Integrating GIS and Genomics for AMR One Health Drug Target Discovery in Imipenem-Resistant Escherichia coli

preprint OA: closed
Full text JSON View at publisher

Abstract

Background Antimicrobial Resistance (AMR) is a major global health challenge, particularly in Africa, where antibiotic misuse worsens resistance. This study aims to identify potential drug targets in imipenem-resistant E. coli isolates from the Vet-LIRN database through a four-phase approach integrating interactive GIS analysis, genomic data analysis, subtractive genomics, and druggability assessments. Methods Phase I involved a literature review and the creation of interactive Geographical Information System (GIS) dashboards to examine resistance patterns for Ampicillin, Minocycline, and Imipenem across North America and Africa, using data from the ATLAS and Vet-LIRN databases. Phase II focused on genomic analysis of resistant and susceptible E. coli isolates to identify non-synonymous mutations linked to imipenem resistance. Phase III applied subtractive genomics to identify essential bacterial proteins unique to E. coli and absent in humans and dogs. Phase IV assessed the druggability of these proteins by matching with proteins in DrugBank, and interactions of the matched proteins with drugs in the DrugBank database. Results GIS analysis revealed significant geographical variations in resistance, with Africa showing higher resistance to Ampicillin (80%) compared to North America (55%). Genomic analysis identified 337 proteins in the imipenem-resistant E. coli isolates, with 68 considered potential drug targets. Of these, 29 proteins were homologous to DrugBank proteins that interacted with over 1,000 drugs. The cell wall/membrane protein group matched with over 80 drugs, metabolic enzymes group with 166 drugs, transport-related proteins group with more than 700 drugs, regulatory proteins with 1 drug, and DNA methylation/epigenetic proteins group with several drugs. Conclusions This study demonstrates that integrating GIS, genomics, substractive genomics, and druggability assessments enhances AMR research and provides a framework for identifying novel drug targets. The matched proteins in DrugBank interacting with over 1,000 drugs offer potential for drug repurposing, particularly against imipenem-resistant E. coli and other multidrug-resistant pathogens.
Full text 44,459 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:'9fe1dfc17a2706eb',t:'MTc3OTE4MDgzNi4wMDAwMDA='};var a=document.createElement('script');a.nonce='';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. This is a recent paper (2026) — 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