A Nine-Level Inverter with Adjustable Turn-Off Time for Helicopter Transient Electromagnetic Detection.

The current inverter is the core component of the helicopter transient electromagnetic (HTEM) detection system. It should meet the concerns of low loss, high power, and fast turn-OFF time. This article proposes a new circuit topology based on nine-level inverter technology to overcome the drawbacks of typical PWM (pulse width modulation) inverters, such as switching losses and harmonics. This circuit topology overcomes the shortcomings of the traditional single constant voltage clamp circuit in which the turn-OFF time is not adjustable. Using an inverter with the proposed topology is able to avoid the complex PWM control method and switching loss. In this way, the current rising edge and falling edge of this inverter are also improved effectively. The proposed inverter has adjustable turn-ON-time and turn-OFF time, which is significantly different from the conventional single-clamp inverter. Through subsequent experiments, the inverter proved to have the capability of generating trapezoidal current waveforms. Moreover, by modifying the FPGA (Field Programmable Gate Array) control program, three different turn-OFF times are achieved. The nine-level inverter has a peak current of 1.5 A with an adjustable turn-OFF time from 129 µs to 162 µs. Moreover, the switching frequency of the inverter is reduced from 10 kHz to below 100 Hz. The experimental results further demonstrate that it achieves lower switching losses and more flexible transmission. Our work in this article provides an efficient way to improve the performance of HTEM detection systems.

A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant.

The clinical impact of therapeutic interventions in Parkinson's disease is often measured as a reduction in OFF-time when the beneficial effects of the standard-of-care L-DOPA formulations wanes off. We investigated the pharmacodynamic interactions of augmentation therapy to standard-of-care using a quantitative systems pharmacology (QSP) model of the basal ganglia motor circuit, essentially a computer model of neuronal firing in the different subregions with anatomically informed connectivity, cell-specific expression of 17 different G-protein coupled receptors and corresponding coupling to voltage-gated ion channel effector proteins based on experimentally observed intracellular signaling. The calculated beta/gamma (b/g) power spectrum of the local field potentials in the subthalamic nucleus was previously calibrated on the clinically relevant Unified Parkinson's Disease Rating Scale (UPDRS). When combining this QSP model with PK modeling of different formulations of L-DOPA, we calculated the b/g fluctuations over a 16 h awake period and used a weighted distance from a specific threshold to determine the cumulative liability of OFF-Time. Prediction of OFF-time with clinical observations of different L-DOPA formulations showed a significant correlation. Simulations show that augmentation with the adenosine A2A antagonist preladenant reduces OFF-time with 6 min for carbidopa/levodopa 950 mg 5-times daily to 37 min for 100 mg L-DOPA - 3 or 5 times daily. Exploring delays between preladenant and L-DOPA intake did not improve the outcome. Hypothetical A2A antagonists with an ideal PK and pharmacology profile can achieve OFF-Time reductions ranging from 9.5 min with DuoDopa to 55 min with low dose L-DOPA formulations. Combination of the QSP model with PK modeling can predict the anticipated OFF-Time reduction of novel A2A antagonists with standard of care. With the large number of GPCR in the model, this combination can support both the design of clinical trials with new therapeutic agents and the optimization of combination therapy in clinical practice.

A method for measuring time spent in bradykinesia and dyskinesia in people with Parkinson's disease using an ambulatory monitor.

BACKGROUND: Fluctuations in motor function in Parkinson's Disease (PD) are frequent and cause significant disability. Frequently device assisted therapies are required to treat them. Currently, fluctuations are self-reported through diaries and history yet frequently people with PD do not accurately identify and report fluctuations. As the management of fluctuations and the outcomes of many clinical trials depend on accurately measuring fluctuations a means of objectively measuring time spent with bradykinesia or dyskinesia would be important. The aim of this study was to present a system that uses wearable sensors to measure the percentage of time that bradykinesia or dyskinesia scores are above a target as a means for assessing levels of treatment and fluctuations in PD. METHODS: Data in a database of 228 people with Parkinson's Disease and 157 control subjects, who had worn the Parkinson's Kinetigraph ((PKG, Global Kinetics Corporation™, Australia) and scores from the Unified Parkinson's Disease Rating Scale (UPDRS) and other clinic scales were used. The PKG's provided score for bradykinesia and dyskinesia every two minutes and these were compared to a previously established target range representing a UPDRS III score of 35. The proportion of these scores above target over the 6 days that the PKG was worn were used to derive the percent time in bradykinesia (PTB) and percent time in dyskinesia (PTD). As well, a previously describe algorithm for estimating the amplitude of the levodopa response was used to determine whether a subject was a fluctuator or non-fluctuator. RESULTS: Using this approach, a normal range of PTB and PTD based on Control subject was developed. The level of PTB and PTD experienced by people with PD was compared with their levels of fluctuation. There was a correlation (Pearson's ρ = 0.4) between UPDRS II scores and PTB: the correlation between Parkinson Disease Questionnaire scores and UPDRS Total scores and PTB and slightly lower. PTB and PTD fell in response to treatment for bradykinesia or dyskinesia (respectively) with greater sensitivity than clinical scales. CONCLUSIONS: This approach provides an objective assessment of the severity of fluctuations in Parkinson's Disease that could be used in in clinical trials and routine care.

Eye Tracking Supported Human Factors Testing Improving Patient Training.

The handling of left ventricular assist devices (LVADs) can be challenging for patients and requires appropriate training. The devices' usability impacts patients' safety and quality of life. In this study, an eye tracking supported human factors testing was performed to reveal problems during use and test the trainings' effectiveness. In total 32 HeartWare HVAD patients (including 6 pre-VAD patients) and 3 technical experts as control group performed a battery change (BC) and a controller change (CC) as an everyday and emergency scenario on a training device. By tracking the patients' gaze point, task duration and pump-off time were evaluated. Patients with LVAD support ≥1 year showed significantly shorter BC task duration than patients with LVAD support <1 year (p = 0.008). In contrast their CC task duration (p = 0.002) and pump-off times (median = 12.35 s) were higher than for LVAD support patients <1 year (median = 5.3 s) with p = 0.001. The shorter BC task duration for patients with LVAD support ≥1 year indicate that with time patients establish routines and gain confidence using their device. The opposite effect was found for CC task duration and pump-off times. This implies the need for intermittent re-training of less frequent tasks to increase patients' safety.

Rasagiline combined with levodopa therapy versus levodopa monotherapy for patients with Parkinson's disease: a systematic review.

OBJECTIVE: The aim of this report was to systematically evaluate the efficacy and safety of rasagiline (R) plus levodopa (L) (R + L) for the treatment of Parkinson's disease (PD) compared with that of L monotherapy, in order to provide a reference resource for rational drug use. METHODS: Randomized controlled trials (RCTs) of R + L for PD published up to September 2018 were searched. Sensitivity analyses were also performed. RESULTS: Fourteen RCTs with 2531 participants were included. Compared with L monotherapy, the pooled effects of R + L combination therapy on unified Parkinson's disease rating scale (UPDRS) score were (SMD - 0.50, 95% CI - 0.70 to - 0.30, P < 0.00001) for UPDRS motor score, (SMD - 0.59, 95% CI - 0.79 to - 0.39, P < 0.00001) for UPDRS activities of daily living (ADL) score, (SMD - 0.65, 95% CI - 0.81 to - 0.49, P < 0.00001) for UPDRS total score. R + L combination therapy was better than L monotherapy in reducing daily off-time (SMD - 1.15, 95% CI - 2.13 to - 0.17, P = 0.02), but there was a statistically nonsignificant result in daily on-time increase (SMD 1.39, 95% CI - 0.69 to 3.48, P = 0.19). There were no statistical differences in number of adverse events (OR 1.33, 95% CI 0.97 to 1.82, P = 0.07) and number of dropout (OR 0.88, 95% CI 0.65 to 1.19, P = 0.39) between R + L combination therapy and L monotherapy. CONCLUSIONS: R + L combination therapy was superior to L monotherapy for improvement of UPDRS scores and off-time in PD patients. Moreover, R + L combination therapy and L monotherapy were similar in terms of safety and tolerability.

Long-term efficacy of opicapone in fluctuating Parkinson's disease patients: a pooled analysis of data from two phase 3 clinical trials and their open-label extensions.

BACKGROUND AND PURPOSE: The aim was to evaluate the efficacy of the catechol-O-methyltransferase inhibitor opicapone (25 and 50 mg) as adjunct therapy to levodopa in a pooled population of Parkinson's disease patients who participated in the pivotal double-blind trials of opicapone and their 1-year open-label extensions. METHODS: Data (placebo, opicapone 25 mg and opicapone 50 mg) from the BIPARK-1 and BIPARK-2 double-blind and open-label studies were combined. The studies had similar designs, eligibility criteria and assessment methods. The primary efficacy variable in both double-blind studies was the change from baseline in absolute OFF time based on patient diaries. RESULTS: Double-blind treatment with opicapone (25 and 50 mg) significantly reduced absolute daily OFF time from a baseline of 6.1-6.6 h. The mean (and 95% confidence interval) treatment effect versus placebo was -35.1 (-62.1, -8.2) min (P = 0.0106) for the 25 mg dose and -58.1 (-84.5, -31.7) min (P < 0.0001) for the 50 mg dose. Reductions in OFF time were mirrored by significant increases in ON time without troublesome dyskinesia (P < 0.05 and P < 0.0001 for the 25 and 50 mg doses, respectively). No significant differences were observed for ON time with troublesome dyskinesia. Patient diary results from the open-label phase indicated a maintenance of effect for patients previously treated with opicapone 50 mg. The group previously treated with the 25 mg dose benefitted with further optimization of therapy during the open-label phase, whilst switching from placebo to opicapone led to significant reductions in OFF time and increased ON time. CONCLUSIONS: Over at least 1 year of open-label therapy, opicapone consistently reduced OFF time and increased ON time without increasing the frequency of troublesome dyskinesia.

Basic MAC Scheme for RF Energy Harvesting Wireless Sensor Networks: Throughput Analysis and Optimization.

Traditionally, how to reduce energy consumption has been an issue of utmost importance in wireless sensor networks. Recently, radio frequency (RF) energy harvesting technologies, which scavenge the ambient RF waves, provided us with a new paradigm for such networks. Without replacement or recharge of batteries, an RF energy harvesting wireless sensor network may live an eternal life. Against theoretical expectations, however, energy is scarce in practice and, consequently, structural naiveté has to be within a MAC scheme that supports a sensor node to deliver its data to a sink node. Our practical choice for the MAC scheme is a basic one, rooted in ALOHA, in which a sensor node simply repeats harvesting energy, backing off for a while and transmitting a packet. The basic medium access control (MAC) scheme is not able to perfectly prevent a collision of packets, which in turn deteriorates the throughput. Thus, we derive an exact expression of the throughput that the basic MAC scheme can attain. In various case studies, we then look for a way to enhance the throughput. Using the throughput formula, we reveal that an optimal back-off time, which maximizes the total throughput, is not characterized by the distribution but only by the mean value when the harvest times are deterministic. Also, we confirm that taking proper back-off times is able to improve the throughput even when the harvest times are random. Furthermore, we show that shaping the back-off time so that its variance is increased while its mean remains unchanged can help ameliorate the throughput that the basic MAC scheme is able to achieve.

Prediction of blastocyst development and implantation potential in utero based on the third cleavage and compaction times in mouse pre-implantation embryos.

Cytokinesis and cell division during pre-implantation embryonic development occur as an orchestrated spatiotemporal program. Cleavage, compaction, and blastulation in pre-implantation embryos are essential for successful implantation and pregnancy. Their alteration is associated with chromosomal imbalance and loss of developmental competence. In this study, we evaluated the time of cleavage and compaction as predictors for in vitro pre- and peri-implantation development and in utero implantation potential by time-lapse monitoring. Mouse 2-cell embryos were collected on 1.5 days post coitum (dpc) and were individually cultured to the outgrowth (OG) stage (7.5 dpc). Developmental stages were classified as 3-cell, 4-cell, 8-cell, morula, blastocyst, and OG. Cut-off times for successful blastocyst development were determined by receiver operating characteristic curve analysis. When cut-off times were set as 9 h for the third cleavage from the 2- to 4-cell stage, and 40 h for compaction from the 2-cell to morula stage, blastocyst and OG development rates, respectively, were significantly higher (P < 0.0001). Embryos were grouped according to the above cut-off time and transferred to the contralateral uterine horn on 3.5 dpc. Implantation rates in utero on 5.5 dpc were significantly higher in early third cleaved (≤ 9 h from 2- to 4-cell) and early compacted embryos (≤ 40 h from 2-cell to morula) than those in delayed embryos (P < 0.05). Therefore, the time of the third cleavage from 2- to the 4-cell stage and compaction from 2-cell to morula stage may be a useful morphokinetic parameter for predicting developmental potential, including successful implantation and pregnancy in human in vitro fertilization-embryo transfer programs.

Health-related quality of life in Parkinson's: impact of 'off' time and stated treatment preferences.

PURPOSE: Long-term levodopa therapy and related fluctuating plasma concentrations are associated with between-dose periods of 'off time' resulting in substantial variation in symptoms and functioning throughout the day in people with Parkinson's (PwP). METHODS: PwP across UK, France, Spain and Italy completed an online survey to explore: the impact of 'off time' on (1) health-related quality of life (HRQL) and (2) on functioning and ability to undertake usual activities; (3) the value of 'off time' relative to other factors associated with Parkinson's through a stated preference discrete choice experiment (SPDCE). RESULTS: In total, 305 PwP completed the online survey. Overall mean HRQL (utility) score was significantly lower for 'off time' (0.37) than for 'on time' (0.60). All attributes within the SPDCE were significant predictors of treatment choice, although increased duration of 'on time' (per hour per day: odds ratio (OR) = 1.40) and predictability of 'off time' to within 30 min (OR = 1.42) were valued most highly. CONCLUSIONS: 'On time' and predictability of 'off time' are highly valued by PwP. Due to substantial diurnal variation of Parkinson's symptoms, standard patient-reported outcome (PRO) assessments may not adequately capture the impact of 'off time' on HRQL and participation in daily activities.

Hands-off Time during Automated Chest Compression Device Application in Out-of-Hospital Cardiac Arrest: A Case Series Report.

INTRODUCTION: During out-of-hospital cardiac arrest (OHCA), chest compression interruptions or hands-off time (HOT) affect the prognosis. Our aim was to measure HOT due to the application of an automated chest compression device (ACD) by an advanced life support team. MATERIALS AND METHODS: This was a prospective observational case series report since the introduction of a new method of installing the ACD. Inclusion criteria were patients over 18 years old with OHCA who were treated with an ACD (Lucas 2(TM), Physio-Control). The ACD application was indicated only for OHCA patients transported to a hospital for Extra Corporeal Life Support (ECLS). We recorded the HOT related to switching from manual to mechanical chest compressions. An ACD consists of dorsal and ventral components, which can be installed either in one or in two steps, separated from a chest compression sequence. HOT was expressed as a median number of seconds [interquartile range]. RESULTS: From January 1, 2012 to January 15, 2013, 30 patients were included. In the case of ACD application in one phase (n = 16), the median HOT was 25.3 s [19.8-30.5]. With regard to patients with an ACD application in two phases (n = 14), the median HOT was, respectively, 9.8 s [7.8-17] and 12.4 s [9.5-16.2], that is, a median global HOT of 23.6 s [19-27.6]. HOT was not different between ACD applications in one or two phases (p = 0.52). For a two phase application, the median chest compression time between the two manipulations was 14.2 s [6.4-18]. CONCLUSION: There was no significant difference between techniques in the application of the Lucas 2(TM) device in terms of HOT. The short time needed to apply the device lends itself well to use as a primary chest compression modality during cardiac arrest as well as a bridge to novel resuscitation strategies (ECLS). A further study is currently underway with a larger number of ECLS patients.

Stochastic dynamic study of optical transition properties of single GFP-like molecules.

Due to high fluctuations and quantum uncertainty, the processes of single-molecules should be treated by stochastic methods. To study fluorescence time series and their statistical properties, we have applied two stochastic methods, one of which is an analytic method to study the off-time distributions of certain fluorescence transitions and the other is Gillespie's method of stochastic simulations. These methods have been applied to study the optical transition properties of two single-molecule systems, GFPmut2 and a Dronpa-like molecule, to yield results in approximate agreement with experimental observations on these systems. Rigorous oscillatory time series of GFPmut2 before it unfolds in the presence of denaturants have not been obtained based on the stochastic method used, but, on the other hand, the stochastic treatment puts constraints on the conditions under which such oscillatory behavior is possible. Furthermore, a sensitivity analysis is carried out on GFPmut2 to assess the effects of transition rates on the observables, such as fluorescence intensities.

Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: final 12-month, open-label results.

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. L-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces L-dopa-plasma-level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, "on" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks.

OFF-times before, during, and after nighttime sleep periods in Parkinson's disease patients with motor fluctuations and the effects of opicapone: A post hoc analysis of diary data from BIPARK-1 and -2.

INTRODUCTION: In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily "OFF"-time relative to placebo in adults with Parkinson's disease (PD) and motor fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize "OFF"-times around nighttime sleep and to explore the effects of opicapone 50 mg. METHODS: "OFF" before sleep (OBS), "OFF during the nighttime sleep period" (ODNSP), early morning "OFF" (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits. RESULTS: At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (-0.9 vs. -0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (-1.0 vs. -0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (-12.8 % vs. -4.5 %, P < 0.05). CONCLUSION: "OFF"-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period "OFF" episodes.

Intrinsic auricular muscle zone stimulation for Parkinson disease: The EARSTIM-PD Phase II multi-center pilot study results.

BACKGROUND: Studies have suggested that intrinsic auricular muscle zones (IAMZ) stimulation alleviates motor features of Parkinson disease (PD). METHODS: A randomized, blinded, active sham-controlled pilot trial was conducted to evaluate the safety and dose-response-time curve of Earstim using a 3-treatment, 3-period crossover design in PD patients experiencing OFF time on levodopa. Treatments were: short (20-min) IAMZ stimulation; long (60-min) IAMZ stimulation; and 20-min active sham stimulation of non-muscular areas. Assessment time points were: prior to treatment, and 20, 40, 60, 90, and 120 min after treatment onset. Primary safety endpoints were adverse events frequency and severity. Primary efficacy endpoint was the change in MDS-UPDRS motor score at 20 min after treatment onset in the IAMZ treatment groups versus sham. RESULTS: Forty-six individuals consented; 38 were randomized (average age 64 years, 65 % male, mean 8.2 years from diagnosis). No serious adverse events or significant device-related events occurred. At 20 min after treatment onset, motor improvements did not differ between IAMZ treatments versus sham. However, at 60 min after treatment onset, motor improvement peaked on IAMZ treatments compared to sham (difference: 3.1 [-5.9 to 0.3], p = 0.03). While the difference in 120-min AUC change between IAMZ treatments versus sham was not significant, the short-stimulation IAMZ treatment showed the largest aggregate motor score improvement (AUC = -456 points, 95 % CI -691 to -221) compared to sham. CONCLUSION: Earstim was well-tolerated. The greatest motor improvement occurred at 60 min after stimulation onset in the short-stimulation IAMZ treatment, and supports its further study to alleviate OFF periods.

The impact of the broad range of gamma doses on follow-up fission fragment track parameters in CR-39 radiation detector.

In this study, the effect of high γ-doses on the track parameters, structure as well as optical properties of pristine and γ-irradiation CR-39 nuclear track detector (NTD) were investigated. CR-39 detectors were exposed to γ-doses from 50 up to 500 kGy and then irradiated by fission ions (F.F) of fluence from 252CF source. The track diameter (D), bulk etch rate (VB), etch induction time (EIT), cut-off or saturated time (tcut-off) for saturated diameters and projected track length (Lo) of normally and inclined incident fission tracks were estimated for different removal layers (h). A linear relationship between D and γ-doses (Dγ) up to 500 k Gy was obtained. The VB for pristine and for γ-irradiated CR-39 was determined. A linear behaviour of VB was obtained up to 300 kGy. Etch induction time (EIT) and saturated time (tcut-off) of pristine and γ-irradiated detectors for normal and inclined fission ions tracks were evaluated respectively up to 500 kGy. Each EIT and tcut-off decreased exponentially fast with increasing γ-doses but the inclined incidence appeared earlier than normal case. Pristine and γ-irradiated CR-39 detectors were examined using FTIR and UV-Vis spectrophotometer. From this study, a linear relation of band gap energies (Egap) as a function of γ-doses, Dγ, was obtained. The value of (Egap) decreased when increasing γ-doses for direct and indirect transitions, respectively. In addition, a systematic increase of Urbach energy (EU) was recorded together with the Dγ increase. Moreover, a linear behavior of the refractive index (n) along with γ-irradiated CR-39 plastic detector was observed via direct and indirect methods.

Off-time Treatment Options for Parkinson's Disease.

Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor - Opicapone-, two MAO-B inhibitors plus channel blocker - Zonisamide and Safinamide and one amantadine extended-release formulation - ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients' preference, caregiver's availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.

Long-term results of carbidopa/levodopa enteral suspension across the day in advanced Parkinson's disease: Post-hoc analyses from a large 54-week trial.

Introduction: Carbidopa/levodopa enteral suspension (CLES) previously demonstrated reduction in total daily OFF from baseline by over 4 hours in advanced Parkinson's disease patients across 54 weeks. Evidence on CLES's long-term effectiveness on patterns of motor-symptom control throughout the day remains limited. Methods: We present post-hoc analyses of a large, open-label study of CLES monotherapy (N = 289). Diary data recorded patients' motor states at 30-minute intervals over 3 days at baseline and weeks 4, 12, 24, 36, and 54. Adjusted generalized linear mixed models assessed changes from baseline at each timepoint for four outcome measures: time to ON without troublesome dyskinesia (ON-woTD) after waking, motor-symptom control as measured by motor states' durations throughout the day, number of motor-state transitions, and presence of extreme fluctuations (OFF to ON with TD). Results: Patients demonstrated short-term (wk4) and sustained (wk54) improvement in all outcomes compared to baseline. At weeks 4 and 54, patients were more likely to reach ON-woTD over the course of their day (HR: 1.86 and 2.51, both P < 0.0001). Across 4-hour intervals throughout the day, patients also experienced increases in ON-woTD (wk4: 58-65 min; wk54: 60-78 min; all P < 0.0001) and reductions in OFF (wk4: 50-61 min; wk54: 56-68 min; all P < 0.0001). At weeks 4 and 54, patients' motor-state transitions were reduced by about half (IRR: 0.53 and 0.49, both P < 0.0001), and fewer patients experienced extreme fluctuations (OR: 0.22 and 0.15, both P < 0.0001). Conclusion: CLES monotherapy was associated with significant long-term reductions in motor-state fluctuations, faster time to ON-woTD upon awakening, and increased symptom control throughout the day.

Off-Time Work-Related Smartphone Use and Bedtime Procrastination of Public Employees: A Cross-Cultural Study.

While previous studies have examined the negative effects of work-related smartphone use after hours, little is known about whether and how it influences employees' unhealthy sleep behavior (i.e., bedtime procrastination). Drawing on the ego depletion theory, this study explored the effects of work-related smartphone use after hours on bedtime procrastination. To further uncover potential cross-cultural differences, a sample of 210 public employees from the United States and 205 public employees from China were used. Results via path analysis revealed that off-time work-related smartphone use positively influenced bedtime procrastination via the mediating role of self-control depletion. These findings were consistent between the United States and Chinese sample; however, off-time work-related smartphone use after hours increased the likelihood of self-control depletion more strongly in the United States than in China. The implications of our findings for both theory and practice were discussed.

Potential utility of amantadine DR/ER in persons with Parkinson's disease meeting 5-2-1 criteria for device aided therapy.

BACKGROUND: The 5-2-1 criteria (≥5 levodopa doses/day, ≥2 h OFF/day, and ≥ 1-hour dyskinesia/day) propose to identify people with Parkinson's disease (PD) who are poorly controlled on oral therapies and who may therefore benefit from device-aided therapies. Amantadine-DR/ER is the only medication FDA-approved for both dyskinesia and OFF episodes in levodopa-treated patients. In this post-hoc analysis of phase 3 clinical trials, we evaluated the efficacy and safety of amantadine-DR/ER in patients meeting 5-2-1 criteria. METHODS: Week-12 treatment differences (Amantadine-DR/ER - placebo) in the Unified Dyskinesia Rating Scale (UDysRS) and PD motor states (patient diaries) were evaluated in pooled, phase-3, double-blind trial participants meeting 5-2-1 criteria at baseline. This 5-2-1 cohort was followed into a 2-year open-label trial, where Movement Disorder Society - Unified Parkinson's Disease Rate Scale (MDS-UPDRS) Part IV scores were assessed relative to double-blind baseline. RESULTS: Of 198 enrolled participants in the phase 3 trials, 65 (33%; n = 29 placebo; n = 36 amantadine-DR/ER) comprised the 5-2-1 cohort. At Week-12 endpoint, amantadine-DR/ER significantly improved UDysRS scores (treatment difference of 9.57 ± 3.15 points, p = 0.004) and ON time without troublesome dyskinesia ('good ON', treatment difference of 2.9 ± 0.90 h/day, p = 0.002). Improvements in good ON time resulted from significant reductions in both troublesome dyskinesia and OFF time. Treatment benefit on MDS-UPDRS-Part IV was sustained through open-label, follow-up. The most common adverse events in patients who met 5-2-1 criteria and were treated with amantadine-DR/ER included falls and peripheral edema. CONCLUSIONS: Findings suggest Amantadine-DR/ER should be considered as an option for people with PD who meet 5-2-1 criteria.

Istradefylline for OFF Episodes in Parkinson's Disease: A US Perspective of Common Clinical Scenarios.

The effective management of OFF episodes remains an important unmet need for patients with Parkinson's disease (PD) who develop motor complications with long-term levodopa therapy. Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with PD experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Originally approved in Japan, istradefylline was recently approved in the USA. In this article, we provide a specific review of the four clinical studies that the FDA included in the approval of istradefylline in the USA, and discuss common clinical scenarios, based on our experience, where treatment with istradefylline may benefit patients experiencing motor fluctuations.