Economic evaluation of adverse events of dabrafenib plus trametinib versus nivolumab in patients with advanced BRAF-mutant cutaneous melanoma for adjuvant therapy in Germany

Background: Adjuvant treatment options have become the standard therapy for stage III and IV resectable cutaneous melanoma. Two recent studies led to the registration of dabrafenib and trametinib as targeted therapies for BRAF-mutated melanoma, and of immunotherapy with nivolumab irrespective of BRAF-mutation status. Both therapies have different spectrums of adverse events. Objective: To estimate the financial impact of side effects from the perspective of the German statutory sick funds to compare both therapeutic options and to relate the burden to the overall costs of the treatment. Study design and setting: Thirty-six adverse event categories for the combination of dabrafenib and trametinib (‘combi treatment’) and for nivolumab were extracted from the original publications of the studies named COMBI-AD and CheckMate 238. Patients and intervention: For all event categories a diagnosis and therapy recommendation were determined according to current national or international guidelines or from leading German textbooks. Main outcome measure: The resulting diagnostic steps, treatments, and therapies were evaluated with unit costs based on the German fee schedule for ambulatory physicians, the German G-DRG scheme, and the German drug price list. Results: The number of events with nivolumab per one hundred treatments amounted to 3.8 mandatory hospitalizations, 3.5 emergency care events and 0.8 life-threatening events. For the combi treatment, the respective number of events per one hundred treatments was 2.7, 1.8, and 0.5. The overall cost burden was calculated as €899 for nivolumab and €861 for combi-treatment. Conclusion: The treatment of adverse events resulting from adjuvant melanoma therapy showed comparable costs for both therapies

Ocean Dynamics and the Inner Edge of the Habitable Zone for Tidally Locked Terrestrial Planets

Recent studies have shown that ocean dynamics can have a significant warming effect on the permanent night sides of 1 to 1 tidally locked terrestrial exoplanets with Earth-like atmospheres and oceans in the middle of the habitable zone. However, the impact of ocean dynamics on the habitable zone's boundaries (inner edge and outer edge) is still unknown and represents a major gap in our understanding of this type of planets. Here we use a coupled atmosphere-ocean global climate model to show that planetary heat transport from the day to night side is dominated by the ocean at lower stellar fluxes and by the atmosphere near the inner edge of the habitable zone. This decrease in oceanic heat transport (OHT) at high stellar fluxes is mainly due to weakening of surface wind stress and a decrease in surface shortwave energy deposition. We further show that ocean dynamics have almost no effect on the observational thermal phase curves of planets near the inner edge of the habitable zone. For planets in the habitable zone's middle range, ocean dynamics moves the hottest spot on the surface eastward from the substellar point. These results suggest that future studies of the inner edge may devote computational resources to atmosphere-only processes such as clouds and radiation. For studies of the middle range and outer edge of the habitable zone, however, fully coupled ocean-atmosphere modeling will be necessary. Note that due to computational resource limitations, only one rotation period (60 Earth days) has been systematically examined in this study; future work varying rotation period as well as other parameters such as atmospheric mass and composition is required.Comment: 34 pages, 13 figures, and 1 tabl

Field-Induced Tunneling Ionization and Terahertz-Driven Electron Dynamics in Liquid Water

Liquid water at ambient temperature displays ultrafast molecular motions and concomitant fluctuations of very strong electric fields originating from the dipolar H2O molecules. We show that such random intermolecular fields induce the tunnel ionization of water molecules, which becomes irreversible if an external terahertz (THz) pulse imposes an additional directed electric field on the liquid. Time-resolved nonlinear THz spectroscopy maps charge separation, transport, and localization of the released electrons on a few-picosecond time scale. The highly polarizable localized electrons modify the THz absorption spectrum and refractive index of water, a manifestation of a highly nonlinear response. Our results demonstrate how the interplay of local electric field fluctuations and external electric fields allows for steering charge dynamics and dielectric properties in aqueous systems. Copyright © 2020 American Chemical Society

Field-Induced Tunneling Ionization and Terahertz-Driven Electron Dynamics in Liquid Water

Liquid water at ambient temperature displays ultrafast molecular motions and concomitant fluctuations of very strong electric fields originating from the dipolar H2O molecules. We show that such random intermolecular fields induce tunnel ionization of water molecules, which becomes irreversible if an external terahertz (THz) pulse imposes an additional directed electric field on the liquid. Time-resolved nonlinear THz spectroscopy maps charge separation, transport and localization of the released electrons on a few-picosecond time scale. The highly polarizable localized electrons modify the THz absorption spectrum and refractive index of water, a manifestation of a highly nonlinear response. Our results demonstrate how the interplay of local electric field fluctuations and external electric fields allows for steering charge dynamics and dielectric properties in aqueous systems

Bethe-Salpeter equation and a nonperturbative quark-gluon vertex

A Ward-Takahashi identity preserving Bethe-Salpeter kernel can always be calculated explicitly from a dressed-quark-gluon vertex whose diagrammatic content is enumerable. We illustrate that fact using a vertex obtained via the complete resummation of dressed-gluon ladders. While this vertex is planar, the vertex-consistent kernel is nonplanar and that is true for any dressed vertex. In an exemplifying model the rainbow-ladder truncation of the gap and Bethe-Salpeter equations yields many results; e.g., pi- and rho-meson masses, that are changed little by including higher-order corrections. Repulsion generated by nonplanar diagrams in the vertex-consistent Bethe-Salpeter kernel for quark-quark scattering is sufficient to guarantee that diquark bound states do not exist.Comment: 16 pages, 12 figures, REVTEX