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the treatment of severe inflammatory acne vulgaris" /></a></div><div class="bkr_bib"><h1 id="_NBK573049_"><span itemprop="name">Addition of oral corticosteroids to oral isotretinoin for the treatment of severe inflammatory acne vulgaris</span></h1><div class="subtitle">Acne vulgaris: management</div><p><b>Evidence review J</b></p><p><i>NICE Guideline, No. 198</i></p><p class="contrib-group"><h4>Authors</h4><span itemprop="author">National Guideline Alliance (UK)</span>.</p><div class="half_rhythm">London: <a href="https://www.nice.org.uk" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=publisher"><span itemprop="publisher">National Institute for Health and Care Excellence (NICE)</span></a>; <span itemprop="datePublished">2021 Jun</span>.<div class="small">ISBN-13: <span itemprop="isbn">978-1-4731-4147-6</span></div></div><div><a href="/books/about/copyright/">Copyright</a> © NICE 2021.</div></div><div class="bkr_clear"></div></div><div id="niceng198er12.s1"><h2 id="_niceng198er12_s1_">Addition of oral corticosteroids to oral isotretinoin for the treatment of severe inflammatory acne vulgaris</h2><div id="niceng198er12.s1.1"><h3>Review question</h3><p>Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</p><div id="niceng198er12.s1.1.1"><h4>Introduction</h4><p>In the small number of patients with a severe inflammatory component to their acne vulgaris there is a risk of increased inflammation and flare of their acne on starting oral retinoid therapy under specialist supervision. The aim of the review is to consider the dosage duration and effectiveness of corticosteroids in preventing this flare.</p></div><div id="niceng198er12.s1.1.2"><h4>Summary of the protocol</h4><p>Please see <a class="figpopup" href="/books/NBK573049/table/niceng198er12.tab1/?report=objectonly" target="object" rid-figpopup="figniceng198er12tab1" rid-ob="figobniceng198er12tab1">Table 1</a> for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figniceng198er12tab1"><a href="/books/NBK573049/table/niceng198er12.tab1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figniceng198er12tab1" rid-ob="figobniceng198er12tab1"><img class="small-thumb" src="/books/NBK573049/table/niceng198er12.tab1/?report=thumb" src-large="/books/NBK573049/table/niceng198er12.tab1/?report=previmg" alt="Table 1. Summary of the protocol." /></a><div class="icnblk_cntnt"><h4 id="niceng198er12.tab1"><a href="/books/NBK573049/table/niceng198er12.tab1/?report=objectonly" target="object" rid-ob="figobniceng198er12tab1">Table 1</a></h4><p class="float-caption no_bottom_margin">Summary of the protocol. </p></div></div><p>For further details see the review protocol in <a href="#niceng198er12.appa">appendix A</a>.</p></div><div id="niceng198er12.s1.1.3"><h4>Methods and process</h4><p>This evidence review was developed using the methods and process described in <a href="https://www.nice.org.uk/process/pmg20/chapter/introduction" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a>. Methods specific to this review question are described in the review protocol in <a href="#niceng198er12.appa">appendix A</a> and the <a href="/books/NBK573049/bin/niceng198er12_bm1.pdf">methods</a> document (supplementary document 1).</p><p>Declarations of interest were recorded according to <a href="https://www.nice.org.uk/about/who-we-are/policies-and-procedures" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NICE’s conflicts of interest policy</a>.</p></div><div id="niceng198er12.s1.1.4"><h4>Clinical evidence</h4><div id="niceng198er12.s1.1.4.1"><h5>Included studies</h5><p>A systematic review of the clinical literature was conducted but no studies were identified which were applicable to this review question.</p><p>See the literature search strategy in <a href="#niceng198er12.appb">appendix B</a> and study selection flow chart in <a href="#niceng198er12.appc">appendix C</a>.</p></div><div id="niceng198er12.s1.1.4.2"><h5>Excluded studies</h5><p>Studies not included in this review are listed, and reasons for their exclusion are provided in <a href="#niceng198er12.appk">appendix K</a>.</p></div></div><div id="niceng198er12.s1.1.5"><h4>Summary of clinical studies included in the evidence review</h4><p>No studies were identified which were applicable to this review question (and so there are no evidence tables in <a href="#niceng198er12.appd">Appendix D</a>). No meta-analysis was undertaken for this review (and so there are no forest plots in <a href="#niceng198er12.appe">Appendix E</a>).</p></div><div id="niceng198er12.s1.1.6"><h4>Quality assessment of clinical studies included in the evidence review</h4><p>No studies were identified which were applicable to this review question.</p></div><div id="niceng198er12.s1.1.7"><h4>Economic evidence</h4><div id="niceng198er12.s1.1.7.1"><h5>Included studies</h5><p>A single economic search was undertaken for all topics included in the scope of this guideline but no economic studies were identified which were applicable to this review question. See the literature search strategy in <a href="#niceng198er12.appb">appendix B</a> and economic study selection flow chart in <a href="#niceng198er12.appg">appendix G</a>.</p></div><div id="niceng198er12.s1.1.7.2"><h5>Excluded studies</h5><p>No economic studies were reviewed at full text and excluded from this review.</p></div></div><div id="niceng198er12.s1.1.8"><h4>Economic model</h4><p>A simple cost calculation was undertaken in order to estimate the average cost of providing a course of oral prednisolone (assuming a dose of 30 mg daily over 4 weeks) in people with severe inflammatory acne treated with oral isotretinoin. The unit cost was taken from national sources. The total cost of a course of oral prednisolone was estimated to be £14.46, comprising the drug acquisition cost, as it can be seen in <a class="figpopup" href="/books/NBK573049/table/niceng198er12.tab2/?report=objectonly" target="object" rid-figpopup="figniceng198er12tab2" rid-ob="figobniceng198er12tab2">Table 2</a>. No additional health professional contacts were assumed for the treatment with oral corticosteroids, as monitoring can be undertaken by specialists at the same time with monitoring of treatment with isotretinoin.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figniceng198er12tab2"><a href="/books/NBK573049/table/niceng198er12.tab2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figniceng198er12tab2" rid-ob="figobniceng198er12tab2"><img class="small-thumb" src="/books/NBK573049/table/niceng198er12.tab2/?report=thumb" src-large="/books/NBK573049/table/niceng198er12.tab2/?report=previmg" alt="Table 2. Drug acquisition cost of a course of treatment with oral prednisolone." /></a><div class="icnblk_cntnt"><h4 id="niceng198er12.tab2"><a href="/books/NBK573049/table/niceng198er12.tab2/?report=objectonly" target="object" rid-ob="figobniceng198er12tab2">Table 2</a></h4><p class="float-caption no_bottom_margin">Drug acquisition cost of a course of treatment with oral prednisolone. </p></div></div></div><div id="niceng198er12.s1.1.9"><h4>The committee’s discussion of the evidence</h4><div id="niceng198er12.s1.1.9.1"><h5>Interpreting the evidence</h5><div id="niceng198er12.s1.1.9.1.1"><h5>The outcomes that matter most</h5><p>Clinician-rated improvement in acne (percentage change in acne lesion count and change or final score on a validated acne severity scale) and improvement of isotretinoin-induced flare (clinician-rated and participant-reported change) were prioritised by the committee as critical outcomes because they indicate whether the treatment is efficacious. The side effect profile of corticosteroids includes particular conditions, such as hypertension, weight gain and osteoporosis which would commonly occur if they are used for 3 months or longer. Therefore, long-term side effects of corticosteroids were a critical outcome, whereas short-term side effects of corticosteroids were important outcomes because they are less likely to occur. Adverse effects of oral isotretinoin were also listed as an important outcome since a flare could be reported as a non-specific adverse event and corticosteroids are meant to supress those. Participant-reported improvement in acne (change in acne severity or symptoms) and skin-specific quality of life were important outcomes because they indicate whether the person with acne vulgaris perceives an improvement in acne symptoms.</p></div><div id="niceng198er12.s1.1.9.1.2"><h5>The quality of the evidence</h5><p>No evidence was identified which was applicable to this review question.</p></div><div id="niceng198er12.s1.1.9.1.3"><h5>Benefits and harms</h5><p>No evidence was identified which was applicable to this review question. The committee discussed that corticosteroids would only be given to a very small group of people: those with acne fulminans who are going to start isotretinoin. The committee agreed that it is known that isotretinoin causes acne flares (severe acute worsening of acne), so it is common practice to also give oral corticosteroids which are known to suppress this due to their anti-inflammatory properties. Such flares can also happen to people with severe acne during treatment with oral isotretinoin and they would therefore also need a corticosteroid to help alleviate these symptoms. They noted that the most commonly used oral corticosteroids with the best balance of benefits and risks for this purpose is prednisolone and the consensus was that this is the most appropriate corticosteroid for this use. The use of prednisolone helps to manage inflammation, however it may be associated with adverse events (such as hypertension, weight gain and osteoporosis) particularly if taken long-term.</p><p>The committee also discussed that there was no evidence to support the duration and dosage of this treatment which should be personalised to individual people. They agreed that this would be tailored to each person by the dermatology consultant-led team when prescribing oral isotretinoin (see evidence report D related to referral). They therefore did not make a specific recommendation related to dosage and duration.</p><p>Even though there was no evidence, the committee did not prioritise a research recommendation in this area because this problem affects a very small proportion of people affected with acne vulgaris and therefore research studies would not be feasible.</p></div></div><div id="niceng198er12.s1.1.9.2"><h5>Cost effectiveness and resource use</h5><p>No economic evidence on the cost-effectiveness of oral corticosteroids added to oral isotretinoin for the treatment of severe inflammatory acne vulgaris was identified. The committee noted both the anticipated benefits following treatment with oral prednisolone in people with severe inflammatory acne vulgaris treated with isotretinoin, and the low intervention cost (£14.46 for a course of treatment with oral prednisolone on average) and agreed that recommendations comprise efficient use of resources. Moreover, the committee advised that recommendations are relevant to a small number of people with acne vulgaris and concluded that the resource impact of recommendations is minimal.</p></div></div><div id="niceng198er12.s1.1.10"><h4>Recommendations supported by this evidence review</h4><p>This evidence review supports recommendations 1.5.24 and 1.5.25 in the guideline.</p></div><div id="niceng198er12.s1.1.rl.r1"><h4>References</h4><ul class="simple-list"><p>There were no studies identified that were applicable to this review question.</p></ul></div></div></div><div id="appendixesappgroup1"><h2 id="_appendixesappgroup1_">Appendices</h2><div id="niceng198er12.appa"><h3>Appendix A. Review protocol</h3><p id="niceng198er12.appa.et1"><a href="/books/NBK573049/bin/niceng198er12-appa-et1.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Review protocol for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</a><span class="small"> (PDF, 284K)</span></p></div><div id="niceng198er12.appb"><h3>Appendix B. Literature search strategies</h3><p id="niceng198er12.appb.et1"><a href="/books/NBK573049/bin/niceng198er12-appb-et1.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Literature search strategies for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</a><span class="small"> (PDF, 373K)</span></p></div><div id="niceng198er12.appc"><h3>Appendix C. Clinical evidence study selection</h3><p id="niceng198er12.appc.et1"><a href="/books/NBK573049/bin/niceng198er12-appc-et1.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Clinical study selection for: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</a><span class="small"> (PDF, 102K)</span></p></div><div id="niceng198er12.appd"><h3>Appendix D. Evidence tables</h3><div id="niceng198er12.appd.s1"><h4>Evidence tables for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</h4><p>No evidence was identified which was applicable to this review question.</p></div></div><div id="niceng198er12.appe"><h3>Appendix E. Forest plots</h3><div id="niceng198er12.appe.s1"><h4>Forest plots for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</h4><p>No evidence was identified which was applicable to this review question.</p></div></div><div id="niceng198er12.appf"><h3>Appendix F. GRADE tables</h3><div id="niceng198er12.appf.s1"><h4>GRADE tables for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</h4><p>No evidence was identified which was applicable to this review question.</p></div></div><div id="niceng198er12.appg"><h3>Appendix G. Economic evidence study selection</h3><p id="niceng198er12.appg.et1"><a href="/books/NBK573049/bin/niceng198er12-appg-et1.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Economic evidence study selection for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</a><span class="small"> (PDF, 174K)</span></p></div><div id="niceng198er12.apph"><h3>Appendix H. Economic evidence tables</h3><div id="niceng198er12.apph.s1"><h4>Economic evidence tables for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</h4><p>No economic evidence was identified which was applicable to this review question.</p></div></div><div id="niceng198er12.appi"><h3>Appendix I. Economic evidence profiles</h3><div id="niceng198er12.appi.s1"><h4>Economic evidence profiles for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</h4><p>No economic evidence was identified which was applicable to this review question.</p></div></div><div id="niceng198er12.appj"><h3>Appendix J. Economic analysis</h3><div id="niceng198er12.appj.s1"><h4>Economic analysis for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</h4><p>No economic analysis was conducted for this review question.</p></div></div><div id="niceng198er12.appk"><h3>Appendix K. Excluded studies</h3><div id="niceng198er12.appk.s1"><h4>Excluded clinical and economic studies for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</h4></div><div id="niceng198er12.appk.s2"><h4>Clinical studies</h4><p id="niceng198er12.appk.et1"><a href="/books/NBK573049/bin/niceng198er12-appk-et1.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Download PDF</a><span class="small"> (136K)</span></p></div><div id="niceng198er12.appk.s3"><h4>Economic studies</h4><p>No economic evidence was identified for this review.</p></div></div><div id="niceng198er12.appl"><h3>Appendix L. Research recommendations</h3><div id="niceng198er12.appl.s1"><h4>Research recommendations for review question: Is the addition of oral corticosteroids to oral isotretinoin of benefit for the treatment of severe acne (including acne conglobata and acne fulminans)?</h4><p>No research recommendations were made for this review question.</p></div></div></div></div><div class="fm-sec"><div><p>Final</p></div><div><p>Evidence review underpinning recommendations 1.5.24 and 1.5.25 in the NICE guideline</p><p>These evidence reviews were developed by the National Guideline Alliance which is a part of the Royal College of Obstetricians and Gynaecologists</p></div><div><p><b>Disclaimer</b>: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.</p><p>Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.</p><p>NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the <a href="http://wales.gov.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Welsh Government</a>, <a href="http://www.scotland.gov.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Scottish Government</a>, and <a href="http://www.northernireland.gov.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Northern Ireland Executive</a>. All NICE guidance is subject to regular review and may be updated or withdrawn.</p></div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © NICE 2021.</div><div class="small"><span class="label">Bookshelf ID: NBK573049</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/34424624" title="PubMed record of this title" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">34424624</a></span></div></div><div class="small-screen-prev"></div><div class="small-screen-next"></div></article><article data-type="table-wrap" id="figobniceng198er12tab1"><div id="niceng198er12.tab1" class="table"><h3><span class="label">Table 1</span><span class="title">Summary of the protocol</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK573049/table/niceng198er12.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__niceng198er12.tab1_lrgtbl__"><table><tbody><tr><th id="hd_b_niceng198er12.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Population</th><td headers="hd_b_niceng198er12.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">People ≥12 years-old with severe acne, including those with acne conglobata or fulminans</td></tr><tr><th id="hd_b_niceng198er12.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Intervention</th><td headers="hd_b_niceng198er12.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Oral isotretinoin plus any of the following listed oral corticosteroids:
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<ul><li class="half_rhythm"><div>Betamethasone</div></li><li class="half_rhythm"><div>Deflazacort</div></li><li class="half_rhythm"><div>Dexamethasone</div></li><li class="half_rhythm"><div>Hydrocortisone</div></li><li class="half_rhythm"><div>Methylprednisolone</div></li><li class="half_rhythm"><div>Prednisone</div></li><li class="half_rhythm"><div>Prednisolone</div></li></ul></td></tr><tr><th id="hd_b_niceng198er12.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comparison</th><td headers="hd_b_niceng198er12.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The following comparisons will be considered:
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<ul><li class="half_rhythm"><div>Oral isotretinoin plus any listed oral corticosteroid vs oral isotretinoin</div></li><li class="half_rhythm"><div>Oral isotretinoin plus any listed oral corticosteroid vs oral isotretinoin plus any other listed oral corticosteroid</div></li></ul></td></tr><tr><th id="hd_b_niceng198er12.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outcomes</th><td headers="hd_b_niceng198er12.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<b>Critical</b>
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<ul><li class="half_rhythm"><div>Clinician-rated improvement:
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<ul class="circle"><li class="half_rhythm"><div>percentage change in acne lesion count</div></li><li class="half_rhythm"><div>change or final score on a validated acne severity scale</div></li></ul></div></li><li class="half_rhythm"><div>Improvement of isotretinoin-induced flare:
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<ul class="circle"><li class="half_rhythm"><div>clinician-rated change</div></li><li class="half_rhythm"><div>participant-reported chafnge</div></li></ul></div></li><li class="half_rhythm"><div>Long-term side effects of corticosteroids</div></li></ul>
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<b>Important</b>
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<ul><li class="half_rhythm"><div>Adverse effects of oral isotretinoin</div></li><li class="half_rhythm"><div>Participant-reported improvement:
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<ul class="circle"><li class="half_rhythm"><div>change in acne severity or symptoms (for example assessed using global self-assessment score)</div></li></ul></div></li><li class="half_rhythm"><div>Short-term side effects of corticosteroids</div></li><li class="half_rhythm"><div>Skin-specific quality of life</div></li></ul>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobniceng198er12tab2"><div id="niceng198er12.tab2" class="table"><h3><span class="label">Table 2</span><span class="title">Drug acquisition cost of a course of treatment with oral prednisolone</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK573049/table/niceng198er12.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__niceng198er12.tab2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_niceng198er12.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Resource</th><th id="hd_h_niceng198er12.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Unit cost</th><th id="hd_h_niceng198er12.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Total cost</th></tr></thead><tbody><tr><td headers="hd_h_niceng198er12.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">30 mg of oral prednisolone per day, over 4 weeks [that is 6 tablets of 5mg per day and 6 boxes of 28 × 5 mg tablets required]</td><td headers="hd_h_niceng198er12.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">28 × 5 mg tablets = £2.41<sup>1</sup></td><td headers="hd_h_niceng198er12.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6 × £2.41 = £14.46</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1</dt><dd><div id="niceng198er12.tab2_1"><p class="no_margin">NHS Business Services Authority, NHS Prescription Services 2020. NHS England and Wales. Electronic Drug Tariff. Issue: February 2020. Compiled on the behalf of the Department of Health and Social Care. <a href="https://www.nhsbsa.nhs.uk/pharmacies-gp-practices-and-appliance-contractors/drug-tariff" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.nhsbsa.nhs<wbr style="display:inline-block"></wbr>​.uk/pharmacies-gp-practices-and-appliance-contractors<wbr style="display:inline-block"></wbr>​/drug-tariff</a></p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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