Budget impact of sequential treatment with first-line afatinib versus first-line osimertinib in non-small-cell lung cancer patients with common EGFR mutations

Background The therapeutic landscape for non-small-cell lung cancer (NSCLC) patients that have common epidermal growth factor receptor (EGFR) mutations has changed radically in the last decade. The availability of these treatment options has an economic impact, therefore a budget impact analysis was performed. Methods A budget impact analysis was conducted from a Dutch healthcare perspective over a 5-year time horizon in EGFR-mutant NSCLC patients receiving first-line afatinib (Gilotrif(R)) versus first-line osimertinib (Tagrisso(R)), followed by subsequent treatments. A decision analysis model was constructed in Excel. Scenario analyses and one-way sensitivity analysis were used to test the models' robustness. Results Sequential treatment with afatinib versus first-line treatment with osimertinib showed mean total time on treatment (ToT) of 29.1 months versus 24.7 months, quality-adjusted life months (QALMs) of 20.2 versus 17.4 with mean cost of euro108,166 per patient versus euro143,251 per patient, respectively. The 5-year total budget impact was euro110.4 million for the afatinib sequence versus euro158.6 million for the osimertinib sequence, leading to total incremental cost savings of euro48.15 million. Conclusions First-line afatinib treatment in patients with EGFR-mutant NSCLC had a lower financial impact on the Dutch healthcare budget with a higher mean ToT and QALM compared to osimertinib sequential treatment

The order parameter-entropy relation in some universal classes: experimental evidence

The asymptotic behaviour near phase transitions can be suitably characterized by the scaling of $\Delta s/Q^2$ with $\epsilon=1-T/T_c$, where $\Delta s$ is the excess entropy and $Q$ is the order parameter. As $\Delta s$ is obtained by integration of the experimental excess specific heat of the transition $\Delta c$, it displays little experimental noise so that the curve $\log(\Delta s/Q^2)$ versus $\log\epsilon$ is better constrained than, say, $\log\Delta c$ versus $\log\epsilon$. The behaviour of $\Delta s/Q^2$ for different universality classes is presented and compared. In all cases, it clearly deviates from being a constant. The determination of this function can then be an effective method to distinguish asymptotic critical behaviour. For comparison, experimental data for three very different systems, Rb2CoF4, Rb2ZnCl4 and SrTiO3, are analysed under this approach. In SrTiO3, the function $\Delta s/Q^2$ does not deviate within experimental resolution from a straight line so that, although Q can be fitted with a non mean-field exponent, the data can be explained by a classical Landau mean-field behaviour. In contrast, the behaviour of $\Delta s/Q^2$ for the antiferromagnetic transition in Rb2CoF4 and the normal-incommensurate phase transition in Rb2ZCl4 is fully consistent with the asymptotic critical behaviour of the universality class corresponding to each case. This analysis supports, therefore, the claim that incommensurate phase transitions in general, and the A$_2$BX$_4$ compounds in particular, in contrast with most structural phase transitions, have critical regions large enough to be observable.Comment: 13 pp. 9 ff. 2 tab. RevTeX. Submitted to J. Phys.: Cond. Matte

Generalized calculation of magnetic coupling constants for Mott-Hubbard insulators: Application to ferromagnetic Cr compounds

Using a Rayleigh-Schr\"odinger perturbation expansion of multi-band Hubbard models, we present analytic expressions for the super-exchange coupling constants between magnetic transition metal ions of arbitrary separation in Mott-Hubbard insulators. The only restrictions are i) all ligand ions are closed shell anions and ii) all contributing interaction paths are of equal length. For short paths, our results essentially confirm the Goodenough-Kanamori-Anderson rules, yet in general there does not exist any simple rule to predict the sign of the magnetic coupling constants. The most favorable situation for ferromagnetic coupling is found for ions with less than half filled d shells, the (relative) tendency to ferromagnetic coupling increases with increasing path length. As an application, the magnetic interactions of the Cr compounds Rb$_2$CrCl$_4$, CrCl$_3$, CrBr$_3$ and CrI$_3$ are investigated, all of which except CrCl$_3$ are ferromagnets.Comment: 13 pages, 6 eps figures, submitted to Phys Rev

Switching between dynamic states in intermediate-length Josephson junctions

The appearance of zero-field steps (ZFS’s) in the current-voltage characteristics of intermediate-length overlap-geometry Josephson tunnel junctions described by a perturbed sine-Gordon equation (PSGE) is associated with the growth of parametrically excited instabilities of the McCumber background curve (MCB). A linear stability analysis of a McCumber solution of the PSGE in the asymptotic linear region of the MCB and in the absence of magnetic field yields a Hill’s equation which predicts how the number, locations, and widths of the instability regions depend on the junction parameters. A numerical integration of the PSGE in terms of truncated series of time-dependent Fourier spatial modes verifies that the parametrically excited instabilities of the MCB evolve into the fluxon oscillations characteristic of the ZFS’s. An approximate analysis of the Fourier mode equations in the presence of a small magnetic field yields a field-dependent Hill’s equation which predicts that the major effect of such a field is to reduce the widths of the instability regions. Experimental measurements on Nb-NbxOy-Pb junctions of intermediate length, performed at different operating temperatures in order to vary the junction parameters and for various magnetic field values, verify the physical existence of switching from the MCB to the ZFS’s. Good qualitative, and in many cases quantitative, agreement between analytic, numerical, and experimental results is obtained

Magnetic correlations and quantum criticality in the insulating antiferromagnetic, insulating spin liquid, renormalized Fermi liquid, and metallic antiferromagnetic phases of the Mott system V_2O_3

Magnetic correlations in all four phases of pure and doped vanadium sesquioxide V_2O_3 have been examined by magnetic thermal neutron scattering. While the antiferromagnetic insulator can be accounted for by a Heisenberg localized spin model, the long range order in the antiferromagnetic metal is an incommensurate spin-density-wave, resulting from a Fermi surface nesting instability. Spin dynamics in the strongly correlated metal are dominated by spin fluctuations in the Stoner electron-hole continuum. Furthermore, our results in metallic V_2O_3 represent an unprecedentedly complete characterization of the spin fluctuations near a metallic quantum critical point, and provide quantitative support for the SCR theory for itinerant antiferromagnets in the small moment limit. Dynamic magnetic correlations for energy smaller than k_BT in the paramagnetic insulator carry substantial magnetic spectral weight. However, the correlation length extends only to the nearest neighbor distance. The phase transition to the antiferromagnetic insulator introduces a sudden switching of magnetic correlations to a different spatial periodicity which indicates a sudden change in the underlying spin Hamiltonian. To describe this phase transition and also the unusual short range order in the paramagnetic state, it seems necessary to take into account the orbital degrees of freedom associated with the degenerate d-orbitals at the Fermi level in V_2O_3.Comment: Postscript file, 24 pages, 26 figures, 2 tables, accepted by Phys. Rev.

Do health systems delay the treatment of poor children? A qualitative study of child deaths in rural Tanzania.

Child mortality remains one of the major public-health problems in Tanzania. Delays in receiving and accessing adequate care contribute to these high rates. The literature on public health often focuses on the role of mothers in delaying treatment, suggesting that they contact the health system too late and that they prefer to treat their children at home, a perspective often echoed by health workers. Using the three-delay methodology, this study focus on the third phase of the model, exploring the delays experienced in receiving adequate care when mothers with a sick child contact a health-care facility. The overall objective is to analyse specific structural factors embedded in everyday practices at health facilities in a district in Tanzania which cause delays in the treatment of poor children and to discuss possible changes to institutions and social technologies. The study is based on qualitative fieldwork, including in-depth interviews with sixteen mothers who have lost a child, case studies in which patients were followed through the health system, and observations of more than a hundred consultations at all three levels of the health-care system. Data analysis took the form of thematic analysis. Focusing on the third phase of the three-delay model, four main obstacles have been identified: confusions over payment, inadequate referral systems, the inefficient organization of health services and the culture of communication. These impediments strike the poorest segment of the mothers particularly hard. It is argued that these delaying factors function as 'technologies of social exclusion', as they are embedded in the everyday practices of the health facilities in systematic ways. The interviews, case studies and observations show that it is especially families with low social and cultural capital that experience delays after having contacted the health-care system. Reductions of the various types of uncertainty concerning payment, improved referral practices and improved communication between health staff and patients would reduce some of the delays within health facilities, which might feedback positively into the other two phases of delay

Crude incidence in two-phase designs in the presence of competing risks.

BackgroundIn many studies, some information might not be available for the whole cohort, some covariates, or even the outcome, might be ascertained in selected subsamples. These studies are part of a broad category termed two-phase studies. Common examples include the nested case-control and the case-cohort designs. For two-phase studies, appropriate weighted survival estimates have been derived; however, no estimator of cumulative incidence accounting for competing events has been proposed. This is relevant in the presence of multiple types of events, where estimation of event type specific quantities are needed for evaluating outcome.MethodsWe develop a non parametric estimator of the cumulative incidence function of events accounting for possible competing events. It handles a general sampling design by weights derived from the sampling probabilities. The variance is derived from the influence function of the subdistribution hazard.ResultsThe proposed method shows good performance in simulations. It is applied to estimate the crude incidence of relapse in childhood acute lymphoblastic leukemia in groups defined by a genotype not available for everyone in a cohort of nearly 2000 patients, where death due to toxicity acted as a competing event. In a second example the aim was to estimate engagement in care of a cohort of HIV patients in resource limited setting, where for some patients the outcome itself was missing due to lost to follow-up. A sampling based approach was used to identify outcome in a subsample of lost patients and to obtain a valid estimate of connection to care.ConclusionsA valid estimator for cumulative incidence of events accounting for competing risks under a general sampling design from an infinite target population is derived

Oceanic biogeochemical characteristic maps identified with holistic use of satellite, model and data

This is the final published version.Ocean province level plankton community exhibit heterogeneity across Arctic, Nordic, Atlantic Gyre and Southern Ocean provinces. GreenSeas research is an international FP7 consortium that includes Arctic, Atlantic and Southern Ocean based research teams who are analysing the planktonic ecosystem. We are looking at how the planktonic ecosystem responds to environmental and climate change. Using Earth Observation monitoring data we report new results on identifying generic plankton characteristics observable at a province level, and also touch on spatial and temporal trends that are evident using a holistic analysis framework. Using advanced statistical methods this framework compares and combines Earth Observation information together with an in-situ Oceanic plankton Analytical Database and up to 40 year ocean general circulation biogeochemical model (OGCBM) time series of the equivalent plankton and sea-state measures of this system. Specifically, we outline the use of the GreenSeas Analytical Database, which is a harmonised set of Oceanic in-situ plankton and sea-state measures covering different cruises and time periods. The Analytical Database information ranges from plankton community, primary production, nutrient cycling to physical sea state temperature and salinity measures. The combined analysis utilises current, 10 year+ Earth Observations of ocean colour and sea surface temperature metrics and interprets these together with biogeochemical model outputs from PELAGOS, ERSEM & NORWECOM model runs to help identify planktonic based biomes. Generic planktonic characteristic maps that are equivalently observable in both the Earth Observations and numerical models are reported on. Both ocean surface and sub-surface signals are analysed together with relevant Analytical Database biome extracts. We present the current results of this inter-comparison & discuss challenges of identifying the province level plankton dominance with the satellite, model and data. In particular we discuss the strategic importance of systematically analysing the knowledge present in the existing key long term Oceanic observation platforms through such holistic analysis frameworks. These maps help to enhance and improve current biogeochemical models, our understanding of the plankton community structure and predictions used for future assessment of climate change