Is GERD a Factor in Osteonecrosis of the Jaw? Evidence of Pathology Linked to G6PD Deficiency and Sulfomucins
Identifieur interne : 008940 ( Ncbi/Merge ); précédent : 008939; suivant : 008941Is GERD a Factor in Osteonecrosis of the Jaw? Evidence of Pathology Linked to G6PD Deficiency and Sulfomucins
Auteurs : Stephanie Seneff [États-Unis] ; Nancy L. Swanson [États-Unis] ; Gerald Koenig [États-Unis] ; Chen Li [États-Unis]Source :
- Disease Markers [ 0278-0240 ] ; 2016.
Abstract
Osteonecrosis of the jaw (ONJ), a rare side effect of bisphosphonate therapy, is a debilitating disorder with a poorly understood etiology. FDA's Adverse Event Reporting System (FAERS) provides the opportunity to investigate this disease. Our goals were to analyze FAERS data to discover possible relationships between ONJ and specific conditions and drugs and then to consult the scientific literature to deduce biological explanations. Our methodology revealed a very strong association between gastroesophageal reflux and bisphosphonate-induced ONJ, suggesting acidosis as a key factor. Overgrowth of acidophilic species, particularly
Url:
DOI: 10.1155/2016/8376979
PubMed: 27773962
PubMed Central: 5059643
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<front><div type="abstract" xml:lang="en"><p>Osteonecrosis of the jaw (ONJ), a rare side effect of bisphosphonate therapy, is a debilitating disorder with a poorly understood etiology. FDA's Adverse Event Reporting System (FAERS) provides the opportunity to investigate this disease. Our goals were to analyze FAERS data to discover possible relationships between ONJ and specific conditions and drugs and then to consult the scientific literature to deduce biological explanations. Our methodology revealed a very strong association between gastroesophageal reflux and bisphosphonate-induced ONJ, suggesting acidosis as a key factor. Overgrowth of acidophilic species, particularly<italic> Streptococcus mutans</italic>
, in the oral microbiome in the context of insufficient acid buffering due to impaired salivary glands maintains the low pH that sustains damage to the mucosa. Significant associations between ONJ and adrenal insufficiency, vitamin C deficiency, and Sjögren's syndrome were found. Glucose 6 phosphate dehydrogenase (G6PD) deficiency can explain much of the pathology. An inability to maintain vitamin C and other antioxidants in the reduced form leads to vascular oxidative damage and impaired adrenal function. Thus, pathogen-induced acidosis, hypoxia, and insufficient antioxidant defenses together induce ONJ. G6PD deficiency and adrenal insufficiency are underlying factors. Impaired supply of adrenal-derived sulfated sterols such as DHEA sulfate may drive the disease process.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Dis Markers</journal-id>
<journal-id journal-id-type="iso-abbrev">Dis. Markers</journal-id>
<journal-id journal-id-type="publisher-id">DM</journal-id>
<journal-title-group><journal-title>Disease Markers</journal-title>
</journal-title-group>
<issn pub-type="ppub">0278-0240</issn>
<issn pub-type="epub">1875-8630</issn>
<publisher><publisher-name>Hindawi Publishing Corporation</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27773962</article-id>
<article-id pub-id-type="pmc">5059643</article-id>
<article-id pub-id-type="doi">10.1155/2016/8376979</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Is GERD a Factor in Osteonecrosis of the Jaw? Evidence of Pathology Linked to G6PD Deficiency and Sulfomucins</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0001-8191-1049</contrib-id>
<name><surname>Seneff</surname>
<given-names>Stephanie</given-names>
</name>
<xref ref-type="aff" rid="I1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Swanson</surname>
<given-names>Nancy L.</given-names>
</name>
<xref ref-type="aff" rid="I2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-6405-9410</contrib-id>
<name><surname>Koenig</surname>
<given-names>Gerald</given-names>
</name>
<xref ref-type="aff" rid="I3"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="I4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Chen</given-names>
</name>
<xref ref-type="aff" rid="I1"><sup>1</sup>
</xref>
</contrib>
</contrib-group>
<aff id="I1"><sup>1</sup>
Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA</aff>
<aff id="I2"><sup>2</sup>
Abacus Enterprises, Lummi Island, WA, USA</aff>
<aff id="I3"><sup>3</sup>
Health-e-Iron, LLC, 2800 Waymaker Way, No. 12, Austin, TX 78746, USA</aff>
<aff id="I4"><sup>4</sup>
Iron Disorders Institute, Greenville, SC 29615, USA</aff>
<author-notes><corresp id="cor1">*Stephanie Seneff: <email>seneff@csail.mit.edu</email>
</corresp>
<fn fn-type="other"><p>Academic Editor: Benedita Sampaio-Maia</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><year>2016</year>
</pub-date>
<pub-date pub-type="epub"><day>28</day>
<month>9</month>
<year>2016</year>
</pub-date>
<volume>2016</volume>
<elocation-id>8376979</elocation-id>
<history><date date-type="received"><day>11</day>
<month>4</month>
<year>2016</year>
</date>
<date date-type="rev-recd"><day>18</day>
<month>5</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>20</day>
<month>7</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2016 Stephanie Seneff et al.</copyright-statement>
<copyright-year>2016</copyright-year>
<license xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<abstract><p>Osteonecrosis of the jaw (ONJ), a rare side effect of bisphosphonate therapy, is a debilitating disorder with a poorly understood etiology. FDA's Adverse Event Reporting System (FAERS) provides the opportunity to investigate this disease. Our goals were to analyze FAERS data to discover possible relationships between ONJ and specific conditions and drugs and then to consult the scientific literature to deduce biological explanations. Our methodology revealed a very strong association between gastroesophageal reflux and bisphosphonate-induced ONJ, suggesting acidosis as a key factor. Overgrowth of acidophilic species, particularly<italic> Streptococcus mutans</italic>
, in the oral microbiome in the context of insufficient acid buffering due to impaired salivary glands maintains the low pH that sustains damage to the mucosa. Significant associations between ONJ and adrenal insufficiency, vitamin C deficiency, and Sjögren's syndrome were found. Glucose 6 phosphate dehydrogenase (G6PD) deficiency can explain much of the pathology. An inability to maintain vitamin C and other antioxidants in the reduced form leads to vascular oxidative damage and impaired adrenal function. Thus, pathogen-induced acidosis, hypoxia, and insufficient antioxidant defenses together induce ONJ. G6PD deficiency and adrenal insufficiency are underlying factors. Impaired supply of adrenal-derived sulfated sterols such as DHEA sulfate may drive the disease process.</p>
</abstract>
</article-meta>
</front>
<floats-group><fig id="fig1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Schematic of the sequential stages of the proposed disease process leading to ONJ and the subsequent protection from IBD due to associated erosion of the oral mucosa.</p>
</caption>
<graphic xlink:href="DM2016-8376979.001"></graphic>
</fig>
<fig id="fig2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Schematic of complex structure of heparan sulfate chains. [<bold>X</bold>
], [<bold>Y</bold>
], and [<bold>Z</bold>
] can each be just a hydrogen atom or an acetyl group or a sulfate in a complex information-bearing pattern.</p>
</caption>
<graphic xlink:href="DM2016-8376979.002"></graphic>
</fig>
<table-wrap id="tab1" orientation="portrait" position="float"><label>Table 1</label>
<caption><p>Evidence that ONJ is associated with a very strong overrepresentation of diseases of the teeth and gums, as well as rhinitis, compared to NOT ONJ.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Side effect</th>
<th align="center" rowspan="1" colspan="1">Count 1</th>
<th align="center" rowspan="1" colspan="1">Count 2</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>1</sub>
/<italic>f</italic>
<sub>2</sub>
</th>
<th align="center" rowspan="1" colspan="1">Score</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">% periodont</td>
<td align="center" rowspan="1" colspan="1">1950</td>
<td align="center" rowspan="1" colspan="1">2081</td>
<td align="center" rowspan="1" colspan="1">65.7</td>
<td align="center" rowspan="1" colspan="1">985</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">% dental</td>
<td align="center" rowspan="1" colspan="1">4281</td>
<td align="center" rowspan="1" colspan="1">9029</td>
<td align="center" rowspan="1" colspan="1">33.5</td>
<td align="center" rowspan="1" colspan="1">971</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Tooth extraction</td>
<td align="center" rowspan="1" colspan="1">1615</td>
<td align="center" rowspan="1" colspan="1">5325</td>
<td align="center" rowspan="1" colspan="1">21.7</td>
<td align="center" rowspan="1" colspan="1">956</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">% rhinitis</td>
<td align="center" rowspan="1" colspan="1">703</td>
<td align="center" rowspan="1" colspan="1">3121</td>
<td align="center" rowspan="1" colspan="1">15.9</td>
<td align="center" rowspan="1" colspan="1">941</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">% mucosa</td>
<td align="center" rowspan="1" colspan="1">1002</td>
<td align="center" rowspan="1" colspan="1">5085</td>
<td align="center" rowspan="1" colspan="1">14.2</td>
<td align="center" rowspan="1" colspan="1">934</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Total count</td>
<td align="center" rowspan="1" colspan="1">10580</td>
<td align="center" rowspan="1" colspan="1">762002</td>
<td align="center" rowspan="1" colspan="1">1.0</td>
<td align="center" rowspan="1" colspan="1">500</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tab2" orientation="portrait" position="float"><label>Table 2</label>
<caption><p>Evidence that ONJ is associated with vitamin C deficiency. The symptoms associated with scurvy as defined in [<xref rid="B33" ref-type="bibr">33</xref>
] are all significantly overrepresented (>95% CI) in association with ONJ compared to NOT ONJ, many by a wide margin.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Side effect</th>
<th align="center" rowspan="1" colspan="1">Count 1</th>
<th align="center" rowspan="1" colspan="1">Count 2</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>1</sub>
/<italic>f</italic>
<sub>2</sub>
</th>
<th align="center" rowspan="1" colspan="1">Score</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Bleeding gums</td>
<td align="center" rowspan="1" colspan="1">841</td>
<td align="center" rowspan="1" colspan="1">1792</td>
<td align="center" rowspan="1" colspan="1">33.5</td>
<td align="center" rowspan="1" colspan="1">971</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Impaired wound healing</td>
<td align="center" rowspan="1" colspan="1">304</td>
<td align="center" rowspan="1" colspan="1">716</td>
<td align="center" rowspan="1" colspan="1">30.3</td>
<td align="center" rowspan="1" colspan="1">968</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Hyperkeratosis</td>
<td align="center" rowspan="1" colspan="1">274</td>
<td align="center" rowspan="1" colspan="1">925</td>
<td align="center" rowspan="1" colspan="1">21.2</td>
<td align="center" rowspan="1" colspan="1">955</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Joint effusions</td>
<td align="center" rowspan="1" colspan="1">401</td>
<td align="center" rowspan="1" colspan="1">1742</td>
<td align="center" rowspan="1" colspan="1">16.5</td>
<td align="center" rowspan="1" colspan="1">943</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Inflamed gums</td>
<td align="center" rowspan="1" colspan="1">458</td>
<td align="center" rowspan="1" colspan="1">2231</td>
<td align="center" rowspan="1" colspan="1">14.6</td>
<td align="center" rowspan="1" colspan="1">936</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Sjögren's</td>
<td align="center" rowspan="1" colspan="1">85</td>
<td align="center" rowspan="1" colspan="1">531</td>
<td align="center" rowspan="1" colspan="1">11.5</td>
<td align="center" rowspan="1" colspan="1">920</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Ecchymosis</td>
<td align="center" rowspan="1" colspan="1">226</td>
<td align="center" rowspan="1" colspan="1">1437</td>
<td align="center" rowspan="1" colspan="1">11.2</td>
<td align="center" rowspan="1" colspan="1">918</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Infection</td>
<td align="center" rowspan="1" colspan="1">15953</td>
<td align="center" rowspan="1" colspan="1">122729</td>
<td align="center" rowspan="1" colspan="1">9.3</td>
<td align="center" rowspan="1" colspan="1">903</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Folliculitis</td>
<td align="center" rowspan="1" colspan="1">73</td>
<td align="center" rowspan="1" colspan="1">582</td>
<td align="center" rowspan="1" colspan="1">9.0</td>
<td align="center" rowspan="1" colspan="1">900</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Dry eye</td>
<td align="center" rowspan="1" colspan="1">331</td>
<td align="center" rowspan="1" colspan="1">2796</td>
<td align="center" rowspan="1" colspan="1">8.5</td>
<td align="center" rowspan="1" colspan="1">895</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Dry mouth</td>
<td align="center" rowspan="1" colspan="1">608</td>
<td align="center" rowspan="1" colspan="1">7289</td>
<td align="center" rowspan="1" colspan="1">6.0</td>
<td align="center" rowspan="1" colspan="1">857</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Petechiae</td>
<td align="center" rowspan="1" colspan="1">63</td>
<td align="center" rowspan="1" colspan="1">1125</td>
<td align="center" rowspan="1" colspan="1">4.0</td>
<td align="center" rowspan="1" colspan="1">801</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Muscular weakness</td>
<td align="center" rowspan="1" colspan="1">734</td>
<td align="center" rowspan="1" colspan="1">13614</td>
<td align="center" rowspan="1" colspan="1">3.9</td>
<td align="center" rowspan="1" colspan="1">795</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Anaemia</td>
<td align="center" rowspan="1" colspan="1">4602</td>
<td align="center" rowspan="1" colspan="1">86759</td>
<td align="center" rowspan="1" colspan="1">3.8</td>
<td align="center" rowspan="1" colspan="1">792</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Haemorrhage</td>
<td align="center" rowspan="1" colspan="1">2996</td>
<td align="center" rowspan="1" colspan="1">62389</td>
<td align="center" rowspan="1" colspan="1">3.4</td>
<td align="center" rowspan="1" colspan="1">775</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Fatigue</td>
<td align="center" rowspan="1" colspan="1">2653</td>
<td align="center" rowspan="1" colspan="1">62014</td>
<td align="center" rowspan="1" colspan="1">3.1</td>
<td align="center" rowspan="1" colspan="1">754</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Myalgia</td>
<td align="center" rowspan="1" colspan="1">1215</td>
<td align="center" rowspan="1" colspan="1">30573</td>
<td align="center" rowspan="1" colspan="1">2.9</td>
<td align="center" rowspan="1" colspan="1">741</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Arthralgia</td>
<td align="center" rowspan="1" colspan="1">3012</td>
<td align="center" rowspan="1" colspan="1">78226</td>
<td align="center" rowspan="1" colspan="1">2.8</td>
<td align="center" rowspan="1" colspan="1">734</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Depression</td>
<td align="center" rowspan="1" colspan="1">3292</td>
<td align="center" rowspan="1" colspan="1">106774</td>
<td align="center" rowspan="1" colspan="1">2.2</td>
<td align="center" rowspan="1" colspan="1">689</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Total count</td>
<td align="center" rowspan="1" colspan="1">10580</td>
<td align="center" rowspan="1" colspan="1">762002</td>
<td align="center" rowspan="1" colspan="1">1.0</td>
<td align="center" rowspan="1" colspan="1">500</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tab3" orientation="portrait" position="float"><label>Table 3</label>
<caption><p>Evidence that ONJ is linked to Sjögren's syndrome. Both the syndrome itself and the various conditions associated with the syndrome are all overrepresented in association with ONJ compared to NOT ONJ, some by a wide margin of significance.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Side effect</th>
<th align="center" rowspan="1" colspan="1">Count 1</th>
<th align="center" rowspan="1" colspan="1">Count 2</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>1</sub>
/<italic>f</italic>
<sub>2</sub>
</th>
<th align="center" rowspan="1" colspan="1">Score</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Sialoadenitis</td>
<td align="center" rowspan="1" colspan="1">103</td>
<td align="center" rowspan="1" colspan="1">209</td>
<td align="center" rowspan="1" colspan="1">34.7</td>
<td align="center" rowspan="1" colspan="1">972</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Vulvovaginal dryness</td>
<td align="center" rowspan="1" colspan="1">121</td>
<td align="center" rowspan="1" colspan="1">444</td>
<td align="center" rowspan="1" colspan="1">19.4</td>
<td align="center" rowspan="1" colspan="1">951</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">% Sjögren's</td>
<td align="center" rowspan="1" colspan="1">85</td>
<td align="center" rowspan="1" colspan="1">531</td>
<td align="center" rowspan="1" colspan="1">11.5</td>
<td align="center" rowspan="1" colspan="1">920</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Dry eye</td>
<td align="center" rowspan="1" colspan="1">331</td>
<td align="center" rowspan="1" colspan="1">2796</td>
<td align="center" rowspan="1" colspan="1">8.5</td>
<td align="center" rowspan="1" colspan="1">895</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">% lymphoma</td>
<td align="center" rowspan="1" colspan="1">196</td>
<td align="center" rowspan="1" colspan="1">2289</td>
<td align="center" rowspan="1" colspan="1">6.1</td>
<td align="center" rowspan="1" colspan="1">860</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Dry mouth</td>
<td align="center" rowspan="1" colspan="1">608</td>
<td align="center" rowspan="1" colspan="1">7289</td>
<td align="center" rowspan="1" colspan="1">6.0</td>
<td align="center" rowspan="1" colspan="1">857</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Dry skin</td>
<td align="center" rowspan="1" colspan="1">129</td>
<td align="center" rowspan="1" colspan="1">5290</td>
<td align="center" rowspan="1" colspan="1">1.8</td>
<td align="center" rowspan="1" colspan="1">637</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Total count</td>
<td align="center" rowspan="1" colspan="1">10580</td>
<td align="center" rowspan="1" colspan="1">762002</td>
<td align="center" rowspan="1" colspan="1">1.0</td>
<td align="center" rowspan="1" colspan="1">500</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tab4" orientation="portrait" position="float"><label>Table 4</label>
<caption><p>Distribution of the main drugs assigned as plausibly causative in the ONJ subset.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Drug class</th>
<th align="center" rowspan="1" colspan="1">Count</th>
<th align="center" rowspan="1" colspan="1">Percent</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Bisphosphonates</td>
<td align="center" rowspan="1" colspan="1">6153</td>
<td align="center" rowspan="1" colspan="1">58.1%</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">N-containing IV bisphosphonates</td>
<td align="center" rowspan="1" colspan="1">4206</td>
<td align="center" rowspan="1" colspan="1">39.8%</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Other bone resorption inhibitors</td>
<td align="center" rowspan="1" colspan="1">89</td>
<td align="center" rowspan="1" colspan="1">0.8%</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Other drugs</td>
<td align="center" rowspan="1" colspan="1">132</td>
<td align="center" rowspan="1" colspan="1">1.2%</td>
</tr>
<tr><td align="center" colspan="3" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Total</td>
<td align="center" rowspan="1" colspan="1">10580</td>
<td align="center" rowspan="1" colspan="1">100%</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tab5" orientation="portrait" position="float"><label>Table 5</label>
<caption><p>Evidence that ONJ is associated with features strongly linked to osteoporosis. Despite small counts in some cases, all of these features are significantly overrepresented (>95% CI) in association with ONJ compared to NOT ONJ, by a wide margin.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Side effect</th>
<th align="center" rowspan="1" colspan="1">Count 1</th>
<th align="center" rowspan="1" colspan="1">Count 2</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>1</sub>
/<italic>f</italic>
<sub>2</sub>
</th>
<th align="center" rowspan="1" colspan="1">Score</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Kyphosis</td>
<td align="center" rowspan="1" colspan="1">550</td>
<td align="center" rowspan="1" colspan="1">702</td>
<td align="center" rowspan="1" colspan="1">54.6</td>
<td align="center" rowspan="1" colspan="1">982</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Postmenopause</td>
<td align="center" rowspan="1" colspan="1">30</td>
<td align="center" rowspan="1" colspan="1">70</td>
<td align="center" rowspan="1" colspan="1">30.3</td>
<td align="center" rowspan="1" colspan="1">968</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Spinal compression fracture</td>
<td align="center" rowspan="1" colspan="1">718</td>
<td align="center" rowspan="1" colspan="1">1764</td>
<td align="center" rowspan="1" colspan="1">29.3</td>
<td align="center" rowspan="1" colspan="1">967</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Spinal cord compression</td>
<td align="center" rowspan="1" colspan="1">208</td>
<td align="center" rowspan="1" colspan="1">587</td>
<td align="center" rowspan="1" colspan="1">25.3</td>
<td align="center" rowspan="1" colspan="1">962</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">% fracture</td>
<td align="center" rowspan="1" colspan="1">11303</td>
<td align="center" rowspan="1" colspan="1">48430</td>
<td align="center" rowspan="1" colspan="1">16.5</td>
<td align="center" rowspan="1" colspan="1">943</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Obesity</td>
<td align="center" rowspan="1" colspan="1">427</td>
<td align="center" rowspan="1" colspan="1">2080</td>
<td align="center" rowspan="1" colspan="1">14.6</td>
<td align="center" rowspan="1" colspan="1">936</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Type 2 diabetes mellitus</td>
<td align="center" rowspan="1" colspan="1">393</td>
<td align="center" rowspan="1" colspan="1">2269</td>
<td align="center" rowspan="1" colspan="1">12.3</td>
<td align="center" rowspan="1" colspan="1">925</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Menopause</td>
<td align="center" rowspan="1" colspan="1">75</td>
<td align="center" rowspan="1" colspan="1">554</td>
<td align="center" rowspan="1" colspan="1">9.6</td>
<td align="center" rowspan="1" colspan="1">906</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Diabetes mellitus</td>
<td align="center" rowspan="1" colspan="1">666</td>
<td align="center" rowspan="1" colspan="1">7614</td>
<td align="center" rowspan="1" colspan="1">6.3</td>
<td align="center" rowspan="1" colspan="1">863</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tab6" orientation="portrait" position="float"><label>Table 6</label>
<caption><p>Evidence that ONJ is linked to adrenal insufficiency. Not only is adrenal insufficiency itself highly overrepresented in association with ONJ compared to NOT ONJ, but also the various symptoms associated with adrenal insufficiency are also unusually common among sufferers of ONJ. The score is defined in (<xref ref-type="disp-formula" rid="EEq1">1</xref>
).</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Side effect</th>
<th align="center" rowspan="1" colspan="1">Count 1</th>
<th align="center" rowspan="1" colspan="1">Count 2</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>1</sub>
/<italic>f</italic>
<sub>2</sub>
</th>
<th align="center" rowspan="1" colspan="1">Score</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Any adrenal</td>
<td align="center" rowspan="1" colspan="1">591</td>
<td align="center" rowspan="1" colspan="1">1541</td>
<td align="center" rowspan="1" colspan="1">27.6</td>
<td align="center" rowspan="1" colspan="1">965</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Addison's disease</td>
<td align="center" rowspan="1" colspan="1">35</td>
<td align="center" rowspan="1" colspan="1">101</td>
<td align="center" rowspan="1" colspan="1">24.6</td>
<td align="center" rowspan="1" colspan="1">961</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Adrenal insufficiency</td>
<td align="center" rowspan="1" colspan="1">133</td>
<td align="center" rowspan="1" colspan="1">561</td>
<td align="center" rowspan="1" colspan="1">16.9</td>
<td align="center" rowspan="1" colspan="1">944</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Orthostatic hypotension</td>
<td align="center" rowspan="1" colspan="1">216</td>
<td align="center" rowspan="1" colspan="1">1592</td>
<td align="center" rowspan="1" colspan="1">9.8</td>
<td align="center" rowspan="1" colspan="1">907</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Myopathy</td>
<td align="center" rowspan="1" colspan="1">628</td>
<td align="center" rowspan="1" colspan="1">5168</td>
<td align="center" rowspan="1" colspan="1">8.7</td>
<td align="center" rowspan="1" colspan="1">897</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Vertigo</td>
<td align="center" rowspan="1" colspan="1">647</td>
<td align="center" rowspan="1" colspan="1">6526</td>
<td align="center" rowspan="1" colspan="1">7.1</td>
<td align="center" rowspan="1" colspan="1">877</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Hypoglycaemia</td>
<td align="center" rowspan="1" colspan="1">225</td>
<td align="center" rowspan="1" colspan="1">2930</td>
<td align="center" rowspan="1" colspan="1">5.5</td>
<td align="center" rowspan="1" colspan="1">846</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Muscular weakness</td>
<td align="center" rowspan="1" colspan="1">734</td>
<td align="center" rowspan="1" colspan="1">13614</td>
<td align="center" rowspan="1" colspan="1">3.9</td>
<td align="center" rowspan="1" colspan="1">795</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Diarrhea</td>
<td align="center" rowspan="1" colspan="1">2265</td>
<td align="center" rowspan="1" colspan="1">48901</td>
<td align="center" rowspan="1" colspan="1">3.3</td>
<td align="center" rowspan="1" colspan="1">769</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Fatigue</td>
<td align="center" rowspan="1" colspan="1">2653</td>
<td align="center" rowspan="1" colspan="1">62014</td>
<td align="center" rowspan="1" colspan="1">3.1</td>
<td align="center" rowspan="1" colspan="1">754</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Vomiting</td>
<td align="center" rowspan="1" colspan="1">1594</td>
<td align="center" rowspan="1" colspan="1">48934</td>
<td align="center" rowspan="1" colspan="1">2.3</td>
<td align="center" rowspan="1" colspan="1">701</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Nausea</td>
<td align="center" rowspan="1" colspan="1">2186</td>
<td align="center" rowspan="1" colspan="1">74796</td>
<td align="center" rowspan="1" colspan="1">2.1</td>
<td align="center" rowspan="1" colspan="1">677</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Disorientation</td>
<td align="center" rowspan="1" colspan="1">107</td>
<td align="center" rowspan="1" colspan="1">4606</td>
<td align="center" rowspan="1" colspan="1">1.7</td>
<td align="center" rowspan="1" colspan="1">625</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tab7" orientation="portrait" position="float"><label>Table 7</label>
<caption><p>The set of symptom classes that were overrepresented by at least a factor of 3 in the B AND G group compared to the predicted occurrence based on the B NOT G group and the G NOT B group. B: bisphosphonates; G: GERD. As indicated, “MUCOSA” was a substring match, and everything else required exact match. Computation of the score is defined in (<xref ref-type="disp-formula" rid="EEq1">1</xref>
) and computation of the bias is defined in (<xref ref-type="disp-formula" rid="EEq2">2</xref>
).</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Side effect</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>B</sub>
/<italic>f</italic>
<sub>0</sub>
</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>G</sub>
/<italic>f</italic>
<sub>0</sub>
</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>BG</sub>
/<italic>f</italic>
<sub>0</sub>
</th>
<th align="center" rowspan="1" colspan="1">Bias</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Osteonecrosis of jaw</td>
<td align="center" rowspan="1" colspan="1">905</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1">966</td>
<td align="center" rowspan="1" colspan="1">195.85</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Bone marrow oedema</td>
<td align="center" rowspan="1" colspan="1">858</td>
<td align="center" rowspan="1" colspan="1">204</td>
<td align="center" rowspan="1" colspan="1">943</td>
<td align="center" rowspan="1" colspan="1">10.68</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Anhedonia</td>
<td align="center" rowspan="1" colspan="1">660</td>
<td align="center" rowspan="1" colspan="1">428</td>
<td align="center" rowspan="1" colspan="1">851</td>
<td align="center" rowspan="1" colspan="1">3.93</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">% mucosa</td>
<td align="center" rowspan="1" colspan="1">738</td>
<td align="center" rowspan="1" colspan="1">595</td>
<td align="center" rowspan="1" colspan="1">941</td>
<td align="center" rowspan="1" colspan="1">3.85</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Sialoadenitis</td>
<td align="center" rowspan="1" colspan="1">884</td>
<td align="center" rowspan="1" colspan="1">395</td>
<td align="center" rowspan="1" colspan="1">949</td>
<td align="center" rowspan="1" colspan="1">3.74</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Lymphoedema</td>
<td align="center" rowspan="1" colspan="1">809</td>
<td align="center" rowspan="1" colspan="1">546</td>
<td align="center" rowspan="1" colspan="1">950</td>
<td align="center" rowspan="1" colspan="1">3.73</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Oedema</td>
<td align="center" rowspan="1" colspan="1">633</td>
<td align="center" rowspan="1" colspan="1">675</td>
<td align="center" rowspan="1" colspan="1">915</td>
<td align="center" rowspan="1" colspan="1">3.00</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tab8" orientation="portrait" position="float"><label>Table 8</label>
<caption><p>List of drug classes that were overrepresented at least fourfold in the B AND G group compared to what is predicted based on the B-only and G-only groups. The ratio was computed according to (<xref ref-type="disp-formula" rid="EEq2">2</xref>
) in the text. B: bisphosphonates; G: GERD.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Side effect</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>B</sub>
/<italic>f</italic>
<sub>0</sub>
</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>G</sub>
/<italic>f</italic>
<sub>0</sub>
</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>BG</sub>
/<italic>f</italic>
<sub>0</sub>
</th>
<th align="center" rowspan="1" colspan="1">Bias</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Estrogen receptor antagonists</td>
<td align="center" rowspan="1" colspan="1">887</td>
<td align="center" rowspan="1" colspan="1">50</td>
<td align="center" rowspan="1" colspan="1">960</td>
<td align="center" rowspan="1" colspan="1">58.09</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Mouth and throat products</td>
<td align="center" rowspan="1" colspan="1">889</td>
<td align="center" rowspan="1" colspan="1">178</td>
<td align="center" rowspan="1" colspan="1">971</td>
<td align="center" rowspan="1" colspan="1">19.31</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">General anesthetic</td>
<td align="center" rowspan="1" colspan="1">614</td>
<td align="center" rowspan="1" colspan="1">442</td>
<td align="center" rowspan="1" colspan="1">921</td>
<td align="center" rowspan="1" colspan="1">9.25</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Mineralocorticoids</td>
<td align="center" rowspan="1" colspan="1">697</td>
<td align="center" rowspan="1" colspan="1">488</td>
<td align="center" rowspan="1" colspan="1">951</td>
<td align="center" rowspan="1" colspan="1">8.85</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Tamiflu</td>
<td align="center" rowspan="1" colspan="1">237</td>
<td align="center" rowspan="1" colspan="1">474</td>
<td align="center" rowspan="1" colspan="1">695</td>
<td align="center" rowspan="1" colspan="1">8.14</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Thalidomide derivatives</td>
<td align="center" rowspan="1" colspan="1">806</td>
<td align="center" rowspan="1" colspan="1">230</td>
<td align="center" rowspan="1" colspan="1">900</td>
<td align="center" rowspan="1" colspan="1">7.25</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Radiation therapy</td>
<td align="center" rowspan="1" colspan="1">855</td>
<td align="center" rowspan="1" colspan="1">271</td>
<td align="center" rowspan="1" colspan="1">937</td>
<td align="center" rowspan="1" colspan="1">6.79</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Transfusion</td>
<td align="center" rowspan="1" colspan="1">539</td>
<td align="center" rowspan="1" colspan="1">268</td>
<td align="center" rowspan="1" colspan="1">743</td>
<td align="center" rowspan="1" colspan="1">6.75</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Aminoglycoside antibiotics</td>
<td align="center" rowspan="1" colspan="1">554</td>
<td align="center" rowspan="1" colspan="1">408</td>
<td align="center" rowspan="1" colspan="1">841</td>
<td align="center" rowspan="1" colspan="1">6.18</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Other immunosuppressants</td>
<td align="center" rowspan="1" colspan="1">711</td>
<td align="center" rowspan="1" colspan="1">286</td>
<td align="center" rowspan="1" colspan="1">851</td>
<td align="center" rowspan="1" colspan="1">5.80</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Opium receptor antagonists</td>
<td align="center" rowspan="1" colspan="1">687</td>
<td align="center" rowspan="1" colspan="1">525</td>
<td align="center" rowspan="1" colspan="1">928</td>
<td align="center" rowspan="1" colspan="1">5.31</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Unspecified hormones</td>
<td align="center" rowspan="1" colspan="1">861</td>
<td align="center" rowspan="1" colspan="1">359</td>
<td align="center" rowspan="1" colspan="1">946</td>
<td align="center" rowspan="1" colspan="1">5.05</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Gonadotropin-releasing hormone</td>
<td align="center" rowspan="1" colspan="1">818</td>
<td align="center" rowspan="1" colspan="1">200</td>
<td align="center" rowspan="1" colspan="1">846</td>
<td align="center" rowspan="1" colspan="1">4.89</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Proteasome inhibitors</td>
<td align="center" rowspan="1" colspan="1">792</td>
<td align="center" rowspan="1" colspan="1">298</td>
<td align="center" rowspan="1" colspan="1">882</td>
<td align="center" rowspan="1" colspan="1">4.62</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">VEGF/VEGFR inhibitors</td>
<td align="center" rowspan="1" colspan="1">612</td>
<td align="center" rowspan="1" colspan="1">359</td>
<td align="center" rowspan="1" colspan="1">803</td>
<td align="center" rowspan="1" colspan="1">4.61</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Glycopeptide antibiotics</td>
<td align="center" rowspan="1" colspan="1">600</td>
<td align="center" rowspan="1" colspan="1">486</td>
<td align="center" rowspan="1" colspan="1">866</td>
<td align="center" rowspan="1" colspan="1">4.56</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Aromatase inhibitors</td>
<td align="center" rowspan="1" colspan="1">849</td>
<td align="center" rowspan="1" colspan="1">307</td>
<td align="center" rowspan="1" colspan="1">915</td>
<td align="center" rowspan="1" colspan="1">4.32</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Smoking cessation agents</td>
<td align="center" rowspan="1" colspan="1">203</td>
<td align="center" rowspan="1" colspan="1">329</td>
<td align="center" rowspan="1" colspan="1">356</td>
<td align="center" rowspan="1" colspan="1">4.43</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Antineoplastic antibiotics</td>
<td align="center" rowspan="1" colspan="1">729</td>
<td align="center" rowspan="1" colspan="1">420</td>
<td align="center" rowspan="1" colspan="1">896</td>
<td align="center" rowspan="1" colspan="1">4.42</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Recombinant human erythropoietin</td>
<td align="center" rowspan="1" colspan="1">753</td>
<td align="center" rowspan="1" colspan="1">391</td>
<td align="center" rowspan="1" colspan="1">889</td>
<td align="center" rowspan="1" colspan="1">4.09</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Antiviral combinations</td>
<td align="center" rowspan="1" colspan="1">170</td>
<td align="center" rowspan="1" colspan="1">453</td>
<td align="center" rowspan="1" colspan="1">408</td>
<td align="center" rowspan="1" colspan="1">4.06</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tab9" orientation="portrait" position="float"><label>Table 9</label>
<caption><p>Overrepresentation in ONJ of cancers typically treated with many of the drugs that were found to be overrepresented in the B AND G group, when compared to NOT ONJ. All of these results are significant at the 95% CI level by a wide margin. B: bisphosphonates; G: GERD.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Side effect</th>
<th align="center" rowspan="1" colspan="1">Count 1</th>
<th align="center" rowspan="1" colspan="1">Count 2</th>
<th align="center" rowspan="1" colspan="1"><italic>f</italic>
<sub>1</sub>
/<italic>f</italic>
<sub>2</sub>
</th>
<th align="center" rowspan="1" colspan="1">Score</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Myeloma recurrence</td>
<td align="center" rowspan="1" colspan="1">141</td>
<td align="center" rowspan="1" colspan="1">62</td>
<td align="center" rowspan="1" colspan="1">141.9</td>
<td align="center" rowspan="1" colspan="1">993</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Breast cancer recurrent</td>
<td align="center" rowspan="1" colspan="1">155</td>
<td align="center" rowspan="1" colspan="1">187</td>
<td align="center" rowspan="1" colspan="1">57.8</td>
<td align="center" rowspan="1" colspan="1">983</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Prostate cancer metastatic</td>
<td align="center" rowspan="1" colspan="1">144</td>
<td align="center" rowspan="1" colspan="1">185</td>
<td align="center" rowspan="1" colspan="1">54.6</td>
<td align="center" rowspan="1" colspan="1">982</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Multiple myeloma</td>
<td align="center" rowspan="1" colspan="1">905</td>
<td align="center" rowspan="1" colspan="1">1404</td>
<td align="center" rowspan="1" colspan="1">44.5</td>
<td align="center" rowspan="1" colspan="1">978</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Prostate cancer</td>
<td align="center" rowspan="1" colspan="1">164</td>
<td align="center" rowspan="1" colspan="1">818</td>
<td align="center" rowspan="1" colspan="1">14.4</td>
<td align="center" rowspan="1" colspan="1">935</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Breast cancer metastatic</td>
<td align="center" rowspan="1" colspan="1">263</td>
<td align="center" rowspan="1" colspan="1">552</td>
<td align="center" rowspan="1" colspan="1">33.5</td>
<td align="center" rowspan="1" colspan="1">971</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Breast cancer</td>
<td align="center" rowspan="1" colspan="1">234</td>
<td align="center" rowspan="1" colspan="1">2311</td>
<td align="center" rowspan="1" colspan="1">7.3</td>
<td align="center" rowspan="1" colspan="1">879</td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list><country><li>États-Unis</li>
</country>
</list>
<tree><country name="États-Unis"><noRegion><name sortKey="Seneff, Stephanie" sort="Seneff, Stephanie" uniqKey="Seneff S" first="Stephanie" last="Seneff">Stephanie Seneff</name>
</noRegion>
<name sortKey="Koenig, Gerald" sort="Koenig, Gerald" uniqKey="Koenig G" first="Gerald" last="Koenig">Gerald Koenig</name>
<name sortKey="Koenig, Gerald" sort="Koenig, Gerald" uniqKey="Koenig G" first="Gerald" last="Koenig">Gerald Koenig</name>
<name sortKey="Li, Chen" sort="Li, Chen" uniqKey="Li C" first="Chen" last="Li">Chen Li</name>
<name sortKey="Swanson, Nancy L" sort="Swanson, Nancy L" uniqKey="Swanson N" first="Nancy L." last="Swanson">Nancy L. Swanson</name>
</country>
</tree>
</affiliations>
</record>
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