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With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The <jats:italic>DigiSep-Trial<\/jats:italic> is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis\/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (<jats:italic>n<\/jats:italic> = 205 per arm) with sepsis\/septic shock, the study examines whether the so-called DOOR-RADAR (Desirability of Outcome Ranking\/Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) intensive\/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive\/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient\u2019s quality of life is expected.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>The authors\u00b4 previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented <jats:italic>DigiSep<\/jats:italic>-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registrations<\/jats:title>\n                <jats:p>DRKS-ID <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.drks.de\/drks_web\/navigate.do?navigationId=trial.HTML&amp;TRIAL_ID=DRKS00022782\">DRKS00022782<\/jats:ext-link>. Registered on August 25, 2020<\/jats:p>\n                <jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\/ct2\/results?cond=&amp;term=NCT04571801&amp;cntry=&amp;state=&amp;city=&amp;dist=\">NCT04571801<\/jats:ext-link>. Registered October 1, 2020<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-021-05667-x","type":"journal-article","created":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T17:49:23Z","timestamp":1634579363000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Optimization of sepsis therapy based on patient-specific digital precision diagnostics using next generation sequencing (DigiSep-Trial)\u2014study protocol for a randomized, controlled, interventional, open-label, multicenter trial"],"prefix":"10.1186","volume":"22","author":[{"given":"Thorsten","family":"Brenner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabell","family":"Skarabis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Axnick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Haug","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Grumaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bruckner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Luntz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Witzke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias W.","family":"Pletz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Ruprecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Marschall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibel","family":"Altin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Greiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6771-3193","authenticated-orcid":false,"given":"Marc Moritz","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the TIFOnet Critical Care Trials Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,18]]},"reference":[{"issue":"10219","key":"5667_CR1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","volume":"395","author":"KE Rudd","year":"2020","unstructured":"Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. 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A first positive ethical vote has been given by the Ethics Committee of the Medical Faculty of the University Duisburg-Essen (Trial Code No. 20-9352-BO). Written, informed consent to participate will be obtained from all participants or their legal representatives.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"TBre received research funding from the Innovation Fund of the Federal Joint Committee (G-BA), Dietmar Hopp Stiftung, German Research Foundation (DFG), Heidelberg Foundation of Surgery, and Stiftung Universit\u00e4tsmedizin Essen. Furthermore, TBre received honoraria for lectures or advisory board participation from Biotest AG, Baxter Deutschland GmbH, Sch\u00f6chl medical education GmbH, Boehringer Ingelheim Pharma GmbH, CSL Behring GmbH, Astellas Pharma GmbH, B. Braun Melsungen AG, and MSD Sharp & Dohme GmbH. PS, JA, PH, and SG are minority shareholders and\/ or employees of Noscendo.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"714"}}