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Ensuring Access to Safe and Nutritious Food for All Through the Transformation of Food Systems
Identifizierung prädiktiver und prognostischer Biomarker in unterschiedlichen Tumorkompartimenten des ösophagealen Adenokarzinoms
Das ösophageale Adenokarzinom zeigt eine global steigende Inzidenz und hat mit einer 5-Jahres-Überlebensrate von weniger als 25% eine schlechte Prognose. Personalisierte Therapieansätze sind selten und prognostische/prädiktive Biomarker des Tumormikromilieus sind unzureichend charakterisiert. Die kumulative Promotion nähert sich dieser Problematik in drei unterschiedlichen Schwerpunkten. 1. Zur Identifizierung Kompartiment-spezifischer Biomarker wurde eine Methode entwickelt, welche als kostengünstige Alternative zum sc-Seq Expressionsprofile individueller Zelltypen generiert. Dabei erfolgt die Extraktion der RNA nicht aus Einzelzellen, sondern aus flowzytometrisch-getrennten Zellkompartimenten. Die Separation der Proben in Epithelzellen, Immunzellen und Fibroblasten wurde durch verschiedene Verfahren validiert und eine suffiziente Ausbeute an RNA auch für kleine Gewebemengen gezeigt. 2. Biomarker des Immunzellkompartiments als therapeutische Angriffspunkte wurden in einem Patientenkollektiv von bis zu 551 Patienten auf ihre Bedeutung beim EAC überprüft. Es zeigte sich eine Expression der Immuncheckpoints LAG3, VISTA und IDO auf TILs durch IHC und RNA-Sonden basierte Verfahren in einem relevanten Anteil (LAG3: 11,4%, VISTA: 29%, IDO: 52,6%). Es konnte eine prognostisch günstige Bedeutung der VISTA, LAG3 und IDO Expression gezeigt werden. Durch den Vergleich von Genexpressionsprofilen aus therapienaiven und vorbehandelten Tumoren konnte zudem ein immunsuppressiver Effekt von neoadjuvanten Therapiekonzepten auf das Tumormikromilieu des EACs gezeigt werden. Dabei kam es zur verminderten Expression von Checkpoints und Anzahl TILs nach (Radio-) Chemotherapie. 3. Im Tumorzellkompartiment wurde die Rolle von Amplifikationen in ErbB-Rezeptor abhängigen Signalwegen durch FISH-Technik und Immunhistochemie evaluiert. Es fanden sich KRAS Amplifikationen in 17,1%, PIK3CA Amplifikationen in 5% sowie eine HER2/neu-Überexpression in 14,9% der untersuchten Tumore
Statistical phase estimation and error mitigation on a superconducting quantum processor
Quantum phase estimation (QPE) is a key quantum algorithm, which has been
widely studied as a method to perform chemistry and solid-state calculations on
future fault-tolerant quantum computers. Recently, several authors have
proposed statistical alternatives to QPE that have benefits on early
fault-tolerant devices, including shorter circuits and better suitability for
error mitigation techniques. However, practical implementations of the
algorithm on real quantum processors are lacking. In this paper we practically
implement statistical phase estimation on Rigetti's superconducting processors.
We specifically use the method of Lin and Tong [PRX Quantum 3, 010318 (2022)]
using the improved Fourier approximation of Wan et al. [PRL 129, 030503
(2022)], and applying a variational compilation technique to reduce circuit
depth. We then incorporate error mitigation strategies including zero-noise
extrapolation and readout error mitigation with bit-flip averaging. We propose
a simple method to estimate energies from the statistical phase estimation
data, which is found to improve the accuracy in final energy estimates by one
to two orders of magnitude with respect to prior theoretical bounds, reducing
the cost to perform accurate phase estimation calculations. We apply these
methods to chemistry problems for active spaces up to 4 electrons in 4
orbitals, including the application of a quantum embedding method, and use them
to correctly estimate energies within chemical precision. Our work demonstrates
that statistical phase estimation has a natural resilience to noise,
particularly after mitigating coherent errors, and can achieve far higher
accuracy than suggested by previous analysis, demonstrating its potential as a
valuable quantum algorithm for early fault-tolerant devices.Comment: 24 pages, 13 figure
Change of depressive symptoms during the course of electroconvulsive therapy (ECT) and predictive value of these symptoms for ECT outcome
Aim: Research examining change in symptoms of depression during treatment with electroconvulsive therapy (ECT) and proposing reliable predictors of ECT outcome is limited and previous studies have led to inconclusive results. This dissertation aims to explore the change of depressive symptomatology assessed with Montgomery-Ă…sberg Depression Rating Scale (MADRS) single items throughout the course of ECT and analyse the predictive value of these MADRS single items and their change throughout the course of ECT treatment regarding ECT outcome.
Methods: This retrospective naturalistic study analysed MADRS data from 96 depressed psychiatric inpatients. MADRS data were routinely collected at three time points during the course of ECT treatment. ANOVAs for repeated measures were used to explore change of depressive symptomatology throughout the course of ECT. In order to analyse the predictive value of depressive symptomatology and its change regarding ECT treatment outcome logistic and linear regression models were applied.
Results: Strongest reductions throughout the course of ECT treatment were found for MADRS items apparent sadness, reported sadness and inability to feel, assessing affective symptoms of depression. Lowest reductions were found for items assessing concentration difficulties and suicidal thoughts. MADRS single items were found to be potent predictors of ECT outcome, particularly the following items addressing affective symptomatology: apparent sadness, reported sadness, and inability to feel. Regression models that contained reported sadness indicated the most potent effects with as much as 80% correct prediction of ECT outcome. In order to determine a favorable MADRS cutoff value for ECT response, we conducted ROC analyses.
Conclusions: Affective symptoms of depression decreased the most throughout the course of antidepressant ECT treatment. A favorable ECT outcome appears to be associated with more pronounced affective depressive symptomatology at baseline before treatment start and a stronger decline of affective symptomatology throughout the course of ECT. Additionally, precise cut-off values for clinical use after future validation were suggested. In search of reliable and easy-to-assess predictors of ECT outcome, depressive symptoms measured with MADRS single items could be regarded as a cost- and time-effective, valuable addition to clinical decision-making. In general, these findings illustrate the potential of a symptom-based approach, which might pose a useful expansion to the prevailing focus on depression sum-scores and generalized diagnostic categories in depression research and treatment.Ziel: Bislang liegen wenig belastbare Ergebnisse zur Veränderung distinkter depressiver
Symptome durch die Behandlung mit EKT sowie zu zuverlässigen Prädiktoren einer
erfolgreichen antidepressiven Behandlung mit EKT vor. Vorangegangene Studien haben
zudem teils widersprüchliche Ergebnisse hervorgebracht. Diese Dissertation untersucht daher die Veränderung depressiver Symptome während der Behandlung mit EKT sowie die
Vorhersagekraft initial bestehender depressiver Symptome und ihrer Veränderungen für eine erfolgreiche EKT-Behandlung. Einzelne depressive Symptome wurden dabei mittels Einzel-Items der Montgomery-Åsberg Depression Rating Scale (MADRS) erfasst.
Methodik: In dieser naturalistischen retrospektiven Studie wurden MADRS Daten von 96
depressiven Patienten ausgewertet, die sich in stationärer psychiatrischer Behandlung
befanden. Dabei wurden Daten von drei Messzeitpunkten im Verlauf der EKT-Behandlung
analysiert. ANOVAs für Messwiederholungen wurden verwendet, um die Veränderung der
depressiven Symptome im Verlauf der EKT-Behandlung zu untersuchen. Logistische und
lineare Regressionsmodelle wurden angewandt, um die Vorhersagekraft distinkter depressiver Symptome und ihrer Veränderungen für eine erfolgreiche EKT-Behandlung zu explorieren.
Ergebnisse: Die stärkste Symptomreduktion im Verlauf der EKT-Behandlung wurde für
affektive Symptome gefunden; fĂĽr die Items Sichtbare Traurigkeit, Berichtete Traurigkeit und
GefĂĽhllosigkeit. Die geringste Symptomreduktion wurde in Bezug auf Konzentrationsschwierigkeiten sowie Suizidgedanken gefunden. MADRS Einzel-Items waren
wirksame Prädiktoren für das Ergebnis der EKT-Behandlung, insbesondere die o.g. affektiven Symptome. Die stärksten Effekte wurden dabei für Regressionsmodelle mit dem Item Berichtete Traurigkeit gefunden, mit bis zu 80% korrekter Vorhersage des
Behandlungsergebnisses. Mittels ROC-Analysen konnten Schwellenwerte fĂĽr die Vorhersage
einer erfolgreichen EKT-Behandlung definiert werden.
Schlussfolgerungen: Im Verlauf der antidepressiven Behandlung mit EKT reduzierte sich die
affektive depressive Symptomatik am meisten. Eine stärker ausgeprägte affektive Symptomatik zu Behandlungsbeginn sowie eine stärkere Abnahme dieser affektiven Symptome im Behandlungsverlauf scheinen mit einem günstigeren Behandlungsergebnis einherzugehen. Dementsprechend könnten depressive Symptome erfasst anhand von MADRS Einzel-Items einfache, zuverlässige sowie zeit- und kostensparende Prädiktoren für erfolgreiche EKTBehandlungen darstellen und somit einen wertvollen Beitrag zur klinischen
Entscheidungsfindung leisten. Diese Befunde verdeutlichen zudem den zusätzlichen Nutzen symptombasierter Depressionsforschung und –behandlung als Ergänzung zur weiterhin
vorherrschenden Fokussierung auf Summenscores und ĂĽbergeordnete Diagnosekriterien
Examples of works to practice staccato technique in clarinet instrument
Klarnetin staccato tekniğini güçlendirme aşamaları eser çalışmalarıyla uygulanmıştır. Staccato
geçişlerini hızlandıracak ritim ve nüans çalışmalarına yer verilmiştir. Çalışmanın en önemli amacı
sadece staccato çalışması değil parmak-dilin eş zamanlı uyumunun hassasiyeti üzerinde de
durulmasıdır. Staccato çalışmalarını daha verimli hale getirmek için eser çalışmasının içinde etüt
çalışmasına da yer verilmiştir. Çalışmaların üzerinde titizlikle durulması staccato çalışmasının ilham
verici etkisi ile müzikal kimliğe yeni bir boyut kazandırmıştır. Sekiz özgün eser çalışmasının her
aşaması anlatılmıştır. Her aşamanın bir sonraki performans ve tekniği güçlendirmesi esas alınmıştır.
Bu çalışmada staccato tekniğinin hangi alanlarda kullanıldığı, nasıl sonuçlar elde edildiği bilgisine
yer verilmiştir. Notaların parmak ve dil uyumu ile nasıl şekilleneceği ve nasıl bir çalışma disiplini
içinde gerçekleşeceği planlanmıştır. Kamış-nota-diyafram-parmak-dil-nüans ve disiplin
kavramlarının staccato tekniğinde ayrılmaz bir bütün olduğu saptanmıştır. Araştırmada literatür
taraması yapılarak staccato ile ilgili çalışmalar taranmıştır. Tarama sonucunda klarnet tekniğin de
kullanılan staccato eser çalışmasının az olduğu tespit edilmiştir. Metot taramasında da etüt
çalışmasının daha çok olduğu saptanmıştır. Böylelikle klarnetin staccato tekniğini hızlandırma ve
güçlendirme çalışmaları sunulmuştur. Staccato etüt çalışmaları yapılırken, araya eser çalışmasının
girmesi beyni rahatlattığı ve istekliliği daha arttırdığı gözlemlenmiştir. Staccato çalışmasını yaparken
doğru bir kamış seçimi üzerinde de durulmuştur. Staccato tekniğini doğru çalışmak için doğru bir
kamışın dil hızını arttırdığı saptanmıştır. Doğru bir kamış seçimi kamıştan rahat ses çıkmasına
bağlıdır. Kamış, dil atma gücünü vermiyorsa daha doğru bir kamış seçiminin yapılması gerekliliği
vurgulanmıştır. Staccato çalışmalarında baştan sona bir eseri yorumlamak zor olabilir. Bu açıdan
çalışma, verilen müzikal nüanslara uymanın, dil atış performansını rahatlattığını ortaya koymuştur.
Gelecek nesillere edinilen bilgi ve birikimlerin aktarılması ve geliştirici olması teşvik edilmiştir.
Çıkacak eserlerin nasıl çözüleceği, staccato tekniğinin nasıl üstesinden gelinebileceği anlatılmıştır.
Staccato tekniğinin daha kısa sürede çözüme kavuşturulması amaç edinilmiştir. Parmakların
yerlerini öğrettiğimiz kadar belleğimize de çalışmaların kaydedilmesi önemlidir. Gösterilen azmin ve
sabrın sonucu olarak ortaya çıkan yapıt başarıyı daha da yukarı seviyelere çıkaracaktır
Model Diagnostics meets Forecast Evaluation: Goodness-of-Fit, Calibration, and Related Topics
Principled forecast evaluation and model diagnostics are vital in fitting probabilistic models and forecasting outcomes of interest. A common principle is that fitted or predicted distributions ought to be calibrated, ideally in the sense that the outcome is indistinguishable from a random draw from the posited distribution. Much of this thesis is centered on calibration properties of various types of forecasts.
In the first part of the thesis, a simple algorithm for exact multinomial goodness-of-fit tests is proposed. The algorithm computes exact -values based on various test statistics, such as the log-likelihood ratio and Pearson\u27s chi-square. A thorough analysis shows improvement on extant methods. However, the runtime of the algorithm grows exponentially in the number of categories and hence its use is limited.
In the second part, a framework rooted in probability theory is developed, which gives rise to hierarchies of calibration, and applies to both predictive distributions and stand-alone point forecasts. Based on a general notion of conditional T-calibration, the thesis introduces population versions of T-reliability diagrams and revisits a score decomposition into measures of miscalibration, discrimination, and uncertainty. Stable and efficient estimators of T-reliability diagrams and score components arise via nonparametric isotonic regression and the pool-adjacent-violators algorithm. For in-sample model diagnostics, a universal coefficient of determination is introduced that nests and reinterprets the classical in least squares regression.
In the third part, probabilistic top lists are proposed as a novel type of prediction in classification, which bridges the gap between single-class predictions and predictive distributions. The probabilistic top list functional is elicited by strictly consistent evaluation metrics, based on symmetric proper scoring rules, which admit comparison of various types of predictions
Effects of weight divisions in time-motion of female high-level Brazilian Jiu-jitsu combat behaviors
Coaches and psychologists can use time-motion analysis to elaborate specific interventions for female BJJ athletes, increasing specific training context and reducing unnecessary psychological and physical demands and injuries. Therefore, the present study aimed to analyze high-level BJJ female athletes in the 2020 Pan-American Games by comparing the weight categories on the time-motion analysis. The time-motion analysis (i.e., approach, gripping, attack, defensive actions, transition, mounting, guard, side control, and submissions) of 422 high-level female BJJ combats was divided and compared by weight category as follows: Rooster (n = 8), Light Feather (n = 18), Feather (n = 122), Light (n = 84), Middle (n = 74), Medium Heavy (n = 44), Heavy (n = 36), Super Heavy (n = 36), using p ≤ 0.05. The main results indicated that the Super heavyweight category [3.1 (5.8;119.9) s] had a shorter gripping time than other weight categories, p ≤ 0.05. In contrast, roosters [7.2 (3.5;64.6) s] had longer gripping, transition [14.0 (4.8;29.6) s], and attack time [76.2 (27.7, 93.2)] than the light feather, middlers, and heavier weight categories, p ≤ 0.05. These findings should be considered for the psychological interventions and training prescription
Heart Rate Variability as a Marker of Homeostatic Level
Many variables have been used as homeostatic level markers. Heart Rate Variability (HRV) has been frequently cited as an indicator of homeostatic status. Low levels of HRV are associated with aging, disease, or increased risk of death. We present a study based on more than 10.5 million data collected from the literature, associating the degree of global clinical impairment of individuals, with their respective HRV data, seeking to establish a classification of Homeostatic Levels. Three specific variables were evaluated: heart rate (HR), the root-mean-square of successive differences between adjacent normal RR intervals in a time interval (RMSSD) and the HF band (HF ms2). It was possible to detect significant differences between the 83,927 data from healthy individuals and the 382,039 data from individuals with significant homeostatic impairment. It was demonstrated that the RMSSD is very sensitive to the worst homeostatic state, presenting a behavior independent of age and that the values found in the general population do not match the values of apparently healthy individuals. An alphanumeric classification of the homeostatic level in a three-level architecture was proposed, with three stages for each level, which may be extremely useful in prognostic assessment and decision-making about individual people
Epilepsy Mortality: Leading Causes of Death, Co-morbidities, Cardiovascular Risk and Prevention
a reuptake inhibitor selectively prevents seizure-induced sudden death in the DBA/1 mouse model of sudden unexpected ... Bilateral lesions of the fastigial nucleus prevent the recovery of blood pressure following hypotension induced by ..
Programmes d'intervention familiale intensive : ajustement des interventions et évolution des familles présentant des profils cliniques distincts
La présente thèse par articles porte sur les programmes d’intervention familiale intensive et s’inscrit dans le cadre du programme de doctorat en psychoéducation de l’Université de Sherbrooke ayant pour thème Les difficultés de comportement des enfants et des adolescents et les interventions psychoéducatives. Les données utilisées pour réaliser cette thèse proviennent de l’étude de Pauzé et ses collègues (2014) visant à examiner l’impact de l’application fidèle du programme Crise-Ado-Famille-Enfance (CAFE).
Les programmes d’intervention familiale intensive, élaborés afin de prévenir le placement d’urgence des jeunes en milieu substitut et s’adressant particulièrement aux adolescent(e)s présentant des problèmes de comportement et à leur famille, sont largement implantés au Québec et en Amérique du Nord. Ces programmes offrent une intervention ajustée aux profils cliniques des familles et ciblent à la fois l’urgence de la situation de crise et les facteurs psychosociaux en cause dans l’émergence et le maintien de la crise familiale et des problèmes de comportement des adolescent(e)s. Plusieurs méta-analyses ont démontré l’efficacité de ces programmes, notamment pour réduire les taux de placement en milieu substitut, diminuer les problèmes de comportement des adolescent(e)s et améliorer le fonctionnement familial. Toutefois, les résultats de ces méta-analyses sont mitigés et la compréhension de l’efficacité des programmes demeure toujours lacunaire, notamment en raison de l’hétérogénéité des difficultés présentées par les familles et de l’utilisation d’indicateurs de changement majoritairement centrés sur le fonctionnement de l’adolescent(e). La présente thèse vise à pallier ces limites en s’intéressant aux processus cliniques au cœur de ces programmes, c’est-à -dire à ce qui prend place avant et pendant l’intervention et à la relation entre ces processus et les résultats de l’intervention.
Le premier article de la thèse, intitulé Intensive family intervention programs: tailoring intervention to family clinical profiles et publié en 2020 dans la revue Children and Youth Services Review, vise à identifier des profils cliniques de familles bénéficiant d’un programme d’intervention familiale intensive et à les comparer en fonction de l’intervention reçue. Réalisée à partir de caractéristiques individuelles de l’adolescent(e) et de caractéristiques familiales de 237 familles ayant bénéficié du programme CAFE, les analyses de profils latents ont mené à l’identification de quatre profils cliniques distincts. Les analyses de comparaison ont permis de mettre en lumière des différences concernant l’intervention reçue par ces familles et signalent un certain manque d’ajustement de l’intervention aux profils cliniques des familles.
Le second article de la thèse, intitulé Intensive family intervention programs: Evolution of families with different clinical profiles et soumis en 2021 à la revue Family Process visait quant à lui à examiner l’évolution des jeunes et des familles présentant des profils cliniques distincts à la fin de l’intervention ainsi qu’une année suivant l’entrée dans le programme. Les résultats montrent que l’ensemble des familles évoluent positivement, tant sur le plan des comportements extériorisés de l’adolescent(e) que sur le plan du fonctionnement familial. Les résultats montrent également que les changements se maintiennent après la fin de l’intervention. Les familles présentant un profil clinique sévère semblent toutefois présenter une évolution plus tardive sur le plan des comportements extériorisés de l’adolescent(e), soulignant l’importance d’ajuster les paramètres de l’intervention offerte aux profils cliniques des familles.
Les résultats de la présente thèse contribuent à l’avancement des connaissances en mettant en lumière la complexité des profils cliniques présentés par les familles bénéficiant d’une intervention familiale intensive et en s’intéressant à l’ajustement de l’intervention aux caractéristiques des jeunes et des familles, principe clé de ce type de programmes. La présente thèse contribue également à l’avancement des connaissances en allant au-delà de l’efficacité générale des programmes et en portant un regard sur les processus cliniques et leur impact sur l’évolution des familles présentant des profils cliniques distincts. Ces résultats permettront d’améliorer les services offerts aux jeunes et aux familles bénéficiant des programmes d’intervention familiale intensive
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