Dynamic Range : the End of Loudness War

Diese Arbeit soll eine aktuelle Tendenz über den Loudness War aufzeigen sowie den Einfluss von zu lauter bzw. zu komprimierter Produktion auf die Dynamik eines Musikstückes darstellen. Dabei soll ebenfalls festgehalten werden, welchen Kriterien eine Musikproduktion gerecht werden sollte, damit sie vom Zuhörer als dynamisch klingend empfunden wird und welches Potential die Dynamic Range besitzt dem Loudness War entgegenzuwirken. Hierfür wurden die Dynamic Ranges von insgesamt 5269 Musiktiteln aus dem Zeitraum von 1982 bis 2017 bestimmt.This study contains a current tendency of the Loudness War which deals with the question in which way a louder and more compressed production impacts the dynamic of a song. The main focus of this study is to give an advice, which criteria should be fulfilled that music reaches an audience in a dynamic way and to show whether the Dynamic Range has got the potential to lead the Loudness War to an end. For this purpose, the Dynamic Ranges of 5,269 songs were determined. All these songs were released in the time period from 1982 to 2017

Ohmic heating - a novel approach for gluten-free bread baking

Gluten-free (GF) batters usually present several technological challenges that limit the performance during conventional baking and the resulting product quality. Due to the volumetric heating principle and faster heating rates, ohmic heating (OH) may be advantageous compared with conventional baking. Therefore, the potential of using ohmic heating as a novel approach for gluten-free bread baking was explored. In detail, the effect of different OH process parameters (power input, holding time) on the chemical and functional properties (specific volume, crumb firmness and relative elasticity, pore properties, color, starch gelatinization) and digestibility of breads was investigated. Results showed that GF breads could benefit from the uniform rapid heating during processing, as these breads showed superior functional properties (specific volume, 2.86-3.44 cm3/g; relative elasticity, 45.05-56.83%; porosity, 35.17-40.92%) compared with conventional oven-baked GF bread (specific volume, 2.60 cm3/g; relative elasticity, 44.23%; porosity, 37.63%). In order to maximize bread expansion and the OH performance, it was found that the OH process could be improved by applying the electrical energy in three descending power steps: first step with high power input (in this study, 2–6 kW for 15 s), followed by 1 kW for 10 s, and 0.3 kW for 1–30 min. In total, ohmic baking only needed a few minutes to obtain a fully expanded GF bread. The determination of pasting properties and starch digestibility demonstrated that these breads were comparable or even superior to GF breads baked in a conventional baking oven

Neoadjuvant chemotherapy is associated with suppression of the B cell-centered immune landscape in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at advanced stages and associated with early distant metastasis and poor survival. Besides clinical factors, the tumor microenvironment (TME) emerged as a crucial determinant of patient survival and therapy response in many tumors, including PDAC. Thus, the presence of tumor-infiltrating lymphocytes and the formation of tertiary lymphoid structures (TLS) is associated with longer survival in PDAC. Although neoadjuvant therapy (NeoTx) has improved the management of locally advanced tumors, detailed insight into its effect on various TME components is limited. While a remodeling towards a proinflammatory state was reported for PDAC-infiltrating T cells, the effect of NeoTx on B cell subsets, including plasma cells, and TLS formation is widely unclear. We thus investigated the frequency, composition, and spatial distribution of PDAC-infiltrating B cells in primary resected (PR) versus neoadjuvant-treated patients using a novel multiplex immunohistochemistry panel. The NeoTx group displayed significantly lower frequencies of pan B cells, GC B cells, plasmablasts, and plasma cells, accompanied by a reduced abundance of TLS. This finding was supported by bulk RNA-sequencing analysis of an independent fresh frozen tissue cohort, which revealed that major B cell pathways were downregulated in the NeoTx group. We further observed that plasma cells frequently formed aggregates that localized close to TLS and that TLS+ patients displayed significantly higher plasma cell frequencies compared to TLS- patients in the PR group. Additionally, high densities of CD20+ intratumoral B cells were significantly associated with longer overall survival in the PR group. While CD20+ B cells held no prognostic value for NeoTx patients, an increased frequency of proliferating CD20+Ki67+ B cells emerged as an independent prognostic factor for longer survival in the NeoTx group. These results indicate that NeoTx differentially affects PDAC-infiltrating immune cells and may have detrimental effects on the existing B cell landscape and the formation of TLS. Gaining further insight into the underlying molecular mechanisms is crucial to overcome the intrinsic immunotherapy resistance of PDAC and develop novel strategies to improve the long-term outcome of PDAC patients

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

Clinical associations and prognostic value of MRI-visible perivascular spaces in patients with ischemic stroke or TIA: a pooled analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH

Taking position for the local. Studying contributions of socially innovative projects in rural regions

Abweichender Titel nach Übersetzung der Verfasserin/des VerfassersDer strukturschwache ländliche Raum ist durch eine ungleiche Entwicklungsdynamik benachteiligt. In dieser Lage müssen ländliche Gemeinden neue Antworten und Problemlösungen im Rahmen ihrer Möglichkeiten finden, wovon eine soziale innovative Projekte sein können, die konkrete soziale Bedürfnisse ins Auge fassen und „von unten“ an einem lokalen Wandel arbeiten. Derartige Gemeinschaftsprojekte, deren Entwicklung, Netzwerke und Beiträge für die Situation vor Ort stehen in dieser Arbeit im Mittelpunkt. Nach der Vorbereitung von Konzepten sozialer Innovation für die Beschreibung der Projektpraxis, wird eine quantitative Analyse mit 14 Strukturschwächeindikatoren durchgeführt. Im Hauptteil finden vier Fallstudien statt, in denen die ausgewählten Projekte über eine Qualitative Inhaltsanalyse und im Hinblick auf Faktoren für den Projekterfolg und ihre lokale Wirkungen untersucht werden. In den Fallstudien zeigt sich, dass projektinterne Faktoren also jene, die vom Projektteam definiert und beeinflusst werden können die bedeutendsten sind und die größte Wirkung darauf haben, ob ein Projekt umgesetzt und etabliert werden kann. Sie bieten die Basis und sind Bausteine für alle Aktivitäten und Angebote, die ein ehrenamtlicher Verein nach innen und außen entfalten kann. Damit können sozial innovative Projekte im ländlichen Raum nicht von oben gesteuert werden, sondern hängen besonders an den Gestaltungsmöglichkeiten und dem Freiraum, den man derartigen Initiativen politisch zugesteht. Gemeinschaftsprojekte entfalten hauptsächlich soziale, aber auch ökonomische Wirkungen in ihren Standortgemeinden und, je nach Größe des Projekts, auch darüber hinaus. Die Projektaktivitäten fokussieren auf die Aneignung von neuem Wissen und Fähigkeiten, kollektive Lernprozesse und gesellschaftlichen Austausch. Langfristig gesehen bauen ehrenamtliche Vereine aktiv Netzwerke auf und ermächtigen involvierte Personen. Sie bestärken BürgerInnen dabei sich auszuprobieren und selbst aktiv zu werden und arbeiten an der Etablierung einer größeren lokalen gesellschaftlichen Offenheit und einer kooperativen Kultur. Insgesamt sind Gemeinschaftsprojekte im peripheren ländlichen Raum damit ein kleiner Puzzlestein eines größeren Bildes, der mithelfen kann, das lokale Angebot diverser zu machen und neue Möglichkeiten der Zusammenarbeit, Vernetzung und Weiterbildung anzustoßen.Structurally weak rural areas are disadvantaged by unequal development dynamics. In this situation, rural municipalities need to find new answers and solutions within their capabilities, one of which can be social innovative projects that take specific social needs into account and work bottom-up on local change. Such community projects, their development, networks and contributions to the local situation are the main focus in this thesis. After preparing concepts of social innovation for the application in the project practice, a quantitative analysis is carried out, using 14 indicators for structural weaknesses. The main section contains four case studies, in which the selected projects are examined applying a qualitative content analysis and with regard to factors for the success of the projects and their local impacts. The case studies show that project-internal factors those that can be steered and influenced by the project team are the most significant and have the greatest impact on whether a project can be implemented and established. They provide the base and are the main components for all activities that a volunteer associa- tion can develop internally and externally. As a result, socially innovative projects in rural areas cannot be controlled from above, but instead depend especially on the possibilities of movement and the degree of freedom that is politically conceded to such initiatives. Socially innovative projects have mainly social but also economic impacts on the municipality where they are located and, depending on the size of the project, also beyond that scope. The project activities focus on the acquisition of new knowledge and skills, collective learning processes and social exchange. In the long run voluntary organizations actively build networks and empower the people involved. They encourage citizens to experiment, to become active themselves and work on opening up local societies as well as on a collaborative culture. Overall, community projects in peripheral rural areas thus represent a small piece of a larger picture, which can help to make local offerings more diverse and to stimulate new opportunities for collaboration, local networks and practical education.18

Untersuchung der immun-modulatorischen Wirkung von Partialstrukturen des Arabinogalaktans in einem humanen Zellkulturmodell und in murinen Modellen für Asthma

Zahlreiche epidemiologische Studien konnten eine Allergie-Protektion durch den Kontakt zu traditioneller Bauernhofumgebung nachweisen ("farm-effect"). Für die Einzelsubstanz Arabinogalaktan (AG) aus dem Stallstaub konnte in humanen Zellkultur- und murinen Asthma-Modellen diese Schutzwirkung ebenfalls gezeigt werden. In dieser Arbeit sind Partialstrukturen des Arabinogalaktans auf diesen Effekte hin untersucht worden. Die einzelnen Partialstrukturen des AGs haben in keinem untersuchten Modell einen immunologischen Einfluss gezeigt. Koppelt man jedoch die Partialstrukturen an ein großes Trägerprotein, kommt es im murinen Ova/Alum Asthma Modell zur Allergie-Protektion. Der immunologische Effekt geht mit der Bildung von Antigen.spefizischen IgG$_1$ Antikörpern einher. Der immmun-regulatorische und entzündungshemmende Effekt von IgG$_1$ Antikörper als Reaktion auf Antigene aus dem Stallstaub könnte ein molekularer Mechanismus des epidemiologischen Bauernhofeffekts sein

Fluoroscopic MR of the pharynx in patients with obstructive sleep apnea

PURPOSE: The purpose of our study was to introduce an ultrafast MR imaging technique of the pharynx as a diagnostic tool for viewing the mechanism of obstruction in patients with obstructive sleep apnea. METHODS: Six healthy volunteers and 16 patients with obstructive sleep apnea were examined on a 1.5-T whole-body imager using a circular polarized head coil. Ultrafast twodimensional fast low-angle shot sequences were obtained in midsagittal and axial projections during transnasal shallow respiration at rest, during simulation of snoring, and during performance of the Müller maneuver. All patients underwent physical examination, transnasal fiberoptic endoscopy, and polysomnography. RESULTS: Five to six images were obtained per second with an in-plane resolution of 2.67 ؋ 1.8 mm and 2.68 ؋ 2.34 mm, allowing visualization of motion of the tongue, soft palate, uvula, and posterior pharyngeal surface. MR findings correlated well with results of clinical examination. The length of obstruction in the oropharynx, which cannot be ascertained by transnasal endoscopy of the pharynx, was clearly visible MR images. Differences between patients with obstructive sleep apnea and healthy subjects in terms of the degree of obstruction in the velopharynx and oropharynx depicted on MR images during the Müller maneuver were highly significant. CONCLUSION: We believe that ultrafast MR imaging is a reliable noninvasive method for use in the evaluation of obstructive sleep apnea. Diagnosis and treatment of obstructive sleep apnea (OSA) are critical, since patients with OSA suffer from excessive daytime sleepiness, shortening of rapid eye movement sleep phases, daytime hypersomnolence, and gastroesophageal reflux. Cardiovascular derangements, such as hypertension, arrhythmias, ST depression, loss of circadian variation, and rise of blood pressure, are additional symptoms that may affect the individual's ability to work and possibly lead to a higher risk of stroke and myocardial infarction (1-12). Several therapeutic approaches have been developed to treat OSA. These include continuous positive nasal airway pressure, uvulopalatopharyngoplasty, mandibular osteotomy/genioglossus advancement with hyoid myotomy/suspension, and maxillary and mandibular advancement osteotomy Recent advances in imaging techniques have fostered the development of new approaches for identification of the dynamic anatomy and physiology of the pharynx. The techniques available include cineradiography (16 -20), CT (21, Method