Scientific publications of the Saarland University
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Overcoming limitations in exhaled breath aerosol analysis - Untargeted breathomics for the identification of endogenous breath biomarkers using LC-HRMS/MS
Full text linkBackground
Human exhaled breath (EB) aerosol is a suitable matrix for the non-invasive bioanalysis of both volatile but also non-volatile compounds. One of the key challenges in drug monitoring studies is the lack of standardization in EB sample collection. The aim of the present study was to use untargeted breathomics for identification of potential endogenous biomarkers in EB that could address these challenges.
Results
The Breath Explor impaction device was used to collect microparticles in EB aerosol from six healthy volunteers and six different sampling time points over a 1-h period (total number of samples = 36). Sample preparation consisted of an extraction with methanol and analysis was performed using reversed-phase and hydrophilic interaction-phase liquid chromatography coupled to high-resolution mass spectrometry. Results revealed the presence of a feature that could be reliably detected across all samples, thus representing a potential biomarker for standardizing EB aerosol sample collection. Although an annotation of this feature was not possible, it showed robustness and reproducibility in EB samples from healthy volunteers and could also be successfully detected in patient samples.
Significance and novelty
This study represents a step forward in overcoming the current limitation of EB analysis, the lack of standardization in sampling procedure. Nevertheless, further investigation including correlation studies and more diverse populations will be essential for the confirmation of the clinical relevance and application of this biomarker
Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses
Full text linkAims
Several systematic reviews/meta-analyses of observational studies have demonstrated associations between circulating trimethylamine-N-oxide (TMAO) and cardiovascular, cerebral, and renal diseases, including mortality. However, causal roles for TMAO in these diseases are controversial. Interventions are lacking to show whether lowering TMAO in clinical trials could reduce the risks of these diseases. TMAO could still serve as a prognostic marker for the mentioned outcomes, but investigating this potential role requires robust methodologies. We conducted a systematic search and critical evaluation of published systematic reviews/meta-analyses in the field.
Data synthesis
We identified 27 systematic reviews/meta-analyses on the association between TMAO and stroke (n = 7), cardiovascular disease including cause-specific and/or all-cause mortality (n = 14), and other related outcomes (n = 6). The majority of the systematic reviews/meta-analyses found higher blood TMAO concentrations in patients who were positive for the outcomes. Primary studies included populations with multiple risk factors for the given outcomes and did not sufficiently account for potential confounders. Prospective studies examining associations between baseline TMAO and subsequent disease outcomes in healthy populations were entirely absent. Furthermore, we identified serious flaws in methods, conduct and reporting in the majority of the published systematic reviews/meta-analyses, thus leading to critically low confidence in the results.
Conclusions
High quality systematic reviews/meta-analyses examining the associations between TMAO and cardiovascular or cerebral disease are needed to examine potential causal and/or predictive roles of TMAO in these diseases. This study is registered at the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024534940)
Gene expression study in the siRNA based aniridia cell model and in primary aniridia limbal epithelial cells following duloxetine and ritanserin treatment
Full text linkProgressive aniridia associated keratopathy is worsening visual acuity of congenital aniridia subjects lifelong. Restoration of PAX6 expression in PAX6 haploinsufficient limbal epithelial cells could be one therapeutic option. In a previous study using aniridia-like CRISPR/Cas9 genome-edited corneal epithelial cells, the antipsychotic drugs duloxetine and ritanserin increased PAX6 mRNA and protein expression. Our purpose was to investigate the effect of duloxetine and ritanserin on cultured primary limbal epithelial cells (pLECs) without and with PAX6 knockdown. pLECs were isolated from 11 aniridia patients and corneoscleral rims of 8 healthy human donors and were treated with 5 µM duloxetine or ritanserin for 24 hours. In addition, pLECs were transfected with small interfering RNA (siRNA) (PAX6 knockdown) in the siRNA-based aniridia cell model and were also treated by 5 µM duloxetine or ritanserin for 24 hours. Gene and protein expression were analyzed using qPCR and Western blot. In both primary aniridia limbal epithelial cells and the siRNA-based aniridia cell model, the expression of PAX6 at the transcriptional or translational level did not show significant changes through duloxetine or ritanserin treatment (p > 0.5). The target genes of PAX6 such as KRT3, KRT12, DSG1, ALDH1A1, ADH7, FABP5, ABCG2 also did not change significantly (p ≥ 0.2). Our study shows that primary cultures of limbal epithelial cells from both aniridia patients and healthy donors were unresponsive to drug treatment. Therefore, our data suggest that different aniridia cell models or cell culture conditions exhibit varying responses to duloxetine and ritanserin. The use of in vivo models could further enhance our understanding of duloxetine and ritanserin treatment in aniridia-associated keratopathy
Retrospektive Analyse von 295 Zystektomien am Städtischen Krankenhaus Kiel zwischen 2010 und 2023
Full text linkDie radikale Zystektomie stellt eine der Standardtherapien des muskelinvasiven bzw. rezidivierenden high-grade Harnblasenkarzinoms dar. In der vorliegenden Arbeit wurden klinische Daten von 295 Patienten ausgewertet, die über einen Zeitraum von 14 Jahren zwischen 2010 und 2023 wegen eines Harnblasenkarzinoms in der Urologischen Klinik des Städtischen Krankenhaus in Kiel mit einer radikalen Zystektomie behandelt wurden. Die klinischen Daten wurden aus dem Krankenhausinformationssystem des Städtischen Krankenhauses Kiel sowie aus den histologisch-pathologischen Befunden des Pathologischen Institutes des SK Kiel und den Patientenakten der Urologischen Gemeinschaftspraxis „Urodock“ Prüner Gang in Kiel entnommen. Das durchschnittliche OP-Volumen lag bei etwas über 20 Zystektomien pro Jahr.
Das Studienziel war, klinische Parameter aus einem großen unizentrischen Kollektiv von 295 Patienten, die mit einer radikalen Zystektomie behandelt wurden, zu beschreiben und auszuwerten. Es wurden u.a. Geschlecht, Alter bei Zystektomie, Body-Mass-Index, ASA-Score, präoperative Hämoglobin- und Kreatininwerte, TNM-Stadium, postoperative stationäre Tage, Harnableitung, Schnitt-Naht-Zeit, Therapie mit Erythrozyten-Konzentraten, und perioperative Chemotherapien analysiert und ausgewertet. Außerdem wurde die postoperative Überlebenszeit des Kollektivs hinsichtlich des Gesamtüberlebens, tumorspezifischen Überlebens und progressionsfreien Überlebens beschrieben. Die Daten wurden mit großen Studienkollektiven aus der Literatur verglichen.
Das mediane Alter der Patienten betrug 73 Jahre (35-90). Von den 295 behandelten Patienten waren 72 (24%) weiblich, und 223 (76%) männlich. Die Überlebenszeit-wahrscheinlichkeit lag für das 5- und 10-Jahres Gesamtüberleben bei 57% und 44%; für das tumorspezifische Überleben bei 71% und 62%; und für das progressionsfreie Überleben bei 51% und 41%. Die 30- und 90-Tage-Mortalität betrug 2,0% bzw. 5,4%. In der multivariaten Analyse (Cox-Regression) konnten für die Überlebenszeitendpunkte unabhängige Variablen wie ASA-Score, UICC-Stadium, Anzahl der entnommenen Lymphknoten und präoperativer Hb-Wert identifiziert werden.
Die erhobenen Daten sind vergleichbar mit denen historischer Kollektive aus der Literatur. Sie liefern zusätzlich einen Beitrag zur Diskussion um Mindestmengen und Behandlungsqualität der Zystektomie- und Harnableitungsoperation in Deutschland.Radical cystectomy is considered the gold-standard treatment for muscle-invasive or
recurrent high-grade bladder cancer. In this study, clinical data from 295 patients who
underwent radical cystectomy for bladder cancer over a 14-year period from 2010 to 2023 at
the Urology Department of Städtisches Krankenhaus Kiel were analyzed. The clinical data
were obtained from the hospital information system and archives of the Städtisches
Krankenhaus Kiel, the histopathological reports from the Pathology Institute of Städtisches
Krankenhaus Kiel and medical records of the Urology practice Prüner Gang in Kiel. The
average surgical volume was slightly above 20 cystectomies per year.
The aim of the study was to describe and analyze clinical parameters from an unicentric
cohort of 295 patients treated with radical cystectomy. Among the analyzed parameters were
gender, age at the time of cystectomy, body mass index, ASA-score, preoperative
hemoglobin and creatinine levels, TNM stage, postoperative hospital stay, urinary diversion,
incision-suture time, blood transfusion and perioperative chemotherapy. In addition,
postoperative survival time was described in terms of overall survival, cancer-specific
survival and progression-free survival. The data was compared with large study cohorts from
the literature.
The median age of patients was 73 years (35-90). Of the 295 patients, 72 (24%) were
female, and 223 (76%) were male. Overall survival rates at 5 and 10 years were 57% and
44%, cancer-specific survival was 71% and 62%; and progression-free survival was 51% and
41%, respectively. The 30-day and 90-day mortality rates were 2,0% and 5,4%, respectively.
In the multivariate analysis (Cox-regression), independent variables such as ASA-score,
UICC-stage, number of lymph nodes removed, and preoperative hemoglobin level were
identified as prognostic factors for survival outcomes.
The analyzed data are comparable to historical cohorts reported in the literature.
Furthermore, they contribute to the discussion on minimum case volume requirements and
treatment quality for cystectomy and urinary diversion procedures in Germany
Analyzing and overcoming low-resource and domain specific problems in the air-traffic control speech processing pipeline
Full text linkRoughly a decade ago, machine learning-based (ML) assistance solutions for air-traffic control (ATC) became a research focus. Since then, many publications aim to reduce the workload of air-traffic controllers (ATCOs). Especially works targeting automatic speech recognition (ASR) and natural language processing have shown drastic improvement in recent years. However, most of the research is focused on the improvement on ATC benchmark datasets and not on key requirements for real-world ML ATC systems such as robustness, explainability and privacy. Addressing these mitigates the risks of incidents and ensures that models are aligned with data protection laws. This thesis therefore focuses on addressing these requirements within an ATC speech processing pipeline. Starting at the beginning of the pipeline, we investigate the influence of acoustic and lexical differences between ATC datasets on ATC-ASR models. Going further in the pipeline, we compare the robustness of combined ASR and speaker role detection architectures. At the end of the pipeline, we propose robust call-sign recognition methods and show how to train a read-back error detection system that generalizes well to unseen airspaces. Finally, we demonstrate at the example of ACTO stress detection that implementing privacy measures in the pipeline does not hurt its performance. The new insights, training procedures and architectures of this thesis bring ML based ATC support systems closer to operation.Vor einem Jahrzehnt rückten maschinell lernende (ML) Assistenzlösungen für die Flugverkehrskontrolle (ATC) in den Forschungsfokus. Seitdem zielen Veröffentlichungen darauf ab, die Belastung von Fluglotsen (ATCOs) zu reduzieren. Besonders bei der automatischen Spracherkennung (ASR) und der Verarbeitung natürlicher Sprache gab es zuletzt drastische Verbesserungen. Jedoch liegt hier der Fokus auf der Verbesserung auf ATC-Benchmark-Datensätzen und nicht auf Schlüsseleigenschaften von ML-ATC-Systemen wie Robustheit, Erklärbarkeit und Datenschutz. Die Berücksichtigung dieser Aspekte vermindert Zwischenfällen und harmonisiert Modelle mit den Datenschutzgesetzen. Diese Arbeit adressiert diese Eigenschaften innerhalb einer ATC-Sprachverarbeitungspipeline. Am Anfang der Pipeline untersuchen wir den Einfluss akustischer und lexikalischer Unterschiede zwischen ATC-Datensätzen auf ATC-ASR-Modelle. Anschließend vergleichen wir die Robustheit kombinierter ASR- und Sprecherrollenerkennungsarchitekturen. Am Ende der Pipeline schlagen wir robuste Methoden zur Rufzeichenerkennung vor und zeigen, wie man ein Read-back- Fehlerdetektionssystem trainiert, das auf unbekannte Lufträume generalisiert. Schließlich demonstrieren wir am Beispiel der ACTO-Stresserkennung, dass Datenschutzmaßnahmen nicht die Leistung der Pipeline beeinträchtigen. Die neuen Erkenntnisse, Trainingsverfahren und Architekturen bringen ML-basierte ATC-Unterstützungssysteme näher an den operationellen Einsatz
[68Ga]Ga-FAPI-04 PET/CT in a patient with endometriosis: a potential game changer?
Full text linkA 43-year-old woman with a known history of endometriosis presented with dysmenorrhea, dyschezia, and hematochezia. She had previously undergone a hysterectomy, during which infiltrative endometriosis in the bowel was identified. To guide further treatment decisions, a magnet resonance imaging (MRI) was performed, confirming bowel involvement and revealing a circumscribed lesion infiltrating the sigmoid colon. Due to persistent symptoms, the patient opted for surgery. For preoperative planning, a fibroblast activation protein inhibitor (FAPI) positron emission tomography/ computed tomography with [68Ga]Ga-FAPI-04 was conducted. PET images, acquired 10 min after administration 148 MBq of [68Ga]Ga-FAPI-04, showed intense tracer uptake (Fig. A; left column: maximum intensity projection; right column: axial slices of PET/CT fusion and PET; big arrow head: endometriosis in the sigmoid colon, SUVmax 9.8) at the same location as the MRI finding (Fig. B, axial and sagittal slices of contrast enhanced T1-weighted fat saturated sequence), thus confirming the MRI result. Additionally, the PET scan revealed intense uptake in the left ovary and the ligamentum teres uteri bilaterally (Fig. A, small arrowheads; SUVmax: 11.3, 7.3 and 5.4, respectively) suggesting the presence of additional endometriotic lesions undetected by MRI. The patient underwent a second surgical procedure, which histopathologically confirmed a deep infiltrating endometriosis extragenitalis.
Endometriosis, characterized by the ectopic growth of endometrial-like tissue, is a common gynecological disease affecting approximately 10% of reproductive-age women [1]. It can cause significant symptoms, including dysmenorrhea, dyspareunia, infertility, and gastrointestinal disturbances [2]. In addition to its physical effects, endometriosis can also affect mental health [3]. Thus, endometriosis significantly impact the quality of life of patients [4]. Diagnosis is primarily symptom-based, which can be challenging due to their variety and the heterogenic phenotype of endometriosis overlapping with other diseases. A definitive diagnosis is mostly confirmed through diagnostic laparoscopy. While transvaginal ultrasound is the first-line imaging modality, MRI is often used as a second-line tool for assessing disease extent and aiding in surgical planning [5].
This case highlights the potential role of 68Ga-FAPI PET/CT in detecting endometriotic lesions. Not only did the scan confirm the known lesion, but also identified additional sites of involvement undetected by MRI. Many studies have demonstrated the biodistribution of the 68Ga-labeled FAPI tracer, often showing intense uptake in the uterus [6,7,8]. There has been a previous case report showing only faint uptake in one endometriotic lesion [9]. To the best of our knowledge, this is the first confirmed case of endometriosis demonstrated on 68Ga-FAPI PET/CT with clear and intensive uptake. Therefore, 68Ga-FAPI PET/CT could represent a promising diagnostic modality for endometriosis, alongside many malignant diseases in which it has proven effective [10,11,12,13]. Our observation is supported by a recent preclinical study that found FAP expression in the immune microenvironment of endometriosis from various locations [14].
This case may provide a rationale for future studies systematically analyzing FAP expression in endometriosis across larger patient cohorts, investigating the value of 68Ga-FAPI PET/CT. A prospective study was recently initiated and is currently underway investigating this issue (NCT06792318)
Prehospital invasive vs. non-invasive blood pressure monitoring: Impact on shock index at hospital admission in critically ill patients - a prospective intervention study
Full text linkObjectives Hypotension and shock are potential modifiable contributors to adverse outcome. Inhospital, invasive
blood pressure (IBP) monitoring is standard, while prehospital care mainly uses non-invasive blood pressure measure ment. This study tested whether prehospital IBP monitoring improves shock index (SI) at hospital admission.
Methods This prospective interventional study included patients requiring prehospital intubation, catechola mines, or fluid resuscitation. Patients were assigned to prehospital IBP or Non-IBP group – according to the direc tives of the emergency physician. Primary endpoint was the SI at hospital admission. Secondary endpoints included
catecholamines doses, fluid volume and arterial blood gas parameters (pH, lactate, base excess) at admission. Multiple
regression analysis assessed whether IBP independently influenced SI at hospital admission.
Results 392 patients were enrolled, and 19.6% (n=77) had prehospital IBP. The IBP group had a significantly lower
shock index at hospital admission (mean±SD: 0.77±0.4 with IBP vs. 0.93±0.5 with NIBP; p=0.002). Multiple regression
analysis showed that IBP was independently associated with a lower shock index. IBP patients received more cat echolamine boluses (2.1±2.5 vs. 1.2±1.8; p<0.001), had more frequent use of continuous catecholamines (35.1% vs.
21.6%; p=0.017), higher pH (7.34±0.13 vs. 7.25±0.16; p<0.001) and less negative base excess (-3,8±5.2 vs. -6.0±7.8;
p=0.004) while lactate levels were lower (3.6±3.2 vs. 4.4±4.2; p=0.047).
Conclusions Prehospital IBP monitoring significantly was associated with a decreased shock index at hospital admis sion in critically ill patients, likely due to earlier detection of hypotension and targeted hemodynamic therapy. IBP
should be considered in patients receiving catecholamines
Synergistic Effects of Polyphenols and Stannous Ions on Pellicle Modification and Erosion Protection In Situ
Full text linkBackground: Stannous ions and polyphenols are effective substances in preventive den tistry. The present study’s aim was to investigate whether a combination of these substance
groups can achieve increased efficacy. Methods: Initial biofilm formation was performed
on bovine enamel slabs, carried by 10 subjects intraorally. The subjects rinsed with tannic
acid, SnCl2, SnF2, a combination (50:50) of tannic acid and SnCl2, or a combination of
tannic acid and SnF2, with no rinsing in the negative control. Bacterial adherence, glucan
formation (8 h, 48 h oral exposition,) and calcium release kinetics were measured (pH 2;
2.3; 3). Statistics were performed with the Kruskal–Wallis test (p < 0.05), Mann–Whitney
U test (p < 0.05), and Bonferroni–Holm correction. Results: All rinsing solutions reduced
bacterial adherence by more than 50%. Initial bacterial colonization and glucan formation
was significantly reduced by SnF2 and SnCl2 as well as their combinations with tannic acid.
The most significant reductions in calcium release at pH 2; 2.3; and 3 were obtained by
SnF2 and the combination of SnF2 and tannic acid. At the acidic pH 2.0, SnF2, SnCl2, and
tannic acid and SnF2 showed significant protection compared to the control (p ≤ 0.01). TEM
micrographs indicated that rinsing with SnF2 and tannic acid leads to pronounced electron
dense, thick pellicle layers. Conclusions: SnCl2 and SnF2, as well as their combinations
with tannic acid, led to a reduction in initial bacterial colonization and glucan formation,
showing an erosion-protective effect. These findings confirm the clinical applicability
hitherto suspected by in vitro findings
Exploratory study of nanoparticle interaction with intraorally formed dental biofilms
Full text linkBackground The development of nanoparticles offers promising potential for improving biofilm management;
however, the biofilm itself acts as a diffusion barrier, limiting effective treatment. This study aimed to investigate the
adsorption and diffusion of nanoparticles in an intraorally formed biofilm.
Methods Bovine enamel specimens (n=24) were mounted on customized maxillary splints and worn intraorally
by two subjects for 24 h to allow biofilm formation. Specimens not exposed to the oral cavity served as controls
(n=12). Ex vivo, 20 nm gold nanoparticles with a low-charge polymer outer layer were applied to the biofilm for 10 to
30 min, followed by either a single wash, 20 washes with water, or 24 h of water storage. The outer surface and basal
layer of the biofilm were analysed using scanning electron microscopy, while cross-sections were examined using
transmission electron microscopy.
Results After 24 h of intraoral exposure, enamel was covered by a globular-structured pellicle with bacterial adhesion
and occasional biofilm formation, more pronounced in subject 2. Both facilitated nanoparticle adsorption, which
increased with exposure time and remained detectable after 20 washes. In subject 2, distinctly more nanoparticles
persisted after 24 h of water storage. Transmission electron microscopy confirmed outer surface retention without
penetration into deeper biofilm layers.
Conclusions The diffusion of 20 nm nanoparticles in dental biofilms appears limited, leaving open questions
regarding the optimal nanoparticle size for effective biofilm management and their toxicological implications
Diagnostic accuracy and predictive value of the QuantiFERON-TB gold plus assay for tuberculosis in immunocompromised individuals: a prospective TBnet study
Full text linkBackground
In low tuberculosis (TB)-endemic countries, tuberculosis preventive therapy (TPT) is recommended for immunocompromised individuals with a positive immunodiagnostic test. This study aimed to assess the performance of the QuantiFERON-TB Gold Plus (QFT+) assay and predictive power for future tuberculosis in immunocompromised individuals.
Methods
In this prospective observational study, immunocompromised adults ≥18 years of age including people living with HIV (PLHIV), chronic renal failure, rheumatoid arthritis, solid-organ transplantation or stem-cell transplantation, and immunocompetent adults with and without TB-disease were recruited at 21 sites in 11 European countries and tested with the QFT+ assay. Individuals without TB-disease were followed up for the development of tuberculosis. TB incidence rates (IR) were calculated, stratified by QFT+ results and acceptance of TPT. This study is registered with Clinicaltrials.gov, NCT02639936.
Findings
A total of 2663 individuals (1115 female, 1548 male) were enrolled from 03/11/2015 to 29/03/2019. Persons without tuberculosis were followed up for at least two years. Among 1758 immunocompromised individuals without active tuberculosis, 13.6% had positive QFT+ results. Sensitivity and specificity for TB-disease were 70.0% (52.1–83.3%) and 91.4% (89.6–92.9%), respectively, in immunocompromised, and 81.4% (76.6–85.3%) and 96.0% (92.5–97.9%), respectively, in immunocompetent individuals. During 2457 cumulative years of follow-up among 932 individuals with chronic renal failure, rheumatoid arthritis, solid-organ transplantation or stem-cell transplantation, including 83 persons with a positive QFT+ test without TPT, no-one developed active tuberculosis. In contrast, among 642 PLHIV without TPT, one with an indeterminate QFT+ and 3/30 individuals with a positive QFT+ developed active tuberculosis; all had detectable HIV-replication and low CD4 T-cell counts (incidence 4.1 (95% CI (1.3–12.4) per 100 person-years). No individuals receiving TPT developed active tuberculosis during 269 years of follow-up.
Interpretation
In immunocompromised individuals in low TB-endemic countries, the 2-year-risk for active tuberculosis was highest among PLHIV with detectable HIV-replication and low CD4-counts. In this study, the QFT+ assay did not strongly predict progression to active tuberculosis, which emphasises the need to incorporate additional risk factors