[Reducing the use of medication in the elderly; why or why not?] / Medicatie minderen bij ouderen.

Many healthcare providers agree that reduction or stopping of medication, so-called deprescribing, would be good in vulnerable people with polypharmacy. However, deprescribing is not yet widely conducted. Physicians and pharmacists experience barriers, such as lack of evidence and guidance to support this process. There is also a tendency to maintain the status quo when there are no acute problems. Patients do want fewer pills but the proposal to stop certain medication can lead to resistance or confusion. The needs and concerns from a patient's perspective are a good starting point for desprescribing. It is important to set new goals and to prioritize together which medication can be stopped. It is not only relevant to react to existing problems but also to act proactively when the potential benefits no longer outweigh the medication burden or risks. Recently, more guidance and tools to support deprescribing became available in the Netherlands.

Statistical controversies in clinical research: futility analyses in oncology-lessons on potential pitfalls from a randomized controlled trial.

BACKGROUND: Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses. MATERIALS AND METHODS: LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS. RESULTS: At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis. CONCLUSIONS: Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate. TRIAL NUMBER: NCT00806819.

Comparative Effects of CT Imaging Measurement on RECIST End Points and Tumor Growth Kinetics Modeling.

Quantitative assessments of tumor burden and modeling of longitudinal growth could improve phase II oncology trials. To identify obstacles to wider use of quantitative measures we obtained recorded linear tumor measurements from three published lung cancer trials. Model-based parameters of tumor burden change were estimated and compared with similarly sized samples from separate trials. Time-to-tumor growth (TTG) was computed from measurements recorded on case report forms and a second radiologist blinded to the form data. Response Evaluation Criteria in Solid Tumors (RECIST)-based progression-free survival (PFS) measures were perfectly concordant between the original forms data and the blinded radiologist re-evaluation (intraclass correlation coefficient = 1), but these routine interrater differences in the identification and measurement of target lesions were associated with an average 18-week delay (range, -20 to 55 weeks) in TTG (intraclass correlation coefficient = 0.32). To exploit computational metrics for improving statistical power in small clinical trials will require increased precision of tumor burden assessments.

Manipulating duckweed through genome duplication.

Significant inter- and intraspecific genetic variation exists in duckweed, thus the potential for genome plasticity and manipulation is high. Polyploidy is recognised as a major mechanism of adaptation and speciation in plants. We produced several genome-duplicated lines of Landoltia punctata (Spirodela oligorrhiza) from both whole plants and regenerating explants using a colchicine-based cocktail. These lines stably maintained an enlarged frond and root morphology. DNA ploidy levels determined by florescence-activated cell sorting indicated genome duplication. Line A4 was analysed after 75 biomass doublings. Frond area, fresh and dry weights, rhizoid number and length were significantly increased versus wild type, while the growth rate was unchanged. This resulted in accumulation of biomass 17-20% faster in the A4 plants. We sought to determine if specific differences in gene products are found in the genome duplicated lines. Non-targeted ultra performance LC-quadrupole time of flight mass spectrometry was employed to compare some of the lines and the wild type to seek identification of up-regulated metabolites. We putatively identified differential metabolites in Line A65 as caffeoyl hexoses. The combination of directed genome duplication and metabolic profiling might offer a path for producing stable gene expression, leading to altered production of secondary metabolites.

Caputo standard α-family of maps: fractional difference vs. fractional.

In this paper, the author compares behaviors of systems which can be described by fractional differential and fractional difference equations using the fractional and fractional difference Caputo standard α-Families of maps as examples. The author shows that properties of fractional difference maps (systems with falling factorial-law memory) are similar to the properties of fractional maps (systems with power-law memory). The similarities (types of attractors, power-law convergence of trajectories, existence of cascade of bifurcations and intermittent cascade of bifurcations type trajectories, and dependence of properties on the memory parameter α) and differences in properties of falling factorial- and power-law memory maps are investigated.

Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.

Universal fractional map and cascade of bifurcations type attractors.

We modified the way in which the Universal Map is obtained in the regular dynamics to derive the Universal α-Family of Maps depending on a single parameter α>0, which is the order of the fractional derivative in the nonlinear fractional differential equation describing a system experiencing periodic kicks. We consider two particular α-families corresponding to the Standard and Logistic Maps. For fractional α<2 in the area of parameter values of the transition through the period doubling cascade of bifurcations from regular to chaotic motion in regular dynamics corresponding fractional systems demonstrate a new type of attractors--cascade of bifurcations type trajectories.

Fractional dissipative standard map.

Using kicked differential equations of motion with derivatives of noninteger orders, we obtain generalizations of the dissipative standard map. The main property of these generalized maps, which are called fractional maps, is long-term memory. The memory effect in the fractional maps means that their present state of evolution depends on all past states with special forms of weights. Already a small deviation of the order of derivative from the integer value corresponding to the regular dissipative standard map (small memory effects) leads to the qualitatively new behavior of the corresponding attractors. The fractional dissipative standard maps are used to demonstrate a new type of fractional attractors in the wide range of the fractional orders of derivatives.

A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Paclitaxel-carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. PATIENTS AND METHODS: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin area under the concentration-time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m(2) on days 1 and 8 plus paclitaxel 200 mg/m(2) on day 1 (GP), or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. RESULTS: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. CONCLUSIONS: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.

Superdiffusion in the dissipative standard map.

We consider transport properties of the chaotic (strange) attractor along unfolded trajectories of the dissipative standard map. It is shown that the diffusion process is normal except for the cases when a control parameter is close to some special values that correspond to the ballistic mode dynamics. Diffusion near the related crises is anomalous and nonuniform in time; there are large time intervals during which the transport is normal or ballistic, or even superballistic. The anomalous superdiffusion seems to be caused by stickiness of trajectories to a nonchaotic and nowhere dense invariant Cantor set that plays a similar role as cantori in Hamiltonian chaos. We provide a numerical example of such a sticky set. Distribution function on the sticky set almost coincides with the distribution function (SRB measure) of the chaotic attractor.

Computational redesign of a protein-protein interface for high affinity and binding specificity using modular architecture and naturally occurring template fragments.

A new method is presented for the redesign of protein-protein interfaces, resulting in specificity of the designed pair while maintaining high affinity. The design is based on modular interface architecture and was carried out on the interaction between TEM1 beta-lactamase and its inhibitor protein, beta-lactamase inhibitor protein. The interface between these two proteins is composed of several mostly independent modules. We previously showed that it is possible to delete a complete module without affecting the overall structure of the interface. Here, we replace a complete module with structure fragments taken from nonrelated proteins. Nature-optimized fragments were chosen from 10(7) starting templates found in the Protein Data Bank. A procedure was then developed to identify sets of interacting template residues with a backbone arrangement mimicking the original module. This generated a final list of 361 putative replacement modules that were ranked using a novel scoring function based on grouped atom-atom contact surface areas. The top-ranked designed complex exhibited an affinity of at least the wild-type level and a mode of binding that was remarkably specific despite the absence of negative design in the procedure. In retrospect, the combined application of three factors led to the success of the design approach: utilizing the modular construction of the interface, capitalizing on native rather than artificial templates, and ranking with an accurate atom-atom contact surface scoring function.

Problem of transport in billiards with infinite horizon.

We consider particles transport in the Sinai billiard with infinite horizon. The simulation shows that the transport is superdiffusive in both continuous and discrete time. Also, it is shown that the moments do not converge to the Gaussian moments even in the logarithmically renormalized time scale, at least for a fairly long computational time. These results are discussed with respect to the existent rigorous theorems. Similar results are obtained for the stadium billiard.

Stochastic web as a generator of three-dimensional quasicrystal symmetry.

It is shown that two coupled oscillators perturbed by periodic kicks generate a thin stochastic web in the four-dimensional phase space, which differs from the Arnold web. Under some resonance-type condition the web possesses a quasicrystal-type symmetry. In three-dimensional coordinate space, the web's symmetry corresponds to the icosahedral one and, due to that, the original four-dimensional map can be considered as a dynamical generator of the quasicrystal-type tiling of three-dimensional space.

Dynamics of the chain of forced oscillators with long-range interaction: from synchronization to chaos.

We consider a chain of nonlinear oscillators with long-range interaction of the type 1l(1+alpha), where l is a distance between oscillators and 0

Chaotic and pseudochaotic attractors of perturbed fractional oscillator.

We consider a nonlinear oscillator of the Duffing type with fractional derivative of the order 1

Polynomial dispersion of trajectories in sticky dynamics.

Hamiltonian chaotic dynamics is, in general, not ergodic and the boundaries of the ergodic or quasiergodic area (stochastic sea, stochastic layers, stochastic webs, etc.) are sticky, i.e., trajectories can spend an arbitrarily long time in the vicinity of the boundaries with a nonexponentially small probability. Segments of trajectories imposed by the stickiness are called flights. The flights have polynomial dispersion that can lead to non-Gaussian statistics of displacements and to anomalous transport in phase space. In particular, the presence of flights influences the distribution of Poincaré recurrences. We use the distribution function of (l,t;epsilon, epsilon0) -separation of trajectories that at time instant t and trajectory length l are separated for the first time by epsilon<<1, being initially at a distance epsilon0 <

Chaos-induced intensification of wave scattering.

Sound-wave propagation in a strongly idealized model of the deep-water acoustic waveguide with a periodic range dependence is considered. It is investigated how the phenomenon of ray and wave chaos affects the sound scattering at a strong mesoscale inhomogeneity of the refractive index caused by the synoptic eddy. Methods derived in the theory of dynamical and quantum chaos are applied. When studying the properties of wave chaos we decompose the wave field into a sum of Floquet modes analogous to quantum states with fixed quasi-energies. It is demonstrated numerically that the "stable islands" from the phase portrait of the ray system reveal themselves in the coarse-grained Wigner functions of individual Floquet modes. A perturbation theory has been derived which gives an insight into the role of the mode-medium resonance in the formation of Floquet modes. It is shown that the presence of a weak internal-wave-induced perturbation giving rise to ray and wave chaos strongly increases the sensitivity of the monochromatic wave field to an appearance of the eddy. To investigate the sensitivity of the transient wave field we have considered variations of the ray travel times--arrival times of sound pulses coming to the receiver through individual ray paths--caused by the eddy. It turns out that even under conditions of ray chaos these variations are relatively predictable. This result suggests that the influence of chaotic-ray motion may be partially suppressed by using pulse signals. However, the relative predictability of travel time variations caused by a large-scale inhomogeneity is not a general property of the ray chaos. This statement is illustrated numerically by considering an inhomogeneity in the form of a perfectly reflecting bar.

Topological instability along invariant surfaces and pseudochaotic transport.

The paper describes the complex topological structure of invariant surfaces that appears in a quasi-stationary regime of the tokamak plasma, and it considers in detail anomalous transport of particles along the invariant surfaces (isosurfaces) that have topological genus greater than 1. Such dynamics is pseudochaotic; i.e. it has a zero Lyapunov exponent. Simulations discover such surfaces in confined plasmas under a fairly low ratio of pressure to the magnetic field energy (beta). The isosurfaces correspond to quasi-coherent structures called "streamers" and the streamers are connected by filaments. We study distribution of time of particle separation, Poincaré; recurrences of trajectories, and first time arrival to the system's edge. A model of a multibar-in-square billiard, introduced by Carreras et al. [Chaos 13, 1175 (2003)] is studied with renormalization group method to obtain a distribution of the first time of particles arrival to the edge as a function of the number of bars, which appears to be power-like. The characteristic exponent of this distribution is discussed with respect to its dependence on the number of filaments that connect adjacent streamers.

Callus induction and regeneration in Spirodela and Lemna.

The development of tissue culture systems in duckweeds has, to date, been limited to species of the genus Lemna. We report here the establishment of an efficient tissue culture cycle (callus induction, callus growth and plant regeneration) for Spirodela oligorrhiza Hegelm SP, Spirodela punctata 8717 and Lemna gibba var. Hurfeish. Significant differences were found among the three duckweed species pertaining to carbohydrate and phytohormone requirements for callus induction, callus growth and frond regeneration. In vitro incubation with poorly assimilated carbohydrates such as galactose ( S. oligorrhiza SP and L. gibba var. Hurfeish) and sorbitol ( S. punctata 8717) as sole carbon source yielded high levels of callus induction on phytohormone-supplemented medium. Sorbitol is required for optimal callus growth of S. oligorrhiza SP and S. punctata 8717, while sucrose is required for callus growth of L. gibba var. Hurfeish. Sucrose either alone ( S. oligorrhiza SP, L. gibba var. Hurfeish) or in addition to sorbitol ( S. punctata 8717) is required for frond regeneration.

Topological instability along filamented invariant surfaces.

In dynamical systems with a zero Lyapunov exponent, weak mixing can be governed by a specific topological structure of some surfaces that are invariant with respect to particle dynamics. In particular, when the genus of the invariant surfaces is more than one, they may have weak mixing and the corresponding fractional kinetics. This possibility is demonstrated by using a typical example from plasma physics, a three-dimensional resistive pressure-gradient-driven turbulence model. In a toroidal geometry and with a low-pressure gradient, this model shows the emergence of quasicoherent structures. In this situation, the isosurfaces of the velocity stream function have a web structure with filamentary surfaces emerging from the outer region of the torus and covering the inner region. The filamentary surfaces can result in stochastic jets of particles that cause a "topological instability." In such a situation, particle transport along the surfaces is of the anomalous superdiffusion type.