CINXE.COM

Just a moment...

<!DOCTYPE html><html lang="en-US"><head><title>Just a moment...</title><meta http-equiv="Content-Type" content="text/html; charset=UTF-8"><meta http-equiv="X-UA-Compatible" content="IE=Edge"><meta name="robots" content="noindex,nofollow"><meta name="viewport" content="width=device-width,initial-scale=1"><style>*{box-sizing:border-box;margin:0;padding:0}html{line-height:1.15;-webkit-text-size-adjust:100%;color:#313131;font-family:system-ui,-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Helvetica Neue,Arial,Noto Sans,sans-serif,Apple Color Emoji,Segoe UI Emoji,Segoe UI Symbol,Noto Color Emoji}body{display:flex;flex-direction:column;height:100vh;min-height:100vh}.main-content{margin:8rem auto;max-width:60rem;padding-left:1.5rem}@media (width <= 720px){.main-content{margin-top:4rem}}.h2{font-size:1.5rem;font-weight:500;line-height:2.25rem}@media (width <= 720px){.h2{font-size:1.25rem;line-height:1.5rem}}#challenge-error-text{background-image:url(data:image/svg+xml;base64,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);background-repeat:no-repeat;background-size:contain;padding-left:34px}@media (prefers-color-scheme:dark){body{background-color:#222;color:#d9d9d9}}</style><meta http-equiv="refresh" content="390"></head><body class="no-js"><div class="main-wrapper" role="main"><div class="main-content"><noscript><div class="h2"><span id="challenge-error-text">Enable JavaScript and cookies to continue</span></div></noscript></div></div><script>(function(){window._cf_chl_opt={cvId: '3',cZone: "www.nejm.org",cType: 'managed',cRay: '8e97d5258c92ce69',cH: 'VC98gk1HzYkS6olFuZCmOtK7ASr._NP48..t2dbHzEQ-1732770427-1.2.1.1-hkU_YDXVyZv.B7df9ID9VINs6aukY8_alXGvMIi9Waz54OJz9GEleum1BeRH7n9u',cUPMDTk: "\/doi\/10.1056\/NEJMoa1401480?__cf_chl_tk=u9hKQ70Ro6E91nfDV0_bXGYhBlMvk57AsfwkNmzLxJc-1732770427-1.0.1.1-3kW3uk3DviV.vz7xKcAm_l8L4fRiDaKjshwwswiXKQE",cFPWv: 'b',cITimeS: '1732770427',cTTimeMs: '1000',cMTimeMs: '390000',cTplC: 0,cTplV: 5,cTplB: 'cf',cK: "",fa: "\/doi\/10.1056\/NEJMoa1401480?__cf_chl_f_tk=u9hKQ70Ro6E91nfDV0_bXGYhBlMvk57AsfwkNmzLxJc-1732770427-1.0.1.1-3kW3uk3DviV.vz7xKcAm_l8L4fRiDaKjshwwswiXKQE",md: "tKdmjgv_pDFaSzJ6taPNb0KVaQ3R4e9dRR4xzGmnY_U-1732770427-1.2.1.1-WnTW0clODuNj6Km4S6KGCfpbZXzu01d77c8vmHO9QLAWfCKqTJhtJXE.vqsTcxGRrPHon_6gtJf.IC00hD_ImfQSdlfCZ7NrCtz9PuerpaNEdQzGsI24U3SH7BsjxOxB42bfY__3VmxmI8WjcWbSwixX0sVUekAeN_BvkCpMhsw6VpIbBdbP.Av03oyqd7RU.nu58MzlaMHk9AAvzKg1..MrYl1L7eBJc.geZ9JTIO9Iemg5AtcBguZvSPtzjM2OdXnX_YgRAIF6prxE6TLYvOXx.cu80wRfkb2RB6U4_eagKgbG3wFDfMfj9DKIWE55lcZlbEGLvzNfIdE3zNysYxX4VKErNjMrzPSbdw3cKCKvw8Pe.pGlYE03dLu6CAMx710dMJUK4zoQuFaHyPuF8m_RcjY5ZAftpz_9yU3bEVkYU_0mox4MDdZYJ6OrYWIG2qMwMDObGjkR8JE2ehDVhHwsuai4fqhL.W4ZU1Xfq.xBzFngS_firp_.mIITFI7DxW3y2UuIyp2i5bkgJm0ILvG4YQLe6OgH3tg1HfTK0Kg7ExgPW13qhH50G.Xk69qfBn0Bp3dbo97f2rz_N4zlt.UqmpERSTR7rYarQbThpucrVBqPtBFCFSXF78JzvLKn.CUOh85bkpr42SHuR7onTr5wuey9AMB.E6FuSd2AEBvgJxXAJ1romOts.wFwVSVxoR2cN9duKHPyDffrr7cdXL2qvM2ORulcjif.N0nl64gTUb7nmbwPYu2X9X_vjD8CQ1iHqKCf48uSz6yYNHYHcyi.SQJXsh308vZ6tPFAROpNBgMaM_W.cD8PZYxbco.a2gjyL8fgaRnFb9cnOfrFTacRKW5d.ZIK.Zt3gW315AAGPs77qPMn3VZtpGHjJSKrY16SazJ89lZ6sRpLxpZg2lnkKVWG0bsIQONuLzjFHVpwqSU07c_c0etISl6ndm19m3dxd384mOdPd3CXB8W3mO.1_5xhbzJ4UYR17_WivIyTKJvYoyq7G3lAYmkqOLq8yBvVUiKDFZZMpR.10ZCcXufOnQNuLXwFidDYu6qq4xYmlhT3vwNzGLeP5sKAHXPYCcYh10OtiXY.miZ6ALt8jjEKH9nhRFQlve9F4sbQc7_Pqd3g6oLn0TSeHOYA4Doroqte3Au1Lz166DGKUE4rdjXrFYonk2PYAQDXSYjXws30cvUyC9PcEdHsaS4km6S799U8JrTlz91ZPWOsh.YQNns8BFlxEvcx3X2eq.OYgsoLBhVT5W62d8jZj1b0mBhOYLGhW0drtHQXDCI9p9iFed.0pSmQIWm89WF2EcojiL_ia1NXhsO.ZL9UukG8sI_wiPBzfUF5wXgXZe.q985NH90kSOn_nvmoRfcPaDlIMMebjcM.nRhXHfaj9NAYRgKR_kxqvcODlsciUbMRA80iLpmGdIVCAfHqpA0ENLXE169da.SJZ8RwZMY.S4cUUb7Bt0yMc7AGZmVgOroFY5_p1kCBGWTQwe3OInVxdmZY4UrjtCGprf_.iKKx0h_p9MP8.WHNtYvjknp7mEUrFWShGqQeuaZ3racJ0Zf8oIXEqlSkzhKZhUPO7qtYf0mw4HdLPaNG2ZBjZzlDFMHOSwpxDPtPJyg1rdmgf3_QwCOupMlwJzGpMshkmtJvCjWhS6yszPJT1BL6I6tip.eZInIrRqpITzs9eHNkUfazrOq_MCyDQYhwe0iqeiAP0DxKAbAPG.WQurvThiuwS8isgYp2zia13GhpNCxIKHIWIHikKPX3fFPodrfr1K82pTRI_bFROM5XM59iUEztNHfxM.IPY.fc.CZrbjffLY6e1eg9mmrMEwhDQzYDN2kICf3IBzDu0DyPm2UMdPuCxCey5A02C0oFsOQksshdav8K0UU5RBEwSp6QdrnjZKdspFJCl9UcpV3o91XXrVQxhURKUk2cjsPoGUqzvQ_PGrilf7klkr7uEQFNqbCJiWKiz4KyTLi49l79bmqVN_3oxX2Qp00qGhbIaMx6DTTQM7dztCvUqIwGl5c0gLco4Z0GWBAfCw.t7RuzsW0h6gsAwfDPFp5ihnjlMJNS7SeiEqeSQcyzLkxUFAZINkBF4R3uQUymDRjQrdhukLty4PS0UnQnVBYMKUVrcKFCzYTIWvLqerUO530lcZZhmCKGcG7w3q1oHcFGj.k5La02kCalKbmSpSbY8h5LFjn2o44z3MDck5pSfBfLAiL2eBn4hKt9Xo1PqNbliKpTJyTq7d3pdP.ajh9u0Pcl.ofMpQmwDQ0Lj7IlgzSguM09ro9CorifKxjyzxDC670DzGpzWnJG4HVX64LEgLt.efZ8sPbRvdnVqT4QQo.GipvZ_nmNFlB3yy_G6wNixbSs9jLTxFiybe4TJn2UaOlakFEcAucmw1NrFTslvTMUWH5LxHQw8pY7VGDorhzHSRB983dxpMoRTtw16FML4Md8tXG73twTgOhbnDqT1dywgAmHJn04nZVP3AIAQw_s6qNk1QJnFENq46_7xKGdydN7ukCJQkgNi20WHOjLuXvEqiVuT5o1HmffokjoMjQygYiFoz9jyesOK2edKB.3DsvkjN4UKSl2NmpXRAjf0anAPifH6QZoiAI19zcGiWU_3gtGlELUUT.Onff_mIpJsxfjih5t_SIDrKIhp9rShYvhc8nDK3H4d981CEzkczwjZ5WI0j1yo_higKHeLB5OQL5zAQ4BlMNMrLmo.W8teRkVZGxapRwDoSjx8y5ZN63zv74.zy43VZd1VZVyL3RTscIKdGTuhI8998PY11OX5wNHXpBJvYJLsZvPju01TYCsps_PTTw3LvLM6YyNa6xrufafkV8pjX5Q8G9UAgj4PVzO_PIQwW_YYrwQ9YuwlBwRX1DKGyGIkKB2KwK4X1Q0KmbHNwNvkW9HI_m_V.3auQ4S5z5ooYSikT0voEJqEftfIY0pAsymkjw6yxTmtzzxeg",mdrd: "dnm_lrHApxoAW0l0O1R3aysIpzXX7gWN1eAUZQu99hs-1732770427-1.2.1.1-QhoQDbLv4g34Z2ukOH_gveADFVzo1u1iFvkdFrS5eAFqiEcl1jJIoHnkf7EMuNgrVs0x11L2uQpbHfdz100N_5dtm6dNKB8eiAKHBhkBSYLbNWFQe9_N3MWaQkBva3qAo9jxOCJ6tM12cAkRl3RHaWLsTL1b24S6NFNfHMGYc1GWD4ZycTjUSUSGgaf87cdKbpxDxz3IlaA.PgnLLGlNlTWnNQ2t62I6JUSuSEsgyqh3MtZaycqO0FOVhegSoaVwNaFiPYVcta.Mv4CHJJ.l2JVw0BAs3waoXqok68BQh0oqmyFDPFgGHxnvS3KTs8dguJZqU6V892cNRUchKtqlQTzFHXYmTGuJbB9EJNb3pjSc6fYrZ.nDpEtITTXgoLEQQND4foaPl6z4SF4CRfhmNxwEhqaGdmYO76kuJiv9yOzET1ScGreAqXL3OUkAi4tqhQjONtRShZlvznR6S00yxWuSuTSwlVVFES_3IoeYSxcYIZobzrNoERgflRvuEiX1v.yms.P0TqFCgaQZ1CLV8P3I3sRrHos.DEA2aYpZhUFMv_WxOo6dLNkItYgya0FncGfX7MmemtfHnOxZ6.rQr9Xg8Ni.dH_VYbjaNw22PIu_sUA1SDhbPVIHIRyPGVXdp8zmmfc7SJ2EN8Lz08klUc.YNI49rpBRDJZSFbOV0QiCeX8UaWe9pd0SDb6k34Xq"};var cpo = document.createElement('script');cpo.src = '/cdn-cgi/challenge-platform/h/b/orchestrate/chl_page/v1?ray=8e97d5258c92ce69';window._cf_chl_opt.cOgUHash = location.hash === '' && location.href.indexOf('#') !== -1 ? '#' : location.hash;window._cf_chl_opt.cOgUQuery = location.search === '' && location.href.slice(0, location.href.length - window._cf_chl_opt.cOgUHash.length).indexOf('?') !== -1 ? '?' : location.search;if (window.history && window.history.replaceState) {var ogU = location.pathname + window._cf_chl_opt.cOgUQuery + window._cf_chl_opt.cOgUHash;history.replaceState(null, null, "\/doi\/10.1056\/NEJMoa1401480?__cf_chl_rt_tk=u9hKQ70Ro6E91nfDV0_bXGYhBlMvk57AsfwkNmzLxJc-1732770427-1.0.1.1-3kW3uk3DviV.vz7xKcAm_l8L4fRiDaKjshwwswiXKQE" + window._cf_chl_opt.cOgUHash);cpo.onload = function() {history.replaceState(null, null, ogU);}}document.getElementsByTagName('head')[0].appendChild(cpo);}());</script></body></html>