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Background: In times of genotype guided therapy options, a total of 3.2 % of people with CF (pwCF) in the German CF Registry[1] only have one or no CFTR-variant detected after genetic analysis. Additionally, genetic data in the Registry can be documented as free text and can therefore be prone to error. In order to allow the greatest possible amount of pwCF access to modern therapies, we conducted a re-evaluation of free text entries and established a custom-whole-CFTR-locus NGS-approach for all pwCF who remained without genetic confirmation afterwards., Methods: To this end, we assembled 731 free text variants of 655 pwCF in the German CF Registry. All variants were evaluated using ClinVar, HGMD and CFTR1/2, corrected in the Registries' database and uploaded to ClinVar. PwCF whose diagnosis remained uncertain as well as additional pwCF or pwCFTR-RD that were assembled through a nationwide call for testing of unclear cases were offered genetic analysis. Samples were analysed using a target-capture based NGS-custom-design-panel covering the entire CFTR-locus., Results: Evaluation of free text variants led to the discovery of 43 variants not formerly reported in the context of CF. The Registries' dropdown list was extended by 497 variants and over 500 pwCF were provided with their most up-to-date genotype. Samples of 47 pwCF/pwCFTR-RD were sequenced via NGS with an overall success rate of 61.7 %, resulting in implementation of entire CFTR-genotyping into routine diagnostics., Conclusion: Entire CFTR-genotyping can greatly increase the genetic diagnostic rate of pwCF/pwCFTR-RD and should be considered after inconspicuous CFTR screening panels in CFTR-diagnostics., Competing Interests: Declaration of Competing Interest The following authors declare a conflict of interest in preparing this article: SN has received grants from the CTN-ECFS, DZL and a Speaker’s fee from Vertex pharmaceuticals. LN has received institutional fees from the German Center for Lung Research, Vertex Pharmaceuticals and the Mukoviszidose Institute. He participated in the Trial Steering Committee for CF STORM and is the Medical lead of the German CF-registry and the Pharmacovigilance study manager of the ECFSPR. CS has received a Speaker’s fee from Vertex, TFF Pharma, Chiesi and Viatris and is an ECFS Board Member.All other author’s declare no conflicts of interest., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objectives: Community-acquired pneumonia (CAP) is associated with a high risk of respiratory failure or septic organ dysfunction. Lactate is an established early marker of prognosis and sepsis severity, but few data exist in patients with CAP., Methods: We performed a retrospective cohort study of consecutive adult CAP patients without treatment restrictions or direct intensive care unit admission. Lactate was measured as a point-of-care test within the capillary admission blood gas analysis, and its prognostic value was compared to the CRB/CURB-65 criteria by multivariate and receiver operating characteristic (ROC) curve analysis. The primary endpoint was the combination of need for mechanical ventilation, vasopressors, intensive care unit admission or hospital mortality., Results: Of 303 included patients, 75 (25%) met the primary endpoint. After ROC analysis, lactate predicted the primary endpoint (area under the curve 0.67) with an optimal cutoff of >1.8 mmol/L. Of the 76 patients with lactate above this threshold, 35 (46%) met the primary endpoint. After multivariate analysis, the predictive value of lactate was independent of the CRB/CURB-65 scores. The addition of lactate >1.8 mmol/L to the CRB/CURB-65 scores resulted in significantly improved area under the curves (0.69 to 0.74, p 0.005 and 0.71 to 0.75, p 0.008 respectively). Fourteen (42%) of 33 and 11 (39%) of 28 patients meeting the endpoint despite presenting with 0 or 1 CRB/CURB-65 criteria had lactate >1.8 mmol/L., Conclusions: Admission lactate levels significantly improved the prognostic value of the CRB/CURB-65 scores in CAP patients. Lactate may therefore be considered a rapid, cheap and broadly available additional criterion for the assessment of risk in patients with CAP., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: How elevated temperature is generated during airway infections represents a hitherto unresolved physiological question. We hypothesized that innate immune defence mechanisms would increase luminal airway temperature during pulmonary infection., Methods: We determined the temperature in the exhaled air of cystic fibrosis (CF) patients. To further test our hypothesis, a pouch inflammatory model using neutrophil elastase-deficient mice was employed. Next, the impact of temperature changes on the dominant CF pathogen Pseudomonas aeruginosa growth was tested by plating method and RNAseq., Results: Here we show a temperature of ~38°C in neutrophil-dominated mucus plugs of chronically infected CF patients and implicate neutrophil elastase:α1-proteinase inhibitor complex formation as a relevant mechanism for the local temperature rise. Gene expression of the main pathogen in CF, P. aeruginosa, under anaerobic conditions at 38°C vs 30°C revealed increased virulence traits and characteristic cell wall changes., Conclusion: Neutrophil elastase mediates increase in airway temperature, which may contribute to P. aeruginosa selection during the course of chronic infection in CF., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Rationale: Optimal risk prediction of early clinical deterioration in community-acquired pneumonia (CAP) remains unresolved. We prospectively examined the predictive value of the new biomarkers copeptin and proadrenomedullin (MR-proADM) in comparison to clinical scores and inflammatory markers to predict early high risk prognosis in CAP., Methods: 51 consecutive hospitalised adult patients were enrolled. We measured CRB-65- and PSI-scores, the ATS/IDSA 2007 minor criteria to predict ICU-admission and the biomarkers CRP, procalcitonin, copeptin and MR-proADM on admission. Predefined outcome parameters were combined mortality or ICU-admission after 7 days and clinical instability after 72 h., Results: Copeptin was the only biomarker significantly elevated in patients with either adverse short term outcome (p = 0.003). According to ROC-curve analysis, copeptin predicted ICU admission or death within 7 days (AUC 0.81, cut-off 35 pmol/l: sensitivity 78%, specificity 79%) and persistent clinical instability after 72 h (AUC 0.74). In Kaplan-Meier-analysis patients with high copeptin showed lower ICU-free survival within 7 days (p = 0.001). The diagnostic accuracy of copeptin was superior to the CRB-65 score and comparable to the PSI-score and the ATS/IDSA minor criteria. If copeptin was included as additional minor criterion for combined 7-day mortality or ICU-admission, the diagnostic accuracy of the minor criteria was significantly improved (p = 0.045)., Conclusion: Copeptin predicts early deterioration and persistent clinical instability in hospitalised CAP and improves the predictive properties of existing clinical scores. It should be evaluated within a biomarker guided strategy for early identification of high risk CAP patients who most likely benefit from early intensified management strategies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)