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Here we describe the rationale and design of MAJIC, a phase III, prospective, multicenter, randomized trial comparing the combination of the BTK inhibitor acalabrutinib plus the BCL2 inhibitor venetoclax versus the combination of venetoclax plus obinutuzumab as frontline treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma. In both treatment arms, disease response (assessed by International Workshop on Chronic Lymphocytic Leukemia criteria) and minimal residual disease will be used to guide therapy duration, with all patients ultimately discontinuing treatment after a maximum of 2 years. The primary end point is progression-free survival. Key secondary end points include rates of undetectable minimal residual disease, overall response and overall survival. This study will address key unanswered questions in frontline chronic lymphocytic leukemia/small lymphocytic lymphoma therapy by investigating the optimal duration of finite treatment and identifying the optimal venetoclax doublet regimen.This article describes the design of the MAJIC clinical trial, which investigates two different treatment combinations for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not received treatment for their disease previously. Patients will be randomized (put into a group by chance) to receive either acalabrutinib + venetoclax (AV) or venetoclax + obinutuzumab (VO). VO is already an approved initial treatment option for CLL/SLL. Acalabrutinib is also an approved initial treatment option when given by itself, but the AV combination is not yet approved. We are doing this study to better understand and directly compare how well AV and VO work when used for the treatment of CLL/SLL. A test done on the blood and bone marrow called ‘minimal residual disease’ will be used to help guide the length of time that patients receive treatment.

eingereicht von Richard Hermann Leberbauer Diplomarbeit Universität Linz 2022

Background and aims We hypothesized that a drug’s clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. Methods Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or “core”) for the 3 variables in published datasets. Results The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; pPolygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; pPolygonum multiflorum from AMX/CLA and cefazolin, respectively (p Conclusions DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

By adjusting the process flow of a newly developed transparent conductive adhesive (TCA), the first mechanically stable interconnection of a glued III-V on Si tandem solar cell was established utilizing a ZnO-based adhesive. The measured $V_{OC}$ of 1691 mV is a first proof of concept for the developed TCA. The functionality of the two sub-cells in the tandem device was proven by external quantum efficiency (EQE) measurements. The reflectance at the bond interface of such a glued tandem solar cell remains the limiting factor. In order to reduce the optical losses, the effect of a textured silicon surface was investigated in test structures, which indeed showed reduced reflectance. Furthermore, this textured test structure showed an improved connecting resistivity as low as $83\ \mathrm{m}\Omega\text{cm}^{2}$ .

This study was conducted using a total of 360 22-day-old Chaohu ducks to evaluate the effect of rearing system on growth performance, carcass traits, meat quality and serum parameters of male and female Chaohu ducks. The birds were divided and raised in separate pens according to sex and rearing system, with three replicate pens of 30 male or 30 female ducks per pen for each rearing system. The rearing systems consisted of a floor rearing system (FRS) and a net rearing system (NRS). Results showed that ducks raised in NRS had better growth performance, whereas, ducks raised in FRS exhibited better carcass traits and meat color, and lower intramuscular fat. For the serum parameters, NRS significantly decreased high-density lipoprotein cholesterol content, and enhanced total protein and triacylglycerol contents. Male ducks had lower abdominal fat percentage, and higher growth performance and shear force, but there were no other significant differences between sexes. No rearing system × sex interaction was observed in the present study, revealing that rearing system had the same effect on both sexes. In conclusion, NRS was beneficial to the growth performance of Chaohu ducks, whereas this system had some negative effects on carcass traits, meat quality and serum profiles.

OBJECTIVE:: The aim of this study was to identify factors associated with the occurrence of adverse events (AEs) or medical errors (MEs) during inpatient psychiatric hospitalizations. METHODS:: A full-probability random sample of 4,371 charts from 14 inpatient psychiatric units at acute care general hospitals in Pennsylvania were reviewed in a two-stage process that comprised screening and flagging by nurses followed by review by psychiatrists. AE and ME rates were calculated overall and then stratified by patient and hospital factors. Unadjusted and adjusted logistic regression models examined predictors of AEs and MEs. RESULTS:: An AE was identified in 14.5% of hospitalizations (95% confidence interval [CI]=11.7-17.9), and an ME was identified in 9.0% (CI=7.5-11.0). In adjusted analyses, patients with a longer length of stay and older patients had higher odds of experiencing an AE or an ME. Patients ages 31-42 (compared with ages 18-30), with commercial insurance (compared with Medicare or Medicaid or uninsured), or treated at high-volume hospitals (compared with low, medium, or very high) had lower odds of an AE. Patients age 54 or older (compared with ages 18-30), admitted during the weekend, admitted to rural hospitals (compared with urban), or treated at very-high-volume hospitals (compared with high) were more likely to experience an ME. CONCLUSIONS:: This study provides insight into factors that put patients and hospitals at increased risk of patient safety events. This information can be used to tailor improvement strategies that enhance the safety of patients treated on general hospital psychiatric units.

The PROTECT Benefit-Risk group is dedicated to research in methods for continuous benefit-risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods.A comprehensive review was performed to identify visuals used for medical risk and benefit-risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual.Sixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit-risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated.We have arrived at recommendations for the use of visual displays for benefit-risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience-visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit-risk analysis information.

PURPOSE: Difficulties may be encountered when undertaking a benefit-risk assessment for an older product with well-established use but with a benefit-risk balance that may have changed over time. This case study investigates this specific situation by applying a formal benefit-risk framework to assess the benefit-risk balance of warfarin for primary prevention of patients with atrial fibrillation. METHODS: We used the qualitative framework BRAT as the starting point of the benefit-risk analysis, bringing together the relevant available evidence. We explored the use of a quantitative method (stochastic multi-criteria acceptability analysis) to demonstrate how uncertainties and preferences on multiple criteria can be integrated into a single measure to reduce cognitive burden and increase transparency in decision making. RESULTS: Our benefit-risk model found that warfarin is favourable compared with placebo for the primary prevention of stroke in patients with atrial fibrillation. This favourable benefit-risk balance is fairly robust to differences in preferences. The probability of a favourable benefit-risk for warfarin against placebo is high (0.99) in our model despite the high uncertainty of randomised clinical trial data. In this case study, we identified major challenges related to the identification of relevant benefit-risk criteria and taking into account the diversity and quality of evidence available to inform the benefit-risk assessment. CONCLUSION: The main challenges in applying formal methods for medical benefit-risk assessment for a marketed drug are related to outcome definitions and data availability. Data exist from many different sources (both randomised clinical trials and observational studies), and the variability in the studies is large. Copyright © 2014 John Wiley & Sons, Ltd.

The KATRIN experiment aims to measure the neutrino mass with a sensitivity of m=0.2 eV/c² (90% C.L.). One parameter, the isotopic composition of the tritium gas source, is measured inline by Raman spectroscopy. The required measurement trueness of the composition is

INTRODUCTION: Anaemia during chemotherapy is often left untreated. Erythropoiesis-stimulating agents are frequently used to treat overt anaemia. Their prophylactic use, however, remains controversial and raises concerns about cost-effectiveness. Therefore, we assessed the efficacy of a dose-reduction schedule in anaemia prophylaxis. MATERIALS AND METHODS: The study included patients with untreated solid tumours about to receive platinum-based chemotherapy and had haemoglobin (Hb) levels ≥11 g/dL. Epoetin-α was administered at a dose level of 3 × 10,000 U weekly as soon as Hb descended to < 13 g/dL. Dose reductions to 3 × 4,000 U and 3 × 2,000 U weekly were planned in 4-week intervals if Hb stabilised in the range of 11-13 g/dL. Upon ascending to ≥13 g/dL, epoetin was discontinued. Iron supplements of 100 mg intravenous doses were given weekly. Of 37 patients who enrolled, 33 could be evaluated. RESULTS AND DISCUSSION: Their median Hb level was 13.7 (10.9-16.2) g/dL at baseline and descended to 11.0 (7.4-13.8) g/dL by the end of chemotherapy. Anaemia (Hb < 10 g/dL) was prevented in 24 patients (73%). The mean dose requirement for epoetin-α was 3 × 5,866 U per week per patient, representing a dose reduction of 41%. Treatment failed in nine patients (27%), in part due to epoetin-α resistance in four (12%) and blood transfusion in three (9%) patients. CONCLUSION: Dose reduction was as effective as fixed doses in anaemia prophylaxis but reduced the amount of prescribed epoetin substantially.

Small, hydrophobic molecules such as n-decane and n-tetradecane are known to be inverse hexagonal $(H\sb{\rm II})$ phase promoters. n-tetradecane also causes an increase in the hexagonal phase repeat distance whereas n-decane shows no change in the repeat distance. In this study NMR spectroscopy and NMR relaxation (T$\sb{\rm 1z},$ T$\sbsp{2}{\rm qe},$ and T$\sbsp{2}{\rm q{-}CPMG})$ were used to study the perdeuterated C$\sb?$D$\sb{30}$ and C$\sb?$D$\sb{30}$ molecules in a DOPE-water system. The tetradecane spectrum and relaxation data showed very little change on reducing the water content from excess water to osmotically stressed, 87.5% weight. The decane showed a slight increase in order and a shortened T$\sbsp{2}{\rm qe}$ on osmotic stressing. These data are inconsistent with the existing "space-filling" model. While no model can be constructed on the basis of this new data, the data provide constraints for new models of alkane-phospholipid interaction.

Alterations in microvascular flow caused by hyperviscosity or thrombosis can lead to neurological symptoms. Sustained reduction in flow may produce permanent central nervous system injury. Chronic hematologic disorders which may produce hyper-viscosity syndromes include multiple myeloma and Waldenstrom’s macroglobulinemia. More ominous, because of their abrupt and potentially catastrophic onset, are the microvascular thrombotic disorders thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Prompt recognition that the neurological findings are of hematologic origin is necessary for reversal of symptoms.

Handschriften und Autographen der ETH-Bibliothek, 147

Concert Music, Rock, and Jazz since 1945: Essays and Analytical Studies. Edited by Elizabeth West Marvin and Richard Hermann. (Eastman Studies in Music.) Rochester, N.Y.: University of Rochester Press, 1995. [x, 449 p. ISBN 1-878822-42-X. $95.00.] "And so, with that discussion of the Bartok Concerto for Orchestra, we conclude our course in the analysis of music of the twentieth century." Presumably, this statement is now heard less often, but it is not difficult to understand why it has persisted. There have been a number of obstacles to the fruitful discussion of music since 1945. Foremost is the appearance of music for which the traditional values of coherence, motivic consistency, and organic process are either peripheral or irrelevant. Since these properties are the tenets upon which most traditional analysis and criticism are based, the usual means of discussing the music intelligently have suddenly become frustrating, misleading, or inappropriate. Moreover, even when the music is meant to cohere, in this Beethovenian sense, it may be based on highly complex systems, which take time to learn and often do not seem terribly relevant to the perception of the music. Finally, the less the coherence of a piece is dependent on pitch structure, the less applicable so much of our analytical arsenal seems to be. Concert Music, Rock, and Jazz since 1945 is a collection of essays dedicated to the sensible analytical discussion of some of the music that is, in general, resistant to traditional analysis. In a sense, it is a snapshot of how we have dealt with the problem of talking about recent music. It assures us it is neither a history nor an exhaustive survey; rather, the editors "have chosen essays that break new ground with respect to the compositions that they address, the perspectives from which they are written, or the analytical methodologies that they introduce or extend" (p. 3). Although one might not call each essay groundbreaking, they comprise a diverse sampling of what appears to be promising analysis these days, and they do present a survey of the issues that seem to be pressing. The book is divided into three sections, but they are not those suggested by the title. The first, "Compositional Poetics," is described by the editors as exploring "current cultural contexts for compositional thought" (p. 5). Part 2 is entitled "Some Structuralist Approaches." These essays are concerned with demonstrating how the music exhibits a comprehensible, organic structure in the traditional sense, and we shall begin here. In some cases, the music in question is dominated by a familiar means of coherence, such as tonality or pitch structure. In others, the musical language is particularly nontraditional, and the essay must develop and present highly idiosyncratic analytical strategies in order to provide a basis for a fruitful discussion of the music. Fortunately, each author is remarkably lucid, and it is easy to imagine any of these essays as an introduction to new analytical methods for otherwise musically experienced readers. In his essay concerning the music of Elliott Carter, Andrew Mead shows how Carter's registral manipulation of pitch classes can be seen as an alternative to the temporal manipulations characterized by serialism, demonstrating "a commonality with Schoenberg's practice" (p. 99). In doing so, however, Mead takes the opportunity to review the relation between the total chromatic and the diatonic set; by consistently using relatively recent terminology such as "row class," he spares the novice reader the confusion usually brought about by older terminology (such as the term "row" signifying the [at most] forty-eight set forms). Therefore, this essay not only takes the reader through certain complex means of pitch organization, but presents a worthwhile and clear account of the twelve-tone tradition as well. The subject of Walter Everett's essay, side two of the Beatles's Abbey Road album, also lends itself to a somewhat traditional approach: here voice-leading graphs demonstrate the large-scale coherence of the song cycle. …

This work presents a new type of transparent conductive adhesive and its electrical and optical properties with regards to an application in III–V on Silicon tandem solar cells. The developed adhesive is based on a doped ZnO and deposited by spray coating. The optical interconnection of the two sub-cells is identified as one of the major challenges due to the reflectance at the bond and possible approaches to reduce the reflectance are investigated by optical simulations. Regarding the electrical interconnection, an ITO-based contact layer reduced the lowest measured connecting resistivity from previously 17 Ω·cm² [1] down to 0.12 Ω·cm². It is shown that the homogeneity of the bond correlates with its conductivity and can be improved by adjusting the glueing process according to the calcination process of the adhesive. Taking both the electrical and optical parameters of the transparent conductive adhesive into account, the efficiency of a triple junction solar cell was estimated.

von Hermann Richard Progr.-Nr. 666