Structured medication reviews in Parkinson's disease: pharmacists' views, experiences and needs - a qualitative study.

Background: Executing structured medication reviews (SMRs) in primary care to optimize drug treatment is considered standard care of community pharmacists in the Netherlands. Patients with Parkinson's disease (PD) often face complex drug regimens for their symptomatic treatment and might, therefore, benefit from an SMR. However, previously, no effect of an SMR on quality of life in PD was found. In trying to improve the case management of PD, it is interesting to understand if and to what extent SMRs in PD patients are of added value in the pharmacist's opinion and what are assumed facilitating and hindering factors. Objectives: To analyse the process of executing SMRs in PD patients from a community pharmacist's point of view. Design: A cross-sectional, qualitative study was performed, consisting of face-to-face semi-structured in-depth interviews. Methods: The interviews were conducted with community pharmacists who executed at least one SMR in PD, till data saturation was reached. Interviews were transcribed verbatim, coded and analysed thematically using an iterative approach. Results: Thirteen pharmacists were interviewed. SMRs in PD were considered of added value, especially regarding patient contact and bonding, individualized care and its possible effect in the future, although PD treatment is found already well monitored in secondary care. Major constraints were time, logistics and collaboration with medical specialists. Conclusion: Although community pharmacist-led SMRs are time-consuming and sometimes logistically challenging, they are of added value in primary care in general, and also in PD, of which treatment occurs mainly in secondary care. It emphasizes the pharmacist's role in PD treatment and might tackle future drug-related issues. Improvements concern multidisciplinary collaboration for optimized SMR execution and results.

Structured medication reviews in Parkinson's disease: pharmacists' views, experiences and needs Why is this research done? In Parkinson's disease (PD), drug therapy is still the most important treatment strategy. Due to disease progression, patients often face complicated medication regimens, polypharmacy, and potential drug-related problems. The execution of structured medication reviews (SMR) in primary care is considered standard care of community pharmacists in the Netherlands, aiming to optimise drug treatment. Although it might also affect clinical outcomes, we found no effect of an SMR in PD on quality of life in our previous study. In trying to improve case management of PD, we need to understand if and to what extent SMRs in PD patients are of added value in the pharmacist's opinion, and what are assumed facilitating and hindering factors. What did the researchers do? We conducted semi-structured interviews with 13 community pharmacists who recently executed ⩾1 SMR in PD. What did the researchers find? We found that SMRs in PD are considered of added value with regard to patient bonding and individualised care. By being known by the pharmacist, and vice versa, by knowing the patient's situation, future drug problems might be tackled earlier. However, executing SMRs comes with barriers, of which lack of time, logistic constraints and difficulties in cooperation with the medical specialist are the most important. What do these findings mean? Taking into account both the pharmacist's effort and additional costs when performing an SMR in the current setting, the valuable time of a pharmacist could potentially better be spent on more (cost-)effective interventions, or a structural solution should be sought for the experienced hindering factors. Since we do not doubt the importance of periodic medication optimization in complex diseases or high-risk patients, we have to focus on either improving the current setting of SMRs in PD, or searching for other strategies in which this can be achieved.

Control-Oriented Models for Hyperelastic Soft Robots Through Differential Geometry of Curves.

The motion complexity and use of exotic materials in soft robotics call for accurate and computationally efficient models intended for control. To reduce the gap between material and control-oriented research, we build upon the existing piece-wise constant curvature framework by incorporating hyperelastic and viscoelastic material behavior. In this work, the continuum dynamics of the soft robot are derived through the differential geometry of spatial curves, which are then related to finite-element data to capture the intrinsic geometric and material nonlinearities. To enable fast simulations, a reduced-order integration scheme is introduced to compute the dynamic Lagrangian matrices efficiently, which in turn allows for real-time (multilink) models with sufficient numerical precision. By exploring the passivity and using the parameterization of the hyperelastic model, we propose a passivity-based adaptive controller that enhances robustness toward material uncertainty and unmodeled dynamics-slowly improving their estimates online. As a study-case, a soft robot manipulator is developed through additive manufacturing, which shows good correspondence with the dynamic model under various conditions, for example, natural oscillations, forced inputs, and under tip-loads. The solidity of the approach is demonstrated through extensive simulations, numerical benchmarks, and experimental validations.

The Effect of a Structured Medication Review on Quality of Life in Parkinson's Disease.

BACKGROUND: Drug therapy is important for controlling symptoms in Parkinson's disease (PD). However, it often results in complex medication regimens and could easily lead to drug related problems (DRP), suboptimal adherence and reduced treatment efficacy. A structured medication review (SMR) could address these issues and optimize therapy, although little is known about clinical effects in PD patients. OBJECTIVE: To analyze whether an SMR improves quality of life (QoL) in PD. METHODS: In this multicenter randomized controlled trial, half of the 202 PD patients with polypharmacy received a community pharmacist-led SMR. The control group received usual care. Assessments at baseline, and after three and six months comprised six validated questionnaires. Primary outcome was PD specific QoL [(PDQ-39; range 0 (best QoL) - 100 (worst QoL)]. Secondary outcomes were disability score, non-motor symptoms, general health status, and personal care giver's QoL. Furthermore, DRPs, proposed interventions, and implemented modifications in medication schedules were analyzed. RESULTS: No improvement in QoL was seen six months after an SMR, with a non-significant treatment effect difference of 2.09 (-0.63;4.80) in favor of the control group. No differences were found in secondary outcomes. In total, 260 potential DRPs were identified (2.6 (±1.8) per patient), of which 62% led to drug therapy optimization. CONCLUSION: In the current setting, a community pharmacist-led SMR did not improve QoL in PD patients, nor improved other pre-specified outcomes.

The Impact of Non-dopaminergic Medication on Quality of Life in Parkinson's Disease.

BACKGROUND AND OBJECTIVES: Quality of life (QoL) in Parkinson's disease (PD) depends on multiple factors. Due to PD treatment and accompanying, age-related or independent comorbidities, pill burden is often high. The relation of QoL and pharmacotherapy for comorbidities in PD has not been widely studied. This study investigated if and to what extent non-dopaminergic drugs are related to QoL in PD. Second, the impact of demographics and non-motor symptoms were evaluated. A better understanding of the impact of different non-dopaminergic drugs and polypharmacy on QoL will have added value in selecting appropriate (medication) interventions. METHODS: In a cross-sectional analysis, medication prescription data of 209 PD patients were analyzed and grouped according to the Rx-Risk comorbidity index. QoL was measured using the PDQ-39 questionnaire. Non-motor symptoms were analyzed with the Non-Motor Symptoms questionnaire. Independent factors associated with a reduced QoL were identified with a multivariate linear regression analysis. RESULTS: Non-dopaminergic drugs, subdivided into Rx-Risk comorbidity categories, were not associated with reduced QoL, except for the use of anti-epileptic drugs. However, using more daily non-dopaminergic drugs was also negatively associated with QoL, as well as female sex, increased PD severity, and more non-motor symptoms. Contraindicated non-dopaminergic medication was barely prescribed (0.4%). CONCLUSION: Non-dopaminergic drugs are frequently prescribed, and higher numbers are associated with impaired QoL in PD. However, when divided in drug types, only anti-epileptic drugs were negatively associated with QoL. In these patients, physicians might improve QoL by further optimizing the condition it was prescribed for (e.g., pain or anxiety), or managing of side effects. TRIAL REGISTRATION: Netherlands Trial Register; NL4360.

Detecting coexisting oscillatory patterns in delay coupled Lur'e systems.

This work addresses the problem of pattern analysis in networks consisting of delay-coupled identical Lur'e systems. We study a class of nonlinear systems, which, being isolated, are globally asymptotically stable. Assembling such systems into a network via time-delayed coupling may result in the change of network equilibrium stability under parameter variation in the coupling. In this work, we focus on cases where a Hopf bifurcation causes the change of stability of the network equilibrium and leads to the occurrence of oscillatory modes (patterns). Moreover, some of these patterns can co-exist for the same set of coupling parameters, which makes the analysis by means of common methods, such as the Lyapunov-Krasovskii method or the analysis of Poincaré maps, cumbersome. A numerically efficient algorithm, aiming at the computation of the oscillatory patterns occurring in such networks, is presented. Moreover, we show that our approach is able to deal with co-existing patterns, and both stable and unstable regimes can be simultaneously computed, which gives deep insight into the network dynamics. In order to illustrate the efficiency of the method, we present two examples in which the instability of the network equilibria is caused by a subcritical and a supercritical Hopf bifurcation. In addition, a bifurcation analysis of the subcritical case is performed in order to further explain the occurrence of the detected coexisting modes.

Coupled liquid crystalline oscillators in Huygens' synchrony.

In the flourishing field of soft robotics, strategies to embody communication and collective motion are scarce. Here we report the synchronized oscillations of thin plastic actuators by an approach reminiscent of the synchronized motion of pendula and metronomes. Two liquid crystalline network oscillators fuelled by light influence the movement of one another and display synchronized oscillations in-phase and anti-phase in a steady state. By observing entrainment between the asymmetric oscillators we demonstrate the existence of coupling between the two actuators. We qualitatively explain the origin of the synchronized motion using a theoretical model and numerical simulations, which suggest that the motion can be tuned by the mechanical properties of the coupling joint. We thus anticipate that the complex synchronization phenomena usually observed in rigid systems can also exist in soft polymeric materials. This enables the use of new stimuli, featuring an example of collective motion by photo-actuation.

Robust partial synchronization of delay-coupled networks.

Networks of coupled systems may exhibit a form of incomplete synchronization called partial synchronization or cluster synchronization, which refers to the situation where only some, but not all, systems exhibit synchronous behavior. Moreover, due to perturbations or uncertainties in the network, exact partial synchronization in the sense that the states of the systems within each cluster become identical, cannot be achieved. Instead, an approximate synchronization may be observed, where the states of the systems within each cluster converge up to some bound, and this bound tends to zero if (the size of) the perturbations tends to zero. In order to derive sufficient conditions for this robustified notion of synchronization, which we refer to as practical partial synchronization, first, we separate the synchronization error dynamics from the network dynamics and interpret them in terms of a nonautonomous system of delay differential equations with a bounded additive perturbation. Second, by assessing the practical stability of this error system, conditions for practical partial synchronization are derived and formulated in terms of linear matrix inequalities. In addition, an explicit relation between the size of perturbation and the bound of the synchronization error is provided.

Data-Rate Constrained Observers of Nonlinear Systems.

In this paper, the design of a data-rate constrained observer for a dynamical system is presented. This observer is designed to function both in discrete time and continuous time. The system is connected to a remote location via a communication channel which can transmit limited amounts of data per unit of time. The objective of the observer is to provide estimates of the state at the remote location through messages that are sent via the channel. The observer is designed such that it is robust toward losses in the communication channel. Upper bounds on the required communication rate to implement the observer are provided in terms of the upper box dimension of the state space and an upper bound on the largest singular value of the system's Jacobian. Results that provide an analytical bound on the required minimum communication rate are then presented. These bounds are obtained by using the Lyapunov dimension of the dynamical system rather than the upper box dimension in the rate. The observer is tested through simulations for the Lozi map and the Lorenz system. For the Lozi map, the Lyapunov dimension is computed. For both systems, the theoretical bounds on the communication rate are compared to the simulated rates.

The Effect of Global and Local Damping on the Perception of Hardness.

In tele-operation systems, damping is often injected to guarantee system stability during contact with hard objects. In this study, we used psychophysical experiments to assess the effect of adding damping on the user's perception of object hardness. In Experiments 1 and 2, combinations of stiffness and damping were tested to assess their effect on perceived hardness. In both experiments, two tasks were used: an in-contact task, starting at the object's surface, and a contact-transition task, including a free-air movement. In Experiment 3, the difference between inserting damping globally (equally throughout the workspace) and locally (inside the object only) was tested. In all experiments, the correlation between the participant's perceptual decision and force and position data was also investigated. Experiments 1 and 2 show that when injecting damping globally, perceived hardness slightly increased for an in-contact task, while it decreased considerably for a contact-transition task. Experiment 3 shows that this effect was mainly due to inserting damping globally, since there was a large perceptual difference between inserting damping globally and locally. The force and position parameters suggest that participants used the same force profile during the two movements of one trial and assessed the system's reaction to this force to perceive hardness.

The sympathy of two pendulum clocks: beyond Huygens' observations.

This paper introduces a modern version of the classical Huygens' experiment on synchronization of pendulum clocks. The version presented here consists of two monumental pendulum clocks--ad hoc designed and fabricated--which are coupled through a wooden structure. It is demonstrated that the coupled clocks exhibit 'sympathetic' motion, i.e. the pendula of the clocks oscillate in consonance and in the same direction. Interestingly, when the clocks are synchronized, the common oscillation frequency decreases, i.e. the clocks become slow and inaccurate. In order to rigorously explain these findings, a mathematical model for the coupled clocks is obtained by using well-established physical and mechanical laws and likewise, a theoretical analysis is conducted. Ultimately, the sympathy of two monumental pendulum clocks, interacting via a flexible coupling structure, is experimentally, numerically, and analytically demonstrated.

Collective almost synchronisation in complex networks.

This work introduces the phenomenon of Collective Almost Synchronisation (CAS), which describes a universal way of how patterns can appear in complex networks for small coupling strengths. The CAS phenomenon appears due to the existence of an approximately constant local mean field and is characterised by having nodes with trajectories evolving around periodic stable orbits. Common notion based on statistical knowledge would lead one to interpret the appearance of a local constant mean field as a consequence of the fact that the behaviour of each node is not correlated to the behaviours of the others. Contrary to this common notion, we show that various well known weaker forms of synchronisation (almost, time-lag, phase synchronisation, and generalised synchronisation) appear as a result of the onset of an almost constant local mean field. If the memory is formed in a brain by minimising the coupling strength among neurons and maximising the number of possible patterns, then the CAS phenomenon is a plausible explanation for it.

Partial synchronization in diffusively time-delay coupled oscillator networks.

We study networks of diffusively time-delay coupled oscillatory units and we show that networks with certain symmetries can exhibit a form of incomplete synchronization called partial synchronization. We present conditions for the existence and stability of partial synchronization modes in networks of oscillatory units that satisfy a semipassivity property and have convergent internal dynamics.

Control of mixing via entropy tracking.

We study mixing of isothermal fluids by controlling the global hydrodynamic entropy . In particular, based on the statistical coupling between the evolution of and the global viscous dissipation <ϵ> , we analyze stirring protocols such that ∼t(α)⇔<ϵ>∼t(α-1), with 0<α≤1. For a model array of vortices [Fukuta and Murakami, Phys. Rev. E 57, 449 (1998)], we show that: (i) feedback control can be achieved via input-output linearization, (ii) mixing is monotonically enhanced for increasing entropy production, and (iii) the mixing time t(m) scales as t(m)∼<ϵ>(-1/2).

State and parameter estimation for canonic models of neural oscillators.

We consider the problem of how to recover the state and parameter values of typical model neurons, such as Hindmarsh-Rose, FitzHugh-Nagumo, Morris-Lecar, from in-vitro measurements of membrane potentials. In control theory, in terms of observer design, model neurons qualify as locally observable. However, unlike most models traditionally addressed in control theory, no parameter-independent diffeomorphism exists, such that the original model equations can be transformed into adaptive canonic observer form. For a large class of model neurons, however, state and parameter reconstruction is possible nevertheless. We propose a method which, subject to mild conditions on the richness of the measured signal, allows model parameters and state variables to be reconstructed up to an equivalence class.

Synchronization of delay-coupled nonlinear oscillators: an approach based on the stability analysis of synchronized equilibria.

We consider the synchronization problem of an arbitrary number of coupled nonlinear oscillators with delays in the interconnections. The network topology is described by a directed graph. Unlike the conventional approach of deriving directly sufficient synchronization conditions, the approach of the paper starts from an exact stability analysis in a (gain, delay) parameter space of a synchronized equilibrium and extracts insights from an analysis of its bifurcations and from the corresponding emerging behavior. Instrumental to this analysis a factorization of the characteristic equation is employed that not only facilitates the analysis and reduces computational cost but also allows to determine the precise role of the individual agents and the topology of the network in the (in)stability mechanisms. The study provides an algorithm to perform a stability and bifurcation analysis of synchronized equilibria. Furthermore, it reveals fundamental limitations to synchronization and it explains under which conditions on the topology of the network and on the characteristics of the coupling the systems are expected to synchronize. In the second part of the paper the results are applied to coupled Lorenz systems. The main results show that for sufficiently large coupling gains, delay-coupled Lorenz systems exhibit a generic behavior that does not depend on the number of systems and the topology of the network, as long as some basic assumptions are satisfied, including the strong connectivity of the graph. Here the linearized stability analysis is strengthened by a nonlinear stability analysis which confirms the predictions based on the linearized stability and bifurcation analysis. This illustrates the usefulness of the exact linearized analysis in a situation where a direct nonlinear stability analysis is not possible or where it yields conservative conditions from which it is hard to get qualitative insights in the synchronization mechanisms and their scaling properties. In the examples several network topologies are considered.

Truncated aperture extrapolation for Fourier-based near-field acoustic holography by means of border-padding.

Although near-field acoustic holography (NAH) is recognized as a powerful and extremely fast acoustic imaging method based on the inverse solution of the wave-equation, its practical implementation has suffered from problems with the use of the discrete Fourier transformation (DFT) in combination with small aperture sizes and windowing. In this paper, a method is presented that extrapolates the finite spatial aperture before the DFT is applied, which is based on the impulse response information of the known aperture data. The developed method called linear predictive border-padding is an aperture extrapolation technique that greatly reduces leakage and spatial truncation errors in planar NAH (PNAH). Numerical simulations and actual measurements on a hard-disk drive and a cooling fan illustrate the low error, high speed, and utilization of border-padding. Border-padding is an aperture extrapolation technique that makes PNAH a practical and accurate inverse near-field acoustic imaging method.

Synchronization in networks of chaotic systems with time-delay coupling.

In this paper, we consider synchronization of N identical nonlinear systems unidirectionally or bidirectionally coupled with time delay. First we show, using the small-gain theorem, that trajectories of coupled strictly semi-passive systems converge to a bounded region. Next, we consider the network structure under which the synchronization error dynamics has a trivial solution at zero and derive a necessary condition for synchronization with respect to the network structure. Using these facts, we then derive sufficient conditions for synchronization of the systems in terms of linear matrix inequalities via the Lyapunov-Krasovskii functional approach. The obtained results are illustrated on networks of Lorentz systems with coupling delay.

Onset of chaotic advection in open flows.

In this paper we investigate the transition to chaos in the motion of particles advected by open flows with obstacles. By means of a topological argument, we show that the separation points on the surface of the obstacle imply the existence of a saddle point downstream from the obstacle, with an associated heteroclinic orbit. We argue that as soon as the flow becomes time periodic, these orbits give rise to heteroclinic tangles, causing passively advected particles to experience transient chaos. The transition to chaos thus coincides with the onset of time dependence in open flows with stagnant points, in contrast with flows with no stagnant points. We also show that the nonhyperbolic nature of the dynamics near the walls causes anomalous scalings in the vicinity of the transition. These results are confirmed by numerical simulations of the two-dimensional flow around a cylinder.

Anticipating synchronization of chaotic Lur'e systems.

In this paper we consider the anticipating synchronization of chaotic time-delayed Lur'e-type systems in a master-slave setting. We introduce three scenarios for anticipating synchronization, and give sufficient conditions for the existence of anticipating synchronizing slave systems in terms of linear matrix inequalities. The results obtained are illustrated on a time-delayed Rossler system and a time-delayed Chua oscillator.

Application of partial observability for analysis and design of synchronized systems.

Synchronization in identical drive-response systems is a problem that can be cast in an observer design framework. In this paper we extend this approach by studying the analysis/design of partial synchronization by means of observer theory. In doing so, we introduce the concept of partial observer--an observer to reconstruct a part of the system state vector. It is also shown how the observability condition can be utilized to analyze the dynamics in an array of coupled identical systems.