[Transcultural German translation of the reflux symptom score-12 questionnaire]. / Transkulturelle deutschsprachige Übersetzung des Fragebogens Reflux Symptom Score-12.

In addition to clinical and instrumental methods as well as medical history, questionnaires are well-established tools in the diagnosis of laryngopharyngeal reflux (LPR). Recently, the reflux symptom score (RSS) as well as the short version of it, the RSS-12, which are self-administered patient-reported outcome questionnaires, have been published as an alternative to the well-established reflux symptom index (RSI). The RSS-12 assesses severity and frequency of LPR symptoms as well as the impact on quality of life and has been shown to have high reliability and validity. However, so far, only French, English, and Portuguese versions of the RSS-12 have been published. Hence, the aim of this study was to prepare a transcultural German translation of the RSS-12 (G-RSS-12) to provide a new clinical and scientific tool for the diagnosis of LPR in German-speaking regions.

[Vocal fatigue as an indicator of complex voice disorders-a diagnostic and therapeutic challenge]. / Vocal Fatigue als Indikator für komplexe Stimmstörungen ­ eine diagnostische und therapeutische Herausforderung.

Vocal fatigue is increasingly observed among professional voice users (e.g., teachers). This pathologic state is associated with restrictions in everyday life and is considered to be an indicator of complex voice disorders. Since there are few systematic studies on the phenomenon, there is currently no uniform definition or diagnostic workup. Based on the case study of a professional speaker, possibilities for a structured vocal fatigue assessment are presented. These are discussed with regard to their laryngoscopic, instrumental acoustic ("performance fatigue") and subjective symptom-related characteristics ("perceived fatigue"). In addition, a differentiation from the vocal effort, vocal demand, and vocal demand response models according to Hunter et al. (2020) is made.

[Prolonged ulcerative laryngitis]. / Prolongierte ulzerierende Laryngitis.

BACKGROUND: Prolonged ulcerative laryngitis is a rare, benign inflammatory alteration of the larynx that persists for months. The laryngoscopic findings suggest a malignant process and can therefore be a challenge for the treating ear, nose and throat (ENT) physician. OBJECTIVES: Presentation of the current database to provide an overview of the etiology, progress and treatment for everyday clinical practice. METHODS: Three case studies from the Department of Phoniatrics and Speech Pathology of the ENT Department, University Hospital Zurich, Switzerland, are presented. Analysis and discussion of the current literature base and of case reports in the English literature. RESULTS: The etiology and predisposing factors for this disease are unclear. Previous respiratory infection with cough and dysphonia seems to be the most common cause. Biopsies should be avoided. CONCLUSIONS: The typical laryngoscopic findings show corresponding circumscribed lancet-shaped ulcerations in the middle third of the vocal fold. The course of the disease appears to be self-limiting and without permanent structural consequences. Therefore, good patient education and close laryngoscopic follow-up should be performed.

[Current possibilities and challenges in the diagnosis of laryngopharyngeal reflux]. / Aktuelle Möglichkeiten und Herausforderungen bei der Diagnostik des laryngopharyngealen Refluxes.

Laryngopharyngeal reflux (LPR) is defined as backflow of gastral or gastroduodenal content into the upper aerodigestive tract and characterized by a variety of unspecific symptoms such as chronic cough, globus sensation, or mucus hypersecretion. Due to the lack of a gold standard and the heterogeneity of studies, the diagnosis of LPR is still problematic and challenging. However, in patients with characteristic symptoms and endoscopic findings, with an increased reflux symptom index, a pathologic reflux finding score (RFS), pathologic 24 h esophageal or oropharyngeal pH monitoring, and without any other underlying condition, the diagnosis of LPR is probable. In the following review, we critically discuss the abovementioned methods as well as more recent tools such as measurements of pepsin concentrations in the saliva for diagnosis of LPR.

[The German Sydney Swallow Questionnaire : Reliability and validity in patients with oropharyngeal dysphagia]. / Der deutsche Sydney Swallow Questionnaire : Reliabilität und Validität bei Patienten mit oropharyngealer Dysphagie.

BACKGROUND: The Sydney Swallow Questionnaire (SSQ) is a self-report inventory assessing subjective symptoms of oropharyngeal dysphagia with strong content, construct, discriminant, and predictive validity and test-retest reliability in a range of patient populations. OBJECTIVE: The main aim of this work was to assess the validity and reliability of the German version of the SSQ (SSQ-G). MATERIALS AND METHODS: In a cross-validation study, 48 adult German-speaking patients (12 women, 36 men) with neurogenic (n = 16), structural (n = 16), and functional (n = 16) oropharyngeal dysphagia were assessed with the SSQ­G and the MD Anderson Dysphagia Inventory (MDADI). Cronbach's α was applied to assess the reliability. Criteria and construct validity were investigated using the Spearman correlation coefficient. RESULTS: With Cronbach's α = 0.94, the internal consistency of the SSQ­G was excellent. The SSQ­G questions 1 and 17 showed a moderately significant and highly significant correlation coefficient of -0.43 and -0.45, respectively, with MDADI question 1 (p < 0.5, p < 0.001). Between questions 8, 11, and 12 of the SSQ­G and questions 7, 13, and 10 of the MDADI, coefficients of -0.48 to -0.55 showed a moderate to strong highly significant correlation (p < 0.001). Thus, the reliability and criterion and construct validity were statistically confirmed. CONCLUSION: The German version of the SSQ (SSQ-G) allows a reliable and valid assessment of functional swallowing difficulties. In combination with questionnaires on symptom-specific quality of life, such as the MDADI, a more differentiated clinical analysis of swallowing problems is thus possible.

Immediate Lip Trill Effects on the Standard Diagnostic Measures Voice Range Profile, Jitter, Maximum Phonation Time, and Dysphonia Severity Index.

OBJECTIVES: Semi-occluded vocal tract exercises are widely applied to improve vocal performance in speakers, singers, and voice patients. This study investigates immediate lip trill effects on standard voice assessment measures including voice range profiles, jitter, maximum phonation time, and Dysphonia Severity Index in vocally healthy women. STUDY DESIGN: Experimental study. SETTING: Otolaryngology clinic within tertiary hospital. SUBJECTS AND METHODS: Twenty-five vocally healthy women between 19 and 58 years (mean 38.4) were assessed before and after 3 minutes of standardized lip trill training combined with defined voice fundamental frequency and intensity modulations. Main outcome measures were fundamental frequency (F0) during counting (F0 counting), the singing voice range profile parameters minimum, maximum and range of F0 and voice sound pressure level (voice SPL), jitter (%), maximum phonation time (MPT), and the Dysphonia Severity Index (DSI). Wilcoxon signed rank test was applied to determine significant changes after exercise. RESULTS: After exercise the singing F0 and SPL range significantly increased from 549 (SD 217) to 612 (238) Hz and 45.1 (10.1) to 47.3 (9.8) dBA, resepctively (P<0.05). Maximum voice SPL significantly increased from 90.9 (10.3) to 94 (9.7) dBA (P<0.05). Mean F0 during counting showed a highly significant increase from 198 (SD 25.6) to 209 Hz (SD 25.4, P<0.01). No significant changes were found for all other parameters. CONCLUSIONS: In vocally healthy women, lip trill training immediately facilitates increases in mean F0 during counting, and singing F0 and SPL range. Future studies should investigate, if changes to these parameters indicate immediate responsiveness to voice exercise also in voice patients, and if these findings transfer to long-term effects through prolonged training.

[Pretesting of the German Vocal Fatigue Index (VFI-D)-transcultural translation and cross validation]. / Prätestung des deutschen Vocal Fatigue Index (VFI-D) ­ transkulturelle Übersetzung und Kreuzvalidierung.

BACKGROUND: In clinical routine, vocal fatigue is a common symptom in patients with dysphonia. OBJECTIVE: The aim of this study was to conduct a transcultural translation of the Vocal Fatigue Index (VFI), a standardized subjective questionnaire. Furthermore, pretesting and prevalidation were performed in 20 subjects, with comparison to the Voice Handicap Index (VHI­9i) and the Vocal Tract Discomfort Scale (VTD). MATERIALS AND METHODS: The translation, content review, and pretest of the German Vocal Fatigue Index (VFI-D) was divided into four sections: 1. transcultural translation, 2. expert voting on comprehensibility, 3. test of comprehensibility through cognitive interviews in 15 participants, 4. pretest of the VFI­D with cross validation compared to VHI­9i and VTD in 20 subjects. This process corresponds to current standards for transcultural translation and adaptation of questionnaires. RESULTS: According to expert voting and cognitive testing, the VFI­D is correct and comprehensible (intercoder reliability κ = 0.66). The factor analysis revealed three distinguishable parts: VFI­D part 1 correlates strongly with VHI­9i and VTD, VFI­D part 2 with VTD only (rho ≈ 0.800 each), and VFI­D part 3 correlates only weakly with VHI­9i and VTD (rho ≈ 0.585). Thus, convergence and divergence validity are proven. CONCLUSION: The first German version of the VFI­D might be a base for further research on symptoms, causes, and treatment options in vocal fatigue. Particularly patients in voice-intensive professions may benefit.

Acoustic Perturbation Measures Improve with Increasing Vocal Intensity in Individuals With and Without Voice Disorders.

OBJECTIVE: In vocally healthy children and adults, speaking voice loudness differences can significantly confound acoustic perturbation measurements. This study examines the effects of voice sound pressure level (SPL) on jitter, shimmer, and harmonics-to-noise ratio (HNR) in adults with voice disorders and a control group with normal vocal status. STUDY DESIGN: This is a matched case-control study. METHODS: We assessed 58 adult female voice patients matched according to approximate age and occupation with 58 vocally healthy women. Diagnoses included vocal fold nodules (n = 39, 67.2%), polyps (n = 5, 8.6%), and muscle tension dysphonia (n = 14, 24.1%). All participants sustained the vowel /a/ at soft, comfortable, and loud phonation levels. Acoustic voice SPL, jitter, shimmer, and HNR were computed using Praat. The effects of loudness condition, voice SPL, pathology, differential diagnosis, age, and professional voice use level on acoustic perturbation measures were assessed using linear mixed models and Wilcoxon signed rank tests. RESULTS: In both patient and normative control groups, increasing voice SPL correlated significantly (P < 0.001) with decreased jitter and shimmer, and increased HNR. Voice pathology and differential diagnosis were not linked to systematically higher jitter and shimmer. HNR levels, however, were statistically higher in the patient group than in the control group at comfortable phonation levels. Professional voice use level had a significant effect (P < 0.05) on jitter, shimmer, and HNR. CONCLUSIONS: The clinical value of acoustic jitter, shimmer, and HNR may be limited if speaking voice SPL and professional voice use level effects are not controlled for. Future studies are warranted to investigate whether perturbation measures are useful clinical outcome metrics when controlling for these effects.

Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.

Discovery and optimization of 2-aryl oxazolo-pyrimidines as adenosine kinase inhibitors using liquid phase parallel synthesis.

Adenosine kinase inhibition is an attractive therapeutic approach for several conditions for example, neurodegeneration, seizures, ischemia, inflammation and pain. Several nucleosidic and non-nucleosidic inhibitors are available. Using a virtual screening approach, we have discovered that 2-aryl oxazolo-pyrimidines are adenosine kinase inhibitors. Subsequent high throughput derivatization enabled the optimization of this new inhibitor chemotype resulting in highly potent derivatives. A variety of analogues were produced by applying liquid phase parallel synthesis to vary the 7-amino residues as well as the 2-aryl moiety.

Identification of a potent analogue of Nazumamide A through iteration of combinatorial tetrapeptide libraries.

Five sets of N-acylated tetrapeptide libraries and sublibraries related to Nazumamide A have been prepared using 25 natural and unnatural amino acids. They were evaluated in antithrombin assay, in order to quantify inhibition at each step of the tetrapeptide sublibrary iteration. The studies led to the identification of 2,5-dihydroxybenzoyl-lysyl-isoleucyl-phenylalanyl-arginine as a novel inhibitor of thrombin and was found to be at least 25 times more potent than the natural tetrapeptide 2,5-dihydroxybenzoyl-arginyl-prolyl-isoleucyl-alpha-aminobutyric acid (NAZA).

Synthesis of hydantoins via N,N'-ureas derived from polymer-bound amino acids.

Starting from carboxy-linked amino acids on trityl functionalized polystyrene resin a highly efficient solid-phase synthesis of hydantoins via N,N'-ureas was elaborated. The polymer-bound hydantoins can be used as a scaffolds for further combinatorial transformations, such as alkylation. Cleavage from the resins yielded the corresponding hydantoins in good yields and purities as shown by ESI-MS and HPLC.