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,PHN2ZyB4bWxucz0iaHR0cDovL3d3dy53My5vcmcvMjAwMC9zdmciIHdpZHRoPSIzMiIgaGVpZ2h0PSIzMiIgZmlsbD0ibm9uZSI+PHBhdGggZmlsbD0iI0IyMEYwMyIgZD0iTTE2IDNhMTMgMTMgMCAxIDAgMTMgMTNBMTMuMDE1IDEzLjAxNSAwIDAgMCAxNiAzbTAgMjRhMTEgMTEgMCAxIDEgMTEtMTEgMTEuMDEgMTEuMDEgMCAwIDEtMTEgMTEiLz48cGF0aCBmaWxsPSIjQjIwRjAzIiBkPSJNMTcuMDM4IDE4LjYxNUgxNC44N0wxNC41NjMgOS41aDIuNzgzem0tMS4wODQgMS40MjdxLjY2IDAgMS4wNTcuMzg4LjQwNy4zODkuNDA3Ljk5NCAwIC41OTYtLjQwNy45ODQtLjM5Ny4zOS0xLjA1Ny4zODktLjY1IDAtMS4wNTYtLjM4OS0uMzk4LS4zODktLjM5OC0uOTg0IDAtLjU5Ny4zOTgtLjk4NS40MDYtLjM5NyAxLjA1Ni0uMzk3Ii8+PC9zdmc+);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: '924e2ca218cd3f8e',cH: '6VWod5mWpy_oyGhpS4Om4Afnx.w7Aip2IzSY2FKJZpw-1742735483-1.2.1.1-O6qil080vRVdT0NvL2Ovh7LCAkEbCn44_yYSUe2RIdfmSJRyfM2UuGkvwkfVV2hv',cUPMDTk: "\/doi\/10.1056\/NEJMe1414112?__cf_chl_tk=BmpJEv5k2aUjMRgPRy6x9BoeM0MeT44g0Zoa._F9Fz0-1742735483-1.0.1.1-6Ee6uH5q6mqTeoueIesren650RQeHKBlFpje4.VrNlE",cFPWv: 'b',cITimeS: '1742735483',cTTimeMs: '1000',cMTimeMs: '390000',cTplC: 0,cTplV: 5,cTplB: 'cf',cK: "",fa: "\/doi\/10.1056\/NEJMe1414112?__cf_chl_f_tk=BmpJEv5k2aUjMRgPRy6x9BoeM0MeT44g0Zoa._F9Fz0-1742735483-1.0.1.1-6Ee6uH5q6mqTeoueIesren650RQeHKBlFpje4.VrNlE",md: ".H2C67rZ3p4cgJQhkdbK2k8FpXQBFn6tKHqRyFd8E.0-1742735483-1.2.1.1-UIzf6.HZ4Hk0VgQorUvVsjx9cGoRy..gCn3BY_7XLmjk2AG16pRUbu5a4dKfgUoHtY_xUdHmDmC5GfxKeIIksTath1sBfeecSimSimxwULnIdcvjBaSOwN8L_TCN9ybTFSuogA.tFjl8sbFuKkMUbCpBM49C5466MP.ZC.saD5irCMZvmyIlUCZeIOIUEkMgLA5SuwfdBMmgOLNd1aIs1FHAsyI.1_2avmzLRdCokIqZjHafFipitv4WcP8xxQGtixQwmsnTHzaqX_szEOrt0Wh_KuPAv0X0LZ_l739sFjtDYKSGba7KZPeo2twnpSOs0LE3x6gf6UhV496IdTO53uXX8RSN_XjNHiSudds9FJawcTXOOU1iZUoHzB4jDCwghjCYL_FzH4AhKMgnanUHSx88cy3pDXXX.ZQkPIHEgmU5zz1iPjDkVXyQdNW3DUdDQ_3UmhbT0Iiquhg2hz.uTDtujvgZ5S0pPtfBjMJTWQmUAC0q4x_YhJb7URpBj2_wB12WBYqy83rjJyuFdnc5wnLrAy2Nu3HNYBfa0cqhJq4vZibFb80YI5gG5Yo35pnRKP17jLkWMYtLobRZ8tfu1V3iTQMH_uGJi6hv9aIG222bvNITIS7.dd77PbS9lWxVrG.jTYmNU9to7O.JOHkE0QNkQg8jTN9oIrXPtk.R5.btJ38vVY.oDGHyxft5IhQetQfp56wN7qz_XeMNgKanfsjdFIle0WvsWMrfoqW4gqUz4zRY4F90VPgVQiEdWZ3mKbjkv_1GgBwC2cVixvGoBiztEIHjOl4nyRWrYv0ImfRmeUBSOcHmkhaP1joTEJdrQgyh4bx6fL1wklDni5Y_21LbxG3khWWBrrKR5Jc3RXNpEINIU0EdgRKCIIPeR_37Tnqf0JeZrJ8Uvn8cdfXDo4YYovdMB90EDzFYxVvD7Lr_ZtWLzjYV1PrLeTO46Xw1TzPMN5vODIGf4oMT8LSTgIGlu24YPbfDRu13epxjNeF20UxomirB54ymCRWRHpxd6tmYGPv4hqk0M2DmP_xqFNcwP_w9gTWY91Nj8OxdLfbMqmbQoAw3SazCbJ5wahdRJNj.Xop5PAZIQLkVJtNhOpe8dQDE8dyuQN3W6eo2.eHD.57_DbbQjdXweSejtmIR2wPidOwVb3z.22qZa5cxGj.nwcRXe70s0UC_y6kv96hOr9tZ4vyTIWGoBqydzYJ94lN1FLVSkBXTUm3obLCiGYGDgVL.aPpHUEeBwv8q5tO6QjGtOlsaYgJG59vf5rJ8",mdrd: "SG3N39GVQNRhp0ydRP5fZvl8AVHmIsSm7SvYdmrJ8zY-1742735483-1.2.1.1-RRo071HPZMg9bIZ8nJq609zyAn9XoC6ZzDAJ8W6M_DfbIA52Jp7FvAVtriPOlx6s7F_yrtKGF1j0.6GAum5LNW3RxCG7fpJDWbyDMaA3ye7RhkZqAE4V0zoe4iHiTL20IB9DfyPrvr.44OUdTI.OcPEhQtO1D10HtAqygD6VmvgnuU5yLDZjho1uJJqxHcEuvBFomombn78Rt.HQtqUQKwVf8p69exvc5p3zSCFYMuxOV7atwPNrNbSTml4DPeey6mrcKWtudfqY9YTK6QJLfexRPgHBJ8SCaTxtovzN2q2sJtqFBJUjfoZXwNoraFAj9hkieg4CU8.tSv5glIw1XPL5qvYfsdZ0GAOk4Hk8I3ghpaw_B6WpYDMlPytYEyky8UMwzd4BwGor4u2UPWIDcukqYoeJJl248bCE0CAqKtJBheElpdBQ501oTCm9zKfc0Jh.R9Qyb9Zky7oylLUeUCCUabo0h5GU0bR5EGsnETCEF0.uUoW4oq_v_50I4.XnPTIweHV6Bl4JmbTyPJq_EAvXXTXfMd5mC32NnNPp7V8VXX9Ox8vtW4SmKG1fC6Qw444Ftn.ZsSz945LbPi85OVJsSKVKY7JqJrSyJFlGAXVE4xmSaI4.YVAFtqCmk.vgl2nUmBOujf4WmeygChYhyw65ZO2Fyj8E25Vs6_aTSAx19.JSvwA8flblibjA9aWGGTP3Pdmts2VfY3F_29qIA6hawAFHAVHaaXTI1nYHvHj_VSna5O08kPl0modFuF3_qzmStlI1DWAR6s9ySksHH7DewPgv.xkoL__VRgCou4ulsmFLhtDs8bzmZwcosIG427LPaWBPrGV5ZP8JctTcPU_LW5f0Y_ms9DJR9VVJxF7BH3d0uxDEaPmYJ0wiK4ClGP8uIURQ22uPi06eLB6ZQtNo_hzaQpl1rRpfYgqpAo9JQ9HcUN5WclMLkqEJJqms0txBtQgkCYoJA8apmIWUAEfgfEsAtfEFAdOCLpXPbYPp6.ELLpZAPGCsRPA.EB7uc.CGNsZwTuf.HVlbgHpKevQNtmMCbdjs4KYVK1aLu7wkVLHUxqfLnodwDqxMDBnX1VrfGkCbMI021BBSlEr_g9pGc3f1ZQgmYvnCuVmWwV8hG7k.JVOObV4HBVRMtoCaoOflj4ARj.3Bz5M43odyGyjDPuK0VBEbBp5T.5b7Rdw33HiEcGS4SSAz2X0PTaRZ1tT3pWWpRr565TRtH6LO5tjOz2oV2OLP2x8dAgDfpnlfBzLnCvFOKnrL371GgZVxqPXxwNiIyDtXuqWqajkBl5uX5U.P2Cdkg32tRUKEsMOYVD_1RjTkrj9u32IoRKMwUjLC073A3dGBB4_4wPxmspoKnGE94Ht3KiOXWsAvyReU34p.cCQTlJq.jvrJfSTLdlgK6plc9CGMzTmOUvweKMXoA1hvTOXxUH34pQaTLeEXOLJYlV7uvWxkGgpBn1BhuPRGEa1G2oTy7.ACLhqW3KBCzkatKzXihfQMZrzP1imO3x4Qr38CPJWFgU7ZWi4WbC69Kq9pw7VwdVAqsoQgwDb2MmF1cImn66wdzRUONolv2Pj4MVup6Nl8It7cSGtIaPlZm8HJC2gKbEoUTtrOdZo9hSc0UjjeIIiJiOvKPVLN5ZXSpktT8rw8gaaNdVWREs88YJ3zlVLwXCst1Iyb9GiXaNL6E7zt2r6HfUoCLqKl3bKnMtp9CWx5vUHUviuAoaJgMtXoZYL0oEKHmrMP1vcw6M4irzdkJtKzlYNCAkp0ZG_l5WAvI5EmEV4NXdWOuNWIKJoYOj5bBEQJki033cNhYMmAEjT22qQs_nfY0Y..tFGjHVlhn7r1Z_QdJAUevQ7v1P_mRNb5JA3YYzQ0NOVEXvsSHWdJZMyDfKti2PwZ0g0prUXUD92cCXdYh9iXYSKX5yxIj.G0C.tUOLdT717G6IdHIleEUbK0w8YQqhCAbsBdHObCxHuAwsZQ17qAIKWve3OPNRIkMPk78xWWdyXzUnKqPXPs.qd44CJ1D5pK8R5xa7l9hcaTE03mGskjz8m2h2q7SR7JHvhdk5.A_Q"};var cpo = document.createElement('script');cpo.src = '/cdn-cgi/challenge-platform/h/b/orchestrate/chl_page/v1?ray=924e2ca218cd3f8e';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\/NEJMe1414112?__cf_chl_rt_tk=BmpJEv5k2aUjMRgPRy6x9BoeM0MeT44g0Zoa._F9Fz0-1742735483-1.0.1.1-6Ee6uH5q6mqTeoueIesren650RQeHKBlFpje4.VrNlE" + window._cf_chl_opt.cOgUHash);cpo.onload = function() {history.replaceState(null, null, ogU);}}document.getElementsByTagName('head')[0].appendChild(cpo);}());</script></body></html>