CINXE.COM

<!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: "content.nejm.org",cType: 'managed',cRay: '8eb013eca8068240',cH: 'Y5BCgrv7zdz9a0gAkjNZXod6mkMxROJlvkXut1JwwKQ-1733024657-1.2.1.1-u5Erqzs9XpcpvmzRZgltlGn3Y_P4hCFJ.BkFA_B5g_UB5rmOr0f0FISUabcrUwoq',cUPMDTk: "\/cgi\/content\/fall\/331\/11\/712?ck=n&__cf_chl_tk=jcqgXLqo5XhTNvAZbeB2ARuq.GVKLsdBNM567mQvRAk-1733024657-1.0.1.1-bqT7_Inb9N2qSpTrabdkjLxdacGjXVY7FjVLFkyTPFg",cFPWv: 'b',cITimeS: '1733024657',cTTimeMs: '1000',cMTimeMs: '390000',cTplC: 0,cTplV: 5,cTplB: 'cf',cK: "",fa: "\/cgi\/content\/fall\/331\/11\/712?ck=n&__cf_chl_f_tk=jcqgXLqo5XhTNvAZbeB2ARuq.GVKLsdBNM567mQvRAk-1733024657-1.0.1.1-bqT7_Inb9N2qSpTrabdkjLxdacGjXVY7FjVLFkyTPFg",md: "4NoqwcxffdyxSm7psgV1IsgZB4A9PLQyI24Q.pE8BFg-1733024657-1.2.1.1-EtzGoigj9b7AWPapgqiZ.pZXEuyZqtRHS2F7nYpRI9EjKzgI1uqmVoFcWct_bw9TXKsIhjdLNMDjzhZX.wscvC3VYdv0MEbs9F3lLiGS4xB_RrZDnYCXwJ7vWYjilrYdQsVRf3EJShziSiIT317jQ_3gxmA.qNlXmhehGWzdWqK9p7pnru2qg_LnOrwnVmdrxutUB0EDeuzzIiPwXkPWn0giwZ1N4w1MaQV4pYSJCUTRXYT3Cy233XdJ.Sjwj_aK3x_N0yirZ5Je7o0s8Vpt4DNl5JzP3OJ_.8Ms6HHDKbtqW0DzHKiDF1d.gWz_fC64UiaTFJ0cx.MHuojWymxGt1zVb9F9bpcEUsx7WCSG00HqG7W6zVOzQcyNM2d3SHf7LvujjwwcpEna4yoyBl65cjgsjAO9xSN7WPQq4sU9sVbqet.B.7eNQRV1UcYuKIIVJi653mJbU2Aw8JM2jJt2S4ZDP8pIbrUNmntFRDV4vAaKmd3lG3cNKWwnxMNYzkl8BM_CKrUJNHdz4bdbA.tBub5fB04jNIG_9BXW32dOEMEb5SWMaCEkRgB.KNdhq9TRgonzlj_boyVUWg2Xw7uyRMqYkeQDHnHnkgh_rxI0YSf4JMM6k.j45CzeSUkpsqOKziBOX1vTzXEioxd2XlsXp77myoJ_mAoJOHewzmUIeZnZcqNKeyo1DZoAwBs5dMofSj6CnAkLV7rhiIjbYJ5NWpAcKcbP_u0vikfx1n8XsvrHkKD9C64SwisYrzEZuLhCBntrJHWqPRHFF9sg3GB5Nc48NvCAMCa4riSX9EYjawTYchM4szstrEvPs9ElcYpKsSTNRA0tXZQJ9kw1SJb7uQMC5gXcE3VNUD8B0YsPtKom9tEPP5FSwokLsNj8oGNwWNU8SfZyJVBzaYAEt82r0GLpXEF2sbhtQu2Sy9HQWXx0IIdI74aIms8Gds599lOq9PW_f13tzB5LrrOuqMLGXq44rqnyr.22wgCUua54ubo8LBfJ.puxoATrMbGowDsznaA47lv8MZzqXDRCro6wR3SwyIg6VRDHXVoDJep8aIS.wY3jejWVwPkWaIZ.76YUORoDejUBBHVnXZjZxzBwKhw3SL84WDGtbE9SyROQuTCSrcXXhbk5JdtRWe3aH9nYm5KP78kfU8LX_vXDloKgyExwwmymzUUqRunRq8WGzQCp5gReaFKrQ9nrlA3ot6WucIOtWwFAPLsKmVuXVAHKwqP5eKbQTDC5bCgUEGXOESYgL8n.9L.JlLy3dgPoqczdtuY0kTS7nKS9hzlgSi9vVyRB4mSBH5F0VYmK3wjfE2JXn6YDaVc5pVU1djh0YCuh6Yt39XkdVnNx8bVzbWCvEX_zbLitXfjXKzgVO.gJUynbiwR_l7_rA22OeySlrghoEG_2R7md7tNeRYcbDxXpeWp1x6HFuZBrFXdeq47r16o6.E.bo4on5xPiLsDconHYYNuXYZAyaayXi8yoH4XAXtfymY6hdDtytNkuGOnoevQwgONeZjn0147Zd5DvYTcq0KOpKl_Toy02CPRub50eLzAhXfkUYgs5El2cWlyN.3kQvezIXlCojL3B0tvpo3jw_Hj71O5veCi3sy_4bQAtyRABZFLrj_2N7IbdNQK4bcINJD61tDwmxRW_XzK02I5e7vkgpDPMIZPMJquezROljQPbGuatM.e0Fm1SkfjzfODBYryubfOP4lEEzJRyt5xhAh4ox9AM9wR0d8cRTdb7adqZ0DnbjIurDlJsltNeK8XZO8TI6fSQkUkRN21r2svqG1d0GldvzvioJBdNqybt2uSLCDDCAkShk80R0NSUamql6BlVw_FrlLZHZrkd3DZ9aBNAwwqSNIut2.LSKA7eLeYjL0VzQH9W0z0cmYNqVpPovSnIokugJggTfr7ETjIpcCLnWSGvfZxutI80mR4OkZgP_g2KG2RvFjYt.qDp.y1VqCcybUBUxsBGvnJ.ZGt5jJjktuSaT.17ayM5LYcLKPDQyCEcY_4U7nI1sLjTaJqgGBVFBxNk2ZlK2KfeFbmsWmf_xQ7nByugwGPjYmF_xOjidb_MWtHCIJt6wBsCeIU_cAFnxx4shTXvkmzUw1YUMkHu2r7T1Z77AzK1r22w.8.AE10n4x2UpPSCuniEzlUhg1zAZLjCCcY9.qHzXTCVJn333ptbfpFj1o9eEE1nwvKXw_S4W_8SYvcjqBnkJGXmRoCBsNvzA4pkURYGtvSY0FKYKUWFRPtd.tBT4lPkvSaGwE.IE0LgZtxxWAua4A.95vrhCDnAZI_JFdDm7PiaBVBeps8WuARInmFZUlNouymaN67EGXYcVOrwQlH_GUUqrxGT2IqR1SRZtmaHek8Uv0gah5pJpPm6c6ZWjfOT_1FrXuSvJ7NgBmn6eeqjaPt_32WVZJE1BjoZ9RYwg0KNKJgBUZivcE05Fj9pvwV7TIktc7zKcYrJMicLB5NcA_t.tkcQz4OrnMmsvb8W9q.0_bJEiacAaALqbl01dRBOTHl27qFyyg849IBK0uHAeEghXNxLitE4eL8Z9dO47BIudA0q17jaq80k_LyjF1Hlmu6C_AB95p13pmBxcuak03HgIwyiQegyXRDwdPcgqa2DeqlcRqBZ9J1o3lGHs7OevBdTCQNP9Tj.BJ6vuE1CaHIRDgcgLU78GHqdCKHXJwFJEfSm0J9W9x9K1_vMCvn0.OSERC7TvGhtbdcLlVzHpfyUKFMAWkuRNz6w3Y35whM8O5RRyhdMMryCrd2oRzW7AO4Vkwk62TpTOoX_4g_rkldvjL1t21txZLzB1NkJ0kKbDxNSiF2JpB73wVG1Sb3loFQdY12TpXZR0nhy6r78cXWDdTNX0sTJNjMrHdIPsCkXVBoz_wpFLMB_UHd5QMl6QbdrQi7nrfqMRzrmMyHDypnBmLbFOpvc.cBhFTcUcCz56yXOG45AL0WaZEUkyYhA3pQpksSsGxD6Ve9nTTjoT60",mdrd: "v_vXaxIQiI6nzBm36_ke5cHlCdFiwf.yLDoi37Vletw-1733024657-1.2.1.1-gp412SGSON9.dAppaZjHYAdAF6lV3gGVlkRcio5Xi9JTH8vC02xsv1yoqYsahqz2LUol8QJNYM1lWM1kpxqfJ4z6hUhh3Z58igYTy2XtMsbEWAZP6mHFqsdTYpAerrsl6VpWAPNEtNxQjDgObh2fGUTBn_6GnNWSIs3B54KBaXA2n6zUxpRH_65TAXkmvI1QtZoQoq4fIT9r5jHp8O7B9TtO58pIM1fCb_V_XX99TxVhHfajMcFv603AN0It3krgh7NUsvznq_2Jc.xGGtISlDzhxEip43fSNbDfm2wmxBMCF7_I747GS.IuPNMWlX9bnP95c29Fhi6V_dplzqNyDBR2FwHm2pNvSyD7HclXHaDscBe6qQJJ9GHuuYYjGovHwx5lQyBJTQAxRtmlmuGVlfqWcXXFjmTX7TEK8wX43_MbWkh.t.f2e1FG5sSPZJWvazZyqiogiKAmqTFVuG4hr2QwvXqrBKfFzFyj8ZfxM5Pa1LA1ur.C2GsuTnwoewwWA6AvAqy9GO66FIITgQwxHJ0G5VfeiVUnPEqEaVTlSYSa7KnAf4rNr.is5fNcabI1DtwuWK1atC_N20AqH1QMhb9jIKUwc4z5DSx.SqMhS54VVOt4KGmEmjy36bgI.DFfl1Y7IxA3iSSadMszjED431iLBaQj3IpT6QW3KsvKoYqh_L4b3tgvJbr2Fip0ofvp"};var cpo = document.createElement('script');cpo.src = '/cdn-cgi/challenge-platform/h/b/orchestrate/chl_page/v1?ray=8eb013eca8068240';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, "\/cgi\/content\/fall\/331\/11\/712?ck=n&__cf_chl_rt_tk=jcqgXLqo5XhTNvAZbeB2ARuq.GVKLsdBNM567mQvRAk-1733024657-1.0.1.1-bqT7_Inb9N2qSpTrabdkjLxdacGjXVY7FjVLFkyTPFg" + window._cf_chl_opt.cOgUHash);cpo.onload = function() {history.replaceState(null, null, ogU);}}document.getElementsByTagName('head')[0].appendChild(cpo);}());</script></body></html>