Post-processing through linear regression

Various post-processing techniques are compared for both deterministic and ensemble forecasts, all based on linear regression between forecast data and observations. In order to evaluate the quality of the regression methods, three criteria are proposed, related to the effective correction of forecast error, the optimal variability of the corrected forecast and multicollinearity. The regression schemes under consideration include the ordinary least-square (OLS) method, a new time-dependent Tikhonov regularization (TDTR) method, the total least-square method, a new geometric-mean regression (GM), a recently introduced error-in-variables (EVMOS) method and, finally, a "best member" OLS method. The advantages and drawbacks of each method are clarified. These techniques are applied in the context of the 63 Lorenz system, whose model version is affected by both initial condition and model errors. For short forecast lead times, the number and choice of predictors plays an important role. Contrarily to the other techniques, GM degrades when the number of predictors increases. At intermediate lead times, linear regression is unable to provide corrections to the forecast and can sometimes degrade the performance (GM and the best member OLS with noise). At long lead times the regression schemes (EVMOS, TDTR) which yield the correct variability and the largest correlation between ensemble error and spread, should be preferred

Trading interactions for topology in scale-free networks

Scale-free networks with topology-dependent interactions are studied. It is shown that the universality classes of critical behavior, which conventionally depend only on topology, can also be explored by tuning the interactions. A mapping, $\gamma' = (\gamma - \mu)/(1-\mu)$, describes how a shift of the standard exponent $\gamma$ of the degree distribution $P(q)$ can absorb the effect of degree-dependent pair interactions $J_{ij} \propto (q_iq_j)^{-\mu}$. Replica technique, cavity method and Monte Carlo simulation support the physical picture suggested by Landau theory for the critical exponents and by the Bethe-Peierls approximation for the critical temperature. The equivalence of topology and interaction holds for equilibrium and non-equilibrium systems, and is illustrated with interdisciplinary applications.Comment: 4 pages, 5 figure

Ising model for distribution networks

An elementary Ising spin model is proposed for demonstrating cascading failures (break-downs, blackouts, collapses, avalanches, ...) that can occur in realistic networks for distribution and delivery by suppliers to consumers. A ferromagnetic Hamiltonian with quenched random fields results from policies that maximize the gap between demand and delivery. Such policies can arise in a competitive market where firms artificially create new demand, or in a solidary environment where too high a demand cannot reasonably be met. Network failure in the context of a policy of solidarity is possible when an initially active state becomes metastable and decays to a stable inactive state. We explore the characteristics of the demand and delivery, as well as the topological properties, which make the distribution network susceptible of failure. An effective temperature is defined, which governs the strength of the activity fluctuations which can induce a collapse. Numerical results, obtained by Monte Carlo simulations of the model on (mainly) scale-free networks, are supplemented with analytic mean-field approximations to the geometrical random field fluctuations and the thermal spin fluctuations. The role of hubs versus poorly connected nodes in initiating the breakdown of network activity is illustrated and related to model parameters

Differential affinity of FLIP and procaspase 8 for FADD’s DED binding surfaces regulates DISC assembly

Death receptor activation triggers recruitment of FADD, which via its death effector domain (DED) engages the DEDs of procaspase 8 and its inhibitor FLIP to form death-inducing signalling complexes (DISCs). The DEDs of FADD, FLIP and procaspase 8 interact with one another using two binding surfaces defined by α1/α4 and α2/α5 helices, respectively. Here we report that FLIP has preferential affinity for the α1/α4 surface of FADD, whereas procaspase 8 has preferential affinity for FADD's α2/α5 surface. These relative affinities contribute to FLIP being recruited to the DISC at comparable levels to procaspase 8 despite lower cellular expression. Additional studies, including assessment of DISC stoichiometry and functional assays, suggest that following death receptor recruitment, the FADD DED preferentially engages FLIP using its α1/α4 surface and procaspase 8 using its α2/α5 surface; these tripartite intermediates then interact via the α1/α4 surface of FLIP DED1 and the α2/α5 surface of procaspase 8 DED2

Formation, dynamics and stability of coreless vortex dipoles in phase-separated binary condensates

We study the motion of the Gaussian obstacle potential created by blue detuned laser beam through a phase-separated binary condensate in pancake-shaped traps. For the velocity of the obstacle above a critical velocity, we observe the generation of vortex dipoles in the outer component which can penetrate the inner component. This is equivalent to finite, although small, transport of outer component across the inner component. In the inner component, the same method can lead to the formation of coreless vortex dipoles.Comment: 12 pages, 9 figure

Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^ndEGFR-TKI administration.</p> <p>Methods</p> <p>We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.</p> <p>Results</p> <p>Three patients (27%) were treated with gefitinib as the 2^ndEGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^ndEGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^ndEGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^ndEGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.</p> <p>Conclusions</p> <p>Our results indicate that a 2^ndEGFR-TKI treatment can be an effective treatment option for gefitinib responders.</p

Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^ndEGFR-TKI administration.</p> <p>Methods</p> <p>We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.</p> <p>Results</p> <p>Three patients (27%) were treated with gefitinib as the 2^ndEGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^ndEGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^ndEGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^ndEGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.</p> <p>Conclusions</p> <p>Our results indicate that a 2^ndEGFR-TKI treatment can be an effective treatment option for gefitinib responders.</p

EGFR-targeting drugs in combination with cytotoxic agents: from bench to bedside, a contrasted reality

The clinical experience recently reported with epidermal growth factor receptor (EGFR)-targeting drugs confirms the synergistic interactions observed between these compounds and conventional cytotoxic agents, which were previously established at the preclinical stage. There are, however, examples of major gaps between the bench and the bedside. Particularly demonstrative is the failure of the tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) combined with chemotherapy in pretreated nonsmall cell lung cancer patients. These discrepancies can be due to several factors such as the methodology used to evaluate TKI plus cytotoxic agent combinations in preclinical models and the insufficient consideration given to the importance of the drug sequences for the tested combinations. Recent advances in understanding the biologic basis of acquired resistance to these agents have great potential to improve their clinical effectiveness. The purpose of this review is to critically examine the experimental conditions of the preclinical background for anti-EGFR drug–cytotoxic agent combinations and to attempt to explain the gap between clinical observations and preclinical data

Attribution of the heavy rainfall events leading to severe flooding in Western Europe during July 2021

In July 2021 extreme rainfall across Western Europe caused severe flooding and substantial impacts, including over 200 fatalities and extensive infrastructure damage within Germany and the Benelux countries. After the event, a hydrological assessment and a probabilistic event attribution analysis of rainfall data were initiated and complemented by discussing the vulnerability and exposure context. The global mean surface temperature (GMST) served as a covariate in a generalised extreme value distribution fitted to observational and model data, exploiting the dependence on GMST to estimate how anthropogenic climate change affects the likelihood and severity of extreme events. Rainfall accumulations in Ahr/Erft and the Belgian Meuse catchment vastly exceeded previous observed records. In regions of that limited size the robust estimation of return values and the detection and attribution of rainfall trends are challenging. However, for the larger Western European region it was found that, under current climate conditions, on average one rainfall event of this magnitude can be expected every 400 years at any given location. Consequently, within the entire region, events of similar magnitude are expected to occur more frequently than once in 400 years. Anthropogenic climate change has already increased the intensity of the maximum 1-day rainfall event in the summer season by 3–19 %. The likelihood of such an event to occur today compared to a 1.2 ∘ C cooler climate has increased by a factor of 1.2–9. Models indicate that intensity and frequency of such events will further increase with future global warming. While attribution of small-scale events remains challenging, this study shows that there is a robust increase in the likelihood and severity of rainfall events such as the ones causing extreme impacts in July 2021 when considering a larger region

Attribution of the heavy rainfall events leading to severe flooding in Western Europe during July 2021

In July 2021 extreme rainfall across Western Europe caused severe flooding and substantial impacts, including over 200 fatalities and extensive infrastructure damage within Germany and the Benelux countries. After the event, a hydrological assessment and a probabilistic event attribution analysis of rainfall data were initiated and complemented by discussing the vulnerability and exposure context. The global mean surface temperature (GMST) served as a covariate in a generalised extreme value distribution fitted to observational and model data, exploiting the dependence on GMST to estimate how anthropogenic climate change affects the likelihood and severity of extreme events. Rainfall accumulations in Ahr/Erft and the Belgian Meuse catchment vastly exceeded previous observed records. In regions of that limited size the robust estimation of return values and the detection and attribution of rainfall trends are challenging. However, for the larger Western European region it was found that, under current climate conditions, on average one rainfall event of this magnitude can be expected every 400 years at any given location. Consequently, within the entire region, events of similar magnitude are expected to occur more frequently than once in 400 years. Anthropogenic climate change has already increased the intensity of the maximum 1-day rainfall event in the summer season by 3–19 %. The likelihood of such an event to occur today compared to a 1.2 $$^{\circ }$$C cooler climate has increased by a factor of 1.2–9. Models indicate that intensity and frequency of such events will further increase with future global warming. While attribution of small-scale events remains challenging, this study shows that there is a robust increase in the likelihood and severity of rainfall events such as the ones causing extreme impacts in July 2021 when considering a larger region