| <!DOCTYPE html> |
| <html lang="en-US"> |
| <head> |
| <meta charset="UTF-8"> |
| <title>9d03724f-e408-429b-a0a9-6d6d1e68a38f</title> |
| <meta name="viewport" content="width=device-width, initial-scale=1"> |
| <link rel="stylesheet" href="https://cdn.mathpix.com/fonts/cmu.css"/> |
| <style>html,body { |
| width: 100%; |
| height: 100%; |
| } |
| *, *::before,*::after { |
| box-sizing: border-box; |
| } |
| body { |
| margin: 0; |
| color: #1E2029; |
| font-size: 14px; |
| line-height: normal; |
| } |
| hr { |
| box-sizing: content-box; |
| height: 0; |
| overflow: visible; |
| } |
| h1, h2, h3, h4, h5, h6 { |
| margin-top: 0; |
| margin-bottom: 0.5em; |
| color: rgba(0, 0, 0, 0.85); |
| font-weight: 500; |
| } |
| p { |
| margin-top: 0; |
| margin-bottom: 1em; |
| } |
| ol, ul, dl { |
| margin-top: 0; |
| margin-bottom: 1em; |
| } |
| ol ol, ul ul, ol ul, ul ol { |
| margin-bottom: 0; |
| } |
| dt { |
| font-weight: 500; |
| } |
| dd { |
| margin-bottom: 0.5em; |
| margin-left: 0; |
| } |
| blockquote { |
| margin: 0 0 1em; |
| } |
| dfn { |
| font-style: italic; |
| } |
| b, strong { |
| font-weight: bolder; |
| } |
| small { |
| font-size: 80%; |
| } |
| sub, sup { |
| position: relative; |
| font-size: 75%; |
| line-height: 0; |
| vertical-align: baseline; |
| } |
| sub { |
| bottom: -0.25em; |
| } |
| sup { |
| top: -0.5em; |
| } |
| a { |
| color: #0B93ff; |
| text-decoration: none; |
| background-color: transparent; |
| outline: none; |
| cursor: pointer; |
| transition: color 0.3s; |
| } |
| a:hover { |
| color: #33aaff; |
| } |
| a:active { |
| color: #0070d9; |
| } |
| a:active, a:hover { |
| text-decoration: none; |
| outline: 0; |
| } |
| a[disabled] { |
| color: rgba(0, 0, 0, 0.25); |
| cursor: not-allowed; |
| pointer-events: none; |
| } |
| pre, code, kbd, samp { |
| font-size: 1em; |
| } |
| pre { |
| margin-top: 0; |
| margin-bottom: 1em; |
| overflow: auto; |
| } |
| figure { |
| margin: 0 0 1em; |
| } |
| img { |
| vertical-align: middle; |
| border-style: none; |
| } |
| svg:not(:root) { |
| overflow: hidden; |
| } |
| table { |
| border-collapse: collapse; |
| } |
| caption { |
| padding-top: 0.75em; |
| padding-bottom: 0.3em; |
| color: rgba(0, 0, 0, 0.45); |
| text-align: left; |
| caption-side: bottom; |
| } |
| th { |
| text-align: inherit; |
| } |
| mjx-container[jax="SVG"] { |
| direction: ltr; |
| } |
| |
| mjx-container[jax="SVG"] > svg { |
| overflow: visible; |
| min-height: 1px; |
| min-width: 1px; |
| } |
| |
| mjx-container[jax="SVG"] > svg a { |
| fill: blue; |
| stroke: blue; |
| } |
| |
| mjx-container[jax="SVG"][display="true"] { |
| display: block; |
| text-align: center; |
| margin: 1em 0; |
| } |
| |
| mjx-container[jax="SVG"][display="true"][width="full"] { |
| display: flex; |
| } |
| |
| mjx-container[jax="SVG"][justify="left"] { |
| text-align: left; |
| } |
| |
| mjx-container[jax="SVG"][justify="right"] { |
| text-align: right; |
| } |
| |
| g[data-mml-node="merror"] > g { |
| fill: red; |
| stroke: red; |
| } |
| |
| g[data-mml-node="merror"] > rect[data-background] { |
| fill: yellow; |
| stroke: none; |
| } |
| |
| g[data-mml-node="mtable"] > line[data-line], svg[data-table] > g > line[data-line] { |
| stroke-width: 70px; |
| fill: none; |
| } |
| |
| g[data-mml-node="mtable"] > rect[data-frame], svg[data-table] > g > rect[data-frame] { |
| stroke-width: 70px; |
| fill: none; |
| } |
| |
| g[data-mml-node="mtable"] > .mjx-dashed, svg[data-table] > g > .mjx-dashed { |
| stroke-dasharray: 140; |
| } |
| |
| g[data-mml-node="mtable"] > .mjx-dotted, svg[data-table] > g > .mjx-dotted { |
| stroke-linecap: round; |
| stroke-dasharray: 0,140; |
| } |
| |
| g[data-mml-node="mtable"] > g > svg { |
| overflow: visible; |
| } |
| |
| [jax="SVG"] mjx-tool { |
| display: inline-block; |
| position: relative; |
| width: 0; |
| height: 0; |
| } |
| |
| [jax="SVG"] mjx-tool > mjx-tip { |
| position: absolute; |
| top: 0; |
| left: 0; |
| } |
| |
| mjx-tool > mjx-tip { |
| display: inline-block; |
| padding: .2em; |
| border: 1px solid #888; |
| font-size: 70%; |
| background-color: #F8F8F8; |
| color: black; |
| box-shadow: 2px 2px 5px #AAAAAA; |
| } |
| |
| g[data-mml-node="maction"][data-toggle] { |
| cursor: pointer; |
| } |
| |
| mjx-status { |
| display: block; |
| position: fixed; |
| left: 1em; |
| bottom: 1em; |
| min-width: 25%; |
| padding: .2em .4em; |
| border: 1px solid #888; |
| font-size: 90%; |
| background-color: #F8F8F8; |
| color: black; |
| } |
| |
| foreignObject[data-mjx-xml] { |
| font-family: initial; |
| line-height: normal; |
| overflow: visible; |
| } |
| |
| mjx-container[jax="SVG"] path[data-c], mjx-container[jax="SVG"] use[data-c] { |
| stroke-width: 3; |
| } |
| #setText > div { |
| justify-content: inherit; |
| margin-top: 0; |
| margin-bottom: 1em; |
| |
| |
| } |
| #setText div:last-child { |
| margin-bottom: 0 !important; |
| } |
| #setText > br, #preview-content br { |
| line-height: 1.2; |
| } |
| #preview-content > div { |
| margin-top: 0; |
| margin-bottom: 1em; |
| |
| } |
| .proof > div, |
| #preview-content .proof > div, #setText .proof > div, |
| .theorem > div, |
| #preview-content .theorem > div, #setText .theorem > div { |
| margin-top: 1rem; |
| } |
| mjx-container { |
| text-indent: 0; |
| overflow-y: hidden; |
| overflow-x: auto; |
| padding-top: 1px; |
| padding-bottom: 1px; |
| |
| } |
| .math-inline mjx-container { |
| display: inline-block !important; |
| page-break-inside: avoid; |
| max-width: 100%; |
| padding: 0; |
| line-height: 0; |
| } |
| .math-inline[data-overflow="visible"] mjx-container { |
| overflow: visible; |
| } |
| .math-inline mjx-container mjx-assistive-mml { |
| max-width: 100%; |
| } |
| .math-block { |
| align-items: center; |
| page-break-after: auto; |
| page-break-inside: avoid; |
| margin: 0; |
| display: block; |
| } |
| .math-inline { |
| display: inline-flex; |
| max-width: 100%; |
| } |
| .math-block[data-width="full"] { |
| overflow-x: auto; |
| display: flex; |
| } |
| .math-block[data-width="full"] mjx-container[jax=SVG][display=true] { |
| display: flex; |
| flex: 1 1; |
| justify-content: center; |
| } |
| svg .math-inline { |
| display: initial; |
| max-width: initial; |
| } |
| svg .math-inline mjx-container { |
| max-width: initial; |
| } |
| svg mjx-container { |
| overflow: visible; |
| padding: 0; |
| } |
| svg .math-block[data-width="full"] { |
| overflow: visible; |
| } |
| .math-block, .math-inline { |
| --mmd-highlight-color: rgba(0, 147, 255, 0.25); |
| --mmd-highlight-text-color: #1e2029; |
| } |
| .math-block[data-highlight-color] mjx-container[jax="SVG"] > svg { |
| background-color: var(--mmd-highlight-color); |
| } |
| .math-block[data-highlight-text-color] mjx-container[jax="SVG"] > svg { |
| color: var(--mmd-highlight-text-color); |
| } |
| .math-inline[data-highlight-color] mjx-container[jax="SVG"] { |
| background-color: var(--mmd-highlight-color); |
| } |
| .math-inline[data-highlight-text-color] mjx-container[jax="SVG"] { |
| color: var(--mmd-highlight-text-color); |
| } |
| .math-block p { |
| flex-shrink: 1; |
| } |
| .math-block mjx-container { |
| margin: 0 !important; |
| } |
| .math-error { |
| background-color: yellow; |
| color: red; |
| } |
| #preview-content img, #setText img { |
| max-width: 100%; |
| } |
| #preview-content blockquote, #setText blockquote { |
| page-break-inside: avoid; |
| color: #666; |
| margin: 0 0 1em 0; |
| padding-left: 3em; |
| border-left: .5em solid #eee; |
| } |
| #preview-content pre, #setText pre { |
| border: none; |
| padding: 0; |
| overflow: auto; |
| font-size: 85%; |
| line-height: 1.45; |
| border-radius: 6px; |
| box-sizing: border-box; |
| background: #f8f8fa; |
| } |
| #preview-content pre code, #setText pre code { |
| padding: 1rem; |
| display: block; |
| overflow-x: auto; |
| line-height: 24px; |
| } |
| #preview-content table, #setText table { |
| display: table; |
| overflow: auto; |
| max-width: 100%; |
| border-collapse: collapse; |
| page-break-inside: avoid; |
| margin-bottom: 1em; |
| } |
| #preview-content table th, #setText table th { |
| text-align: center; |
| font-weight: bold; |
| } |
| #preview-content table td, #setText table td, |
| #preview-content table th, #setText table th { |
| border: 1px solid #dfe2e5; |
| padding: 6px 13px; |
| } |
| #preview-content table tr, #setText table tr { |
| background-color: #fff; |
| border-top: 1px solid #c6cbd1; |
| } |
| #preview-content table tr:nth-child(2n), #setText table tr:nth-child(2n) { |
| background-color: #f6f8fa; |
| } |
| .main-title, |
| #preview-content .main-title, #setText .main-title { |
| text-align: center; |
| line-height: 1.2; |
| margin: 0 auto 1em auto; |
| } |
| .author, |
| #preview-content .author, #setText .author { |
| text-align: center; |
| margin: 0 auto; |
| display: flex; |
| justify-content: center; |
| flex-wrap: wrap; |
| } |
| .author p, |
| #preview-content .author p, #setText .author p { |
| min-width: 30%; |
| max-width: 50%; |
| padding: 0 7px; |
| } |
| .author > p > span, |
| #preview-content .author > p > span, #setText .author > p > span { |
| display: block; |
| text-align: center; |
| } |
| .section-title, |
| #preview-content .section-title, #setText .section-title { |
| margin-top: 1.5em; |
| } |
| .abstract, |
| #preview-content .abstract, #setText .abstract { |
| text-align: justify; |
| margin-bottom: 1em; |
| } |
| .abstract p, |
| #preview-content .abstract p, #setText .abstract p { |
| margin-bottom: 0; |
| } |
| #preview-content sup, #setText sup { |
| top: -.5em; |
| position: relative; |
| font-size: 75%; |
| line-height: 0; |
| vertical-align: baseline; |
| } |
| .text-url, |
| #preview-content .text-url, #setText .text-url { |
| color: #0B93ff; |
| cursor: text; |
| pointer-events: none; |
| } |
| .text-url a:hover, |
| #preview-content .text-url a:hover, #setText .text-url a:hover { |
| color: #0B93ff; |
| } |
| mark, |
| #preview-content mark, #setText mark { |
| background-color: #feffe6; |
| } |
| span[data-underline-type] mark, |
| #preview-content span[data-underline-type] mark, |
| #setText span[data-underline-type] mark { |
| background: inherit; |
| background-color: #feffe6; |
| padding-top: 0; |
| padding-bottom: 0; |
| } |
| *[data-has-dotfill] { |
| position: relative; |
| overflow: hidden; |
| } |
| *[data-has-dotfill] .dotfill::after { |
| position: absolute; |
| padding-left: .25ch; |
| content: " . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . "; |
| text-align: right; |
| } |
| .smiles, |
| #preview-content .smiles, #setText .smiles { |
| text-align: center; |
| } |
| div.svg-container, |
| #preview-content > div.svg-container, |
| #setText > div.svg-container { |
| display: flex; |
| justify-content: center; |
| } |
| @media print { |
| #preview { |
| font-size: 10pt !important; |
| } |
| .math-block svg, .math-inline svg { |
| shape-rendering: crispEdges; |
| margin-top: 1px; |
| } |
| #preview-content img, #setText img { |
| display: block; |
| } |
| #preview-content .figure_img img, #setText .figure_img img { |
| display: inline; |
| } |
| #preview-content h1, #preview-content h2, #preview-content h3, |
| #preview-content h4, #preview-content h5, #preview-content h6, |
| #setText h1, #setText h2, #setText h3, |
| #setText h4, #setText h5, #setText h6 { |
| page-break-inside: avoid; |
| position: relative; |
| border: 2px solid transparent; |
| } |
| #preview-content h1::after, #preview-content h2::after, #preview-content h3::after, |
| #preview-content h4::after, #preview-content h5::after, #preview-content h6::after, |
| #setText h1::after, #setText h2::after, #setText h3::after, |
| #setText h4::after, #setText h5::after, #setText h6::after { |
| content: ""; |
| display: block; |
| height: 100px; |
| margin-bottom: -100px; |
| position: relative; |
| } |
| } |
| #preview-content code, #setText code { |
| font-family: Inconsolata; |
| font-size: inherit; |
| display: initial; |
| background: #f8f8fa; |
| } |
| #preview-content .mmd-highlight code, #setText .mmd-highlight code, |
| #preview-content pre.mmd-highlight code, #setText pre.mmd-highlight code { |
| background-color: transparent; |
| } |
| #preview-content pre code, #setText pre code { |
| font-family: 'DM Mono', Inconsolata, monospace; |
| color: #333; |
| font-size: 15px; |
| } |
| .hljs-comment, .hljs-quote, |
| #preview-content .hljs-comment, #setText .hljs-comment, |
| #preview-content .hljs-quote, #setText .hljs-quote { |
| color: #998; |
| font-style: italic; |
| } |
| .hljs-command, |
| #preview-content .hljs-command, #setText .hljs-command { |
| color: #005cc5; |
| } |
| .hljs-keyword, .hljs-selector-tag, .hljs-subst, |
| #preview-content .hljs-keyword, #setText .hljs-keyword, |
| #preview-content .hljs-selector-tag, #setText .hljs-selector-tag, |
| #preview-content .hljs-subst, #setText .hljs-subst { |
| color: #d73a49; |
| font-weight: bold; |
| } |
| .hljs-number, .hljs-literal, .hljs-variable, |
| .hljs-template-variable, .hljs-tag .hljs-attr, |
| #preview-content .hljs-number, #setText .hljs-number, |
| #preview-content .hljs-literal, #setText .hljs-literal, |
| #preview-content .hljs-variable, #setText .hljs-variable, |
| #preview-content .hljs-template-variable, #setText .hljs-template-variable, |
| #preview-content .hljs-tag .hljs-attr, #setText .hljs-tag .hljs-attr { |
| color: #005cc5; |
| } |
| .hljs-string, .hljs-doctag, |
| #preview-content .hljs-string, #setText .hljs-string, |
| #preview-content .hljs-doctag, #setText .hljs-doctag { |
| color: #24292e; |
| } |
| .hljs-title, .hljs-section, .hljs-selector-id, |
| #preview-content .hljs-title, #setText .hljs-title, |
| #preview-content .hljs-section, #setText .hljs-section, |
| #preview-content .hljs-selector-id, #setText .hljs-selector-id { |
| color: #6f42c1; |
| font-weight: bold; |
| } |
| .hljs-subst, |
| #preview-content .hljs-subst, #setText .hljs-subst { |
| font-weight: normal; |
| } |
| .hljs-type, .hljs-class .hljs-title, |
| #preview-content .hljs-type, #setText .hljs-type, |
| #preview-content .hljs-class .hljs-title, #setText .hljs-class .hljs-title { |
| color: #458; |
| font-weight: bold; |
| } |
| .hljs-tag, .hljs-name, .hljs-attribute, |
| #preview-content .hljs-tag, #setText .hljs-tag, |
| #preview-content .hljs-name, #setText .hljs-name, |
| #preview-content .hljs-attribute, #setText .hljs-attribute { |
| color: #000080; |
| font-weight: normal; |
| } |
| .hljs-regexp, .hljs-link, |
| #preview-content .hljs-regexp, #setText .hljs-regexp, |
| #preview-content .hljs-link, #setText .hljs-link { |
| color: #009926; |
| } |
| .hljs-symbol, .hljs-bullet, |
| #preview-content .hljs-symbol, #setText .hljs-symbol, |
| #preview-content .hljs-bullet, #setText .hljs-bullet { |
| color: #990073; |
| } |
| .hljs-built_in, .hljs-builtin-name, |
| #preview-content .hljs-built_in, #setText .hljs-built_in, |
| #preview-content .hljs-builtin-name, #setText .hljs-builtin-name { |
| color: #24292e; |
| } |
| .hljs-meta, |
| #preview-content .hljs-meta, #setText .hljs-meta { |
| color: #999; |
| font-weight: bold; |
| } |
| .hljs-meta-keyword, |
| #preview-content .hljs-meta-keyword, #setText .hljs-meta-keyword { |
| color: #d73a49; |
| } |
| .hljs-meta-string, |
| #preview-content .hljs-meta-string, #setText .hljs-meta-string { |
| color: #032f62; |
| } |
| .hljs-deletion, |
| #preview-content .hljs-deletion, #setText .hljs-deletion { |
| background: #fdd; |
| } |
| .hljs-addition, |
| #preview-content .hljs-addition, #setText .hljs-addition { |
| background: #dfd; |
| } |
| .hljs-emphasis, |
| #preview-content .hljs-emphasis, #setText .hljs-emphasis { |
| font-style: italic; |
| } |
| .hljs-strong, |
| #preview-content .hljs-strong, #setText .hljs-strong { |
| font-weight: bold; |
| } |
| .table_tabular, |
| #preview-content .table_tabular, #setText .table_tabular { |
| overflow-x: auto; |
| padding: 0 2px 0.5em 2px; |
| } |
| .tabular, |
| #preview-content .tabular, #setText .tabular { |
| display: inline-table !important; |
| width: auto; |
| table-layout: auto; |
| border-collapse: collapse; |
| border-spacing: 0; |
| margin: 0 0 1em; |
| font-size: inherit; |
| height: fit-content; |
| } |
| .tabular th, |
| #preview-content .tabular th, #setText .tabular th { |
| border: none !important; |
| padding: 6px 13px; |
| background-color: transparent; |
| font-weight: bold; |
| } |
| .tabular tr, |
| #preview-content .tabular tr, #setText .tabular tr { |
| border-top: none !important; |
| border-bottom: none !important; |
| background-color: transparent; |
| } |
| .tabular td, |
| #preview-content .tabular td, #setText .tabular td { |
| border-style: none !important; |
| background-color: #fff; |
| border-color: #000 !important; |
| word-break: keep-all; |
| padding: 0.1em 0.5em !important; |
| } |
| .tabular td > p, |
| #preview-content .tabular td > p, #setText .tabular td > p { |
| margin-bottom: 0; |
| margin-top: 0; |
| } |
| .tabular td._empty, |
| #preview-content .tabular td._empty, #setText .tabular td._empty { |
| height: 1.3em; |
| } |
| .tabular td .f, |
| #preview-content .tabular td .f, #setText .tabular td .f { |
| opacity: 0; |
| } |
| #preview-content .sub-table table, #setText .sub-table table { |
| margin-bottom: 0; |
| } |
| html[data-theme="dark"] .tabular tr, |
| html[data-theme="dark"] #preview-content .tabular tr, html[data-theme="dark"] #setText .tabular tr, |
| html[data-theme="dark"] .tabular td, |
| html[data-theme="dark"] #preview-content .tabular td, html[data-theme="dark"] #setText .tabular td { |
| background-color: #202226; |
| border-color: #fff !important; |
| } |
| .figure_img, |
| #preview-content .figure_img, #setText .figure_img { |
| margin-bottom: 0.5em; |
| overflow-x: auto; |
| } |
| div.figure_img img, |
| #preview-content div.figure_img img, #setText div.figure_img img { |
| display: inline; |
| margin: 0; |
| } |
| ol.enumerate, ul.itemize, |
| #preview-content ol.enumerate, #setText ol.enumerate, |
| #preview-content ul.itemize, #setText ul.itemize { |
| padding-inline-start: 40px; |
| margin: 0 0 1em 0; |
| } |
| li > ol.enumerate, li > ul.itemize, |
| #preview-content li > ol.enumerate, #setText li > ol.enumerate, |
| #preview-content li > ul.itemize, #setText li > ul.itemize { |
| margin: 0; |
| } |
| ul.itemize > li, |
| #preview-content ul.itemize > li, #setText ul.itemize > li { |
| position: relative; |
| min-height: 1.4em; |
| margin-bottom: 0; |
| } |
| .enumerate > .li_enumerate, |
| #preview-content .enumerate > .li_enumerate, #setText .enumerate > .li_enumerate { |
| margin-bottom: 0; |
| } |
| .itemize > li > span.li_level, .li_enumerate.not_number > span.li_level, |
| #preview-content .itemize > li > span.li_level, #setText .itemize > li > span.li_level, |
| #preview-content .li_enumerate.not_number > span.li_level, #setText .li_enumerate.not_number > span.li_level { |
| position: absolute; |
| right: 100%; |
| white-space: nowrap; |
| width: max-content; |
| display: flex; |
| justify-content: flex-end; |
| padding-right: 10px; |
| box-sizing: border-box; |
| } |
| .li_enumerate.not_number, |
| #preview-content .li_enumerate.not_number, #setText .li_enumerate.not_number { |
| position: relative; |
| display: inline-block; |
| list-style-type: none; |
| min-height: 1.4em; |
| } |
| .itemize > li > span.li_level .math-inline, |
| .enumerate > li > span.li_level .math-inline, |
| #preview-content .itemize > li > span.li_level .math-inline, |
| #setText .itemize > li > span.li_level .math-inline, |
| #preview-content .enumerate > li > span.li_level .math-inline, |
| #setText .enumerate > li > span.li_level .math-inline { |
| display: inline-block; |
| } |
| #preview { |
| font-family: 'CMU Serif', 'Georgia', Helvetica, Arial, sans-serif; |
| font-size: 17px; |
| visibility: visible; |
| word-break: break-word; |
| padding: 2.5em; |
| max-width: 800px; |
| margin: auto; |
| box-sizing: content-box; |
| } |
| #preview h1, #preview h2, #preview h3, #preview h4, #preview h5, #preview strong { |
| font-family: 'CMU Serif Bold', 'Georgia', Helvetica, Arial, sans-serif; |
| } |
| #preview i, #preview em { |
| font-family: 'CMU Serif Italic', 'Georgia', Helvetica, Arial, sans-serif; |
| } |
| .mmd-menu { |
| max-width: 320px; |
| position: absolute; |
| background-color: white; |
| color: black; |
| width: auto; |
| padding: 5px 0; |
| border: 1px solid #E5E6EB; |
| margin: 0; |
| cursor: default; |
| font: menu; |
| text-align: left; |
| text-indent: 0; |
| text-transform: none; |
| line-height: normal; |
| letter-spacing: normal; |
| word-spacing: normal; |
| word-wrap: normal; |
| white-space: nowrap; |
| float: none; |
| z-index: 201; |
| border-radius: 5px; |
| -webkit-border-radius: 5px; |
| -moz-border-radius: 5px; |
| -khtml-border-radius: 5px; |
| box-shadow: 0 10px 20px #808080; |
| -webkit-box-shadow: 0 10px 20px #808080; |
| -moz-box-shadow: 0 10px 20px #808080; |
| -khtml-box-shadow: 0 10px 20px #808080; |
| } |
| .mmd-menu:focus { outline: none; } |
| .mmd-menu.mmd-menu-sm { |
| max-width: 100vw; |
| padding-bottom: 34px; |
| border-radius: 0; |
| -webkit-border-radius: 0; |
| -moz-border-radius: 0; |
| -khtml-border-radius: 0; |
| } |
| .mmd-menu-item-icon { |
| color: #1E2029; |
| margin-left: auto; |
| align-items: center; |
| display: none; |
| flex-shrink: 0; |
| } |
| .mmd-menu-item { |
| padding: 8px 1.25rem; |
| display: flex; |
| background: transparent; |
| height: 52px; |
| max-height: 52px; |
| } |
| .mmd-menu-item:focus { outline: none; } |
| .mmd-menu-item.active { |
| background-color: #e1e0e5; |
| } |
| .mmd-menu-item.active .mmd-menu-item-icon { |
| display: flex; |
| } |
| .mmd-menu-item-container { |
| overflow: hidden; |
| } |
| .mmd-menu-item-title { |
| color: #1E2029; |
| white-space: nowrap; |
| text-overflow: ellipsis; |
| overflow: hidden; |
| font-size: 14px; |
| line-height: 20px; |
| } |
| .mmd-menu-item-value { |
| color: #7d829c; |
| white-space: nowrap; |
| text-overflow: ellipsis; |
| overflow: hidden; |
| font-size: 12px; |
| line-height: 16px; |
| } |
| html[data-theme="dark"] .mmd-menu-item-title { |
| color: #ebefe7; |
| } |
| html[data-theme="dark"] .mmd-menu-item.active .mmd-menu-item-title { |
| color: #1E2029; |
| } |
| html[data-theme="dark"] .mmd-menu { |
| background-color: #33363a; |
| } |
| .mmd-context-menu-overlay { |
| background: rgba(0, 0, 0, 0.56); |
| } |
| .ClipboardButton { |
| padding: 0; |
| margin: 0.5rem; |
| display: inline-block; |
| cursor: pointer; |
| color: rgb(36, 41, 47); |
| background: rgb(246, 248, 250); |
| border-radius: 6px; |
| border: 1px solid rgba(31, 35, 40, 0.15); |
| box-shadow: rgba(31, 35, 40, 0.04) 0 1px 0 0, rgba(255, 255, 255, 0.25) 0 1px 0 0 inset; |
| position: relative; |
| } |
| .ClipboardButton:hover { |
| background-color: rgb(243, 244, 246); |
| border-color: rgba(31, 35, 40, 0.15); |
| transition-duration: .1s; |
| } |
| td .mmd-clipboard-copy-container { |
| line-height: 0; |
| } |
| td .ClipboardButton { |
| margin: 1px; |
| line-height: 0; |
| } |
| td .ClipboardButton .mmd-clipboard-icon { |
| margin: 1px !important; |
| transform: scale(0.6); |
| } |
| .mmd-clipboard-icon { |
| fill: currentColor; |
| vertical-align: text-bottom; |
| } |
| .mmd-clipboard-copy-icon { |
| color: rgb(101, 109, 118); |
| } |
| .mmd-clipboard-check-icon { |
| color: rgb(26, 127, 55); |
| } |
| .mmd-tooltipped-no-delay:hover::before, |
| .mmd-tooltipped-no-delay:hover::after { |
| animation-delay: 0s; |
| } |
| .mmd-tooltipped:hover::before, |
| .mmd-tooltipped:hover::after { |
| display: inline-block; |
| text-decoration: none; |
| animation-name: tooltip-appear; |
| animation-duration: .1s; |
| animation-fill-mode: forwards; |
| animation-timing-function: ease-in; |
| animation-delay: .4s; |
| } |
| .mmd-tooltipped-w::before { |
| top: 50%; |
| bottom: 50%; |
| left: -7px; |
| margin-top: -6px; |
| border-left-color: rgb(36, 41, 47); |
| } |
| .mmd-tooltipped::before { |
| position: absolute; |
| z-index: 1000001; |
| display: none; |
| width: 0; |
| height: 0; |
| color: rgb(36, 41, 47); |
| pointer-events: none; |
| content: ""; |
| border: 6px solid transparent; |
| opacity: 0; |
| } |
| .mmd-tooltipped-w::after { |
| right: 100%; |
| bottom: 50%; |
| margin-right: 6px; |
| transform: translateY(50%); |
| } |
| .mmd-tooltipped::after { |
| position: absolute; |
| z-index: 1000000; |
| display: none; |
| padding: 0.5em 0.75em; |
| font: normal normal 11px/1.5 'CMU Serif', 'Georgia', Helvetica, Arial, sans-serif; |
| -webkit-font-smoothing: subpixel-antialiased; |
| color: white; |
| text-align: center; |
| text-decoration: none; |
| text-shadow: none; |
| text-transform: none; |
| letter-spacing: normal; |
| word-wrap: break-word; |
| white-space: pre; |
| pointer-events: none; |
| content: attr(aria-label); |
| background: rgb(36, 41, 47); |
| border-radius: 6px; |
| opacity: 0; |
| }</style> |
| </head> |
| <body> |
| <div id="preview" class="preview scrollEditor"> |
| <div id="container-ruller" /> |
| <div id="preview-content"> |
| <h1 type="title" class="main-title" id="randomized%2C-controlled-dietary-treatment-study-of-pediatric-nafld"> |
| Randomized, Controlled Dietary Treatment Study of Pediatric NAFLD </h1> |
| <div><div class="author"> |
| <p><span>Funding Source: Nutrition Science Initiative</span><span>Principal Investigators: Miriam Vos, MD, MSPH and Jeff Schwimmer, MD</span></p> |
| </div></div> |
| <div>Draft or Version Number: 7.0</div> |
| <div>February 10, 2016</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="table-of-contents"> |
| TABLE OF CONTENTS</h2> |
| <div>TABLE OF CONTENTS ..... 1<br> |
| LIST OF ABBREVIATIONS ..... 3<br> |
| PROTOCOL SUMMARY ..... 4<br> |
| 1 KEY ROLES ..... 6<br> |
| 2 Introduction: Background Information and Scientific Rationale ..... 9<br> |
| 2.1 Background Information ..... 9<br> |
| 2.2 Justification ..... 11<br> |
| 2.3 Potential Risks and Benefits ..... 12<br> |
| 2.3.1 Potential Risks ..... 12<br> |
| 2.3.2 Potential Benefits ..... 13<br> |
| 2.3.3 Alternative treatments and procedures ..... 13<br> |
| 2.3.4 Protection against risks ..... 13<br> |
| 3 OBJECTIVES ..... 14<br> |
| 3.1 General hypothesis ..... 14<br> |
| 3.2 Specific Hypothesis ..... 14<br> |
| 3.3 Implications ..... 14<br> |
| 3.4 Primary Outcome Measure ..... 14<br> |
| 3.5 Secondary Outcome Measures ..... 14<br> |
| 4 Study Design ..... 15<br> |
| 4.1 Overview ..... 15<br> |
| 4.2 Intervention ..... 15<br> |
| 4.3 Dietary Assessment ..... 16<br> |
| 4.4 Sweetness Perception Testing ..... 17<br> |
| 4.4.1 Participant preparation ..... 17<br> |
| 4.4.2 Sensory Ratings ..... 17<br> |
| 4.5 Insulin Sensitivity Measurements ..... 18<br> |
| 4.6 Study duration for participants ..... 18<br> |
| 4.7 Study Timeline ..... 18<br> |
| 5 Study Enrollment and Withdrawal ..... 19<br> |
| 5.1 Participant Inclusion Criteria ..... 19<br> |
| 5.2 Participant Exclusion Criteria ..... 19<br> |
| 5.3 Strategies for Recruitment ..... 20<br> |
| 5.4 Reasons for Withdrawal ..... 20<br> |
| 5.4.1 Handling of Withdrawal ..... 20<br> |
| 5.4.2 Termination of Study ..... 20<br> |
| 6 Study Schedule ..... 22<br> |
| 6.1 Screening ..... 22<br> |
| 6.2 Day 0: Baseline Visit ..... 23<br> |
| 6.3 Follow-up Visit Day 28 ..... 24<br> |
| 6.4 Follow-up Visit Day 56 ..... 24<br> |
| 6.5 End of study follow-up ..... 24<br> |
| 7 Statistical Considerations ..... 25<br> |
| 7.1 Sample Size Considerations ..... 25<br> |
| 8 Ethics/Protection of Human Participants ..... 27<br> |
| 8.1 Ethical Standard ..... 27<br> |
| 8.2 Institutional Review Board ..... 27<br> |
| 8.3 Informed Consent Process ..... 27<br> |
| 8.4 Informed Assent Process ..... 27<br> |
| 8.5 Participant Confidentiality ..... 27<br> |
| 8.6 Study Discontinuation ..... 28<br> |
| 8.7 Data Safety Monitoring Plan ..... 28<br> |
| 9 Data Handling and Record Keeping ..... 29<br> |
| 9.1 Data Management Responsibilities ..... 29<br> |
| 9.2 MRI Data Coordination ..... 29<br> |
| 9.3 Types of Data ..... 29<br> |
| 9.5 Study Records Retention ..... 29<br> |
| 10 Literature References ..... 30<br> |
| 11 Attachments 11.1 SCHEDULE OF EVENTS ..... 32<br> |
| 11.2 BLOOD DRAW SCHEDULE ..... 33</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="list-of-abbreviations"> |
| LIST OF ABBREVIATIONS</h2> |
| <div class="table_tabular" style="text-align: center"> |
| <div class="inline-tabular"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Adipo-IR</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Adipose Tissue Insulin Resistance</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">AE</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Adverse Event</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">ALT</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Alanine Transaminase</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">AST</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Aspartate Aminotransferase</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">BMI</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Body Mass Index</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">CFR</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Code of Federal Regulations</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">CRF</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Case Report Form</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">GCP</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Good Clinical Practice</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">GGT</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Gamma-glutamyl Transpeptidase</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">HIPAA</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Health Insurance Portability and Accountability Act</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">ICH</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">International Conference on Harmonization</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">IRB</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Institutional Review Board</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">MRI</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Magnetic Resonance Imaging</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">NDSR</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Nutrition Data System for Research</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">NAFLD</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Nonalcoholic Fatty Liver Disease</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">NASH</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Nonalcoholic Steatohepatitis</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">NuSI</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Nutrition Science Initiative</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Pl</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Principal Investigator</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">RCT</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Randomized Control Trial</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">SOM</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">School of Medicine</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">TPN</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Total Parenteral Nutrition</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></div> |
| <div class="table_tabular" style="text-align: center"> |
| <div class="inline-tabular"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">PROTOCOL SUMMARY</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Title:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Randomized, Controlled Dietary Treatment Study of Pediatric NAFLD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Summary:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">This is a multisite, randomized, controlled, 8 -week outpatient feeding study at Emory University and University of California, San Diego. Participants will be non-diabetic male adolescents with biopsy-proved NAFLD. Two groups of 20 participants will be followed for 8 weeks with hepatic fat content assessed by MRI PDFF at weeks 0,4 , and 8 . One group will be a standard of care control to track the naturally-occurring changes in hepatic fat content in children over time. The other group will be provided with a low free sugars (<3% total daily calories) version of their habitual diets. The primary outcome is % change in MRI PDFF over time in the treatment group compared to the control group. Additional parameters of liver function and metabolic status (e.g., serum ALT) will also be assessed.</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Objectives:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">To evaluate hepatic fat by MRI PDFF before and after 8 weeks of a study-provided low free sugars diet (<3%) compared to a prospective, standard of care, control group receiving only imaging.</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Population:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Males age 11 to 16 with a history of liver biopsy confirming NAFLD and hepatic fat by MRI PDFF <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.312ex;" xmlns="http://www.w3.org/2000/svg" width="6.536ex" height="2.009ex" role="img" focusable="false" viewBox="0 -750 2888.8 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> during screening.</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Type of Trial:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Phase llb, randomized clinical trial</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Study Duration:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">2 years</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Participant Participation Duration:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Up to 16 weeks</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Total Number of</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">40 complete (20 per site - 10 interventions and 10 controls)</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Participants:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">May enroll up to 60 across sites to account for screen fails and drop outs</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="schematic-of-study-design"> |
| SCHEMATIC OF STUDY DESIGN</h2> |
| <div><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/9d03724f-e408-429b-a0a9-6d6d1e68a38f-06.jpg?height=715&width=1627&top_left_y=433&top_left_x=320" alt="" data-align="center"></figure></div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="1-key-roles"> |
| 1 KEY ROLES</h2> |
| <div class="table_tabular" style="text-align: center"> |
| <div class="inline-tabular"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; vertical-align: top; width: auto; border-top-style: solid !important; border-top-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " rowspan="2">Principal Investigators:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Jeffrey Schwimmer, MD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">University of California, San Diego UCSD Medical Center 200 West Arbor Drive, MC 8450</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">San Diego, CA 92103</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Miriam Vos, MD, MSPH</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">1760 Haygood Drive, W450</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Atlanta, GA 30322</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; vertical-align: top; width: auto; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " rowspan="11">Co-Investigators:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Adina Alazraki, MD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Children's Healthcare of Atlanta</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Claude Sirlin, MD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">University of California, San Diego</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Jonathan Africa, MD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">University of California, San Diego</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Michael Middleton, MD, PhD University of California, San Diego</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Ariel Feinstein, MD Children Specialists of San Diego</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Joel Lavine, MD, PhD Columbia University</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Jean Welsh, PhD, RN, MPH</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Jay Freeman, MD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Nitika Gupta, MD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Saul Karpen, MD, PhD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Rene Romero, MD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| </tbody> |
| </table> |
| </div></div> |
| <div>Dellys Soler Rodriguez, MD<br> |
| Emory University School of Medicine<br> |
| Nitika Gupta, MD<br> |
| Emory University School of Medicine<br> |
| Saul Karpen, MD, PhD<br> |
| Emory University School of Medicine<br> |
| Rene Romero, MD<br> |
| Emory University School of Medicine<br> |
| Dellys Soler Rodriguez, MD<br> |
| Emory University School of Medicine<br> |
| Institutions: Emory University and Children's Healthcare of Atlanta<br> |
| University of California, San Diego and UCSD Medical Center</div> |
| <div class="table_tabular" style="text-align: center"> |
| <div class="inline-tabular"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; vertical-align: top; width: auto; border-top-style: solid !important; border-top-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " rowspan="7">Study staff:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Project Management</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Rebecca Cleeton, MPH, CCRP</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Research Manager</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Maria C. Cordero</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Research Coordinator</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Janis Durelle, BS</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Project Manager</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">University of California, San Diego</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Patricia Ugalde Nicalo, MD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Lead Coordinator</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">University of California, San Diego</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Jennifer Sanford, BA</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Research Coordiantor</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">University of California, San Diego</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Nutritionists</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Juna Konomi, PhD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Cynthia Knott, RD</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">University of California, San Diego</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; vertical-align: top; width: auto; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " rowspan="3">Institutional Review Boards:</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Statistician</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Courtney McCracken, PhD Emory University School of Medicine</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Emory University IRB</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">1599 Clifton Road NE, <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="3.231ex" height="1.981ex" role="img" focusable="false" viewBox="0 -853.7 1428 875.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g><g data-mml-node="msup" transform="translate(500,0)"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mtext"><path data-c="74" d="M27 422Q80 426 109 478T141 600V615H181V431H316V385H181V241Q182 116 182 100T189 68Q203 29 238 29Q282 29 292 100Q293 108 293 146V181H333V146V134Q333 57 291 17Q264 -10 221 -10Q187 -10 162 2T124 33T105 68T98 100Q97 107 97 248V385H18V422H27Z"></path><path data-c="68" d="M41 46H55Q94 46 102 60V68Q102 77 102 91T102 124T102 167T103 217T103 272T103 329Q103 366 103 407T103 482T102 542T102 586T102 603Q99 622 88 628T43 637H25V660Q25 683 27 683L37 684Q47 685 66 686T103 688Q120 689 140 690T170 693T181 694H184V367Q244 442 328 442Q451 442 463 329Q464 322 464 190V104Q464 66 466 59T477 49Q498 46 526 46H542V0H534L510 1Q487 2 460 2T422 3Q319 3 310 0H302V46H318Q379 46 379 62Q380 64 380 200Q379 335 378 343Q372 371 358 385T334 402T308 404Q263 404 229 370Q202 343 195 315T187 232V168V108Q187 78 188 68T191 55T200 49Q221 46 249 46H265V0H257L234 1Q210 2 183 2T145 3Q42 3 33 0H25V46H41Z" transform="translate(389,0)"></path><path data-c="A0" d="" transform="translate(945,0)"></path></g></g></g></g></g></svg></mjx-container></span> Floor</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Atlanta, GA 30322</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><div class="inline-tabular sub-table"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">University of California, San Diego</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">Human Research Protections Program 9500 Gilman Drive, Mail Code 0052</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left: none !important; border-bottom: none !important; border-top: none !important; width: auto; vertical-align: middle; ">La Jolla, California 92093</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></td> |
| </tr> |
| </tbody> |
| </table> |
| </div></div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="2-introduction%3A-background-information-and-scientific-rationale"> |
| 2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE</h2> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.1-background-information"> |
| 2.1 Background Information</h3> |
| <div>The field of pediatric nonalcoholic fatty liver disease (NAFLD) has grown exponentially over the past decade in response to the growth of the disease and increased awareness of this important liver disease. NAFLD is now the most common liver disease for both adults and children in the US and is estimated to affect more than 20 million persons <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="2.232ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 986.7 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span>. It is a chronic liver disease closely associated with the metabolic syndrome, although its role as cause, effect or innocent bystander has yet to be defined <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="3.032ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 1340.2 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1278,0)"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path></g></g></g></g></g></svg></mjx-container></span>. NAFLD is an umbrella term and it is histologically categorized into nonalcoholic fatty liver (NAFL), defined as hepatic steatosis (fat) without hepatocellular injury and nonalcoholic steatohepatitis (NASH), defined as hepatic fat plus hepatocellular injury with or without fibrosis <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>.</div> |
| <div>In the US, Mexican-Americans are the group most affected by NAFLD and it is estimated that 1 of 4 Mexican American adults has NAFLD <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span>. Hispanic-Americans are 2.5 times more likely to have NAFLD compared to African Americans <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="5.077ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 2243.9 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1778,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(2056,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Liver disease is the <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="3.231ex" height="1.981ex" role="img" focusable="false" viewBox="0 -853.7 1428 875.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="mn"><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z"></path></g><g data-mml-node="TeXAtom" transform="translate(533,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mtext"><path data-c="74" d="M27 422Q80 426 109 478T141 600V615H181V431H316V385H181V241Q182 116 182 100T189 68Q203 29 238 29Q282 29 292 100Q293 108 293 146V181H333V146V134Q333 57 291 17Q264 -10 221 -10Q187 -10 162 2T124 33T105 68T98 100Q97 107 97 248V385H18V422H27Z"></path><path data-c="68" d="M41 46H55Q94 46 102 60V68Q102 77 102 91T102 124T102 167T103 217T103 272T103 329Q103 366 103 407T103 482T102 542T102 586T102 603Q99 622 88 628T43 637H25V660Q25 683 27 683L37 684Q47 685 66 686T103 688Q120 689 140 690T170 693T181 694H184V367Q244 442 328 442Q451 442 463 329Q464 322 464 190V104Q464 66 466 59T477 49Q498 46 526 46H542V0H534L510 1Q487 2 460 2T422 3Q319 3 310 0H302V46H318Q379 46 379 62Q380 64 380 200Q379 335 378 343Q372 371 358 385T334 402T308 404Q263 404 229 370Q202 343 195 315T187 232V168V108Q187 78 188 68T191 55T200 49Q221 46 249 46H265V0H257L234 1Q210 2 183 2T145 3Q42 3 33 0H25V46H41Z" transform="translate(389,0)"></path><path data-c="A0" d="" transform="translate(945,0)"></path></g></g></g></g></g></svg></mjx-container></span> leading cause of death for Hispanic adults compared to <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.362ex" height="2ex" role="img" focusable="false" viewBox="0 -883.8 1928 883.8"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(500,0)"></path></g><g data-mml-node="TeXAtom" transform="translate(1033,393.1) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mtext"><path data-c="74" d="M27 422Q80 426 109 478T141 600V615H181V431H316V385H181V241Q182 116 182 100T189 68Q203 29 238 29Q282 29 292 100Q293 108 293 146V181H333V146V134Q333 57 291 17Q264 -10 221 -10Q187 -10 162 2T124 33T105 68T98 100Q97 107 97 248V385H18V422H27Z"></path><path data-c="68" d="M41 46H55Q94 46 102 60V68Q102 77 102 91T102 124T102 167T103 217T103 272T103 329Q103 366 103 407T103 482T102 542T102 586T102 603Q99 622 88 628T43 637H25V660Q25 683 27 683L37 684Q47 685 66 686T103 688Q120 689 140 690T170 693T181 694H184V367Q244 442 328 442Q451 442 463 329Q464 322 464 190V104Q464 66 466 59T477 49Q498 46 526 46H542V0H534L510 1Q487 2 460 2T422 3Q319 3 310 0H302V46H318Q379 46 379 62Q380 64 380 200Q379 335 378 343Q372 371 358 385T334 402T308 404Q263 404 229 370Q202 343 195 315T187 232V168V108Q187 78 188 68T191 55T200 49Q221 46 249 46H265V0H257L234 1Q210 2 183 2T145 3Q42 3 33 0H25V46H41Z" transform="translate(389,0)"></path><path data-c="A0" d="" transform="translate(945,0)"></path></g></g></g></g></g></svg></mjx-container></span> for the general population <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="3.832ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 1693.8 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1000,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(1278,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. NAFLD increases the risk of liver disease but also increases risk of type II diabetes, cardiovascular disease (CVD) and the metabolic syndrome <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.632ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 2047.3 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1000,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1778,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. For example, a person with NAFLD and fibrosis has <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="8.549ex" height="1.692ex" role="img" focusable="false" viewBox="0 -666 3778.4 748"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(778,0)"></path></g><g data-mml-node="mo" transform="translate(1500.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(2500.4,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(778,0)"></path></g></g></g></svg></mjx-container></span> times the risk of cardiovascular disease death and increased risk of type II diabetes compared to a similarly overweight person without NAFLD (reviewed in Armstrong et al²1). An estimated <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="3.394ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 1500 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(500,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mn" transform="translate(1000,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span> of adults with nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD, will go on to develop cirrhosis and liver cancer <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span> and it is the most rapidly increasing reason for liver transplants in adults. The morbidity and mortality of NAFLD, along with its high prevalence in a vulnerable population make NAFLD a public health priority <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>.</div> |
| <div>In a healthy person, almost no fat ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="5.404ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 2388.8 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g><g data-mml-node="mi" transform="translate(1555.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> of the liver by volume) is stored in the liver, despite the fact that the liver is a major site of metabolism for dietary fat, cholesterol, triglyceride, free fatty acids and more. NAFLD develops when the balance of triglyceride metabolism in the liver becomes dysregulated in the setting of insulin resistance (IR). Triglyceride rich lipoproteins either originate in the intestine or liver and the sources of fatty acids used for lipoprotein assembly are derived either from de novo lipogenesis (DNL), the diet or from the plasma pool of nonesterified FA (NEFA) <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Hepatic DNL appears to underlie the mechanism of excess hepatic storage of triglyceride during carbohydrate feeding in individuals with NAFLD <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.632ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 2047.3 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1000,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1778,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Compared to subjects with metabolic syndrome and no increased hepatic fat, subjects with NAFLD have 3 fold higher rates of DNL in addition to higher plasma levels of FFA during the nighttime <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. The mechanisms of NASH, in which hepatic fat is associated with inflammation and hepatocellular injury are complex but likely involve lipotoxicity and increased oxidative stress.</div> |
| <div>Because of the high level of consumption and its metabolic fate, fructose has been studied in relation to many health problems, including NAFLD. Fructose was initially linked to steatosis and NAFLD in animal models but more recently, a number of human studies have demonstrated links. Fructose enters the diet primarily from sugars that are in processed food and beverages, often referred to as added sugars. The World Health Organization (WHO) has provided a draft of guidelines on sugar consumption and has clarified the term "free sugars" which includes all monosaccharides (fructose, glucose, galactose) and disaccharides (sucrose, maltose, trehalose) which are added to the foods by the manufacturer, the cook, or the consumer. The "free sugars" category includes naturally occurring sugars in honey, fruit juices, and syrups and excludes sugars from fruits, vegetables or the lactose from dairy. Naturally occurring sources of fructose include fruit and vegetables, but only account for a small percentage of fructose in the diet <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.903ex" role="img" focusable="false" viewBox="0 -841 790.1 841"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. In the U.S., added sugar consumption rose over most of the past century <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="3.832ex" height="1.903ex" role="img" focusable="false" viewBox="0 -841 1693.8 841"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1000,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(1278,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span> until the 2000 's when consumption of sugar sweetened beverages began to decline <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Recent estimates indicate a slightly declined consumption of total added sugar, fructose, and sugar sweetened beverages <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.632ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 2047.3 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1000,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Even with this decline, the amount of added sugars, and thus the amount of fructose, in the typical US diet remains elevated at <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="6.536ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 2888.8 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="223C" d="M55 166Q55 241 101 304T222 367Q260 367 296 349T362 304T421 252T484 208T554 189Q616 189 655 236T694 338Q694 350 698 358T708 367Q722 367 722 334Q722 260 677 197T562 134H554Q517 134 481 152T414 196T355 248T292 293T223 311Q179 311 145 286Q109 257 96 218T80 156T69 133Q55 133 55 166Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> of total calories, which exceeds the upper recommendation of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="9.832ex" height="2.071ex" role="img" focusable="false" viewBox="0 -833.2 4345.6 915.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="msup" transform="translate(2722.4,0)"><g data-mml-node="mi"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g><g data-mml-node="TeXAtom" transform="translate(866,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>.</div> |
| <div>Fructose is absorbed from the lower part of duodenum and jejunum both passively and actively primarily through GLUT5. After absorption across the brush border of the small intestine into the portal blood supply, fructose is cleared from the blood in the liver on the first pass and almost exclusively metabolized in hepatocytes. Most absorbed fructose is cleaved into glyceraldehyde and dihydroxyacetone phosphate, and these trioses further go to glycerol phosphate and pyruvate metabolic pathways, promoting gluconeogenesis and DNL, respectively. It is this stimulation of DNL that has been studied closely and may be a critical environmental contributor to NAFLD. When compared with a isocaloric diet with the same macronutrient distribution, a fructose containing diet (25% of calories) was associated with both higher DNL and higher liver fat in a short term study of healthy adults <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>.</div> |
| <div>NAFLD patients have been found to be high consumers of fructose. In a cross-sectional analysis, Quyang et al. found a 2-3 fold increase of fructose consumption in patients with biopsy-proven NAFLD as compared to their sex, age, and BMI matched controls <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. A longitudinal study in obese adolescents indicated that energy-adjusted fructose intake was independently associated with NAFLD during a 3 -year follow up <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. And fructose may be associated with the severity of NAFLD. For example, work by Abdelmalek et al. reported a significant association between fructose intake and fibrosis severity in a cohort of 427 adults with histologically-confirmed NAFLD <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.903ex" role="img" focusable="false" viewBox="0 -841 790.1 841"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>.</div> |
| <div>There are a few small studies demonstrating improvement in features of NAFLD with fructose reduction but this is an area that deserves more research. In a randomized controlled trial, 4 -week fructose restriction in children with NAFLD improved their adipose insulin sensitivity, high sensitivity C-reactive protein (hs-CRP), and LDL<br> |
| oxidation; whereas their liver enzymes and intrahepatic fat remained unchanged <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Over a longer intervention as of 6 months, improvement of liver enzyme was seen with lowering dietary component of fructose and glycemic load in NAFLD subjects <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Finally, a recently reported 10 day study in children on a fructose-free diet demonstrated a 20 percent drop in liver fat.</div> |
| <div>Of note, while the studies above isolated fructose as the dietary component being evaluated, in real life, most fructose in the diet is from added sugars. Thus, while fructose is important to evaluate for the mechanism of effect, added sugars are a human health relevant environmental exposure that is being considered in this study.</div> |
| <div>Another technology utilized in this protocol is magnetic resonance imaging-estimated liver proton density fat fraction (MRI-estimated liver PDFF) for the measurement of hepatic fat. This is a research technology that is not yet clinically available, but has recently been validated for use in children and is highly beneficial because it can be used instead of a liver biopsy to measure hepatic fat <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. In the validation study, MRIestimated liver PDFF was used to measure hepatic steatosis and was compared this to histopathologic grading in 174 children with a mean age of 14 years (range 8 to 16 years) <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. All the children completed the MRI acquisition protocol without difficulty demonstrating the feasibility of MR-based steatosis measurements in young children. The correlation of the MRI-estimated liver PDFF with the pathology assigned steatosis grade was very good <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="8.702ex" height="2.47ex" role="img" focusable="false" viewBox="0 -841.7 3846.1 1091.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="28" d="M94 250Q94 319 104 381T127 488T164 576T202 643T244 695T277 729T302 750H315H319Q333 750 333 741Q333 738 316 720T275 667T226 581T184 443T167 250T184 58T225 -81T274 -167T316 -220T333 -241Q333 -250 318 -250H315H302L274 -226Q180 -141 137 -14T94 250Z"></path></g><g data-mml-node="mn" transform="translate(389,0)"><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z" transform="translate(778,0)"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(1278,0)"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(1778,0)"></path></g><g data-mml-node="msup" transform="translate(2667,0)"><g data-mml-node="mo"><path data-c="29" d="M60 749L64 750Q69 750 74 750H86L114 726Q208 641 251 514T294 250Q294 182 284 119T261 12T224 -76T186 -143T145 -194T113 -227T90 -246Q87 -249 86 -250H74Q66 -250 63 -250T58 -247T55 -238Q56 -237 66 -225Q221 -64 221 250T66 725Q56 737 55 738Q55 746 60 749Z"></path></g><g data-mml-node="TeXAtom" transform="translate(422,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Further, it is a precise, low risk technology <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. No MRI contrast is required and the scan time can be brief ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="4.651ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 2055.8 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="223C" d="M55 166Q55 241 101 304T222 367Q260 367 296 349T362 304T421 252T484 208T554 189Q616 189 655 236T694 338Q694 350 698 358T708 367Q722 367 722 334Q722 260 677 197T562 134H554Q517 134 481 152T414 196T355 248T292 293T223 311Q179 311 145 286Q109 257 96 218T80 156T69 133Q55 133 55 166Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g></g></g></svg></mjx-container></span> minutes) thus making MRI PDFF ideal for measuring hepatic fat in this research protocol.</div> |
| <div>In summary, free sugars are associated with severity of NAFLD and may be an important environmental cause of increased DNL leading to hepatic steatosis. In this proposal, we will test the effect of a low "free sugars" (<3% total daily calories) diet in children with biopsy-proven NAFLD using innovative, low risk, non-invasive tools like MRI for hepatic fat measurement.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.2-justification"> |
| 2.2 Justification</h3> |
| <div>Before designing a large RCT it is prudent to first test effect size of reducing sugar in male children with a history of NAFLD on hepatic fat, ALT, and other markers in a smaller, randomized, controlled study.</div> |
| <div>Population studies demonstrate that NAFLD is more than twice as likely in boys compared to girls <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="3.032ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 1340.2 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. In the recently completed NIH sponsored NASH randomized, controlled trial, <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="5.74ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 2537 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D44B" d="M42 0H40Q26 0 26 11Q26 15 29 27Q33 41 36 43T55 46Q141 49 190 98Q200 108 306 224T411 342Q302 620 297 625Q288 636 234 637H206Q200 643 200 645T202 664Q206 677 212 683H226Q260 681 347 681Q380 681 408 681T453 682T473 682Q490 682 490 671Q490 670 488 658Q484 643 481 640T465 637Q434 634 411 620L488 426L541 485Q646 598 646 610Q646 628 622 635Q617 635 609 637Q594 637 594 648Q594 650 596 664Q600 677 606 683H618Q619 683 643 683T697 681T738 680Q828 680 837 683H845Q852 676 852 672Q850 647 840 637H824Q790 636 763 628T722 611T698 593L687 584Q687 585 592 480L505 384Q505 383 536 304T601 142T638 56Q648 47 699 46Q734 46 734 37Q734 35 732 23Q728 7 725 4T711 1Q708 1 678 1T589 2Q528 2 496 2T461 1Q444 1 444 10Q444 11 446 25Q448 35 450 39T455 44T464 46T480 47T506 54Q523 62 523 64Q522 64 476 181L429 299Q241 95 236 84Q232 76 232 72Q232 53 261 47Q262 47 267 47T273 46Q276 46 277 46T280 45T283 42T284 35Q284 26 282 19Q279 6 276 4T261 1Q258 1 243 1T201 2T142 2Q64 2 42 0Z"></path></g><g data-mml-node="mi" transform="translate(852,0)"><path data-c="1D44B" d="M42 0H40Q26 0 26 11Q26 15 29 27Q33 41 36 43T55 46Q141 49 190 98Q200 108 306 224T411 342Q302 620 297 625Q288 636 234 637H206Q200 643 200 645T202 664Q206 677 212 683H226Q260 681 347 681Q380 681 408 681T453 682T473 682Q490 682 490 671Q490 670 488 658Q484 643 481 640T465 637Q434 634 411 620L488 426L541 485Q646 598 646 610Q646 628 622 635Q617 635 609 637Q594 637 594 648Q594 650 596 664Q600 677 606 683H618Q619 683 643 683T697 681T738 680Q828 680 837 683H845Q852 676 852 672Q850 647 840 637H824Q790 636 763 628T722 611T698 593L687 584Q687 585 592 480L505 384Q505 383 536 304T601 142T638 56Q648 47 699 46Q734 46 734 37Q734 35 732 23Q728 7 725 4T711 1Q708 1 678 1T589 2Q528 2 496 2T461 1Q444 1 444 10Q444 11 446 25Q448 35 450 39T455 44T464 46T480 47T506 54Q523 62 523 64Q522 64 476 181L429 299Q241 95 236 84Q232 76 232 72Q232 53 261 47Q262 47 267 47T273 46Q276 46 277 46T280 45T283 42T284 35Q284 26 282 19Q279 6 276 4T261 1Q258 1 243 1T201 2T142 2Q64 2 42 0Z"></path></g><g data-mml-node="mi" transform="translate(1704,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> of the subjects enrolled were boys, despite best efforts to increase recruitment of girls. Puberty is a strong modifier of NAFLD severity <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Girls undergo puberty earlier than boys. Together, these effects could confound the study results because more girls would be in later stages of puberty compared to the boys. Increasing the sample size would allow for subgroup analysis and controlling for sex, however budget constraints did not allow for a larger cohort. Thus, the study was<br> |
| designed with boys alone, excluding girls. There are limitations of including only boys including that it makes the study less generalizable. This will hopefully be addressed by proceeding with a larger, longer trial including both sexes justified by the data of this initial study.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.3-potential-risks-and-benefits"> |
| 2.3 Potential Risks and Benefits</h3> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.3.1-potential-risks"> |
| 2.3.1 Potential Risks</h3> |
| <div>There is minimal risk in this study. Potential risks are related to 1) the MRI PDFF 2) blood draws, 3) NPO status, 4) cumulative blood loss, 5) confidentiality and 6) diet low in free sugars.</div> |
| <ol> |
| <li>MRI PDFF - Some children may find the MRI examination to be a fear invoking one. These will be done at a research imaging facility where the staff is experienced in working with children. The MRI scanner also has movies for improving the experience.</li> |
| <li>The placement of an intravenous catheter and drawing of blood specimens has minimal risk of discomfort, bruising, or bleeding. There is minimal risk of infection or extravasation. Experienced staff with pediatric expertise will place all catheters and draw blood.</li> |
| <li>Patients will remain NPO from 8 pm the evening before the study until the fasting portion of the study is concluded. Some children may become agitated with NPO status. Blood sugar will be monitored at the beginning of the study and water will be encouraged to maintain hydration. Each participant will be asked to drink one glass of water at bedtime prior to the study and one glass in the morning before leaving home for the research center. Food and water will be provided immediately following the conclusion of fasting visits</li> |
| <li>Blood loss: During the study visits, blood will be drawn from an indwelling IV at 19 time-points. To minimize risk to the patient, we will limit amounts in accordance with the guidelines of our IRB and the NIH. The total blood volume drawn over the course of the study will be 97 mL . We expect all of our patients to be <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="6.909ex" height="2.034ex" role="img" focusable="false" viewBox="0 -694 3053.8 899"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="1D458" d="M121 647Q121 657 125 670T137 683Q138 683 209 688T282 694Q294 694 294 686Q294 679 244 477Q194 279 194 272Q213 282 223 291Q247 309 292 354T362 415Q402 442 438 442Q468 442 485 423T503 369Q503 344 496 327T477 302T456 291T438 288Q418 288 406 299T394 328Q394 353 410 369T442 390L458 393Q446 405 434 405H430Q398 402 367 380T294 316T228 255Q230 254 243 252T267 246T293 238T320 224T342 206T359 180T365 147Q365 130 360 106T354 66Q354 26 381 26Q429 26 459 145Q461 153 479 153H483Q499 153 499 144Q499 139 496 130Q455 -11 378 -11Q333 -11 305 15T277 90Q277 108 280 121T283 145Q283 167 269 183T234 206T200 217T182 220H180Q168 178 159 139T145 81T136 44T129 20T122 7T111 -2Q98 -11 83 -11Q66 -11 57 -1T48 16Q48 26 85 176T158 471L195 616Q196 629 188 632T149 637H144Q134 637 131 637T124 640T121 647Z"></path></g><g data-mml-node="mi" transform="translate(2576.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> making these amounts well within the NIH clinical center guidelines recommending less than <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="7.181ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 3174 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(1378,0)"><path data-c="1D459" d="M117 59Q117 26 142 26Q179 26 205 131Q211 151 215 152Q217 153 225 153H229Q238 153 241 153T246 151T248 144Q247 138 245 128T234 90T214 43T183 6T137 -11Q101 -11 70 11T38 85Q38 97 39 102L104 360Q167 615 167 623Q167 626 166 628T162 632T157 634T149 635T141 636T132 637T122 637Q112 637 109 637T101 638T95 641T94 647Q94 649 96 661Q101 680 107 682T179 688Q194 689 213 690T243 693T254 694Q266 694 266 686Q266 675 193 386T118 83Q118 81 118 75T117 65V59Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1676,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(2176,0)"><path data-c="1D458" d="M121 647Q121 657 125 670T137 683Q138 683 209 688T282 694Q294 694 294 686Q294 679 244 477Q194 279 194 272Q213 282 223 291Q247 309 292 354T362 415Q402 442 438 442Q468 442 485 423T503 369Q503 344 496 327T477 302T456 291T438 288Q418 288 406 299T394 328Q394 353 410 369T442 390L458 393Q446 405 434 405H430Q398 402 367 380T294 316T228 255Q230 254 243 252T267 246T293 238T320 224T342 206T359 180T365 147Q365 130 360 106T354 66Q354 26 381 26Q429 26 459 145Q461 153 479 153H483Q499 153 499 144Q499 139 496 130Q455 -11 378 -11Q333 -11 305 15T277 90Q277 108 280 121T283 145Q283 167 269 183T234 206T200 217T182 220H180Q168 178 159 139T145 81T136 44T129 20T122 7T111 -2Q98 -11 83 -11Q66 -11 57 -1T48 16Q48 26 85 176T158 471L195 616Q196 629 188 632T149 637H144Q134 637 131 637T124 640T121 647Z"></path></g><g data-mml-node="mi" transform="translate(2697,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> at a single research visit and no more than <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="7.181ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 3174 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(1378,0)"><path data-c="1D459" d="M117 59Q117 26 142 26Q179 26 205 131Q211 151 215 152Q217 153 225 153H229Q238 153 241 153T246 151T248 144Q247 138 245 128T234 90T214 43T183 6T137 -11Q101 -11 70 11T38 85Q38 97 39 102L104 360Q167 615 167 623Q167 626 166 628T162 632T157 634T149 635T141 636T132 637T122 637Q112 637 109 637T101 638T95 641T94 647Q94 649 96 661Q101 680 107 682T179 688Q194 689 213 690T243 693T254 694Q266 694 266 686Q266 675 193 386T118 83Q118 81 118 75T117 65V59Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1676,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(2176,0)"><path data-c="1D458" d="M121 647Q121 657 125 670T137 683Q138 683 209 688T282 694Q294 694 294 686Q294 679 244 477Q194 279 194 272Q213 282 223 291Q247 309 292 354T362 415Q402 442 438 442Q468 442 485 423T503 369Q503 344 496 327T477 302T456 291T438 288Q418 288 406 299T394 328Q394 353 410 369T442 390L458 393Q446 405 434 405H430Q398 402 367 380T294 316T228 255Q230 254 243 252T267 246T293 238T320 224T342 206T359 180T365 147Q365 130 360 106T354 66Q354 26 381 26Q429 26 459 145Q461 153 479 153H483Q499 153 499 144Q499 139 496 130Q455 -11 378 -11Q333 -11 305 15T277 90Q277 108 280 121T283 145Q283 167 269 183T234 206T200 217T182 220H180Q168 178 159 139T145 81T136 44T129 20T122 7T111 -2Q98 -11 83 -11Q66 -11 57 -1T48 16Q48 26 85 176T158 471L195 616Q196 629 188 632T149 637H144Q134 637 131 637T124 640T121 647Z"></path></g><g data-mml-node="mi" transform="translate(2697,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> over any 6 week period.</li> |
| <li>There is a small risk of loss of confidentiality. We will follow all procedures required by respective institutions to protect participants. Efforts will be made to ensure that all personal information remains confidential. All data will be stored in locked offices and password-protected computers. Personal identity will be protected in any publication.</li> |
| <li>Potential risks of a low "free sugars" diet: sugar is not a required nutrient but it is known to have some addictive qualities. Elimination of "free sugars" in the diet may at first result in cravings of sugar and this is expected to fade over <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="5.028ex" height="1.692ex" role="img" focusable="false" viewBox="0 -666 2222.4 748"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span> weeks.</li> |
| </ol> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.3.2-potential-benefits"> |
| 2.3.2 Potential Benefits</h3> |
| <div>The proposed research has substantial potential benefits for children. Sugar is known to increase adiposity in children over time and even a short reduction of 8 weeks is likely to have benefits from a BMI and cardiovascular standpoint, although these may not be sustained after the trial ends. In the standard of care control group, families will receive gift cards to cover groceries and this may allow them to purchase healthier foods such as vegetables.</div> |
| <div>Participants in both groups will benefit from the knowledge that they are helping to contribute to the knowledge of how diet changes can help treat NAFLD.</div> |
| <div>In addition, at the conclusion of the study, all participants in the studies will receive copies of their liver transaminases, lipid results and baseline MRI PDFF results and these will be discussed with them by one of the investigators. Education will be provided as appropriate regarding the results and standard of care advice for diet and physical activity levels.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.3.3-alternative-treatments-and-procedures"> |
| 2.3.3 Alternative treatments and procedures</h3> |
| <div>Patients that are approached about the study can choose not to participate. If they decide not to participate it will not impact their standard of care treatment.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.3.4-protection-against-risks"> |
| 2.3.4 Protection against risks</h3> |
| <div>Risk will be minimized to the children by using nurses and staff experienced in pediatrics for the research studies. As discussed above, the risks associated with heavy water will be minimized by giving the first dose at the research center under supervision. Risk to confidentiality will be reduced by using non-identifying participant numbers and removing all identifiers as early as feasible. Only study personnel will have access to identifying data. Laboratory personnel will only have access to numeric identifiers and the key will be kept in a password protected database.</div> |
| <div>Children will provide written assent (11-16 y). Children are able to decline to continue to participate at any time before and during the study or study visit. During study visits, if an IV fails, we will attempt to replace it. If the child does not wish to have it replaced, we encourage them to tell us this and the visit will be stopped immediately. Study stipends are provided at a standardized pro-rated level appropriate for the time/study procedures completed.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="3-objectives"> |
| 3 OBJECTIVES</h2> |
| <div>What is the role of sugar consumption in the etiology and treatment of pediatric NALFD?</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.1-general-hypothesis"> |
| 3.1 General hypothesis</h3> |
| <div>Sugar restriction will reduce hepatic fat content and reverse liver histopathology in children with NAFLD (and by extension, such foods/beverages that trigger the condition).</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.2-specific-hypothesis"> |
| 3.2 Specific Hypothesis</h3> |
| <div>Restricting sugar in beverages, in food, or in both will decrease hepatic fat content and reverse liver histopathology in children with NAFLD in relation to the type and/or degree of restriction (and by extension, such foods/beverages that trigger the condition).</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.3-implications"> |
| 3.3 Implications</h3> |
| <div>Improvement in NAFLD/NASH in children can be achieved by limiting all sugars, or by limiting a specific form of sugar (free sugars in beverages or in food) alone. Avoiding such foods will prevent development of NAFLD and NASH.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.4-primary-outcome-measure"> |
| 3.4 Primary Outcome Measure</h3> |
| <div>Change in hepatic steatosis (%) by MRI PDFF in the intervention group compared to change in the control group.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.5-secondary-outcome-measures"> |
| 3.5 Secondary Outcome Measures</h3> |
| <div>ALT, AST, GGT, Adipo-IR, fasting glucose, insulin, serum lipids, sweetness perception testing, compliance (all baseline compared to 8 weeks, change in intervention group compared to control).</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="4-study-design"> |
| 4 STUDY DESIGN</h2> |
| <div>A study that tests nutritional interventions that clinicians currently prescribe, such as ad libitum weight-reducing diets, has the potential to directly and rapidly affect clinical practice, but does not necessarily provide significant insight into the dietary trigger of disease or the dietary mechanism driving any observed effects. Conversely, a highly controlled diet study may more clearly identify the nutritional trigger and mechanism (necessary for the successful prevention of the disease in public health campaigns) but may be dismissed by many clinicians as divorced from actual practice. Here we describe a trial that hopes to balance the need for establishing practical clinical guidelines for dietary treatment and experimental controls sufficient to identify the dietary trigger for NAFLD in a pediatric population.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="4.1-overview"> |
| 4.1 Overview</h3> |
| <div>This is a 2 site, 8 -week randomized, controlled, outpatient feeding study at Emory University and UCSD. Participants will be non-diabetic male adolescents with biopsyproven NAFLD. Two groups of 20 participants will be followed for 8 weeks with hepatic fat content assessed by MRI PDFF at weeks 0,4 , and 8 . The participants will be randomized to either standard of care control arm to track the naturally-occurring changes in hepatic fat content over time, or replacement of habitual diet with a low "free sugars" (<3% of total daily calories) version, intervention arm. The primary outcome is percent change in liver fat content over time in the treatment group compared to the control group. Additional parameters of liver function and metabolic status (e.g., serum ALT) will also be assessed.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="4.2-intervention"> |
| 4.2 Intervention</h3> |
| <div>The intervention is replacement of habitual diet with a low "free sugars" diet (<3% of total calories). The intervention will be applied by family and will aim to alter the diet by specifically targeting the foods that contain free sugars (WHO definition: glucose, fructose, galactose, sucrose, maltose, trehalose) added to food by consumer, cook, or manufacturer, while preserving the family's other food group choices. At recruitment, families will be randomized to either the low "free sugars" diet (intervention) or remain on their regular diet (standard of care control). Following screening procedures and prior to study initiation, a home visit will be scheduled at which current food consumption, food preferences, and weekly food volume required for the family will be assessed and recorded. Additionally, common recipes used by the family will be collected. One day prior to study initiation (Day 0), the nutritionist/coordinator/staff will assist the parent or guardian in selecting and removing all sugar and sugar-containing products from the home. The items will be replaced with similar foods that contain no free sugars. In general, artificial sweeteners will be avoided although in some instances it will be necessary to use them.</div> |
| <div>For each week of the study ( 8 weeks total), families will be able to choose meals from a list of foods similar to their usual diet including ready-to-eat foods, breakfast foods, lunch items, dinner entrees, fruits, and snacks. Food will be prepared by dieticians/nutritionists at the research metabolic kitchen and supplies for several days at a time will be delivered to the family by the study staff. Each child will be provided with a lunch bag and instructed to bring lunch to school to maintain the study diet.</div> |
| <div>Families will have the opportunity to choose from a list of pre-prepared evening meals that are similar to what they consumed before study initiation but not containing any free sugars. Dinners will typically be fresh or frozen and re-heating in the oven or microwave may be required. The families will be instructed to not eat any food outside of assigned diet. For the duration of the study a water dispenser will be provided. Families will be instructed to avoid all fruit juice and sweet drinks. Fruit consumption will be allowed but restricted in amount (to <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="5.028ex" height="1.692ex" role="img" focusable="false" viewBox="0 -666 2222.4 748"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></svg></mjx-container></span> portions/ day per family member).</div> |
| <div>Methods to improve compliance: Twice a week, a coordinator/study staff member will conduct home visits or phone calls to assess food satisfaction as well as diet compliance in the intervention arm. In the standard of care control arm, study staff will visit the home once a week to check on their compliance and provide them with any study-related items (water, gift cards etc.). To enhance compliance, the family will be allowed 1 meal "off" of the diet 4 times during the study. These meals will be planned in coordination with the staff and may include holidays or special family events or other days that they select. These "off" meals may not be used during the last week of the intervention.</div> |
| <div>Compliance will also be increased by informing participants that the investigators can assess compliance with the diet by measuring sugar in the blood work. If there is evidence of the participant not complying, the study coordinator or investigator will meet with the participant and family members and explain the importance of only consuming the study diet. If the study coordinator/staff perceives evidence of persistent noncompliance by the participant, families will be withdrawn from study and the diet will be stopped.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="4.3-dietary-assessment"> |
| 4.3 Dietary Assessment</h3> |
| <div>Baseline diet by 24 -hour recalls will include <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="6.159ex" height="1.532ex" role="img" focusable="false" viewBox="0 -677 2722.4 677"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="D7" d="M630 29Q630 9 609 9Q604 9 587 25T493 118L389 222L284 117Q178 13 175 11Q171 9 168 9Q160 9 154 15T147 29Q147 36 161 51T255 146L359 250L255 354Q174 435 161 449T147 471Q147 480 153 485T168 490Q173 490 175 489Q178 487 284 383L389 278L493 382Q570 459 587 475T609 491Q630 491 630 471Q630 464 620 453T522 355L418 250L522 145Q606 61 618 48T630 29Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g></g></g></svg></mjx-container></span>-hour recalls to reflect diet during weekdays and <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="6.159ex" height="1.532ex" role="img" focusable="false" viewBox="0 -677 2722.4 677"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="D7" d="M630 29Q630 9 609 9Q604 9 587 25T493 118L389 222L284 117Q178 13 175 11Q171 9 168 9Q160 9 154 15T147 29Q147 36 161 51T255 146L359 250L255 354Q174 435 161 449T147 471Q147 480 153 485T168 490Q173 490 175 489Q178 487 284 383L389 278L493 382Q570 459 587 475T609 491Q630 491 630 471Q630 464 620 453T522 355L418 250L522 145Q606 61 618 48T630 29Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g></g></g></svg></mjx-container></span>-hour recall to reflect diet on a weekend day. Families will be asked to specify times that work best to conduct the 24 -hour recalls and will be called at random, to minimize diet change. The 24 -hour recalls will aid in getting a better sense of the food groups consumed by the participant and his family and in the preparation of a personalized, tailored diet. Following study participant randomization, two weeks prior to study initiation, a home visit will be scheduled where current food consumption, food preferences, and weekly food volume required for the family will be recorded. Additionally, common recipes will be collected. During the study, every week a coordinator/study staff member will conduct two home visits to assess food satisfaction and diet compliance. If the study coordinator/staff perceives non-compliance by the<br> |
| family at any point of the study, the intervention will be stopped and families will be withdrawn from the study.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="4.4-sweetness-perception-testing"> |
| 4.4 Sweetness Perception Testing</h3> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="4.4.1-participant-preparation"> |
| 4.4.1 Participant preparation</h3> |
| <div>Participants will be asked to undergo sweetness taste perception testing at three points in the study: baseline (study initiation, week 0), follow-up visit 1 (week 4), and follow up visit 2 (study end, week 8). Participants will arrive at the clinic after an overnight fast to conduct the sweetness perception testing and MRI. Prior to each study visit, participants will be reminded not to eat or drink anything except for water after 8 pm the night before the visit. At each visit height, weight, and vital signs will be collected.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="4.4.2-sensory-ratings"> |
| 4.4.2 Sensory Ratings</h3> |
| <div>Sweetness perception will be assessed in a test session of about 1 hour. Participants will rate both the intensity and pleasantness of model beverages that vary widely in sucrose concentration. The model beverages will be formulated using unsweetened Kool-Aid <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.548ex" height="2.021ex" role="img" focusable="false" viewBox="0 -893.3 684 893.3"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mtext"><text data-variant="normal" transform="scale(1,-1)" font-size="884px" font-family="serif">™</text><path data-c="A0" d="" transform="translate(600,0)"></path></g></g></g></g></g></svg></mjx-container></span> drink mix at a fixed concentration. Concentrations of sucrose (ranging from barely sweet to very sweet) will be added to this fixed concentration of drink mix. Model beverages will be presented chilled. Over the course of a 1 -hour session, participants will consume about 120 ml of model beverage, or the equivalent of about <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="5.498ex" height="2.497ex" role="img" focusable="false" viewBox="0 -853.7 2430.1 1103.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(500,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="msup" transform="translate(1000,0)"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="TeXAtom" transform="translate(533,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mtext"><path data-c="72" d="M36 46H50Q89 46 97 60V68Q97 77 97 91T98 122T98 161T98 203Q98 234 98 269T98 328L97 351Q94 370 83 376T38 385H20V408Q20 431 22 431L32 432Q42 433 60 434T96 436Q112 437 131 438T160 441T171 442H174V373Q213 441 271 441H277Q322 441 343 419T364 373Q364 352 351 337T313 322Q288 322 276 338T263 372Q263 381 265 388T270 400T273 405Q271 407 250 401Q234 393 226 386Q179 341 179 207V154Q179 141 179 127T179 101T180 81T180 66V61Q181 59 183 57T188 54T193 51T200 49T207 48T216 47T225 47T235 46T245 46H276V0H267Q249 3 140 3Q37 3 28 0H20V46H36Z"></path><path data-c="64" d="M376 495Q376 511 376 535T377 568Q377 613 367 624T316 637H298V660Q298 683 300 683L310 684Q320 685 339 686T376 688Q393 689 413 690T443 693T454 694H457V390Q457 84 458 81Q461 61 472 55T517 46H535V0Q533 0 459 -5T380 -11H373V44L365 37Q307 -11 235 -11Q158 -11 96 50T34 215Q34 315 97 378T244 442Q319 442 376 393V495ZM373 342Q328 405 260 405Q211 405 173 369Q146 341 139 305T131 211Q131 155 138 120T173 59Q203 26 251 26Q322 26 373 103V342Z" transform="translate(392,0)"></path><path data-c="A0" d="" transform="translate(948,0)"></path></g></g></g></g></g></svg></mjx-container></span> of a 12 oz can of soda.</div> |
| <div>The first 10-15 minutes of each session will be devoted to instructions and practice ratings. Participants will rate perceived sweetness intensity using visual analog scales (i.e., vertical lines with the anchor labels "Tasteless" on the bottom and "Extremely Strong" on the top). Such scales are easy for participants to understand and use. Participants will practice by rating the sweetness of 8 sucrose solutions (different concentrations of Kool-Aid) that cover the range of sucrose concentrations to be using in sensory testing. Participants will rate pleasantness using a standard category scale ranging from "Dislike Extremely" (-4), to "Neither Like Nor Dislike" (0), to "Like Extremely" <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="4.652ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 2056 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="28" d="M94 250Q94 319 104 381T127 488T164 576T202 643T244 695T277 729T302 750H315H319Q333 750 333 741Q333 738 316 720T275 667T226 581T184 443T167 250T184 58T225 -81T274 -167T316 -220T333 -241Q333 -250 318 -250H315H302L274 -226Q180 -141 137 -14T94 250Z"></path></g><g data-mml-node="mo" transform="translate(389,0)"><path data-c="2B" d="M56 237T56 250T70 270H369V420L370 570Q380 583 389 583Q402 583 409 568V270H707Q722 262 722 250T707 230H409V-68Q401 -82 391 -82H389H387Q375 -82 369 -68V230H70Q56 237 56 250Z"></path></g><g data-mml-node="mn" transform="translate(1167,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g><g data-mml-node="mo" transform="translate(1667,0)"><path data-c="29" d="M60 749L64 750Q69 750 74 750H86L114 726Q208 641 251 514T294 250Q294 182 284 119T261 12T224 -76T186 -143T145 -194T113 -227T90 -246Q87 -249 86 -250H74Q66 -250 63 -250T58 -247T55 -238Q56 -237 66 -225Q221 -64 221 250T66 725Q56 737 55 738Q55 746 60 749Z"></path></g></g></g></svg></mjx-container></span>. Again, the use of such scales is fairly intuitive.</div> |
| <div>After scaling practice, participants will be instructed to rate the sweetness and pleasantness of 16 model drink samples. The 16 samples will be presented in 5 ml aliquots (in160 ml disposable plastic medicine cups). The 16 samples will be presented in two blocks of 8 trials. Each block will include all 8 sucrose concentrations, presented in random order. Prior to the first trial of each block, participants will be asked to rinse their mouth four times with water (same water used to make test beverage) and spit it out. Next, participants will sample each of the 8 cups by sipping, rolling the liquid sample<br> |
| around in the mouth for several seconds, and then swallowing the sample. After swallowing, participants will rate both the sweet taste intensity and pleasantness of the sample. After each trial, the participant will rinse the mouth a few times with water (same water used to make test beverage), spit, and wait <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="4.651ex" height="1.581ex" role="img" focusable="false" viewBox="0 -677 2055.8 699"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="223C" d="M55 166Q55 241 101 304T222 367Q260 367 296 349T362 304T421 252T484 208T554 189Q616 189 655 236T694 338Q694 350 698 358T708 367Q722 367 722 334Q722 260 677 197T562 134H554Q517 134 481 152T414 196T355 248T292 293T223 311Q179 311 145 286Q109 257 96 218T80 156T69 133Q55 133 55 166Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g><g data-mml-node="mn" transform="translate(1555.8,0)"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g></g></g></svg></mjx-container></span> seconds before tasting the next sample. Each block (all 8 concentrations, once each, in randomized order) will be followed by a five minute break. The first block will be used as practice and will not be included in analysis. The second and third blocks (replicate ratings for each of the 8 concentrations) will be used for analysis.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="4.5-study-duration-for-participants"> |
| 4.5 Study duration for participants</h3> |
| <ul> |
| <li>Screening MRI must occur within 14 days of baseline (Day 0)</li> |
| <li>56 days of treatment</li> |
| <li>14 days post-treatment assessment (by phone)</li> |
| </ul> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="4.6-study-timeline"> |
| 4.6 Study Timeline</h3> |
| <ul> |
| <li>Study initiation phase: 3 months (IRB, meal testing, etc.)</li> |
| <li>Recruitment phase: 4-8 months depending on enrollment pace</li> |
| <li>Follow-up phase: 10 months</li> |
| <li>Close out phase: 2 months (data analysis etc.)</li> |
| <li>Expected recruitment is 10 intervention participants and 10 control participants per clinical center, approximately 1 of each type per month per center</li> |
| </ul> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="5-study-enrollment-and-withdrawal"> |
| 5 STUDY ENROLLMENT AND WITHDRAWAL</h2> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="5.1-participant-inclusion-criteria"> |
| 5.1 Participant Inclusion Criteria</h3> |
| <ul> |
| <li>Boys age 11-16</li> |
| <li>Standard of care liver biopsy</li> |
| <li>Clinical history consistent with NAFLD</li> |
| <li>Definite NAFLD based on liver histology</li> |
| <li>Hepatic fat by MRI PDFF <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.312ex;" xmlns="http://www.w3.org/2000/svg" width="6.536ex" height="2.009ex" role="img" focusable="false" viewBox="0 -750 2888.8 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> on baseline MRI</li> |
| <li>Serum ALT <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="8.617ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 3808.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="1D462" d="M21 287Q21 295 30 318T55 370T99 420T158 442Q204 442 227 417T250 358Q250 340 216 246T182 105Q182 62 196 45T238 27T291 44T328 78L339 95Q341 99 377 247Q407 367 413 387T427 416Q444 431 463 431Q480 431 488 421T496 402L420 84Q419 79 419 68Q419 43 426 35T447 26Q469 29 482 57T512 145Q514 153 532 153Q551 153 551 144Q550 139 549 130T540 98T523 55T498 17T462 -8Q454 -10 438 -10Q372 -10 347 46Q345 45 336 36T318 21T296 6T267 -6T233 -11Q189 -11 155 7Q103 38 103 113Q103 170 138 262T173 379Q173 380 173 381Q173 390 173 393T169 400T158 404H154Q131 404 112 385T82 344T65 302T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(2627.8,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(3127.8,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span></li> |
| <li>Written informed consent from parent or legal guardian</li> |
| <li>Written informed assent from the child</li> |
| <li>Currently consumes <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.312ex;" xmlns="http://www.w3.org/2000/svg" width="3.52ex" height="1.819ex" role="img" focusable="false" viewBox="0 -666 1555.8 804"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></svg></mjx-container></span> eight ounce sugar drinks (or juice) per week</li> |
| </ul> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="5.2-participant-exclusion-criteria"> |
| 5.2 Participant Exclusion Criteria</h3> |
| <ul> |
| <li>Participants with a history of health issues that make it unsafe for them to participate in the opinion of the investigators</li> |
| <li>History of significant alcohol intake (AUDIT questionnaire) or inability to quantify alcohol consumption</li> |
| <li>Chronic use (more than 2 consecutive weeks) of medications known to cause hepatic steatosis or steatohepatitis (systemic glucocorticoids, tetracycline, anabolic steroids, valproic acid, salicylates, tamoxifen) in the past year.</li> |
| <li>The use of other known hepatotoxins within 90 days of liver biopsy or within 120 of baseline</li> |
| <li>New medications or vitamins/supplements started within the past 6 months intended to treat NAFLD/NASH</li> |
| <li>History of total parenteral nutrition (TPN) use in the year prior to screening</li> |
| <li>History of bariatric surgery or planning to undergo bariatric surgery during the study duration</li> |
| <li>Significant depression</li> |
| <li>Non-compensated liver disease with any one of the following hematologic, biochemical, and serological criteria on entry into protocol:<br> |
| a. Hemoglobin <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="9.579ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4233.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(2532.8,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(3032.8,0)"><path data-c="1D451" d="M366 683Q367 683 438 688T511 694Q523 694 523 686Q523 679 450 384T375 83T374 68Q374 26 402 26Q411 27 422 35Q443 55 463 131Q469 151 473 152Q475 153 483 153H487H491Q506 153 506 145Q506 140 503 129Q490 79 473 48T445 8T417 -8Q409 -10 393 -10Q359 -10 336 5T306 36L300 51Q299 52 296 50Q294 48 292 46Q233 -10 172 -10Q117 -10 75 30T33 157Q33 205 53 255T101 341Q148 398 195 420T280 442Q336 442 364 400Q369 394 369 396Q370 400 396 505T424 616Q424 629 417 632T378 637H357Q351 643 351 645T353 664Q358 683 366 683ZM352 326Q329 405 277 405Q242 405 210 374T160 293Q131 214 119 129Q119 126 119 118T118 106Q118 61 136 44T179 26Q233 26 290 98L298 109L352 326Z"></path></g><g data-mml-node="mi" transform="translate(3552.8,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span><br> |
| b. White blood cell <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="7.92ex" height="1.946ex" role="img" focusable="false" viewBox="0 -666 3500.4 860"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mo" transform="translate(1555.8,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(2000.4,0)"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(1000,0)"></path></g></g></g></svg></mjx-container></span> cells <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="5.104ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 2256 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(1378,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g></g></g></svg></mjx-container></span><br> |
| c. Neutrophil count <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="7.92ex" height="1.946ex" role="img" focusable="false" viewBox="0 -666 3500.4 860"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mo" transform="translate(1555.8,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(2000.4,0)"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(1000,0)"></path></g></g></g></svg></mjx-container></span> cells <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="6.235ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 2756 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(1378,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mn" transform="translate(2256,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span> of blood<br> |
| d. Platelets <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="10.182ex" height="1.946ex" role="img" focusable="false" viewBox="0 -666 4500.4 860"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(1000,0)"></path></g><g data-mml-node="mo" transform="translate(2555.8,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(3000.4,0)"><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(1000,0)"></path></g></g></g></svg></mjx-container></span> cells <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="6.235ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 2756 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(1378,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mn" transform="translate(2256,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span> of blood<br> |
| e. Direct bilirubin <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="12.194ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 5389.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(778,0)"></path></g><g data-mml-node="mi" transform="translate(2333.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3211.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(3688.8,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(4188.8,0)"><path data-c="1D451" d="M366 683Q367 683 438 688T511 694Q523 694 523 686Q523 679 450 384T375 83T374 68Q374 26 402 26Q411 27 422 35Q443 55 463 131Q469 151 473 152Q475 153 483 153H487H491Q506 153 506 145Q506 140 503 129Q490 79 473 48T445 8T417 -8Q409 -10 393 -10Q359 -10 336 5T306 36L300 51Q299 52 296 50Q294 48 292 46Q233 -10 172 -10Q117 -10 75 30T33 157Q33 205 53 255T101 341Q148 398 195 420T280 442Q336 442 364 400Q369 394 369 396Q370 400 396 505T424 616Q424 629 417 632T378 637H357Q351 643 351 645T353 664Q358 683 366 683ZM352 326Q329 405 277 405Q242 405 210 374T160 293Q131 214 119 129Q119 126 119 118T118 106Q118 61 136 44T179 26Q233 26 290 98L298 109L352 326Z"></path></g><g data-mml-node="mi" transform="translate(4708.8,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span><br> |
| f. Total bilirubin <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="10.434ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4611.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mi" transform="translate(1555.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2433.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(2910.8,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(3410.8,0)"><path data-c="1D451" d="M366 683Q367 683 438 688T511 694Q523 694 523 686Q523 679 450 384T375 83T374 68Q374 26 402 26Q411 27 422 35Q443 55 463 131Q469 151 473 152Q475 153 483 153H487H491Q506 153 506 145Q506 140 503 129Q490 79 473 48T445 8T417 -8Q409 -10 393 -10Q359 -10 336 5T306 36L300 51Q299 52 296 50Q294 48 292 46Q233 -10 172 -10Q117 -10 75 30T33 157Q33 205 53 255T101 341Q148 398 195 420T280 442Q336 442 364 400Q369 394 369 396Q370 400 396 505T424 616Q424 629 417 632T378 637H357Q351 643 351 645T353 664Q358 683 366 683ZM352 326Q329 405 277 405Q242 405 210 374T160 293Q131 214 119 129Q119 126 119 118T118 106Q118 61 136 44T179 26Q233 26 290 98L298 109L352 326Z"></path></g><g data-mml-node="mi" transform="translate(3930.8,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span><br> |
| g. Albumin <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="10.208ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4511.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(778,0)"></path></g><g data-mml-node="mi" transform="translate(2333.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(2810.8,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(3310.8,0)"><path data-c="1D451" d="M366 683Q367 683 438 688T511 694Q523 694 523 686Q523 679 450 384T375 83T374 68Q374 26 402 26Q411 27 422 35Q443 55 463 131Q469 151 473 152Q475 153 483 153H487H491Q506 153 506 145Q506 140 503 129Q490 79 473 48T445 8T417 -8Q409 -10 393 -10Q359 -10 336 5T306 36L300 51Q299 52 296 50Q294 48 292 46Q233 -10 172 -10Q117 -10 75 30T33 157Q33 205 53 255T101 341Q148 398 195 420T280 442Q336 442 364 400Q369 394 369 396Q370 400 396 505T424 616Q424 629 417 632T378 637H357Q351 643 351 645T353 664Q358 683 366 683ZM352 326Q329 405 277 405Q242 405 210 374T160 293Q131 214 119 129Q119 126 119 118T118 106Q118 61 136 44T179 26Q233 26 290 98L298 109L352 326Z"></path></g><g data-mml-node="mi" transform="translate(3830.8,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span><br> |
| h. International normalized ratio <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="0.88ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 389 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="28" d="M94 250Q94 319 104 381T127 488T164 576T202 643T244 695T277 729T302 750H315H319Q333 750 333 741Q333 738 316 720T275 667T226 581T184 443T167 250T184 58T225 -81T274 -167T316 -220T333 -241Q333 -250 318 -250H315H302L274 -226Q180 -141 137 -14T94 250Z"></path></g></g></g></svg></mjx-container></span> INR <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="6.789ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 3000.6 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="29" d="M60 749L64 750Q69 750 74 750H86L114 726Q208 641 251 514T294 250Q294 182 284 119T261 12T224 -76T186 -143T145 -194T113 -227T90 -246Q87 -249 86 -250H74Q66 -250 63 -250T58 -247T55 -238Q56 -237 66 -225Q221 -64 221 250T66 725Q56 737 55 738Q55 746 60 749Z"></path></g><g data-mml-node="mo" transform="translate(666.8,0)"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1722.6,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(778,0)"></path></g></g></g></svg></mjx-container></span></li> |
| <li>Diabetes</li> |
| <li>Evidence of other chronic liver disease</li> |
| <li>Children who are currently enrolled in a clinical trial or who received an investigational study drug within the past 60 days</li> |
| <li>Participants who are not able or willing to comply with the diet protocol or have any other condition that would impede compliance or hinder completion of the study, in the opinion of the investigator</li> |
| <li>Unable to have an MRI due to metal device, claustrophobia or other reason</li> |
| <li>Failure to give informed consent</li> |
| <li>Recipient of a liver transplant</li> |
| </ul> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="5.3-strategies-for-recruitment"> |
| 5.3 Strategies for Recruitment</h3> |
| <div>Recruitment will be through discussions of the study in the pediatric clinics, community gastroenterology offices and through recruitment of eligible previous research participants who have previously consented to be contacted regarding future studies.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="5.4-reasons-for-withdrawal"> |
| 5.4 Reasons for Withdrawal</h3> |
| <div>Participants are free to withdraw from participation in the study at any time. They can notify the study coordinator that they would like to discontinue from the study for any reason during any part of the study. They may also mail in the letter of revocation given along with the consent form if they desire.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="5.4.1-handling-of-withdrawal"> |
| 5.4.1 Handling of Withdrawal</h3> |
| <div>Collected data for participants who ask to be withdrawn from the study will be maintained in the database and will be used for future studies unless the participant specifically requests that data be destroyed. The participant's file will be flagged to ensure that no further contact is made.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="5.4.2-termination-of-study"> |
| 5.4.2 Termination of Study</h3> |
| <div>This study may be prematurely terminated if, in the opinion of the investigator or the sponsor, there is sufficient reasonable cause. Written notification, documenting the reason for study termination, will be provided to the investigator or sponsor by the terminating party.</div> |
| <div>Circumstances that may warrant termination include, but are not limited to:</div> |
| <ul> |
| <li>Determination of unexpected, significant, or unacceptable risk to participants.</li> |
| <li>Insufficient adherence to protocol requirements.</li> |
| <li>Data that is not sufficiently complete and/or evaluable.</li> |
| </ul> |
| <div>If the study is prematurely terminated or suspended, the sponsor will promptly inform the investigator/institution, of the termination or suspension and the reason(s) for the termination or suspension. The IRB will also be informed promptly and provided the<br> |
| reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s).</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="6-study-schedule"> |
| 6 STUDY SCHEDULE</h2> |
| <div>The schedule of events (Section 11.1) summarizes the procedures to be done at each visit. The visit windows are the goal for the study and serve as a guideline for the clinical sites. These visit windows are not strictly set; conducting a study visit outside of the visit window will not be considered a protocol deviation. Visit windows are outlines in the Schedule of Events.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="6.1-screening"> |
| 6.1 Screening</h3> |
| <div>Screening visits/procedures may be combined or changed to accommodate the substudy schedule.</div> |
| <div>Day-60 Screening visit: Participants will provide verbal consent or in-person written consent indicating that they wish to participate in the study so that a screening visit may be scheduled to assess eligibility. Informed consent will be obtained prior to initiating any research procedures. The screening visit may be conducted at a clinical visit if that is convenient for the participant. The ALT for eligibility must be drawn at or within 7 days before this visit.</div> |
| <div>Vital signs, height, and weight, waist and hip circumference measures will be obtained at the screening visit as well as a physical exam. Alcohol use will be assessed using the Alcohol Use Disorders Identification Test (AUDIT) and baseline beverage consumption will be assessed using the Bev-Q beverage questionnaire. A background medical history will be obtained and concomitant medications will be reviewed as well.</div> |
| <div>The following labs will be drawn at the screening visit:</div> |
| <ul> |
| <li>CMP</li> |
| <li>CBC</li> |
| <li>Direct bilirubin</li> |
| <li>PT/INR</li> |
| <li>HbA1c</li> |
| <li>Plasma and serum for storage</li> |
| </ul> |
| <div>Day -25 Dietary Assessment: After the screening visit, the baseline usual diet will be assessed using three 24 -hour, interviewer assisted, dietary recalls ( 1 weekend day and 2 week days). These will be administered by telephone or in person by a trained study nutritionist or coordinator after the screening visit/enrollment and prior to Day 0.</div> |
| <div>Day -14 MRI,: MRI will be used to assess level of liver fat within 10 days of Day 0 (diet initiation). At the Emory site, both the usual MRI based quantification of hepatic fat and a 10 -minute HISTO protocol will be collected during a single 30 minute MRI. The HISTO<br> |
| protocol is a highly precise measurement of hepatic fat and will be used to determine eligibility for the study. If the hepatic fat is <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="6.536ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 2888.8 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> by MRI PDFF, the participant will be enrolled. The % hepatic fat for the outcome measurements will be determined by the UCSD center's hepatic PDFF MRI protocol. The MRI may be repeated if images are inadequate and the MRI may be used to measure visceral fat.</div> |
| <div>Re-screening: Participants that screenfail for any reason may re-screen after a period of 6 months.</div> |
| <div>Day -9 Randomization: Randomization will be assigned after the initial screening visit and the participant will be informed of their assignment after the 24-hour dietary recalls but before Day 0 .</div> |
| <div>Day -7 Home Visit Food Assessment: A study coordinator and nutritionist will visit the home of intervention-arm participants and complete the assessment of the family's usual consumption patterns, recipes and the initial menus.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="6.2-day-0%3A-baseline-visit"> |
| 6.2 Day 0: Baseline Visit</h3> |
| <div>Once the screening assessments are complete and the participant is deemed eligible to participate in the study the participant will be scheduled for their Day 0 visit. This visit may be scheduled up to 60 days after the screening visit.<br> |
| Height, weight, waist and hip circumference measurements and vital signs will be collected at this visit. Any adverse events and changes to any concomitant medications will be reviewed as well. A sweetness perception test will be administered at this visit.</div> |
| <div>For the intervention arm, the nutritionist will meet with the family during this visit to review the details of the intervention. The standard of care participants will have diet assessment but no instructions on diet. Instructions will be given for compliance and the nutritionist will arrange a time to meet with the family in the home.</div> |
| <div>The following labs will also be drawn at this visit:</div> |
| <ul> |
| <li>CMP</li> |
| <li>GGT</li> |
| <li>Lipid Profile</li> |
| <li>Insulin</li> |
| <li>Plasma and serum for storage</li> |
| <li>Stool sample collection</li> |
| </ul> |
| <div>After the research visit, the food for the first several days of the study will be delivered to the home of the intervention participants and the sugar-containing non-perishable foods will be boxed up and stored at the home (or another location at the discretion of the family). Perishable sugar-containing foods will be disposed of and replaced with no free sugars containing versions.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="6.3-follow-up-visit-day-28"> |
| 6.3 Follow-up Visit Day 28</h3> |
| <div>The Day 28 visit will take place 28 days ( 4 weeks) after baseline. All assessments and testing done at the baseline visit will be repeated at this visits with the exception of the nutrition counseling, and stool collection.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="6.4-follow-up-visit-day-56"> |
| 6.4 Follow-up Visit Day 56</h3> |
| <div>Up to 6 weeks prior to the Day 56 visit three 24 -hour, interviewer assisted, dietary recalls ( 1 weekend day and 2 week days) will be performed. These will be administered by telephone or in person by a trained study nutritionist or coordinator at least 1 week prior to the Day 56 visit. This visit will take place 56 days ( 8 weeks) after baseline. All assessments and testing done at the baseline visit will be repeated at this visit with the exception of the nutrition counseling.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="6.5-end-of-study-follow-up"> |
| 6.5 End of study follow-up</h3> |
| <div>A phone visit will take place two weeks after the Day 56 visit. The purpose of this call is to discuss feedback about the study with the participant and his or her family. We will ask for details about what they liked or disliked about study participation and ask for any suggestions for future studies.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="7-statistical-considerations"> |
| 7 STATISTICAL CONSIDERATIONS</h2> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="7.1-sample-size-considerations"> |
| 7.1 Sample Size Considerations</h3> |
| <div>Initial analyses will be undertaken to inspect data for errors, inconsistencies, and incomplete information. This will include examining the data with simple frequency tables and dot plots for univariate data and scatter plots and multi-way dot plots with bivariate and multivariate data. Data anomalies and outliers will be examined and corrected if necessary. To summarize bivariate relationships between predictors and hepatic fat percent, Spearman's rank correlation coefficient, <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.355ex;" xmlns="http://www.w3.org/2000/svg" width="1.958ex" height="1.355ex" role="img" focusable="false" viewBox="0 -442 865.6 599.1"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msub"><g data-mml-node="mi"><path data-c="1D45F" d="M21 287Q22 290 23 295T28 317T38 348T53 381T73 411T99 433T132 442Q161 442 183 430T214 408T225 388Q227 382 228 382T236 389Q284 441 347 441H350Q398 441 422 400Q430 381 430 363Q430 333 417 315T391 292T366 288Q346 288 334 299T322 328Q322 376 378 392Q356 405 342 405Q286 405 239 331Q229 315 224 298T190 165Q156 25 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 114 189T154 366Q154 405 128 405Q107 405 92 377T68 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="TeXAtom" transform="translate(484,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mi"><path data-c="1D460" d="M131 289Q131 321 147 354T203 415T300 442Q362 442 390 415T419 355Q419 323 402 308T364 292Q351 292 340 300T328 326Q328 342 337 354T354 372T367 378Q368 378 368 379Q368 382 361 388T336 399T297 405Q249 405 227 379T204 326Q204 301 223 291T278 274T330 259Q396 230 396 163Q396 135 385 107T352 51T289 7T195 -10Q118 -10 86 19T53 87Q53 126 74 143T118 160Q133 160 146 151T160 120Q160 94 142 76T111 58Q109 57 108 57T107 55Q108 52 115 47T146 34T201 27Q237 27 263 38T301 66T318 97T323 122Q323 150 302 164T254 181T195 196T148 231Q131 256 131 289Z"></path></g></g></g></g></g></svg></mjx-container></span>, will be used. For reporting inferential statistics, such as differences in means, 95 percent confidence intervals will be used extensively to quantify degree of clinical efficacy. For any models, appropriate assumptions and model conditions will be verified prior to analysis.</div> |
| <div>Analyses will include descriptive statistics at baseline and for each treatment group for all outcome variables, plots of longitudinal data over time, and examination of distributions within groups at important nodal points (e.g., Baseline, 4 weeks and 8 weeks). All longitudinal models will include baseline measurements as a covariate to adjust for potential differences between treatment groups at baseline. All efficacy analysis will follow the intention-to-treat convention (inclusion of all randomized participants in the analysis). Participants that drop out or are lost to follow-up will be compared to those that remain in the study to assess for bias and generalizability of the results. All analyses will be conducted using SAS v9.3 for Windows (Cary, NC, USA).</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="power-analysis"> |
| Power Analysis</h2> |
| <div>The primary outcome is change in MRI PDFF from baseline to 8 weeks in the intervention group compared to the standard of care group. Participants will be screened at baseline and confirmed that their hepatic fat is <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="6.536ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 2888.8 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span>. Given 40 completed participants, ( 20 randomized to the diet low in free sugars and 20 randomized to usual diet), our goal is show a <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> improvement in MRI PDFF with intervention over control. For example:</div> |
| <div>Intervention: 15% hepatic fat baseline - (30% change <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="7.165ex" height="1.882ex" role="img" focusable="false" viewBox="0 -750 3166.8 832"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3D" d="M56 347Q56 360 70 367H707Q722 359 722 347Q722 336 708 328L390 327H72Q56 332 56 347ZM56 153Q56 168 72 173H708Q722 163 722 153Q722 140 707 133H70Q56 140 56 153Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(778,0)"></path></g><g data-mml-node="mi" transform="translate(2333.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> ) <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="1.76ex" height="1.505ex" role="img" focusable="false" viewBox="0 -583 778 665"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3D" d="M56 347Q56 360 70 367H707Q722 359 722 347Q722 336 708 328L390 327H72Q56 332 56 347ZM56 153Q56 168 72 173H708Q722 163 722 153Q722 140 707 133H70Q56 140 56 153Z"></path></g></g></g></svg></mjx-container></span> Hepatic fat of 10.5% at 8 weeks</div> |
| <div>Control: 15% hepatic fat at baseline - (5% change <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="8.296ex" height="1.882ex" role="img" focusable="false" viewBox="0 -750 3666.8 832"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3D" d="M56 347Q56 360 70 367H707Q722 359 722 347Q722 336 708 328L390 327H72Q56 332 56 347ZM56 153Q56 168 72 173H708Q722 163 722 153Q722 140 707 133H70Q56 140 56 153Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z" transform="translate(778,0)"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(1278,0)"></path></g><g data-mml-node="mi" transform="translate(2833.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> ) <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="1.76ex" height="1.505ex" role="img" focusable="false" viewBox="0 -583 778 665"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3D" d="M56 347Q56 360 70 367H707Q722 359 722 347Q722 336 708 328L390 327H72Q56 332 56 347ZM56 153Q56 168 72 173H708Q722 163 722 153Q722 140 707 133H70Q56 140 56 153Z"></path></g></g></g></svg></mjx-container></span> Hepatic fat of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="7.038ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 3111 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(1000,0)"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(1278,0)"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(1778,0)"></path></g><g data-mml-node="mi" transform="translate(2278,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> at 8 weeks</div> |
| <div>A two sample, two-tailed <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.025ex;" xmlns="http://www.w3.org/2000/svg" width="0.817ex" height="1.441ex" role="img" focusable="false" viewBox="0 -626 361 637"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D461" d="M26 385Q19 392 19 395Q19 399 22 411T27 425Q29 430 36 430T87 431H140L159 511Q162 522 166 540T173 566T179 586T187 603T197 615T211 624T229 626Q247 625 254 615T261 596Q261 589 252 549T232 470L222 433Q222 431 272 431H323Q330 424 330 420Q330 398 317 385H210L174 240Q135 80 135 68Q135 26 162 26Q197 26 230 60T283 144Q285 150 288 151T303 153H307Q322 153 322 145Q322 142 319 133Q314 117 301 95T267 48T216 6T155 -11Q125 -11 98 4T59 56Q57 64 57 83V101L92 241Q127 382 128 383Q128 385 77 385H26Z"></path></g></g></g></svg></mjx-container></span> test with an overall sample size of 40 participants ( 20 per group) achieves greater than <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> power to detect a true difference of means of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="3.016ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1333 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> when the sigma is <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="3.016ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1333 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span>. Power was calculated assuming that <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> of patients in each group will be lost to follow-up with a 0.05 significance level.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="plan-for-missing-data%3A"> |
| Plan for missing data:</h2> |
| <div>We note that attrition, participant compliance and systematic data collection are fundamental requirements for this study. Successful coordination of participants and management of data are important prerequisites for a subsequent trial. Thus, we focus appropriate attention to missing data. Prevention is the first line for controlling bias and loss of power from missing data. Upon entry, alternative contacts will be identified for all participants to minimize loss-to follow-up. Consistent with the intent to treat principle, we will follow-up with all randomized participants regardless of the actual treatment received (we will invite families who miss visits to return for assessments later if possible). Participants who express intent to dropout completely will be asked to attend an early termination visit to collect endpoint measures. Timely data entry combined with monthly missing data reports will prompt tracking down missing outcome assessments. Despite these prevention efforts, missing data will occur. Our primary analysis is valid under the assumption that missing data are missing at random (MAR). To evaluate this assumption, we will examine the extent of missing data and missing data patterns, and determine the reasons and time of dropout.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="8-ethics%2Fprotection-of-human-participants"> |
| 8 ETHICS/PROTECTION OF HUMAN PARTICIPANTS</h2> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="8.1-ethical-standard"> |
| 8.1 Ethical Standard</h3> |
| <div>The investigator will ensure that this study is conducted in full conformity with the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Participants of Research, as drafted by the US National Commission for the Protection of Human Participants of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 (1997).</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="8.2-institutional-review-board"> |
| 8.2 Institutional Review Board</h3> |
| <div>Permission to perform this study will be sought from the Emory University IRB and the USCD IRB. All future modifications of the study or changes in the protocol will receive IRB approval.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="8.3-informed-consent-process"> |
| 8.3 Informed Consent Process</h3> |
| <div>Informed consent is a process that is initiated prior to the individual's agreeing to participate in the study and continues throughout the individual's study participation. Informed consents and HIPAA waivers will be obtained prior to initiating any study procedure. Participants and their parents or legal guardian will be approached to participate in the study. The research coordinators and PI/Co-I will discuss the study with them and give them all the information listed above in language understandable at the level of the parent/guardian and all information needed to make an informed choice about participation, including information about NAFLD, the study intervention, possible risks to participation, study procedures, study visits/contacts and potential benefits to the participant. Consent will be documented by signature of the parent/guardian.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="8.4-informed-assent-process"> |
| 8.4 Informed Assent Process</h3> |
| <div>All children must provide written assent (11-16 y) in a language appropriate for the age of the child. Written assent will be documented by signature in age <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="10.481ex" height="1.971ex" role="img" focusable="false" viewBox="0 -666 4632.4 871"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1222.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(2222.4,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(3222.4,0)"><path data-c="1D466" d="M21 287Q21 301 36 335T84 406T158 442Q199 442 224 419T250 355Q248 336 247 334Q247 331 231 288T198 191T182 105Q182 62 196 45T238 27Q261 27 281 38T312 61T339 94Q339 95 344 114T358 173T377 247Q415 397 419 404Q432 431 462 431Q475 431 483 424T494 412T496 403Q496 390 447 193T391 -23Q363 -106 294 -155T156 -205Q111 -205 77 -183T43 -117Q43 -95 50 -80T69 -58T89 -48T106 -45Q150 -45 150 -87Q150 -107 138 -122T115 -142T102 -147L99 -148Q101 -153 118 -160T152 -167H160Q177 -167 186 -165Q219 -156 247 -127T290 -65T313 -9T321 21L315 17Q309 13 296 6T270 -6Q250 -11 231 -11Q185 -11 150 11T104 82Q103 89 103 113Q103 170 138 262T173 379Q173 380 173 381Q173 390 173 393T169 400T158 404H154Q131 404 112 385T82 344T65 302T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3712.4,0)"><path data-c="1D45F" d="M21 287Q22 290 23 295T28 317T38 348T53 381T73 411T99 433T132 442Q161 442 183 430T214 408T225 388Q227 382 228 382T236 389Q284 441 347 441H350Q398 441 422 400Q430 381 430 363Q430 333 417 315T391 292T366 288Q346 288 334 299T322 328Q322 376 378 392Q356 405 342 405Q286 405 239 331Q229 315 224 298T190 165Q156 25 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 114 189T154 366Q154 405 128 405Q107 405 92 377T68 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(4163.4,0)"><path data-c="1D460" d="M131 289Q131 321 147 354T203 415T300 442Q362 442 390 415T419 355Q419 323 402 308T364 292Q351 292 340 300T328 326Q328 342 337 354T354 372T367 378Q368 378 368 379Q368 382 361 388T336 399T297 405Q249 405 227 379T204 326Q204 301 223 291T278 274T330 259Q396 230 396 163Q396 135 385 107T352 51T289 7T195 -10Q118 -10 86 19T53 87Q53 126 74 143T118 160Q133 160 146 151T160 120Q160 94 142 76T111 58Q109 57 108 57T107 55Q108 52 115 47T146 34T201 27Q237 27 263 38T301 66T318 97T323 122Q323 150 302 164T254 181T195 196T148 231Q131 256 131 289Z"></path></g></g></g></svg></mjx-container></span>. Assent will be documented by signature of the child participant.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="8.5-participant-confidentiality"> |
| 8.5 Participant Confidentiality</h3> |
| <div>Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the sponsor(s) and their agents. The study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any third party without prior approval of the participant.</div> |
| <div>Authorized representatives of the sponsor may inspect all documents and records required to be maintained by the investigator.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="8.6-study-discontinuation"> |
| 8.6 Study Discontinuation</h3> |
| <div>In the event that the study is discontinued, participants will be notified of the date of discontinuation.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="8.7-data-safety-monitoring-plan"> |
| 8.7 Data Safety Monitoring Plan</h3> |
| <div>Data Management: Data for each subject will be collected in individual folders kept in a locked filing cabinet in a secure office. Data will be entered into a secure RedCap database within the same division. The study statistician will run routine reports for completeness and send to the site Pls.</div> |
| <div>Adverse Events: The PI at each site will monitor adverse events throughout the course of the study. Any adverse events occurring during the study will be documented and reported according to applicable IRB policies and procedures. AE's will be entered into RedCap in a timely fashion. The study statistician will run quarterly reports and will send out pooled analyses to the Pl's at both sites. A status report will be provided to the IRB at the time of continuing review.</div> |
| <div>Serious Adverse Events: SAE's are not anticipated in this study, however, any SAE that occurs will be reported to the other site, respective IRBs, and sponsor within 10 business days of first knowledge of the event.</div> |
| <div>Monitoring: A representative from the sponsor will conduct a site monitoring visit after the <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="2.972ex" height="1.805ex" role="img" focusable="false" viewBox="0 -797.9 1313.4 797.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="TeXAtom" transform="translate(533,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mtext"><path data-c="73" d="M295 316Q295 356 268 385T190 414Q154 414 128 401Q98 382 98 349Q97 344 98 336T114 312T157 287Q175 282 201 278T245 269T277 256Q294 248 310 236T342 195T359 133Q359 71 321 31T198 -10H190Q138 -10 94 26L86 19L77 10Q71 4 65 -1L54 -11H46H42Q39 -11 33 -5V74V132Q33 153 35 157T45 162H54Q66 162 70 158T75 146T82 119T101 77Q136 26 198 26Q295 26 295 104Q295 133 277 151Q257 175 194 187T111 210Q75 227 54 256T33 318Q33 357 50 384T93 424T143 442T187 447H198Q238 447 268 432L283 424L292 431Q302 440 314 448H322H326Q329 448 335 442V310L329 304H301Q295 310 295 316Z"></path><path data-c="74" d="M27 422Q80 426 109 478T141 600V615H181V431H316V385H181V241Q182 116 182 100T189 68Q203 29 238 29Q282 29 292 100Q293 108 293 146V181H333V146V134Q333 57 291 17Q264 -10 221 -10Q187 -10 162 2T124 33T105 68T98 100Q97 107 97 248V385H18V422H27Z" transform="translate(394,0)"></path><path data-c="A0" d="" transform="translate(783,0)"></path></g></g></g></g></g></svg></mjx-container></span> patient is randomized and then again approximately every 6 months. This site visit will review the informed consent process, eligibility, CRFs, and AE reporting. A monitoring report will be provided to the Pls within 10 business days of review. The PI will review the monitoring report and follow up on any corrective actions on the site monitoring log and will notify the respective IRB according to applicable policies and procedures.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9-data-handling-and-record-keeping"> |
| 9 DATA HANDLING AND RECORD KEEPING</h2> |
| <div>All data will be entered, stored and processed within REDCap, a secure, web-based application for managing databases. All access to office space containing paper source documents requires badged entry. All computer files are stored on secure servers.</div> |
| <div>Data management staff members are required to complete and pass an on-line HIPAA course and other confidentiality certification procedures upon employment. All computer systems and programs are password protected, and all web-based electronic communications of study information is encrypted. Good computer security practices (restricting physical access to computers, prohibition of password sharing, timing out of system access interfaces, etc.) is required. Virus protection software is installed on all study machines. The virus protection tools are used, maintained, and updated as necessary on all computers and pathways into the system.</div> |
| <div>Only study personnel (PI, co-Is, study coordinators, research assistants, and nutritionists) will have access to identifiable data. Data will be de-identified before analysis and will be stored in locked research material cabinets.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="9.1-data-management-responsibilities"> |
| 9.1 Data Management Responsibilities</h3> |
| <div>Emory University will serve as the data coordinating center for this study and will be responsible for data management, quality review, analysis, and reporting of the study data. The statistician will review data completion monthly during the active portion of the study.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="9.2-mri-data-coordination"> |
| 9.2 MRI Data Coordination</h3> |
| <div>UCSD will serve as the radiology coordinating center for this study. Anonymized CD's will be shipped to UCSD and all MRI's will be read and interpreted at this site. The screening MRI will be transferred to UCSD via a secure cloud-based network for a faster read turnaround for eligibility.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="9.3-types-of-data"> |
| 9.3 Types of Data</h3> |
| <div>Data for this study will include self-report patient data, nutritional data from NDSR, laboratory values, medical records, and imaging data.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="9.5-study-records-retention"> |
| 9.5 Study Records Retention</h3> |
| <div>Study documents will be retained for the minimum number of years per Emory University and UCSD requirements. No records will be destroyed without the written consent of the sponsor. It is the responsibility of the sponsor to inform the investigator when these documents no longer need to be retained. Electronic data, stripped of identifiers, will be stored on a secure server and will be kept indefinitely.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="10-literature-references"> |
| 10 LITERATURE REFERENCES</h2> |
| <ol> |
| <li>Lazo M, Hernaez R, Eberhardt MS, Bonekamp S, Kamel I, Guallar E, Koteish A, Brancati FL and Clark JM. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013;178:38-45.</li> |
| <li>Welsh JA, Karpen S and Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Peds. 2013;162:496-500.</li> |
| <li>Fishbein MH, Miner M, Mogren C and Chalekson J. The spectrum of fatty liver in obese children and the relationship of serum aminotransferases to severity of steatosis. J Pediatr Gastroenterol Nutr. 2003;36:54-61.</li> |
| <li>Lavine JE and Schwimmer JB. Nonalcoholic fatty liver disease in the pediatric population. Clinics in liver disease. 2004;8:549-58, viii-ix.</li> |
| <li>Louthan MV, Barve S, McClain CJ and Joshi-Barve S. Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease. J Pediatr. 2005;147:835-8.</li> |
| <li>Louthan MV, Theriot JA, Zimmerman E, Stutts JT and McClain CJ. Decreased prevalence of nonalcoholic fatty liver disease in black obese children. J Pediatr Gastroenterol Nutr. 2005;41:426-9.</li> |
| <li>Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R and Lavine JE. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. The Journal of pediatrics. 2003;143:500-5.</li> |
| <li>Schwimmer JB, McGreal N, Deutsch R, Finegold MJ and Lavine JE. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics. 2005;115:e561-5.</li> |
| <li>Schwimmer JB, Pardee PE, Lavine JE, Blumkin AK and Cook S. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation. 2008;118:277-83.</li> |
| <li>Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M and Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology (Baltimore, Md). 2012;55:2005-23.</li> |
| <li>Schwimmer JA, McGreal N, Deutch R, Finegold MJ and Lavine JE. Influence of gender, race and ethnicity on suspected fatty liver in obese adolescents Pediatrics. 2005;115:e561-e565.</li> |
| <li>Wagenknecht LE, Scherzinger AL, Stamm ER, Hanley AJ, Norris JM, Chen YD, Bryer-Ash M, Haffner SM and Rotter JI. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring, Md). 2009;17:1240-6.</li> |
| <li>Hoyert D and Xu J. Deaths: Preliminary Data for 2011. National Vital Statistics Reports Centers for Disease Control and Prevention. 2012;61.</li> |
| <li>Heron M. Deaths: Leading Causes for 2009. National Vital Statistics Reports Center for Disease Control and Prevention. 2012;61.</li> |
| <li>Adams L, Lymp J, Sauver J, Sanderson S, Lindor K, Feldstein A and Angulo P.</li> |
| </ol> |
| <div>The natural history of nonalcoholic fatty liver disease: a population based cohort study.<br> |
| Gastroenterology. 2005;129:113-121.<br> |
| 16. Ramilli S, Pretolani S, Muscari A, Pacelli B and Arienti V. Carotid lesions in outpatients with nonalcoholic fatty liver disease. World J Gastroenterol. 2009;15:4770-4.<br> |
| 17. Targher G, Chonchol M, Bertolini L, Rodella S, Zenari L, Lippi G, Franchini M, Zoppini G and Muggeo M. Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease. J Am Soc Nephrol. 2008;19:1564-70.<br> |
| 18. Kontush A and Chapman M. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev. 2006;58:342-74.<br> |
| 19. Hanley AJ, Williams K, Festa A, Wagenknecht LE, D'Agostino RB, Jr., Kempf J, Zinman B and Haffner SM. Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2004;53:2623-32.<br> |
| 20. Hanley AJ, Williams K, Festa A, Wagenknecht LE, D'Agostino RB, Jr. and Haffner SM. Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. Diabetes. 2005;54:3140-7.<br> |
| 21. Armstrong MJ, Adams LA, Canbay A and Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology (Baltimore, Md). 2014;59:1174-97.<br> |
| 22. Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J and Hultcrantz R. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2009.<br> |
| 23. Fielding J. Disparities in Deaths from Chronic Liver Disease and Cirrhosis. Office of Health Assessment and Epidemiology 2012;June.<br> |
| 24. Jacome-Sosa MM and Parks EJ. Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans. Curr Opin Lipidol. 2014;25:213-20.<br> |
| 25. Lambert JE, Ramos-Roman MA, Browning JD and Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726-35.<br> |
| 26. Sevastianova K, Santos A, Kotronen A, Hakkarainen A, Makkonen J, Silander K, Peltonen M, Romeo S, Lundbom J, Lundbom N, Olkkonen VM, Gylling H, Fielding BA, Rissanen A, Yki-Jarvinen HCINAJCNO and Pmid. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. The American journal of clinical nutrition. 2012;96:727-34.<br> |
| 27. Vos MB, Kimmons JE, Gillespie C, Welsh J and Blanck HM. Dietary fructose consumption among US children and adults: the Third National Health and Nutrition Examination Survey. Medscape J Med. 2008;10:160.<br> |
| 28. Bray GA and Popkin BM. Calorie-sweetened beverages and fructose: what have we learned 10 years later. Pediatric obesity. 2013;8:242-8.<br> |
| 29. Welsh JA, Sharma AJ, Grellinger L and Vos MB. Consumption of added sugars is decreasing in the United States. The American journal of clinical nutrition.<br> |
| 2011;94:726-34.<br> |
| 30. Makarem N, Scott M, Quatromoni P, Jacques P and Parekh N. Trends in dietary carbohydrate consumption from 1991 to 2008 in the Framingham Heart Study Offspring Cohort. The British journal of nutrition. 2014:1-14.<br> |
| 31. Ng SW, Slining MM and Popkin BM. Turning point for US diets? Recessionary effects or behavioral shifts in foods purchased and consumed. The American journal of clinical nutrition. 2014;99:609-16.<br> |
| 32. Kit BK, Fakhouri TH, Park S, Nielsen SJ and Ogden CL. Trends in sugarsweetened beverage consumption among youth and adults in the United States: 19992010. The American journal of clinical nutrition. 2013;98:180-8.<br> |
| 33. Bray GA and Popkin BM. Dietary sugar and body weight: have we reached a crisis in the epidemic of obesity and diabetes?: health be damned! Pour on the sugar. Diabetes care. 2014;37:950-6.<br> |
| 34. Schwarz JM, Noworolski SM, Wen MJ, Dyachenko A, Prior JL, Weinberg ME, Herraiz LA, Tai VW, Bergeron N, Bersot TP, Rao MN, Schambelan M and Mulligan K. Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat. J Clin Endocrinol Metab. 2015:jc20143678.<br> |
| 35. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, Johnson RJ and Abdelmalek MF. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48:993-9.<br> |
| 36. O'Sullivan TA, Oddy WH, Bremner AP, Sherriff JL, Ayonrinde OT, Olynyk JK, Beilin LJ, Mori TA and Adams LA. Lower fructose intake may help protect against development of nonalcoholic fatty liver in adolescents with obesity. Journal of pediatric gastroenterology and nutrition. 2014;58:624-31.<br> |
| 37. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ and Diehl AM. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961-71.<br> |
| 38. Jin R, Welsh JA, Le NA, Holzberg J, Sharma P, Martin DR and Vos MB. Dietary fructose reduction improves markers of cardiovascular disease risk in HispanicAmerican adolescents with NAFLD. Nutrients. 2014;6:3187-201.<br> |
| 39. Mager DR, Iniguez IR, Gilmour S and Yap J. The Effect of a Low Fructose and Low Glycemic Index/Load (FRAGILE) Dietary Intervention on Indices of Liver Function, Cardiometabolic Risk Factors, and Body Composition in Children and Adolescents With Nonalcoholic Fatty Liver Disease (NAFLD). JPEN J Parenter Enteral Nutr. 2015;39:7384.<br> |
| 40. Schwimmer JB, Middleton MS, Behling C, Newton KP, Awai HI, Paiz MN, Lam J, Hooker JC, Hamilton G, Fontanesi J and Sirlin CB. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology. 2014.<br> |
| 41. Zand KA, Shah A, Heba E, Wolfson T, Hamilton G, Lam J, Chen J, Hooker JC, Gamst AC, Middleton MS, Schwimmer JB and Sirlin CB. Accuracy of multiecho magnitude-based MRI (M-MRI) for estimation of hepatic proton density fat fraction (PDFF) in children. J Magn Reson Imaging. 2015.<br> |
| 42. Artz NS, Haufe WM, Hooker CA, Hamilton G, Wolfson T, Campos GM, Gamst AC, Schwimmer JB, Sirlin CB and Reeder SB. Reproducibility of MR-based liver fat quantification across field strength: Same-day comparison between 1.5T and 3T in obese subjects. J Magn Reson Imaging. 2015.<br> |
| 43. Suzuki A, Abdelmalek MF, Schwimmer JB, Lavine JE, Scheimann AO, UnalpArida A, Yates KP, Sanyal AJ, Guy CD, Diehl AM and Nonalcoholic Steatohepatitis</div> |
| <div>Clinical Research N. Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012;10:786-94.<br> |
| 44. Uwaifo GI, Parikh SJ, Keil M, Elberg J, Chin J and Yanovski JA. Comparison of insulin sensitivity, clearance, and secretion estimates using euglycemic and hyperglycemic clamps in children. The Journal of clinical endocrinology and metabolism. 2002;87:2899-905.<br> |
| 45. Gungor N, Saad R, Janosky J and Arslanian S. Validation of surrogate estimates of insulin sensitivity and insulin secretion in children and adolescents. J Pediatr. 2004;144:47-55.<br> |
| 46. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF and Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-9.<br> |
| 47. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G and Quon MJ. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. The Journal of clinical endocrinology and metabolism. 2000;85:2402-10.<br> |
| 48. Mather KJ, Hunt AE, Steinberg HO, Paradisi G, Hook G, Katz A, Quon MJ and Baron AD. Repeatability characteristics of simple indices of insulin resistance: implications for research applications. The Journal of clinical endocrinology and metabolism. 2001;86:5457-64.<br> |
| 49. Yokoyama H, Emoto M, Fujiwara S, Motoyama K, Morioka T, Komatsu M, Tahara H, Shoji T, Okuno Y and Nishizawa Y. Quantitative insulin sensitivity check index and the reciprocal index of homeostasis model assessment in normal range weight and moderately obese type 2 diabetic patients. Diabetes Care. 2003;26:2426-32. 50. Uwaifo GI, Fallon EM, Chin J, Elberg J, Parikh SJ and Yanovski JA. Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children. Diabetes Care. 2002;25:2081-7.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="11-attachments"> |
| 11 Attachments</h2> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="11.1-schedule-of-events"> |
| 11.1 SCHEDULE OF EVENTS</h3> |
| <div>*unless participating in DNL substudy, then see diagram</div> |
| <div class="table_tabular" style="text-align: center"> |
| <div class="inline-tabular"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Study Procedure</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Screening (up to -60 Days)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">-14 Days* ( ± 1 week)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">-9 Days ( ± Days)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">-7 Days ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span> Days)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Baseline (Day 0)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Day 28 ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g></g></g></svg></mjx-container></span> Days)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Day 56 ( ± 3 Days)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Follow-up Day 68 <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="3.771ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 1667 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="28" d="M94 250Q94 319 104 381T127 488T164 576T202 643T244 695T277 729T302 750H315H319Q333 750 333 741Q333 738 316 720T275 667T226 581T184 443T167 250T184 58T225 -81T274 -167T316 -220T333 -241Q333 -250 318 -250H315H302L274 -226Q180 -141 137 -14T94 250Z"></path></g><g data-mml-node="mo" transform="translate(389,0)"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(1167,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span> Days)</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Informed Consent and HIPAA Authorization</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Review Inclusion/Exclusion Criteria</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">x</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Randomization</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">x</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Demographics & Medical History</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Vital Signs</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">x</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Height and Weight</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">x</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Waist and Hip</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Physical Exam</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">MRI</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">AUDIT Questionnaire</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="6.159ex" height="1.581ex" role="img" focusable="false" viewBox="0 -677 2722.4 699"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="D7" d="M630 29Q630 9 609 9Q604 9 587 25T493 118L389 222L284 117Q178 13 175 11Q171 9 168 9Q160 9 154 15T147 29Q147 36 161 51T255 146L359 250L255 354Q174 435 161 449T147 471Q147 480 153 485T168 490Q173 490 175 489Q178 487 284 383L389 278L493 382Q570 459 587 475T609 491Q630 491 630 471Q630 464 620 453T522 355L418 250L522 145Q606 61 618 48T630 29Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mn" transform="translate(2222.4,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g></g></g></svg></mjx-container></span>-hour food recalls (NDS-R)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Beverage Questionnaire (Bev-Q)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Instructions for Compliance</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Home Visit Food Assessment</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Sweet Taste Test</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Adverse Events Review</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Concomitant Medication Review</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Stool Collection</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Initiate Heavy Water (30 min Observation)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Blood Draw</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">End of study phone interview</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td> |
| </tr> |
| </tbody> |
| </table> |
| </div></div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="11.2-blood-draw-schedule"> |
| 11.2 BLOOD DRAW SCHEDULE</h3> |
| <div class="table_tabular" style="text-align: center"> |
| <div class="inline-tabular"><table class="tabular"> |
| <tbody> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Blood Test</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Screening (-60 days)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Baseline (Day 0)</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Follow-up 1 Day 28</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Follow-up 2 Day 56</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top-style: solid !important; border-top-width: 1px !important; width: auto; vertical-align: middle; ">Total Volume</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Complete Blood Count</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Comprehensive Metabolic Panel</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">4</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">HbA1c</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">3</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">3</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Lipid Profile</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">3</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">3</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">3</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">9</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Direct bilirubin</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">GGT</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">3</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Insulin</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">1</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Serum</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">6</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">6</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">6</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">6</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">24</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Plasma</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">12</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">12</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">12</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">12</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">48</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">PT/INR</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">3</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">-</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">3</td> |
| </tr> |
| <tr style="border-top: none !important; border-bottom: none !important;"> |
| <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Total</td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="6.355ex" height="1.595ex" role="img" focusable="false" viewBox="0 -683 2809 705"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mn" transform="translate(500,0)"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path></g><g data-mml-node="mtext" transform="translate(1000,0)"><path data-c="A0" d=""></path></g><g data-mml-node="mi" transform="translate(1250,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2128,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.025ex;" xmlns="http://www.w3.org/2000/svg" width="6.355ex" height="1.57ex" role="img" focusable="false" viewBox="0 -683 2809 694"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mn" transform="translate(500,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g><g data-mml-node="mtext" transform="translate(1000,0)"><path data-c="A0" d=""></path></g><g data-mml-node="mi" transform="translate(1250,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2128,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="6.355ex" height="1.595ex" role="img" focusable="false" viewBox="0 -683 2809 705"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mn" transform="translate(500,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mtext" transform="translate(1000,0)"><path data-c="A0" d=""></path></g><g data-mml-node="mi" transform="translate(1250,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2128,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="6.355ex" height="1.595ex" role="img" focusable="false" viewBox="0 -683 2809 705"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mn" transform="translate(500,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mtext" transform="translate(1000,0)"><path data-c="A0" d=""></path></g><g data-mml-node="mi" transform="translate(1250,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2128,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span></td> |
| <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="6.355ex" height="1.595ex" role="img" focusable="false" viewBox="0 -683 2809 705"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path></g><g data-mml-node="mn" transform="translate(500,0)"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path></g><g data-mml-node="mtext" transform="translate(1000,0)"><path data-c="A0" d=""></path></g><g data-mml-node="mi" transform="translate(1250,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2128,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span></td> |
| </tr> |
| </tbody> |
| </table> |
| </div></div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="optional-sub-study-amendment%3A"> |
| Optional Sub-study Amendment:</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="de-novo-lipogenesis-sub-study-for-the-protocol-%22randomized%2C-controlled-dietary-treatment-of-pediatric-nafld%22"> |
| De novo lipogenesis sub-study for the protocol "Randomized, Controlled Dietary Treatment of Pediatric NAFLD"</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="background%3A"> |
| Background:</h2> |
| <div>The diet treatment study is an 8 week, randomized, controlled clinical trial of a low sugar diet as a treatment for NAFLD. In the main study, children will be evaluated at baseline, 4 weeks and 8 weeks using magnetic resonance spectroscopy and labs. Because carbohydrates and especially simple sugars stimulate de novo lipogenesis (DNL - new fat synthesis in the liver), an important secondary outcome of the study is change in DNL. In this optional sub-study, we propose to add the use of heavy water <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.791ex;" xmlns="http://www.w3.org/2000/svg" width="7.654ex" height="2.713ex" role="img" focusable="false" viewBox="0 -849.5 3383.1 1199"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mrow"><g data-mml-node="mo" transform="translate(0 -0.5)"><path data-c="28" d="M152 251Q152 646 388 850H416Q422 844 422 841Q422 837 403 816T357 753T302 649T255 482T236 250Q236 124 255 19T301 -147T356 -251T403 -315T422 -340Q422 -343 416 -349H388Q359 -325 332 -296T271 -213T212 -97T170 56T152 251Z"></path></g><g data-mml-node="msup" transform="translate(458,0)"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(894.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(2162.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="mo" transform="translate(2925.1,0) translate(0 -0.5)"><path data-c="29" d="M305 251Q305 -145 69 -349H56Q43 -349 39 -347T35 -338Q37 -333 60 -307T108 -239T160 -136T204 27T221 250T204 473T160 636T108 740T60 807T35 839Q35 850 50 850H56H69Q197 743 256 566Q305 425 305 251Z"></path></g></g></g></g></svg></mjx-container></span> metabolite measurement as a tool for determining DNL and markers of fibrogenesis at baseline and at 8 weeks.</div> |
| <div>Heavy water is a form of water that is enriched for the hydrogen isotope deuterium compared to the common hydrogen-1 isotope that makes up most hydrogen in water. Heavy water is not radioactive and is physically and chemically similar to regular water. The human body naturally contains some deuterium. Stable isotopes have a long history as a safe, effective tracer for measuring synthesis of molecules in humans <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>. Small oral doses of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.582ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 2467.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(436.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1704.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span> are routinely used in human metabolic experiments and there are no known health risks with small amounts.</div> |
| <div>Utilizing in vivo heavy water labeling and a small amount of plasma, multiple pathways related to protein metabolism (fibrogenesis) and lipid metabolism can be quantified in a minimally invasive fashion in human subjects. Recently, new developments in stable isotope labeling techniques and advances in mass spectrometry have made in vivo kinetic measurement of slow metabolic processes possible. Through the use of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.582ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 2467.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(436.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1704.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span> (heavy water) as the source of labeling, our collaborators and others have measured Tcell proliferation <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>, mammary epithelial cell proliferation <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>, prostate epithelial cell proliferation <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>, triglyceride synthesis <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span> and protein synthesis <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 790.1 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span> in humans. DNL as well as hepatic TG assembly and cholesterogenesis are easily measured in plasma from patients consuming <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.582ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 2467.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(436.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1704.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span>, after 5-14 days of labeling the plasma DNL reaches a steady state and reflects hepatic DNL rates.</div> |
| <div>Both Emory and UCSD research entities and IRBs have previous experience with heavy water based research studies and this sub-study is minimal risk to participants.</div> |
| <div>Hypothesis: We hypothesize that DNL will significantly decrease in the children with NAFLD randomized to the low sugar diet.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="risks%3A"> |
| Risks:</h2> |
| <ol start="7"> |
| <li>Heavy water - <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.725ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 2530.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="msub" transform="translate(500,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1767.6,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span> Intake - Participants will be given heavy water (deuterated water, <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.582ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 2467.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(436.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1704.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span> ) for up to 28 days over the course of the study. There are no known medical risks of heavy water <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.791ex;" xmlns="http://www.w3.org/2000/svg" width="7.654ex" height="2.713ex" role="img" focusable="false" viewBox="0 -849.5 3383.1 1199"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mrow"><g data-mml-node="mo" transform="translate(0 -0.5)"><path data-c="28" d="M152 251Q152 646 388 850H416Q422 844 422 841Q422 837 403 816T357 753T302 649T255 482T236 250Q236 124 255 19T301 -147T356 -251T403 -315T422 -340Q422 -343 416 -349H388Q359 -325 332 -296T271 -213T212 -97T170 56T152 251Z"></path></g><g data-mml-node="msup" transform="translate(458,0)"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(894.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(2162.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="mo" transform="translate(2925.1,0) translate(0 -0.5)"><path data-c="29" d="M305 251Q305 -145 69 -349H56Q43 -349 39 -347T35 -338Q37 -333 60 -307T108 -239T160 -136T204 27T221 250T204 473T160 636T108 740T60 807T35 839Q35 850 50 850H56H69Q197 743 256 566Q305 425 305 251Z"></path></g></g></g></g></svg></mjx-container></span> intake. <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.582ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 2467.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(436.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1704.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span> is not radioactive. Rarely, individuals (<3%) may experience temporary light-headedness, dizziness, or vertigo (room spinning) when they take the first doses of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.582ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 2467.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(436.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1704.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span>. These symptoms are selflimited and resolve within <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="5.028ex" height="1.692ex" role="img" focusable="false" viewBox="0 -666 2222.4 748"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span> hours. Participants will also be instructed to avoid driving or performing other potentially hazardous activities for one hour after drinking the initial dose of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.582ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 2467.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(436.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1704.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span> in case they become dizzy. Participants will be instructed on the intake of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.582ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 2467.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(436.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(1704.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span> to ensure a slow rise in initial body water enrichment and thereby avoid these symptoms. This is achieved by drinking 50 mL of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="9.729ex" height="2.226ex" role="img" focusable="false" viewBox="0 -833.9 4300.1 983.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g><g data-mml-node="msup" transform="translate(1833,0)"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(2269.6,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(3537.1,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g></g></g></svg></mjx-container></span> twice a day. This labeling protocol has been shown in <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.09ex;" xmlns="http://www.w3.org/2000/svg" width="5.782ex" height="1.597ex" role="img" focusable="false" viewBox="0 -666 2555.8 706"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(1000,0)"></path></g></g></g></svg></mjx-container></span> human participants in studies to produce a steady rise to plateau body water enrichments of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="17.802ex" height="2.244ex" role="img" focusable="false" viewBox="0 -841.7 7868.7 991.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(778,0)"></path></g><g data-mml-node="mo" transform="translate(1500.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(2500.4,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(778,0)"></path></g><g data-mml-node="mi" transform="translate(3778.4,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g><g data-mml-node="msup" transform="translate(4611.4,0)"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="msub" transform="translate(5048,0)"><g data-mml-node="mi"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" transform="translate(864,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mi" transform="translate(6315.6,0)"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="msup" transform="translate(7078.6,0)"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span>.</li> |
| </ol> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="potential-benefits%3A"> |
| Potential Benefits:</h2> |
| <div>There are no additional benefits to the participants from this additional study measure.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="protection-against-risks%3A"> |
| Protection Against Risks:</h2> |
| <div>Participants will be given their first dose of heavy water in the pediatric research unit and observed for at least 90 minutes afterwards. The heavy water dose is divided into twice daily doses so that the dose is small at each consumption. No large loading dose (sometimes used in studies) is being used to improve safety for the children.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="outcomes%3A"> |
| Outcomes:</h2> |
| <div>Results of this sub-study are secondary outcomes for the main study. Outcomes include baseline rates of DNL, fibrogenesis markers, change in DNL from baseline, and other metabolites of interest.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="inclusion-and-exclusion-criteria%3A"> |
| Inclusion and Exclusion Criteria:</h2> |
| <div>Same as main study.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="consenting-and-assenting-process%3A"> |
| Consenting and Assenting Process:</h2> |
| <div>After the main study is explained, the sub-study will also be explained. Participants will be provided ample time to ask questions about the sub-study. There is no penalty for not participating in the sub-study.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="sub-study-schedule-and-procedures"> |
| Sub-Study Schedule and Procedures</h2> |
| <div>The heavy water labeling will occur in two time periods - one at the beginning of the study and one at the end.</div> |
| <div>Day -7 to -5 : For all screening subjects participating in the sub-study, heavy water labeling will be initiated at a study visit in the pediatric research unit. Subjects will be monitored for 30 minutes and vitals will be obtained. Instructions and heavy water doses for 7 days will be provided to the participants to take home. The heavy water will be provided in sealed single dose bottles and participants will be asked to consume one in the morning and one any time after dinner.</div> |
| <div>If subjects do not enroll in the full study because of their screening MRI results they will be instructed to dispose of the water at home and will not have any further visits.</div> |
| <div>Day 0: 6 mL of fasting plasma will be collected along with a blood spot during their day 0 visit at the research center.</div> |
| <div>Day 47 to 53: Saliva sample and a blood spot will be collected during a home visit. After the specimen collection, the participant will resume heavy water twice a day for up to 7 days (completing the evening before the final study visit).</div> |
| <div>Day 56: At the final study visit, 6 mL of fasting plasma and saliva will be collected from the participants. A blood spot on filter paper will also be collected at this visit.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="sample-handling-and-data-transfers%3A"> |
| Sample Handling and Data Transfers:</h2> |
| <div>The saliva and plasma samples will be shipped to KineMed for measurement of the sub-study markers. A second reserved plasma sample will be retained at each study site as back up in case of issues with the first sample.</div> |
| <div>All samples will be de-identified and will be provided to KineMed collated and in random order in batches over the course of the study. Saliva and plasma samples will be batchshipped to Kinemed from each site. These samples will be used to assess the methods and sample quality. Technicians at KineMed will be blinded to study assignment (intervention or control).</div> |
| <div>The results of the analysis of the saliva and plasma will be entered into the study Redcap database through coordination between the study statistical team and KineMed using secure systems.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="power-analysis-and-statistical-considerations%3A"> |
| Power Analysis and Statistical Considerations:</h2> |
| <div>There are no previous studies reported in children with NAFLD evaluating de novo lipogenesis and thus the effect size is unknown. Consistent with the intent of the main study to provide pilot data for a larger RCT, this sub-study will provide important, novel information on the rates of DNL and response to diet change in a cohort of children.</div> |
| <div class="table" number="1"> |
| <div class="caption_figure">Study Design<br> |
| Repeated Measures Study with Blood Biomarkers</div><div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/9d03724f-e408-429b-a0a9-6d6d1e68a38f-40.jpg?height=751&width=1488&top_left_y=863&top_left_x=259" alt="" style="max-width: 100%;"/></div></div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="sub-study-references%3A"> |
| Sub-Study References:</h2> |
| <ol> |
| <li>Jones, P.J., et al., Human cholesterol synthesis measurement using deuterated water. Theoretical and procedural considerations. Arterioscler Thromb, 1993. 13(2): p. 247-53.</li> |
| <li>Hellerstein, M., et al., Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med, 1999. 5(1): p. 83-9.</li> |
| <li>Misell, L.M., et al., Development of a novel method for measuring in vivo breast epithelial cell proliferation in humans. Breast Cancer Reseach and Treatment, In Press.</li> |
| <li>Misell, L., et al., Development of an in vivo stable isotope-mass spectrometric method for measuring proliferation of prostate epithelial cells (PEC) from prostate tissue and ejaculated seminal. Proceedings of the American Association for Cancer Research, 2004. 45: p. 1032-1033.</li> |
| <li>Turner, S.M., et al., Measurement of TG synthesis and turnover in vivo by 2 H 2 O incorporation into the glycerol moiety and application of MIDA. Am J Physiol Endocrinol Metab, 2003. 285(4): p. E790-803.</li> |
| <li>Hellerstein M, N.R., Kim Y-K, Schade- and C.M. Serin V, Measurement of synthesis rates of slow-turnover proteins from 2 H 2 O incorporation into non-essential amino acids (NEAA) and application of mass isotopomer distribution analysis (MIDA). FASEB J., 2002. 16: p. A256 (abstract).</li> |
| <li>Neese, R.A., et al., Measurement in vivo of proliferation rates of slow turnover cells by 2H2O labeling of the deoxyribose moiety of DNA. Proc Natl Acad Sci U S A, 2002. 99(24): p. 15345-50.</li> |
| </ol> |
|
|
| </div> |
| </div> |
| </body> |
| </html> |
