Liquefied capsules containing nanogrooved microdiscs and umbilical cord-derived cells for bone tissue engineering

preprint OA: closed
Full text JSON View at publisher

Abstract

Background Surface topography has been shown to influence cell behavior and direct stromal cell differentiation into distinct lineages. Whereas this phenomenon has been verified in two-dimensional cultures, there is an urgent need for a thorough investigation of topography’s role within a three-dimensional (3D) environment, as it better replicates the natural cellular environment. Methods A co-culture of Wharton’s jelly-derived mesenchymal stem/stromal cells (WJ-MSCs) and human umbilical vein endothelial cells (HUVECs) was encapsulated in a 3D system consisting of a permselective liquefied environment containing freely dispersed spherical microparticles (spheres) or nanogrooved microdiscs (microdiscs). Microdiscs presenting 358 ± 23 nm grooves and 944 ± 49 nm ridges were produced via nanoimprinting of spherical polycaprolactone microparticles between water-soluble polyvinyl alcohol counter molds of nanogrooved templates. Spheres and microdiscs were cultured in vitro with umbilical cord-derived cells in a basal or osteogenic medium within liquefied capsules for 21 days. Results WJ-MSCs and HUVECs were successfully encapsulated within liquefied capsules containing spheres and microdiscs, ensuring high cellular viability. Results show an enhanced osteogenic differentiation in microdiscs compared to spheres, even in basal medium, evidenced by alkaline phosphatase activity and osteopontin expression. Conclusions This work suggests that the topographical features present in microdiscs induce the osteogenic differentiation of adhered WJ-MSCs along the contact guidance, without additional differentiation factors. The developed 3D bioencapsulation system comprising topographical features might be suitable for bone tissue engineering approaches with minimum in vitro manipulation.
Full text 43,537 characters · extracted from preprint-html · click to expand
"use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317078",licenseKey:"97f8f67f26",applicationID:"772317077"}; ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317077",sa:1}; ;/*! For license information please see nr-loader-spa-1.242.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={234:(e,t,r)=>{r.d(t,{P_:()=>g,Mt:()=>v,C5:()=>s,DL:()=>w,OP:()=>S,lF:()=>N,Yu:()=>x,Dg:()=>m,CX:()=>c,GE:()=>A,sU:()=>j});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}const u=e=>{if(!e||"string"!=typeof e)return!1;try{document.createDocumentFragment().querySelector(e)}catch{return!1}return!0};var d=r(7056),l=r(50);const f=()=>{const e={mask_selector:"*",block_selector:"[data-nr-block]",mask_input_options:{color:!1,date:!1,"datetime-local":!1,email:!1,month:!1,number:!1,range:!1,search:!1,tel:!1,text:!1,time:!1,url:!1,week:!1,textarea:!1,select:!1,password:!0}};return{proxy:{assets:void 0,beacon:void 0},privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,block_internal:!0,enabled:!0,harvestTimeSeconds:10,autoStart:!0},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:d.oD,inactiveMs:d.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10,autoStart:!0},metrics:{enabled:!0,autoStart:!0},page_action:{enabled:!0,harvestTimeSeconds:30,autoStart:!0},page_view_event:{enabled:!0,autoStart:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1,autoStart:!0},session_trace:{enabled:!0,harvestTimeSeconds:10,autoStart:!0},harvest:{tooManyRequestsDelay:60},session_replay:{autoStart:!0,enabled:!1,harvestTimeSeconds:60,sampling_rate:50,error_sampling_rate:50,mask_all_inputs:!0,get mask_text_selector(){return e.mask_selector},set mask_text_selector(t){u(t)?e.mask_selector=t+",[data-nr-mask]":null===t?e.mask_selector=t:(0,l.Z)("An invalid session_replay.mask_selector was provided and will not be used",t)},get block_class(){return"nr-block"},get ignore_class(){return"nr-ignore"},get mask_text_class(){return"nr-mask"},get block_selector(){return e.block_selector},set block_selector(t){u(t)?e.block_selector+=",".concat(t):""!==t&&(0,l.Z)("An invalid session_replay.block_selector was provided and will not be used",t)},get mask_input_options(){return e.mask_input_options},set mask_input_options(t){t&&"object"==typeof t?e.mask_input_options={...t,password:!0}:(0,l.Z)("An invalid session_replay.mask_input_option was provided and will not be used",t)}},spa:{enabled:!0,harvestTimeSeconds:10,autoStart:!0}}},h={},p="All configuration objects require an agent identifier!";function g(e){if(!e)throw new Error(p);if(!h[e])throw new Error("Configuration for ".concat(e," was never set"));return h[e]}function m(e,t){if(!e)throw new Error(p);h[e]=(0,i.D)(t,f()),(0,n.Qy)(e,h[e],"config")}function v(e,t){if(!e)throw new Error(p);var r=g(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.242.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>s,IF:()=>d,Nk:()=>f,Tt:()=>c,_A:()=>o,cv:()=>h,iS:()=>a,il:()=>n,ux:()=>u,v6:()=>i,w1:()=>l});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=Boolean("hidden"===o?.document?.visibilityState),s=""+o?.location,c=/iPad|iPhone|iPod/.test(o.navigator?.userAgent),u=c&&"undefined"==typeof SharedWorker,d=(()=>{const e=o.navigator?.userAgent?.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),l=Boolean(n&&window.document.documentMode),f=!!o.navigator?.sendBeacon,h=Math.floor(o?.performance?.timeOrigin||o?.performance?.timing?.navigationStart||Date.now())},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(8325),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((t=>{let[r]=t;s[e].delete(r),a(r)})))}function l(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},8325:(e,t,r)=>{r.d(t,{A:()=>c,ee:()=>u});var n=r(8632),i=r(2210),o=r(234);class a{constructor(e){this.contextId=e}}var s=r(3117);const c="nr@context:".concat(s.a),u=function e(t,r){var n={},s={},d={},f=!1;try{f=16===r.length&&(0,o.OP)(r).isolatedBacklog}catch(e){}var h={on:g,addEventListener:g,removeEventListener:function(e,t){var r=n[e];if(!r)return;for(var i=0;i<r.length;i++)r[i]===t&&r.splice(i,1)},emit:function(e,r,n,i,o){!1!==o&&(o=!0);if(u.aborted&&!i)return;t&&o&&t.emit(e,r,n);for(var a=p(n),c=m(e),d=c.length,l=0;l {let[n,i]=e;s[i]=t,t in r||(r[t]=[])}))},abort:l,aborted:!1,isBuffering:function(e){return!!b()[s[e]]},debugId:r,backlog:f?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return h;function p(e){return e&&e instanceof a?e:e?(0,i.X)(e,c,(()=>new a(c))):new a(c)}function g(e,t){n[e]=m(e).concat(t)}function m(e){return n[e]||[]}function v(t){return d[t]=d[t]||e(h,t)}function b(){return h.backlog}}(void 0,"globalEE"),d=(0,n.fP)();function l(){u.aborted=!0,u.backlog={}}d.ee||(d.ee=u)},5546:(e,t,r)=>{r.d(t,{E:()=>n,p:()=>i});var n=r(8325).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},3117:(e,t,r)=>{r.d(t,{a:()=>n});const n=(0,r(4402).Rl)()},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(8325),i=r(5546),o=r(3325);const a={stn:[o.D.sessionTrace],err:[o.D.jserrors,o.D.metrics],ins:[o.D.pageAction],spa:[o.D.spa],sr:[o.D.sessionReplay,o.D.sessionTrace]},s=new Set;function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(s.has(t)||Object.entries(e).forEach((e=>{let[t,n]=e;a[t]?a[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n)})),Object.keys(a).forEach((e=>{void 0===u[e]&&(a[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),s.add(t))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(8325);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"===document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>b,u5:()=>S,QU:()=>C,_L:()=>I,Gm:()=>H,Lg:()=>L,BV:()=>G,Kf:()=>K});var n=r(8325),i=r(3117);const o="nr@original:".concat(i.a);var a=Object.prototype.hasOwnProperty,s=!1;function c(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");const a="-"===n.charAt(0);for(let s=0;s 2?n-2:0),o=2;o {r(E[T],e,A),r(_[T],e,A)})),r(f._A,"fetch",w),t.on(w+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(w+"done",[null,r],n)}else t.emit(w+"done",[e],n)})),t}const j={},N=["pushState","replaceState"];function C(e){const t=function(e){return(e||n.ee).get("history")}(e);return!f.il||j[t.debugId]++||(j[t.debugId]=1,c(t).inPlace(window.history,N,"-")),t}var O=r(3239);const P={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!f.il||P[t.debugId])return t;P[t.debugId]=!0;var r=c(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function s(e,t){if(!e)return t;const r=e.match(a),n=r[1];return s(r[3],t[n])}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,c=a.match(i),c?c[1]:null);var a,c;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:s(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function l(){t.emit("jsonp-end",[],d),e.removeEventListener("load",l,(0,O.m$)(!1)),e.removeEventListener("error",f,(0,O.m$)(!1))}function f(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",l,(0,O.m$)(!1)),e.removeEventListener("error",f,(0,O.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",l,(0,O.m$)(!1)),e.addEventListener("error",f,(0,O.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}const k={};function H(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!f.il||k[t.debugId])return t;k[t.debugId]=!0;var r=c(t),i=f._A.MutationObserver;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function L(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=t.context,i=c(t),a=f._A.Promise;return a&&function(){function e(r){var n=t.context(),o=i(r,"executor-",n,null,!1);const s=Reflect.construct(a,[o],e);return t.context(s).getCtx=function(){return n},s}f._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,o=r(e);o.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c 3&&!a.resolved&&(a.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,l,"fn-",A)}),(0,O.m$)(!1))}catch(e){(0,W.Z)("An error occurred while intercepting XHR",e);try{r.emit("internal-error",[e])}catch(e){}}var a;return t};function g(e,t){i.inPlace(t,["onreadystatechange"],"fn-",A)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,Q,"-xhr-",A),r.on("send-xhr-start",(function(e,t){g(e,t),function(e){h.push(e),a&&(m?m.then(w):u?u(w):(v=-v,y.data=v))}(t)})),r.on("open-xhr-start",g),a){var m=s&&s.resolve();if(!u&&!s){var v=1,y=document.createTextNode(v);new a(w).observe(y,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||w()}));function w(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.jserrors},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewEvent},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},7144:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.sessionReplay},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>x,CB_END:()=>E,CB_START:()=>u,END:()=>A,FEATURE_NAME:()=>i,FETCH:()=>T,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>g,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>f,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>p,JS_TIME:()=>_,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>l,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(234);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",l="remaining",f="interaction",h="spaNode",p="jsonpNode",g="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",A="-end",x="-body",E="cb"+A,_="jsTime",T="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(234),i=r(8325);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},7530:(e,t,r)=>{r.d(t,{j:()=>b});var n=r(3325),i=r(234),o=r(5546),a=r(8325),s=r(7894),c=r(8e3),u=r(3960),d=r(385),l=r(50),f=r(3081),h=r(8632);function p(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId","setApplicationVersion","start"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var g=r(2587);const m=e=>{r.p=e};let v=!1;function b(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},b=arguments.length>2?arguments[2]:void 0,y=arguments.length>3?arguments[3]:void 0,{init:w,info:A,loader_config:x,runtime:E={loaderType:b},exposed:_=!0}=t;const T=(0,h.gG)();A||(w=T.init,A=T.info,x=T.loader_config),(0,i.Dg)(e,w||{}),(0,i.GE)(e,x||{}),A.jsAttributes??={},d.v6&&(A.jsAttributes.isWorker=!0),(0,i.CX)(e,A);const D=(0,i.P_)(e),S=[A.beacon,A.errorBeacon];v||(v=!0,D.proxy.assets&&(m(D.proxy.assets+"/"),S.push(D.proxy.assets)),D.proxy.beacon&&S.push(D.proxy.beacon)),E.denyList=[...D.ajax.deny_list||[],...D.ajax.block_internal?S:[]],(0,i.sU)(e,E),p();const j=function(e,t){t||(0,c.R)(e,"api");const h={};var p=a.ee.get(e),g=p.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),A(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>{h[e]=A(m,e,!0,"api")})),h.addPageAction=A(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=A(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,A(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,l.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,l.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,l.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.setApplicationVersion=function(e){if("string"==typeof e||null===e)return b("application.version",e,"setApplicationVersion",!1);(0,l.Z)("Failed to execute setApplicationVersion. Expected , but got ."))},h.start=e=>{try{const t=e?"defined":"undefined";(0,o.p)(f.xS,["API/start/".concat(t,"/called")],void 0,n.D.metrics,p);const r=Object.values(n.D);if(void 0===e)e=r;else{if((e=Array.isArray(e)&&e.length?e:[e]).some((e=>!r.includes(e))))return(0,l.Z)("Invalid feature name supplied. Acceptable feature names are: ".concat(r));e.includes(n.D.pageViewEvent)||e.push(n.D.pageViewEvent)}e.forEach((e=>{p.emit("".concat(e,"-opt-in"))}))}catch(e){(0,l.Z)("An unexpected issue occurred",e)}},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,p),function(){if(g.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw g.emit("fn-err",[arguments,this,e],r),e}finally{g.emit("fn-end",[(0,s.z)()],r)}}}};function A(e,t,r,i){return function(){return(0,o.p)(f.xS,["API/"+t+"/called"],void 0,n.D.metrics,p),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,p),r?void 0:this}}function x(){r.e(111).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,l.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=A(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(f.xS,["API/noticeError/called"],void 0,n.D.metrics,p),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,p)},d.il?(0,u.b)((()=>x()),!0):x(),h}(e,y);return(0,h.Qy)(e,j,"api"),(0,h.Qy)(e,_,"exposed"),(0,h.EZ)("activatedFeatures",g.T),j}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>({111:"nr-spa",164:"nr-spa-compressor",433:"nr-spa-recorder"}[e]+"-1.242.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA-1.242.0.PROD:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(f.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=f.bind(null,s.onerror),s.onload=f.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.p="https://js-agent.newrelic.com/",(()=>{var e={801:0,92:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {var e=i(50);class t{addPageAction(t,r){(0,e.Z)("Call to agent api addPageAction failed. The session trace feature is not currently initialized.")}setPageViewName(t,r){(0,e.Z)("Call to agent api setPageViewName failed. The page view feature is not currently initialized.")}setCustomAttribute(t,r,n){(0,e.Z)("Call to agent api setCustomAttribute failed. The js errors feature is not currently initialized.")}noticeError(t,r){(0,e.Z)("Call to agent api noticeError failed. The js errors feature is not currently initialized.")}setUserId(t){(0,e.Z)("Call to agent api setUserId failed. The js errors feature is not currently initialized.")}setApplicationVersion(t){(0,e.Z)("Call to agent api setApplicationVersion failed. The agent is not currently initialized.")}setErrorHandler(t){(0,e.Z)("Call to agent api setErrorHandler failed. The js errors feature is not currently initialized.")}finished(t){(0,e.Z)("Call to agent api finished failed. The page action feature is not currently initialized.")}addRelease(t,r){(0,e.Z)("Call to agent api addRelease failed. The agent is not currently initialized.")}start(t){(0,e.Z)("Call to agent api addRelease failed. The agent is not currently initialized.")}}var r=i(3325),n=i(234);const o=Object.values(r.D);function a(e){const t={};return o.forEach((r=>{t[r]=function(e,t){return!1!==(0,n.Mt)(t,"".concat(e,".enabled"))}(r,e)})),t}var s=i(7530);var c=i(8e3),u=i(5938),d=i(3960),l=i(385);class f extends u.W{constructor(e,t,r){let i=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=i,this.abortHandler=void 0,this.featAggregate=void 0,this.onAggregateImported=void 0,!1===(0,n.Mt)(this.agentIdentifier,"".concat(this.featureName,".autoStart"))&&(this.auto=!1),this.auto&&(0,c.R)(e,r)}importAggregator(){let t=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate)return;if(!this.auto)return void this.ee.on("".concat(this.featureName,"-opt-in"),(()=>{(0,c.R)(this.agentIdentifier,this.featureName),this.auto=!0,this.importAggregator()}));const r=l.il&&!0===(0,n.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let o;this.onAggregateImported=new Promise((e=>{o=e}));const a=async()=>{let n;try{if(r){const{setupAgentSession:e}=await i.e(111).then(i.bind(i,3228));n=e(this.agentIdentifier)}}catch(t){(0,e.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",t)}try{if(!this.shouldImportAgg(this.featureName,n))return(0,c.L)(this.agentIdentifier,this.featureName),void o(!1);const{lazyFeatureLoader:e}=await i.e(111).then(i.bind(i,8582)),{Aggregate:r}=await e(this.featureName,"aggregate");this.featAggregate=new r(this.agentIdentifier,this.aggregator,t),o(!0)}catch(t){(0,e.Z)("Downloading and initializing ".concat(this.featureName," failed..."),t),this.abortHandler?.(),(0,c.L)(this.agentIdentifier,this.featureName),o(!1)}};l.il?(0,d.b)((()=>a()),!0):a()}shouldImportAgg(e,t){return e!==r.D.sessionReplay||!!n.Yu.MO&&(!1!==(0,n.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!t?.isNew||!!t?.state.sessionReplay))}}var h=i(7633);class p extends f{static featureName=h.t;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,h.t,r),this.importAggregator()}}var g=i(1117),m=i(1284);class v extends g.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,m.D)(e,(function(e,r){t[e]=b(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,m.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=b(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=y(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=b(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,t,N.t,r),l.il&&((0,D.N)((()=>(0,T.p)("docHidden",[(0,j.z)()],void 0,N.t,this.ee)),!0),(0,S.bP)("pagehide",(()=>(0,T.p)("winPagehide",[(0,j.z)()],void 0,N.t,this.ee))),this.importAggregator())}}var O=i(3081);class P extends f{static featureName=O.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,O.t9,r),this.importAggregator()}}var R=i(6660);class I{constructor(e,t,r,n){this.name="UncaughtError",this.message=e,this.sourceURL=t,this.line=r,this.column=n}}class k extends f{static featureName=R.t;#e=new Set;constructor(e,t){let n=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,R.t,n);try{this.removeOnAbort=new AbortController}catch(e){}this.ee.on("fn-err",((e,t,n)=>{this.abortHandler&&!this.#e.has(n)&&(this.#e.add(n),(0,T.p)("err",[this.#t(n),(0,j.z)()],void 0,r.D.jserrors,this.ee))})),this.ee.on("internal-error",(e=>{this.abortHandler&&(0,T.p)("ierr",[this.#t(e),(0,j.z)(),!0],void 0,r.D.jserrors,this.ee)})),l._A.addEventListener("unhandledrejection",(e=>{this.abortHandler&&(0,T.p)("err",[this.#r(e),(0,j.z)(),!1,{unhandledPromiseRejection:1}],void 0,r.D.jserrors,this.ee)}),(0,S.m$)(!1,this.removeOnAbort?.signal)),l._A.addEventListener("error",(e=>{this.abortHandler&&(this.#e.has(e.error)?this.#e.delete(e.error):(0,T.p)("err",[this.#n(e),(0,j.z)()],void 0,r.D.jserrors,this.ee))}),(0,S.m$)(!1,this.removeOnAbort?.signal)),this.abortHandler=this.#i,this.importAggregator()}#i(){this.removeOnAbort?.abort(),this.#e.clear(),this.abortHandler=void 0}#t(e){return e instanceof Error?e:void 0!==e?.message?new I(e.message,e.filename||e.sourceURL,e.lineno||e.line,e.colno||e.col):new I("string"==typeof e?e:(0,_.P)(e))}#r(e){let t="Unhandled Promise Rejection: ";if(e?.reason instanceof Error)try{return e.reason.message=t+e.reason.message,e.reason}catch(t){return e.reason}if(void 0===e.reason)return new I(t);const r=this.#t(e.reason);return r.message=t+r.message,r}#n(e){return e.error instanceof Error?e.error:new I(e.message,e.filename,e.lineno,e.colno)}}var H=i(2210);let z=1;const L="nr@id";function M(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===l._A?0:(0,H.X)(e,L,(function(){return z++}))}function B(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,_.P)(e).length}catch(e){return}}}var F=i(1214),U=i(7243);class Z{constructor(e){this.agentIdentifier=e}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var t=(0,n.DL)(this.agentIdentifier);if(!t)return null;var r=(t.accountID||"").toString()||null,i=(t.agentID||"").toString()||null,o=(t.trustKey||"").toString()||null;if(!r||!i)return null;var a=(0,E.M)(),s=(0,E.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,r,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,r,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof l._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,_.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var t=!1,r={};if((0,n.Mt)(this.agentIdentifier,"distributed_tracing")&&(r=(0,n.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)t=!0;else if(r.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];if(super(e,t,V.t,i),(0,n.OP)(e).xhrWrappable){this.dt=new Z(e),this.handler=(e,t,r,n)=>(0,T.p)(e,t,r,n,this.ee);try{const e={xmlhttprequest:"xhr",fetch:"fetch",beacon:"beacon"};l._A?.performance?.getEntriesByType("resource").forEach((t=>{if(t.initiatorType in e&&0!==t.responseStatus){const n={status:t.responseStatus},i={rxSize:t.transferSize,duration:Math.floor(t.duration),cbTime:0};K(n,t.name),this.handler("xhr",[n,i,t.startTime,t.responseEnd,e[t.initiatorType]],void 0,r.D.ajax)}}))}catch(e){}(0,F.u5)(this.ee),(0,F.Kf)(this.ee),function(e,t,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=x,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){E(t,e)}),(0,S.m$)(!1)),l.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,S.m$)(!1))}function s(e){this.params={method:e[0]},K(this,e[1]),this.metrics={}}function c(t,r){var i=(0,n.DL)(e);i.xpid&&this.sameOrigin&&r.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(r.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(r.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&r.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function u(e,r){var n=this.metrics,i=e[0],o=this;if(n&&i){var a=B(i);a&&(n.txSize=a)}this.startTime=(0,j.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof r.onload)&&"function"==typeof o.end)&&o.end(r)}catch(e){try{t.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}}function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function w(e,t){this.params={},this.metrics={},this.startTime=(0,j.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof W?r=i.url:l._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),K(this,r);var o=(""+(i&&i instanceof W&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=B(n.body)||0}function A(e,t){var n;this.endTime=(0,j.z)(),this.params||(this.params={}),this.params.status=t?t.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,j.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,r.D.ajax)}function x(e){var t=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,se.t,r),this.importAggregator()}}var ue=i(7836);const{FEATURE_NAME:de,START:le,END:fe,BODY:he,CB_END:pe,JS_TIME:ge,FETCH:me,FN_START:ve,CB_START:be,FN_END:ye}=ue;var we=i(4649);class Ae extends f{static featureName=we.t;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class extends t{constructor(t){let r=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,E.ky)(16);super(),l._A?(this.agentIdentifier=r,this.sharedAggregator=new v({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(t.features||[]),this.desiredFeatures.add(p),Object.assign(this,(0,s.j)(this.agentIdentifier,t,t.loaderType||"agent")),this.run()):(0,e.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,n.C5)(this.agentIdentifier),init:(0,n.P_)(this.agentIdentifier),loader_config:(0,n.DL)(this.agentIdentifier),runtime:(0,n.OP)(this.agentIdentifier)}}run(){const t="features";try{const n=a(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((e,t)=>r.p[e.featureName]-r.p[t.featureName])),i.forEach((t=>{if(n[t.featureName]||t.featureName===r.D.pageViewEvent){const i=function(e){switch(e){case r.D.ajax:return[r.D.jserrors];case r.D.sessionTrace:return[r.D.ajax,r.D.pageViewEvent];case r.D.sessionReplay:return[r.D.sessionTrace];case r.D.pageViewTiming:return[r.D.pageViewEvent];default:return[]}}(t.featureName);i.every((e=>n[e]))||(0,e.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,_.P)(i),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,x.Qy)(this.agentIdentifier,this.features,t)}catch(r){(0,e.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",r);for(const e in this.features)this.features[e].abortHandler?.();const n=(0,x.fP)();return delete n.initializedAgents[this.agentIdentifier]?.api,delete n.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,n.ee?.abort(),delete n.ee?.get(this.agentIdentifier),!1}}addToTrace(t){(0,e.Z)("Call to agent api addToTrace failed. The page action feature is not currently initialized.")}setCurrentRouteName(t){(0,e.Z)("Call to agent api setCurrentRouteName failed. The spa feature is not currently initialized.")}interaction(){(0,e.Z)("Call to agent api interaction failed. The spa feature is not currently initialized.")}}({features:[Q,p,C,class extends f{static featureName=ne;constructor(e,t){if(super(e,t,ne,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!l.il)return;const n=this.ee;let i;(0,F.QU)(n),this.eventsEE=(0,F.em)(n),this.eventsEE.on(oe,(function(e,t){this.bstStart=(0,j.z)()})),this.eventsEE.on(ie,(function(e,t){(0,T.p)("bst",[e[0],t,this.bstStart,(0,j.z)()],void 0,r.D.sessionTrace,n)})),n.on(ae+te,(function(e){this.time=(0,j.z)(),this.startPath=location.pathname+location.hash})),n.on(ae+re,(function(e){(0,T.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,r.D.sessionTrace,n)}));try{i=new PerformanceObserver((e=>{const t=e.getEntries();(0,T.p)(J,[t],void 0,r.D.sessionTrace,n)})),i.observe({type:ee,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},ce,P,Ae,k,class extends f{static featureName=de;constructor(e,t){if(super(e,t,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!l.il)return;if(!(0,n.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let r,i=0;const o=this.ee.get("tracer"),a=(0,F._L)(this.ee),s=(0,F.Lg)(this.ee),c=(0,F.BV)(this.ee),u=(0,F.Kf)(this.ee),d=this.ee.get("events"),f=(0,F.u5)(this.ee),h=(0,F.QU)(this.ee),p=(0,F.Gm)(this.ee);function g(e,t){h.emit("newURL",[""+window.location,t])}function m(){i++,r=window.location.hash,this[ve]=(0,j.z)()}function v(){i--,window.location.hash!==r&&g(0,!0);var e=(0,j.z)();this[ge]=~~this[ge]+e-this[ve],this[ye]=e}function b(e,t){e.on(t,(function(){this[t]=(0,j.z)()}))}this.ee.on(ve,m),s.on(be,m),a.on(be,m),this.ee.on(ye,v),s.on(pe,v),a.on(pe,v),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),d.buffer([ve],this.featureName),c.buffer(["setTimeout"+fe,"clearTimeout"+le,ve],this.featureName),u.buffer([ve,"new-xhr","send-xhr"+le],this.featureName),f.buffer([me+le,me+"-done",me+he+le,me+he+fe],this.featureName),h.buffer(["newURL"],this.featureName),p.buffer([ve],this.featureName),s.buffer(["propagate",be,pe,"executor-err","resolve"+le],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),b(f,me+le),b(f,me+"-done"),b(a,"new-jsonp"),b(a,"jsonp-end"),b(a,"cb-start"),h.on("pushState-end",g),h.on("replaceState-end",g),window.addEventListener("hashchange",g,(0,S.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",g,(0,S.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){g(0,i>1)}),(0,S.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#i,this.importAggregator()}#i(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})()})();

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

Ask this paper AI returns verbatim quotes from the full text · source: preprint-html

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Citation neighborhood (no data yet)

We don't have any in-corpus citations linked to this paper yet. This is a recent paper (2024) — citers typically take a year or two to land, and the OpenAlex reference graph may still be filling in.

Source provenance

europepmc
last seen: 2026-05-20T01:45:00.602351+00:00