You cannot select more than 25 topics Topics must start with a letter or number, can include dashes ('-') and can be up to 35 characters long.
AMR/docs/articles/MDR.html

423 lines
23 KiB
HTML

4 years ago
<!DOCTYPE html>
<!-- Generated by pkgdown: do not edit by hand --><html lang="en">
<head>
<meta http-equiv="Content-Type" content="text/html; charset=UTF-8">
<meta charset="utf-8">
<meta http-equiv="X-UA-Compatible" content="IE=edge">
<meta name="viewport" content="width=device-width, initial-scale=1.0">
<title>How to determine multi-drug resistance (MDR) • AMR (for R)</title>
4 years ago
<!-- favicons --><link rel="icon" type="image/png" sizes="16x16" href="../favicon-16x16.png">
<link rel="icon" type="image/png" sizes="32x32" href="../favicon-32x32.png">
<link rel="apple-touch-icon" type="image/png" sizes="180x180" href="../apple-touch-icon.png">
<link rel="apple-touch-icon" type="image/png" sizes="120x120" href="../apple-touch-icon-120x120.png">
<link rel="apple-touch-icon" type="image/png" sizes="76x76" href="../apple-touch-icon-76x76.png">
<link rel="apple-touch-icon" type="image/png" sizes="60x60" href="../apple-touch-icon-60x60.png">
<!-- jquery --><script src="https://cdnjs.cloudflare.com/ajax/libs/jquery/3.4.1/jquery.min.js" integrity="sha256-CSXorXvZcTkaix6Yvo6HppcZGetbYMGWSFlBw8HfCJo=" crossorigin="anonymous"></script><!-- Bootstrap --><link href="https://cdnjs.cloudflare.com/ajax/libs/bootswatch/3.4.0/flatly/bootstrap.min.css" rel="stylesheet" crossorigin="anonymous">
<script src="https://cdnjs.cloudflare.com/ajax/libs/twitter-bootstrap/3.4.1/js/bootstrap.min.js" integrity="sha256-nuL8/2cJ5NDSSwnKD8VqreErSWHtnEP9E7AySL+1ev4=" crossorigin="anonymous"></script><!-- bootstrap-toc --><link rel="stylesheet" href="../bootstrap-toc.css">
3 years ago
<script src="../bootstrap-toc.js"></script><!-- Font Awesome icons --><link rel="stylesheet" href="https://cdnjs.cloudflare.com/ajax/libs/font-awesome/5.12.1/css/all.min.css" integrity="sha256-mmgLkCYLUQbXn0B1SRqzHar6dCnv9oZFPEC1g1cwlkk=" crossorigin="anonymous">
<link rel="stylesheet" href="https://cdnjs.cloudflare.com/ajax/libs/font-awesome/5.12.1/css/v4-shims.min.css" integrity="sha256-wZjR52fzng1pJHwx4aV2AO3yyTOXrcDW7jBpJtTwVxw=" crossorigin="anonymous">
<!-- clipboard.js --><script src="https://cdnjs.cloudflare.com/ajax/libs/clipboard.js/2.0.6/clipboard.min.js" integrity="sha256-inc5kl9MA1hkeYUt+EC3BhlIgyp/2jDIyBLS6k3UxPI=" crossorigin="anonymous"></script><!-- headroom.js --><script src="https://cdnjs.cloudflare.com/ajax/libs/headroom/0.11.0/headroom.min.js" integrity="sha256-AsUX4SJE1+yuDu5+mAVzJbuYNPHj/WroHuZ8Ir/CkE0=" crossorigin="anonymous"></script><script src="https://cdnjs.cloudflare.com/ajax/libs/headroom/0.11.0/jQuery.headroom.min.js" integrity="sha256-ZX/yNShbjqsohH1k95liqY9Gd8uOiE1S4vZc+9KQ1K4=" crossorigin="anonymous"></script><!-- pkgdown --><link href="../pkgdown.css" rel="stylesheet">
3 years ago
<script src="../pkgdown.js"></script><link href="../extra.css" rel="stylesheet">
4 years ago
<script src="../extra.js"></script><meta property="og:title" content="How to determine multi-drug resistance (MDR)">
<meta property="og:description" content="AMR">
<meta property="og:image" content="https://msberends.github.io/AMR/logo.png">
4 years ago
<!-- mathjax --><script src="https://cdnjs.cloudflare.com/ajax/libs/mathjax/2.7.5/MathJax.js" integrity="sha256-nvJJv9wWKEm88qvoQl9ekL2J+k/RWIsaSScxxlsrv8k=" crossorigin="anonymous"></script><script src="https://cdnjs.cloudflare.com/ajax/libs/mathjax/2.7.5/config/TeX-AMS-MML_HTMLorMML.js" integrity="sha256-84DKXVJXs0/F8OTMzX4UR909+jtl4G7SPypPavF+GfA=" crossorigin="anonymous"></script><!--[if lt IE 9]>
<script src="https://oss.maxcdn.com/html5shiv/3.7.3/html5shiv.min.js"></script>
<script src="https://oss.maxcdn.com/respond/1.4.2/respond.min.js"></script>
<![endif]-->
</head>
3 years ago
<body data-spy="scroll" data-target="#toc">
4 years ago
<div class="container template-article">
<header><div class="navbar navbar-default navbar-fixed-top" role="navigation">
<div class="container">
<div class="navbar-header">
<button type="button" class="navbar-toggle collapsed" data-toggle="collapse" data-target="#navbar" aria-expanded="false">
<span class="sr-only">Toggle navigation</span>
<span class="icon-bar"></span>
<span class="icon-bar"></span>
<span class="icon-bar"></span>
</button>
<span class="navbar-brand">
<a class="navbar-link" href="../index.html">AMR (for R)</a>
<span class="version label label-default" data-toggle="tooltip" data-placement="bottom" title="Latest development version">1.5.0</span>
4 years ago
</span>
</div>
<div id="navbar" class="navbar-collapse collapse">
<ul class="nav navbar-nav">
<li>
<a href="../index.html">
<span class="fas fa-home"></span>
4 years ago
Home
</a>
</li>
<li class="dropdown">
<a href="#" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-expanded="false">
<span class="fas fa-question-circle"></span>
4 years ago
How to
<span class="caret"></span>
</a>
<ul class="dropdown-menu" role="menu">
<li>
<a href="../articles/AMR.html">
<span class="fas fa-directions"></span>
4 years ago
Conduct AMR analysis
</a>
</li>
<li>
<a href="../articles/resistance_predict.html">
<span class="fas fa-dice"></span>
4 years ago
Predict antimicrobial resistance
</a>
</li>
<li>
<a href="../articles/datasets.html">
<span class="fas fa-database"></span>
Data sets for download / own use
</a>
</li>
<li>
<a href="../articles/PCA.html">
<span class="fas fa-compress"></span>
Conduct principal component analysis for AMR
</a>
</li>
4 years ago
<li>
<a href="../articles/MDR.html">
<span class="fas fa-skull-crossbones"></span>
4 years ago
Determine multi-drug resistance (MDR)
</a>
</li>
<li>
<a href="../articles/WHONET.html">
<span class="fas fa-globe-americas"></span>
4 years ago
Work with WHONET data
</a>
</li>
<li>
<a href="../articles/SPSS.html">
<span class="fas fa-file-upload"></span>
4 years ago
Import data from SPSS/SAS/Stata
</a>
</li>
<li>
<a href="../articles/EUCAST.html">
<span class="fas fa-exchange-alt"></span>
4 years ago
Apply EUCAST rules
</a>
</li>
<li>
<a href="../reference/mo_property.html">
<span class="fas fa-bug"></span>
4 years ago
Get properties of a microorganism
</a>
</li>
<li>
<a href="../reference/ab_property.html">
<span class="fas fa-capsules"></span>
4 years ago
Get properties of an antibiotic
</a>
</li>
<li>
<a href="../articles/benchmarks.html">
<span class="fas fa-shipping-fast"></span>
4 years ago
Other: benchmarks
</a>
</li>
</ul>
</li>
<li>
<a href="../reference/index.html">
<span class="fas fa-book-open"></span>
4 years ago
Manual
</a>
</li>
<li>
<a href="../authors.html">
<span class="fas fa-users"></span>
4 years ago
Authors
</a>
</li>
<li>
<a href="../news/index.html">
<span class="far fa-newspaper"></span>
4 years ago
Changelog
</a>
</li>
</ul>
<ul class="nav navbar-nav navbar-right">
<li>
<a href="https://github.com/msberends/AMR">
<span class="fab fa-github"></span>
4 years ago
Source Code
</a>
</li>
<li>
<a href="../survey.html">
<span class="fas fa-clipboard-list"></span>
4 years ago
Survey
4 years ago
</a>
</li>
</ul>
</div>
<!--/.nav-collapse -->
</div>
<!--/.container -->
</div>
<!--/.navbar -->
</header><script src="MDR_files/header-attrs-2.6/header-attrs.js"></script><div class="row">
4 years ago
<div class="col-md-9 contents">
<div class="page-header toc-ignore">
3 years ago
<h1 data-toc-skip>How to determine multi-drug resistance (MDR)</h1>
4 years ago
<small class="dont-index">Source: <a href="https://github.com/msberends/AMR/blob/master/vignettes/MDR.Rmd"><code>vignettes/MDR.Rmd</code></a></small>
4 years ago
<div class="hidden name"><code>MDR.Rmd</code></div>
</div>
<p>With the function <code><a href="../reference/mdro.html">mdro()</a></code>, you can determine which micro-organisms are multi-drug resistant organisms (MDRO).</p>
<div id="type-of-input" class="section level4">
<h4 class="hasAnchor">
<a href="#type-of-input" class="anchor"></a>Type of input</h4>
<p>The <code><a href="../reference/mdro.html">mdro()</a></code> function takes a data set as input, such as a regular <code>data.frame</code>. It tries to automatically determine the right columns for info about your isolates, like the name of the species and all columns with results of antimicrobial agents. See the help page for more info about how to set the right settings for your data with the command <code><a href="../reference/mdro.html">?mdro</a></code>.</p>
<p>For WHONET data (and most other data), all settings are automatically set correctly.</p>
</div>
<div id="guidelines" class="section level4">
<h4 class="hasAnchor">
<a href="#guidelines" class="anchor"></a>Guidelines</h4>
<p>The function support multiple guidelines. You can select a guideline with the <code>guideline</code> parameter. Currently supported guidelines are (case-insensitive):</p>
4 years ago
<ul>
<li>
<p><code>guideline = "CMI2012"</code> (default)</p>
<p>Magiorakos AP, Srinivasan A <em>et al.</em> “Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.” Clinical Microbiology and Infection (2012) (<a href="https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)61632-3/fulltext">link</a>)</p>
</li>
<li>
<p><code>guideline = "EUCAST3.2"</code> (or simply <code>guideline = "EUCAST"</code>)</p>
<p>The European international guideline - EUCAST Expert Rules Version 3.2 “Intrinsic Resistance and Unusual Phenotypes” (<a href="https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Expert_Rules/2020/Intrinsic_Resistance_and_Unusual_Phenotypes_Tables_v3.2_20200225.pdf">link</a>)</p>
</li>
<li>
<p><code>guideline = "EUCAST3.1"</code></p>
<p>The European international guideline - EUCAST Expert Rules Version 3.1 “Intrinsic Resistance and Exceptional Phenotypes Tables” (<a href="https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Expert_Rules/Expert_rules_intrinsic_exceptional_V3.1.pdf">link</a>)</p>
</li>
<li>
<p><code>guideline = "TB"</code></p>
<p>The international guideline for multi-drug resistant tuberculosis - World Health Organization “Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis” (<a href="https://www.who.int/tb/publications/pmdt_companionhandbook/en/">link</a>)</p>
</li>
<li>
<p><code>guideline = "MRGN"</code></p>
<p>The German national guideline - Mueller et al. (2015) Antimicrobial Resistance and Infection Control 4:7. DOI: 10.1186/s13756-015-0047-6</p>
</li>
<li>
<p><code>guideline = "BRMO"</code></p>
<p>The Dutch national guideline - Rijksinstituut voor Volksgezondheid en Milieu “WIP-richtlijn BRMO (Bijzonder Resistente Micro-Organismen) (ZKH)” (<a href="https://www.rivm.nl/wip-richtlijn-brmo-bijzonder-resistente-micro-organismen-zkh">link</a>)</p>
</li>
4 years ago
</ul>
<p>Please suggest your own (country-specific) guidelines by letting us know: <a href="https://github.com/msberends/AMR/issues/new" class="uri">https://github.com/msberends/AMR/issues/new</a>.</p>
</div>
<div id="examples" class="section level4">
<h4 class="hasAnchor">
<a href="#examples" class="anchor"></a>Examples</h4>
<p>The <code><a href="../reference/mdro.html">mdro()</a></code> function always returns an ordered <code>factor</code>. For example, the output of the default guideline by Magiorakos <em>et al.</em> returns a <code>factor</code> with levels Negative, MDR, XDR or PDR in that order.</p>
<p>The next example uses the <code>example_isolates</code> data set. This is a data set included with this package and contains 2,000 microbial isolates with their full antibiograms. It reflects reality and can be used to practice AMR analysis. If we test the MDR/XDR/PDR guideline on this data set, we get:</p>
<div class="sourceCode" id="cb1"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://dplyr.tidyverse.org">dplyr</a></span><span class="op">)</span> <span class="co"># to support pipes: %&gt;%</span>
<span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://github.com/msberends/cleaner">cleaner</a></span><span class="op">)</span> <span class="co"># to create frequency tables</span></code></pre></div>
<div class="sourceCode" id="cb2"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="va">example_isolates</span> <span class="op">%&gt;%</span>
<span class="fu"><a href="../reference/mdro.html">mdro</a></span><span class="op">(</span><span class="op">)</span> <span class="op">%&gt;%</span>
<span class="fu"><a href="https://rdrr.io/pkg/cleaner/man/freq.html">freq</a></span><span class="op">(</span><span class="op">)</span> <span class="co"># show frequency table of the result</span>
<span class="co"># Warning: NA introduced for isolates where the available percentage of antimicrobial</span>
<span class="co"># classes was below 50% (set with `pct_required_classes`)</span></code></pre></div>
<p><strong>Frequency table</strong></p>
<p>Class: factor &gt; ordered (numeric)<br>
3 years ago
Length: 2,000<br>
Levels: 4: Negative &lt; Multi-drug-resistant (MDR) &lt; Extensively drug-resistant …<br>
Available: 1,747 (87.35%, NA: 253 = 12.65%)<br>
Unique: 2</p>
<table class="table">
<thead><tr class="header">
<th align="left"></th>
<th align="left">Item</th>
<th align="right">Count</th>
<th align="right">Percent</th>
<th align="right">Cum. Count</th>
<th align="right">Cum. Percent</th>
</tr></thead>
<tbody>
<tr class="odd">
<td align="left">1</td>
<td align="left">Negative</td>
<td align="right">1616</td>
<td align="right">92.50%</td>
<td align="right">1616</td>
<td align="right">92.50%</td>
</tr>
<tr class="even">
<td align="left">2</td>
<td align="left">Multi-drug-resistant (MDR)</td>
<td align="right">131</td>
<td align="right">7.50%</td>
<td align="right">1747</td>
<td align="right">100.00%</td>
</tr>
</tbody>
</table>
<p>For another example, I will create a data set to determine multi-drug resistant TB:</p>
<div class="sourceCode" id="cb3"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="co"># random_rsi() is a helper function to generate</span>
<span class="co"># a random vector with values S, I and R</span>
<span class="va">my_TB_data</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>rifampicin <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
isoniazid <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
gatifloxacin <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
ethambutol <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
pyrazinamide <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
moxifloxacin <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
kanamycin <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span><span class="op">)</span></code></pre></div>
4 years ago
<p>Because all column names are automatically verified for valid drug names or codes, this would have worked exactly the same:</p>
<div class="sourceCode" id="cb4"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="va">my_TB_data</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>RIF <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
INH <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
GAT <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
ETH <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
PZA <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
MFX <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span>,
KAN <span class="op">=</span> <span class="fu"><a href="../reference/random.html">random_rsi</a></span><span class="op">(</span><span class="fl">5000</span><span class="op">)</span><span class="op">)</span></code></pre></div>
<p>The data set now looks like this:</p>
<div class="sourceCode" id="cb5"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/utils/head.html">head</a></span><span class="op">(</span><span class="va">my_TB_data</span><span class="op">)</span>
3 years ago
<span class="co"># rifampicin isoniazid gatifloxacin ethambutol pyrazinamide moxifloxacin</span>
<span class="co"># 1 S R S S I R</span>
<span class="co"># 2 R I S I S I</span>
<span class="co"># 3 I I R S I S</span>
<span class="co"># 4 R S R I R S</span>
<span class="co"># 5 I R I I I R</span>
<span class="co"># 6 I R I R S R</span>
3 years ago
<span class="co"># kanamycin</span>
<span class="co"># 1 R</span>
<span class="co"># 2 I</span>
<span class="co"># 3 I</span>
<span class="co"># 4 I</span>
<span class="co"># 5 S</span>
<span class="co"># 6 S</span></code></pre></div>
<p>We can now add the interpretation of MDR-TB to our data set. You can use:</p>
<div class="sourceCode" id="cb6"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="fu"><a href="../reference/mdro.html">mdro</a></span><span class="op">(</span><span class="va">my_TB_data</span>, guideline <span class="op">=</span> <span class="st">"TB"</span><span class="op">)</span></code></pre></div>
<p>or its shortcut <code><a href="../reference/mdro.html">mdr_tb()</a></code>:</p>
<div class="sourceCode" id="cb7"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="va">my_TB_data</span><span class="op">$</span><span class="va">mdr</span> <span class="op">&lt;-</span> <span class="fu"><a href="../reference/mdro.html">mdr_tb</a></span><span class="op">(</span><span class="va">my_TB_data</span><span class="op">)</span>
<span class="co"># NOTE: No column found as input for `col_mo`, assuming all records contain</span>
<span class="co"># Mycobacterium tuberculosis.</span></code></pre></div>
<p>Create a frequency table of the results:</p>
<div class="sourceCode" id="cb8"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/cleaner/man/freq.html">freq</a></span><span class="op">(</span><span class="va">my_TB_data</span><span class="op">$</span><span class="va">mdr</span><span class="op">)</span></code></pre></div>
<p><strong>Frequency table</strong></p>
4 years ago
<p>Class: factor &gt; ordered (numeric)<br>
3 years ago
Length: 5,000<br>
Levels: 5: Negative &lt; Mono-resistant &lt; Poly-resistant &lt; Multi-drug-resistant &lt;<br>
3 years ago
Available: 5,000 (100%, NA: 0 = 0%)<br>
4 years ago
Unique: 5</p>
<table class="table">
<thead><tr class="header">
<th align="left"></th>
<th align="left">Item</th>
<th align="right">Count</th>
<th align="right">Percent</th>
<th align="right">Cum. Count</th>
<th align="right">Cum. Percent</th>
</tr></thead>
<tbody>
<tr class="odd">
<td align="left">1</td>
<td align="left">Mono-resistant</td>
<td align="right">3286</td>
<td align="right">65.72%</td>
<td align="right">3286</td>
<td align="right">65.72%</td>
4 years ago
</tr>
<tr class="even">
<td align="left">2</td>
<td align="left">Negative</td>
<td align="right">992</td>
<td align="right">19.84%</td>
<td align="right">4278</td>
<td align="right">85.56%</td>
4 years ago
</tr>
<tr class="odd">
<td align="left">3</td>
<td align="left">Multi-drug-resistant</td>
<td align="right">424</td>
<td align="right">8.48%</td>
<td align="right">4702</td>
<td align="right">94.04%</td>
4 years ago
</tr>
<tr class="even">
<td align="left">4</td>
<td align="left">Poly-resistant</td>
<td align="right">214</td>
<td align="right">4.28%</td>
<td align="right">4916</td>
<td align="right">98.32%</td>
4 years ago
</tr>
<tr class="odd">
<td align="left">5</td>
<td align="left">Extensively drug-resistant</td>
<td align="right">84</td>
<td align="right">1.68%</td>
<td align="right">5000</td>
<td align="right">100.00%</td>
4 years ago
</tr>
</tbody>
</table>
</div>
</div>
4 years ago
<div class="col-md-3 hidden-xs hidden-sm" id="pkgdown-sidebar">
4 years ago
</div>
</div>
4 years ago
<footer><div class="copyright">
<p>Developed by <a href="https://www.rug.nl/staff/m.s.berends/">Matthijs S. Berends</a>, <a href="https://www.rug.nl/staff/c.f.luz/">Christian F. Luz</a>, <a href="https://www.rug.nl/staff/a.w.friedrich/">Alexander W. Friedrich</a>, <a href="https://www.rug.nl/staff/b.sinha/">Bhanu N. M. Sinha</a>, <a href="https://www.rug.nl/staff/c.j.albers/">Casper J. Albers</a>, <a href="https://www.rug.nl/staff/c.glasner/">Corinna Glasner</a>.</p>
4 years ago
</div>
<div class="pkgdown">
<p>Site built with <a href="https://pkgdown.r-lib.org/">pkgdown</a> 1.6.1.</p>
4 years ago
</div>
4 years ago
</footer>
</div>
3 years ago
</body>
4 years ago
</html>