Impact of shipping temperature on cell viability and T cell responses to bacterial antigens

preprint OA: closed CC-BY-4.0

Abstract

Background: Interferon-γ (IFN-γ) secretion by T cells is a key correlate of immune protection against many pathogens including tuberculosis and the neglected tropical disease melioidosis. Clinical studies in tropical regions of immune responses to pathogens and vaccine monitoring studies require the collection of samples in resource-limited rural areas and subsequent shipment to central laboratories for downstream assays and long-term storage. Here, we studied the impact of two different shipping temperatures on the viability, composition and function of peripheral blood mononuclear cells (PBMC) using multi-colour flow cytometry and IFN-g enzyme-linked immunospot assay (IFN-g ELISpot), in order to provide guidance on sample shipment conditions for future clinical studies. Methods: : Paired peripheral blood mononuclear cell (PBMC) samples from recovered melioidosis patients were stored in liquid nitrogen (-196°C) and then shipped from Bangkok, Thailand to Oxford, UK at either -80°C (dry ice) or -196°C (dry shipper). After thawing, cell viability and composition were assessed by flow cytometry and antigen specific responses to Burkholderia pseudomallei (BP) were measured using IFN-g ELISpot. Results: : We observed modest lowering of viability in the majority of samples and a reduction in IFN-g responses to BP which correlated to a decrease of monocytes and natural killer cells in samples shipped at -80°C compared to -196°C. Despite being lower in magnitude antigen-specific responses remained detectable in the majority of samples. Conclusions: : Here we demonstrate that shipment of cryopreserved PBMC at -196°C has a benefit on cell viability, recovery and T cell responses to bacterial antigens, although useful information can still be obtained from samples shipped at -80°C, thus providing important guidance for sample management in future clinical trials.
Full text 44,440 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$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#i,this.importAggregator()}#i(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})()})(); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a1f8136468a2ecda',t:'MTc4NDc4MjM0Ng=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();

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. The paper's references may be in our DB but unresolved to ``paper_id`` (resolution happens at ingest when the cited DOI matches a row we already have). Run the cross-source citation reconcile pass to retry.

Source provenance

europepmc
last seen: 2026-05-19T01:45:01.086888+00:00
unpaywall
last seen: 2026-05-26T02:00:01.498150+00:00
License: CC-BY-4.0