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Multi-criteria decision analysis (MCDA) involves asking decision makers difficult questions, and can leave them thinking that their judgements are not as coherent as they might have thought. This experience can be distressing and may even lead to rejection of the analysis. The psychology of preference sheds light both on how people naturally make choices without decision analytic assistance, and on how people think about the MCDA elicitation questions. As such, it can help the analyst to respond helpfully to difficulties which decision makers may face. In this paper, we review research from Behavioural Decision Theory relevant to MCDA. Our review follows the MCDA process, discussing research relevant to the structuring, value elicitation, and weighting phases of the analysis, outlining relevant and important findings, and open questions for research and practice.

This review is about decision technology-the rules and tools that help us make wiser decisions. First, we review the three rules that are at the heart of most traditional decision technology-multi-attribute utility, Bayes' theorem, and subjective expected utility maximization.

Aim: To examine the preference for two dosing regimens of 20 mg of tadalafil, on demand or three times per week, in men affected with erectile dysfunction (ED) in Italy. Methods: Scheduled Use versus on demand Regimen Evaluation (SURE) is a multicenter, crossover and open‐label study, involving 94 urology centers in Italy. Patients aged 18 years or older affected with ED for at least 3 months were enrolled and randomized to 20 mg of tadalafil treatment on demand or three times per week for 5‐6 weeks. After a 1‐week washout, patients were crossed over to the alternate regimen for 5‐6 weeks. A treatment preference question was used to determine the preferred treatment regimen. International Index of Erectile Function (IIEF) and Sexual Encounter Profile (SEP) questionnaire were used as efficacy measures. Results: A total of 1 058 men (mean age 54.8 years), were randomized to treatment. Overall, 59.1% of patients preferred the on‐demand regimen and 41.9% preferred the three times per week dosing. Both regimens were efficacious and well tolerated. Although a statistically higher improvement of the IIEF erectile function (IIEF‐EF) domain score and the SEP questionnaire was reported for the three times per week compared to the on‐demand treatment regimen, this difference was numerically minimal and lacking in clinical significance. Conclusion: Tadalafil is effective and well tolerated whether used on demand or three times per week. Patients should be given the option to choose the best treatment regimen according to personal needs and preferences.

Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma. This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110. Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4–32·3) and 15 (33%; 95% CI 20–49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1–47·8). Nine (69%; 95% CI 39–91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]). Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. Novartis.

Summary Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Protein phosphorylation is estimated to affect 30% of the proteome and is a major regulatory mechanism that controls many basic cellular processes. Until recently, our biochemical understanding of protein phosphorylation on a global scale has been extremely limited; only one half of the yeast kinases have known in vivo substrates and the phosphorylating kinase is known for less than 160 phosphoproteins. Here we describe, with the use of proteome chip technology, the in vitro substrates recognized by most yeast protein kinases: we identified over 4,000 phosphorylation events involving 1,325 different proteins. These substrates represent a broad spectrum of different biochemical functions and cellular roles. Distinct sets of substrates were recognized by each protein kinase, including closely related kinases of the protein kinase A family and four cyclin-dependent kinases that vary only in their cyclin subunits. Although many substrates reside in the same cellular compartment or belong to the same functional category as their phosphorylating kinase, many others do not, indicating possible new roles for several kinases. Furthermore, integration of the phosphorylation results with protein-protein interaction and transcription factor binding data revealed novel regulatory modules. Our phosphorylation results have been assembled into a first-generation phosphorylation map for yeast. Because many yeast proteins and pathways are conserved, these results will provide insights into the mechanisms and roles of protein phosphorylation in many eukaryotes.

Less than 1% of all microorganisms of the available environmental microbiota can be cultured with the currently available techniques. Metagenomics is a new methodology of high-throughput DNA sequencing, able to provide taxonomic and functional profiles of microbial communities without the necessity to culture microbes in the laboratory. Metagenomics opens to a ‘hypothesis-free’ approach, giving important details for future research and treatment of ocular diseases in ophthalmology, such as ocular infection and ocular surface diseases.

Reducing noise to the quantum limit over a large bandwidth is a fundamental requirement for future applications operating at millikelvin temperatures, such as the neutrino mass measurement, the next-generation X-ray observatory, the CMB measurement, the dark matter and axion detection, and the rapid high-fidelity readout of superconducting qubits. The read out sensitivity of arrays of microcalorimeter detectors, resonant axion-detectors, and qubits, is currently limited by the noise temperature and bandwidth of the cryogenic amplifiers. The Detector Array Readout with Traveling Wave Amplifiers project has the goal of developing high-performing innovative traveling wave parametric amplifiers with a high gain, a high saturation power, and a quantum-limited or nearly quantum-limited noise. The practical development follows two different promising approaches, one based on the Josephson junctions and the other one based on the kinetic inductance of a high-resistivity superconductor. In this contribution, we present the aims of the project, the adopted design solutions and preliminary results from simulations and measurements.

Superconducting parametric amplifiers offer the capability to amplify feeble signals with extremely low levels of added noise, potentially reaching quantum-limited amplification. This characteristic makes them essential components in the realm of high-fidelity quantum computing and serves to propel advancements in the field of quantum sensing. In particular, Traveling-Wave Parametric Amplifiers (TWPAs) may be especially suitable for practical applications due to their multi-Gigahertz amplification bandwidth, a feature lacking in Josephson Parametric Amplifiers (JPAs), despite the latter being a more established technology. This paper presents recent developments of the DARTWARS (Detector Array Readout with Traveling Wave AmplifieRS) project, focusing on the latest prototypes of Kinetic Inductance TWPAs (KITWPAs). The project aims to develop a KITWPA capable of achieving 20 dB of amplification. To enhance the production yield, the first prototypes were fabricated with half the length and expected gain of the final device. In this paper, we present the results of the characterization of one of the half-length prototypes. The measurements revealed an average amplification of approximately 9 dB across a 2 GHz bandwidth for a KITWPA spanning 17 mm in length.

The standard serological methods present limitations for the measurement of immunity against H5N1 influenza strains. The hemagglutination inhibition (HI) assay lacks sensitivity and requires standardization, while the viral micro-neutralization (MN) assay needs handling of live virus. We produced pseudoparticles expressing hemagglutinin from clades 1 or 2 H5N1 in order to measure neutralizing antibodies in human sera after prime-boost vaccination with plain or MF59-adjuvanted H5N1 clade 1 subunit vaccines. Titers measured by pseudoparticle neutralization (PPN) assay significantly correlated with those measured by HI, single radial haemolysis or MN, with a PPN titer of 1:357 corresponding to an MN titer of 1:80. Notably, results from the PPN assay, confirm that MF59-H5N1 vaccine induces potent and long-lasting neutralizing antibody responses not only against the vaccine strain, but also against several heterologous clade 2 strains. Overall, the PPN assay represents a valid alternative to conventional serological methods for the evaluation of H5N1 vaccine immunogenicity.