Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders.

BACKGROUND: Clinical evidence is required about the long-term efficacy and safety of melatonin treatment for sleep problems in children with neurodevelopmental disorders (NDDs) who underwent adequate sleep hygiene interventions. METHODS: We conducted a 26-week, multicenter, collaborative, uncontrolled, open-label, phase III clinical trial of melatonin granules in children 6 to 15 years of age who had NDDs and sleep problems. The study consisted of the 2-week screening phase, the 26-week medication phases I and II, and the 2-week follow-up phase. Children received 1, 2, or 4 mg melatonin granules orally in the medication phases. Variables of sleep status including sleep onset latency (SOL), aberrant behaviors listed on the Aberrant Behavior Check List-Japanese version (ABC-J), and safety were examined. The primary endpoint was SOL in the medication phase I. RESULTS: Between June 2016 and July 2018, 99 children (80 males and 19 females, 10.4 years in mean age) were enrolled at 17 medical institutions in Japan-74, 60, 22, 9, 6, and 1 of whom had autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disabilities, motor disorders, specific learning disorder, and communication disorders, respectively, at baseline. Fifteen children received the maximal dose of 4 mg among the prespecified dose levels. SOL recorded with the electronic sleep diary shortened significantly (mean ± standard deviation [SD], - 36.7 ± 46.1 min; 95% confidence interval [CI], - 45.9 to - 27.5; P <  0.0001) in the medication phase I from baseline, and the SOL-shortening effect of melatonin persisted in the medication phase II and the follow-up phase. Temper upon wakening and sleepiness after awakening improved significantly (P <  0.0001 each) in the medication phase I from baseline and persisted in the follow-up phase. The following subscales of the ABC-J improved significantly: stereotypic behavior (P = 0.0322) in the medication phase I; and irritability, hyperactivity, and inappropriate speech (P <  0.0001) in the medication phase II. Treatment-emergent adverse events did not occur subsequent to week 16 after medication onset, and NDDs did not deteriorate in the follow-up phase. CONCLUSIONS: Long-term melatonin treatment in combination with adequate sleep hygiene interventions may afford clinical benefits to children with NDDs and potentially elevates their well-being. TRIAL REGISTRATION: ClinicalTrils.gov , NCT02757066 . Registered April 27, 2016.

Nonlinear thermokinetic phenomena due to the Seebeck effect.

We propose a novel mechanism to produce nonlinear thermokinetic vortex flows around a circular cylinder with ideally high thermal conductivity in an electrolyte. That is, the nonlinear thermokinetic slip velocity, which is proportional to the square of the temperature gradient [∇(T)0(2)], is derived based on the electrolyte Seebeck effect, heat conduction equation, and Helmholtz­Smoluchowski formula. Different from conventional linear thermokinetic theory, our theory predicts that the inversion of the temperature gradient does not change the direction of the thermokinetic flows and thus a Janus particle using this phenomenon can move to the both hotter and colder regions in a temperature gradient field by changing the direction of its dielectric end. Our findings bridge the gap between the electro- and thermo-kinetic phenomena and provide an integrated physical viewpoint for the interface science.

Melatonin Treatment and Adequate Sleep Hygiene Interventions in Children with Autism Spectrum Disorder: A Randomized Controlled Trial.

Robust clinical evidence has not been available for melatonin, a drug commonly administered for treating sleep problems of children with autism spectrum disorder (ASD). In a phase 3 randomized, placebo-controlled clinical trial, we administered 1-mg melatonin (n = 65), 4-mg melatonin (n = 65), or placebo (n = 66) to196 children with ASD once daily before bedtime under adequate sleep hygiene interventions. The primary outcome was sleep onset latency (SOL) assessed with the electronic sleep diary. SOL shortened significantly in the 1- and 4-mg melatonin groups compared to the placebo group (- 22.0, - 28.0, and - 5.0 min, respectively; p < 0.0001 each). This therapeutic regimen of melatonin is a reasonable clinical approach to cope with ASD-emergent difficulties in children with ASD.

Microcolumn formation between electrodes in a narrow channel from metallic colloidal suspension through induced-charge electrophoresis.

It is desirable to achieve the self-organization of a microcolumn between electrodes in a flow channel because the microcolumn can be used as a biosensor with high sensitivity. A direct simulation of a dispersed system of metallic particles in water is performed to show that a microcolumn between electrodes is formed by the application of an ac electric field. By the multiphysics coupled simulation technique between fluidics and electrostatics based on the boundary element method along with the double layer approximation, we find that microcolumns are formed by the growth of clusters perpendicular to the electrodes under the condition that the number density of particles is larger than the percolation threshold. Further, we propose a simple model that efficiently explains the time dependence of the probability of the formation of a microcolumn by considering standard collision theory and percolation theory. By this analysis, we can greatly contribute to developments in studies on the self-organization of microcolumns and biosensors.

Suppression of reverse flows in pumping by induced-charge electro-osmosis using asymmetrically stacked elliptical metal posts.

Several researchers have analyzed pumps that employ induced-charge electro-osmosis (ICEO) using mainly coplanar electrode array structures in a lateral electric field. We propose ICEO pumps that remove reverse flows using asymmetrically stacked elliptical metal posts and numerically examine the pumping performance. By the boundary element method along with double layer approximation, we find that the asymmetrical stacking configuration efficiently suppresses the unwanted reverse flow and yields velocities of the order of a few millimeters per second, and this configuration is compatible with that of an optimized half-coating pump. Further, we propose a simple model for the stacking pump and predict that the velocity of such a stacking pump with a thin limit is larger than 67% of that of a circular cylindrical half-coating pump of the same length. Using this stacking pump, we can expect to significantly improve the pumping performance.

High-speed broadband elastic actuator in water using induced-charge electro-osmosis with a skew structure.

An artificial cilium using ac electro-osmosis (ACEO) is attractive because of its large potentiality for innovative microfluidic applications. However, the ACEO cilium has not been probed experimentally and has a shortcoming that the working frequency range is very narrow. Thus, we here propose an ACEO elastic actuator having a skew structure that broadens a working frequency range and experimentally demonstrate that the elastic actuator in water can be driven with a high-speed (∼10 Hz) and a wide frequency range (∼0.1 to ∼10 kHz). Moreover, we propose a simple self-consistent model that explains the broadband characteristic due to the skew structure with other characteristics. By comparing the theoretical results with the experimental results, we find that they agree fairly well. We believe that our ACEO elastic actuator will play an important role in microfluidics in the future.

Direct simulation of phase delay effects on induced-charge electro-osmosis under large ac electric fields.

The standard theory of induced-charge electro-osmosis (ICEO) often overpredicts experimental values of ICEO velocities. Using a nonsteady direct multiphysics simulation technique based on the coupled Poisson-Nernst-Planck and Stokes equations for an electrolyte around a conductive cylinder subject to an ac electric field, we find that a phase delay effect concerning an ion response provides a fundamental mechanism for electrokinetic suppression. A surprising aspect of our findings is that the phase delay effect occurs even at much lower frequencies (e.g., 50 Hz) than the generally believed charging frequency of an electric double layer (typically, 1 kHz) and it can decrease the electrokinetic velocities in one to several orders. In addition, we find that the phase delay effect may also cause a change in the electrokinetic flow directions (i.e., flow reversal) depending on the geometrical conditions. We believe that our findings move toward a more complete understanding of complex experimental nonlinear electrokinetic phenomena.

Strategies on improving the micro-fluidic devices using the nonlinear electro- and thermo-kinetic phenomena.

Surface science is key to innovations on microfluidics, smart materials, and future non-equilibrium systems. However, challenging issues still exist in this field. In this article, from the viewpoint of the fundamental design, we will briefly review our strategies on improving the micro-fluidic devices using the nonlinear electro- and thermo-kinetic phenomena. In particular, we will review the microfluidic applications using ICEO, the correction based on the ion-conserving Poisson-Boltzmann theory, the direct simulation on ICEO, and the new horizon such as nonlinear thermo-kinetic phenomena and the artificial cilia.

dc Step response of induced-charge electro-osmosis between parallel electrodes at large voltages.

Induced-charge electro-osmosis (ICEO) is important since it can be used for realizing high performance microfluidic devices. Here, we analyze the simplest problem of ion relaxation around a circular polarizable cylinder between parallel blocking electrodes in a closed cell by using a multiphysics coupled simulation technique. This technique is based on a combination of the finite-element method and finite-volume method for the Poisson-Nernst-Planck (PNP) equations having a flow term and the Stokes equation having an electric stress term. Through this analysis, we successfully demonstrate that on application of dc voltages, quadorapolar ICEO vortex flows grow during the charging time of the cylinder for both unbounded and bounded problems and decay during the charging time of the parallel electrodes only for the bounded problem using blocking electrodes. Further, by proposing a simple model that considers the two-dimensional (2D) PNP equations analytically, we successfully explain the step response time of the ICEO flow for the both unbounded and bounded problems. Furthermore, at low applied voltages, we find analytical formulations on steady diffused-ion problems and steady ICEO-flow problems and examine that our numerical results agree well with the analytical results. Moreover, by considering an ion-conserving condition with 2D Poisson-Boltzmann equations, we explain significant decrease of the maximum slip velocity at large applied voltages fairly well. We believe that our analysis will contribute greatly to the realistic designs of prospective high-performance microfluidic devices.

Ion-conserving Poisson-Boltzmann theory.

It is well known that the Poisson-Nernst-Planck (PNP) theory and the classical Gouy-Chapman theory are inconsistent at a high applied voltage. For solving this problem, we propose an ion-conserving Poisson-Boltzmann theory, which shows remarkable agreement with the numerical PNP solutions, even at a high applied voltage. In other words, we have found the exact analytical solutions for steady PNP equations; we believe that this finding greatly contributes to understanding surface science between solids and liquids.

Asymmetrical reverse vortex flow due to induced-charge electro-osmosis around carbon stacking structures.

Broken symmetry of vortices due to induced-charge electro-osmosis (ICEO) around stacking structures is important for the generation of a large net flow in a microchannel. Following theoretical predictions in our previous study, we herein report experimental observations of asymmetrical reverse vortex flows around stacking structures of carbon posts with a large height (~110 µm) in water, prepared by the pyrolysis of a photoresist film in a reducing gas. Further, by the use of a coupled calculation method that considers boundary effects precisely, the experimental results, except for the problem of anomalous flow reversal, are successfully explained. That is, unlike previous predictions, the precise calculations here show that stacking structures accelerate a reverse flow rather than suppressing it for a microfluidic channel because of the deformation of electric fields near the stacking portions; these structures can also generate a large net flow theoretically in the direction opposite that of a previous prediction for a standard vortex flow. Furthermore, by solving the one-dimensional Poisson-Nernst-Plank (PNP) equations in the presence of ac electric fields, we find that the anomalous flow reversal occurs by the phase retardation between the induced diffuse charge and the tangential electric field. In addition, we successfully explain the nonlinearity of the flow velocity on the applied voltage by the PNP analysis. In the future, we expect to improve the pumping performance significantly by using stacking structures of conductive posts along with a low-cost process.

Rotation of a microvalve near conductive electrodes via induced-charge electrophoresis.

The development of a high-speed microactuator in water is difficult because of hydrodynamic resistance and the lack of the knowledge of complex electrostatic problems combined with flow fields and ion dynamics. Previously, to overcome these problems, we proposed rotary microvalves in water using hydrodynamic force due to induced-charge electrophoresis (ICEP). In this study, by using an elliptical conductive carbon element fabricated by the pyrolysis of a photoresist film coated with gold, we experimentally demonstrate that microvalves can rotate near conductive electrodes. Namely, by numerically analyzing video data, we show the time evolution of the rotation angle, the flow field, and the center position of the microvalve. Further, we compare them with the theoretical results and find that they are in good agreement qualitatively. In the future, by using ICEP valves as a latch device, we can significantly improve the size and processing speed of a fluidic integrated circuit.

High-speed rotary microvalves in water using hydrodynamic force due to induced-charge electrophoresis.

The development of a high-speed microactuator in water is difficult because of electrostatic problems and hydrodynamic resistance. To overcome these problems, we consider using induced-charge electrophoresis (ICEP) to move actuators. We propose rotary microvalves in water using hydrodynamic force due to ICEP and numerically examine the performance of valves. By the multiphysics coupled simulation technique between fluidics and electrostatics based on the boundary element method along with the thin-double-layer approximation, we find rotary valves using ICEP function effectively at high frequency. In the calculations, the electric and flow field problems in a bounded domain are solved, and the proper boundary conditions are discussed. By employing similar actuators using ICEP, we can dramatically improve the performance of promising microfluidic systems such as lab-on-a-chip.

Chaotic mixer using electro-osmosis at finite Péclet number.

Two pressure-driven streams of two miscible liquids can only mix by diffusion in microfluidic channels because of the low Reynolds number. We present an idea to generate mixing by "chaotic advection" in microscale geometries. That is, we consider using induced-charge electro-osmosis to generate a second flow and then modulate between the pressure-driven and induced-charge flows. By using the combined method consisting of the boundary element method, the Lagrangian particle tracking method, and the random-walk method, we analyze mixing efficiency, mixing time, and mixing length, with the effects of modulation frequency and molecular diffusivity, and compare our proposed mixer with other mixers. By this analysis, we find that chaotic mixing can be produced efficiently in a microfluidic channel by switching between pressure-driven and induced-charge flows in a wide range of Péclet number under the specific condition of Strouhal number. By using our proposed mixer, we can expect to realize efficient chaotic mixing with minimum voltage in an ordinary flow channel with a simple structure without an oblique electric field even at large Péclet number.