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<front>
<journal-meta>
<journal-id>JEVTM</journal-id>
<journal-title-group>
<journal-title>Journal of Endovascular Resuscitation and Trauma Management</journal-title>
<abbrev-journal-title>JEVTM</abbrev-journal-title>
</journal-title-group>
<issn pub-type="pdf">2002-7567</issn>
<publisher>
<publisher-name>Universitetssjukhuset &#x00D6;rebro</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.26676/jevtm.22378</article-id>
<article-id pub-id-type="publisher-id">JEVTM_22378</article-id>
<article-categories>
<subj-group>
<subject>Narrative Review Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Anatomy and Classification of Pelvic Trauma</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author"><name><surname>Giuliani</surname><given-names>Jacopo</given-names></name><xref ref-type="aff" rid="aff-1"><sup>1</sup></xref></contrib>
<contrib contrib-type="author"><name><surname>Guelfi</surname><given-names>Riccardo</given-names></name><xref ref-type="aff" rid="aff-1"><sup>1</sup></xref></contrib>
<contrib contrib-type="author"><name><surname>Cremonini</surname><given-names>Camilla</given-names></name><xref ref-type="aff" rid="aff-1"><sup>1</sup></xref></contrib>
<contrib contrib-type="author"><name><surname>Tartaglia</surname><given-names>Dario</given-names></name><xref ref-type="aff" rid="aff-1"><sup>1</sup></xref></contrib>
<contrib contrib-type="author"><name><surname>Zocco</surname><given-names>Giuseppe</given-names></name><xref ref-type="aff" rid="aff-1"><sup>1</sup></xref></contrib>
<contrib contrib-type="author"><name><surname>Chiarugi</surname><given-names>Massimo</given-names></name><xref ref-type="aff" rid="aff-1"><sup>1</sup></xref></contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Coccolini</surname><given-names>Federico</given-names></name><xref ref-type="aff" rid="aff-1"><sup>1</sup></xref></contrib>
</contrib-group>
<aff id="aff-1"><label>1</label>General, Emergency and Trauma Surgery Department, Pisa University Hospital, Pisa, Italy</aff>
<author-notes>
<corresp id="cor1"><bold>Corresponding author:</bold> Federico Coccolini MD, General, Emergency and Trauma Surgery, Pisa University Hospital, Via Paradisia 1, 56100, Pisa, Italy. Email: <email xlink:href="mailto:federico.coccolini@gmail.com">federico.coccolini@gmail.com</email>.</corresp>
<fn><label>Conflicts of Interest</label><p>The authors declare that they have no conflicts of interest.</p></fn>
<fn fn-type="financial-disclosure"><label>Funding</label><p>The authors received no financial support for the research, authorship, and/or publication of this article.</p></fn></author-notes>
<pub-date iso-8601-date="2024-04-11" date-type="pub" publication-format="electronic">
<day>11</day>
<month>04</month>
<year>2024</year>
</pub-date>
<volume>8</volume>
<issue>1</issue>
<fpage>12</fpage>
<lpage>16</lpage>
<history>
<date iso-8601-date="2024-02-08" date-type="received">
<day>08</day>
<month>02</month>
<year>2024</year></date>
<date iso-8601-date="2024-02-13" date-type="accepted">
<day>13</day>
<month>02</month>
<year>2024</year></date></history>
<permissions>
<copyright-statement>Copyright: &#x00A9; 2024 The Author(s)</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>The Author(s)</copyright-holder>
<license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/">
<license-p>This is an open access article published under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<abstract>
<p>Pelvic fracture is one of the most complex injuries in trauma treatment. Bleeding continues to be one of the primary causes of death from pelvic fracture, and the severity of bleeding is not necessarily correlated with the fracture pattern. The priorities in managing pelvic fractures include controlling bleeding. Historically, classification systems only consider the anatomical fracture pattern, which does not correlate with the outcomes. The World Society of Emergency Surgery (WSES) classification considers both the pelvic fracture pattern and the hemodynamic condition of the patient. Vascular injuries caused by pelvic fractures are potentially lethal because they often manifest as non-compressible multifocal venous bleeding (80&#x2013;85% of pelvic bleeding) and less frequently as arterial bleeding (15&#x2013;20% of pelvic bleeding). The presence of vascular injury and open pelvic fractures are independent factors contributing to mortality. Another fundamental factor in the management of pelvic vascular trauma is time [<xref ref-type="bibr" rid="r1">1</xref>]. In this context, the assessment of potentially significant vascular injury and timely hemorrhage control should be the highest priorities in the acute management of these injuries. Classification of pelvic injuries that considers both the fracture pattern and the hemodynamic status of the patient, such as the WSES classification, appears to have greater utility in clinical practice compared to the diffused anatomical classification.</p>
</abstract>
<kwd-group>
<title>Keywords</title>
<kwd>Pelvic Fracture</kwd>
<kwd>Blunt Trauma</kwd>
<kwd>Hemodynamic Status</kwd>
<kwd>Bleeding</kwd>
<kwd>Vascular Injuries</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<sec id="s1">
<title>INTRODUCTION</title>
<p>Pelvic fracture is one of the most complex injuries in trauma treatment and is often the result of high-energy blunt trauma, accounting for approximately 3% of all skeletal injuries [<xref ref-type="bibr" rid="r2">2</xref>&#x2013;<xref ref-type="bibr" rid="r4">4</xref>]. Patients are typically young and exhibit a high Injury Severity Score (ISS). Mortality rates remain elevated, ranging from 5 to 16%, particularly in patients with hemodynamic instability and severe associated injuries [<xref ref-type="bibr" rid="r5">5&#x2013;</xref><xref ref-type="bibr" rid="r7">7</xref>].</p>
<p>Bleeding continues to be one of the primary causes of death from pelvic fracture, and the severity of bleeding is not necessarily correlated with the fracture pattern. In patients with pelvic trauma, the prognosis is more closely linked to the severity of pelvic vascular injury than to pelvic ring fractures [<xref ref-type="bibr" rid="r8">8</xref>]. The initial management of pelvic trauma primarily focuses on physiological alterations and associated injuries, placing less emphasis on fracture patterns. The priorities in managing pelvic fractures include controlling bleeding, stabilizing hemodynamics, correcting coagulopathy and physiology, followed by achieving definitive mechanical stabilization of the pelvic ring.</p>
<p>Historically, the Young&#x2013;Burgess [<xref ref-type="bibr" rid="r9">9</xref>] and Tile [<xref ref-type="bibr" rid="r10">10</xref>] classifications are the two most commonly recognized in the literature. These two classification systems only consider the anatomical fracture pattern, which does not correlate with the outcomes of patients with pelvic trauma. Rommens et al. [11] recently developed a radiographic classification (anatomical fracture pattern) for managing fragility fractures of the pelvis (FFPs) [<xref ref-type="bibr" rid="r11">11</xref>,<xref ref-type="bibr" rid="r12">12</xref>].</p>
<p>In 2017, the World Society of Emergency Surgery (WSES) published its guidelines for the classification and management of pelvic trauma. The WSES classification categorizes pelvic trauma injuries into mild, moderate, and severe, taking into consideration both the pelvic fracture pattern and the hemodynamic condition of the patient [<xref ref-type="bibr" rid="r13">13</xref>]. Pelvic fractures may be open or closed. Open pelvic fractures are relatively rare but more complex due to concurrent internal and external bleeding [<xref ref-type="bibr" rid="r14">14</xref>]. They are also usually associated with the onset of infection that may progress to sepsis, contributing to mortality [<xref ref-type="bibr" rid="r4">4</xref>,<xref ref-type="bibr" rid="r15">15</xref>&#x2013;<xref ref-type="bibr" rid="r18">18</xref>]. Sepsis is associated with only 2&#x2013;4% of all pelvic fractures but carries a mortality rate of up to 45% [<xref ref-type="bibr" rid="r19">19</xref>&#x2013;<xref ref-type="bibr" rid="r21">21</xref>]. Therefore, an open pelvic fracture can be regarded as a specific pattern of disease with distinct injury severity and treatment strategies [<xref ref-type="bibr" rid="r22">22</xref>].</p>
<sec id="s1_1">
<title>Ethical Approval and Informed Consent</title>
<p>Ethical approval was not required. Informed consent was not required.</p>
</sec>
</sec>
<sec id="s2">
<title>YOUNG&#x2013;BURGESS CLASSIFICATION</title>
<p>The Young&#x2013;Burgess classification (<xref ref-type="fig" rid="F1">Figure 1</xref>) categorizes pelvic fractures according to the mechanism of injury [<xref ref-type="bibr" rid="r9">9</xref>]:</p>
<fig id="F1">
<label>Figure 1</label>
<caption><p>Young&#x2013;Burgess classification for skeletal pelvic lesions.</p></caption>
<p><italic>Credit: Reproduced from Coccolini, F. et al. World J Emerg Surg. 2017;12:1&#x2013;18, under CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/).</italic></p>
<graphic xlink:href="JEVTM_22378_Figure01.jpg" mimetype="image/jpeg"><alt-text>Figure 1</alt-text></graphic>
</fig>
<list list-type="bullet" id="listun001">
<list-item><p>Antero-Posterior Compression (APC):</p>
<list list-type="bullet" id="listun002">
<list-item><p>APC I: less than 2.5 cm of widening of the pubic symphysis with no posterior instability, both clinically and radiographically;</p></list-item>
<list-item><p>APC II: widening of the pubic symphysis and posterior pelvic instability due to the rupture of the anterior sacroiliac complex;</p></list-item>
<list-item><p>APC III: associated with complete posterior ligamentous disruption.</p></list-item></list></list-item>
<list-item><p>Lateral Compression (LC): LC injuries occur when a force, applied laterally and directed medially, is exerted on the pelvis. Fractures are more common with LC injuries compared to APC injuries.</p>
<list list-type="bullet" id="listun003">
<list-item><p>LC I: lateral force applied to the back of the pelvis, representing a spectrum of injuries. The severity of sacral injury varies from an incomplete anterior iliac wing fracture to a complete sacral fracture, depending on the amount of energy applied to the pelvis at the time of injury. The degree of pelvic instability correlates with the severity of the injury, and there might be a role for stress radiographs in classifying this instability;</p></list-item>
<list-item><p>LC II: sacral fracture, rupture of the sacroiliac ligament and joint, or a crescent-shaped fracture dislocation of the ilium;</p></list-item>
<list-item><p>LC III: injuries result from a greater force. Ipsilateral internal rotation of the hemipelvis causes injuries to the contralateral hemipelvis in the form of anterior sacroiliac ligament rupture and injury to the sacrospinous and sacrotuberous ligaments.</p></list-item></list></list-item>
<list-item><p>Vertical Shear (VS): These injuries result from an axial force applied to one or both hemipelvis lateral to the midline. The sacrum is pushed downward, causing complete ligamentous injury. Pelvic ring fracture may be present instead of ligamentous injury.</p></list-item>
<list-item><p>Complex: A combination of the three primary patterns (APC, LC, or VS). Most of them result from combined LC injuries with APC or VS patterns.</p></list-item></list>
</sec>
<sec id="s3">
<title>TILE CLASSIFICATION</title>
<p>The Tile Classification (1980) is based on the type of mechanical instability of the pelvic ring [<xref ref-type="bibr" rid="r10">10</xref>].</p>
<list list-type="bullet" id="listun004">
<list-item><p>Type A: does not involve the pelvic ring itself and it is mechanically stable;</p></list-item>
<list-item><p>Type B: rotational instability;</p></list-item>
<list-item><p>Type C: vertical instability.</p></list-item></list>
</sec>
<sec id="s4">
<title>ROMMENS CLASSIFICATION FOR FFPs </title>
<p>The Rommens Classification is a classification for managing FFPs resulting from low-energy impacts (typically in elderly patients). It is based on morphological criteria and corresponds to the degree of instability of the pelvis [<xref ref-type="bibr" rid="r11">11</xref>,<xref ref-type="bibr" rid="r12">12</xref>].</p>
<list list-type="bullet" id="listun005">
<list-item><p>FFP type I:</p>
<list list-type="bullet" id="listun006">
<list-item><p>a: unilateral anterior pelvic ring disruption;</p></list-item>
<list-item><p>b: bilateral anterior pelvic ring disruption;</p></list-item></list></list-item>
<list-item><p>FFP type II:</p>
<list list-type="bullet" id="listun007">
<list-item><p>a: dorsal non-displaced posterior injury;</p></list-item>
<list-item><p>b: only sacral crush with anterior disruption;</p></list-item>
<list-item><p>c: non-displaced sacral, sacroiliac, or iliac fracture with anterior disruption;</p></list-item></list></list-item>
<list-item><p>FFP type III:</p>
<list list-type="bullet" id="listun008">
<list-item><p>a: displaced unilateral ilium fracture and anterior disruption;</p></list-item>
<list-item><p>b: displaced unilateral sacroiliac disruption and anterior disruption;</p></list-item>
<list-item><p>c: displaced unilateral sacral fracture together with anterior disruption;</p></list-item></list></list-item>
<list-item><p>FFP type IV:</p>
<list list-type="bullet" id="listun009">
<list-item><p>a: bilateral iliac fractures or bilateral sacroiliac disruptions together with anterior disruption;</p></list-item>
<list-item><p>b: spinopelvic dissociation together with anterior disruption;</p></list-item>
<list-item><p>c: a combination of various posterior instabilities together with anterior disruption.</p></list-item></list></list-item></list>
</sec>
<sec id="s5">
<title>WSES CLASSIFICATION</title>
<p>The WSES classification takes into account both the anatomical pattern of pelvic fracture and physiological changes in the patient (hemodynamic stability or instability). The WSES Classification divides pelvic ring injuries into three classes (<xref ref-type="table" rid="T1">Table 1</xref>):</p>
<table-wrap id="T1" position="float">
<label>Table 1</label>
<caption><p>WSES Classification.</p></caption>
<table frame="hsides" rules="all">
<thead>
<tr>
<th align="left" valign="bottom"><italic>WSES Classification</italic></th>
<th align="left" valign="bottom"><italic>WSES Grade</italic></th>
<th align="left" valign="bottom"><italic>Young&#x2013;Burgess Classification</italic></th>
<th align="left" valign="bottom"><italic>Hemodynamics</italic></th>
<th align="left" valign="bottom"><italic>Mechanic</italic></th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top">Minor</td>
<td align="left" valign="top">WSES grade I</td>
<td align="left" valign="top">APC I &#x2013; LC I</td>
<td align="left" valign="top">Stable</td>
<td align="left" valign="top">Stable</td>
</tr>
<tr>
<td align="left" valign="top">Moderate</td>
<td align="left" valign="top">WSES grade II</td>
<td align="left" valign="top">LC II/III &#x2013; APC II/III</td>
<td align="left" valign="top">Stable</td>
<td align="left" valign="top">Unstable</td>
</tr>
<tr>
<td align="left" valign="top"/>
<td align="left" valign="top">WSES grade III</td>
<td align="left" valign="top">VS &#x2013; CM</td>
<td align="left" valign="top">Stable</td>
<td align="left" valign="top">Unstable</td>
</tr>
<tr>
<td align="left" valign="top">Severe</td>
<td align="left" valign="top">WSES grade IV</td>
<td align="left" valign="top">Any</td>
<td align="left" valign="top">Unstable</td>
<td align="left" valign="top">Any</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn-group>
<fn><p>Credit: Reproduced from Coccolini, R. et al. World J Emerg Surg. 2017;12:1&#x2013;18, under CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/).</p></fn>
</fn-group>
</table-wrap-foot>
</table-wrap>
<list list-type="bullet" id="listun010">
<list-item><p>Minor (WSES Grade I): hemodynamically and mechanically stable injuries (APC 1 and LC 1);</p></list-item>
<list-item><p>Moderate (WSES Grades II and III): hemodynamically stable and mechanically unstable injuries (APC 2&#x2013;3 and LC 2&#x2013;3);</p></list-item>
<list-item><p>Severe (WSES Grade IV): hemodynamically unstable injuries regardless of mechanical status.</p></list-item></list>
<p>As previously mentioned, the ATLS definition considers a patient &#x201C;hemodynamically unstable&#x201D; when blood pressure &lt;90 mmHg and heart rate &gt;120 bpm, with evidence of cutaneous vasoconstriction (cold, moist, reduced capillary refill), an altered level of consciousness and/or dyspnea [<xref ref-type="bibr" rid="r23">23</xref>].</p>
<p>Based on this classification, WSES has provided a management algorithm for patients with pelvic trauma [<xref ref-type="bibr" rid="r13">13</xref>].</p>
</sec>
<sec id="s6">
<title>DISCUSSION</title>
<p>The management of pelvic trauma continues to be a challenge. Pelvic fractures are often the result of high-energy impact and are generally associated with multisystem injuries and catastrophic bleeding. Most deaths related to pelvic fractures have been caused by associated injuries (i.e., brain trauma) [<xref ref-type="bibr" rid="r24">24</xref>&#x2013;<xref ref-type="bibr" rid="r26">26</xref>]. Vascular injuries caused by pelvic fractures are potentially lethal because they often manifest as non-compressible multifocal venous bleeding (80&#x2013;85% of pelvic bleeding) and less frequently arterial bleeding (15&#x2013;20% of pelvic bleeding). In pelvic trauma, hemorrhage is indeed the most common cause of preventable death [<xref ref-type="bibr" rid="r8">8</xref>]. However, the Young&#x2013;Burgess and Tile classification models do not correlate with the number of transfusions and do not show a consistent correlation with the need for urgent embolization.</p>
<p>The WSES classification of pelvic trauma, in addition to pelvic fracture stability, takes into consideration the hemodynamic conditions of the patient, allowing for an approach that directly targets the stabilization of hemodynamics and the control of pelvic bleeding.</p>
<p>Wang et al. [<xref ref-type="bibr" rid="r27">27</xref>], in line with the WSES classification, confirm that in patients with pelvic trauma mortality rates increase significantly with the severity of the injury class (from minor to severe injuries). They also note that the stability/instability of the pelvic ring does not have a significant impact on mortality. Furthermore, Wang et al. highlight the presence of vascular injury and open pelvic fractures as independent factors contributing to mortality [<xref ref-type="bibr" rid="r27">27</xref>]. Pelvic vascular injuries have been identified in 7&#x2013;10% of stable pelvic fractures, often considered minor injuries and typically managed conservatively. Some of these fractures may even require angiographic embolization. Not only should the mechanical stability be assessed, but the associated vascular injury should also be considered in the management algorithm. The impact of mechanical pelvic stability on pelvic fracture mortality was statistically non-significant. However, the associated vascular injury served as an independent risk factor for mortality. Unlike closed fractures, open pelvic fractures can lead to concurrent external bleeding, internal hemorrhage, associated injuries to the ano-rectal or urogenital regions, infections related to contaminated wounds, and other complications (sepsis and multi-organ dysfunction). Patients with open pelvic fractures exhibit significantly worse outcomes (higher mortality rate, increased infection rate, longer hospitalization time, and extended stay in the intensive care unit) compared to patients with closed pelvic fractures of the same WSES class (minor, moderate, and severe) [<xref ref-type="bibr" rid="r27">27</xref>].</p>
<p>Li et al. [<xref ref-type="bibr" rid="r22">22</xref>] evaluated the application of the WSES classification to patients with open pelvic fractures. In their study, they highlight that even in the case of open pelvic fractures, mortality, duration of intensive care unit admission, and hospitalization duration increase with the rising WSES grade of pelvic trauma. Furthermore, there is a correlation between open pelvic fractures and the development of sepsis. Sepsis proves to be an independent risk factor for mortality in patients with open pelvic fractures. Additionally, patients with sepsis exhibit significantly higher percentages of pelvic instability and associated vascular injuries compared to patients without septicemia. Besides hemorrhage control, the management of wound infection and the potential development of sepsis are crucial in the management of open pelvic fractures (broad-spectrum antibiotics for gram-positive and gram-negative bacteria, surgical debridement, and creation of a diverting colostomy). According to Li et al., the WSES classification is applicable when managing patients with open pelvic fractures; however, they emphasize that by adding the onset of sepsis as an additional variable (WSES classification + sepsis), a better prediction of mortality is achieved in cases of open pelvic fractures [<xref ref-type="bibr" rid="r22">22</xref>].</p>
<p>Another fundamental factor in the management of pelvic vascular trauma is time [<xref ref-type="bibr" rid="r1">1</xref>]. In this context, the assessment of potentially significant vascular injury and timely hemorrhage control should be the highest priorities in acute management [<xref ref-type="bibr" rid="r8">8</xref>].</p>
<p>In a retrospective cohort study, Spering et al. proposed a score to detect pelvic vascular injury in patients with severe pelvic fractures in pre-hospital trauma management. They identified nine predictive factors incorporated into a clinical score to identify patients with pelvic fractures at risk of significant vascular injury (P-VIS) [<xref ref-type="bibr" rid="r1">1</xref>].</p>
<list list-type="bullet" id="listun011">
<list-item><p>Patient condition:</p>
<list list-type="bullet" id="listun012">
<list-item><p>Age &#x2265;70 years;</p></list-item>
<list-item><p>High-energy trauma;</p></list-item>
<list-item><p>Penetrating trauma/open pelvic injury;</p></list-item>
<list-item><p>Shock index &#x2265;1;</p></list-item></list></list-item>
<list-item><p>Pre-hospital interventions:</p>
<list list-type="bullet" id="listun013">
<list-item><p>Cardiopulmonary Resuscitation;</p></list-item>
<list-item><p>Replacement of &gt;1 liter of fluid;</p></list-item>
<list-item><p>Intubation;</p></list-item></list></list-item>
<list-item><p>Compensation:</p>
<list list-type="bullet" id="listun014">
<list-item><p>Need for vasoactive drug therapy;</p></list-item>
<list-item><p>Residual shock (systolic blood pressure SBP &#x2264;90 mmHg) under therapy.</p></list-item></list></list-item></list>
<p>A score of 0&#x2013;2 points represents almost no risk of vascular injury, 3&#x2013;5 points indicate a probable pelvic vascular injury, 6&#x2013;8 points identify a very probable pelvic vascular injury, and 9 points represent an apparent vascular injury. This score is easy to apply and would suggest early pelvic stabilization through pelvic binding, as well as immediate transfer to a Level I Trauma Center and the subsequent early activation of an extended trauma team with vascular repair capabilities and high transfusion availability.</p>
</sec>
<sec id="s7">
<title>CONCLUSIONS</title>
<p>The severity of hemodynamic and physio-metabolic derangement represents a fundamental issue in the early management of patients with pelvic trauma.</p>
<p>Therefore, a classification of pelvic injuries that considers both the fracture pattern and the hemodynamic status of the patient, such as the WSES classification, appears to have greater utility in clinical practice compared to the diffused anatomical classification.</p>
</sec>
</body>
<back>
<sec id="s8">
<title>Ethics Statement</title>
<list list-type="order" prefix-word="(" id="list001">
<list-item><p>All the authors mentioned in the manuscript have agreed to authorship, read and approved the manuscript, and given consent for submission and subsequent publication of the manuscript.</p></list-item>
<list-item><p>The authors declare that they have read and abided by the JEVTM statement of ethical standards including rules of informed consent and ethical committee approval as stated in the article.</p></list-item>
</list>
</sec>
<ref-list>
<title>REFERENCES</title>
<ref id="r1"><mixed-citation publication-type="journal"><person-group person-group-type="author"><string-name><surname>Spering</surname> <given-names>C</given-names></string-name>, <string-name><surname>Lehmann</surname> <given-names>W</given-names></string-name>, <string-name><surname>M&#x00F6;ller</surname><given-names>S</given-names></string-name>, <etal>et al</etal></person-group>. <article-title>The pelvic vascular injury score (P-VIS): a prehospital instrument to detect significant vascular injury in pelvic fractures</article-title>. <source>Eur J Trauma Emerg Surg Off Publ Eur Trauma Soc</source>. <year>2023</year>; doi: <pub-id pub-id-type="doi">10.1007/s00068-023-02374-x</pub-id>.</mixed-citation></ref>
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