for the association of GSD and cholecystectomy with PLC were 1.77 (1.05&#x02013;2.94), 5.25 (1.95&#x02013;14.17). In the CS model, the multivariable HRs (95%CI) was 1.76 (1.05&#x02013;2.94) for the association of GSD and cholecystectomy with PLC and 5.25 (1.95&#x02013;14.17) for GSD and cholecystectomy. Similar results were also obtained in the SD model with corresponding multivariate HRs (95%CI) of 1.75 (1.01&#x02013;3.00), 5.22 (1.90&#x02013;14.07) in the GSD group and cholecystectomy group, respectively. GSD and cholecystectomy were associated with an elevated risk of PLC.</p><p>Registration number: ChiCTR&#x02013;TNRC&#x02013;11001489.</p></abstract><kwd-group><title>Keywords</title><kwd>cholecystectomy</kwd><kwd>competing risk models</kwd><kwd>gallstone disease</kwd><kwd>incidence</kwd><kwd>primary liver cancer</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common types of primary liver cancer (PLC) and account for approximately 70% and 15% of PLC cases.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Results from Global Burden of Disease Liver Cancer Collaboration revealed that there were 854,000 incidents of liver cancer and 810,000 deaths in 2015 globally.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} PLC has one of the highest incidences of cancers worldwide and ranks as the fourth leading cause of cancer death in 2015 after lung, colorectal, and stomach cancer. The highest incidences (greater than 20/100,000 persons) of PLC were reported in Asia and Africa, with Chinese registries alone reporting more than half.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} These areas are suffering from a high prevalence of chronic infection of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) as well as an elevated consumption of aflatoxin B₁ (AFB₁) contaminated foods. On the contrary, low-rate (less than 10/100,000 persons) PLC areas included Europe and North America, where excessive consumption of alcohol, diabetes and obesity are prevalent.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]}</p><p>Risk factors including HBV and HCV infection, AFB₁, alcohol consumption, diabetes and excess body mass index are thought to be key mediators of PLC development.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>&#x02013;<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} However, the etiology of PLC remains largely exclusive apart from the aforementioned factors. Gallstone disease (GSD) as well as cholecystectomy are proven to be closely related to increased risk of several cancers, especially the risk of rectal cancer, colorectal cancer and pancreatic cancer.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>&#x02013;<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} The relationship between GSD, cholecystectomy and PLC is still controversial. Patients with gallstones were observed to have an elevated risk of PLC in recent studies.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} However, Tavani A et al failed to find such a relationship between GSD and PLC.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} As for cholecystectomy, several studies have demonstrated its strong association with the risk of liver cancer,^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>,<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} whereas others failed to illustrate a significant association.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Previous studies had several limitations. First, most were case-control studies which cannot eliminate the possibility of recall bias. Second, the majority of existing studies overestimated the effects of GSD and cholecystectomy on the risk of PLC as other confounders were hardly assessed. Third, during the long period of the follow-up, PLC cases due to the various primary causes of interest are precluded by death due to other causes, thus traditional Cox regression models and Kaplan&#x02013;Meier survival curves may not appropriately estimate the absolute risks when competing events are censored. No large-scale prospective study has been used a competing risk method to address the question of whether GSD and cholecystectomy elevate the risk of PLC. Therefore, the goal of this study is to examine the relationship between GSD, cholecystectomy and new-onset PLC based on Kailuan study by using competing risk analyses (Trial identification: ChiCTR&#x02013;TNRC&#x02013;11001489; Registration number: 11001489).</p></sec><sec><label>2</label><title>Materials and methods</title><sec><label>2.1</label><title>Kailuan study</title><p>The Kailuan study is a prospective population-based study in the Kailuan community in Tangshan of China, located 150&#x0200a;km southeast of Beijing. Tangshan is in Hebei Province and has approximately 7.2 million inhabitants. From a socioeconomic perspective, Tangshan can be viewed as a legitimate representation of the Chinese population. The Kailuan Group is a company that is mainly comprised of the coal industry, along with healthcare, education, machine manufacturing and others. This study was designed to explore risk factors related to chronic diseases like hypertension, diabetes and cancers.</p></sec><sec><label>2.2</label><title>Study population</title><p>Between June 2006 to October 2007, 101,510 participants aged 18 to 98 years underwent a clinical examination and a standardized interview, where relevant data was collected and documented as their baseline. Thereafter, the participants received follow-up examinations and a questionnaire interview biennially. All clinical examinations took place in 11 hospitals that were affiliated with the Kailuan Group. In this current study, 543 participants with a history of cancer at baseline were excluded. Two thousand three hundred twenty participants who lacked gallbladder ultrasound data and 3636 participants without data of potential risk factors for PLC at baseline were also excluded. These potential risk factors include age, gender, body mass index (BMI, in kg/m²), total cholesterol (TC, in mmol/L), triglyceride (TG, in mmol/L), fasting blood glucose (FBG, in mmol/L), alanine aminotransferase (ALT, in &#x003bc;/L), alcoholic liver disease, Hepatitis B virus infection, cirrhosis, nonalcoholic fatty liver disease (NAFLD), physical activity, drinking status, smoking status. A total of 95,021 participants, 75,886 males and 19,135 females, were left in the study. Participants were then divided into 3 groups: normal group, GSD group and cholecystectomy group. This study was approved by the Ethics Review Committee of Kailuan General Hospital as well as Aerospace Center Hospital and was performed according to the Declaration of Helsinki. Written informed consent was obtained from all participants. Details of participant's screening were shown in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>The procedure of participants screening.</p></caption><graphic xlink:href=\"medi-99-e22428-g001\"/></fig></sec><sec><label>2.3</label><title>Questionnaire assessment</title><p>From July 2006 to October 2007, face-to-face interviews were facilitated by trained physicians and research nurses using a standardized questionnaire. Information including age, sex, tobacco consumption, alcohol consumption, physical activity, family medical history (specifically the history of familial cancer) was obtained at baseline. Smoking status was defined as having smoked an average of 1 cigarette/day for more than 1 year. Alcohol consumption was defined as having drunk &#x02265;100&#x0200a;ml/day of &#x02265;50% alcohol content for more than one year. Physical activity was defined as aerobic exercise &#x02265;30 minutes, &#x02265;3&#x0200a;times/week, for more than 1 year. Participants who did not meet the criterion were described as negative for the above classifications.^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>,<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]}</p></sec><sec><label>2.4</label><title>Anthropometric measurements and blood pressure measurement</title><p>During each interview, the participants height, weight, waist circumference and blood pressure were measured. Height was measured to the nearest 0.1&#x0200a;cm and weight was measured to the nearest 0.1&#x0200a;kg. Body mass index (BMI) was calculated as weight/square of height. Waist circumference was measured to the nearest 0.1&#x0200a;cm midway between the lowest rib and the pelvis during expiration. Two readings of blood pressure were taken at a 5 minutes interval, both on the left arm, with participants in a seated position. The average of the 2 readings was used.</p></sec><sec><label>2.5</label><title>Laboratory assessment</title><p>Overnight fasting (&#x02265;8&#x0200a;hours) venous blood samples were obtained using vacuum tubes containing EDTA at the baseline examination. Plasma was separated and stored at &#x02212;80 C for subsequent analyses. The colorimetric enzymatic method (Mind Bioengineering Co Ltd, Shanghai, China) was used to measure the concentrations of both TC and TG. The detectable upper limit was 20.68 and 11.30&#x0200a;mmol/L, respectively. The direct test method (Mind Bioengineering Co. Ltd, Shanghai, China) was used to measure LDL-C and HDL-C concentrations and their detectable upper limit was 12.9 and 3.88&#x0200a;mmol/L, respectively. The hexokinase/glucose-6-phosphate dehydrogenase method was used to measure FBG concentrations. ALT was measured using the enzymatic rate method. For each measurement, the inter-assay coefficient of variation was less than 10%. All of the plasma samples were analyzed at the central laboratory in Kailuan General Hospital using an auto-analyzer (Hitachi 747; Hitachi, Tokyo, Japan).</p></sec><sec><label>2.6</label><title>Metabolic syndrome definition</title><p>According to the IDF (International Diabetes Federation) definition, Metabolic syndrome (MetS) is defined as central obesity (waist circumference &#x02265;90 cm in men and &#x02265;80 cm in women) with any 2 of the following 4 factors:</p><list list-type=\"simple\"><list-item><label>1.</label><p>Hyperglycemia fasting glucose level &#x0003e;5.6 mmol/L (100 mg/dl) or previously diagnosed diabetes.</p></list-item><list-item><label>2.</label><p>HDL cholesterol &#x0003c;1.0 mmol/L (40 mg/dl) in men, &#x0003c;1.3 mmol/L (50 mg/dl) in women, or drug treatment for these lipid abnormalities.</p></list-item><list-item><label>3.</label><p>Blood triglycerides &#x0003e;1.7 mmol/L (150 mg/dl) or drug treatment for elevated triglycerides.</p></list-item><list-item><label>4.</label><p>Blood pressure &#x0003e;130/85 mm Hg or treatment for previously diagnosed high blood pressure.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]}</p></list-item></list></sec><sec><label>2.7</label><title>Type-B ultrasonic examination and assessment</title><p>All participants were required to fast for &#x02265;8&#x0200a;hours before the ultrasonic examination. The abdominal region, including liver, gallbladder, pancreas and spleen, were examined by a panel of specialists from Kailuan General Hospital and its 10 affiliated hospitals. Liver cirrhosis, fatty liver, and GSD were diagnosed using real-time ultrasound sonography (PHILIPS HD-15) with 3.5&#x0200a;MHz according to previous clinically established criteria.^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]}</p></sec><sec><label>2.8</label><title>Outcome ascertainment</title><p>During the study period, PLC cases were collected via biennial follow-up examinations of both questionnaires and medical examinations and were classified using ICD-10 codes. Discharge summaries and medical records (obtained from the 11 affiliated hospitals) were evaluated for further information to prevent missed diagnoses. The outcome information of participants who were unable to attend face-to-face follow-ups was obtained from Provincial Vital Statistics Offices (PVSO) which provided death certificates. The diagnosis of incident PLC was checked by reviewing medical archives and pathology reports.^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>,<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]}</p></sec><sec><label>2.9</label><title>Statistical analysis</title><p>All statistical analysis was performed using a commercially available software program (SAS software, version 9.4). Person-year was calculated from the date of their first examination until the date of incidence (PLC cases), death, or termination of follow-up (December 31, 2018), whichever happened first. Normally distributed variables were presented as means &#x000b1; standard deviation and compared using one-way analysis of variance (ANOVA). Parameters in the skewed distribution were presented as median &#x000b1; interquartile range and compared using nonparametric tests. Categorical variables were expressed as percentages and comparison among groups was conducted with &#x003c7;² test. Multivariate Cox proportional hazard regressions were used to estimate the risk of gallstones and cholecystectomy associated with new-onset PLC. Three models were fitted with adjustments for confounding variables. Model 1 was a univariate analysis. Model 2 was adjusted for age and sex. Model 3 was further adjusted for BMI, FBG, TC, TG, ALT, HBV infection (positive/negative), cirrhosis (yes/no), alcoholic liver disease (yes/no), NAFLD (yes/no), MetS (yes/no), smoking status (yes/no), physical activity (yes/no), and drinking status (yes/no). In epidemiologic data, death can preclude the occurrence of the event of interest and traditional multivariate COX regression model may lead to overestimation of the absolute risk in the presence of competing risks. In these cases, competing risk regression models (cause-specific hazard model and sub-distribution hazard function model), more appropriate to calculate the accurate risk of PLC, were estimated by censoring patients with the competing events(death) and then fitting standard Cox regression models. Statistical tests were 2-sided, and <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05 was recorded as statistically significant.</p></sec></sec><sec><label>3</label><title>Results</title><sec><label>3.1</label><title>Population characteristics</title><p>Participant baseline characteristics stratified by gallbladder status (normal, GSD, cholecystectomy) are summarized in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>. Compared with the normal group, participants in the GSD group and cholecystectomy group were more likely to be older, to present with higher SBP, WC, BMI, FBG, ALT levels, and lower DBP, LDL-C and TC levels. GSD group and cholecystectomy group were also linked with a higher percentage of cirrhosis, hepatitis B virus infection, physical activity, alcohol drinking, smoking, and NALFD. There was no difference in the HDL-C concentrations and prevalence of the alcoholic liver disease among the 3 groups. It should be noted that the TG concentration and the prevalence of hypertension and MetS were highest in the GSD group.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Baseline characteristics of the participants.</p></caption><graphic xlink:href=\"medi-99-e22428-g002\"/></table-wrap></sec><sec><label>3.2</label><title>Incidence of PLC</title><p>During a median follow-up of 9.05(8.75&#x02013;9.22) years, 306 incidental PLC cases were identified over a total of 828,720 person-years among 95,021 participants. The mean age was 51.55 &#x000b1; 12.47 with 75,886 (79.86%) males and 19,135 (20.13%) females in our study. The crude incidence of PLC per 10,000 person-years was 3.69 in all participants (1.13/10,000 person-years for females, 4.34/10,000 person-years for males). A clear trend based on gallbladder status was observed, where age- and sex- standardized incidence of PLC increased from 3.48 per 10,000 person-years to 9.43 per 10,000 person-years and 23.41 per 10,000 person-years in the normal group, GSD group and cholecystectomy group, respectively.</p></sec><sec><label>3.3</label><title>Association between gallbladder disease and PLC risk</title><p>Table <xref rid=\"T2\" ref-type=\"table\">2</xref> showed the crude and adjusted HRs (95% CI) of new-onset PLC according to gallbladder status using Cox proportional hazards models. In univariate analysis, compared with the normal group, the HRs (95% CI) for the association of GSD and cholecystectomy with PLC were 2.60 (1.57&#x02013;4.30) and 6.83 (2.54&#x02013;18.31), respectively. Adjusting for age and sex did not attenuate the trend (Model 2). After the adjustment was made for confounding factors including age, gender, FBG, TC, BMI, TG, ALT, cirrhosis, NAFLD, MetS, HBV infection, alcoholic liver disease, smoking status, drinking status, and physical activity, the association between gallbladder status and PLC was attenuated but remained significant, the corresponding HRs (95%CI) in GSD group and cholecystectomy group were 1.77 (1.05&#x02013;2.94), 5.25 (1.95&#x02013;14.17) respectively.</p><table-wrap id=\"T2\" orientation=\"portrait\" position=\"float\"><label>Table 2</label><caption><p>Hazard ratios and 95%confidence interval (CI) for risk of PLC among participants stratified by gallbladder status in different regression models.</p></caption><graphic xlink:href=\"medi-99-e22428-g003\"/></table-wrap></sec><sec><label>3.4</label><title>The association between gallbladder disease and PLC risk in competing risk regression model</title><p>Results of the cause-specific proportional hazard model (CS model) and sub-distribution hazard function model (SD model) for PLC and the competing event were displayed in Table <xref rid=\"T2\" ref-type=\"table\">2</xref>. During the median 9.05(8.75&#x02013;9.22) years of follow-up, 7789 death events were identified before the occurrence of PLC. In the CS model, the HRs (95%CI) for developing PLC among participants in the GSD group and cholecystectomy group were 1.76 (1.05&#x02013;2.94) and 5.25 (1.95&#x02013;14.07) in the multivariate-adjusted analysis. In the SD model, after adjustment according to confounding factors as mentioned above, the multivariate HRs (95%CI) for the association of gallbladder status with PLC were 1.75 (1.01&#x02013;3.00) and 5.22 (1.90&#x02013;14.07) in the GSD group and cholecystectomy group, respectively.</p></sec></sec><sec><label>4</label><title>Discussion</title><p>This study was the first to investigate the relationship between GSD, cholecystectomy, and new-onset PLC among the Chinese population. In this large prospective population-based study, we found that gallstone disease and cholecystectomy were significantly associated with an increased risk of PLC despite being adjusted for suspected confounders including age, gender, FBG, TC, TG, BMI, ALT, NAFLD, MetS, cirrhosis, HBV infection, alcoholic liver disease, smoking status, drinking status, and physical activity. Participants with GSD or who have experienced cholecystectomy had 77% and 425% increased risk of PLC compared with the normal group. The findings of this study were in agreement with the observations made in previous research. A population-based study in US showed that gallstones and cholecystectomy were associated with elevated risk of liver cancer (OR = 2.35 (95% CI: 2.18, 2.54) and OR = 1.26 (95% CI: 1.12, 1.41)). A study conducted in the Swiss showed that people hospitalized with GSD and with post-cholecystectomy status could expect a 117% and 12% increase in the risk of PLC compared with normal participants.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} However, there is controversy regarding GSD and cholecystectomy being risk factors for PLC. Emily Vogtmann et al reported a statistically significant positive association of GSD with PLC, but failed to find such a relationship between cholecystectomy and PLC.^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} Similarly, a study conducted in Italy and Switzerland by drawing data from a network of case-control studies failed to such a relationship between GSD and PLC (OR&#x0200a;=&#x0200a;1.17 (95% CI: 0.83, 1.63).^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} Nonsignificant relationship between cholecystectomy and PLC have also been reported in several studies.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]}</p><p>Competing risks are common in epidemiologic research.^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>]} In this study, individuals are observed from the time of their baseline examination until the occurrence of PLC, a competing event (death), or time of censoring. Predicting PLC risk grows more difficult when the incidence of competing for events increases, as these competing events might lead to the underestimation of PLC incidence. Thus, when competing events are censored, traditional multivariate COX regression might not appropriately estimate the accurate risk. Competing risk regression models are crucial to estimate the actual individual risk in a time-to-event analysis.^{[<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} In this study, both the SD model and the CS model illustrated the circumstances in which the positive association of GSD and cholecystectomy with new-onset PLC cases. There is a substantial difference between the CS model and the SD model, and the application of either model should be dependent on research purposes. CS model should be used when the etiology of a disease is being studied, yet the SD model would be more applicable when the outcome risk of an individual is being predicted.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>]}</p><p>Previous studies have demonstrated the overestimation of standard survival prediction among elderly or frail populations. Application of prognostic models for estimating individual risk requires as much precision as possible to allow for medical decision-making and preventive analytic strategies to be most effective. Competing risk models are encouraged as a standardized tool for the development of predictive models, especially in the elderly population whereby the event of interest may not occur due to a competing event.</p><p>GSD is a significant health problem of the biliary tract and is the main reason for inpatient admissions related to gastrointestinal problems. Cholecystectomy is now the gold standard for symptomatic cholelithiasis. The number of surgical procedures for GSD has increased markedly since 1950. The advent of laparoscopic cholecystectomy further drove the cholecystectomy rate in 1989.^{[<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]} Despite a lack of definitive conclusions for the relationship between GSD, cholecystectomy, and the risk of PLC, previous studies have demonstrated the potential risk of GSD or cholecystectomy with various other cancers including colorectal, esophageal, pancreatic and gastric cancer, resulting in GSD and cholecystectomy being major public health concerns.</p><p>Treatment of GSD and PLC is costly and causes much human suffering. Cholecystectomy is almost inevitably performed to cure GSD patients with complications like acute cholecystitis, gallstone ileus, pancreatitis, gallbladder empyema or perforation. To avoid cholecystectomy, effective prevention of GSD has become a prominent aspect of modern medicine. Primary preventions including maintaining an ideal body weight, a regular exercise program, and a low-fat diet have been recommended in previous studies to prevent GSD. With greater lengths taken to prevent GSD, prevalence should decline, thereby also causing incidence of PLC to decrease.</p><p>The possible mechanisms for the close association between GSD, cholecystectomy, and PLC are complex and not fully elucidated. Gallstones are known to be closely related to biliary inflammation.^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} A highly significant increase in bile duct diameter and bile duct pressure was demonstrated after cholecystectomy which accounts for subsequent chronic inflammation.^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} Furthermore, the post-cholecystectomy bile duct dilatation increases with time, leading to greater severity of biliary inflammation. Studies have proved that chronic inflammation can fuel the release of reactive oxygen species, chemokines, cytokines, growth factors, and reactive nitrogen intermediates, which are all crucial for tumors development.^{[<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} Besides, it has been speculated that GSD and cholecystectomy lead to the accumulation of bile and secondary bile acids. Studies based on in-vitro or animal experiments have concluded lithocholic acid and deoxycholic acid, with a similar molecular structure as carcinogenic polycyclic aromatic hydrocarbon, can act as carcinogens in the etiology of cancers.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>,<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]}</p><p>To our knowledge, this is the first study concerning the relation between GSD, cholecystectomy, and new-onset PLC by using competing risk regression models. The current study is a large-scale prospective cohort study that is less susceptible to selection bias than case-control studies. Other strengths include a broad assessment of potential confounders and high incidence rate of PLC cases, thereby permitting a well-rounded consideration of the related risk factors, as well as the almost 100% follow-up rate during an almost 10-year follow-up period among the target population. This was carried out through the biennial follow-up examinations and extensive healthcare system which included death certificates, medical archives, and health insurance. However, some potential limitations should also be taken note of in this study. First, we could not distinguish between the 2 main different types of primary liver cancers, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which originates in liver cells and intrahepatic bile duct, respectively. Second, we lacked information about the consumption of AFB₁ contaminated foods and infection of HCV in baseline examination which may alter the relative risk values of the factors we chose to include. However, previous studies have demonstrated that Chinese patients with HBV are affected 37 times more frequently than Chinese patients with HCV, suggesting that HCV has much less of an effect on the development of PLC in the Chinese population.^{[<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} Third, due to the industrial character of the Kailuan Community, the number of males far exceeded females enrolled in this study. Nevertheless, the influence of imbalance in the results because of sex distribution was minimal as all regression models were adjusted for sex.</p><p>In conclusion, this prospective cohort study demonstrated that GSD and cholecystectomy were positively associated with an elevated risk of PLC even when competing risk regression models were applied. Although HBV vaccination was mandatory for all newborns in China beginning in the 1980s, the vaccinated population will not contribute to the current PLC incidence in the population until they reach middle age. Since related risk factors may also pathogenically be connected with the development of the disease, the findings of this study may also be interesting for further elucidating the pathogenesis of PLC and regarded as a clinical screening tool to distinguish individuals with an elevated risk of PLC in the Chinese population.</p></sec><sec><title>Acknowledgments</title><p>We thank all staff and participants from the Kailuan study for their vital contributions.</p></sec><sec><title>Author contributions</title><p>Tong Liu and Sarah Tan Siyin executed the study and drafted the manuscript. Tong Liu, Sarah Tan Siyin, and Nan Yao participated in the study design and performed the statistical analyses. Guoshuai Xu, Wenqiang Li, Yi-Tsun Chen, and Ning Duan contributed to the discussion. Siqing Liu and Jun Qu reviewed the manuscript.</p><p><bold>Data curation:</bold> Sarah Tan Siyin, Nan Yao, Yi-Tsun Chen, Ning Duan.</p><p><bold>Formal analysis:</bold> Sarah Tan Siyin.</p><p><bold>Investigation:</bold> Wenqiang Li.</p><p><bold>Methodology:</bold> Tong Liu, Yi-Tsun Chen.</p><p><bold>Software:</bold> Tong Liu, Nan Yao, Guoshuai Xu.</p><p><bold>Supervision:</bold> Qu Jun, Siqing Liu.</p><p><bold>Writing &#x02013; original draft:</bold> Tong Liu, Sarah Tan Siyin.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Qu Jun, Siqing Liu.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: HCC = hepatocellular carcinoma, ICC = intrahepatic cholangiocarcinoma, PLC = primary liver cancer, HBV = hepatitis B virus, HCV = hepatitis C virus, GSD = gallstone disease, BMI = body mass index, TC = total cholesterol, TG = triglyceride, FBG = fasting blood glucose, ALT = alanine aminotransferase, NAFLD = nonalcoholic fatty liver disease, MetS = Metabolic syndrome, CS Model = cause-specific hazard model, SD Model = sub-distribution hazard function model.</p></fn><fn fn-type=\"COI-statement\"><p>How to cite this article: Liu T, Siyin ST, Yao N, Xu G, Chen YT, Duan N, Li W, Qu J, Liu S. Risk of primary liver cancer associated with gallstones and cholecystectomy: a competing risks analysis. <italic>Medicine</italic>. 2020;99:39(e22428).</p></fn><fn fn-type=\"equal\"><p>SL and JQ contributed equally to this paper and share the corresponding author.</p></fn><fn fn-type=\"con\"><p>TL and STS had an equal contribution to this manuscript and share the title of the first author.</p></fn><fn fn-type=\"COI-statement\"><p>The authors declare that no competing interests exist.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>McGlynn</surname><given-names>KA</given-names></name><name><surname>London</surname><given-names>WT</given-names></name></person-group>\n<article-title>The global epidemiology of hepatocellular carcinoma present and future</article-title>. <source>Clin Liver Dis</source>\n<year>2011</year>;<volume>15</volume>:<fpage>223</fpage>&#x02013;<lpage>43</lpage>. <comment>vii-x</comment>.<pub-id pub-id-type=\"pmid\">21689610</pub-id></mixed-citation></ref><ref id=\"R2\"><label>[2]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Akinyemiju</surname><given-names>T</given-names></name><name><surname>Abera</surname><given-names>S</given-names></name><etal/></person-group>\n<collab>Global Burden of Disease Liver Cancer Collaboration</collab>. <article-title>The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015</article-title>. <source>JAMA Oncol</source>\n<year>2017</year>;<volume>3</volume>:<fpage>1683</fpage>&#x02013;<lpage>91</lpage>.<pub-id pub-id-type=\"pmid\">28983565</pub-id></mixed-citation></ref><ref id=\"R3\"><label>[3]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Ferlay</surname><given-names>J</given-names></name><name><surname>Parkin</surname><given-names>DM</given-names></name><name><surname>Curado</surname><given-names>MP</given-names></name></person-group>\n<article-title>Cancer incidence in five continents, volumes I to IX: IARC CANCERBase No. 9 [Internet]</article-title>. <source>XXXX</source> XXXX;<comment>Available at: <ext-link ext-link-type=\"uri\" xlink:href=\"http://ci5.iarc.fr/\">http://ci5.iarc.fr</ext-link> [Accessed November 9, 2010]</comment>.</mixed-citation></ref><ref id=\"R4\"><label>[4]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Perz</surname><given-names>JF</given-names></name><name><surname>Armstrong</surname><given-names>GL</given-names></name><name><surname>Farrington</surname><given-names>LA</given-names></name><etal/></person-group>\n<article-title>The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide</article-title>. <source>J Hepatol</source>\n<year>2006</year>;<volume>45</volume>:<fpage>529</fpage>&#x02013;<lpage>38</lpage>.<pub-id pub-id-type=\"pmid\">16879891</pub-id></mixed-citation></ref><ref id=\"R5\"><label>[5]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Hanafy</surname><given-names>AS</given-names></name><name><surname>Soliman</surname><given-names>S</given-names></name><name><surname>Abd-Elsalam</surname><given-names>S</given-names></name></person-group>\n<article-title>Rescue therapy for chronic hepatitis C virus infection after repeated treatment failures: Impact on disease progression and risk of hepatocellular carcinoma</article-title>. <source>Hepatol Res</source>\n<year>2019</year>;<volume>49</volume>:<fpage>377</fpage>&#x02013;<lpage>84</lpage>.<pub-id pub-id-type=\"pmid\">30570817</pub-id></mixed-citation></ref><ref id=\"R6\"><label>[6]</label><mixed-citation publication-type=\"journal\"><collab>IARC</collab>. <article-title>In: working group on the evaluation of carcinogenic risks to humans, international agency for research on cancer. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"research-article\"><?properties open_access?><?properties manuscript?><front><journal-meta><journal-id journal-id-type=\"nlm-journal-id\">101729955</journal-id><journal-id journal-id-type=\"pubmed-jr-id\">47734</journal-id><journal-id journal-id-type=\"nlm-ta\">Front Young Minds</journal-id><journal-title-group><journal-title>Frontiers for young minds</journal-title></journal-title-group><issn pub-type=\"epub\">2296-6846</issn></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32999881</article-id><article-id pub-id-type=\"pmc\">PMC7523848</article-id><article-id pub-id-type=\"doi\">10.3389/frym.2018.00029</article-id><article-id pub-id-type=\"manuscript\">NIHMS978800</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>Article</subject></subj-group></article-categories><title-group><article-title>HAND GESTURES AND HOW THEY HELP CHILDREN LEARN</article-title></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Clough</surname><given-names>Sharice</given-names></name><xref ref-type=\"aff\" rid=\"A1\">1</xref></contrib><contrib contrib-type=\"author\"><name><surname>Hilverman</surname><given-names>Caitlin</given-names></name><xref ref-type=\"aff\" rid=\"A2\">2</xref></contrib></contrib-group><aff id=\"A1\">\n<label>1</label>University of Iowa, Iowa City, IA, United States</aff><aff id=\"A2\">\n<label>2</label>Vanderbilt University Medical Center, Nashville, TN, United States</aff><pub-date pub-type=\"nihms-submitted\"><day>8</day><month>7</month><year>2018</year></pub-date><pub-date pub-type=\"epub\"><day>26</day><month>6</month><year>2018</year></pub-date><pub-date pub-type=\"ppub\"><year>2018</year></pub-date><pub-date pub-type=\"pmc-release\"><day>29</day><month>9</month><year>2020</year></pub-date><volume>6</volume><elocation-id>29</elocation-id><permissions><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0/\"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><self-uri xlink:href=\"https://kids.frontiersin.org/article/10.3389/frym.2018.00029\"/></article-meta></front><body><p id=\"P1\">When we talk, we often make hand movements called gestures at the same time. Although just about everyone gestures when they talk, we usually do not even notice the gestures. Our hand gestures play an important role in helping us learn and remember! When we see other people gesturing when they talk&#x02014;or when we gesture when we talk ourselves&#x02014;we are more likely to remember the information being talked about than if gestures were not involved. Our hand gestures can even indicate when we are ready to learn new things! In this article, we explain how gestures can help learning. To investigate this, we studied children learning a new mathematical concept called equivalence. We hope that this article will help you notice when you, your friends and family, and your teachers are gesturing, and that it will help you understand how those gestures can help people learn.</p><sec id=\"S1\"><title>WHAT KINDS OF HAND GESTURES ARE THERE?</title><p id=\"P2\">We all make spontaneous hand movements, called gestures, when we talk. These <bold>co-speech gestures</bold> are produced in rhythm with our speech and are related to the meaning of what we are saying. For example, when talking about attending a piano recital, you might move your fingers right and left in front of you to illustrate what playing a piano looks like.</p><p id=\"P3\">There are several different types of gestures that serve different purposes. Some gestures describe objects or actions, like the piano example above. These are called <bold>iconic gestures</bold>, because they create a picture. Sometimes our gestures do not make pictures, but they move in rhythm with our speech. These are called <bold>beat gestures</bold>, because they follow the beat of our speech. For example, you might flick both wrists downward when saying the word amazing in the following sentence: &#x0201c;The recital was amazing.&#x0201d; These gestures can help the speaker emphasize certain words. <bold>Deictic (DIKE-tick) gestures</bold> help the speaker direct the listener&#x02019;s attention by pointing something out. For example, at a recital, you might use your forefinger to point toward the pianist when whispering to your friend about a song that you particularly enjoyed.</p><p id=\"P4\">These terms for the different types of gestures are useful for the people who study gestures, including psychologists, cognitive scientists, linguists, and neuroscientists. These scientists often study related ideas: psychologists study thinking and human behavior, cognitive scientists study thinking and learning, linguists study language and communication, and neuroscientists study the structure and function of the brain. Many different researchers are beginning to study co-speech gestures, because they can tell us more about what is happening in people&#x02019;s minds.</p><p id=\"P5\">Even though gestures are related to speech, they can sometimes show us information that is not present in speech. For example, if I said, &#x0201c;I caught a fish last weekend,&#x0201d; you would not know how big it was. What if, while telling you I caught a fish, I put my hands out 18 inches apart? (<xref rid=\"F1\" ref-type=\"fig\">Figure 1</xref>). You would know I caught a big fish, even though I did not say anything about its size! People use gestures to convey information that is not present in speech, and they sometimes do this without even realizing it. The listener uses the unstated information in the gesture to understand what is being said. Gestures can be helpful to both the listener viewing the gestures and to the speaker producing them, and we are going to tell you how.</p></sec><sec id=\"S2\"><title>HOW DO GESTURES HELP THE LISTENER?</title><p id=\"P6\">Because gestures can show information that is not present in speech, researchers have tested whether gestures help us understand what a speaker is saying. This has been tested by many different researchers using a simple method. To test the importance of gestures to understanding, researchers compare two groups of people&#x02014;one group that views someone talking <italic>and</italic> gesturing and a second group that views someone talking <italic>without</italic> gesturing. Then they test whether the people in the group that sees gestures learn better than those in the group that do not see gestures. What the research usually finds is that seeing gestures while hearing someone talk helps the listener remember that information better. One researcher performed a <bold>meta-analysis</bold> of this work [<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]. In a meta-analysis, researchers combine the results of many studies investigating similar questions. This allows researchers to make conclusions with more confidence, because they are looking at a lot of data from different studies. So, this researcher compared the findings of 38 of these studies, to try to understand when gestures can be most helpful for learning. She found that gestures helped people learn better when the gestures represented motor (movement) actions (such as throwing a baseball) than when gestures were abstract (such as clenching a fist to represent <italic>anger</italic>). Motor gestures are iconic, because they demonstrate how to do something. When children and adults saw iconic gestures with speech, they understood the message better and remembered it more than did people who only heard speech but did not see gestures. And although gestures helped everyone learn and understand, they were extra helpful for children!</p><p id=\"P7\">By testing math learning, researchers have studied how children learn through gestures. One such study investigated whether second, third, and fourth graders learned math better when their teacher gestured [<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]. The teacher taught the students how to solve a math problem about <bold>equivalence</bold>. An example of an equivalence problem is shown here: \n<disp-formula id=\"FD1\"><mml:math id=\"M1\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mn>4</mml:mn><mml:mo>+</mml:mo><mml:mn>3</mml:mn><mml:mo>+</mml:mo><mml:mn>6</mml:mn><mml:mo>=</mml:mo><mml:mo>_</mml:mo><mml:mo>+</mml:mo><mml:mn>6</mml:mn></mml:mrow></mml:math></disp-formula></p><p id=\"P8\">Students had to decide what number to put in the blank, to make the right side equal to the left. For example, in the above equation, the number seven belongs in the blank, so that both sides equal 13. The teacher taught half the kids using just speech. In this condition, the teacher verbally explained that in an equivalence equation, &#x0201c;<italic>one side is equal to the other side</italic>.&#x0201d; The teacher taught the other half of the kids using speech <italic>and</italic> gestures. Whenever she said, &#x0201c;one side,&#x0201d; she pointed to the left side of the equation with a sweeping gesture. Whenever she said, &#x0201c;the other side,&#x0201d; she pointed to the right side of the equation with a sweeping gesture.</p><p id=\"P9\">All students were then tested on the equivalence problems twice: Posttest 1 was immediately after learning and Posttest 2 was 24 h later. The students were also given a Transfer Test. A transfer test is designed to test students&#x02019; ability to apply their knowledge in new ways. The researchers wanted to determine whether the children could extend their knowledge of equivalence to other types of problems using similar rules. For example, third and fourth graders solved a multiplication equivalence problem such as: \n<disp-formula id=\"FD2\"><mml:math id=\"M2\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mn>3</mml:mn><mml:mo>&#x000d7;</mml:mo><mml:mn>4</mml:mn><mml:mo>&#x000d7;</mml:mo><mml:mn>2</mml:mn><mml:mo>=</mml:mo><mml:mo>_</mml:mo><mml:mo>&#x000d7;</mml:mo><mml:mn>4</mml:mn></mml:mrow></mml:math></disp-formula></p><p id=\"P10\">Second graders, who were not quite ready for multiplication, solved more complicated addition problems on the Transfer Test, which did not have any of the same numbers on both sides, such as: \n<disp-formula id=\"FD3\"><mml:math id=\"M3\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mn>7</mml:mn><mml:mo>+</mml:mo><mml:mn>2</mml:mn><mml:mo>+</mml:mo><mml:mn>5</mml:mn><mml:mo>=</mml:mo><mml:mn>9</mml:mn><mml:mo>+</mml:mo><mml:mo>_</mml:mo><mml:mo>.</mml:mo></mml:mrow></mml:math></disp-formula></p><p id=\"P11\">The scientists compared the number of correct answers from children who saw gestures to those of the children who were taught with only speech. On Posttest 1, Posttest 2, and the Transfer Test, the students who saw gestures scored better than the students who only learned with speech. <xref rid=\"F2\" ref-type=\"fig\">Figure 2</xref> shows the difference between these two groups of children. Furthermore, students who learned with gestures also performed significantly better on Posttest 2 than they had on Posttest 1. This showed that gestures not only helped students learn better but gestures also helped their performance get better over time. Students who learned with only speech did not perform better on Posttest 2 than they did on Posttest 1.</p></sec><sec id=\"S3\"><title>HOW DO GESTURES HELP THE SPEAKER?</title><p id=\"P12\">Not only do students learn better when their teacher gestures but they also learn better when they use gestures themselves. A group of scientists studied whether third and fourth graders learned math better when they gestured during class [<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]. The teachers taught the students how to solve addition equivalence math problems like the ones above. One group of students repeated the teacher&#x02019;s words, &#x0201c;<italic>I want you to make one side equal to the other side</italic>.&#x0201d; A second group repeated the teachers&#x02019; gestures but <italic>not</italic> her words: they used one hand to point first to the numbers on the left side of the equation and then used the other hand to point to the numbers on the right side of the equation. A third group repeated the teacher&#x02019;s gestures <italic>and</italic> words. After instruction, all students took a posttest that consisted of new addition equivalence problems. Then, 4 weeks later, all students completed a follow-up test with similar types of questions. The follow-up test allowed the researchers to test if gestures helped learning over time.</p><p id=\"P13\">Students from all three conditions performed similarly on the posttest that they completed right after learning: making gestures when learning did not benefit learning immediately. However, on the follow-up test 4 weeks later, the students who learned by only making gestures and the students who learned by making gestures along with speech performed better than the students who learned only by speech (<xref rid=\"F3\" ref-type=\"fig\">Figure 3</xref>). Gesturing helped the students&#x02019; learning last over time, while the students who learned only with speech did not get this benefit. The researchers think that gesturing during learning helped the children produce stronger memories, because while gesturing they activated motor areas of the brain that were not activated in children who did not gesture.</p></sec><sec id=\"S4\"><title>CAN GESTURES SHOW US WHEN CHILDREN ARE READY TO LEARN?</title><p id=\"P14\">We have now shown you that gestures can improve learning, both when children see other people using gestures and when the children themselves use gestures. Is there something about gestures that can help us know when children are <italic>ready</italic> to learn something new? This seems to be the case for babies learning language. Before babies can talk, they communicate by pointing. Between 9 and 12 months, babies begin pointing to request objects like a bottle or a toy. The use of these early gestures tends to predict the first words that babies say a few months later. Babies usually say their first word at about 12 months. Before babies begin to combine multiple words together, they combine words and gestures. For example, a baby might point to a ball and say &#x0201c;mine&#x0201d; to indicate that the ball belongs to them. These combinations are called <italic>gesture-speech mismatches</italic> because the information in speech and gesture is different, or mismatched. By contrast, an example of a gesture-speech match would be the baby pointing to the ball and saying &#x0201c;ball.&#x0201d; Gesture-speech mismatches are a good thing because they show the baby is combining two ideas. In fact, these mismatches predict how well the babies will learn language: babies who produce more of these gesture-speech mismatches when they are 18 months old go on to produce more complex sentences when they are 3 years old! [<xref rid=\"R4\" ref-type=\"bibr\">4</xref>].</p><p id=\"P15\">In these cases, gestures tell us what the child already knows and help us predict when the child will learn new words. Researchers were curious about whether gestures predicted learning in school-age children as well. The researchers studied the gestures children made when explaining how they solved mathematical <italic>equivalence</italic> problems, like the ones described earlier [<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]. The researchers thought that, even though children might not be able to communicate how to solve these problems using speech, they might express some knowledge of equivalence in their gestures. For example, for the problem 4 + 3 + 6 = __ + 6, an 8-year-old child might <italic>say</italic>, &#x0201c;I added all the numbers and got 19.&#x0201d; This shows that the student does not understand the concept of equivalence, because the equal sign symbolizes that there are two separate sides that needed to be made equal. However, it might be evident from their <italic>gestures</italic> that the children are beginning to understand that the two sides of the equation are separate units. For example, the student might sweep his or her hand first under the left side of the equation and then under the right side, like the teachers did in the experiment above. The researchers wondered whether gesturing toward each side of the equal sign separately was signaling that the child was beginning to understand the concept of equivalence but could not yet form the idea into words.</p><p id=\"P16\">To test this, the researchers gave third and fourth graders a test of mathematical equivalence problems before they had learned how to solve them. When they were solving these problems, the students were asked to explain how they got their answers. Then, the students who did not get any questions correct on the pretest were taught how to solve equivalence problems. The teacher did not gesture but guided the students through the problems and asked them to again explain how they got their answers. Students then took a posttest to assess how well they had learned.</p><p id=\"P17\">The researchers then examined the students&#x02019; explanations for gesture-speech mismatches, like the hand-sweeping motion described above. Some children did use gesture-speech mismatches before and during learning. Those students provided two solutions: one in speech and another in gestures. The children were more likely to express the correct solution in gestures than they were in speech. The researchers then wanted to see if the children who used gesture-speech mismatches performed better on the posttest than did children who did not use gesture-speech mismatches during learning. The researchers compared the performance of three groups: (1) students who used gesture-speech mismatches when explaining their solutions before learning; (2) students who started to produce mismatches later, during learning; and (3) students who did not use any gesture-speech mismatches at all. Even though all the children started out providing incorrect solutions in speech, the children who used gesture-speech mismatches before learning and during learning got more answers correct on the post-test than did the children who did not use any gesture-speech mismatches (<xref rid=\"F4\" ref-type=\"fig\">Figure 4</xref>).</p><p id=\"P18\">Similar to the way babies communicate different information in their gestures and in their speech, children can do the same when explaining math problems. The researchers thought that mismatches between gestures and speech demonstrated that the children were beginning to understand the concept of equivalence but could not yet put it into words. All the children needed was a little instruction from a teacher and they successfully completed equivalence problems on the posttest. Children who did <italic>not</italic> show these gesture-speech mismatches were not really helped by the teacher&#x02019;s instruction, and they got very few problems correct on the posttest. Not only can gestures help children learn but also children&#x02019;s spontaneous gestures can show us when they are beginning to grasp a new concept!</p></sec><sec id=\"S5\"><title>EXPLORING THE CONNECTION BETWEEN GESTURES AND LEARNING</title><p id=\"P19\">Hand gestures are not just hand waving. We have now shown you that gestures enhance learning in children who view and make them. Furthermore, children&#x02019;s gestures reveal when they are on the cusp of understanding a new concept. An important unanswered question that scientists are still trying to figure out is <italic>how</italic>? How do gestures help learning?</p><p id=\"P20\">Even though we do not yet have an answer to this, scientists have some ideas. One possibility is that gestures offer a visual way to communicate ideas that can complement what children hear or say with spoken language. Instead of just hearing something in speech, children get to <italic>see</italic> it as well. Another possibility is that gestures help children focus their attention on the most important points of what is being learned, at exactly the right time. For example, when children are learning about mathematical equivalence and are being told, &#x0201c;<italic>this side is equal to this side</italic>,&#x0201d; the teacher&#x02019;s gestures can bring children&#x02019;s attention to the relevant pieces as they talk. Gestures increase the chance that the children will know exactly which part of the equation the teacher is talking about. Finally, it is also possible that gestures help memory by engaging more parts of the brain. Gesturing engages the motor (movement) parts of the brain in addition to the parts of the brain already active for producing language. Engagement of multiple brain areas may lead to better, deeper learning.</p><p id=\"P21\">These unanswered questions are exciting opportunities for scientists to better understand how we learn and remember. Gestures come along for free with our speech and can play a critical role in helping children learn. By continuing to study gestures, we will better understand how we can help children learn both in the classroom and out.</p><p id=\"P22\">Have you noticed your teachers gesturing in class? If not, it is time to tell them to start!</p></sec></body><back><fn-group><fn fn-type=\"COI-statement\" id=\"FN1\"><p><bold>CONFLICT OF INTEREST STATEMENT:</bold> The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></fn></fn-group><glossary id=\"GL\"><def-list><def-item><term id=\"G1\">CO-SPEECH GESTURES</term><def><p>Gestures that we produce spontaneously while talking.</p></def></def-item><def-item><term id=\"G2\">ICONIC GESTURES</term><def><p>Hand movements that create pictures to describe objects or actions.</p></def></def-item><def-item><term id=\"G3\">BEAT GESTURES</term><def><p>Repeated hand movements that follow the rhythm of speech.</p></def></def-item><def-item><term id=\"G4\">DEICTIC GESTURES</term><def><p>Gestures that direct the listener&#x02019;s attention, such as pointing.</p></def></def-item><def-item><term id=\"G5\">META-ANALYSIS</term><def><p>A mathematical approach that combines the results of many studies investigating similar questions, to make more powerful conclusions.</p></def></def-item><def-item><term id=\"G6\">EQUIVALENCE</term><def><p>Having the same value or being equal. For example, in a math equation, the value of the left side of the equal sign is equivalent to the value of the right side.</p></def></def-item></def-list></glossary><bio id=\"B1\"><p>\n<graphic xlink:href=\"nihms978800b1.gif\" position=\"float\" orientation=\"portrait\"/></p><p><bold>SHARICE CLOUGH</bold></p><p>I am a speech-language pathologist. I study language and help people who have a difficult time communicating. I work with kids who are learning language for the first time and adults who are re-learning to communicate (for example, after a brain injury or stroke). It is such a rewarding job. I am interested in how gestures help us communicate and how the brain supports learning and memory. I plan to get my Ph.D. and continue to be a scientist who investigates these questions! I enjoy the outdoors, reading, cats, and making art. <email>sharice-clough@uiowa.edu</email></p></bio><bio id=\"B2\"><p>\n<graphic xlink:href=\"nihms978800b2.gif\" position=\"float\" orientation=\"portrait\"/></p><p><bold>CAITLIN HILVERMAN</bold></p><p>I am a researcher at Vanderbilt University Medical Center. I work with a group of scientists who are trying to understand the relationship between language and memory. I study how co-speech hand gestures affect communication and learning in children, adults, and patients with brain injuries. In my free time I like to hike, ride my bike, and play with my super fun toddler and our sweet dog. <email>caitlin.hilverman@vanderbilt.edu</email></p></bio><ref-list><ref id=\"R1\"><label>1</label><element-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Hostetter</surname><given-names>AB</given-names></name></person-group><year>2011</year><article-title>When do gestures communicate? A meta-analysis</article-title><source>Psychol Bull</source><volume>137</volume><fpage>297</fpage><lpage>315</lpage><pub-id pub-id-type=\"doi\">10.1037/a0022128</pub-id><pub-id pub-id-type=\"pmid\">21355631</pub-id></element-citation></ref><ref id=\"R2\"><label>2</label><element-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Cook</surname><given-names>SW</given-names></name><name><surname>Duffy</surname><given-names>RG</given-names></name><name><surname>Fenn</surname><given-names>KM</given-names></name></person-group><year>2013</year><article-title>Consolidation and transfer of learning after observing hand gesture</article-title><source>Child Dev</source><volume>84</volume><fpage>863</fpage><lpage>1871</lpage><comment>doi:10.1111/ cdev.12097</comment></element-citation></ref><ref id=\"R3\"><label>3</label><element-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Cook</surname><given-names>SW</given-names></name><name><surname>Mitchell</surname><given-names>Z</given-names></name><name><surname>Goldin-Meadow</surname><given-names>S</given-names></name></person-group><year>2008</year><article-title>Gesturing makes learning last</article-title><source>Cognition</source><volume>106</volume><issue>2</issue><fpage>1047</fpage><lpage>58</lpage><pub-id pub-id-type=\"doi\">10.1016/j.cognition.2007.04.010</pub-id><pub-id pub-id-type=\"pmid\">17560971</pub-id></element-citation></ref><ref id=\"R4\"><label>4</label><element-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Rowe</surname><given-names>ML</given-names></name><name><surname>Goldin-Meadow</surname><given-names>S</given-names></name></person-group><year>2009</year><article-title>Early gesture selectively predicts later language learning</article-title><source>Dev Sci</source><volume>12</volume><issue>1</issue><fpage>182</fpage><lpage>7</lpage><pub-id pub-id-type=\"doi\">10.1111/j.1467-7687.2008.00764.x</pub-id><pub-id pub-id-type=\"pmid\">19120426</pub-id></element-citation></ref><ref id=\"R5\"><label>5</label><element-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Goldin-Meadow</surname><given-names>S</given-names></name><name><surname>Singer</surname><given-names>MA</given-names></name></person-group><year>2003</year><article-title>From children&#x02019;s hands to adults&#x02019; ears: gesture&#x02019;s role in the learning process</article-title><source>Dev Psychol</source><volume>39</volume><issue>3</issue><fpage>509</fpage><pub-id pub-id-type=\"doi\">10.1037/0012-1649.39.3.509</pub-id><pub-id pub-id-type=\"pmid\">12760519</pub-id></element-citation></ref></ref-list></back><floats-group><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>FIGURE 1</label><caption><p>By gesturing about the fish that she caught last week, this woman shows us exactly how big the fish was.</p></caption><graphic xlink:href=\"nihms978800f1\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>FIGURE 2</label><caption><p>When teachers taught equivalence problems using both speech and gestures, children did better when tested on similar problems later. Children who were taught with gestures did better than children who learned without gestures immediately after learning (Posttest 1), 24 h later (Posttest 2), and on a Transfer Test that tested their ability to use the same rules to solve new problems (for example, using multiplication problems instead of addition). The height of each bar represents the average test scores for students in both conditions. The vertical lines at the top of each bar are error bars that represent how spread out scores are around the average. Larger error bars mean that scores are more spread out. Smaller error bars mean that scores are less spread out and closer to the average. Scientists have more confidence in their findings when their error bars are smaller. This figure is adapted with permission from Cook et al. [<xref rid=\"R2\" ref-type=\"bibr\">2</xref>].</p></caption><graphic xlink:href=\"nihms978800f2\"/></fig><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>FIGURE 3</label><caption><p>Each bar represents the average number of correct answers on the follow-up test for one of the three conditions. Children who learned with gestures or with speech and gestures combined performed better on the follow-up test 4 weeks later than children who learned with just speech.</p></caption><graphic xlink:href=\"nihms978800f3\"/></fig><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>FIGURE 4</label><caption><p>Children who produced gesture-speech MMs learned better than those who did not. Children who produced MMs before and during learning had higher average scores on the posttest than did students who produced no MMs at all. Abbreviation: MM, mismatch. This figure is adapted with permission from Goldin-Meadow and Singer [<xref rid=\"R5\" ref-type=\"bibr\">5</xref>].</p></caption><graphic xlink:href=\"nihms978800f4\"/></fig></floats-group></article>\n" ]

[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"research-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991399</article-id><article-id pub-id-type=\"pmc\">PMC7523849</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-05024</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000021363</article-id><article-id pub-id-type=\"art-access-id\">21363</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3700</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Clinical Trial</subject></subj-group></article-categories><title-group><article-title>Effectiveness and safety of light vegetarian diet and Qingjiang Tiaochang Recipe for functional constipation</article-title><subtitle>An exploratory study protocol for randomized controlled trial</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-3914-9035</contrib-id><name><surname>Liu</surname><given-names>Xinyuan</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Yu</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Chen</surname><given-names>Jialiang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Huijing</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Qianqian</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Niu</surname><given-names>Zuohu</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yun</surname><given-names>Zhangjun</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Ma</surname><given-names>Bingzhi</given-names></name><degrees>MM</degrees><xref ref-type=\"aff\" rid=\"aff4\">^d</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yao</surname><given-names>Shunkun</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>School of Graduates, Beijing University of Chinese Medicine</aff><aff id=\"aff2\"><label>b</label>Department of Gastroenterology of Traditional Chinese Medicine, China-Japan Friendship Hospital</aff><aff id=\"aff3\"><label>c</label>Peking University China-Japan Friendship School of Clinical Medicine, Peking University</aff><aff id=\"aff4\"><label>d</label>Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Shunkun Yao, China-Japan Friendship Hospital, Beijing 100029, China (e-mail: <email>yaoshukundr@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e21363</elocation-id><history><date date-type=\"received\"><day>17</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>19</day><month>6</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e21363.pdf\"/><abstract abstract-type=\"toc\"><p>Supplemental Digital Content is available in the text</p></abstract><abstract><title>Abstract</title><sec sec-type=\"intro\"><title>Introduction:</title><p>Functional constipation is a chronic disease that is common in children and adults around the world. The treatments for functional constipation include diet and lifestyle interventions, medications, and surgery. The diet pattern plays an important role in the occurrence of constipation. We found in clinical practice that simple application of drugs cannot achieve long-term relief of constipation, and a large number of patients are not satisfied with the existing treatment. We have concluded that Qingjiang Tiaochang Recipe (QJTCR) and light vegetarian diet (LVD) can effectively improve constipation. However, there is no enough evidence for the description of the effect. This protocol aims at exploratorily investigating effectiveness and safety of LVD and QJTCR following a rigorous clinical trial.</p></sec><sec sec-type=\"methods\"><title>Methods and analysis:</title><p>We will recruit 90 patients to participate in this prospective, placebo-controlled, randomized trial, and exploratory study at the China-Japan Friendship Hospital, including traditional Chinese medicine group, placebo + diet group, traditional Chinese medicine + diet group. Patients in the diet intervention group must strictly abide by LVD, and the study will continue for 28 days. During the intervention period, we need to record a designed diary to assess diet quality and defecation. The primary outcomes for this clinical study were weekly complete spontaneous bowel movements. The secondary outcomes were constipation-related symptom rating scale, traditional Chinese medicine syndrome scale, and 48-hour gastrointestinal transit time, high-resolution anorectal manometry, Bristol stool score, constipation quality of life assessment scale, constipation symptoms self-assessment scale, short-chain fatty acids in feces. In addition, the study will determine the safety of the intervention.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>clinical trials</kwd><kwd>functional constipation</kwd><kwd>herbal medicine</kwd><kwd>RCT</kwd><kwd>vegetarian</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Leap-forward Development Program for Beijing Biopharmaceutical Industry (G20)</funding-source><award-id>No. Z171100001717008</award-id><principal-award-recipient>XINYUAN LIU</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Shanxi Provincial Key Research and Development Project (CN)</funding-source><award-id>No. 2017YFC0910000</award-id><principal-award-recipient>XINYUAN LIU</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Functional constipation (FC) is a common functional gastrointestinal disease and one of the most common gastrointestinal diseases of outpatients. The incidence of constipation in the world is about 15%,^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} In China, the prevalence rate varied from 6% to 13% from 2010 to 2016,^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} and the prevalence rate of constipation among the elderly in Beijing was 13%.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} FC does not threaten the life of the patient, but it seriously affects the patient's quality of life (QOL) and causes high medical expenses.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]}</p><p>Prolonged colonic transit time, pelvic floor muscle dysfunction, and their combined effects are recognized mechanisms for the development of FC. Gender, age, diet, education, and neurological diseases are the main influencing factors of FC.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} The occurrence of constipation is inversely related to the intake of dietary fiber (fruits, vegetables). A low-fiber diet can induce constipation. The latest diagnosis of FC is based on the criteria of Rome IV Standard, including laborious defecation, dry or lumpy stool, incomplete defecation, anorectal obstruction, prolonged defecation cycle, and manually assisted defecation. Two or more of the above items need to be included with at least 25% frequency for each one. Meanwhile, loose stool is rarely present without laxative and irritable bowel syndrome should be excluded.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]}</p><p>The treatment of constipation should pay attention to comprehensive management. The routine management of adult functional constipation includes lifestyle intervention, pelvic floor intervention (rectal emptying disorder), and drug treatment. Currently, medical treatment is not satisfactory in continuously improving the symptoms and quality of life of FC patients, and side effects such as electrolyte disturbance, diarrhea, and nausea are often reported.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Therefore, it is necessary to find a safe and effective treatment. Reports show that out of 6318 Chinese constipation adults, only 25.1% choose laxatives, and 81.7% of them prefer lifestyle and eating habits as treatment options.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]}</p><p>Studies have confirmed that the fecal microbiome of FC patients will change, such as the reduction of the number of Preobacterium strains and the decrease of the abundance of microflora.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} These microbiome changes may be result from low-fiber diet.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} Different dietary habits, such as low intake of water, fruits and vegetables, and high intake of spicy and greasy foods, all contribute to the increased prevalence of FC. Similarly, increasing the intake of whole fruits can protect the health of the colon and gastrointestinal tract.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R11\" ref-type=\"bibr\">11</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} The report pointed out that 57% of the intestinal flora depends on the diet structure. Five days of dietary changes may quickly change the human intestinal flora. Therefore, diet is closely related to intestinal flora.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Diet can cause constipation by affecting the flora. For example, a lack of isoflavones can cause intestinal flora imbalance, which can lead to constipation.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} Light vegetarian diet (LVD) is a healthy eating pattern summarized in clinical work. LVD is characterized by vegetarianism, avoiding high-temperature processing, and reducing flavoring.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]}</p><p>Traditional Chinese medicine formula can effectively improve gastrointestinal symptoms and intestinal health of adults with digestive system diseases. The mechanism is to reduce intestinal permeability, enhance the richness of intestinal flora, and increase the number of probiotics.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} Chinese herbal medicine can improve various chronic diseases, such as coronary heart disease, diabetes, obesity, depression, tumors, etc., by regulating the intestinal flora.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} Qingjiang Tiaochang Recipe (QJTCF) is a Chinese medicine prescription for treating functional constipation summarized in the clinical practice. The prescription does not contain drugs that can cause melanosis of the colon, such as rhubarb and aloe.</p><p>To date, there is no rigorous evidence to support the effectiveness and safety of LVD and QJTCR; thus, this needs authentication based on clinical trials in human subjects. In this protocol, we will design a randomized controlled trial (RCT) to systematically verify that point.</p></sec><sec><label>2</label><title>Methods and design</title><sec><label>2.1</label><title>Study objective and hypotheses</title><p>This exploratory research project aims to study the effectiveness of QJTCF and light vegetarian therapy for functional constipation and the changes of short-chain fatty acids in feces before and after treatment.</p></sec><sec><label>2.2</label><title>Study design</title><p>The protocol was drafted using the SPIRIT guidelines and the results will be reported following the checklist of the Consolidated Standards of Reporting Trials statement (see Supplementary Table 1). All participants will be informed of the purpose of the study and obtain their informed consent before participating in this parallel group study. According to the inclusion and exclusion criteria, a total of 90 patients with functional constipation are expected to be recruited. Then they were randomly assigned to the Chinese medicine group (group A), placebo + diet group (group B), Chinese medicine + diet group (group&#x0200a;C) at the ratio of 1: 1: 1. The patient filled out the case report form (CRF) after confirming enrollment, and the researchers recorded the patient's symptoms, bowel movements, etc., on day 14 (phone follow-up) and day 28. Interventions were provided to subjects based on the enrollment number, but neither the patient nor the investigator knew whether the patient was receiving drug or placebo. The entire study design is shown in the figure (see Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). A SPIRIT figure for the schedule of enrolment, interventions, and assessments is also presented (see Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Study design. 48-h GITT&#x0200a;=&#x0200a;48-hour gastrointestinal transit time, AEs&#x0200a;=&#x0200a;adverse events, BR&#x0200a;=&#x0200a;blood routine, BSFS&#x0200a;=&#x0200a;Bristol stool form scale, CSBM/W&#x0200a;=&#x0200a;complete spontaneous bowel movements per week, CSS&#x0200a;=&#x0200a;constipation-related symptom rating scale, DCR&#x0200a;=&#x0200a;dietary compliance rate, DQ&#x0200a;=&#x0200a;diet quality, F-SCFAs&#x0200a;=&#x0200a;short-chain fatty acids in feces, HRAM&#x0200a;=&#x0200a;high-resolution anorectal manometry, LKF&#x0200a;=&#x0200a;liver and kidney function, PAC-QOL&#x0200a;=&#x0200a;patient assessment of constipation quality of life, PAC-SYM&#x0200a;=&#x0200a;patient assessment of constipation symptom, TCMSS&#x0200a;=&#x0200a;traditional Chinese medicine syndrome scale.</p></caption><graphic xlink:href=\"medi-99-e21363-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>SPIRIT figure: schedule of enrolment, interventions, and assessments. 48-h GITT&#x0200a;=&#x0200a;48-hour gastrointestinal transit time, AEs&#x0200a;=&#x0200a;adverse events, BR&#x0200a;=&#x0200a;blood routine, BSFS&#x0200a;=&#x0200a;Bristol stool form scale, CSBW&#x0200a;=&#x0200a;complete spontaneous bowel movements per week, CSS&#x0200a;=&#x0200a;constipation-related symptom rating scale, DCR&#x0200a;=&#x0200a;dietary compliance rate, DQ&#x0200a;=&#x0200a;diet quality, F-SCFAs&#x0200a;=&#x0200a;short-chain fatty acids in feces, HRAM&#x0200a;=&#x0200a;high-resolution anorectal manometry, LKF&#x0200a;=&#x0200a;liver and kidney function, PAC-QOL&#x0200a;=&#x0200a;patient assessment of constipation quality of life, PAC-SYM&#x0200a;=&#x0200a;patient assessment of constipation symptom, TCMSS&#x0200a;=&#x0200a;traditional Chinese medicine syndrome scale.</p></caption><graphic xlink:href=\"medi-99-e21363-g002\"/></fig></sec><sec><label>2.3</label><title>Exploratory study</title><p>Light vegetarian diet is a new type of dietary model, and QJTCF is a safe and effective prescription. So far, there are no randomized controlled studies on LVD and QJTCF, so this study is an exploratory study. The essence of diet therapy is cognitive behavior therapy. Chinese medicine is complementary and alternative medicine in many countries. Through this research, doctors can pay more attention to the application of cognitive behavioral therapy and traditional Chinese medicine.</p></sec><sec><label>2.4</label><title>Inclusion criteria, exclusion criteria, and exit criteria</title><p>Participants must meet inclusion criteria (see Table <xref rid=\"T1\" ref-type=\"table\">1</xref>) and be excluded from exclusion criteria (see Table <xref rid=\"T1\" ref-type=\"table\">1</xref>), while exit criteria (see Table <xref rid=\"T1\" ref-type=\"table\">1</xref>) are set for participants who cannot complete the study. Once a patient is included in the trial, the researchers in our team will keep in touch with him or her and try to solve the problems during the treatment to reduce the loss of the intervention. During the trial, patients have the right to withdraw at any condition and will not affect subsequent treatment. The data will be recorded truthfully for further analysis.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>The inclusion criteria, exclusion criteria, and exit criteria for the trial.</p></caption><graphic xlink:href=\"medi-99-e21363-g003\"/></table-wrap></sec><sec><label>2.5</label><title>Sample size</title><p>Because there is still insufficient clinical evidence, this study is a small sample exploratory study with a total sample size of 90 people (each treatment group has 30 samples).</p></sec><sec><label>2.6</label><title>Recruitment</title><p>Participants will be recruited from the outpatients and inpatients of Gastroenterology Department and traditional Chinese medicine (TCM) Gastroenterology Department in China-Japan Friendship Hospital in Beijing through roll-up banners, posters, Wechat, and the hospital official website. Two or more experts (at least 1 from Gastroenterology Department and 1 from TCM Gastroenterology Department) will decide the eligibility unanimously following the inclusion and exclusion criteria. It will be insured that both physicians and patients have no financial interests. All eligible recruiters will sign a written informed consent and those who accept the purpose, benefits, and adverse effects of the study will be enrolled.</p></sec><sec><label>2.7</label><title>Intervention</title><p>The 2 interventions are light vegetarian diet (see Table <xref rid=\"T2\" ref-type=\"table\">2</xref>) and QJTCF (see Table <xref rid=\"T3\" ref-type=\"table\">3</xref>). QJTCF (Tongrentang Chinese Medicine) will be made into dry Chinese medicine powder. The placebo will be composed of bitters (Zhejiang Bodanheng Food Ingredients Co, Ltd), caramel color (Guilin Hongxing Food Ingredients Co, Ltd), QJTCF powder and dextrin (Liaoning Dongyuan Pharmaceutical Co, Ltd) with 2: 3: 5: 100 made into brown powder. Use the same type of aluminum foil to pack herbal powder and placebo (12 g per pack). The time for taking Chinese medicine and placebo is half an hour after breakfast and dinner, one sachet at a time, rinsed with warm water.</p><table-wrap id=\"T2\" orientation=\"portrait\" position=\"float\"><label>Table 2</label><caption><p>Specific content of light vegetarian food.</p></caption><graphic xlink:href=\"medi-99-e21363-g004\"/></table-wrap><table-wrap id=\"T3\" orientation=\"portrait\" position=\"float\"><label>Table 3</label><caption><p>The component of Chinese herb powder.</p></caption><graphic xlink:href=\"medi-99-e21363-g005\"/></table-wrap><p>Patients with dietary interventions should follow the above, while patients without dietary interventions will continue their previous dietary habits. The treatment period is 28 days. During the treatment period, record the daily diet and defecation diary. The diet diary will be designed using a semi-quantitative food frequency method, and the defecation diary will collect information about the feeling of defecation, the shape of feces, and the time of each bowel movement. On the 14th day, the patient will be followed up by phone to know the status of the treatment process, and calculate the average number of complete spontaneous bowel movements (CSBMs) per week for the first 14 days, the average score of constipation symptoms and TCM syndrome. After 28 days of treatment, a second follow-up visit will be conducted to understand the condition of constipation (same as the first follow-up visit), and the patient will be required to complete the examination (48&#x0200a;hours gastrointestinal transit Time [GITT], high-resolution anorectal manometry [HRAM], blood routine [BR], liver and kidney function [LKF]). The short-chain fatty acids of the patient 's fresh stool (&#x0003c;30&#x0200a;min) should also be checked and the diary should be retrieved. During the intervention, patients will keep in touch with the researchers. The patient's diet and stool diary will be filled out by the doctor. Keep in touch with each patient in the treatment period through mobile phone software (WeChat), ask the patient to send 3 meals to the doctor's mobile phone, ask the patient about the stool on the day at 7 o&#x02019;clock every night, and urge patients in the diet intervention group to insist on light vegetarian diet.</p></sec><sec><label>2.8</label><title>Randomization, allocation concealment, and partly double-blind</title><p>Third parties not involved in the study will use Excel 2013 software (Microsoft Corporation, Redmond, WA) to generate 90 independent random numbers and divide them by 3. The rest will be 1 in group A, 2 in group A, and 0 in group C. A, B, and C are defined as Chinese medicine group, placebo + diet group, Chinese medicine + diet group. If the enrolled patients fall off, the total number of enrolled patients exceeds 90, and they will be randomly grouped again according to needs. Patient serial numbers will be generated in the order of enrollment. When distributing medicines, neither the doctor nor the patient can know what kind of medicine. The drug number information will be retained, encapsulated, and stored in an opaque envelope, and kept by a third party. When the patient is enrolled, the envelope based on their serial number will be delivered to the researcher. After the trial, the third party will expose blindness. Because dietary intervention is a set of dietary principles rather than specific foods, it is difficult to be blinded, so only drugs are double-blind to reduce information bias.</p></sec><sec><label>2.9</label><title>Emergency unblinding</title><p>In case of any serious adverse events or emergency, the researcher will report to the supervisor and the main researcher to decide whether to open the emergency letter. Once opened, the case will be treated as exfoliated, excluded from the efficacy analysis, but will remain included in the adverse reaction analysis. Details of the unblinding cause, date, treatment situation, and results will be reported in the CRF and will be signed by the administrator.</p></sec><sec><label>2.10</label><title>Quality control</title><p>Participants&#x02019; diet quality (DQ) will be assessed at the baseline and after the intervention. The foods involved are in LVD content.</p></sec><sec><label>2.11</label><title>Data collection</title><sec><label>2.11.1</label><title>Baseline information</title><p>Baseline information will include demographic data and clinical data from the participants. Demographic data includes gender, age, height, weight, nationality, occupation, and education level, etc. Clinical data includes past medical history, drug allergy history, the history of medications used to treat or induce constipation, dietary habits in the past year (see Supplementary Table 1), the primary outcome, and secondary outcomes.</p></sec><sec><label>2.11.2</label><title>Primary outcome</title><p>The number of CSBM per week is the primary outcome. It is effective when the number before the intervention subtracted from the number after the intervention is more than or equal to 1.</p></sec><sec><label>2.11.3</label><title>Secondary outcomes</title><p>Constipation-related symptom rating scale: The scale for constipation-related symptoms is used for investigating the degree and frequency of symptoms mentioned in Roman IV diagnostic criteria for FC. The degree of discomfort is assessed by visual analog scale, in which 0 represents no discomfort and 10 represents very strong discomfort. The final scores are obtained with the multiplication of the 2 and then divided by the average number of defecations per week (see Supplementary Table 2). Percent improvement will be calculated as follows:&#x000a0;<disp-formula id=\"MU1\"><graphic xlink:href=\"medi-99-e21363-g006.jpg\" position=\"float\" orientation=\"portrait\"/></disp-formula></p><p>Recovery means symptoms disappeared; Marked improvement means percent improvement is more than or equal to 80%; Progress means percent improvement is more than or equal to 50% but less than 80%; Ineffective means percent improvement is less than 50%.</p><p>Traditional Chinese medicine syndrome scale (TCMSS): The TCMSS is established by collecting information about effects of relevant syndromes of TCM constipation, which are assigned 0, 1, 2, and 3 points representing normal, mild, moderate, and severe degrees, respectively. Normal refers to the absence of this syndrome, mild refers to a slight impact on life, moderate means a significant impact on life, and severe refers to the serious impact on life (see Supplementary Table 3). Nimodipine method is used for evaluating the effects of relevant syndromes of TCM constipation.&#x000a0;<disp-formula id=\"MU2\"><graphic xlink:href=\"medi-99-e21363-g007.jpg\" position=\"float\" orientation=\"portrait\"/></disp-formula></p><p>Symptoms, signs disappeared or basically disappeared and syndrome integral reduced more than or equal to 95% is considered clinical cure; Significantly effective means that symptoms, signs significantly have improved, and syndrome integral has reduced more than or equal to 70%; Effective means that symptoms, signs have improved and syndrome integral has reduced more than or equal to 30%; Ineffective means that symptoms, signs have no improved or have even aggravated and syndrome score has reduced less than 30%.</p><p>Forty-eight hours GITT: 48-hour GITT is a simple method for evaluating the function of gastrointestinal motility. The barium residue rate is the ratio of the number of barium remaining in the body 48&#x0200a;hours after swallowing 20 barium bars with a standard meal. Higher residue rate indicates the worse gastrointestinal transport function. The parameters include barium excretion rate after 48 hours, residue rate above rectosigmoid colon and residue rate within rectosigmoid colon. The barium excretion rate in normal people is more than or equal to 90%.</p><p>HRAM: HRAM is used to estimate the function of anal sphincter, rectal sensation, and anorectal reflex for diagnosing the defecation disorder constipation. The parameters include mean pressure of resting anal sphincter, maximum contraction pressure of resting anal sphincter, anal relaxation rate during analog defecation, first sensory value, defecation sensory value, and maximum tolerance.</p><p>BSFS: The Bristol stool score is used to assess fecal traits under the naked eye. 1 point: scattered hard lumps, like nuts; 2 points: sausage-like, but agglomerate; 3 points: sausage-like, but with cracks on the surface; 4 points: sausage-like or snake-like, smooth, and soft; 5 points: soft balls, clear edges; 6 points: unclear edges, mushy stools; 7 points: watery, no solids.</p><p>PAC-QOL: The quality of life assessment scale for patients with constipation includes 4 parts, including physiological, psychological, constipation's impact on life and treatment satisfaction, a total of 28 items, using Linker 5 grade. The higher the total score, the lower the quality of life, which means the more dissatisfied with the current state of life (see Supplementary Table 4).</p><p>PAC-SYM: The symptom self-assessment scale for patients with constipation includes 3 dimensions (abdominal symptoms, rectal symptoms, and stool symptoms) and 12 items. The Linker 5 scale is used. The higher the score, the more severe the constipation symptoms (see Supplementary Table 5).</p><p>F-SCFAs: Detection of short-chain fatty acids in feces contains acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and caproic acid. Feces samples were collected before and after the intervention and stored in the &#x02212;80&#x000b0;C refrigerator in the biological sample bank of the China-Japan Friendship Hospital. Inspection and analysis after the test.</p></sec><sec><label>2.11.4</label><title>Safety outcomes</title><p>Safety parameters include AEs and laboratory examinations (BR, LKF).</p></sec><sec><label>2.11.5</label><title>DQ and compliance measures</title><p>After the test, the proportion of qualified diets and the frequency of various food intakes will be calculated. The diet intervention group should strictly follow the requirements of light vegetarian diet, while the nondiet intervention group does not need to observe the light vegetarian diet. Dietary compliance rate (DCR) means the ratio of qualified meals to total meals times 100. When DCR is greater than or equal to 80%, high compliance is achieved, while low DCR is less than 80%.</p></sec></sec><sec><label>2.12</label><title>Adverse event</title><p>Adverse events refer to the negative effects caused by the intervention. During the trial, any abnormal reactions of the participants will be reported to the researchers. The time of onset, symptoms, degree, duration, and mitigation measures will be recorded in the CRF.</p></sec><sec><label>2.13</label><title>Data monitoring and confidentiality</title><p>Researchers will be trained in a unified way before the study to ensure it is performed correctly. Data will be locked in the airtight cabinet and will be entered and checked by double entry into the database established by data administrator using Excel 2019 edition (Microsoft Corporation, Redmond, WA) for management after completion of the study. An independent statistician will analyze the data while the procedure will be monitored by a third individual. The data of the patients involved in the trial will be confidential and will be used only by scientific research institutes. The publication or reporting of any research findings will not reveal the individual identity.</p></sec><sec><label>2.14</label><title>Planned statistical analysis</title><p>Continuous variables will be described as the mean &#x000b1; standard deviation, median, or interquartile range. The number of cases, frequency, the rate, and the constituent ratio will be described by categorical variables. Variance analysis will be used for continuous variables in the baseline data having normal distribution and same variance. Wilcoxon rank sum test or Kruskal&#x02013;Wallis H test will be used for the comparison of differences between groups that are not normally distributed or have uneven variance. Categorical variables will be tested by <italic>&#x003c7;</italic>² test or Fisher exact test. Wilcoxon rank sum test or Kruskal&#x02013;Wallis H test will be used for the number of CSBM per week in primary outcome. <italic>&#x003c7;</italic>² test or Fisher exact test will be used for percent improvement of each symptom scale score in secondary outcome indicators. The result of 48-hour GITT will be analyzed using <italic>&#x003c7;</italic>² or Fisher test. Wilcoxon rank sum test or Kruskal&#x02013;Wallis H test will be used for measurement data in HRAM, while <italic>&#x003c7;</italic>² test or Fisher exact test will be used for counting data. Safety, dietary quality, compliance indicators will be tested by <italic>&#x003c7;</italic>² test or Fisher exact test. Complying with the intent-to-treat and per-protocol principle, all data of the patients randomized and at least 1 assessment (include baseline assessment) will be analyzed. For dropouts and terminations, their missing data will be obtained by last-observation-carried-forward method. All statistical analyses will be performed by SPSS23 software (IBM, Chicago, IL), and <italic>P</italic> value &#x0003c;.5 will be considered statistically significant.</p></sec><sec><label>2.15</label><title>Ethics and dissemination</title><p>This study has been approved by China-Japan Friendship Hospital clinical research ethics committee (No. 2017-46-1). Participants will need to sign the informed consent before the entering the study. During the intervention, patients have the right to withdraw at any condition and will not affect subsequent treatment (personal treatments from the expert team). We must submit a written application to the ethics committee if the protocol needs to be modified. The committee members will decide whether to modify it. The results of the study will be sent to researchers, participants, and disseminated to the public through academic conferences and journals. This is an open access article, which permits unrestricted use when the original work is correctly cited.</p></sec></sec><sec><label>3</label><title>Discussion</title><p>FC is a common disease of the digestive system and is characterized by persistent or recurrent difficulty in defecation. Constipation can cause digestive symptoms such as loss of appetite, abdominal distension, hemorrhoids, and colon polyps. It can also lead to cardiovascular and cerebrovascular diseases,^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>&#x02013;<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} kidney diseases,^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>,<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} and even sudden death. At present, traditional Chinese and Western medicines used to treat functional constipation can only temporarily improve constipation. Constipation can easily recur after stopping the medication. Some traditional Chinese medicines also cause damage to the intestinal tract (melanosis coli).^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} Long-term improvement of constipation can be achieved through the management of patients&#x02019; cognitive behavioral patterns. Studies have shown that dietary fiber supplementation can improve chronic constipation, but there is no intervention study on constipation with a vegan diet.^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>&#x02013;<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} In clinical practice, maintenance of FC improvement has been observed in patients who persist in LVD for a period of time without any drug use. TCM is a national medicine in China.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} It has been caring for the health of Chinese people from ancient times to present. TCM has mature experience in the treatment of constipation. Qing Jiang Tiao Chang Fang is a safe and effective prescription. However, these are only the results of clinical observations and need to be scientifically validated in clinical trials. This RCT aims to clarify the efficacy and safety of LVD and QJTCF on FC by designing rigorous trials. The results of the study can provide more evidence for dietary intervention and TCM intervention on FC, and to some extent, clarify the complementary effect of diet on drugs. There are still some limitations in this study:</p><list list-type=\"simple\"><list-item><label>1.</label><p>Dietary intervention is a cognitive behavioral therapy, and there are many objective factors that will hinder the practice of light vegetarian diet and affect the experimental results.</p></list-item><list-item><label>2.</label><p>The experiment explored the metabolic effects of vegetarian diet and traditional Chinese medicine on fecal short-chain fatty acids, but no other metabolites were studied.</p></list-item><list-item><label>3.</label><p>The current study belongs to exploratory study with small sample size.</p></list-item></list><p>Therefore, based on this study, a large sample size, multicenter RCT should be designed in the future to verify the effectiveness and safety of LVD and QJTCF on FC. In terms of mechanism, if intestinal flora, metabolism, power, and other angles can be integrated to study, it can be more convincing.</p></sec><sec><title>Acknowledgment</title><p>The authors thank the doctors and other staff in the Department of Gastroenterology and Gastroenterology of Chinese Medicine of China-Japan Friendship Hospital for their assistance. LX is the first author. The authors thank MB of the Pharmacy Department of China-Japan Friendship Hospital for assisting in the packaging of drugs and placebos. They thank Sun Ruihua, Clinical Research Institute of China-Japan Friendship Hospital, for providing statistical guidance.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Xinyuan Liu, Yu Liu, Shukun Yao.</p><p><bold>Data curation:</bold> Xinyuan Liu, Yu Liu, Jialiang Chen, Huijing Wang.</p><p><bold>Formal analysis:</bold> Xinyuan Liu.</p><p><bold>Funding acquisition:</bold> Shukun Yao.</p><p><bold>Investigation:</bold> Yuehua Ding, Yuanchen Zhou, Xinyuan Liu, Huijing Wang, Qianqian Wang, Zuohu Niu, Zhangjun Yun.</p><p><bold>Methodology:</bold> Xinyuan Liu, Yu Liu, Jialiang Chen, Qianqian Wang, Bingzhi Ma, Shukun Yao.</p><p><bold>Project administration:</bold> Xinyuan Liu, Shukun Yao.</p><p><bold>Resources:</bold> Shukun Yao.</p><p><bold>Software:</bold> Xinyuan Liu, Jialiang Chen, Shukun Yao, Zuohu Niu, Zhangjun Yun.</p><p><bold>Supervision:</bold> Shukun Yao.</p><p><bold>Visualization:</bold> Xinyuan Liu, Bingzhi Ma.</p><p><bold>Writing &#x02013; original draft:</bold> Xinyuan Liu, Yu Liu</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Xinyuan Liu, Shukun Yao.</p></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD1\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e21363-s001.docx\" orientation=\"portrait\" id=\"d38e799\" position=\"anchor\"/></supplementary-material></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD2\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e21363-s002.docx\" orientation=\"portrait\" id=\"d38e807\" position=\"anchor\"/></supplementary-material></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD3\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e21363-s003.docx\" orientation=\"portrait\" id=\"d38e815\" position=\"anchor\"/></supplementary-material></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD4\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e21363-s004.docx\" orientation=\"portrait\" id=\"d38e823\" position=\"anchor\"/></supplementary-material></sec><sec sec-type=\"supplementary-material\"><title>Supplementary Material</title><supplementary-material content-type=\"local-data\" id=\"SD5\"><caption><title>Supplemental Digital Content</title></caption><media mimetype=\"application\" mime-subtype=\"pdf\" xlink:href=\"medi-99-e21363-s005.docx\" orientation=\"portrait\" id=\"d38e831\" position=\"anchor\"/></supplementary-material></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: BR = blood routine, BSFS = Bristol stool form scale, CRF = case report form, CSBM = complete spontaneous bowel movements, DCR = dietary compliance rate, DQ = diet quality, FC = functional constipation, F-SCFAs = short-chain fatty acids in feces, GITT = gastrointestinal transit time, HRAM = high-resolution anorectal manometry, LKF = liver and kidney function, LVD = light vegetarian diet, PAC-QOL = patient assessment of constipation quality of life, PAC-SYM = patient assessment of constipation symptom, QJTCF = Qingjiang Tiaochang Recipe, RCT = randomized controlled trial, TCM = traditional Chinese medicine, TCMSS= traditional Chinese medicine syndrome scale.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Liu X, Liu Y, Chen J, Wang H, Wang Q, Niu Z, Yun Z, Ma B, Yao S. Effectiveness and safety of light vegetarian diet and Qingjiang Tiaochang Recipe for functional constipation: An exploratory study protocol for randomized controlled trial. <italic>Medicine</italic>. 2020;99:39(e21363).</p></fn><fn fn-type=\"other\"><p>XL is the first author.</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by the Leap-forward Development Program for Beijing Biopharmaceutical Industry (G20), No. Z171100001717008, and National Key Research and Development Program, No. 2017YFC0910000.</p></fn><fn fn-type=\"other\"><p>Participants&#x02019; recruitment is ongoing. The trial is scheduled to end on December 31, 2020. The protocol version 2.0 (February 23, 2020) is currently active.</p></fn><fn fn-type=\"other\"><p>This study has been approved by China-Japan Friendship Hospital clinical research ethics committee (No. 2017-46-1). A SPIRIT checklist is available for this protocol.</p></fn><fn fn-type=\"other\"><p>Trial registration number: ChiCTR2000030106 in Chinese Clinical Trial Registry (WHO ICTRP member).</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Bharucha</surname><given-names>AE</given-names></name><name><surname>Lacy</surname><given-names>BE</given-names></name></person-group>\n<article-title>Mechanisms, evaluation, and management of chronic constipation</article-title>. <source>Gastroenterology</source>\n<year>2020</year>;<volume>158</volume>: 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991459</article-id><article-id pub-id-type=\"pmc\">PMC7523850</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08199</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022383</article-id><article-id pub-id-type=\"art-access-id\">22383</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>7400</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>Acupuncture for pain relief of women undergoing transvaginal oocyte retrieval</article-title><subtitle>A meta analysis and systematic review protocol</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-4147-5542</contrib-id><name><surname>Guo</surname><given-names>Xiao-Li</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Li</surname><given-names>Xiang</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Wei</surname><given-names>Wei</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Rong-Rong</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Xiao</surname><given-names>Fang</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Li-Ying</given-names></name><degrees>MD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Xu</surname><given-names>Jing</given-names></name><degrees>PhD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff>Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Li-Ying Liu, Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No.37 Shi&#x02019;er Qiao Road, Chengdu, Sichuan 610075, China (e-mail: <email>767000032@qq.com</email>); Jing Xu, Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No.37 Shi&#x02019;er Qiao Road,Chengdu, Sichuan 610075, China (e-mail: <email>195940644@qq.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22383</elocation-id><history><date date-type=\"received\"><day>25</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>26</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22383.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Pain during oocyte retrieval, which can make the in-vitro fertilization process an unpleasant experience, is becoming a common problem. Although there are many analgesic methods available in the clinical setting, they are not therapeutically equivalent, and some are associated with varying adverse reactions. In recent years, acupuncture analgesia has been used in the perioperative period of oocyte retrieval because of its perceived efficacy and safety. The purpose of this systematic review and meta-analysis is to provide evidence that acupuncture is effective in the treatment of vaginal oocyte retrieval pain.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>Electronic searches of the following six databases will be conducted by two qualified reviewers: MEDLINE, EMBASE, China National Knowledge Infrastructure, Chinese Biomedical Medicine database, VIP database and Wanfang database. Three clinical trial registries will also be searched: World Health Organization International Clinical Trial Registry Platform, Chinese Clinical Trial Registry, Cochrane Central Register of Controlled Trials and ClinicalTrials.Gov. All searches will cover the period from inception of the database/registry to March 2020 and will be limited to publications in English and Chinese. Data identification, data selection, data extraction, and bias risk assessment will be conducted independently by3&#x003bd; two or more qualified reviewers, including those who selected the studies. Visual analogue scale scores will be calculated as the primary outcome. Secondary outcomes will include results of other subjective pain rating scales, including Likert scales or other defined numerical or non-numerical scales, self-assessed by patients before, during, and after oocyte retrieval. We will use STATA software (Version 16) to perform meta-analyses, and the Grading of Recommendations, Assessment, Development and Evaluations framework to grade the quality of evidence. If quantitative analysis is not available, a systematic narrative synthesis will be provided.</p></sec><sec><title>PROSPERO registration number:</title><p>CRD42020170095.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>acupuncture</kwd><kwd>meta-analysis</kwd><kwd>pain relief</kwd><kwd>systematic review</kwd><kwd>transvaginal oocyte retrieval</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>the National Natural Science Foundation of China</funding-source><award-id>81973966</award-id><principal-award-recipient>xiaoli guo</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Distinguished Middle-Aged and Young Scientist Encourage and Reward Foundation of Shandong Province (CN)</funding-source><award-id>2020JDJQ0051</award-id><principal-award-recipient>xiaoli guo</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Oocyte retrieval is a crucial step of the in vitro fertilization and embryo transfer (IVF-ET) process. It is well known that ultrasound-guided vaginal oocyte retrieval is a routine procedure of IVF.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} The procedural time is generally short, however, mechanical stimulation of the needle through the vaginal wall and the ovaries can be painful for the patient.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} One study reported that 59.5% of patients experienced pain during oocyte retrieval.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Other studies also confirmed that more than half of the women suffer pain during oocyte retrieval.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Moreover, pelvic organs and blood vessels can be damaged by aspiration needles, and life-threatening complications related to infection or anesthesia may occur. Types of analgesia that have been used clinically for oocyte extraction include conscious sedation,^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} general anesthesia,^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} local injection as a paracervical block (PCB)^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>&#x02013;<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} and patient-controlled analgesia. PCB is the main analgesic method and has been widely used in some IVF units^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} to relief pain. And a research has proved that the use of lignocaine in PCB did reach statistical significance.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} Although several meta-analyses and systematic reviews of analgesic interventions for oocyte retrieval have been published in recent years, there is currently no consensus on the optimal method.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>,<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} These analgesia methods can relieve pain, but may cause nausea, vomiting, dizziness, suppression of the nervous system, possible impairment of respiration or blood circulation and other adverse reactions.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]}</p><p>Nowadays, acupuncture is clinically accepted for analgesia.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R19\" ref-type=\"bibr\">19</xref>&#x02013;<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} Acupuncture is widely used for pain relieve based on a principle of Traditional Chinese Medicine theory. Traditional Chinese Medicine theory states that the movement of qi and blood in the meridians is not smooth, block blocked, or the consumption of qi and blood is not nourish the meridians, which will form pain. The main pathologies of pain are &#x0201c;pain without general rule&#x0201d; and &#x0201c;pain without honor.&#x0201d; Acupuncture is also believed to nourish the meridians, regulate the flow of qi and blood to relieve pain.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} According to modern medical theory, acupuncture can relieve pain by stimulating receptors or nerve fibers in the tissue and producing a rhythmic discharge in the nerve fibers, leading to the release of endogenous neurotransmitters.^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>&#x02013;<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} Acupuncture also relieves pain by inhibiting visceral nociceptors, inflammatory cytokines, and by activating the central nervous system. Acupuncture analgesia for ultrasound-guided vaginal oocyte retrieval has been associated with few adverse reactions.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} A previous meta-analysis^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} compared the pain relief effects of electro-acupuncture and conventional medical analgesic methods in 12 studies, concluding that there was no consensus on the best method for oocyte retrieval. However, the meta-analysis was limited by studies with insufficient sample sizes and low-quality literature, necessitating studies with larger sample sizes and a higher quality of evidence.</p><p>Therefore, the purpose of this study will be to review more new and larger randomized controlled trials (RCTs) of acupuncture analgesia compared with other analgesia methods during transvaginal oocyte retrieval, and to provide reliable clinical data on its safety and efficacy.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Registration</title><p>This protocol has been registered in PROSPERO (registration number: CRD42020170095). This system and meta-analysis will follow the Preferred Reporting Item for Systematic Evaluation and Meta-analysis (PRISMA)^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} statement guidelines and the software STATA (version 16.0) will be used to construct the meta-analysis.</p></sec><sec><label>2.2</label><title>Eligibility criteria</title><sec><label>2.2.1</label><title>Types of study and participants</title><p>This review will only include RCTs (published and unpublished). Animal studies, case reports, commentaries, uncontrolled clinical trials and crossover trials will be excluded. Women undergoing transvaginal oocyte retrieval as part of a course of IVF treatments will be enrolled in the analysis.</p></sec><sec><label>2.2.2</label><title>Types of interventions</title><p>The treatment group will receive acupuncture therapy. Traditional acupuncture, in which needles are inserted into definite acupoints, as well as modern acupuncture techniques such as transcutaneous electrical nerve stimulation (TENS), electro-acupuncture, point injection, acupressure, laser acupuncture, tap-pricking or cupping on pricked superficial blood vessels, will be included. The timing of acupuncture treatment will not be limited.</p></sec><sec><label>2.2.3</label><title>Types of controls</title><p>All participants will receive PCB for analgesia during oocyte retrieval, with the following comparators:</p><list list-type=\"bullet\"><list-item><p>Acupuncture with PCB versus PCB alone;</p></list-item><list-item><p>Acupuncture with PCB, versus invasive sham or minimal or noninvasive placebo acupuncture with PCB;</p></list-item><list-item><p>Acupuncture with PCB, versus conscious sedation or drug analgesia with PCB;</p></list-item><list-item><p>Acupuncture and conscious sedation or drug analgesia with PCB, versus conscious sedation or drug analgesia with PCB.</p></list-item></list></sec><sec><label>2.2.4</label><title>Types of outcome measures</title><p>Participants must use the scale to self-assess pain at three time points: before, during and after the oocyte retrieval procedure. We define postoperative pain as pain measured over a period of time after oocyte retrieval.</p><list list-type=\"bullet\"><list-item><p>Primary outcome</p><p>The visual analogue scale (VAS) will be the primary outcome for all studies.</p></list-item><list-item><p>Secondary outcomes</p><p>Studies must include a subjective pain rating scale such as a Likert scale or other defined numerical or non-numerical scale.</p></list-item></list></sec></sec><sec><label>2.3</label><title>Search strategy</title><sec><label>2.3.1</label><title>Information sources</title><p>Six databases will be searched from inception to March 2020: MEDLINE, EMBASE, China National Knowledge Infrastructure, Chinese Biomedical Medicine database, VIP database and Wanfang database.</p><p>The main English-language retrieval terms will be as follows: &#x0201c;oocyte retrieval,&#x0201d; &#x0201c;transvaginal ultrasound oocyte retrieval,&#x0201d; &#x0201c;acupuncture,&#x0201d; &#x0201c;transcutaneous electrical nerve stimulation,&#x0201d; &#x0201c;electro-acupuncture,&#x0201d; &#x0201c;point injection,&#x0201d; &#x0201c;acupressure,&#x0201d; &#x0201c;laser acupuncture,&#x0201d; &#x0201c;tap-pricking,&#x0201d; and &#x0201c;cupping.&#x0201d;</p><p>Searching of the Chinese databases will be carried out using the corresponding search terms in Chinese.</p></sec><sec><label>2.3.2</label><title>Other sources</title><p>The ongoing trials with unpublished data will be searched by following clinical trial registries: World Health Organization International Clinical Trial Registry Platform, Chinese Clinical Registry, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Manually retrieve and review a list of references to all possible published papers, including relevant systematic reviews, to identify any other trials.</p></sec></sec></sec><sec><label>3</label><title>Study selection and data collection</title><sec><label>3.1</label><title>Data management</title><p>All of the documents will be under the charge of LYL. Each time one of the two independent reviewers has collected data from a paper, the original document will be screened and recorded. Once a source file has been entered, it will be recorded in the paper record sheet. Only study colleagues and other approved individuals will have access to the data used in this study.</p></sec><sec><label>3.2</label><title>Selection process</title><p>Two researchers (RRW and FX) will import the retrieved literature into Excel by title, abstract and full text, and review each article independently. The inclusion of studies for the review will be based on the PRISMA^{[<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} flow diagram (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). If there is disagreement regarding selections by the two researchers, the disagreements will be resolved through discussion. If no agreement can be reached, a third researcher (LYL) will make the decision independently.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flowchart of study selection. RCT&#x0200a;=&#x0200a;randomized controlled trial.</p></caption><graphic xlink:href=\"medi-99-e22383-g001\"/></fig></sec><sec><label>3.3</label><title>Data collection process</title><p>Similar to screening, data extraction will be carried out in duplicate by two independent reviewers (RRW and FX) to reduce bias and potential errors. Relevant information will then be entered into a unified data statistics table. Any disagreement will be resolved by discussion; if consensus cannot be reached, a third researcher (LYL) will make the final decision. All data will be cross-checked by FX and RRW, then transferred into STATA software (Version 16).</p></sec><sec><label>3.4</label><title>Data items</title><p>The information we plan to extract from each study includes general information (study title, first author, publication year and journal); characteristics (study object, diagnostic criteria, inclusion criteria, exclusion criteria, intervention details); outcome indicators and values. All included studies must meet the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA)^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} guidelines.</p></sec><sec><label>3.5</label><title>Missing data</title><p>If the full text of an article is not available or the information is incomplete, we will contact the original author for more information. If this method does not yield sufficient information, we will analyze the available data, report any missing data, and discuss the potential impact on the study.</p></sec><sec><label>3.6</label><title>Outcomes and prioritization</title><p>We will list and define each of the outcomes found in the retrieved articles and datasets. We will also prioritize these results based on the number of times each type of outcome appears in the collection of studies.</p></sec></sec><sec><label>4</label><title>Data synthesis</title><sec><label>4.1</label><title>Meta-analysis</title><p>STATA (Version 16) will be used to perform the meta-analysis. Dichotomous data will be represented as relative risk, and the Peto odds ratio method will be used to calculate 95% confidence intervals (CIs). The mean difference (MD) with 95% CI will express continuous variables. Standardized MDs and 95% CIs will be used for continuous variables when the units are different. Hedges&#x02019; g will be used to measure the statistical effect size after intervention as a continuous variable; accurate calculations will be used to calculate the bias-correction factor; and standard errors calibrated with Hedges and Olkin will be used to calculate the effect size. Two models will be used for this meta-analysis: random effects and fixed effects. The DerSimonian&#x02013;Laird method and Mantel&#x02013;Haenszel method will be applied in the random effects model, and the inverse-variance method will be applied in the fixed-effects model.</p></sec><sec><label>4.2</label><title>Assessment of heterogeneity</title><p>We will use the <italic>I</italic>-square (<italic>I</italic>²) and Cochran Q^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>,<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} tests to evaluate the heterogeneity of articles. If <italic>I</italic>² is &#x0003c;50% or the <italic>P</italic> value is &#x0003e;0.01, the heterogeneity is considered to be small. The fixed-effect model will be used to interpret low-heterogeneity results; the random-effect model will be used otherwise. Meta-regression will be adopted to investigate the potential sources of heterogeneity.</p></sec><sec><label>4.3</label><title>Additional analyses</title><p>If potential sources of heterogeneity are identified, such as types of acupuncture, control interventions, we will conduct sensitivity analysis, meta-regression analysis and subgroup analysis. If the sources of heterogeneity are insufficient, qualitative synthesis will be performed.</p><sec><label>4.3.1</label><title>Sensitivity analysis</title><p>Where appropriate, remove tests with a high risk of bias and then conduct a sensitivity analysis to determine whether the results of the evaluation are reliable. Independent studies will be categorized into groups according to research characteristics, such as statistical method, research methodology quality, and sample size. Combination analysis will be carried out using the Mantel&#x02013;Haenszel method, followed by comparisons of the significant differences between each group and any combination effects.</p></sec><sec><label>4.3.2</label><title>Subgroup analysis</title><p>In the case of sufficient data, subgroup analysis will be performed according to the following content:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>general information (eg region, age, baseline pain);</p></list-item><list-item><label>(2)</label><p>acupuncture stimulation type (eg manual stimulation, electro-acupuncture, TENS, point injection, acupressure, laser acupuncture, tap-pricking or cupping on pricked superficial blood vessels);</p></list-item><list-item><label>(3)</label><p>control intervention type (eg no treatment, sham acupuncture, drug anesthesia intervention).</p></list-item></list></sec><sec><label>4.3.3</label><title>Meta-regression</title><p>If there is statistical or methodological heterogeneity, the meta-regression of the random-effect models will be used to explore the relationship between acupuncture therapy and oocyte retrieval pain. We will use the following factors as covariables for meta regression analysis:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>Participant characteristics: mean age and number of oocytes retrieved;</p></list-item><list-item><label>(2)</label><p>Intervention characteristics: duration of acupuncture therapy and dose of PCB used for the pain;</p></list-item><list-item><label>(3)</label><p>Reference characteristic: year of publication.</p></list-item></list><p>If the principle of this meta-regression technique cannot be proved, we will perform meta-regression analysis with limited covariates.</p></sec></sec><sec><label>4.4</label><title>Assessment of reporting bias</title><p>If the meta-analysis contains &#x02265;10 RCTS, we will use funnel plots and statistical tests (Egger's regression test^{[<xref rid=\"R37\" ref-type=\"bibr\">37</xref>]} and Begg's rank test) to examine the presence of publication bias. If the publication bias is non-ignorable, we will use the fill and trim method to correct the probable publication bias.</p></sec><sec><label>4.5</label><title>Assessment of risk of bias</title><p>Two reviewers (RRW and FX) will use the Cochrane Handbook for Systematic Reviews to evaluate the risk bias of each included trial.^{[<xref rid=\"R38\" ref-type=\"bibr\">38</xref>]} The following items will be included in risk of bias assessment categories, such as allocation concealment; random sequence generation; blinding of participants and outcome assessors; completeness of outcome data; selective outcome reporting and other biases. The risk of bias in each area will be divided into three grades: low risk, unclear risk, and high risk. The scores from all independent domains will be combined into an overall score that can be used to assess the risk of bias in the literature. If there is any disagreement, the decision will be made by the third researcher (LYL).</p></sec><sec><label>4.6</label><title>Systematic review</title><p>If quantitative synthesis is not appropriate, our team will provide a systematic narrative, in the form of text and tables, to explain and summarize the features and results of the included literature, and to explore and the relationships between the studies.</p></sec><sec><label>4.7</label><title>Quality of evidence</title><p>We will use the Grading of Recommendations Assessment Development and Evaluation^{[<xref rid=\"R39\" ref-type=\"bibr\">39</xref>]} (GRADE; Grade Pro version 3.6.1) to evaluate the results of the systematic evaluation based on the risk of bias, inconsistency, inaccuracy, publication bias and other factors. The quality of evidence will be divided into four grades: high, medium, low, and very low.</p></sec></sec><sec><label>5</label><title>Discussion</title><p>It is currently difficult to assess the effectiveness and safety of acupuncture in women undergoing transvaginal oocyte retrieval because of the paucity of relevant, published RCTs. This review and meta-analysis will allow us to make adequate conclusions regarding the effectiveness of acupuncture for pain relief in women undergoing transvaginal oocyte retrieval. Further studies will be required to determine the optimal acupuncture treatment approach and investigate the neural pathways and molecular mechanisms of pain relief of this common procedure.</p></sec><sec><title>Author contributions</title><p>Data curation: LYL, JX; Formal analysis: XLG, XL, LYL, JX; Investigation: XLG, WW; Methodology: RRW, FX; Project administration: JX; Resources: LYL; Software: RRW, FX, WW; Supervision: LYL; Writing &#x02013; original draft: XLG, XL; Review &#x00026; editing: XLG, XL, LYL, JX.</p><p><bold>Data curation:</bold> Li-Ying Liu, Jing Xu.</p><p><bold>Formal analysis:</bold> xiaoli guo, Xiang Li, Li-Ying Liu, Jing Xu.</p><p><bold>Investigation:</bold> xiaoli guo, Wei Wei.</p><p><bold>Methodology:</bold> Rong-Rong Wang, Fang Xiao.</p><p><bold>Project administration:</bold> Jing Xu.</p><p><bold>Resources:</bold> Li-Ying Liu.</p><p><bold>Software:</bold> Wei Wei, Rong-Rong Wang, Fang Xiao.</p><p><bold>Supervision:</bold> Li-Ying Liu.</p><p><bold>Writing &#x02013; original draft:</bold> xiaoli guo, Xiang Li.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> xiaoli guo, Xiang Li, Li-Ying Liu, Jing Xu.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: ART = assisted reproductive technology, CI = confidence interval, COH = controlled ovarian hyperstimulation, GRADE = grading of recommendations assessment development and evaluation, <italic>I</italic>² = <italic>I</italic>-square heterogeneity, IVF-ET = in vitro fertilization and embryo transfer, MD = mean difference, PCB = paracervical block, PRISMA = preferred reporting item for systematic evaluation and meta-analysis, RCTs = randomized controlled trials, STRICTA = standards for reporting interventions in controlled trials of acupuncture, TENS = transcutaneous electrical nerve stimulation, VAS = visual analogue scale.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Guo XL, Li X, Wei W, Wang RR, Xiao F, Liu LY, Xu J. Acupuncture for pain relief of women undergoing transvaginal oocyte retrieval: a meta analysis and systematic review protocol. <italic>Medicine</italic>. 2020;99:39(e22383).</p></fn><fn fn-type=\"equal\"><p>XLG and XL contributed equally to this work.</p></fn><fn fn-type=\"other\"><p>Ethical approval and informed consent are not required, as the study will be a literature review and will not involve direct contact with patients or alterations to patient care.</p></fn><fn fn-type=\"other\"><p>This work was funded by the National Natural Science Foundation of China (grant number: 81973966) and Sichuan Province Foundation for Distinguished Young Youths (grant number: 2020JDJQ0051).</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>Amendments: If we need to amend this protocol, we will give the date of each amendment, describe the change and give the rationale in this section. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991466</article-id><article-id pub-id-type=\"pmc\">PMC7523851</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08493</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022403</article-id><article-id pub-id-type=\"art-access-id\">22403</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>5700</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>The clinical efficacy of traditional Chinese medicine in the treatment of malignant pleural effusion</article-title><subtitle>A protocol of systematic review and meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-7749-7399</contrib-id><name><surname>Lin</surname><given-names>Zhen</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Jiang</surname><given-names>Mengyuan</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Gao</surname><given-names>Lirong</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Huachun</given-names></name><degrees>MD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff>Department of Oncology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Huachun Zhang, Department of Oncology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (e-mail: <email>zv7777@126.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22403</elocation-id><history><date date-type=\"received\"><day>27</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>28</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22403.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>The objective of this meta-analysis was to summarize and identify the available evidence from studies to estimate the clinical value of traditional Chinese medicine (TCM) in the treatment of malignant pleural effusion (MPE). And provides clinicians with evidence on which to base their clinical decision making.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>This review will include all studies comparing clinical efficacy of TCM in the treatment of MPE. The search strategy will be performed in 9 databases. We will not establish any limitations to language and publication status, published from inception to the July, 2020. Two reviewers will screen, select studies, extract data, and assess quality independently. Outcome is clinical efficacy, QLQ-C30 questionnaire and safety. The methodological quality including the risk of bias of the included studies will be evaluated. We will carry out statistical analysis using RevMan 5.3 software.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>This study will summarize current evidence to assess the efficacy and safety of TCM in the treatment of MPE.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>The findings of this study will provide helpful evidence for the clinician, and will promote further studies, as well as studying the value of TCM.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>malignant pleural effusion</kwd><kwd>protocol</kwd><kwd>systematic review</kwd><kwd>traditional Chinese medicine</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Research project of Shanghai University of Chinese Medicine</funding-source><award-id>18HL16</award-id><principal-award-recipient>Zhen Lin</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>The three-year action Plan for the development of TCM in Shanghai</funding-source><award-id>LH02.68.015.005</award-id><principal-award-recipient>Huachun Zhang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Malignant pleural effusion (MPE) is 1 of the commonest causes of an exudative pleural effusion, and its incidence is increasing with increasing cancer prevalence and as more effective cancer therapy that prolongs life. It is the commonest cause of a unilateral massive pleural effusion, although 10% to 13% can be bilateral. Median survival after a diagnosis of MPE depends on the underlying malignancy and stage at diagnosis, and varies between 3 and 12 months.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Most MPEs are secondary to metastases to the pleura from other sites, most commonly lung and breast, which together cause 50% to 65% of all MPE. Breathlessness, dyspnea and other symptoms often seriously distress and affect the quality of life (QOL).^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>&#x02013;<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]}</p><p>In recent years, traditional Chinese medicine (TCM) has played an increasingly important role with its unique advantages. Several studies have evaluated its clinical outcomes of TCM in the treatment of MPE. To the best of our knowledge, there is no meta-analysis analysis the clinical efficacy of TCM for MEP. Consequently, the objective of this meta-analysis was to summarize and identify the available evidence from these studies to estimate the clinical value of TCM. And provides clinicians with evidence on which to base their clinical decision making.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Study registry</title><p>The protocol was registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY202080105). The preferred reporting items for systematic review and meta-analysis protocols (PRISMA) will serve as guidelines for reporting present review protocol and subsequent formal paper.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]}</p></sec><sec><label>2.2</label><title>Eligibility criteria for including studies</title><sec><label>2.2.1</label><title>Types of studies</title><p>We will include all researches studying the clinical efficacy of TCM in the treatment of MPE, including observational study and RCT. Any other types of studies, such as animal studies, case reports, case series and review will all be excluded.</p></sec><sec><label>2.2.2</label><title>Types of interventions</title><sec><label>2.2.2.1</label><title>Experimental group</title><p>All patients in the experimental group received TCM for their treatment in this study (including oral Chinese medicine or external application of Chinese medicine). 2.2.2.2. Control group.</p><p>The participants in the control group could receive any other treatments in this study</p></sec></sec><sec><label>2.2.3</label><title>Types of patients</title><p>To be involved in this study, all the patients were required to meet the inclusion criteria as follows:</p><list list-type=\"simple\"><list-item><label>(1)</label><p>aged 18 to 80 years;</p></list-item><list-item><label>(2)</label><p>definite pleural effusion with medium or above amount confirmed by X-ray or ultrasound;</p></list-item><list-item><label>(3)</label><p>advanced malignant tumor with MPE confirmed by histopathology or cytology; (4) the estimated survival time is more than 3 months;</p></list-item><list-item><label>(4)</label><p>Karnofsky score &#x02265; 60, ECOG PS score &#x02264; 2.</p></list-item></list></sec><sec><label>2.2.4</label><title>Types of outcome measurements</title><sec><label>2.2.4.1</label><title>Primary outcomes</title><p>The criterion of efficacy was divided into 4 categories refer to WHO standard. Complete Remission (CR): effusion disappears and symptoms are relieved for at least 4 weeks; Partial Remission (PR): the effusion was reduced by more than 50% compared with that before treatment, and the symptoms were relieved and maintained for at least 4 weeks; Stable (SD): the effusion decreased by less than 50% compared with that before treatment, with no increasing trend, and the symptoms partially relieved; Invalid (PD): effusion grows rapidly. The total effective rate was (CR+PR)/ (CR+PR+SD+PD) &#x000d7; 100%.</p></sec><sec><label>2.2.4.2</label><title>Secondary outcomes</title><p>QLQ-C30 questionnaire: QLQ-C30 was developed the European Organization for Research and Treatment of Cancer (EORTC) in 1986. It is widely used to evaluate the quality of life for patients with oncology. The QLQ-C30 incorporates nine multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, nausea and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures are also included.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]}</p></sec><sec><label>2.2.4.3</label><title>Literature sources and search</title><p>We will perform literature searches using the following electronic bibliographic databases from their inception onwards to the July, 2020: MEDLINE, Springer, Web of Science, PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Evidence Based Medicine Reviews, VIP, and CNKI. We will not establish any limitations to language and publication status. The following electronic databases were searched from their inception dates through August 2020. The search terms were integrated as follows: &#x0201c;&#x02217; malignant pleural effusion &#x02217; AND (&#x02217;Traditional Chinese Medicine&#x02217; OR &#x02217;Traditional Chinese Medicine Formula&#x02217; OR &#x02217;Chinese Herb Formula&#x02217; OR &#x02217;Chinese herbal drug&#x02217;)&#x0201d;.</p></sec><sec><label>2.2.4.4</label><title>Study selection</title><p>All duplicated studies will be imported into Endnote X7 software and excluded before the screening. Two authors will independently scan all the records from title and abstract and all irrelevant literatures will be removed. Then, full manuscripts of all remaining studies will be further identified to check if they meet all inclusion criteria. We will note all excluded citations with specific reasons. If there are any different opinions between 2 authors, we will invite another author for consultation and final decision will be made after discussion. The detail of the study selection will be presented in a PRISMA flow diagram (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>)</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Study flow.</p></caption><graphic xlink:href=\"medi-99-e22403-g001\"/></fig></sec><sec><label>2.2.4.5</label><title>Data extraction</title><p>Two authors will independently extract the following associated information from each included trial: first author, time of publication, location, sample size, randomization methods, blinding, concealment, pathologic types, details of intervention and controls, duration of follow-up, outcome measurement tools, and any other relevant information. A third senior author will help to reconcile any divergences between 2 authors.</p></sec></sec><sec><label>2.2.5</label><title>Missing data dealing with</title><p>If we identify any unclear or missing data, we will contact original authors to obtain them. If we cannot get reply, we will only analyze available data and will discuss its potential affect as limitation.</p></sec><sec><label>2.2.6</label><title>Quality assessment</title><p>Two independent reviewers assessed the methodological quality by using the Newcastle-Ottawa Scale with some modifications to match the needs of this study.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} The quality was evaluated by examining 3 items: selection, comparability, and exposure, with higher scores representing studies of higher quality. The quality of each study was graded as either level 1 (0&#x02013;5) or level 2 (6&#x02013;9).^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} This review also assessed the clinical heterogeneity to evaluate whether the trials were similar enough to pool data.</p></sec><sec><label>2.2.7</label><title>Subgroup analysis</title><p>We will preside over subgroup analysis to explore any potential heterogeneity and inconsistency based on the treatment</p></sec><sec><label>2.2.8</label><title>Sensitivity analysis</title><p>We will consider running sensitivity analysis to identify the robustness and stability of merged results by excluding studies with high risk of bias.</p></sec><sec><label>2.2.9</label><title>Reporting bias</title><p>If necessary, we will examine the reporting bias using funnel plot and Egger regression test when &#x0003e;10 trials are included.</p></sec></sec><sec><label>2.3</label><title>Data synthesis</title><p>We will undertake RevMan 5.3 software to analyze data and to perform meta-analysis if it is necessary. We will calculate all continuous data using mean difference or standardized mean difference and 95% confidence intervals. As for dichotomous data, we will exert it using risk ratio and 95% CI. The heterogeneity as determined by the Cochran statistics was &#x0003c;0.10 of the &#x003c7;² test. If the <italic>I</italic>² value was &#x0003e;50%, we marked it as a considerable level of heterogeneity; otherwise, we considered it to be a good homogeneity. We also assessed clinical heterogeneity. Statistically and clinically homogeneous studies were pooled using a fixed-effects model; otherwise, a random-effects model was used when the heterogeneity was significant. Additionally, subgroup analysis will be operated to explore any possible reasons for the high heterogeneity. Whenever it is possible, we will conduct meta-analysis if at least 3 eligible criteria are fulfilled. Otherwise, meta-analysis will not be carried out if only 1 or 2 studies meet the inclusion criteria. Under such situation, the findings will be presented in a narrative summary. We will perform narrative synthesis if running meta-analysis is inappropriate due to the high heterogeneity. All narrative descriptions will be carried out based on the Guidance on the Conduct of Narrative Synthesis in Systematic Reviews.</p></sec></sec><sec><label>3</label><title>Discussion</title><p>MPE is mainly caused by lung cancer or other chest malignant tumors. About 50% of lung cancer or breast cancer patients will have pleural effusion in the course of disease. Once MPE appears, it indicates that the primary tumor has local focus or adjacent important organ metastasis, and the chance of radical operation is lost. According to statistics, the median survival time of patients with MPE is only 3&#x02013;12 months. MPE often grows rapidly and aggravates asthma which patients can seldom tolerate. In severe cases, it may be life-threatening. Therefore, for patients with MPE, it is particularly important to prolong their survival period and improve their quality of life.</p><p>The treatment of MPE with combination of TCM and western medicine has been widely recognized. It is not only superior to simple use of western medicine, but also has advantages in control of adverse reactions. TCM has certain characteristics and advantages in the treatment of MPE. It can enhance immunity, relieve symptoms, improve life quality, and has little side effects, which is easy for patients to accept. It can be the first choice especially for those who cannot receive chemotherapy. However, there is few relevant clinical report of large cases.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>&#x02013;<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]}</p><p>The strength of this systematic review and meta-analysis will include: search a comprehensive range of databases, including Chinese and English databases, more rigorous and detailed concerning quality assessment and data extraction. In addition, the findings obtained in the present study will provide helpful evidence in clinical practice. Furthermore, it will also help to promote further studies and clarify the direction for the future research.</p><p>On the contrary, this study has several potential limitation. There may be a language bias, although there is not language limitation in this study. Moreover, there may be a large heterogeneity, which may bias the results.</p></sec><sec><title>Author contributions</title><p>LZ, MYJ, and LRG conducted of the protocol and drafting the manuscript. All authors participated in the design of the study. HCZ is co-corresponding author of this manuscript. All authors read and approved the final manuscript.</p><p><bold>Conceptualization:</bold> Huachun Zhang.</p><p><bold>Data curation:</bold> Zhen Lin, Mengyuan Jiang, Huachun Zhang.</p><p><bold>Funding acquisition:</bold> Huachun Zhang.</p><p><bold>Methodology:</bold> Lirong Gao.</p><p><bold>Software:</bold> Zhen Lin.</p><p><bold>Supervision:</bold> Zhen Lin.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: MPE = malignant pleural effusion, TCM = traditional Chinese medicine.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Lin Z, Jiang M, Gao L, Zhang H. The clinical efficacy of traditional Chinese medicine in the treatment of malignant pleural effusion: A protocol of systematic review and meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22403).</p></fn><fn fn-type=\"other\"><p>Registration number: INPLASY202080105 (DOI number: 10.37766/inplasy2020.8.0105)</p></fn><fn fn-type=\"other\"><p>This study will analyze data from published or unpublished trials, thus, no ethics approval is needed.</p></fn><fn fn-type=\"other\"><p>Consent for publication was not applicable</p></fn><fn fn-type=\"other\"><p>Availability of data and materials: The datasets generated during and/or analyzed during the current study are publicly available. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by the Research project of Shanghai University of Chinese Medicine: 18HL16 and The three-year action Plan for the development of TCM in Shanghai; Award ID: LH02.68.015.005.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article and its supplementary information files.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Basso</surname><given-names>SMM</given-names></name><name><surname>Lumachi</surname><given-names>F</given-names></name><name><surname>Del Conte</surname><given-names>A</given-names></name><etal/></person-group>\n<article-title>Diagnosis of malignant pleural effusion using ct scan and pleural-fluid cytology together: a preliminary case-control study</article-title>. <source>Anticancer Res</source>\n<year>2020</year>;<volume>40</volume>:<fpage>1135</fpage>&#x02013;<lpage>9</lpage>.<pub-id pub-id-type=\"pmid\">32014965</pub-id></mixed-citation></ref><ref id=\"R2\"><label>[2]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Tian</surname><given-names>T</given-names></name><name><surname>Zhang</surname><given-names>P</given-names></name><name><surname>Zhong</surname><given-names>F</given-names></name><etal/></person-group>\n<article-title>Nomogram construction for predicting survival of patients with non-small cell lung cancer with malignant pleural or pericardial effusion based on SEER analysis of 10,268 patients</article-title>. <source>Oncol Lett</source>\n<year>2020</year>;<volume>19</volume>:<fpage>449</fpage>&#x02013;<lpage>59</lpage>.<pub-id pub-id-type=\"pmid\">31897158</pub-id></mixed-citation></ref><ref id=\"R3\"><label>[3]</label><mixed-citation publication-type=\"book\"><person-group person-group-type=\"author\"><name><surname>Adeyinka</surname><given-names>A</given-names></name><name><surname>Kondamudi</surname><given-names>NP</given-names></name></person-group>\n<article-title>Pediatric malignant pleural effusion</article-title>. <comment>In: StatPearls [Internet]. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991444</article-id><article-id pub-id-type=\"pmc\">PMC7523852</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-01131</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022330</article-id><article-id pub-id-type=\"art-access-id\">22330</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>7100</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Ankle distraction arthroplasty for the treatment of severe ankle arthritis</article-title><subtitle>Case report, technical note, and literature review</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Xiao-Ning</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Chang</surname><given-names>Fei</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Zhang</surname><given-names>Han-Yang</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Zhong</surname><given-names>Zhuan</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Xue</surname><given-names>Pan</given-names></name><degrees>MB</degrees></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-3947-1999</contrib-id><name><surname>Huang</surname><given-names>Bing-Zhe</given-names></name><degrees>MD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff>Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, Jilin Province, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Bing-Zhe Huang, Orthopaedic Medical Center, The Second Hospital of Jilin University, 218 Ziqiang Road, Changchun, Jilin Province, China (e-mail: <email>huangbingzhe1205@126.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22330</elocation-id><history><date date-type=\"received\"><day>8</day><month>2</month><year>2020</year></date><date date-type=\"rev-recd\"><day>2</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>24</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22330.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Widely applied in the treatment of severe ankle arthritis (AA), ankle distraction arthroplasty (ADA) can avoid not only the ankle range of motion loss but also ankle fusion. However, the clinical outcomes of ADA for severe AA are poorly understood. This study aims to present our clinical outcomes of severe AA treated by ADA.</p></sec><sec><title>Patient concerns:</title><p>A 53-year-old man suffered right ankle sprain 10 years ago, endured right ankle pain and limited movement for 6 years.</p></sec><sec><title>Diagnosis:</title><p>The patient was diagnosed as severe AA.</p></sec><sec><title>Interventions:</title><p>He received ankle distraction arthroplasty. No adjuvant procedures were performed. The visual analog scale (VAS), the American Orthopaedic Foot and Ankle Society (AOFAS) score, the short-form (SF)-36 physical component summary (PCS) score and ankle activity score (AAS) were recorded to access the clinical outcomes pre- and postoperatively. Moreover, ankle joint space distance was evaluated on weight-bearing radiographs.</p></sec><sec><title>Outcomes:</title><p>The patient derived effective pain relief and restored a satisfactory range of movement. There was a 13-month follow-up period after frame removal. The AOFAS score improved from 56 preoperatively to 71 postoperatively. The VAS score decreased from 6 prior to surgery to 1 after surgery. The SF-36 PCS was 47.2 and 71.8 pre- and postoperative, respectively. The AAS scores were improved from 3.4 preoperatively to 7.3 postoperatively.</p></sec><sec><title>Lessons:</title><p>ADA is reliable to achieve pain relief, functional recovery, and serve AA resolution. Besides, it is an alternative to ankle arthrodesis or total ankle arthroplasty in selected patients with severe AA.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>ankle arthritis</kwd><kwd>ankle distraction arthroplasty</kwd><kwd>arthrodesis</kwd><kwd>pain</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Science and Technology Project of the 13th Five-Year Plan of Jilin Provincial Department of Education</funding-source><award-id>JJKH20190057KJ</award-id><principal-award-recipient>Bing-Zhe Huang</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Special Foundation for Science and Technology Innovation of Jilin Province</funding-source><award-id>20200201566JC</award-id><principal-award-recipient>Bing-Zhe Huang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Ankle arthritis (AA) is a progressive disease caused by trauma, characterized by weight-bearing pain, spontaneous pain and limited function, which usually has a great impact on life and work.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]}</p><p>According to previous studies, the traditional methods to treat advanced-stage AA require the internal fixation of ankle joint, such as tibial-talus arthrodesis, total ankle arthrodesis.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>&#x02013;<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} However, these methods may affect adjacent joints and lead to arthritis of adjacent joints, especially in case of malunion after fusion.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} To preserve ankle motion and avoid the occurrence of adjacent arthritis, scholars have developed several strategies for the treatment of AA, including total ankle arthroplasty,^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>,<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} ankle joint debridement,^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} treatment of cartilage and bone marrow microfracture,^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} autogenous cartilage transplantation, and allogenic cartilage transplantation. However, the long-term results remain less than satisfactory.</p><p>In recent years, ankle distraction arthroplasty (ADA) was identified as a promising method to treat AA. However, the clinical outcomes of ADA for severe AA are poorly understood. Therefore, the purpose of this paper is to present the clinical findings of our study, as well as to review the origin, mechanism, devices type, technique, advantages, prognostic indicators, and complications of ADA.</p><sec><label>1.1</label><title>Ethics</title><p>This case report was approved by the institutional review board of the second hospital of Jilin University. Informed written consent was obtained from the patient for publication of this case report and accompanying images.</p></sec></sec><sec><label>2</label><title>Case report</title><sec><label>2.1</label><title>Patient characteristics</title><p>A 53-year-old man presented himself to the Foot and Ankle Department of the Second Hospital of Jilin University. His major symptoms included right ankle pain and limited movement that had been persistent for 6 years. He had a 10-year history of right ankle sprain. The patient was only capable of limited movement due to the persistent pain in his ankle.</p><p>As revealed by the weight-bearing anteroposterior and lateral radiograph of the right ankle, the joint space narrowed, especially in the medial side, and there were plenty of osteophytes around the joint (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). A three-dimensional computed tomography (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>) showed sclerotic borders under cartilage and cystic changes in tibia and talus. It also revealed narrowing joint space and osteophytes both on the talus and around the ankle joint.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>The weight-bearing positive (A) and lateral (B) radiograph of right ankle revealed many osteophytes and narrow joint space, especially in the medial side.</p></caption><graphic xlink:href=\"medi-99-e22330-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>CT scan (A to C) showed sclerotic borders under cartilage and cystic changes in tibia and talus. It also revealed narrowing joint space and osteophytes on the talus and around the ankle joint (D).</p></caption><graphic xlink:href=\"medi-99-e22330-g002\"/></fig><p>The conservative approaches to treatment include restricted activity, oral non-steroidal anti-inflammatory drugs, bracing, physical therapy, and steroid injection therapy, all of which were trialled but failed. Under this circumstance, the patient received ADA.</p><p>The visual analog scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) score, the short-form (SF)-36 physical component summary (PCS) score, and ankle activity score (AAS) were recorded to access the clinical outcomes pre- and postoperatively. Ankle joint space distance was evaluated as well by weight-bearing radiograph plains and CT.</p></sec><sec><label>2.2</label><title>Surgical technique</title><p>After general anesthesia, the electric tourniquet was tied to the patient's thigh. The operative approach involved midline incision, which was performed between the tibialis anterior and extensor hallucis longus tendons and was approximately 7.0&#x0200a;cm in length. The capsular was opened after initial exposure, and the ankle was revealed. Several loose bodies were discovered and then removed. Osteophytes on the anterior, medial, and lateral aspects of the joint were resected. However, impingement remained visible when the ankle was passively dorsiflexed, inversed, and reversed. Thus, osteophytes, along with the anterior, medial, and lateral aspects of the talus, were resected as well. The cartilage damage with a size of about 5&#x0200a;cm&#x0200a;&#x000d7;&#x0200a;3.5&#x0200a;cm was found out in tibia and talus, and under the damaged cartilage sclerotic borders were discovered. A spatula was applied to trim the damaged areas, and a Kirschner wire with a diameter of 1.5&#x0200a;mm was used to drill at the site of cartilage damage until bleeding. Then, the incision was sutured layer by layer after repeated washing with physiological saline. A circular external fixator was mounted onto the right calf 5&#x0200a;cm clear of the ankle and fixed with 4 tension needles. Then an articulated fixator was mounted onto the right foot with its axial parallel to the ankle joint. Two tension needles were attached to the U-shaped ring in 2 different directions for the purpose of making the ring parallel to the plantar of the foot. A tension needle was also fixed to the U-shaped ring by the 5 metatarsals. As a result, a 7-mm distraction was applied across the joint intraoperatively.</p></sec><sec><label>2.3</label><title>Clinical outcomes and follow-up</title><p>Intravenous antibiotics were prescribed to the patient within 24&#x0200a;hours after surgery. The patient took intravenous non-steroidal anti-inflammatory drugs (NSAIDs) in the first 3 days and NSAIDs orally for 1 week. The incision care was carried out every 2 or 3 days until the sutures were removed at the 14th day postoperatively. Pin care started from day 2 after surgery and involved the cleaning of pin sites with 75% alcohol. The patient came for follow-up at the 1st week. The radiographs showed functional joint space and alignment (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>). The next follow-up was scheduled for the 3rd month after the operation. The radiograph (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>) revealed that the joint space remained in good condition, so that the external fixator was removed in the operating room without anesthesia. The weight-bearing radiographs (Fig. <xref ref-type=\"fig\" rid=\"F5\">5</xref>) showed that the joint space remained in good condition postoperatively, so that the patient was asked to walk with the assistance of a walking cast after the operation. The weight-bearing radiograph showed that the joint space remained clear 3 months after the external fixator was removed (Fig. <xref ref-type=\"fig\" rid=\"F6\">6</xref>).</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>The radiograph 1st week postoperative showed good joint space and alignment.</p></caption><graphic xlink:href=\"medi-99-e22330-g003\"/></fig><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>The weight-bearing radiograph 3rd month postoperative showed that the joint space remained good.</p></caption><graphic xlink:href=\"medi-99-e22330-g004\"/></fig><fig id=\"F5\" orientation=\"portrait\" position=\"float\"><label>Figure 5</label><caption><p>The weight-bearing radiograph showed that the joint space remained good after the external fixator was removed.</p></caption><graphic xlink:href=\"medi-99-e22330-g005\"/></fig><fig id=\"F6\" orientation=\"portrait\" position=\"float\"><label>Figure 6</label><caption><p>The weight-bearing radiograph showed that the joint space remained clear 3&#x0200a;mo after the external fixator was removed.</p></caption><graphic xlink:href=\"medi-99-e22330-g006\"/></fig><p>The AOFAS score was improved from 56 preoperatively to 71 postoperatively. The VAS score decreased from 6 prior to surgery to 1 after surgery. The SF-36 PCS was 47.2 and 71.8 pre- and postoperative, respectively. The AAS scores were improved from 3.4 preoperatively to 7.3 postoperatively. No complication occurred during 13 months of follow-up visit.</p></sec></sec><sec><label>3</label><title>Discussion</title><p>AA is usually caused by the alteration to bone structure and ligament damage after trauma.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>&#x02013;<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} Although suitable open treatment is beneficial to improve ankle function, it can still cause changes to biomechanics and anatomical structure.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} The initial goal for the management of AA is to reduce pain and restore ankle function as much as possible.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} Joint preservation surgical strategies for the management of AA mainly include lifestyle adjustment and oral non-steroidal anti-inflammatory drugs.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} However, it is only suitable for the early stage of AA and is ineffective for the treatment of advanced and severe AA. Meanwhile, joint sacrifice is mainly related to arthrodesis.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>&#x02013;<xref rid=\"R11\" ref-type=\"bibr\">11</xref>,<xref rid=\"R21\" ref-type=\"bibr\">21</xref>,<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} However, arthrodesis carries such potential risks as continuous pain, declining function, and adjacent joint arthritis.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>,<xref rid=\"R11\" ref-type=\"bibr\">11</xref>,<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]} Superior malleolus osteotomy is suitable for the early stage of ankle arthritis with partial reservation of ankle joint surface, frontal alignment deformity of ankle joint, and reservation of ankle joint motion.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>&#x02013;<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} Therefore, it is of considerable significance to develop a method that can maintain the range of movement in the treatment of advanced AA. In this study, ADA was applied to treat serve AA and a satisfactory effect was achieved. The purpose of this study is to present our case and to review the characteristics of ADA (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>).</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Literature review.</p></caption><graphic xlink:href=\"medi-99-e22330-g007\"/></table-wrap><p>Concerning the origin of ADA technique, in 1978, Judet and Judet^{[<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} first reported a technique of mechanical opposite direction of the joint surface using an external fixator that allows &#x0201c;fibrous tissue between the bones ends&#x0201d; to find an alternative to total arthroplasty for arthritis. They first removed the joint cartilage from the end of the tibiotarsal of the dog, gave it 30-day and 4 to 8&#x0200a;mm distraction, and then conducted a histological analysis of the regenerated tissue. A year later, they found out that hyaline cartilage, similar to normal cartilage, was regenerated on the surface of the joint.^{[<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} In 1994, Aldegheri et al^{[<xref rid=\"R37\" ref-type=\"bibr\">37</xref>]} described 80 cases of hip arthritis treated with distraction therapy. After the good results of 46 patients who were followed for at least 5 years, it was concluded that the results of radiographic findings are not necessarily associated with the clinical outcomes. In 1995, van Valburg et al^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} published a report on ADA, after which this technique became widely applied.</p><p>The mechanism of ADA remains unclear. Despite this, it was demonstrated by scholars that it is related to non-weight-bearing on the surface of the ankle joint after mechanical distraction, which is beneficial to cartilage regeneration.^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>,<xref rid=\"R38\" ref-type=\"bibr\">38</xref>&#x02013;<xref rid=\"R41\" ref-type=\"bibr\">41</xref>]} The rigidity of the circular ring fixator can provide enough stress shielding at the ankle joint and allow subchondral bone reconstruction, which has been proved to bring clinical benefits.^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} However, its clinical relevance to pain relief is still controversial. In the present study, the pain was effectively controlled postoperatively. In our view, the pain caused by ankle arthritis is associated with the pressure of the fluid in the joint into the subchondral bone. Subsequent to the arthroplasty, the mechanical stress and irritation of the cartilage are reduced, thus alleviating the pain and promoting cartilage repair.</p><p>Regarding the devices type of ADA, it can be divided into fixed distraction and mobilizable distraction.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} Saltzman and his colleagues^{[<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} conducted a prospective randomized controlled trial, which led to the discovery that the clinical outcomes of mobilizable distraction were better compared to a fixed distraction. This view is also supported by Xu et al.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} On the contrary, Nguyen et al^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]} counterargued that mobilizable distraction was superior to fixed distraction due to the limited number of patients. However, the preoperative and postoperative distraction distance in their study was not referred to.</p><p>Meanwhile, a circular frame may be better than a mono-lateral fixator, which is because the latter conveys uneven distraction by the cantilever mechanics. Moreover, it is challenging to place the mono-lateral fixator with a simple hinge along the ankle axis.^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} Therefore, in our study, a fixed frame with a circular shape was selected for ankle distraction and excellent clinical outcomes were achieved. The positive results are partially attributed to the proper selection of the distraction device.</p><p>As for the technique of ADA, in 1995, van Valburg et al^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} established the clinical standard for ankle distraction, which is weight-bearing radiographs showing an ankle gap of 5&#x0200a;mm during 12 weeks of joint distraction. In 2017, Xu et al^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} found out that the space of ankle joint distraction was reduced after the external fixator was removed. However, if the joint gap is greater or equal to the standard value within 1 year postoperatively, the joint gap may remain in this state for a long time. According to previous studies,^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>,<xref rid=\"R27\" ref-type=\"bibr\">27</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R42\" ref-type=\"bibr\">42</xref>]} it was found out that chondrocytes may require 3 to 6 months of non-weight-bearing state to rebuild the cartilage matrix, and the full clinical benefit was not received until many months after joint distraction. Therefore, it was speculated that time plays a significant role in achieving stable soft-tissue intervention.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} In the present case, ankle distraction distances of 7&#x0200a;mm were maintained for 4 months, and no reduction in ankle gap was observed by radiographic after the fixation frame was removed. In our view, after joint distraction, subchondral sclerosis of the ankle is effectively prevented as the axial load is transmitted through the external fixator rather than through the joint. Besides, vascular reconstruction is conducive to the repair of osteoarthritis.</p><p>With reference to the prognostic indicators of ADA, it includes the ankle space, Ankle Osteoarthritis Scale (AOS) score, age, and gender. Postoperatively, ankle space was validated as an important prognostic indicator by Tellisi et al.^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} If the ankle joint space distance exceeds the range of 3 to 5&#x0200a;mm at the 1-year follow-up under the weight-bearing condition, the prognosis is usually better than if the ankle joint space distance is less than 3 to 5&#x0200a;mm.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R21\" ref-type=\"bibr\">21</xref>,<xref rid=\"R27\" ref-type=\"bibr\">27</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R42\" ref-type=\"bibr\">42</xref>]} AOS score was another significant indicator of ankle survival as reported by Nguyen et al,^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]} who concluded that the patients with a AOS score of less than 42 at 2 years postoperatively have better outcomes. Age as a prognostic indicator after ankle detraction is controversial. It is believed among some scholars^{[<xref rid=\"R35\" ref-type=\"bibr\">35</xref>]} that the patients aged over 60 years can obtain better results, while other^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} reports claim that the recovery effect after ADA bears no association with age. Gender is also likely a contributory factor to distraction arthroplasty failure.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} It was revealed that females suffered a higher rate of treatment failure.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} In the present study, a man approaching the age of 60 was found to have adequate ankle distraction distance during follow-up, and these factors contributed to a desirable outcome. However, unfortunately, AOS scores at 2 years postoperatively were not evaluated in this study.</p><p>With regard to the treatment effect of ADA alone and combined treatment, as recommended by scholars, applying the combined strategies for AA could produce the optimal treatment effect.^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} The common surgical options include arthroscopy, arthrotomy, or superolateral osteotomy combined with ADA.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>,<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} Zhang et al^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} suggested that the combination of ankle distraction arthroplasty and arthroscopic microfracture could achieve better results in respect of pain relief and functional recovery for AA than if ADA is used alone. Previous studies show that the clinical outcomes of ankle distraction are better compared to debridement.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>,<xref rid=\"R43\" ref-type=\"bibr\">43</xref>]}</p><p>Moreover, this combination therapy has significantly improved the mean AOFAS scores and SF-36 scores. As suggested by these findings, ankle distraction may be more conducive to functional improvement and pain relief when combined with other appropriate approaches. In our study, though only ADA was applied, the AOFAS score, VAS score, SF-36 PCS score, and AAS score improved after operation. Moreover, the results were partially better compared to previous studies.^{[<xref rid=\"R44\" ref-type=\"bibr\">44</xref>&#x02013;<xref rid=\"R46\" ref-type=\"bibr\">46</xref>]} According to our analysis, this may be related to the standard surgical techniques, the strict control of indications, the prescription of perioperative ankle motion exercises by the surgeon, and the small number of cases in this study.</p><p>As regards the complications ADA, pin-site infection is the most frequent surgical complication of ADA.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Xu et al^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} reported 2 cases of pin-site infection in their study, which was successfully solved by routinely dressing changes and oral antibiotics. The reported incidence ranges from 14% to 100%.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R31\" ref-type=\"bibr\">31</xref>,<xref rid=\"R33\" ref-type=\"bibr\">33</xref>,<xref rid=\"R35\" ref-type=\"bibr\">35</xref>,<xref rid=\"R44\" ref-type=\"bibr\">44</xref>]} Osteomyelitis requiring hospitalization and intravenous antibiotics is rare, with a reported incidence ranging from 1.2% to 5.5%.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R47\" ref-type=\"bibr\">47</xref>]} Besides, K-wire breakage and deep vein thrombosis were also reported in the literature.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} In most cases, this breakage occurs at the junction of the wire connectors onto the ring. Therefore, it can be corrected by modifying the connection of the needle fixation bolt closer to the skin.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} The estimated incidence ranges from 14% to 24% in 2 studies of 74 patients.^{[<xref rid=\"R28\" ref-type=\"bibr\">28</xref>,<xref rid=\"R44\" ref-type=\"bibr\">44</xref>]}</p><p>It is necessary to educate patients about the correct use of external fixation devices before operation and discharge. Besides, Bernstein et al^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} suggested the use of 50% hydrogen peroxide and 50% normal saline solution and sterile cotton swabs for daily needle position care.</p><p>A deep understanding of the anatomy of the lower extremities can avoid accidental damage to the neurovascular structure. In particular, there is a risk of injury to the anterior tibial tendon and the anterior neurovascular bundle during the process of tibial ring installation. To prevent bone thermal injury and needle position infection, surgeons are supposed to use a new, sharp 4.8&#x0200a;mm half needles in each case. To avoid the medial neurovascular structure, great care should be taken when the foot ring is used. Nevertheless, Bernstein et al^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} reported that patients complained of heel numbness, which can be caused by medial calcaneal branch nerve irritation from the crossed hindfoot wires. The symptoms of plantar numbness of forefoot should not be misdiagnosed as tibial nerve injury. The compromise of the posterior tibial nerve is frequent to occur with cute distractions which more than 5&#x0200a;mm.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Besides, Tellisi et al^{[<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]} claimed that they would not carry out longer than 5 to 6&#x0200a;mm for acute ankle joint distraction in the operating room, and the remaining distraction distance, if demanded, could be performed during the postoperative hospitalization.</p><p>In our study, no complications were found during 13 months follow-up period. Although our initial distraction distance was 7&#x0200a;mm, it was slightly larger than the safety distance reported in the literature. However, our surgery is performed under intraoperative neuralogical monitoring. To protect the soft tissue, each set of pins was wrapped in a 2-inch gauze. This positive outcome is attribute to standardized surgical techniques, regular follow-up, intraoperative neuralogical monitoring, and careful perioperative care.</p><p>Despite the satisfying clinical outcomes achieved in this case, there remain several limitations. The number of cases is relatively small, so that it is necessary to further conduct a large number of randomized controlled trials. Besides, good clinical results were obtained in the short-term follow-up of this study, and the long-term follow-up results need to be further evaluated.</p><p>In conclusion, ADA is reliable to achieve pain relief, functional recovery, and serve AA resolution. Besides, it is an alternative to ankle arthrodesis or total ankle arthroplasty in selected patients with severe AA.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Bing-Zhe Huang.</p><p><bold>Data curation:</bold> Xiao-Ning Liu, Fei Chang, Zhuan Zhong, Pan Xue.</p><p><bold>Formal analysis:</bold> Xiao-Ning Liu, Fei Chang, Zhuan Zhong.</p><p><bold>Investigation:</bold> Han-Yang Zhang, Bing-Zhe Huang.</p><p><bold>Methodology:</bold> Xiao-Ning Liu, Han-Yang Zhang, Zhuan Zhong, Pan Xue.</p><p><bold>Project administration:</bold> Fei Chang.</p><p><bold>Resources:</bold> Fei Chang, Pan Xue.</p><p><bold>Supervision:</bold> Bing-Zhe Huang.</p><p><bold>Writing &#x02013; original draft:</bold> Xiao-Ning Liu, Fei Chang.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Bing-Zhe Huang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: AA = ankle arthritis, AAS = ankle activity score, ADA = ankle distraction arthroplasty, AOFAS = American Orthopaedic Foot and Ankle Society, AOS = Ankle Osteoarthritis Scale, NSAIDs = non-steroidal anti-inflammatory drugs, PCS = physical component summary, SF = short-form, VAS = visual analog scale.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Liu XN, Chang F, Zhang HY, Zhong Z, Xue P, Huang BZ. Ankle distraction arthroplasty for the treatment of severe ankle arthritis: Case report, technical note, and literature review. <italic>Medicine</italic>. 2020;99:39(e22330).</p></fn><fn fn-type=\"supported-by\"><p>This study was supported by grants from (i) the Science and Technology Project of the 13th Five-Year Plan of Jilin Provincial Department of Education (JJKH20190057KJ) and (ii) Special Foundation for Science and Technology Innovation of Jilin Province (No. 20200201566JC).</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991490</article-id><article-id pub-id-type=\"pmc\">PMC7523853</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-00389</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022499</article-id><article-id pub-id-type=\"art-access-id\">22499</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>5600</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Using a cervical ripening balloon to penetrate the placenta and quickly reduce bleeding by pressing against the placenta during pregnancy termination for patients with placenta previa in the second trimester</article-title><subtitle>Two cases report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Su</surname><given-names>Chang</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Chen</surname><given-names>Danqing</given-names></name><degrees>MD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff>Obstetrical Department, Women's Hospital,School of Medicine, Zhejiang University, Hangzhou, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Danqing Chen, Obstetrical Department, Women's Hospital,School of Medicine, Zhejiang University, Hangzhou, China (e-mail: <email>chendq@zju.edu.cn</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22499</elocation-id><history><date date-type=\"received\"><day>18</day><month>1</month><year>2020</year></date><date date-type=\"rev-recd\"><day>24</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>1</day><month>9</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22499.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"intro\"><title>Introduction:</title><p>The clinical treatment is complicated for patients with placenta previa who must terminate pregnancy due to fetal malformation, death, or inevitable abortion in the second trimester. It is difficult to manage excessive bleeding during pregnancy termination; and those patients face risks of removing the uterus, infection and other complications.</p></sec><sec><title>Patient concerns:</title><p>Two patients had placenta previa in the second trimester. Both cases had to terminate pregnancy. Case 1 patient had intrauterine fetal death. Case 2 patient had life-threatening vaginal bleeding. Both patients had bleeding and their cervix was not mature during vaginal delivery.</p></sec><sec><title>Diagnosis:</title><p>After hospitalization, placenta previa was confirmed by magnetic resonance imaging for case 1 patient. Placenta previa was confirmed by ultrasound examination for case 2 patient. Both patients had to terminate pregnancy.</p></sec><sec><title>Interventions:</title><p>We designed a new procedure using a cervical ripening balloon to reduce the risks during pregnancy termination for patients with placenta previa. A cervical ripening balloon was inserted through the placenta and placed between the fetus and placenta; external force was applied to keep the cervical ripening balloon pressing against the placenta that covers the cervical os. The cervical ripening balloon dilated the cervix, quickly reduced bleeding, and induced vaginal delivery during pregnancy termination for patients with placenta previa. This method was applied to 2 patients with placenta previa who must terminate pregnancy.</p></sec><sec><title>Outcomes:</title><p>Using the new method, both patients had a successful pregnancy termination and vaginal delivery with minimal bleeding. Total time from the balloon placement to the end of the delivery was about 3 hours. The procedure only used a cervical ripening balloon without uterine artery embolization needed. The fetus was delivered through the vagina; and the uterus was fully retained. There was no postpartum infection.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>This new method using a cervical ripening balloon could be a quick and effective way to reduce the risks during pregnancy termination for patients with placenta previa. It is especially helpful in emergency situations with minimal requirements of personnel and equipment. Our study showed great potential of this new utilization of a cervical ripening balloon, and is worthy of further research.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>cervical ripening balloon</kwd><kwd>placenta previa</kwd><kwd>pregnancy termination</kwd><kwd>second trimester</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>National Natural Science Foundation of China</funding-source><award-id>81873839</award-id><principal-award-recipient>Danqing Chen</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Key Project of Science and Technology Department of Zhejiang Province</funding-source><award-id>2018C03010</award-id><principal-award-recipient>Danqing Chen</principal-award-recipient></award-group><award-group id=\"award3\" award-type=\"Fundref\"><funding-source>Zhejiang Provincial &#x00026;amp; Ministry of Health Research Fund for Medical Sciences</funding-source><award-id>WKJ-ZJ-1722</award-id><principal-award-recipient>Danqing Chen</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Placenta previa is an obstetric condition when the placenta partially or completely covers the cervical os. The incidence rate of placenta previa earlier in pregnancy (approximately 24 weeks) is 4% to 5%.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} It occurs approximately in 1 of every 200 pregnancies globally. Mainland China has the highest prevalence of placenta previa in the world, at an average of 12.2 per 1000 pregnancies.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Risk factors for placenta previa include multiple abortion history, uterine cavity operation, puerperal infection, older age, cesarean section, multiple births, poor living habits (eg. smoking, drugs), twin pregnancy, assisted reproductive technology, and abnormal uterine morphology. The exact cause of placenta previa is unclear, and may be related to placental abnormalities, endometrial lesions or injuries, and developmental delay in the fertilized egg trophoblast.</p><p>Placenta previa can cause serious bleeding and other complications that lead to morbidity and mortality during pregnancy. Occasionally, patients with placenta previa need to terminate the pregnancy due to severe fetal malformations, stillbirth, or inevitable abortion in the second trimester. It is challenging for clinicians to manage massive hemorrhage and choose the appropriate delivery method during pregnancy termination for such patients. Vascular interventional techniques have been utilized to reduce bleeding due to placental previa. However, those techniques usually associate with embolism complications such as ovarian dysfunction, pain, fever and infection. Uterine artery embolization is a complicated and expensive procedure that requires a radiology surgical team and equipment. In severe cases, hysterotomy abortion or even hysterectomy is still needed.</p><p>This study here only used a cervical ripening balloon in 2 patients with placenta previa who underwent pregnancy termination in the second trimester. This new method not only rapidly stopped bleeding but also gently increased the cervical opening. Both patients safely delivered the fetus through the vagina in a short period of time with minimal bleeding.</p><p>The following are the technical details of using a cervical ripening balloon (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>A) to manage hemorrhage and promote cervical opening during pregnancy termination for patients with placenta previa. The exact position of the placenta is evaluated via pre-procedural magnetic resonance imaging (MRI) (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>B). Pregnant women are placed in the lithotomy position, the vulva is disinfected, and cervix is exposed and disinfected. Vascular forceps are inserted through the cervical os and allowed to rapidly penetrate the placenta attached to the cervix. Under ultrasound guidance, a cervical ripening balloon is carefully inserted through the placenta using toothless oval forceps and was placed in between the fetus and placenta. Certain amount of saline is injected into the cervical ripening balloon, so that the balloon diameter is similar to fetal biparietal diameter at the second trimester (150&#x0200a;mL saline is equal to the 6&#x0200a;cm of balloon diameter). After the balloon end plug is closed, external traction force (a bag of 500&#x0200a;mL saline) was connected to the balloon to maintain the tension for the cervical ripening balloon to press against the placenta that covers the cervical os (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>C). The positional relationship between the cervical ripening balloon and the placenta is evaluated again by ultrasound (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>D).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Technical details of using a cervical ripening balloon during pregnancy termination for patients with placenta previa. 1A. A cervical ripening balloon was used. 1B. The exact position of the placenta was evaluated via pre-procedural MRI. 1C. A cervical ripening balloon is inserted through the placenta using toothless oval forceps and was placed in between the fetus and placenta. After the balloon end plug is closed, external traction force (a bag of 500&#x0200a;mL saline) was connected to the balloon to maintain the tension for the cervical ripening balloon to press against the placenta that covers the cervical os. 1D. The positional relationship between the cervical ripening balloon and the placenta is evaluated again by ultrasound. MRI = magnetic resonance imaging.</p></caption><graphic xlink:href=\"medi-99-e22499-g001\"/></fig></sec><sec><label>2</label><title>Case reports</title><p>This method was applied to 2 patients who had placenta previa in the second trimester. Both patients safely delivered the fetus through the vagina in a short period of time with minimal bleeding.</p><sec><label>2.1</label><title>Case 1</title><p>A 26-year-old woman (gravida 1, para 0) at 24 weeks of pregnancy with placenta previa was referred to our hospital for intrauterine fetal death in March 2019. MRI on March 15, 2019 showed that the lower edge of the placenta completely covered the cervical os, with no obvious infiltration of placenta in uterine wall or cervix. The estimated thickness of the placenta at the os was 3 centimeters. After an intra amniotic injection of 100&#x0200a;mg ethacridine lactate solution, 50&#x0200a;mg mifepristone was administered orally once every 12&#x0200a;hours 3 times. At 18:45 on March 16, uterine contractions were normal at 3-min intervals and lasting for 25&#x0200a;seconds. The cervix opening was dilated to 1.5&#x0200a;cm. The total volume of intermittent vaginal bleeding was 200&#x0200a;mL (by weight) in 40 minutes. The patient's hemoglobin level was 127&#x0200a;g/L. Under the ultrasound guidance, a cervical ripening balloon was inserted through the placenta and placed between the fetus and the placenta using toothless oval forceps. Saline (150&#x0200a;mL) was injected into the cervical ripening balloon. At the time of cervix expansion, an external traction force was applied to the balloon; vaginal bleeding was immediately reduced due to the cervical ripening balloon compressing against the placenta. At 21:09, when the cervical ripening balloon was slipped out of the vagina, the cervix opening was dilated to 3&#x0200a;cm, with fetal presentation at S-1&#x0200a;cm (the lowest point of fetal skull is 1&#x0200a;cm above the ischial spine plane) and fetal head close to the cervix; contractions were normal. Six minutes later, the fetus was delivered via the vagina; there was total 50&#x0200a;mL of bleeding during the delivery. Placenta and fetal membranes were naturally delivered afterward without placental defect. The total time from the balloon placement to the end of the delivery was 2 hours and 30 minutes. The patient recovered in the hospital for 3 days with no complications. The hypersensitive C-reactive protein level was 22.2&#x0200a;mg/L and the hemoglobin level was 115&#x0200a;g/L post-delivery. The patient was discharged from the hospital on day 3 post-delivery. After 10 days, the follow-up transabdominal ultrasound showed normal endometrial thickness of 0.2&#x0200a;cm (single layer) and endometrial cavity width of 0.4&#x0200a;cm.</p></sec><sec><label>2.2</label><title>Case 2</title><p>A 30-year-old woman (gravida 2, para 0, early abortion 1) at 21 weeks of pregnancy was referred to our hospital for placenta previa with a small amount of vaginal bleeding in April 2019. Three days before hospitalization, the patient experienced dark red vaginal bleeding due to unknown etiology. Ultrasound examination indicated placenta previa. On the day of her hospital admission, ultrasound examination showed that the lower edge of the placenta covered the cervical os, and the cervical length was 2.6&#x02013;2.7&#x0200a;cm with internal os closed. The estimated thickness of the placenta at the os was 1&#x0200a;cm. A 1.3&#x0200a;&#x000d7;&#x0200a;1.3&#x0200a;&#x000d7;&#x0200a;1.0&#x0200a;cm area with uneven flocculating echo was found between the cervical internal os and the edge of the placenta. The patient's hemoglobin level was 118&#x0200a;g/L. A small amount of vaginal bleeding continued after hospital admission. Two daily intravenous infusion of 25% magnesium sulfate was applied to inhibit uterine smooth muscle contraction and 1.5&#x0200a;g cefuroxime was administered to prevent infection. At 17:40 on April 3, 2019, the patient suffered vaginal bleeding of 380&#x0200a;mL. Her uterine tension was low, and the abdomen was soft. At 18:10, the cumulative vaginal bleeding volume was nearly 800&#x0200a;mL (by weight) with bright red color. Because the severe vaginal bleeding was possibly life threatening, the patient decided to terminate the pregnancy. Her hemoglobin level was 104&#x0200a;g/L and hypersensitive C- reactive protein level was 7.6&#x0200a;mg/L. At 19:20, the blood pressure was dropped to 87/51 mm Hg, the patient was given 3 units of red blood cell suspension and 410&#x0200a;mL of fresh frozen plasma. At 19:30, a cervical ripening balloon was inserted through the placenta and was placed between the fetus and placenta with ultrasound guidance. Vaginal bleeding was rapidly reduced as the external force pulled the cervical ripening balloon to press against the placenta while expanding the cervix. At 22:55, the cervical ripening balloon was slipped out of the vagina. The cervix opening was 2&#x0200a;cm, the fetal head was close to the cervix; contractions were normal. At 23:00, the fetus was delivered via vagina; there was 350 ml of blood loss during the delivery. The placenta and fetal membranes were naturally delivered with placental defects of 4&#x0200a;&#x000d7;&#x0200a;3&#x0200a;&#x000d7;&#x0200a;3 cubic centimeters and fetal membrane defects of 2/3. Intravenous infusion of oxytocin (20 IU) was administered to promote uterine contraction, and curettage was conducted with ultrasound guidance. There was another 380 ml of blood loss during the curettage procedure. The uterus was massaged associated with intramuscular injections of 20IU oxytocin and 250&#x0200a;&#x003bc;g carboprost tromethamine, and intravenous injections of 100&#x0200a;&#x003bc;g carbetocin. At 23:15, the bleeding stopped after using 1 piece of intrauterine iodoform gauze. On the next day, her hemoglobin level was 88&#x0200a;g/L. There was no bleeding after intrauterine iodoform gauze removal. Next, 1.5 g cefuroxime was intravenously infused 2 times daily for 2 days to prevent infection. The patient's temperature was normal. On post-delivery day 5, hypersensitive C- reactive protein level was 25.8&#x0200a;mg/L, and hemoglobin level was 86&#x0200a;g/L. Transabdominal ultrasound showed a 0.8&#x0200a;cm wide echo band in the uterine cavity with no blood flow signal. The patient was successfully discharged at post-delivery day 6.</p></sec></sec><sec><label>3</label><title>Discussion</title><p>Placenta previa is a condition in which the placenta reaches or covers the cervical internal os.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Many scholars believe that at the second trimester, placenta previa should be called placenta previa status^.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>&#x02013;<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} The placenta previa status depends on the relationship between the placenta edge and the cervical internal os. Placenta previa is normally confirmed by vaginal ultrasound, MRI, and computed tomography angiography. The sensitivity and specificity of transabdominal ultrasound is lower for the diagnosis of placental previa. Vaginal ultrasound has a high rate of accuracy for placental previa diagnosis. One study found that vaginal ultrasound helped diagnose low-lying placenta or placenta previa in nearly 1 in 10 women.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} MRI has good soft tissue contrast and clearly shows the placenta position and the depth of myometrial invasion. MRI and computed tomography can be valuable for a placenta previa diagnosis when ultrasound results are unclear.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]}</p><p>Placenta previa can cause serious bleeding and other complications that lead to morbidity and mortality during pregnancy. Occasionally, patients with placenta previa need to terminate the pregnancy due to severe fetal malformations, stillbirth, or inevitable abortion in the second trimester. For pregnancy termination, 1 study compared 5 ways of terminating pregnancy during the second trimester, including intra-amniotic injection of ethacridine lactate, intravenous infusion of oxytocin, cervical ripening balloon placement, and vaginal medication with prostaglandin E2 or misoprostol. The study showed that the first 3 methods were more effective than the later 2.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Another study found that the intra-amniotic injection of ethacridine lactate combined with oral mifepristone tablets could shorten the abortion time compared with an amniotic injection of ethacridine lactate solution alone. ^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} However, all these pregnancy termination methods couldn&#x02019;t decrease the risk of bleeding for patients with placenta previa. Obstetric hemorrhage is the leading cause of maternal morbidity and mortality. Regardless of the method of labor induction, cervical dilatation is needed for vaginal delivery. For patients with placenta previa, the placenta is attached to the lower part of the uterus and the cervical internal os. The placenta has poor stretch ability and could detach, leading to life-threatening bleeding. Takashi Yamada et al^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} reported 2 cases of hysterotomy abortion due to massive bleeding during pregnancy termination at 18 weeks. Although the pregnant woman was safe and the uterus was retained, hysterotomy abortion caused uterine scarring. The risk of placenta previa, placental implantation and massive hemorrhage is increased in the future pregnancy. ^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} The interval between hysterotomy and the next pregnancy is longer. ^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} Even if the hysterotomy is performed, there are still risks of uncontrolled bleeding, disseminated intravascular coagulation, shock, blood transfusion, and even hysterectomy.</p><p>Vascular interventional techniques such as uterine artery embolization, internal iliac artery balloon occlusion and abdominal aortic balloon occlusion have been utilized by obstetricians to reduce bleeding due to placenta previa. However, preventive use of any vascular intervention techniques cannot completely prevent bleeding. There are embolism complications such as ovarian dysfunction, pain, fever, and infection. In severe cases, hysterotomy abortion or even hysterectomy is still needed due to sepsis or labor induction failure.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} In the case of severe bleeding, emergency uterine artery embolization requires a radiology surgical team, additional equipment, extra time for patient transfer and operation. Bleeding may be aggravated during the process; uterine contraction medicine may lead to vasoconstriction and then increase the operational difficulties. This is a significantly challenging procedure with potential risks.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} Studies have shown that preventive uterine artery embolization does not significantly improve the outcomes of pregnancy termination in patients with complete placenta previa, but increases the risk of complications and leads to a longer hospital stay.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} Therefore, the application of vascular interventional techniques in obstetrics is a complicated and expensive procedure that also needs additional personnel and equipment. The necessity and safety of vascular interventional techniques need to be further explored.</p><p>Tang et al^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} reported 3 cases of uterine artery embolization combined with double balloon catheter for patients with placenta previa who had an abortion due to fetal malformations during the second trimester. Patients undergoing induced labor suffered hemorrhage after an intra-amniotic injection of ethacridine lactate solution and oral mifepristone tablets. Uterine artery embolization was applied first, and subsequently a double balloon catheter was placed in the lower part of the uterine cavity and outside the cervical external os, the balloon was left there for 12&#x0200a;hours. After the cervix was opened at 2&#x0200a;cm, the balloon was taken out. Although the vaginal delivery was successful, the operation procedure was complicated with long induction time and increased risk of infection.</p><p>This study here only used a single cervical ripening balloon without uterine artery embolization needed. The cervical ripening balloon was inserted through the placenta and placed between the fetus and the placenta. This method not only rapidly stopped bleeding by pressing against the placenta that covers the cervical os, but also gently increased the cervical opening and induced uterine contraction. Total time from the balloon placement to the end of the delivery was about 3&#x0200a;hours for both patients. Both patients safely delivered the fetus through the vagina in a short period of time with minimal bleeding. For the first patient, the hemorrhage volume before placement of the cervical ripening balloon was 200&#x0200a;mL. The total time from the balloon placement to the end of the delivery was 2 hours and 30 minutes, with 50&#x0200a;mL of bleeding. For the second patient, the hemorrhage volume before placement of the cervical ripening balloon was 800&#x0200a;mL. The whole procedure lasted for 3&#x0200a;hours and 30 minutes, with 740&#x0200a;mL of bleeding. This new method in this study had a shorter operation time compared to other methods in previous studies. The shorter procedure time could reduce the risk of continued bleeding and infection. Even the second patient had hemorrhage and placental membrane residues after the delivery; the methods of curettage, uterine gauze packing, or uterine balloon packing could be applied to stop bleeding and preserve the integrity of the uterus.</p><p>Some complications may occur during pregnancy termination for patients with placenta previa, including uncontrolled bleeding, unsuccessful conservative treatment, and the risk of amniotic fluid embolism; hysterotomy abortion or even hysterectomy may be needed in certain situations. A study in Canada showed that the risk of amniotic fluid embolism doubled due to induction of labor.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} However, another study in the US showed that amniotic fluid embolism was not associated with labor induction.^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} Another complication is intrauterine or systemic infection due to bleeding and intrauterine operations. Hysterotomy increases the risks of wound infection, endometritis and other complications. A study showed that preventive use of antibiotics does reduce the incidence of infection by 60% to 70%.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} The short operation and delivery time could possibly reduce the risk of infection. Indeed, in this study, there was no amniotic fluid embolism and infection in either patient.</p><p>This study showed that a cervical ripening balloon could be used as a simple, rapid and effective way to terminate pregnancy and manage bleeding in patients with placenta previa. The requirements for personnel and equipment are minimal for this method. It is a practical way to reduce bleeding during pregnancy termination for patients with placenta previa. The operation could be considered under emergency situations even in rural areas to minimize the risks of major hemorrhagic shock or even death during the hospital transferring. This new method can quickly stop bleeding, decrease the operation time, retain uterus integrity, and reduce the occurrence rate of hysterotomy, scarring or uterus loss. Whether this operation will increase the risk of amniotic fluid embolism remains to be further explored. Currently, there are no similar clinical operations using a cervical ripening balloon to penetrate the placenta and manage the bleeding in patients with placenta previa. Our study showed great potential for this new application of a cervical ripening balloon, and is worthy of further research.</p></sec><sec><title>Acknowledgments</title><p>The authors are grateful to the patient who signed informed consent for publication.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Chang Su, Danqing Chen.</p><p><bold>Data curation:</bold> Chang Su.</p><p><bold>Funding acquisition:</bold> Danqing Chen.</p><p><bold>Investigation:</bold> Chang Su, Danqing Chen.</p><p><bold>Methodology:</bold> Chang Su, Danqing Chen.</p><p><bold>Project administration:</bold> Chang Su, Danqing Chen.</p><p><bold>Resources:</bold> Danqing Chen.</p><p><bold>Supervision:</bold> Danqing Chen.</p><p><bold>Visualization:</bold> Chang Su.</p><p><bold>Writing &#x02013; original draft:</bold> Chang Su.</p><p><bold>Writing &#x02013; review and editing:</bold> Danqing Chen.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviation: MRI = magnetic resonance imaging.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Su C, Chen D. Using a cervical ripening balloon to penetrate the placenta and quickly reduce bleeding by pressing against the placenta during pregnancy termination for patients with placenta previa in the second trimester: two cases report. <italic>Medicine</italic>. 2020;99:39(e22499).</p></fn><fn fn-type=\"con\"><p>CS made substantial contributions to conception of the study; acquisition of data; drafting the manuscript. DC involved in interpretation of data; revising the manuscript. All authors read and approved the manuscript.</p></fn><fn fn-type=\"other\"><p>In this study, the procedure received ethics approval by the Ethics Committee of Women's Hospital, Zhejiang University School of Medicine on Nov 25th, 2019 (2019-Ethics Review Divison NO. 066). All patients signed written informed consent for the procedure and the publication.</p></fn><fn fn-type=\"other\"><p>This study was funded by the National Natural Science Foundation of China (81873839 to D.C.), Key Project of Science and Technology Department of Zhejiang Province (2018C03010 to D.C.), and Zhejiang Provincial &#x00026; Ministry of Health Research Fund for Medical Sciences (WKJ-ZJ-1722 to D.C.).</p></fn><fn fn-type=\"other\"><p>Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"book\"><person-group person-group-type=\"author\"><name><surname>Beckmann</surname><given-names>CRB</given-names></name><name><surname>Ling</surname><given-names>FW</given-names></name><name><surname>Herbert</surname><given-names>WNP</given-names></name><etal/></person-group>\n<article-title>Obstetrics and 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991447</article-id><article-id pub-id-type=\"pmc\">PMC7523854</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-09141</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022340</article-id><article-id pub-id-type=\"art-access-id\">22340</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>3500</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>A novel <italic>FGFR2</italic> (S137W) mutation resulting in Apert syndrome</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Shi</surname><given-names>Qingyang</given-names></name><degrees>MSc</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Dai</surname><given-names>Rulin</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Wang</surname><given-names>Ruixue</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Jing</surname><given-names>Jili</given-names></name><degrees>MSc</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Yu</surname><given-names>Xiaowei</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Ruizhi</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Liu</surname><given-names>Yanhong</given-names></name><degrees>MSc</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff>Center of Reproductive Medicine and Center of Prenatal Diagnosis, the First Hospital, Jilin University, Changchun, Jilin, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Yanhong Liu, Center for Reproductive Medicine and Center for Prenatal Diagnosis, First Hospital, Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, Jilin Province 130021, China (e-mail: <email>bluesky@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22340</elocation-id><history><date date-type=\"received\"><day>9</day><month>1</month><year>2020</year></date><date date-type=\"rev-recd\"><day>27</day><month>6</month><year>2020</year></date><date date-type=\"accepted\"><day>24</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22340.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Apert syndrome (AS) is an autosomal dominant inheritance pattern of the most severe craniosynostosis syndrome. AS is characterized by synostosis of cranial sutures and acrocephaly, including brachycephaly, midfacial hypoplasia, and syndactyly of the hands and feet. Patients with AS often present with craniosynostosis, severe syndactyly, and skin, skeletal, brain, and visceral abnormalities.</p></sec><sec><title>Patient concerns:</title><p>A pregnant Chinese woman presented with a fetus at 23&#x0200a;+&#x0200a;5 weeks of gestation with suspected AS in a prenatal ultrasound examination. Following ultrasound, the pregnancy underwent spontaneous abortion. Gene sequencing was performed on the back skin of the dead fetus.</p></sec><sec><title>Diagnosis:</title><p>The diagnosis of AS was confirmed on the basis of clinical manifestations of the fetus, and a de novo mutation in the fibroblast growth factor receptor 2 (<italic>FGFR2</italic>) gene was identified.</p></sec><sec><title>Interventions:</title><p>The couple finally chose to terminate the pregnancy based on the ultrasonic malformations and the risk of the parents having a neonate with AS in the future is small. However, any future pregnancy must be assessed by prenatal diagnosis.</p></sec><sec><title>Outcomes:</title><p>The dead fetus presented with bilateral skull deformation. Additionally, there were bilateral changes to the temporal bone caused by inwards movement leading to concave morphology, a &#x0201c;clover&#x0201d; sign, and syndactyly from the index finger/second toe to the little finger/little toe. AS was diagnosed by genetic testing, which showed a p.S137W (c.410C&#x0003e;G, chr10:123279677) mutation in the <italic>FGFR2</italic> gene.</p></sec><sec><title>Lessons:</title><p>Clinicians should be aware that there are a variety of ultrasound findings for AS. Therefore, genetic testing should be used when appropriate to confirm diagnosis of AS.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>Apert syndrome</kwd><kwd>autosomal dominant inheritance</kwd><kwd>de novo mutation</kwd><kwd>fibroblast growth factor receptor 2 (FGFR2)</kwd><kwd>syndactyly</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Finance Department Health Special Project of Jilin Province, China</funding-source><award-id>JLSCZD2019-022</award-id><principal-award-recipient>Ruizhi Liu</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Apert syndrome (AS) is a rare genetic disorder, which was first reported by Wilkie et al and characterized by craniosynostosis, severe syndactyly, and a variety of skin, skeletal, brain, and visceral abnormalities.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} AS exhibits an autosomal dominant inheritance pattern and the incidence of AS has been reported to be 1 in 65,000 individuals.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]}</p><p>The primary cause of AS is mutation in the fibroblast growth factor receptor 2 (<italic>FGFR2</italic>) gene. In fact, more than 98% of AS cases are caused by <italic>de novo FGFR2</italic> mutations, referred to as S252W and P253R.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} The mechanism underlying the exquisite genotype/phenotype correlation associated with AS mutations needs to be understood in terms of the biology of fibroblast growth factor/receptor signaling and the structural pathophysiology of <italic>FGFR2</italic> mutations.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} The <italic>FGFR2</italic> gene is located on chromosome 10q26. <italic>FGFR2</italic> encodes a transmembrane receptor with an extracellular region comprising 3 immunoglobulin-like domains (IgI, IgII, and IgIII), a hydrophobic transmembrane segment, and a cytoplasmic tyrosine-kinase1 domain. The immunoglobulin domains are encoded by exons 8, 9, and 10 of the <italic>FGR2</italic> gene in which 25 to 75 of patients with AS have mutations.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]}</p><p>In this study, we report the case of a Chinese fetus at 23&#x0200a;+&#x0200a;5 weeks of gestation with unclear prenatal ultrasound findings (acrocephalosyndactyly) and abnormal physical characteristics. The fetus was subsequently diagnosed with AS on the basis of DNA sequencing analysis of <italic>FGFR</italic>. We detected a novel mutation in the <italic>FGR2</italic> gene, p.S137W (c.410C&#x0003e;G chr10:123279677).</p></sec><sec><label>2</label><title>Case report</title><p>On 29 December 2016, a 32-year-old pregnant Chinese woman was admitted to the Prenatal Diagnosis Department of the First Hospital of Changchun, Jilin Province, northeastern China. She had previously undergone routine prenatal screening of her fetus (23&#x0200a;+&#x0200a;5 weeks of age). However, prenatal ultrasound findings were not clear. The woman had experienced a spontaneous abortion during the first trimester (8 weeks of gestation) of a previous pregnancy but without any known cause. She had not been exposed orally to harmful or hazardous substances during her pregnancies. During the second pregnancy, the pregnant woman had a febrile illness and received oral cold medication, although no specific records were available to confirm this. Following ultrasound, the second pregnancy underwent spontaneous abortion. The parents wanted to know the reason for the spontaneous abortion and brought the fetus to our department for analysis. There was no history of consanguineous marriage in the family and no family history of genetic disorders.</p><p>The study protocol was approved by the Ethics Committee of the First Hospital of Jilin University (No. 2016-365). Informed written consent was obtained from the parents for publication of this case report and accompanying images.</p></sec><sec><label>3</label><title>Materials and methods</title><p>Sequencing analysis was conducted on the dead fetus and the parents. First, the DNA was disrupted and a library was prepared. DNA of the targeted gene coding region and the adjacent cleavage region was then captured and enriched by a chip. Finally, detection of mutations was performed using a high-throughput sequencing platform.</p></sec><sec><label>4</label><title>Results</title><p>During prenatal ultrasound, a number of anomalies were detected. These included a wide angle after the left ventricle (1.03&#x0200a;cm), bilateral skull deformation, bilateral temporal bone abnormalities showing inwards movement and a concave appearance, a &#x0201c;clover&#x0201d; sign, and syndactyly from the index finger/second toe to the little finger/little toe (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Prenatal ultrasound findings. (A) Syndactyly from the index finger to the little finger. (B&#x02013;D) Physical characteristics of acrocephalia. The left ventricle was wider than normal.</p></caption><graphic xlink:href=\"medi-99-e22340-g001\"/></fig><p>The physical characteristics of the dead fetus were consistent with the prenatal ultrasound findings (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>). The dead fetus presented with the physical characteristics of acrocephalosyndactyly and hypertelorism. X-ray results showed that there was no craniosynostosis. Because of the prenatal ultrasound findings and the clinical manifestations evident upon physical examination of the dead fetus, we initially suspected that the fetus may have had AS.</p><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>The dead fetus after induced labor. (A&#x02013;C) Physical characteristics of acrocephalosyndactyly. (D&#x02013;F) Presentation of acrocephalia as shown by X-ray. Craniosynostosis was not evident.</p></caption><graphic xlink:href=\"medi-99-e22340-g002\"/></fig><p>We took a sample of skin from the back of the dead fetus for gene sequencing. We found that the fetus had a heterozygous p.S137W (c.410C&#x0003e;G, chr10:123279677) mutation in the <italic>FGFR2</italic> gene (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>A). However, further analysis showed that neither of the parents carried this mutation (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>B and C). The diagnosis of AS was confirmed on the basis of clinical manifestations of the fetus and identification of a de novo mutation in the <italic>FGFR2</italic> gene.</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Sanger sequencing results for (A) the fetus, (B) the fetus's father, and (C) the fetus's mother. We identified the presence of a p.S137W (c.410C&#x0003e;G chr10:123279677) mutation in the <italic>FGFR2</italic> gene (red circle) in the fetus and the absence of a mutation at c.410C (red circles) in the parents.</p></caption><graphic xlink:href=\"medi-99-e22340-g003\"/></fig></sec><sec><label>5</label><title>Discussion</title><p>We report here a new case of the rare genetic syndrome AS. AS is primarily characterized by cutaneous and osseous symmetric syndactyly in the hands and feet, with variable presentations in the bones, brain, skin, and other internal organs. AS is one of the most severe craniosynostosis syndromes.</p><p>During craniofacial development at different stages of embryonic formation, signaling pathways involving fibroblast growth factors, their receptors (FGFRs), and specifically, FGFR2, regulate the balance between proliferation and differentiation of progenitor osteogenic cells on the neural crest.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Later in development, these pathways are also involved in formation of cartilage, skull bones, and the maxilla, as well as migration of the plates that give rise to the palate and lips.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]}</p><p>The S252W and P253R mutations were originally described by Wilkie et al^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]}and are associated specifically with AS. These mutations present with more severe syndactyly in patients with the Pro253Arg mutation compared with the Ser252Trp mutation. However, the fetus described above showed no association of these mutations and syndactyly. Instead, the fetus had a novel mutation, which, to the best of our knowledge, has not been reported previously. Molecular analysis detected a p.S137W (c.410C&#x0003e;G chr10:123279677) mutation in the <italic>FGFR2</italic> gene. Because the parents of the fetus did not have this mutation, the fetus had a de novo heterozygous mutation, which led to AS.</p><p>Early surgery is currently advocated by many craniofacial centers to prevent complications arising from AS.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Generally, the most important management protocol for patients with AS involves immediate craniotomy, hand and feet surgery, and long-term follow-up. However, in most developing countries, early intervention of AS is hampered by late diagnosis, a lack of facilities, and financial constraints.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]}</p></sec><sec><label>6</label><title>Conclusion</title><p>In conclusion, clinicians should be aware that there are a variety of ultrasound findings for AS. In the present study, the fetus showed abnormal prenatal ultrasound findings (acrocephalosyndactyly). However, craniosynostosis was not clearly indicative of AS. Therefore, genetic testing should be used when appropriate to confirm diagnosis of AS. Our data indicate that the case of fetal AS was caused by a new mutation. The risk of the parents having a neonate with AS in the future is small. However, any future pregnancy must be assessed by prenatal diagnosis.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Yanhong Liu.</p><p><bold>Data curation:</bold> Qingyang Shi.</p><p><bold>Funding acquisition:</bold> Ruizhi Liu.</p><p><bold>Investigation:</bold> Qingyang Shi, Ruixue Wang.</p><p><bold>Methodology:</bold> Xiaowei Yu.</p><p><bold>Software:</bold> Jili Jing.</p><p><bold>Writing &#x02013; original draft:</bold> Rulin Dai.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Qingyang Shi, Yanhong Liu.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: AS = Apert syndrome, FGFR2 = fibroblast growth factor receptor 2.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Shi Q, Dai R, Wang R, Jing J, Yu X, Liu R, Liu Y. A novel <italic>FGFR2</italic> (S137W) mutation resulting in Apert syndrome: A case report. <italic>Medicine</italic>. 2020;99:39(e22340).</p></fn><fn fn-type=\"supported-by\"><p>This work was kindly supported by the Finance Department Health Special Project of Jilin Province, China (JLSCZD2019- 022).</p></fn><fn fn-type=\"COI-statement\"><p>The authors report no conflicts of interest.</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article [and its supplementary information files].</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Wilkie</surname><given-names>AO</given-names></name><name><surname>Slaney</surname><given-names>SF</given-names></name><name><surname>Oldridge</surname><given-names>M</given-names></name><etal/></person-group>\n<article-title>Apert syndrome results from 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991489</article-id><article-id pub-id-type=\"pmc\">PMC7523855</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-03494</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022495</article-id><article-id pub-id-type=\"art-access-id\">22495</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>6800</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Diagnosis of multiple pulmonary cavernous hemangiomas via dual-layer spectral CT</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Bae</surname><given-names>Kyungsoo</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>An</surname><given-names>Hyo Jung</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Jung</surname><given-names>Jae Jun</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff4\">^d</xref></contrib><contrib contrib-type=\"author\"><name><surname>Kim</surname><given-names>Ho Cheol</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff5\">^e</xref></contrib><contrib contrib-type=\"author\"><name><surname>Jeon</surname><given-names>Kyung Nyeo</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref ref-type=\"aff\" rid=\"aff2\">^b</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Radiology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju</aff><aff id=\"aff2\"><label>b</label>Department of Radiology, Gyeongsang National University Changwon Hospital, Changwon</aff><aff id=\"aff3\"><label>c</label>Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, and Gyeongsang National University School of Medicine, Jinju</aff><aff id=\"aff4\"><label>d</label>Department of Thoracic Surgery, Gyeongsang National University Changwon Hospital, Changwon</aff><aff id=\"aff5\"><label>e</label>Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Kyung Nyeo Jeon, Department of Radiology, Gyeongsang National University School of Medicine, Jinju, Gyeongsang National University Changwon Hospital, 555 Samjeongja-dong, Seongsan-gu, Changwon 51472, Korea (e-mail: <email>knjeon@gnu.ac.kr</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22495</elocation-id><history><date date-type=\"received\"><day>16</day><month>4</month><year>2020</year></date><date date-type=\"rev-recd\"><day>27</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>1</day><month>9</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22495.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Cavernous hemangioma is a benign vascular tumor, which very rarely occurs in the lung. When appearing as multiple nodules on chest CT, this tumor can be misdiagnosed as metastatic malignancy.</p></sec><sec><title>Patient concerns:</title><p>A 72-year-old woman presented with incidentally found multiple lung nodules on chest radiograph.</p></sec><sec><title>Diagnoses:</title><p>Based on information derived from dual-layer spectral CT images, the possibility of slow flow vascular tumor such as cavernous hemangioma was suggested. A pathologic diagnosis of pulmonary cavernous hemangioma was made via video-assisted thoracoscopic biopsy.</p></sec><sec><title>Interventions:</title><p>After tissue confirmation, the patient was discharged without further intervention.</p></sec><sec><title>Outcomes:</title><p>The patient recovered without any event. Follow-up chest CT performed 6 months later showed no significant interval change in nodule size and distribution.</p></sec><sec><title>Lessons:</title><p>Material decomposition images obtained from dual energy CT can help physicians understand the character of tumor vascularity for an accurate diagnosis of pulmonary cavernous hemangioma.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>cavernous hemangioma</kwd><kwd>computed tomography</kwd><kwd>dual-energy spectral CT</kwd><kwd>lung</kwd><kwd>vascular tissue neoplasm</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Pulmonary cavernous hemangioma (PCH) is an extremely rare benign tumor. When PCH presents as multiple nodules in both lungs, it mimics metastatic malignancy.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Although the CT features of PCH have been reported in previous studies, particular diagnostic findings have not been described. Multi-energy applications of CT have improved the characterization of pulmonary nodules such as the differentiation between benign and malignant lesions and the assessment of tumor angiogenesis.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Here, we describe dual-layer spectral CT findings of multiple PCHs in a 72-year-old woman with pathological correlations for a better understanding of PCH to avoid unnecessary invasive procedures.</p></sec><sec><label>2</label><title>Case report</title><p>This study was approved by the Institutional Review Board of Gyeongsang National University Changwon Hospital. The patient provided written consent for publication of this case. A 72-year-old female presented with incidentally found multiple lung nodules on chest radiograph. She was a nonsmoker. The patient was treated with appendectomy due to appendicitis a month before. Other medical history was unremarkable. Chest radiograph showed multiple nodules in both lungs (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>A). Under suspicion of metastatic malignancy, a chest CT scan was performed using a dual-layer detector spectral CT scanner (IQon, Philips Healthcare). The scanning parameters were as follows: 120 kVp, 140&#x02013;250&#x0200a;mA (reference mAs, 73), pitch of 0.609, rotation time of 0.4 seconds, 64&#x0200a;&#x000d7;&#x0200a;0.625&#x0200a;mm collimation, 1-mm slice thickness, 1-mm slice increment, and smooth filter (filter A). The nonenhanced scanning was performed first in the helical mode. Dual-phasic images were obtained after administration of 90&#x0200a;mL iodinated contrast material (Omnipaque 300, GE Healthcare) at a rate of 2.5&#x0200a;mL/s. Early-phase images were obtained using bolus tracking with the threshold set at 150 HU in aortic arch followed by a 7-second delay. Delayed phase images were obtained with a delay of 60 seconds from the beginning of contrast injection.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>A 72-year-old female presented with an abnormal chest radiograph. (A) Chest radiograph shows multiple nodules in both lungs, especially mid and lower lung zone. (B) Chest computed tomography (CT) images in the lung window setting show multiple variable-sized nodules in both lungs. (C) Conventional chest CT images obtained using dual-layer spectral CT show multiple nodules in the right middle lobe and the right lower lobe. In pre-contrast scan (images in left column), suspicious high density foci in a few nodules (arrows) suggest calcification. In the early phase (images in middle column), a nodule in the right lower lobe shows strong enhancement (black arrow). However, other nodules show a focal peripheral dot-like enhancement (dotted arrow) or no remarkable enhancement (arrowhead). In the delayed phase (images in right column), a nodule in the right lower lobe shows extensive enhancement, whereas other nodules show no remarkable changes. (D) Iodine density images from early phase (upper row) show the contrast in each nodule (dotted arrows). Iodine density images from the delayed phase (lower row) show more extensive or centripetal filling of contrast (solid arrows). (E) Video-assisted thoracoscopic surgery (left upper) shows multiple hemorrhagic nodules in the surface of the lung. Microscopic examination (right upper) reveals well-circumscribed vascular tumors (arrows) with different sizes. Under higher magnification of the larger tumor (left lower), each vascular space shares the vein-like septate vascular walls. Calcification is noted in vessel wall (arrow). CD31 staining (right lower) shows linear, strong positive expression along the vascular endothelial cells, indicating vascular origin.</p></caption><graphic xlink:href=\"medi-99-e22495-g001\"/></fig><p>Chest CT showed random distribution of variable-sized nodules in both lungs (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>B). The pre-contrast scan revealed high density area in some nodules suggesting calcification (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>C). After contrast enhancement, a nodule in the right lower lobe showed focal strong enhancement in the early phase. Other nodules did not show such a strong enhancement pattern. Some nodules showed peripheral dot-like enhancing foci or no obvious enhancing area. In the delayed phase, the nodule in the right lower lobe showed more extensive enhancement, whereas other nodules showed no remarkable change. In iodine density images derived from spectral based image, the iodine distribution was noted not only in the right lower lobe but also in other nodules (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>D). The pattern of iodine distribution in the nodules reflected peripheral or smaller zone of enhancement in the early phase and centripetal filling in the delayed phase. Significant iodine concentration was detected in the nodules of both early (1.9&#x0223c;5.3&#x0200a;mg/mL) and delayed (2.5&#x0223c;6.1&#x0200a;mg/mL) phases. Based on information derived from conventional CT and iodine density images, the possibility of slow flow vascular tumor such as cavernous hemangioma was suggested. Hypervascular metastasis was also considered as a differential diagnostic possibility. Additional imaging studies and physical examinations did not reveal any significant lesions in other body parts.</p><p>Video-assisted thoracoscopic biopsy was performed for tissue confirmation. Grossly, multiple hemorrhagic nodules were found diffusely distributed throughout in all the lobes and pleura (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>E). Microscopic examination revealed nodules composed of large and dilated vascular channels separated from one another by scanty connective tissue stroma, and the channels were filled with blood (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>E). Calcification was observed along some of the vessel walls. Immunohistochemical staining demonstrated that the cells lining the cavernous structure stained positively for CD31, which suggested that the lesions were of vascular origin. A final pathologic diagnosis of PCH was made. The patient recovered without any event and postoperative follow-up chest CT taken 3 months later showed no significant interval change in nodule size and distribution.</p></sec><sec><label>3</label><title>Discussion</title><p>Unlike other organs such as the skin, subcutaneous tissues, and liver, cavernous hemangiomas very rarely occur as primary neoplasms in the lung.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} A recent literature review of PCH found that &#x0003c;20 cases have ever been reported.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} The clinical presentation of PCH varies depending on the size and number of tumors. Although some patients present with life-threatening symptoms such as severe bleeding or dyspnea, others show absent or nonspecific symptoms.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>&#x02013;<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]}</p><p>PCH presents as single or multiple solid nodules on imaging studies. Multiple PCHs have been reported to mimic metastatic lesions.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>&#x02013;<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Metastatic nodules appear as multiple variable-sized nodules scattered in the lung and pleura. A cavernous hemangioma is an unencapsulated mass of dilated, endothelium-lined vascular channels filled with slow-flowing blood.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} In contrast to cavernous hemangiomas involving other solid organs such as the liver, a typical centripetal enhancement pattern has not been reported in PCH, hindering preoperative diagnosis.</p><p>Recent advances in CT technology have led to improved detection and characterization of nodules. In particular, dual-energy techniques enabled better characterization of nodules via material differentiation.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} The dual-layer detector spectral CT system consists of a single tube and 2-layered detectors, which simultaneously capture high- and low-energy photons during each CT examination. Because energy separation occurs on the detector, the decision to use a single- or dual-energy protocol before scanning is not necessary. Spectral information can be obtained from all examinations using a routine protocol.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} In the present study, enhancement pattern of nodules was not obvious on conventional CT images, except for a nodule in the right lower lobe because of small lesion size and high density (calcification) of the nodules. However, iodine density images derived from spectral based image clearly showed the presence and the pattern of iodine uptake in each nodule, reflecting blood supply. The pattern of iodine distribution in PCHs was similar to the contrast enhancement pattern in hepatic cavernous hemangiomas, peripheral nodular, or entire enhancement with gradual filling.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} The high-density areas observed in some nodules in the precontrast images were caused by dystrophic calcification in vessel wall as shown in pathology.</p><p>The etiology of cavernous hemangiomas is not completely understood; however, they are considered to be congenital vascular malformations, which may be attributed to genetic loss-of-function mutations.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} Management of PCH varies depending on the severity of symptoms and extent of the lesions. In a solitary PCH, surgical excision is considered as the most effective treatment. Interferon alfa-2a has been reported to be effective in treating multiple PCHs. However, because of the rarity of cases, the management of PCH remains a topic of controversy. Radiographic follow-up may play an important role in asymptomatic and stable PCH.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]}</p><p>We presented a rare case of multiple PCHs based on dual-layer spectral CT findings. Since percutaneous biopsy of PCH can lead to bleeding complications, a proper imaging diagnosis is important. To the best of our knowledge, this is the first report of PCH describing spectral CT findings. Despite its rarity, our informative case may help physicians understand the characteristics of the tumor based on CT and correlative pathologic findings, obviating the need for unnecessary invasive procedures.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Kyungsoo Bae, Kyung Nyeo Jeon.</p><p><bold>Formal analysis:</bold> Kyungsoo Bae, Hyo Jung An.</p><p><bold>Investigation:</bold> Kyungsoo Bae, Hyo Jung An.</p><p><bold>Methodology:</bold> Jae Jun Jung, Ho Cheol Kim.</p><p><bold>Resources:</bold> Hyo Jung An, Jae Jun Jung.</p><p><bold>Supervision:</bold> Kyung Nyeo Jeon.</p><p><bold>Writing &#x02013; original draft:</bold> Kyungsoo Bae, Kyung Nyeo Jeon.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Kyungsoo Bae, Hyo Jung An, Jae Jun Jung, Ho Cheol Kim, Kyung Nyeo Jeon.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CT = computed tomography, PCH = pulmonary cavernous hemangioma.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Bae K, An HJ, Jung JJ, Kim HC, Jeon KN. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"research-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991411</article-id><article-id pub-id-type=\"pmc\">PMC7523857</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-07877</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022180</article-id><article-id pub-id-type=\"art-access-id\">22180</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>7100</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Clinical Trial</subject></subj-group></article-categories><title-group><article-title>Evaluation of the impact of Tacrolimus-based immunosuppression on Heidelberg liver transplant cohort (HDTACRO)</article-title><subtitle>Study protocol for an investigator initiated, non-interventional prospective study</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Khajeh</surname><given-names>Elias</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Polychronidis</surname><given-names>Georgios</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Ramouz</surname><given-names>Ali</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Alamdari</surname><given-names>Parnian</given-names></name><degrees>MSc</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Lemekhova</surname><given-names>Anastasia</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Saracevic</surname><given-names>Melisa</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Ali-Hasan-Al-Saegh</surname><given-names>Sadeq</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Ghamarnejad</surname><given-names>Omid</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Majlesara</surname><given-names>Ali</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Abbasi Dezfouli</surname><given-names>Sepehr</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Nickkholgh</surname><given-names>Arash</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Weiss</surname><given-names>Karl Heinz</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Rupp</surname><given-names>Christian</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff3\">^c</xref></contrib><contrib contrib-type=\"author\"><name><surname>Mehrabi</surname><given-names>Arianeb</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Mieth</surname><given-names>Markus</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital</aff><aff id=\"aff2\"><label>b</label>Department of Gastroenterology and Hepatology, University of Heidelberg</aff><aff id=\"aff3\"><label>c</label>Department of Internal Medicine, Heidelberg University Hospital, Heidelberg, Germany.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Markus Mieth, Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg 69120, Germany (e-mail: <email>Markus.Mieth@med.uni-heidelberg.de</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22180</elocation-id><history><date date-type=\"received\"><day>13</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>14</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22180.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Tacrolimus-based immunosuppression has resulted in enormous improvements on liver transplantation (LTx) outcomes. However, dose adjustment and medication adherence play a key role in post-transplant treatment success. The aim of the present study is to assess the trough levels and the need for adaptation of therapeutic doses in de novo LTx patients treated with Tacrolimus in the clinical routine, without any intervention to the treatment regimen.</p></sec><sec sec-type=\"methods\"><title>Methods and analysis:</title><p>This is a pilot, prospective, exploratory, monocentric, non-interventional and non-randomized investigator-initiated study. Prospectively maintained data of 100 patients treated with various oral Tacrolimus-based immunosuppressants (Prograf or Envarsus) will be analyzed. The number of required dose adjustments of Tacrolimus formulations used in clinical routine for achieving the target trough level, Tacrolimus trough level, Tacrolimus dosing, concentration/dose ratio, routine laboratory tests, efficacy data (incl. survival, acute rejection, re-transplantation), patients therapy adherence, and infections requiring the need to reduce individual immunosuppressant dosing will be evaluated for each patient.</p></sec><sec><title>Result:</title><p>This study will evaluate the trough levels and the need for adaptation of therapeutic doses in de novo LTx patients treated with Tacrolimus in the clinical routine, without any intervention to the treatment regimen.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>The HDTACRO study will be the first study to systematically and prospectively evaluate various oral Tacrolimus-based immunosuppressants in de novo liver transplanted patients. If a difference between the therapy-subgroups is evident at the end of the trial, a randomized control trial will eventually be designed. Registration number: ClinicalTrials.gov: NCT04444817.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>immunosuppression</kwd><kwd>liver transplantation</kwd><kwd>tacrolimus</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Chiesi Farmaceutici</funding-source><award-id>no</award-id><principal-award-recipient>Not Applicable</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Modern immunosuppression is characterized by a combination of different immunosuppressants.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Immunosuppression based on low-dose calcineurin inhibitors (CNI), with comparatively low CNI target levels, have shown satisfying outcomes in preventing chronic graft rejection.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>&#x02013;<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Low-dose CNI immunosuppression is of great importance considering the often poor condition of the transplant candidates in the course of the model for end-stage liver disease (MELD) score-based organ allocation system. Despite all efforts to optimize the treatment regimen after liver transplantation (LTx) from deceased donors, the amount of postoperative medication remains high, with CNIs being the main component of immunosuppressive treatment. Tacrolimus is known as the main substance, which can be administered in combination with steroids and possibly mycophenolic acid. Tacrolimus requires an individual dose titration due to its narrow therapeutic index, to achieve a satisfactory balance between maximizing efficacy and minimizing dose-related toxicity.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} The pharmacokinetic profile of Tacrolimus is characterized by a high degree of inter- and intraindividual variability. Although it is rapidly absorbed, the bioavailability of Tacrolimus in the twice-daily capsule formulation is low and variable, ranging from 17% to 23%.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} This could be due to poor water solubility, extensive first pass metabolism, p-glycoprotein-mediated efflux and the ingestion of food.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Tacrolimus twice-daily capsules are also associated with a unique high peak following dosing, which may be associated with increased toxicity.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Furthermore, graft recipients ought to receive very demanding medication regimen for a long time, which might be associated with decreased patients adherence.,^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>&#x02013;<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} which can lead to rejection and possibly graft loss.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>,<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]}</p><p>The development of once-daily Tacrolimus formulations has already been shown to increase patients adherence.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>,<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} Although, it has slightly influenced the Tacrolimus pharmacokinetic profile, while the dissolving form still remains intact.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>,<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} The pharmacokinetic profile of once-daily Tacrolimus is characterized by flatter kinetics (i.e., less fluctuation and swing) compared to a twice-daily regimen. Thus, once-daily Tacrolimus can also lead to reduced incidence and/or intensity of drug toxicity-related adverse events, by providing a more balanced concentration-time consistency over 24&#x0200a;hours. Since the development of LCP-Tacrolimus once-daily tablets, using the MeltDose technology, clinical data have shown lower peak and reduced peak-to-trough fluctuations.,^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>,<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} as well as an improved clinical safety profile.^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} Furthermore, trials with stable kidney or liver transplant recipients who were switched from twice-daily Tacrolimus capsules to once-daily LCP-Tacrolimus tablets showed a similar area under the concentration&#x02013;time profile (AUC24) with reduced doses of LCP-Tacrolimus.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>&#x02013;<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]}</p><p>The aim of the present study is to assess the trough levels and the need for adaptation of therapeutic doses in de novo LTx patients treated with Tacrolimus in the clinical routine, without any intervention to the treatment regimen.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Study settings</title><p>This is a pilot, prospective, exploratory, monocentric, non-interventional, and non-randomized investigator-initiated study to assess practicability and efficacy of Tacrolimus used in de novo liver transplant recipients. The study protocol has been registered at ClinicalTrials.gov (registration number: NCT04444817). Prospectively maintained data of 100 patients treated with various oral Tacrolimus-based immunosuppressants (Prograf or Envarsus) will be analyzed. The study is expected to last for at least 3 years.</p></sec><sec><label>2.2</label><title>Course of the study</title><p>As shown in Table <xref rid=\"T3\" ref-type=\"table\">3</xref>, the treatment and patient care will follow standard clinical practice for liver transplant patients at the Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg. The individual treatment decision will be taken independently from the participation in this non-interventional study. For all patients a total of 8 visits, as part of clinical routine, is planned from visit 1/day 0 until visit 8/day 180 (end of study) (Table <xref rid=\"T3\" ref-type=\"table\">3</xref>). All data until visit 5 (day 7) will retrospectively be observed via clinical IT-System i.s.h.med of the University Hospital Heidelberg. On the fifths patient visit (post-operative day 7), the informed consent will be obtained from all participants. From this time point on, all data will be observed prospectively and documented (Table <xref rid=\"T3\" ref-type=\"table\">3</xref>). Similar to the clinical routine, as soon as a patient is able to swallow and has a sufficient gastrointestinal activity, Tacrolimus-based immunosuppression using Prograf, or Envarsus will be started. Furthermore, CNI-based immunosuppression will be used (initial dose based on the patients body weight) with the goal of trough levels of 3 to 7&#x0200a;ng/ml within the first seven days after LTx, depending on immune status and indication for transplantation. Further trough levels will be determined based on factors such as patients history and indication for LTx. To minimize renal and infectious complications, a &#x0201c;bottom-up&#x0201d; dosing procedure (as a concept of delayed CNI-based immunosuppression) will be routinely used.</p></sec><sec><label>2.3</label><title>Patient selection</title><p>Inclusion criteria has been determined according to the standard clinical practice for liver transplant patients. Inclusion and exclusion criteria have been summarized in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>. The eligibility will be determined based on the informed consent status, age, present condition, and planned surgery.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Inclusion and exclusion criteria of the HDTACRO study.</p></caption><graphic xlink:href=\"medi-99-e22180-g001\"/></table-wrap></sec><sec><label>2.4</label><title>Outcome measures</title><sec><label>2.4.1</label><title>Primary endpoint</title><p>The primary endpoint of the present study is to analyze the number of required dose adjustments of various Tacrolimus formulations, as used in clinical routine, until the individual target trough level in de novo liver transplant patients is achieved.</p></sec><sec><label>2.4.2</label><title>Secondary endpoints</title><p>As presented in Table <xref rid=\"T2\" ref-type=\"table\">2</xref>, demographics and clinical characteristics of donors and recipients will be reported. Tacrolimus related information including: Tacrolimus trough level, Tacrolimus dosing, concentration/dose ratio, mean cumulative dose for cost analysis, will be recorded during patient visits. Furthermore, routine laboratory tests will be assessed and reported for each patient. Finally, efficacy data (incl. survival, acute rejection, re-transplantation), patients therapy adherence, and infections requiring the need to reduce individual Immunosuppressant dosing will be evaluated for each patient. Afterwards, the number of patients who require a change in immunosuppressive therapy, the stability of Tacrolimus trough levels and effectiveness of delayed CNI-based immunosuppression with Tacrolimus will be determined and the renal and transplant function under delayed CNI-based immunosuppression with Tacrolimus will be assessed.</p><table-wrap id=\"T2\" orientation=\"portrait\" position=\"float\"><label>Table 2</label><caption><p>Secondary endpoints of the HDRACRO study.</p></caption><graphic xlink:href=\"medi-99-e22180-g002\"/></table-wrap><table-wrap id=\"T3\" orientation=\"portrait\" position=\"float\"><label>Table 3</label><caption><p>HDTACRO study design according to the SPIRIT checklist.</p></caption><graphic xlink:href=\"medi-99-e22180-g003\"/></table-wrap></sec></sec><sec><label>2.5</label><title>Patient and public involvement</title><p>The patients and public were not involved in the planning of this study.</p></sec><sec><label>2.6</label><title>Modification of the protocol</title><p>Protocol amendments will be considered by the principal investigator. All potential amendments will be submitted to the independent Ethics Committee of the University of Heidelberg for approval. No patients will be recruited until the modifications are accepted.</p></sec><sec><label>2.7</label><title>Methods for minimizing bias</title><p>To avoid selection bias and heterogeneity, all patients admitted to University Hospital Heidelberg for LTx will be screened for eligibility. Every patient who meets the eligibility criteria will be informed of the study seven days after transplantation, and will be included if he/she gives consent to participate. Data will only be analyzed after all data have been collected. Any financial relationship and any conflict of interest will also be declared.</p></sec><sec><label>2.8</label><title>Data management</title><p>Medical history and adverse drug reactions will be coded using the MedDRA dictionary. Medications will be coded using the WHO Drug dictionary and Anatomical Therapeutic Chemical classification. All collected data will be documented in a paper-based case report form (CRF). Data entry into CRFs at the site will be accomplished by qualified site personnel only. Entered data will be reviewed by manual reviews. Front-end edit checks will be used in addition to the manual data review to check for discrepancies and to ensure consistency and completeness of the data. After cleaning of data, a review meeting will be held to determine the occurrence of any protocol violation and to define the subject populations for the analysis. Once the database has been declared to be complete and accurate, it will be locked and the planned statistical analysis will be performed. Only authorized and well-documented updates to the study data are possible after database lock.</p></sec><sec><label>2.9</label><title>Statistical design and analysis</title><sec><label>2.9.1</label><title>Sample size</title><p>Since no confirmatory approach will be followed in this non-interventional study, no formal sample size estimation was carried out. For practical reasons, the number of included subjects was set to 100, which are deemed to be sufficient to provide stable estimates of the primary variable.</p></sec><sec><label>2.9.2</label><title>Statistical analysis</title><p>Dichotomous data will be presented as frequencies. Continuous data will be presented as means&#x0200a;&#x000b1;&#x0200a;standard deviation, and in case of skewed distributions medians and ranges. To evaluate the difference between various Tacrolimus types, subgroup analysis will be performed. Accordingly, dichotomous data will be analyzed using Pearsons Chi-Squared test and continues data using repeated measure analysis of variance (ANOVA) model. A two-sided <italic>P</italic> value &#x0003c;.05 will be considered statistically significant in all analyses.</p><p>Since the amount of dose adjustments has only been partially described, the total number will be documented for each patient and evaluated as a dichotomous variable for each visit as well as a continuous variable for the time-frame between visits. Recent literature suggests that a stabilization of trough levels does not require longer than a period of 30 days for both de novo immunosuppression and conversion.^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>,<xref rid=\"R23\" ref-type=\"bibr\">23</xref>]}</p></sec></sec><sec><label>2.10</label><title>Ethics and dissemination</title><p>The independent Ethics Committee of the University of Heidelberg has approved the protocol of present study (registration number: S-630/18). This study was designed in accordance with the Declaration of Helsinki, version 2013. Participation will be voluntary and consent may be withdrawn at any time, without explanation and with no impact on further medical care. The execution of the trial is carried out in the Department of General, Visceral and Transplantation Surgery of the University Hospital Heidelberg. According to paragraph 4 Abs. 23 AMG the medical treatment of the patients will be undertaken based on their diagnosis and clinical treatment and not based on this protocol. The results of this study will be published in a peer-reviewed journal, and will also be presented at medical meetings.</p></sec></sec><sec><label>3</label><title>Discussion</title><p>LTx is widely used as a life-saving operation for patients with end-stage liver disease. LTx is also a standard therapy for some inherited metabolic disorders like familial hypercholesterolemia and malignancies with liver involvement such as hepatocellular carcinoma and hepatoblastoma. Recent progress in immunosuppression and medical management, procurement and preservation, and technical accomplishments have continually improved patient survival.^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} Orthotopic LTx has shown a noticeable survival rate (83% for 1 year and 75% for 5 years) with remarkable improvements over the past 3 decades, owing to new agents and changed regimens of post-transplant immunosuppression.^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>]} Although long-term post-transplant immunosuppression reduces rejection in LTx recipients, it increases the risk of infections, malignancies, and specific adverse side-effects unique to each agent.^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>&#x02013;<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} Numerous immunosuppression protocols are used by transplant centers worldwide, while each LTx recipient might need an individually customized immunosuppression regimen to keep a balance between the benefits and detriments of therapy.^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>&#x02013;<xref rid=\"R26\" ref-type=\"bibr\">26</xref>]} LTx recipients are maintained on lower levels of immunosuppression compared to other solid organ transplant recipients. Furthermore, long-term allograft survival is achieved in some LTx recipients, even after immunosuppression withdrawal.^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>&#x02013;<xref rid=\"R29\" ref-type=\"bibr\">29</xref>]} Progresses made within the past 3 decades in describing the mechanisms of immune response have provided multiple therapeutic options to reduce the rejection rates and improve the graft survival in transplantations, as well as providing alternatives to cytotoxic therapy in immune-mediated diseases.^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R31\" ref-type=\"bibr\">31</xref>]}</p><p>Post-transplant immunosuppressive regimens are based on a calcineurin inhibitor; either cyclosporine or tacrolimus. These medications were shown to have a similar mechanism of action through inhibition of calcineurin phosphatase.^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} Tacrolimus acts as an immunomodulatory agent by inhibiting the transcription of the gene encoding interleukin-2 which is necessary for the T-cell-mediated immune response.^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} The distribution of tacrolimus plays a considerable role in its metabolism. The uptake process begins in the stomach and/or proximal small bowel and the complete disintegration (and presumably optimal absorption) occurs in the distal small bowel or the colon.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>&#x02013;<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} Therefore, this can lead to lower clearance and further increased bioavailability with the potential of toxicity.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>&#x02013;<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} Evidence suggests that neurotoxicity, nephrotoxicity, akinetic mutism, new onset diabetes (post-transplant), gastro-intestinal toxicity, hepatotoxicity, and thrombotic microangiopathy could be associated with high levels of tacrolimus after LTx.^{[<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} As an immediate-release formulation, tacrolimus was first administered twice daily (Prograf). Two formulations of tacrolimus have been provided to be administered once daily: a prolonged-release formulation (Advagraf) and more recently an extended-release formulation (Envarsus).^{[<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>&#x02013;<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} It is necessary to mention that the blood level of different types of tacrolimus should be determined and compared with each other. It is not yet clear which type is preferred. HDTACRO study is the first study to make a comparative assessment of different types of Tacrolimus. Is cannot be denied that the non-randomized selection of participants is considered as a weakness in this study.</p><p>In summary, Tacrolimus revolutionized postoperative care after LTx. Various types of this immunosuppressive drug are known, but it is not yet clear which one is preferred in terms of patient adherence and acceptance, the stability of blood level and also the rate of complications of different types of this immunosuppressive medication. The HDTACRO study will be the first study which systematically and prospectively evaluates various oral Tacrolimus-based immunosuppressives.</p><p>As a future perspective, if at the end of the trial a difference between the therapy-subgroups would be evident, a randomized control trial will eventually be designed and conducted after submission to the local ethics committee and federal authorities. All diagnostic tests and medications are in accordance with our clinical routine, without any deviation from standard care in transplant patients.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Arianeb Mehrabi, Markus Mieth.</p><p><bold>Methodology:</bold> Arianeb Mehrabi, Elias Khajeh, Ali Ramouz, Markus Mieth, Sadeq Ali-Hasan-Al-Saegh, Omid Ghamarnejad.</p><p><bold>Project administration:</bold> Arianeb Mehrabi, Markus Mieth, Elias Khajeh.</p><p><bold>Review and editing:</bold> Karl Heinz Weiss, Christian Rupp, Sepehr Abbasi Dezfouli, Anastasia Lemekhova, Melisa Saracevic, Markus W. B&#x000fc;chler, Arianeb Mehrabi.</p><p><bold>Statistical design:</bold> Elias Khajeh, Ali Ramouz, Sadeq Ali-Hasan-Al-Saegh.</p><p><bold>Writing &#x02013; original draft:</bold> Elias Khajeh, Omid Ghamarnejad, Ali Ramouz, Ali Majlesara, Sadeq Ali-Hasan-Al-Saegh, Parnian Alamdari, Sepehr Abbasi Dezfouli.</p><p>All authors read and approved the final manuscript.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CNI = calcineurin inhibitors, CRF = case report form, LTx = liver transplantation, MELD = model for end-stage liver disease.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Khajeh E, Polychronidis G, Ramouz A, Alamdari P, Lemekhova A, Saracevic M, Ali-Hasan-Al-Saegh S, Ghamarnejad O, Majlesara A, Dezfouli SA, Nickkholgh A, Weiss KH, Rupp C, Mehrabi A, Mieth M. Evaluation of the impact of Tacrolimus-based immunosuppression on Heidelberg liver transplant cohort (HDTACRO): Study protocol for an investigator initiated, non-interventional prospective study. <italic>Medicine</italic>. 2020;99:39(e22180).</p></fn><fn fn-type=\"supported-by\"><p>This study is partially funded by Chiesi GmbH for quality control. This external financing will be used for logistics and organizational purposes only. The company will not be granted access to any source data. The investigators are not additionally compensated for the execution of the trial. Participants in the trial will not be financially supported or paid. Since the entire trial incorporates fully licensed and approved methods in the regular treatment course, no additional compensation for harmful outcomes is provided.</p></fn><fn fn-type=\"other\"><p>The HDTACRO study is currently recruiting participants.</p></fn><fn fn-type=\"other\"><p>This protocol study received approval from the independent Ethics Committee of the University of Heidelberg (registration number: S-630/18).</p></fn><fn fn-type=\"other\"><p>Provenance is not commissioned; externally peer reviewed.</p></fn><fn fn-type=\"COI-statement\"><p>The authors declare that they have no conflicts of interest.</p></fn><fn fn-type=\"other\"><p>Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Budde</surname><given-names>K</given-names></name><name><surname>Giessing</surname><given-names>M</given-names></name><name><surname>Liefeldt</surname><given-names>L</given-names></name><etal/></person-group>\n<article-title>Modern immunosuppression following renal transplantation. 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991486</article-id><article-id pub-id-type=\"pmc\">PMC7523858</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-10245</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022475</article-id><article-id pub-id-type=\"art-access-id\">22475</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>6200</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Bronchiectasis with secondary pulmonary infection in a child</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Zhu</surname><given-names>Ting</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Gu</surname><given-names>Haoxiang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Vinturache</surname><given-names>Angela</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Ding</surname><given-names>Guodong</given-names></name><degrees>MD, PhD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Lu</surname><given-names>Min</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Respiratory Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China</aff><aff id=\"aff2\"><label>b</label>Department of Obstetrics and Gynecology, Queen Elizabeth II Hospital, Alberta, Canada.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Min Lu, Department of Respiratory Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, 1400 West Beijing Road, Shanghai 200040, China (e-mail: <email>lum@shchildren.com.cn</email>); Guodong Ding, Department of Respiratory Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China (e-mail: <email>dingguodong@shchildren.com.cn</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22475</elocation-id><history><date date-type=\"received\"><day>1</day><month>1</month><year>2020</year></date><date date-type=\"rev-recd\"><day>7</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>31</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22475.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Although bronchiectasis is conventionally considered a chronic pulmonary disease of adulthood, knowledge of pediatric bronchiectasis not related to cystic fibrosis started to emerge. Limited information in this field is available and the management is based on expert opinion.</p></sec><sec><title>Patient concerns:</title><p>An 8-year-old girl admitted for 7 days history of wet cough, purulent fetid sputum, shortness of breath and low-grade fever. The wet cough has presented for the past 4 years, during which she had frequent hospitalization for recurrent lower respiratory tract infections.</p></sec><sec><title>Diagnosis:</title><p>Chest high-resolution computerized tomography revealed diffuse bronchial dilations accompanied by inflammation in the bilateral lung fields. Microbiologic investigation for bronchoalveolar lavage fluid was positive for <italic>Pseudomonas aeruginosa</italic>.</p></sec><sec><title>Interventions:</title><p>With a working diagnosis of bronchiectasis with secondary pulmonary infection, sensitive <italic>cefoperazone-sulbactam</italic> was administrated for 14 days with gradual improvement of clinical symptoms. Bronchoscopy washing substantially soothed the symptoms, reducing the cough and sputum volumes.</p></sec><sec><title>Outcomes:</title><p>The child was discharged after 14 days, and treated on long-term prophylactic antibiotic use (<italic>amoxicillin-clavulanic acid</italic>, 20&#x0200a;mg/kg/d, &#x02265; 4 weeks).</p></sec><sec><title>Lessons:</title><p>Although bronchiectasisis are condition in childhood, the diagnosis is suspected in children with persistent wet or productive cough, and should be confirmed by a chest high-resolution computerized tomography scan. Antibiotics and airway clearance techniques represent the milestones of bronchiectasis management although there are only a few guidelines in children.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>bronchiectasis</kwd><kwd>children</kwd><kwd>pulmonary infection</kwd><kwd>wet cough</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Bronchiectasis is a chronic pulmonary disease characterized by a progressive and often irreversible bronchial dilatation that presents clinically as chronic wet or productive cough accompanied by recurrent pulmonary exacerbations.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} The diagnosis is confirmed by a chest high-resolution computerized tomography (HRCT) scan. Although regarded as an orphan disease in high-income countries, bronchiectasis remains a major contributor to chronic respiratory morbidity in low- and middle-income countries.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Moreover, delays in diagnosis of bronchiectasis of years commonly occur in children, and it is likely that many remain undiagnosed and untreated, risking premature and accelerated pulmonary decline.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} In this article we presented a case of delayed diagnosis of bronchiectasis in a child that attended respirology services with an acute event of a secondary pulmonary infection. We discuss elements of pathobiology, diagnosis, and management of our patient in the context of the present knowledge of bronchiectasis in children.</p></sec><sec><label>2</label><title>Case presentation</title><p>An 8-year-old girl from a countryside community, Jiangsu province, Southeast China was admitted to the Department of Respiratory Medicine, Shanghai Children's Hospital, with complains of 7 days history of wet cough, purulent fetid sputum, shortness of breath, and low-grade fever (axillary temperature 37.8&#x000b0;C). Her mother reported that girl's symptoms initially presented at the age of 4, in the absence of obvious predisposing factors. Subsequently, recurrent respiratory exacerbations and lower respiratory tract infections occurred, requiring frequent hospitalizations in the local primary healthcare facilities of the province. The child had no other significant past medical history, no history of tuberculosis or HIV infection, and there was no family history of a similar condition. Physical examination showed chronic undernourishment [body mass index 11.3&#x0200a;kg/m², &#x0003c; 3th percentile (12.7&#x0200a;kg/m²) for age and sex according to the body mass index growth curves for Chinese children and adolescents aged 0&#x02013;18 years],^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} nail clubbing, and diffuse fine crackles on chest auscultation. Chest HRCT revealed diffuse bronchial dilations accompanied by inflammation in the bilateral lung fields (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>: Panel A). Immune function parameters including cellular and humoral immunity were within the normal range. Spirometry test demonstrated a mixed obstructive and restrictive airway pattern (VC_max1.03&#x0200a;L, FEV₁0.73&#x0200a;L/s, FVC 0.99 L, FEV₁/FVC 0.74, FEF_{25&#x02013;75}0.45&#x0200a;L/s). Flexible bronchoscopy showed an excess amount of thick and sticky mucus and inflammatory products within the bronchial lumen (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>: Panel B), and several aliquots of sterile normal saline were instilled into the most macroscopically inflamed bronchi and suctioned immediately into a mucus trap (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>: Panel C). Microbiologic investigation for bronchoalveolar lavage (BAL) fluid was positive for <italic>Pseudomonas aeruginosa</italic>. Genetic investigation was launched to identify the primary cause of bronchiectasis. Absence of mutations in <italic>DNAI1</italic>, <italic>DNAH5</italic>, and <italic>CFTR</italic> genes ruled out primary ciliary dyskinesia and cystic fibrosis (CF). With a working diagnosis of bronchiectasis with secondary pulmonary infection, sensitive <italic>cefoperazone-sulbactam</italic> (150&#x0200a;mg/kg/d) was administrated for 14 days with gradual improvement of clinical symptoms. Bronchoscopy washing substantially soothed the symptoms, reducing the cough and sputum volumes. The child was discharged on long-term prophylactic antibiotic use (<italic>amoxicillin-clavulanic acid</italic>, 20&#x0200a;mg/kg/d, &#x02265; 4 weeks). Immunizations including routine vaccinations and timely annual influenza and pneumococcal vaccinations according to national guidelines were recommended. Further genetic testing for alpha-1 antitrypsin deficiency and primary immunodeficiency was considered.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Chest high-resolution computerized tomography scan (A) and bronchoscopy (B and C) in an8-year-old girl with bronchiectasis. Dilatated bronchi and the adjacent blood vessels are visible, with the typical signet ring shape: cylindrical bronchiectasisis present (blue arrow), and varicose-to-cystic bronchiectasis is present (yellow arrow). Non-tapering of the bronchi is visible (green arrow), and visible bronchi adjacent to the mediastinal pleura or within the outer 1 to 2&#x0200a;cm of the lung fields are present (red arrow). Flexible bronchoscopy showed an excess amount of thick and sticky mucus and inflammatory products within the bronchial lumen (B) (white arrow), and several aliquots of sterile normal saline were instilled into the most macroscopically inflamed bronchi and suctioned immediately into a mucus trap (C) (white arrow).</p></caption><graphic xlink:href=\"medi-99-e22475-g001\"/></fig></sec><sec><label>3</label><title>Discussion and conclusion</title><p>Although bronchiectasis is conventionally considered a chronic pulmonary disease of adulthood, knowledge of pediatric bronchiectasis not related to CF started to emerge. Limited information in this field is available and the management is based on expert opinion.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Therefore, we discuss the elements of pathobiology, diagnosis, and management of our patient in the context of the present knowledge of bronchiectasis in children.</p><sec><label>3.1</label><title>Epidemiology</title><p>Epidemiological information on pediatric bronchiectasis is scarce, with large variability in the incidence rate of the disease reported worldwide (0.2&#x02013;735.0 cases per 1,00,000 children).^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Although the prevalence of bronchiectasis has declined significantly in most developed countries, in socially disadvantaged indigenous pediatric populations in high-income countries, and by extrapolation, for children in low- and middle-income countries, where there is overcrowding, poor hygiene, and limited access to healthcare, the prevalence remains high.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} In China, the reported prevalence of bronchiectasisis of 1200 per 1,00,000 adults &#x0003e;40 years of age;^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} however, the prevalence in children is unknown.</p></sec><sec><label>3.2</label><title>Etiology</title><p>Pediatric bronchiectasis has multiple etiologies and is often associated with other diseases. A systematic review of non-CF bronchiectasis in children found that 63% had an identifiable underlying cause. Previous pneumonia and recurrent lower airway infections were the most common causes; others risk factors included primary immune deficiencies, primary ciliary dyskinesia, foreign body aspiration, and structural airways abnormalities.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} With the universal national immunization program and effective anti-tuberculosis therapy, the major causes of bronchiectasis have shifted from pertussis, measles, and tuberculosis to bacterial, mycoplasmal, and viral pneumonia during the past 5 decades.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} The child in our case is from a rural, economically disadvantaged background, suffering of previous pneumonia and recurrent lower airway infections. At present we cannot infer if the repeated respiratory infections were the cause of bronchiectasis in this child, but it is likely they acted as promoting, if not etiological factors in the progression of the disease. The malnutrition and possible suboptimal management of the respiratory tract infections in the primary care facilities may have contributed in the persistence of chronic respiratory changes and recurrence of symptoms.</p></sec><sec><label>3.3</label><title>Diagnosis</title><p>The clinical features of pediatric bronchiectasis are different from the adult and vary considerably, depending on age, disease severity, and clinical setting. Chronic cough is the most dominant and consistent symptom. Of note, as young children usually do not expectorate, the cough is rather wet than productive. Other clinical findings include exertional dyspnea, recurrent wheezing, digital clubbing, chest wall deformity, failure to thrive, and haemoptysis.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} In our study, the patient exhibited recurrent wet cough for several years, which was accompanied by exertional dyspnea, digital clubbing, and malnutrition. The child presented in our service, however, with what we considered to be an exacerbation of the disease. There is no validated definition of exacerbation in pediatric bronchiectasis. Exacerbation criteria used in adults (increased cough, sputum volume and worsening of purulence) are less useful in children who are often unable to expectorate. As defined elsewhere, we used the increase in cough frequency and changes in its features, and the increase in crepitations and wheezing on chest auscultation as clinical indicators of exacerbation.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]}</p><p>Presence of the signet ring sign (increased broncho-arterial ratio) is the pathognomonic sign of bronchiectasis on chest HRCT scans, the gold standard diagnostic tool. In children, a ratio &#x0003e; 0.8 is considered typical sign of bronchiectasis,^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} as shown in our case. The scan showed additional radiological signs indicative of bronchiectasis: bronchial wall thickening and lack of bronchial tapering due to diffuse bronchial inflammation in both lungs, and bronchi visible close to the pleural surface.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} Of note, scans may appear normal due to suboptimal imaging or motion artefact.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Therefore, bronchiectasis diagnosis should not be based purely on radiographic criteria but should be supported by relevant clinical history and findings.</p><p>Although spirometry is challenging to perform in children, it may provide useful functional information on disease severity. Spirometry can diagnose either an obstructive or mixed obstructive/restrictive airflow pattern, the child from our report showing the mixed pattern of disease.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]}</p></sec><sec><label>3.4</label><title>Management</title><p>Bronchiectasis requires multidisciplinary management in order to control symptoms, reduce exacerbations, and preserve lung function. Antibiotics and airway clearance techniques represent the milestones of bronchiectasis management, although there are only a few guidelines in children.</p><p>Antibiotics are prescribed to treat acute exacerbations or as prophylaxis to reduce the frequency of acute events and diminish the bacterial load and inflammation. The use and choice of antibiotics is guided by severity of exacerbations and microbiology results of the sputum culture and, whenever possible, by the BAL culture. The most commonly isolated bacteria in children are <italic>Haemophilus influenzae</italic>, <italic>Streptococcus pneumonia</italic>, and <italic>Moraxella catarrhalis.</italic>^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]}<italic>Pseudomonas aeruginosa</italic> and <italic>Staphylococcus aureus</italic> are more often detected in older children or associated with underlying diseases with increased lung damage.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} In the present study, <italic>Pseudomonas aeruginosa</italic> isolated from the BAL culture was treated with cephalosporins with gradual improvement of symptomatology.</p><p>It is unclear which pediatric patients are more likely to benefit from long-term antibiotics and what is the optimum duration of the antibiotic treatment. A course of at least 10&#x02013;14 days of parenteral antibiotic administration was recommended for children in whom the oral course fail to control the acute exacerbations.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} A recent review of 15 studies including 925 adults and children with non-CF bronchiectasis showed that a prolonged course of antibiotics (&#x02265;4 weeks) reduced the rates of exacerbations and hospitalization, although the risk of drug resistance also increased more than 3 fold.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]}</p><p>Despite lacking a robust evidence-based clinical efficacy, numerous airway clearance techniques are used for stable or in exacerbations of bronchiectasis.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>,<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} A Cochrane review concluded that airway clearance techniques appear to be safe for children and adults with stable bronchiectasis, improving sputum expectoration, lung function, and health-related quality of life.^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} In our study, bronchoscopy washing soothed the symptoms, reducing the cough and sputum volumes, suggesting that BAL may be another direct and effective method to improve airway clearance and shorten the duration of illness.</p><p>Immunization and prevention of infections are integral part of the management in childhood. Measles, pertussis, seasonal influenza, Haemophilus influenzae type B, and pneumococcal vaccines should be recommended.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>,<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} The vaccination status was reviewed in our patient and an immunization plan was devised. Surgical intervention (segmentectomy, lobectomy) is uncommon in children. Our patient was not a candidate for this surgical management as she had no severe damage or localized bronchiectasis and responded well to medical therapy.</p><p>Although bronchiectasisis are condition during childhood, the diagnosis should be considered in children with persistent symptomatology. The diagnosis is confirmed by a chest HRCT scan. Antibiotics and airway clearance techniques represent the milestones of bronchiectasis management although there are only a few guidelines in children.</p></sec></sec><sec><title>Author contributions</title><p><bold>Conceptualization</bold>: Min Lu, Guodong Ding.</p><p><bold>Resources</bold>: Haoxiang Gu.</p><p><bold>Validation</bold>: Haoxiang Gu.</p><p><bold>Supervision</bold>: Guodong Ding, Min Lu</p><p><bold>Visualization</bold>: Guodong Ding, Min Lu.</p><p><bold>Writing &#x02013; original draft</bold>: Ting Zhu.</p><p><bold>Writing &#x02013; review and editing</bold>: Angela Vinturache.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: BAL = bronchoalveolar lavage, CF = cystic fibrosis, HRCT = high-resolution computerized tomography.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Zhu T, Gu H, Vinturache A, Ding G, Lu M. Bronchiectasis with secondary pulmonary infection in a child: a case report. <italic>Medicine</italic>. 2020;99:39(e22475).</p></fn><fn fn-type=\"other\"><p>Ethics approval and consent to participate was no approval was required by the institutional review board at Shanghai Children's Hospital.</p></fn><fn fn-type=\"other\"><p>Written informed consent was obtained from the parent for the publication of this case report.</p></fn><fn fn-type=\"other\"><p>The data and materials used in this study are available from the first author on reasonable request.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no funding and conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991430</article-id><article-id pub-id-type=\"pmc\">PMC7523859</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-06346</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022284</article-id><article-id pub-id-type=\"art-access-id\">22284</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>7100</subject></subj-group><subj-group><subject>Research Article</subject><subject>Systematic Review and Meta-Analysis</subject></subj-group></article-categories><title-group><article-title>Plate fixation versus intramedullary nail or Knowles pin fixation for displaced midshaft clavicle fractures</article-title><subtitle>A meta-analysis of randomized controlled trials</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Li</surname><given-names>Lang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yang</surname><given-names>Xiaodong</given-names></name><degrees>Master</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Xing</surname><given-names>Fei</given-names></name><degrees>Master</degrees><xref ref-type=\"aff\" rid=\"aff2\">^b</xref></contrib><contrib contrib-type=\"author\"><name><surname>Jiang</surname><given-names>Jun</given-names></name><degrees>Master</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref></contrib><contrib contrib-type=\"author\"><name><surname>Tang</surname><given-names>Xueyang</given-names></name><degrees>MD</degrees><xref ref-type=\"aff\" rid=\"aff1\">^a</xref><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Li.</surname><given-names>Yan</given-names></name></contrib></contrib-group><aff id=\"aff1\"><label>a</label>Department of Pediatric Surgery</aff><aff id=\"aff2\"><label>b</label>Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Xueyang Tang, Department of Pediatric Surgery, West China Hospital, Sichuan University, 37, Guo Xue Xiang, Chengdu 610041, Sichuan, P.R. China (e-mail: <email>xueyangtwch@163.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22284</elocation-id><history><date date-type=\"received\"><day>12</day><month>8</month><year>2019</year></date><date date-type=\"rev-recd\"><day>31</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>19</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22284.pdf\"/><abstract><title>Abstract</title><sec sec-type=\"background\"><title>Background:</title><p>Plate fixation and intramedullary nail/Knowles pin fixation methods are commonly used to treat displaced midshaft clavicle fractures. However, the differences between these 2 methods are unclear.</p></sec><sec><title>Objective:</title><p>This meta-analysis aimed to compare plate fixation and intramedullary nail/Knowles pin fixation for displaced midshaft clavicle fractures.</p></sec><sec sec-type=\"methods\"><title>Methods:</title><p>We searched PubMed, EBM reviews, and Ovid Medline online for studies related to comparison of plate fixation versus intramedullary nail/Knowles pin fixation for displaced midshaft clavicle fracture from inception to June 30, 2019. Relevant literature search, data extraction, and quality assessment will be performed by 2 researchers independently. The methodological quality of all included studies was appraised using the Cochrane system for randomized trials. The RevMan 5.2 software was used for heterogeneity assessment, generating funnel-plots, data synthesis, sensitivity analysis, and determining publication bias. The fixed-effects or random-effects model was used to calculate mean difference (MD)/relative risks (RRs) and 95% confidence intervals (CIs).</p></sec><sec sec-type=\"results\"><title>Results:</title><p>This meta-analysis included 839 patients from 12 randomized controlled trials. We found that compared to plate fixation, intramedullary nail/Knowles pin fixation yielded a higher shoulder constant score [MD = &#x02212;2.43, 95% CI (&#x02212;3.46 to &#x02212;1.41), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001] and lower disabilities of the arm, shoulder and hand (DASH) score [MD = 2.98, 95% CI (0.16&#x02013;5.81), <italic>P</italic>&#x0200a;=&#x0200a;.04], and lower infection rates [RR&#x0200a;=&#x0200a;2.05, 95% CI (1.36&#x02013;3.09), <italic>P</italic>&#x0200a;=&#x0200a;.003], operation time [MD&#x0200a;=&#x0200a;20.20, 95% CI (10.80&#x02013;29.60), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.0001], incision size [MD&#x0200a;=&#x0200a;6.09, 95% CI (4.54&#x02013;7.65), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001], and hospital stay [MD&#x0200a;=&#x0200a;1.10, 95% CI (0.56&#x02013;1.64), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001] but with a higher removal rate [RR&#x0200a;=&#x0200a;0.52, 95% CI (0.41&#x02013;0.65), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001] compared to plate fixation. There were no significant differences in nonunion, reintervention, or revision and refracture between these two methods. The limitation is that many studies did not demonstrate the random generated details, and only English articles were enrolled in this meta-analysis.</p></sec><sec sec-type=\"conclusion\"><title>Conclusions:</title><p>Intramedullary nail/Knowles pin fixation might be an optimum choice for treating displaced midshaft clavicle fractures, with similar performance in terms of the nonunion, reintervention, or revision and refracture, and better shoulder constant and DASH scores, infection rates, and operative parameters.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>clavicle</kwd><kwd>intramedullary</kwd><kwd>meta-analysis</kwd><kwd>plate</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>Sichuan Province Science and Technology Support Program</funding-source><award-id>2019YFS0265</award-id><principal-award-recipient>Xueyang Tang</principal-award-recipient></award-group><award-group id=\"award2\" award-type=\"Fundref\"><funding-source>Post-Doctor Research Project of Sichuan university</funding-source><award-id>2019SCU12034</award-id><principal-award-recipient>Lang Li</principal-award-recipient></award-group><award-group id=\"award3\" award-type=\"Fundref\"><funding-source>Post-Doctor Research Project, West China Hospital, Sichuan University</funding-source><award-id>2018HXBH076</award-id><principal-award-recipient>Lang Li</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Approximately 80% of all clavicle fractures commonly reported in adults are concentrated in the middle (midshaft) of the clavicle.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Displaced midshaft clavicle fractures are managed using conventional, nonsurgical treatments in the past.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>,<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} Recently, there has been a shift toward surgical treatments, enabling a reduction in nonunion and malunion, with improved shoulder function.^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>&#x02013;<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Thus, surgical treatment has become a popular option for displaced midshaft clavicle fractures.</p><p>Both plate and intramedullary nail/Knowles pin fixation have been commonly used as surgical treatments.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>,<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} However, plate and intramedullary nail fixation have different characteristics.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Although several retrospective and randomized controlled trial (RCTs) studies have compared plate and intramedullary nail fixation, the optimal treatment method remains controversial.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>&#x02013;<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} In addition, some systematic reviews have reported the safety and effectiveness of plate and intramedullary nail/Knowles pin.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>&#x02013;<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} However, Zhang et al^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} reviewed only 4 RCTs and Hussain et al^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} compared 7 RCTs and 3 quasirandomized trials, but we found that the complications were divided into 2 major categories, those requiring or not requiring surgery. Therefore, it was impossible to conclude the differences in complications between the 2 treatment methods. In addition, the removal rate has not been reported in previous systematic reviews or meta-analysis.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>,<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]}</p><p>In order to know more about 2 methods, the objective of this meta-analysis was to compare the shoulder constant score; disabilities of the arm, shoulder, and hand (DASH) score; complications; operation time; incision size; hospital stay; and removal rate of plate and intramedullary/Knowles pin fixation for the RCTs of displaced midshaft clavicle fractures in patients.</p></sec><sec><label>2</label><title>Methods</title><sec><label>2.1</label><title>Eligibility criteria and literature search</title><p>This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.^{[<xref rid=\"R21\" ref-type=\"bibr\">21</xref>]} The process of article selection is shown in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>. We searched PubMed, EBM, and Ovid Medline online from inception to June 30, 2019, using the medical subject heading (MESH): clavicle, clavicular, plate, plating, pin, intramedullary, and Knowles pin. All studies related to comparison of plate and intramedullary nail/Knowles pin fixation for displaced midshaft clavicle fractures were screened. The bibliographies and citations of each relevant article were reviewed to ensure that no article was missed. As a secondary analysis of the original research, the ethical approval was not necessary for this study.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flow chart of the literature.</p></caption><graphic xlink:href=\"medi-99-e22284-g001\"/></fig><p><bold>I</bold>nclusion criteria for this study were patients (age &#x0003e;16 years) diagnosed with displaced midshaft clavicle fracture; intervention: patients treated with plate fixation; comparison treatment: patients treated with intramedullary nail/Knowles pin; outcome: related studies reported operation time, hospital time, shoulder constant score, DASH score, removal rate, and complications; study design: only RCTs were included; and language limited to English. Exclusion criteria were systematic review, case report, repeated published study, and retrospective and prospective cohort studies; studies without full-text available; and presence of pathological fractures.</p></sec><sec><label>2.2</label><title>Outcome of interest</title><p>The primary outcomes of this meta-analysis were shoulder constant score, DASH score, and complications. We divided complications into 4 categories: nonunion, reintervention or revision, refracture, and infection. The secondary outcomes were operation time, incision size, hospital stay, and removal rate.</p></sec><sec><label>2.3</label><title>Data extraction and quality assessment</title><p>All data were extracted independently by 2 reviewers according to the selection criteria (LL and FX), any disagreements were discussed and documented. Data on design type, age, sex sample size, length of follow-up, interventions, and outcomes of interest were independently extracted by 2 researchers. For quality assessment of included studies, the Cochrane system^{[<xref rid=\"R22\" ref-type=\"bibr\">22</xref>]} was used. Selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), and reporting bias (selective reporting) and other sources of bias were used to evaluate the quality of included studies.</p></sec><sec><label>2.4</label><title>Statistical analysis</title><p>The RevMan software (Version 5.2, The Nordic Cochrane Centre, The Cochrane Collaboration, 2013) was used for meta-analysis and determining publication bias. For continuous variables, the MD and 95% confidence intervals (CIs) were reported. For dichotomous variables, the relative risk (RR) and 95% CI were reported. If the heterogeneity of meta-analysis results was small (<italic>I</italic>²&#x0200a;&#x0003c;&#x0200a;50%), the fixed effect model was used. If <italic>I</italic>²&#x0200a;&#x0003e;&#x0200a;50%, the random effect model was used. Sensitivity analysis was also conducted when <italic>I</italic>²&#x0200a;&#x0003e;&#x0200a;50%. Publication bias was also evaluated using the RevMan software. <italic>P</italic> values of &#x0003c;.05 were considered statistically significant.</p></sec></sec><sec><label>3</label><title>Results</title><sec><label>3.1</label><title>Characteristics and methodological quality of included studies</title><p>The search strategy, according to PRISMA, is shown in Figure <xref ref-type=\"fig\" rid=\"F1\">1</xref>. After screening 308 studies, 12 RCTs^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>&#x02013;<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} that enrolled 839 patients with displaced midshaft clavicle fractures were included, the characteristics of included studies are shown in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>. Five studies^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} reported the random sequence generation, 8 studies^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R24\" ref-type=\"bibr\">24</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>&#x02013;<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} reported allocation concealment, no studies reported blinding of participants and personnel and outcome assessment, 11 studies^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>&#x02013;<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R28\" ref-type=\"bibr\">28</xref>&#x02013;<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} reported complete outcomes, and 10 studies^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>&#x02013;<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} reported low reporting bias. The details are shown in Figure <xref ref-type=\"fig\" rid=\"F2\">2</xref>.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>characteristics of included studies.</p></caption><graphic xlink:href=\"medi-99-e22284-g002\"/></table-wrap><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Summary of the bias risk of included studies.</p></caption><graphic xlink:href=\"medi-99-e22284-g003\"/></fig></sec><sec><label>3.2</label><title>Shoulder constant and DASH scores</title><p>The shoulder constant score was reported in 10 studies that enrolled 674 patients^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>&#x02013;<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R31\" ref-type=\"bibr\">31</xref>&#x02013;<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} of whom 326 were treated with plate fixation and the remaining 348 were treated with intramedullary nail/Knowles pin fixation. There was obvious heterogeneity (<italic>I</italic>²&#x0200a;=&#x0200a;84%), whereas no significant differences were observed between the 2 methods (<italic>P</italic>&#x0200a;=&#x0200a;.32) (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>A). When 3 studies^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} were excluded from the analysis, the heterogeneity decreased to 0% and a fixed effect model was conducted, which indicated that intramedullary nail/Knowles pin fixation could significantly improve the shoulder constant score significantly [MD&#x0200a;=&#x0200a;&#x02212;2.43, 95% CI (&#x02212;3.46&#x02013;1.41), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.000 01] (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>B). The DASH score was reported in 5 studies involving 360 patients,^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} and our analysis found that intramedullary nail/Knowles pin fixation showed significantly better shoulder function than plate fixation [MD&#x0200a;=&#x0200a;2.98, 95% CI (0.16&#x02013;5.81), <italic>P</italic>&#x0200a;=&#x0200a;.04, <italic>I</italic>²&#x0200a;=&#x0200a;89%] (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>C). We conducted sensitivity analysis by eliminating each study one by one while the heterogeneity was stable.</p><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Forest plot for the constant score (A); sensitive analysis of constant score (B); and disabilities of the arm, shoulder, and hand (DASH) score (C). CI = confidence interval, SD = standard deviation.</p></caption><graphic xlink:href=\"medi-99-e22284-g004\"/></fig></sec><sec><label>3.3</label><title>Complications</title><p>All studies included in the meta-analysis comprising 2822 fractures (1374 treated with plate and 1448 treated with intramedullary nail/Knowles pin fixation) were analyzed for complications, such as nonunion, reintervention, or revision, refracture, and infection. The fixed effects model was used to analyze the complications associated with both the fixation methods, and our analysis revealed that the incidence rate of complications, particularly infection rates [RR&#x0200a;=&#x0200a;3.22, 95% CI (1.48&#x02013;7.01), <italic>P</italic>&#x0200a;=&#x0200a;.003, <italic>I</italic>²&#x0200a;=&#x0200a;0%] associated with plate fixation, was significantly higher [RR&#x0200a;=&#x0200a;2.05, 95% CI (1.36&#x02013;3.09), <italic>P</italic>&#x0200a;=&#x0200a;.0006, <italic>I</italic>²&#x0200a;=&#x0200a;0%] than those associated with intramedullary nail/Knowles pin fixation. However, there were no significant differences in nonunion (<italic>P</italic>&#x0200a;=&#x0200a;.53), reintervention or revision (<italic>P</italic>&#x0200a;=&#x0200a;.14), and refracture (<italic>P</italic>&#x0200a;=&#x0200a;.14), between these 2 fixation methods (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>). Although publication bias was detected, there were no significant bias existed (Fig. <xref ref-type=\"fig\" rid=\"F5\">5</xref>).</p><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>Forest plot for the complications including nonunion, reintervention or revision, refracture, and infection. CI = confidence interval, SD = standard deviation.</p></caption><graphic xlink:href=\"medi-99-e22284-g005\"/></fig><fig id=\"F5\" orientation=\"portrait\" position=\"float\"><label>Figure 5</label><caption><p>Funnel plot of the publication bias. RR = relative risk.</p></caption><graphic xlink:href=\"medi-99-e22284-g006\"/></fig></sec><sec><label>3.4</label><title>Operation time, incision size, and hospital stay</title><p>Six studies^{[<xref rid=\"R25\" ref-type=\"bibr\">25</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R27\" ref-type=\"bibr\">27</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} that enrolled 409 patients reported operation time and concluded that the operation time was longer with plate fixation for displaced midshaft clavicle fracture than with intramedullary nail/Knowles pin fixation [MD&#x0200a;=&#x0200a;20.20, 95% CI (10.80&#x02013;29.60), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, <italic>I</italic>²&#x0200a;=&#x0200a;94%] (Fig. <xref ref-type=\"fig\" rid=\"F6\">6</xref>A). Five studies^{[<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R28\" ref-type=\"bibr\">28</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} that reported incision size in 338 patients found that intramedullary nail/Knowles pin fixation decreased the incision size significantly [MD&#x0200a;=&#x0200a;6.09, 95% CI (4.54&#x02013;7.65), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, <italic>I</italic>²&#x0200a;=&#x0200a;97%] (Fig. <xref ref-type=\"fig\" rid=\"F6\">6</xref>B). Five studies^{[<xref rid=\"R23\" ref-type=\"bibr\">23</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R27\" ref-type=\"bibr\">27</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R33\" ref-type=\"bibr\">33</xref>]} that reported hospital stay in 285 patients found that hospital stay after plate fixation was significantly longer than it was after intramedullary nail/Knowles pin fixation group [MD&#x0200a;=&#x0200a;1.10, 95% CI (0.56&#x02013;1.64), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.0001, <italic>I</italic>²&#x0200a;=&#x0200a;82%] (Fig. <xref ref-type=\"fig\" rid=\"F6\">6</xref>C). We conducted sensitive analysis for operation time, incision size, and hospital stay. For operation time and incision size, we found that the heterogeneity was stable when each study was eliminated one by one. For hospital stay, one study^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} was found to contribute to the heterogeneity. After exclusion of this study, no significant difference was observed between the 2 fixation methods with no heterogeneity [MD 0.73, 95% CI (0.53&#x02013;0.93), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, <italic>I</italic>²&#x0200a;=&#x0200a;36%].</p><fig id=\"F6\" orientation=\"portrait\" position=\"float\"><label>Figure 6</label><caption><p>Forest plot for the operation time (A), incision size (B) and hospital stay (C). CI = confidence interval, SD = standard deviation.</p></caption><graphic xlink:href=\"medi-99-e22284-g007\"/></fig></sec><sec><label>3.5</label><title>Removal rate</title><p>A second surgery could increase several risks and increase the economic burden on the patient. Removal rates were reported for 594 patients in 8 studies,^{[<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R27\" ref-type=\"bibr\">27</xref>,<xref rid=\"R29\" ref-type=\"bibr\">29</xref>&#x02013;<xref rid=\"R32\" ref-type=\"bibr\">32</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} and our analysis showed a higher removal rate with intramedullary nail/Knowles pin fixation than with plate fixation [RR&#x0200a;=&#x0200a;0.55, 95% CI (0.34&#x02013;0.87), <italic>P</italic>&#x0200a;=&#x0200a;.01, <italic>I</italic>²&#x0200a;=&#x0200a;78%] (Fig. <xref ref-type=\"fig\" rid=\"F7\">7</xref>A). We found 2 studies^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} that contributed to the heterogeneity. After exclusion of these studies, we found no significant difference was observed between the 2 fixation methods with no heterogeneity (RR 0.52, 95% CI (0.41&#x02013;0.65), <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.00001, <italic>I</italic>²&#x0200a;=&#x0200a;0%) (Fig. <xref ref-type=\"fig\" rid=\"F7\">7</xref>B).</p><fig id=\"F7\" orientation=\"portrait\" position=\"float\"><label>Figure 7</label><caption><p>Forest plot of the removal rate (A) and sensitive analysis of removal rate (B). CI = confidence interval, SD = standard deviation.</p></caption><graphic xlink:href=\"medi-99-e22284-g008\"/></fig></sec></sec><sec><label>4</label><title>Discussion</title><p>In this study, we found that compared with plate fixation, intramedullary nail/Knowles pin fixation offered several complications related to operation time, incision size, hospital stay, shoulder constant score, and DASH scores and was associated with a higher removal rate and a fewer infections compared to plate fixation. Nonunion, refracture, and reintervention were comparable between the 2 methods.</p><p>Recently, some previous meta-analysis have been reported the comparison of plate versus intramedullary nail//Knowles pin fixation.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>,<xref rid=\"R19\" ref-type=\"bibr\">19</xref>,<xref rid=\"R20\" ref-type=\"bibr\">20</xref>,<xref rid=\"R35\" ref-type=\"bibr\">35</xref>,<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} Gao et al^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} reported only 6 RCTs and Duan et al^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} reported only 4 RCTs. Compared with study by Gao et al^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} and Duan et al,^{[<xref rid=\"R17\" ref-type=\"bibr\">17</xref>]} our meta-analysis included 12 RCTs. For shoulder constant score, the heterogeneity decreased from 84% to 0% after eliminating 3 studies,^{[<xref rid=\"R24\" ref-type=\"bibr\">24</xref>,<xref rid=\"R26\" ref-type=\"bibr\">26</xref>,<xref rid=\"R34\" ref-type=\"bibr\">34</xref>]} thus improving the shoulder constant score with the intramedullary nail fixation, which is consistent with the findings reported by Zhu et al.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} For DASH scores, compared with plate fixation, intramedullary nail/Knowles pin fixation resulted in significantly lower scores despite the high heterogeneity (<italic>I</italic>²&#x0200a;=&#x0200a;89%). The heterogeneity was stable after eliminating each included study, which may be due to data subjectivity as well as not blinding. However, we found that the DASH score with intramedullary nail/Knowles pin fixation for all the 5 studies was less than that with plate fixation, although without significance, which may be because of the sample size being too small.</p><p>In addition to the functional assessment, Surgeons also paid more attention to complications. A review by Barlow et al^{[<xref rid=\"R18\" ref-type=\"bibr\">18</xref>]} indicated a trend toward a lower complication rate with intramedullary fixation. However, we found that the major complications included wound infection, nonunion, and implant failures; therefore, we could not determine the details of each type of complications. In our study, we divided complications into nonunion, reintervention or revision, refracture, and infection, which could provide more details for clinicians. Although the incidence rates of nonunion, reintervention or revision, and refracture with the 2 fixation methods are similar and consistent with previously reported incidence rates of nonunion at 12 and 24 weeks^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} and refracture.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} However, the reason of these complications is not the same in the 2 fixation methods. For plate fixation, the implant failure is mainly caused by excessive movements, which caused the plate to bend or even break. For intramedullary nail/Knowles pin fixation, the lack of stability caused migration of the intramedullary nail/Knowles pin device. The higher infection rate associated with plate fixation versus intramedullary nail fixation in our meta-analysis was consistent with that reported by a previous study.^{[<xref rid=\"R19\" ref-type=\"bibr\">19</xref>]} We believe that this is because the plate fixation usually requires a larger incision, wider exposure, more soft tissue dissection, and longer operation time, which increases the incidence of infection. The surgical treatment of displaced midshaft clavicle fractures could be considered a 2-stage process. Intramedullary nail/Knowles pin fixation usually requires a secondary surgery, which is not the case with plate fixation. In our meta-analysis, the number of patients who required implant removal after intramedullary nail/Knowles pin fixation was twice the number of patients who required plate fixation, and this was mainly due to pain from the nail's entry portal, which was related to the protruding nail's instability.^{[<xref rid=\"R30\" ref-type=\"bibr\">30</xref>]}</p><p>Our findings related to operation time, incision size, and hospital stay were consistent with those reported by a previous study.^{[<xref rid=\"R20\" ref-type=\"bibr\">20</xref>]} We observed significance in operation time and incision size when a sensitivity analysis was performed by eliminating each study that was included in the meta-analysis, indicating the reliability and validity of our findings. Regarding the hospital stay, when one study^{[<xref rid=\"R27\" ref-type=\"bibr\">27</xref>]} was excluded, the heterogeneity decreased from 82% to 36%. We believe that this may be due to different hospital management systems, such that the hospital stay is significantly longer than that reported by other hospitals.</p><p>The present study had some strengths. First, compared with previous review studies,^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>,<xref rid=\"R16\" ref-type=\"bibr\">16</xref>,<xref rid=\"R37\" ref-type=\"bibr\">37</xref>,<xref rid=\"R38\" ref-type=\"bibr\">38</xref>]} the present study enrolled 3 recent studies,^{[<xref rid=\"R29\" ref-type=\"bibr\">29</xref>,<xref rid=\"R30\" ref-type=\"bibr\">30</xref>,<xref rid=\"R32\" ref-type=\"bibr\">32</xref>]} and 12 trials in total were enrolled. Second, the present study had a prospective randomized controlled design with a longer follow-up duration of 12 to 66 months for enrolled trials. Third, the complications were divided into nonunion, reinvention or revision, infection, and refracture, which provided more guidance for surgeons involved in these procedures unlike that in other studies.^{[<xref rid=\"R36\" ref-type=\"bibr\">36</xref>]} However, the present study also had some limitations. First, some RCTs included in this study did not demonstrate the random generated details. Second, the duration of follow-up was not consistent in all the included studies and the shoulder function in early stage and late stage was different than that in a previous study.^{[<xref rid=\"R39\" ref-type=\"bibr\">39</xref>]} Third, the present meta-analysis enrolled only full-text articles in English, which could lead to selection bias.</p><p>Intramedullary nail/Knowles pin fixation could improve shoulder function and have lower infection. Considering the better performance of intramedullary nail/Knowles pin fixation for displaced midshaft clavicle fractures, we recommend this procedure as the first choice for treatment. However, RCTs with good methodology should be performed in the future due to some limitations in the current evidence.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Xueyang Tang.</p><p><bold>Data curation:</bold> Lang Li, Fei Xing.</p><p><bold>Formal analysis:</bold> Lang Li, Fei Xing.</p><p><bold>Funding acquisition:</bold> Lang Li, Xueyang Tang.</p><p><bold>Investigation:</bold> Fei Xing.</p><p><bold>Methodology:</bold> Lang Li, Fei Xing.</p><p><bold>Project administration:</bold> Xueyang Tang.</p><p><bold>Resources:</bold> Xiaodong Yang, Xueyang Tang.</p><p><bold>Software:</bold> Fei Xing.</p><p><bold>Supervision:</bold> Jun Jiang.</p><p><bold>Writing &#x02013; original draft:</bold> Lang Li.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Lang Li, Xueyang Tang.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CI = confidence interval, DASH = disabilities of the arm, shoulder and hand, MD = mean difference, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analysis, RCT = randomized controlled trial, RR = relative risk.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Li L, Yang X, Xing F, Jiang J, Tang X. Plate fixation versus intramedullary nail or Knowles pin fixation for displaced midshaft clavicle fractures: A meta-analysis of randomized controlled trials. <italic>Medicine</italic>. 2020;99:39(e22284).</p></fn><fn fn-type=\"supported-by\"><p>The study was supported by International cooperation project of Sichuan provincial science and technology department (2019YFS0265), Post-Doctor Research Project of Sichuan University (2019SCU12034) and Post-Doctor Research Project, West China Hospital, Sichuan University (2018HXBH076).</p></fn><fn fn-type=\"other\"><p>Plate fixation versus intramedullary nail or Knowles pin fixation for displaced midshaft clavicle fractures :a meta-analysis of randomized controlled trials.</p></fn><fn fn-type=\"COI-statement\"><p>The authors have no conflicts of interest to disclose.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991434</article-id><article-id pub-id-type=\"pmc\">PMC7523865</article-id><article-id pub-id-type=\"publisher-id\">MD-D-19-09985</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022298</article-id><article-id pub-id-type=\"art-access-id\">22298</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>4500</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Multi-donor multi-course faecal microbiota transplantation relieves the symptoms of chronic hemorrhagic radiation proctitis</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Zheng</surname><given-names>Ya-Mei</given-names></name><degrees>MS</degrees></contrib><contrib contrib-type=\"author\"><name><surname>He</surname><given-names>Xing-Xiang</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Xia</surname><given-names>Harry Hua-Xiang</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Yuan</surname><given-names>Yu</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Xie</surname><given-names>Wen-Rui</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Cai</surname><given-names>Jie-Yi</given-names></name><degrees>MS</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Xu</surname><given-names>Jia-Ting</given-names></name><degrees>MS</degrees></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0003-4674-8287</contrib-id><name><surname>Wu</surname><given-names>Li-Hao</given-names></name><degrees>MD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff>Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Li-Hao Wu, Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, 19 Nonglin Road, Yuexiu District, Guangzhou 510080, Guangdong Province, China (e-mail: <email>wulihao888@126.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22298</elocation-id><history><date date-type=\"received\"><day>5</day><month>1</month><year>2020</year></date><date date-type=\"rev-recd\"><day>28</day><month>7</month><year>2020</year></date><date date-type=\"accepted\"><day>21</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22298.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>There are many treatments for chronic hemorrhagic radiation colorectal inflammation, but only a few treatments are supported by high-quality research evidence. Studies have shown that the occurrence and development of radiation proctitis are closely associated with the intestinal flora. Animal studies have indicated that faecal microbiota transplantation (FMT) can improve radiation enteropathy in a mouse model.</p></sec><sec><title>Patient concerns:</title><p>A 45-year-old female patient suffered from recurrent hematochezia and diarrhea for half a year after radiotherapy and underwent recurrent transfusion treatments. Colonoscopy showed obvious congestion of the sigmoid colon and rectal mucosa, a smooth surface, and bleeding that was easily induced by touch, which are consistent with radiation proctitis. The pathological findings revealed chronic mucosal inflammation. The magnetic resonance imaging examination of the pelvic cavity with a plain scan and enhancement showed changes after radiotherapy and chemotherapy, and no obvious tumor recurrence or metastasis was found. The laboratory examinations excluded pathogen infection.</p></sec><sec><title>Diagnoses:</title><p>Based on the history and examinations, the final diagnosis of this patient was chronic hemorrhagic radiation proctitis.</p></sec><sec><title>Interventions:</title><p>The patient was treated with a total of 4 individual courses of FMT.</p></sec><sec><title>Outcomes:</title><p>After the six-month follow-up, her hematochezia, abdominal pain and diarrhea were relieved. Furthermore, 16S rRNA sequencing of the feces showed that the intestinal bacterial composition of the patient obviously changed after FMT and became similar to that of the donors.</p></sec><sec><title>Lessons:</title><p>This case report shows that FMT can relieve the symptoms of hematochezia and diarrhea by changing the bacterial community structure in patients with chronic hemorrhagic radiation proctitis.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>chronic hemorrhagic radiation proctitis</kwd><kwd>faecal microbiota transplantation</kwd><kwd>intestinal bacteria</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>The main clinical manifestations of chronic hemorrhagic radiation proctitis include hematochezia, diarrhea, tenesmus, rectal stricture, bowel fistula, and anal incontinence, and these symptoms usually occur several months after pelvic radiotherapy for pelvic cancer. The current treatments for chronic hemorrhagic radiation proctitis mainly include anti-inflammatory medications, antioxidants, probiotics, antibiotics, formalin, endoscopic therapy (endoscopic argon beam plasma coagulation), and surgery.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} These treatments have shown some efficacy, but few treatment methods are supported by high-quality research evidence.</p><p>In recent years, the relationships between intestinal bacteria and diseases have been increasingly revealed. Faecal microbiota transplantation (FMT) has shown good clinical efficacy in the treatment of various clinical diseases, such as refractory <italic>Clostridium difficile</italic> infection,^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} irritable bowel syndrome,^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>]} inflammatory bowel disease,^{[<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} and constipation.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Animal studies have proven that FMT can improve radiation enteropathy in a mouse model by restoring the structural composition of the gut bacteria.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} In addition, a case report in which the donor was the patients son showed that radiation enteritis was alleviated by FMT.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} This paper reports a case of a chronic hemorrhagic radiation enteritis patient who was treated with multi-donor and multi-course FMT and achieved significant remission. The analysis of the gut microbiota of the patient and donors by 16S rRNA sequencing showed that compared to before the treatment, after the FMT treatment, the patients intestinal bacterial composition structure obviously changed and was similar to that of the donors.</p></sec><sec><label>2</label><title>Case presentation</title><sec><label>2.1</label><title>Chief complaints and history of present illness</title><p>The patient was a 45-year-old female who was admitted to the Department of Gastroenterology on March 2, 2019 for &#x0201c;recurrent hematochezia for half a year after radiotherapy&#x0201d;. In 2017, due to cervical cancer, the patient underwent 28 radiotherapy treatments and 8 rounds of chemotherapy at a local hospital. During radiotherapy, diarrhea consisting of a black pasty stool occurred 7 to 8 times per day. After radiotherapy, the diarrhea resolved. Half a year ago (September 2018), the patient began to repeatedly experience mucus-containing bloody stool alternately with black pasty stool. The blood in the bloody stool was a bright red color accompanied by dark red clots, and mucus was present. The volume was approximately 30 to 50&#x0200a;ml occurring 5 to 6 times per day and approximately 2 to 3 days per week. The black pasty stool occurred 1 to 2 times per day with a volume of approximately 100 to 250 g each time and occurred approximately 2 to 3 days per week. The diarrhea was occasionally accompanied by abdominal pain and tenesmus, and there was no fever. Dizziness, fatigue, and polypnea gradually appeared after daily activities. The patient was admitted to a local hospital 3 times for severe anemia. The routine blood examination showed a minimum hemoglobin concentration of 30&#x0200a;g/L, and after transfusion, dizziness, polypnea, and fatigue improved. However, the above symptoms continued to repeatedly occur, and the patient sought further treatment at our hospital.</p></sec><sec><label>2.2</label><title>Physical examination upon admission</title><p>The patients temperature was 36.4&#x000b0;C, heart rate was 100 bpm, respiratory rate was 20 breaths per minute, blood pressure was 114/76 mm Hg and body mass index was 20.8&#x0200a;kg/m². The patient presented an anemic face and a soft abdomen, and no mass was palpated. There was tenderness in the lower abdomen and no rebound pain. Bowel sounds occurred 5&#x0200a;times/minute.</p></sec><sec><label>2.3</label><title>Laboratory examination upon admission</title><p>A routine stool and faecal occult blood test showed a positive faecal occult blood test and a positive faecal fat test. The faecal pathogenic bacterial cultures showed fungal growth on March 2. However, there was no fungal growth on March 12, and we hypothesized that contamination was detected on March 2. The Epstein-Barr virus (EBV) antibody and DNA quantity, cytomegalovirus (CMV) antibody, <italic>Clostridium. difficile</italic> antigen, tuberculosis antibody, T cell spot test for tuberculosis infection, and coagulation function detection showed no abnormalities. The routine blood examinations showed a hemoglobin concentration of 53&#x0200a;g/L, indicating microcytic hypochromic anemia.</p></sec><sec><label>2.4</label><title>Imaging examinations</title><p>The magnetic resonance imaging examination of the pelvic cavity with a plain scan and enhancement showed changes after radiotherapy and chemotherapy for cervical cancer, and no obvious tumor recurrence or metastasis was found in the pelvic cavity. The walls of the sigmoid colon and rectum were slightly thickened and swollen, which was considered to have occurred after radiotherapy (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). Colonoscopy showed obvious congestion of the sigmoid colon and rectal mucosa and a smooth surface, and bleeding was easily induced by touch. The sigmoid colon was narrow, rendering the passage of the colonoscope difficult (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>a-2b). The colonoscopy diagnosis was radiation proctitis. The pathological findings revealed chronic mucosal inflammation with mild atypical hyperplasia of the glands (Fig. <xref ref-type=\"fig\" rid=\"F3\">3</xref>).</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Magnetic resonance imaging examination of the patient before the treatment showed thickening and swelling of the colorectal wall.</p></caption><graphic xlink:href=\"medi-99-e22298-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Colonoscopy showed mucosal inflammation of the sigmoid colon and rectum before the faecal microbiota transplantation and improvement in inflammation after the treatment with faecal microbiota transplantation (FMT). 2a-2b: colonoscopy before the treatment; 2c-2d: colonoscopy 4 weeks after the first course of FMT; 2e-2f: colonoscopy 4 weeks after the second course of FMT. These figures show that marked congestion and narrowing of the intestinal cavity at the sigmoid colon 20&#x0200a;cm from the anus occurred; thus, the passage of the colonoscope was difficult. Additionally, following the FMT treatment, the intestinal mucosal congestion was significantly improved.</p></caption><graphic xlink:href=\"medi-99-e22298-g002\"/></fig><fig id=\"F3\" orientation=\"portrait\" position=\"float\"><label>Figure 3</label><caption><p>Rectal mucosal pathology of the patient before the treatment shows chronic mucosal inflammation with mild atypical hyperplasia of the glands.</p></caption><graphic xlink:href=\"medi-99-e22298-g003\"/></fig><p>Based on the above examination results and after the exclusion of diseases, such as tumor recurrence, invasion of the rectum, fungal infection, <italic>Clostridium difficile</italic> infection, EBV or CMV infection, and ulcerative colitis, a diagnosis of &#x0201c;chronic hemorrhagic radiation proctitis&#x0201d; was rendered. Considering that many studies have reported that intestinal bacteria are involved in the incidence of radiation enteritis and that both animal model experiments and case reports have shown that FMT can improve the symptoms of radiation enteritis and mucosal inflammation,^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>&#x02013;<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} the patient and her family agreed to FMT treatment after being fully informed.</p></sec><sec><label>2.5</label><title>Faecal microbiota transplantation process</title><p>Faecal bacteria were obtained from 8 healthy people aged 21 to 24 years without digestive system diseases, tumors, infectious diseases, metabolic diseases, genetic diseases, or other related diseases after auxiliary examination. Additionally, the subjects did not take antibiotics, drugs affecting gastrointestinal dynamics or other drugs causing intestinal microecological disorders in the prior 3 months. Fresh faecal liquid was separated by an automatic purification system (GenFMTer; FMT Medical, Nanjing, China). Two FMT treatment approaches^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} were utilized as follows: the lower-gut approach was adopted in the first course of treatment, and the mid-gut approach was utilized in the second to fourth courses of treatment because it was difficult to pass the endoscope through the narrow intestinal cavity. The faecal liquid was moved from the donor to the patient within 1 hour to keep it as fresh as possible to achieve maximum clinical efficacy. The regimen of 1 course of treatment was 200&#x0200a;ml/treatment/donor once a day for 3 days.</p><p>Treatment courses: The patient received a total of 4 individual courses of FMT, which were completed in March, April, May, and July.</p><p>This study was approved and monitored by the Ethics Committee of the First Affiliated Hospital of Guangdong Pharmaceutical University (Approval No. Yilun Shen [2019] No. 188).</p></sec><sec><label>2.6</label><title>Clinical efficacy and follow-up</title><p>At the six-month follow-up after all 4 courses of FMT were completed, hematochezia, abdominal pain and diarrhea were resolved, and the patient did not experience any side effects from the FMT treatment. Compared to her symptoms before the treatment, her stool frequency decreased from a maximum of 6 times to 2 times per day, and the mucus-containing bloody stool and pasty stool became soft yellow stool. Additionally, the European Organization for Research and Treatment of Cancer Therapy Oncology Group (RTOG/EORTC) score^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} improved from level 2 to level 1. The patient was elated because she did not need a blood transfusion, proving that no blood was lost, and the hemoglobin concentration remained above 60&#x0200a;g/L (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>). The sigmoid colon and rectal mucosal inflammation showed improvement via colonoscopy (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>c-2f).</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Patient disease changes over half a year.</p></caption><graphic xlink:href=\"medi-99-e22298-g004\"/></table-wrap><p>The faecal samples collected from the patient before the treatment (1), 28 days after the first course of the FMT treatment (2), 30 days after the second course of the FMT treatment (3), and 70 days after the third course of treatment (4) and the donors (mix of the first course faecal liquid from 3 donors, GZ) were subjected to 16S rRNA sequencing. On average, 340.06 operational taxonomic units (OTUs) were identified with a minimum of 231 OTUs and a maximum of 500 OTUs. According to the analysis of the alpha diversity index, the species richness, evenness and inter-species differences significantly increased concurrently with the extension of time and increases in the transplantation time (Table <xref rid=\"T2\" ref-type=\"table\">2</xref>). At the phylum level (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>a), the predominant bacteria were firmicutes before the transplantation (1) and bacteroidetes after the transplantation. However, at the genus level (Fig. <xref ref-type=\"fig\" rid=\"F4\">4</xref>b), the primary bacteria were bacteroidetes before the transplantation (1) and Prevotella after the transplantation. As the FMT course progressed, the composition of the microbiota of the patient tended to become similar to that of the donors.</p><table-wrap id=\"T2\" orientation=\"portrait\" position=\"float\"><label>Table 2</label><caption><p>Statistical table of the alpha diversity index.</p></caption><graphic xlink:href=\"medi-99-e22298-g005\"/></table-wrap><fig id=\"F4\" orientation=\"portrait\" position=\"float\"><label>Figure 4</label><caption><p>Distribution of the bacterial flora in the donor group and the patient before and after the faecal microbiota transplantation (FMT) treatment at the phylum and genus levels. 1, before the treatment; 2, 28 days after the first course of FMT; 3, 30 days after the second course of FMT; 4, 70 days after the third course of FMT; GZ, donor. 4a shows the changes in the bacterial flora in the donor group and the patient before and after the FMT treatment at the phylum level, whereas 4b shows the changes at the genus level.</p></caption><graphic xlink:href=\"medi-99-e22298-g006\"/></fig></sec></sec><sec><label>3</label><title>Discussion</title><p>In this case report, we presented a patient who developed chronic hemorrhagic radiation proctitis after chemoradiotherapy for cervical cancer and experienced relief of hematochezia after 4 courses of FMT treatment. The composition of the intestinal bacteria showed significant changes by 16S rRNA sequencing, indicating that FMT is effective for patients with chronic hemorrhagic proctitis.</p><p>Acute radiation proctitis occurs in more than 75% of patients who receive pelvic radiotherapy, and 5% to 20% of patients develop chronic radiation proctitis.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} The exposure of the intestinal tissue to radiation can induce apoptosis in epithelial cells, leading to mucosal inflammation, edema and ulceration, and subsequently to occlusive endarteritis, submucosal fibrosis and angiogenesis. Eventually, diarrhea, bleeding, pain and an impaired quality of life occur, representing the histopathological process of acute and chronic radiation proctitis.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]} In this case, we show that colorectal inflammation improved after FMT. Thus, intestinal bacteria can improve proctitis.</p><p>Several studies have shown that the intestinal microbiota is associated with radiation-associated intestinal disease. One animal study showed that the survival rate of mice receiving a systemic lethal dose of radiation after antibiotic treatment was significantly higher than that of the control mice (after saline treatment), suggesting that the intestinal radiation sensitivity is related to the microbiota.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Studies of radiation-induced proctitis in mice have shown that the composition of intestinal bacteria in the irradiated area changes, the diversity of firmicutes and bacteroidetes decreases, and the abundance of the proteus increases.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} The increased proteus abundance increases the expression of interleukin-1&#x003b2; and tumor necrosis factor-&#x003b1; in intestinal epithelial cells, suggesting that interleukin-1 is a major driver of tissue damage in radiation proctitis. In a study involving 9 gynecological tumor patients who received pelvic radiotherapy, the abundance of firmicutes and <italic>Clostridium</italic> was significantly reduced by 10% and 3%, respectively.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]} Animal and human studies have shown that the diversity and composition of the intestinal flora significantly changes after radiotherapy. Intestinal microbiota may play a role by affecting and regulating oxidative stress, inflammatory processes, intestinal permeability, the composition of the mucous layer, epithelial repair, resistance to harmful stimuli, and the expression and release of immune molecules in the intestinal tract. Some studies used bacteria for the treatment of radiation proctitis. In 2014, a study showed that synbiotics could alleviate the symptoms of radiation proctitis and improve the quality of life of patients.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>]} The results showed that diarrhea decreased in patients treated with <italic>Lactobacillus acidophilus</italic> and <italic>L. acidophilus</italic> combined with <italic>Bifidobacterium</italic>. The Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology guidelines support the use of probiotics to prevent diarrhea caused by radiotherapy.^{[<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} However, the results of a recent meta-analysis suggest that currently, evidence suggesting that probiotics are beneficial for preventing radiation-induced diarrhea is lacking.^{[<xref rid=\"R15\" ref-type=\"bibr\">15</xref>]} As symbiotic microbial flora, intestinal bacteria play an indispensable role in human health and diseases; thus, changing an individual bacterial species alone may not have an effect. FMT of the whole intestinal flora has been increasingly recognized as a treatment for diseases. Studies using mice have shown that FMT can reduce and protect against radiation-induced injury, improve the survival rate of irradiated mice, improve gastrointestinal functionality and epithelial integrity, and thus reduce radiation-induced gastrointestinal toxicity.</p><p>According to research, after radiotherapy, the microbiota diversity is decreased, with a high ratio of firmicutes to bacteroidetes increasing the likelihood of diarrhea.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]} The symptoms of the patient were mainly characterized by diarrhea and blood, which obviously improved after the treatment with 4 courses of FMT. The endoscopic results showed that the colorectal mucous membrane inflammation was improved. The 16S rRNA sequencing showed an increase in the intestinal flora diversity and altered composition with a decreased abundance of firmicutes and an increased abundance of bacteroidetes, which is consistent with the results of the aforementioned research reports.^{[<xref rid=\"R16\" ref-type=\"bibr\">16</xref>]}</p><p>In this case, a multi-donor, multi-course fresh faecal suspension for FMT was adopted. The purpose of multiple donors is to increase the diversity of the microbiota. The multi-course treatment is based on the reconstruction and consolidation of the intestinal bacterial balance in patients to maintain new intestinal bacterial homeostasis, consolidate the therapeutic effect, maintain clinical remission, and finally achieve a clinical cure. In this case, after 4 courses of FMT, the hematochezia and diarrhea disappeared, proving that FMT was effective in the treatment of chronic hemorrhagic radiation proctitis. However, we are uncertain which type of bacteria was responsible for the treatment effect. It is also possible that all bacteria worked together to produce the effect because symbiotic intestinal bacteria do not act alone. Additionally, studies investigating radiation-induced intestinal disease revealed that intestinal bacterial changes are different. Different studies of probiotic use for the treatment of radiation-induced intestinal disease have produced different or contrasting results. Therefore, we still conclude that the whole intestinal microbial flora plays a role in treatment. The increased microbial diversity may be the most obvious reason for the treatment efficacy.</p></sec><sec><label>4</label><title>Conclusion and prospects</title><p>This case report shows that FMT can relieve the symptoms of hematochezia and diarrhea in patients with chronic hemorrhagic radiation proctitis and that the bacterial community structure changes after treatment. FMT therapy may be a new and enhanced treatment for patients with radiation enteritis, which needs to be further confirmed by prospective and clinical trials involving large sample sizes.</p></sec><sec><title>Author contributions</title><p><bold>Conceptualization:</bold> Xing-xiang He, Jia-Ting Xu.</p><p><bold>Data curation:</bold> Ya-Mei Zheng, Jie-Yi Cai.</p><p><bold>Formal analysis:</bold> Yu Yuan, Wen-Rui Xie.</p><p><bold>Investigation:</bold> Ya-Mei Zheng.</p><p><bold>Methodology:</bold> Wen-Rui Xie.</p><p><bold>Validation:</bold> Jia-Ting Xu.</p><p><bold>Visualization:</bold> Harry Hua-Xiang Xia.</p><p><bold>Writing &#x02013; original draft:</bold> Ya-Mei Zheng.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Harry Hua-Xiang Xia, Jia-Ting Xu.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CMV = cytomegalovirus, EBV = Epstein-Barr virus, FMT = faecal microbiota transplantation, OTUs = operational taxonomic units, RTOG/EORTC = European Organization for Research and Treatment of Cancer Therapy Oncology Group.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Zheng YM, He XX, Xia HX, Yuan Y, Xie WR, Cai JY, Xu JT, Wu LH. Multi-donor multi-course faecal microbiota transplantation relieves the symptoms of chronic hemorrhagic radiation proctitis: A case report. <italic>Medicine</italic>. 2020;99:39(e22298).</p></fn><fn fn-type=\"other\"><p>The patient was anonymized and granted permission for the publication of this case.</p></fn><fn fn-type=\"COI-statement\"><p>The authors declare that they have no conflicts of interest.</p></fn><fn fn-type=\"other\"><p>All data generated or analyzed during this study are included in this published article [and its supplementary information files].</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Paquette</surname><given-names>IM</given-names></name><name><surname>Vogel</surname><given-names>JD</given-names></name><name><surname>Abbas</surname><given-names>MA</given-names></name><etal/></person-group>\n<article-title>The American 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[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"case-report\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991436</article-id><article-id pub-id-type=\"pmc\">PMC7523866</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-01230</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022301</article-id><article-id pub-id-type=\"art-access-id\">22301</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>6700</subject></subj-group><subj-group><subject>Research Article</subject><subject>Clinical Case Report</subject></subj-group></article-categories><title-group><article-title>Osimertinib induced cardiomyopathy</article-title><subtitle>A case report</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Shinomiya</surname><given-names>Shun</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Kaira</surname><given-names>Kyoichi</given-names></name><degrees>MD, PhD</degrees><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib><contrib contrib-type=\"author\"><name><surname>Yamaguchi</surname><given-names>Ou</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Ishikawa</surname><given-names>Keitaro</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type=\"author\"><name><surname>Kagamu</surname><given-names>Hiroshi</given-names></name><degrees>MD, PhD</degrees></contrib></contrib-group><contrib-group><contrib contrib-type=\"editor\"><name><surname>Saranathan.</surname><given-names>Maya</given-names></name></contrib></contrib-group><aff>Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama University Hospital, 1397-1 Yamane, Hidaka-City, Saitama, Japan.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Kyoichi Kaira, Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama University Hospital, 1397-1 Yamane, Hidaka-City, Saitama 350-1298, Japan (e-mail: <email>kkaira1970@yahoo.co.jp</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22301</elocation-id><history><date date-type=\"received\"><day>14</day><month>2</month><year>2020</year></date><date date-type=\"rev-recd\"><day>10</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>21</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22301.pdf\"/><abstract><title>Abstract</title><sec><title>Rationale:</title><p>Cardiotoxicity related to osimertinib, including cardiac failure, QT prolongation, and atrial fibrillation, has been reported as an extremely rare incidence in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the occurrence of osimertinib-induced cardiomyopathy.</p></sec><sec><title>Patient concerns:</title><p>A 76-year old woman was treated with afatinib (40&#x0200a;mg/day) as the 1st line treatment due to recurrence after surgical resection for pulmonary adenocarcinoma. However, she experienced recurrence with positive T790&#x0200a;M, and osimertinib (80&#x0200a;mg/day) was administered as the 2nd line therapy.</p></sec><sec><title>Diagnosis:</title><p>Four months after osimertinib initiation, she complained of fever and progressive dyspnea, and a diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, indicating osimertinib-induced cardiomyopathy.</p></sec><sec><title>Interventions and outcomes:</title><p>She was treated with furosemide, carvedilol, and enalapril, and her cardiac function, her symptoms, and condition improved 3 weeks after the withdrawal of osimertinib.</p></sec><sec><title>Lessons:</title><p>Physicians should be alert of the cardiomyopathy-causing potential of osimertinib in advanced NSCLC patients.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>cardiac dysfunction</kwd><kwd>cardiomyopathy</kwd><kwd>lung cancer</kwd><kwd>osimertinib</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Osimertinib is a 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), proven effective as 1st line treatment in patients with advanced non-small cell lung cancer (NSCLC) harboring the <italic>EGFR</italic> mutation.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} As an EGFR-TKI, osimertinib has reported milder toxicities compared with the other EGFR-TKIs such as gefitinib, erlotinib, and afatinib. Recently, some studies have reported cardiac dysfunction as an adverse event secondary to osimertinib.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>&#x02013;<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} The frequency of cardiac dysfunction is less than 1.0%.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Hence, it has been classified as an extremely rare incidence. However, physicians should remain alert to the potential of cardiac toxicity resulting from osimertinib treatment. Here, we presented a case of osimertinib-induced cardiomyopathy in a patient with advanced NSCLC.</p></sec><sec><label>2</label><title>Case report</title><p>A 76-year old female underwent surgical resection of the left upper lobe plus lymph node dissection, 4 years ago following a diagnosis of primary lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) deletion mutation in exon 19. One month after surgery, the patient received adjuvant chemotherapy with cisplatin plus vinorelbine. Three years after surgical resection, evidence of bone metastases was noted. Therefore, the patient was initially treated with afatinib 40&#x0200a;mg once daily orally. She experienced recurrence with the T790&#x0200a;M <italic>EGFR</italic> mutation 2 years after afatinib initiation. Hence, osimertinib 80&#x0200a;mg once daily orally was administered. Four months after osimertinib initiation, she complained of fever and progressive dyspnea and was hospitalized at our institution. She had no prior smoking history, and physical examination revealed coarse crackles in both lung fields without any murmur and external edema. Laboratory investigations on admission reported an increased level of brain natriuretic peptide of 1394&#x0200a;pg/ml and troponin I of 40.9&#x0200a;pg/ml. However, no abnormalities concerning antinuclear antibody (ANA), rheumatoid factor (RF), anti-neutrophil cytoplasmic antibody (ANCA), angiotensin-converting enzyme (ACE), IgG4, coxsackievirus, echovirus, and adenovirus were observed. The chest radiography displayed an enlarged cardiac shadow and diffused ground-glass opacities in both lung fields (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). The electrocardiogram demonstrated tachycardia without QT prolongation. The chest computed tomography (CT) revealed cardiac enlargement, pleural effusion, and ground-glass opacities in both lung fields (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>). Furthermore, the echocardiogram indicated an obvious finding of severe hypokinesis, with an ejection fraction of 17% and left ventricular enlargement. Moreover, coronary angiography revealed normal study without ischemic change. A diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, without inflammatory cell infiltration, amyloid deposits, and necrosis (Fig. <xref ref-type=\"fig\" rid=\"F2\">2</xref>). As we strongly suspected the potential of osimertinib-induced cardiomyopathy with CTCAE grade 3, osimertinib was discontinued. The patient was treated with furosemide, carvedilol, and enalapril, and her cardiac function and condition improved 3 weeks after osimertinib withdrawal. The finding of echocardiogram revealed normal study and there was reversal of the cardiomyopathy. Moreover, there were no cardiovascular risk factors that would have predisposed to cardiomyopathy in our patient. Therefore, cardiomyopathy secondary to osimertinib was diagnosed.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Chest radiography indicates an enlarged cardiac shadow and diffuse ground-glass opacities in both lung fields on admission (A). After osimertinib discontinuation, the chest radiograph displays an improvement in enlarged cardiac shadow (B). Chest CT exhibits cardiac enlargement, pleural effusion, and ground-glass opacities in both lung fields (C).</p></caption><graphic xlink:href=\"medi-99-e22301-g001\"/></fig><fig id=\"F2\" orientation=\"portrait\" position=\"float\"><label>Figure 2</label><caption><p>Endomyocardial biopsy of the right ventricle shows non-specific cardiomyopathy, without inflammatory cell infiltration, amyloid deposits, and necrosis. There is evidence of karyotypic irregularities, lipofuscin deposit, cytoplasmic airborne degeneration, and slight interstitial fibrosis. (A) HE and (B) Massons trichrome immunostaining.</p></caption><graphic xlink:href=\"medi-99-e22301-g002\"/></fig></sec><sec><label>3</label><title>Discussion</title><p>Previously, from 2016 to 2018, a rare incidence (3.7%) had been reported regarding the occurrence of cardiotoxicity linked to EGFR-TKIs (osimertinib, erlotinib, afatinib, or gefitinib) based on the data from 8450 adverse events (AEs).^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Although cardiac failure, atrial fibrillation, QT prolongation, myocardial infarction, and pericardial effusion have already been reported as cardiac toxicities related to EGFR-TKIs, the frequency (6.1%) of cardiac AEs due to osimertinib was high compared to that (2.1%) of other EGFR-TKIs.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Notably, osimertinib reported an increased risk of cardiac failure compared to other reported cardiac AEs. However, the underlying mechanism of osimertinib-related cardiotoxicity remains unclear. Notably, it has been reported that 7 cases have experienced cardiac dysfunction related to osimertinib treatment (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>).^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>&#x02013;<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} Of the 8 cases, including our patient, 7 were female, 6 had an exon 19 <italic>EGFR</italic> sensitive mutation, and osimertinib was administered to 7 cases as 2nd or greater line of treatment. An endomyocardial biopsy was performed in 2 of the 8 cases. Therefore, little information is available regarding pathological findings. Our case indicated non-specific cardiomyopathy, with consistent findings in the echocardiogram, chest radiography, and cardiac examinations. Furthermore, after the discontinuation of osimertinib, our patient improved. Cardiac toxicities have been classified as 2 types, reversible and irreversible. Little is known about the detailed features of cardiac toxicity due to osimertinib. However, our patient demonstrated reversible cardiotoxicity. Although 4 previous cases received retreatment with osimertinib (Table <xref rid=\"T1\" ref-type=\"table\">1</xref>), it remains unclear whether retreatment with osimertinib should be undertaken after discontinuation due to cardiotoxicity.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Previous reports regarding cardiac dysfunction due to osimertinib.</p></caption><graphic xlink:href=\"medi-99-e22301-g003\"/></table-wrap><p>Regarding cardiac toxicities associated with osimertinib, a previous investigation reported the incidence of cardiac failure (1.6%), arterial fibrillation (1.2%), QT prolongation (1.3%), and cardiac failure (0.7%).^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]} Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has been linked to the occurrence of cardiotoxicity. Although HER2 signaling is necessary for maintaining cardiac function, osimertinib, like trastuzumab, also inhibits the HER2 pathway.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} Therefore, cardiotoxicity related to osimertinib could occur, albeit rarely. Oncologists should take considerable caution regarding cardiac accidents associated with cancer molecular targeting agents. Recently, we reported a case with ventricular fibrillation followed by QT prolongation attributed to osimertinib administration, with sudden cardiopulmonary arrest, needing cardiopulmonary resuscitation.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} Hence, an awareness of the life-threatening cardiotoxicity related to osimertinib is crucial. In the present case, evidence of congestive heart failure associated with cardiomyopathy was observed without severe arrhythmia. We hypothesize that cardiomyopathy may be identified as the reason for cardiac dysfunction linked to osimertinib, including reports in previous case series.</p><p>In conclusion, physicians should be alert of the cardiomyopathy potential as one of the cardiotoxicities associated with osimertinib administration in patients with advanced NSCLC.</p></sec><sec><title>Acknowledgments</title><p>The authors thank Dr. Tsugumi Sato at the Department of Diagnostic Pathology, International Medical Center, Saitama Medical University.</p></sec><sec><title>Author contribution</title><p><bold>Project administration:</bold> Kyoichi Kaira, Shun Shinomiya, Ou Yamaguchi.</p><p><bold>Supervision:</bold> Kyoichi Kaira, Hiroshi Kagamu.</p><p><bold>Validation:</bold> Keitaro Ishikawa, Ou Yamaguchi.</p><p><bold>Writing &#x02013; original draft:</bold> Kyoichi Kaira, Shun Shinomiya.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Hiroshi Kagamu.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: ACE = angiotensin-converting enzyme, AEs = adverse events, ANA = antinuclear antibody, ANCA = anti-neutrophil cytoplasmic antibody, CT = computed tomography, CTCAE = Common Terminology Criteria for Adverse Events, EGFR = epidermal growth factor receptor, HER2 = human epidermal growth factor receptor 2 (HER2), NSCLC = non-small cell lung cancer, RF = rheumatoid factor, TKI = tyrosine kinase inhibitor.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Shinomiya S, Kaira K, Yamaguchi O, Ishikawa K, Kagamu H. Osimertinib induced cardiomyopathy: A case report. <italic>Medicine</italic>. 2020;99:39(e22301).</p></fn><fn fn-type=\"financial-disclosure\"><p>This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.</p></fn><fn fn-type=\"other\"><p>Written informed consent was obtained from the patient for publication of this case report and accompanying images.</p></fn><fn fn-type=\"COI-statement\"><p>KK, OY, and HK have received research grants and a speaker honorarium from AstraZeneca PLC. All remaining authors have declared no conflicts of interest.</p></fn><fn fn-type=\"other\"><p>The datasets generated during and/or analyzed during the current study are publicly available.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Mok</surname><given-names>TS</given-names></name><name><surname>Wu</surname><given-names>YL</given-names></name><name><surname>Ahn</surname><given-names>MJ</given-names></name><etal/></person-group>\n<article-title>Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer</article-title>. <source>N Engl J Med</source>\n<year>2017</year>;<volume>376</volume>:<fpage>629</fpage>&#x02013;<lpage>40</lpage>.<pub-id pub-id-type=\"pmid\">27959700</pub-id></mixed-citation></ref><ref id=\"R2\"><label>[2]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Oyakawa</surname><given-names>T</given-names></name><name><surname>Nakashima</surname><given-names>K</given-names></name><name><surname>Naito</surname><given-names>T</given-names></name></person-group>\n<article-title>Cardiac dysfunction caused by osimertinib</article-title>. <source>J Thorac Oncol</source>\n<year>2017</year>;<volume>10</volume>:<fpage>e159</fpage>&#x02013;<lpage>73</lpage>.</mixed-citation></ref><ref id=\"R3\"><label>[3]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Watanabe</surname><given-names>H</given-names></name><name><surname>Ichihara</surname><given-names>E</given-names></name><name><surname>Kano</surname><given-names>H</given-names></name><etal/></person-group>\n<article-title>Congestive heart failure during osimertinib treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC)</article-title>. <source>Intern Med</source>\n<year>2017</year>;<volume>56</volume>:<fpage>2195</fpage>&#x02013;<lpage>7</lpage>.<pub-id pub-id-type=\"pmid\">28781309</pub-id></mixed-citation></ref><ref id=\"R4\"><label>[4]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Reale</surname><given-names>ML</given-names></name><name><surname>Bianco</surname><given-names>M</given-names></name><name><surname>Tabbo</surname><given-names>F</given-names></name><etal/></person-group>\n<article-title>Osimertinib-induced cardiac dysfunction in EGFR-mutated lung cancer: a case series of five patients</article-title>. <source>Am J Cancer Case Reports</source>\n<year>2018</year>;<volume>6</volume>:<fpage>52</fpage>&#x02013;<lpage>60</lpage>.</mixed-citation></ref><ref id=\"R5\"><label>[5]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Anad</surname><given-names>K</given-names></name><name><surname>Ensor</surname><given-names>J</given-names></name><name><surname>Trachtenberg</surname><given-names>B</given-names></name><etal/></person-group>\n<article-title>Osimertinib induced cardiotoxicity: a retrospective review of the FDA adverse events reporting system (FAERS)</article-title>. <source>JACC Cardiooncology</source>\n<year>2019</year>;<volume>1</volume>:<fpage>172</fpage>&#x02013;<lpage>9</lpage>.</mixed-citation></ref><ref id=\"R6\"><label>[6]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Cross</surname><given-names>DA</given-names></name><name><surname>Ashton</surname><given-names>SE</given-names></name><name><surname>Ghiorghiu</surname><given-names>S</given-names></name><etal/></person-group>\n<article-title>AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer</article-title>. <source>Cancer Discov</source>\n<year>2014</year>;<volume>4</volume>:<fpage>1046</fpage>&#x02013;<lpage>61</lpage>.<pub-id pub-id-type=\"pmid\">24893891</pub-id></mixed-citation></ref><ref id=\"R7\"><label>[7]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Kaira</surname><given-names>K</given-names></name><name><surname>Ogiwara</surname><given-names>Y</given-names></name><name><surname>Naruse</surname><given-names>I</given-names></name></person-group>\n<article-title>Occurrence of ventricular fibrillation in a patient with lung cancer receiving osimertinib</article-title>. <source>J Thorac Oncol</source>\n<year>2020</year>;<comment>in press</comment>.</mixed-citation></ref></ref-list></back></article>\n" ]

[ "<!DOCTYPE article\nPUBLIC \"-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.2 20190208//EN\" \"JATS-archivearticle1-mathml3.dtd\">\n<article xmlns:xlink=\"http://www.w3.org/1999/xlink\" xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" article-type=\"review-article\"><?properties open_access?><front><journal-meta><journal-id journal-id-type=\"nlm-ta\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"iso-abbrev\">Medicine (Baltimore)</journal-id><journal-id journal-id-type=\"publisher-id\">MEDI</journal-id><journal-title-group><journal-title>Medicine</journal-title></journal-title-group><issn pub-type=\"ppub\">0025-7974</issn><issn pub-type=\"epub\">1536-5964</issn><publisher><publisher-name>Lippincott Williams &#x00026; Wilkins</publisher-name><publisher-loc>Hagerstown, MD</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type=\"pmid\">32991428</article-id><article-id pub-id-type=\"pmc\">PMC7523867</article-id><article-id pub-id-type=\"publisher-id\">MD-D-20-08192</article-id><article-id pub-id-type=\"doi\">10.1097/MD.0000000000022279</article-id><article-id pub-id-type=\"art-access-id\">22279</article-id><article-categories><subj-group subj-group-type=\"heading\"><subject>7100</subject></subj-group><subj-group><subject>Research Article</subject><subject>Study Protocol Systematic Review</subject></subj-group></article-categories><title-group><article-title>The effect of trauma care systems on the mortality of injured adult patients</article-title><subtitle>A protocol for systematic review and meta-analysis</subtitle></title-group><contrib-group><contrib contrib-type=\"author\"><name><surname>Jifang</surname><given-names>Wu</given-names></name></contrib><contrib contrib-type=\"author\"><name><surname>Liping</surname><given-names>Yang</given-names></name></contrib><contrib contrib-type=\"author\"><name><surname>Jing</surname><given-names>Zhu</given-names></name></contrib><contrib contrib-type=\"author\"><contrib-id contrib-id-type=\"orcid\" authenticated=\"false\">http://orcid.org/0000-0002-9559-0634</contrib-id><name><surname>Jie</surname><given-names>Song</given-names></name><xref rid=\"cor1\" ref-type=\"corresp\">^&#x02217;</xref></contrib></contrib-group><aff>Trauma Center, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu Province, China.</aff><author-notes id=\"cor1\"><corresp><label>&#x02217;</label>Correspondence: Song Jie, Trauma Center, The First People's Hospital of Lianyungang, Lianyungang 222000, Jiangsu Province, China (e-mail: <email>jsong78@126.com</email>).</corresp></author-notes><pub-date pub-type=\"collection\"><day>25</day><month>9</month><year>2020</year></pub-date><pub-date pub-type=\"epub\"><day>25</day><month>9</month><year>2020</year></pub-date><volume>99</volume><issue>39</issue><elocation-id>e22279</elocation-id><history><date date-type=\"received\"><day>18</day><month>8</month><year>2020</year></date><date date-type=\"accepted\"><day>20</day><month>8</month><year>2020</year></date></history><permissions><copyright-statement>Copyright &#x000a9; 2020 the Author(s). Published by Wolters Kluwer Health, Inc.</copyright-statement><copyright-year>2020</copyright-year><license license-type=\"open-access\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\" specific-use=\"CC-BY\"><license-p>This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0\">http://creativecommons.org/licenses/by/4.0</ext-link></license-p></license></permissions><self-uri xlink:href=\"medi-99-e22279.pdf\"/><abstract><title>Abstract</title><sec><title>Purpose:</title><p>The aim of this study was to have a comprehensive evaluation of the effect of trauma care systems on the mortality of injured adult patients.</p></sec><sec sec-type=\"materials\"><title>Materials and methods:</title><p>This protocol established in this study has been reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. Web of Science, PubMed, EMBASE, Scopus, and the Cochrane Library were searched for all clinical trials evaluating the effect of trauma care systems on the mortality of injured adult patients until July 31, 2020. We will use a combination of Medical Subject Heading and free-text terms with various synonyms to search based on the eligibility criteria. Two investigators independently reviewed the included studies and extracted relevant data. The odds ratio (OR) and 95% confidence intervals (CIs) were used as effect estimate. I-square (I²) test, substantial heterogeneity, sensitivity analysis, and publication bias assessment will be performed accordingly. Stata 15.0 and Review Manger 5.3 are used for meta-analysis and systematic review.</p></sec><sec sec-type=\"results\"><title>Results:</title><p>The results will be published in a peer-reviewed journal.</p></sec><sec sec-type=\"conclusion\"><title>Conclusion:</title><p>The results of this review will be widely disseminated through peer-reviewed publications and conference presentations. This evidence may also provide a comprehensive evaluation of the effect of trauma care systems on the mortality of injured adult patients.</p></sec><sec><title>Registration number:</title><p>INPLASY202080058</p></sec></abstract><kwd-group><title>Keywords</title><kwd>meta-analysis</kwd><kwd>mortality</kwd><kwd>trauma care systems</kwd></kwd-group><funding-group><award-group id=\"award1\" award-type=\"Fundref\"><funding-source>The First People's Hospital of Lianyungang</funding-source><award-id>no</award-id><principal-award-recipient>Wu Jifang</principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><label>1</label><title>Introduction</title><p>Trauma is one of the leading causes of death worldwide.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Approximately 5.8 million people die each year as a result of trauma.^{[<xref rid=\"R2\" ref-type=\"bibr\">2</xref>]} Before the modern era of resuscitative medicine and surgery, and the reorganization of emergency hospital care into major trauma centers, the likelihood of survival following a traumatic injury was down to the individual's physiological response to injury.^{[<xref rid=\"R3\" ref-type=\"bibr\">3</xref>,<xref rid=\"R4\" ref-type=\"bibr\">4</xref>]} Survival is achieved via a complex set of metabolic, endocrine, and immunological pathways that mobilize fuel sources and minimize blood loss, so that our vital organs may continue to be perfused and function.^{[<xref rid=\"R5\" ref-type=\"bibr\">5</xref>]}</p><p>Implementation of a comprehensive mature trauma care system has led to a decrease in mortality and morbidity among injured patients in many high-income countries such as the United States (US), Canada, and Australia.^{[<xref rid=\"R6\" ref-type=\"bibr\">6</xref>]} The trauma care system is designed to provide specialized trauma care for all injured patients and to enhance accessibility to acute health care facilities among those injured, ensuring they have access to higher levels of care.^{[<xref rid=\"R7\" ref-type=\"bibr\">7</xref>]} A coordinated trauma care system encompasses authority, strategies, and services to optimize injury prevention, prehospital emergency medical service (EMS), acute care hospitalization, and posthospital care.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} Currently, there is a growing interest in how the trauma care systems could affect this physiological response to major trauma and how to manipulate recovery to improve patient outcomes further.^{[<xref rid=\"R1\" ref-type=\"bibr\">1</xref>]} However, there is rare systematic review and meta-analysis to access the effect of trauma care systems on the mortality of injured adult patients.</p><p>To tackle with those problems, we further performed a systematic review and meta-analysis to provide a comprehensive evaluation of the effect of trauma care systems on the mortality of injured adult patients.</p></sec><sec><label>2</label><title>Study aim</title><p>The aim of our study is to have a comprehensive evaluation of the effect of trauma care systems on the mortality of injured adult patients.</p></sec><sec><label>3</label><title>Methods</title><p>The protocol of our meta-analysis followed the guideline of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) recommendations.^{[<xref rid=\"R8\" ref-type=\"bibr\">8</xref>]} It has been registered with INPLASY database as INPLASY202080058 (<ext-link ext-link-type=\"uri\" xlink:href=\"https://inplasy.com/inplasy-2020-8-0058/\">https://inplasy.com/inplasy-2020-8-0058/</ext-link>).</p><sec><label>3.1</label><title>Search strategy</title><p>A systematic search was performed in Web of Science, PubMed, EMBASE, Scopus, and the Cochrane Library until July 31, 2020. The MeSH search and text word will be used with the terms related to &#x0201c;trauma care system.&#x0201d; To perform a comprehensive and focused search, experienced systematic review researchers will be invited to develop a search strategy. An example of search strategy for PubMed database is summarized in Table <xref rid=\"T1\" ref-type=\"table\">1</xref>, which will be modified and used for the other databases. The reference lists of all relevant studies will be searched for additional relevant studies not retrieved from the electronic database search.</p><table-wrap id=\"T1\" orientation=\"portrait\" position=\"float\"><label>Table 1</label><caption><p>Searching strategy in PubMed.</p></caption><graphic xlink:href=\"medi-99-e22279-g001\"/></table-wrap></sec><sec><label>3.2</label><title>Eligibility criteria</title><p>Inclusion criteria include English language, randomized controlled trials, nonrandomized controlled trials, before and after studies, interrupted time series, cohort studies, and case&#x02013;control studies. Studies evaluating the effect of a trauma system on the primary outcome, adult patient mortality, will be included. Due to the numerous definitions of a trauma system, studies will be deemed eligible for inclusion if the study authors define their intervention as a trauma system and if the intervention has 2 of the following clinical components identified by the Trauma Association of Canada.^{[<xref rid=\"R9\" ref-type=\"bibr\">9</xref>]}</p><p>Exclusion criteria include studies solely reporting pediatric outcomes and studies without a comparator will be excluded. Combat data and trauma systems in developing countries will also be excluded. The Central Intelligence Agency World Factbook will be used to identify developed and developing countries.</p></sec><sec><label>3.3</label><title>Study selection</title><p>All initial records from 4 electronic databases will be imported into the web-based systematic review Rayyan software.^{[<xref rid=\"R10\" ref-type=\"bibr\">10</xref>]} First, the titles and abstracts of records will be reviewed independently by 2 reviewers to identify potential trials according to eligibility criteria. Then, full-text of all potentially relevant trials will be downloaded to make sure eligible trials. Any conflict will be resolved by discussion. A flow diagram (Fig. <xref ref-type=\"fig\" rid=\"F1\">1</xref>) will be used to describe the selection process of eligible papers.</p><fig id=\"F1\" orientation=\"portrait\" position=\"float\"><label>Figure 1</label><caption><p>Flow diagram: selection process for the studies.</p></caption><graphic xlink:href=\"medi-99-e22279-g002\"/></fig></sec><sec><label>3.4</label><title>Data extraction and management</title><p>The data will be extracted out by 2 independent reviewers in accordance with the Cochrane Handbook of Systematic Reviews of Interventions. Two investigators will independently screen all the included studies. The main outcome will be the mortality of injured adult patients. Additional outcomes will be the disability rate and length of hospital stay.</p></sec><sec><label>3.5</label><title>Risk of bias of individual study and quality assessment</title><p>Two reviewers will evaluate independently the risk of bias of included studies using a modified Version of Cochrane tool^{[<xref rid=\"R11\" ref-type=\"bibr\">11</xref>]} in which we will check for allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias, each of which makes high risk, low-risk, and unclear grades. Any discrepancy was resolved by discussion or by a third reviewer.</p></sec><sec><label>3.6</label><title>Data analyses</title><p>All the statistical analysis was achieved in Rev Man 5.3 (Cochrane Library Software, Oxford, UK). The trial data were processed according to the Cochrane Reviewers&#x02019; Handbook. We calculated standard deviations (SDs) based on 95% confidence interval (CI) or <italic>P</italic> values if not reported. Dichotomous data were expressed as odds ratio (OR), while continuous variables were presented as mean difference (MD), both with 95% CI. The <italic>z</italic> test was performed to determine all pooled effects, and statistical significance was defined as <italic>P</italic>&#x0200a;&#x0003c;&#x0200a;.05. If <italic>I</italic>²&#x0200a;&#x0003c;&#x0200a;50% or <italic>P</italic>&#x0200a;&#x0003e;&#x0200a;.1 was reported according to the Chi-square-based Q test and <italic>I</italic>² test, heterogeneity was assessed as low, and the fixed-effects model was used. Otherwise, the random-effects model was used. Certain literature was removed each time for sensitivity analysis.</p></sec><sec><label>3.7</label><title>Publication bias</title><p>If included studies were more than 10, funnel plot will be used to identify the possible publication bias. In addition, Egg regression and Begg tests will be utilized to detect the funnel plot asymmetry.^{[<xref rid=\"R12\" ref-type=\"bibr\">12</xref>]}</p></sec><sec><label>3.8</label><title>Subgroup analysis</title><p>If there is enough research, we will conduct a subgroup analysis to investigate differences in age, gender, and so on.</p></sec></sec><sec><label>4</label><title>Discussion</title><p>Previous studies have reported that trauma care systems could have effects on the mortality of injured adult patients.^{[<xref rid=\"R13\" ref-type=\"bibr\">13</xref>,<xref rid=\"R14\" ref-type=\"bibr\">14</xref>]} Thus, this systematic review and meta-analysis will have a comprehensive evaluation of the effect of trauma care systems on the mortality of injured adult patients. The results of this review will be widely disseminated through peer-reviewed publications and conference presentations. This evidence may also assist clinicians in assessing the effect of trauma care systems on the mortality of injured adult patients.</p></sec><sec><title>Author contributions</title><p>Conceptualization: Wu Jifang and Song Jie; Acquisition: Wu Jifang, Yang Liping, Zhu Jing and Song Jie; Registration: Song Jie; Methodology: Wu Jifang, Yang Liping, Zhu Jing and Song Jie; Project administration: Wu Jifang and Song Jie; Writing and original draft: Wu Jifang, Yang Liping, Zhu Jing and Song Jie.</p><p><bold>Conceptualization:</bold> Wu Jifang, Song Jie.</p><p><bold>Formal analysis:</bold> Wu Jifang.</p><p><bold>Funding acquisition:</bold> Song Jie.</p><p><bold>Investigation:</bold> Wu Jifang, Yang Liping, Song Jie.</p><p><bold>Methodology:</bold> Wu Jifang, Song Jie.</p><p><bold>Project administration:</bold> Yang Liping.</p><p><bold>Resources:</bold> Wu Jifang, Zhu Jing, Song Jie.</p><p><bold>Software:</bold> Zhu Jing, Song Jie.</p><p><bold>Supervision:</bold> Yang Liping, Song Jie.</p><p><bold>Validation:</bold> Zhu Jing.</p><p><bold>Writing &#x02013; original draft:</bold> Song Jie.</p><p><bold>Writing &#x02013; review &#x00026; editing:</bold> Song Jie.</p></sec></body><back><fn-group><fn fn-type=\"abbr\"><p>Abbreviations: CIs = confidence intervals, OR = odds ratio, PRISMA-P = Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols.</p></fn><fn fn-type=\"other\"><p>How to cite this article: Jifang W, Liping Y, Jing Z, Jie S. The effect of trauma care systems on the mortality of injured adult patients: A protocol for systematic review and meta-analysis. <italic>Medicine</italic>. 2020;99:39(e22279).</p></fn><fn fn-type=\"other\"><p>WJ, YL, and SJ all have a Master's Degree, who is granted as Associate Chief Senior Nurse.</p></fn><fn fn-type=\"other\"><p>ZJ has a Master's Degree, who is granted as Senior Nurse.</p></fn><fn fn-type=\"other\"><p>This article is a protocol for systematic review and it does not involve Human Participants or Animal. Therefore, ethical approval would be unnecessary.</p></fn><fn fn-type=\"other\"><p>This manuscript was funded by The First People's Hospital of Lianyungang.</p></fn><fn fn-type=\"COI-statement\"><p>The author(s) declared no potential conflicts of interest with respect to the research, authorship, or publication of this article.</p></fn><fn fn-type=\"other\"><p>Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.</p></fn></fn-group><ref-list><title>References</title><ref id=\"R1\"><label>[1]</label><mixed-citation publication-type=\"journal\"><person-group person-group-type=\"author\"><name><surname>Alharbi</surname><given-names>RJ</given-names></name><name><surname>Lewis</surname><given-names>V</given-names></name><name><surname>Mosley</surname><given-names>I</given-names></name><etal/></person-group>\n<article-title>Current trauma care system in Saudi Arabia: a scoping literature review</article-title>. <source>Accid Anal 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