Individualized assessment of post-arthroplasty recovery by actigraphy: a methodology study.

Previous studies using actigraphy to monitor recovery after total knee arthroplasty (TKA) have reported activity as maximum and average count/min, but not utilized the full potential of the data by stratifying activity into various intensities or analysed the individual development in activity over time. The aim of this study was to describe a novel methodology using actigraphy data to describe specific activity-intensities potentially affected by surgery and patients with poor rehabilitation trajectories. Actigraphy data from 10 patients scheduled for primary unilateral TKA were recorded preoperatively and for 3 weeks postoperatively. Data were individualized by comparing pre- and post-operative values, and activity intensities stratified by division into 5 percentiles (10th, 25th, 50th, 75th and 90th). Changes in activity were assessed visually and by non-parametric testing. Individualized recovery trajectories were described by the gradient of the regression line of post- versus pre-operative physical activity over the study period. TKA had a negative impact on all activity intensities with gradual improvement towards preoperative values during the study period. The inter-individual variation increased with intensified activity. Identification of individual patients with positive, neutral or negative activity trajectories was possible. The methodology should be considered in future interventional studies to improve rehabilitation strategies.

Guidelines for the recording and evaluation of pharmaco-sleep studies in man: the International Pharmaco-EEG Society (IPEG).

The International Pharmaco-EEG Society (IPEG) presents guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-sleep data in man. Over the past years, technical and data-processing methods have advanced steadily, thus enhancing data quality and expanding the palette of sleep assessment tools that can be used to investigate the activity of drugs on the central nervous system (CNS), determine the time course of effects and pharmacodynamic properties of novel therapeutics, hence enabling the study of the pharmacokinetic/pharmacodynamic relationship, and evaluate the CNS penetration or toxicity of compounds. However, despite the presence of robust guidelines on the scoring of polysomnography -recordings, a review of the literature reveals inconsistent -aspects in the operating procedures from one study to another. While this fact does not invalidate results, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. The present guidelines are intended to assist investigators, who are using pharmaco-sleep measures in clinical research, in an effort to provide clear and concise recommendations and thereby to standardise methodology and facilitate comparability of data across laboratories.

The Emerging Role of Virtual Reality as an Adjunct to Procedural Sedation and Anesthesia: A Narrative Review.

Over the past 20 years, there has been a significant reduction in the incidence of adverse events associated with sedation outside of the operating room. Non-pharmacologic techniques are increasingly being used as peri-operative adjuncts to facilitate and promote anxiolysis, analgesia and sedation, and to reduce adverse events. This narrative review will briefly explore the emerging role of immersive reality in the peri-procedural care of surgical patients. Immersive virtual reality (VR) is intended to distract patients with the illusion of "being present" inside the computer-generated world, drawing attention away from their anxiety, pain, and discomfort. VR has been described for a variety of procedures that include colonoscopies, venipuncture, dental procedures, and burn wound care. As VR technology develops and the production costs decrease, the role and application of VR in clinical practice will expand. It is important for medical professionals to understand that VR is now available for prime-time use and to be aware of the growing body in the literature that supports VR.

Validity of activity monitors in health and chronic disease: a systematic review.

The assessment of physical activity in healthy populations and in those with chronic diseases is challenging. The aim of this systematic review was to identify whether available activity monitors (AM) have been appropriately validated for use in assessing physical activity in these groups. Following a systematic literature search we found 134 papers meeting the inclusion criteria; 40 conducted in a field setting (validation against doubly labelled water), 86 in a laboratory setting (validation against a metabolic cart, metabolic chamber) and 8 in a field and laboratory setting. Correlation coefficients between AM outcomes and energy expenditure (EE) by the criterion method (doubly labelled water and metabolic cart/chamber) and percentage mean differences between EE estimation from the monitor and EE measurement by the criterion method were extracted. Random-effects meta-analyses were performed to pool the results across studies where possible. Types of devices were compared using meta-regression analyses. Most validation studies had been performed in healthy adults (n=118), with few carried out in patients with chronic diseases (n=16). For total EE, correlation coefficients were statistically significantly lower in uniaxial compared to multisensor devices. For active EE, correlations were slightly but not significantly lower in uniaxial compared to triaxial and multisensor devices. Uniaxial devices tended to underestimate TEE (-12.07 (95%CI; -18.28 to -5.85) %) compared to triaxial (-6.85 (95%CI; -18.20 to 4.49) %, p=0.37) and were statistically significantly less accurate than multisensor devices (-3.64 (95%CI; -8.97 to 1.70) %, p<0.001). TEE was underestimated during slow walking speeds in 69% of the lab validation studies compared to 37%, 30% and 37% of the studies during intermediate, fast walking speed and running, respectively. The high level of heterogeneity in the validation studies is only partly explained by the type of activity monitor and the activity monitor outcome. Triaxial and multisensor devices tend to be more valid monitors. Since activity monitors are less accurate at slow walking speeds and information about validated activity monitors in chronic disease populations is lacking, proper validation studies in these populations are needed prior to their inclusion in clinical trials.

Representation of neck velocity and neck-vestibular interactions in pursuit neurons in the simian frontal eye fields.

The smooth pursuit system must interact with the vestibular system to maintain the accuracy of eye movements in space (i.e., gaze-movement) during head movement. Normally, the head moves on the stationary trunk. Vestibular signals cannot distinguish whether the head or whole body is moving. Neck proprioceptive inputs provide information about head movements relative to the trunk. Previous studies have shown that the majority of pursuit neurons in the frontal eye fields (FEF) carry visual information about target velocity, vestibular information about whole-body movements, and signal eye- or gaze-velocity. However, it is unknown whether FEF neurons carry neck proprioceptive signals. By passive trunk-on-head rotation, we tested neck inputs to FEF pursuit neurons in 2 monkeys. The majority of FEF pursuit neurons tested that had horizontal preferred directions (87%) responded to horizontal trunk-on-head rotation. The modulation consisted predominantly of velocity components. Discharge modulation during pursuit and trunk-on-head rotation added linearly. During passive head-on-trunk rotation, modulation to vestibular and neck inputs also added linearly in most neurons, although in half of gaze-velocity neurons neck responses were strongly influenced by the context of neck rotation. Our results suggest that neck inputs could contribute to representing eye- and gaze-velocity FEF signals in trunk coordinates.

Frequency-dependent spatiotemporal tuning properties of non-eye movement related vestibular neurons to three-dimensional translations in squirrel monkeys.

Responses of vestibular-only translation sensitive (VOTS) neurons in vestibular nuclei of two squirrel monkeys were studied at multiple frequencies to three-dimensional translations and rotations. A novel frequency-dependent spatiotemporal analysis examined in each neuron whether complex models, with unrestricted response dynamics in three-dimensional (3D) space, provided significantly better fits than restricted models following simple, cosine rule. Subsequently, the statistically selected optimal model was used to predict the maximum translation direction, expressed as a unitary vector, Vt(max), and its associated sensitivity and phase across frequencies. Simple models were sufficient to quantify the 3D translational responses of 66% of neurons. Most VOTS neurons, complex or simple, exhibited flat-gain or low-pass response dynamics. The Vt(max) of simple neurons was fixed, whereas that of complex neurons changed with frequency. The spatial distribution of Vt(max) in simple neurons, which fell within 30 degrees of either the horizontal plane or/and the sagittal plane, was closely aligned with Vt(max) of vestibular afferents. In contrast, the frequency-dependent Vt(max) of most complex neurons migrated from the dorsoventral axis at higher frequency toward the horizontal plane, especially the interaural axis, at lower frequency. When the maximum rotation direction was estimated from responses of the same VOTS neurons to 1.2 Hz yaw, pitch, and roll rotations, complex neurons were more likely to respond to rotations activating vertical canals. Responses to 0.15-0.3 Hz linear accelerations produced by inertial or gravitational forces were indistinguishable in most complex neurons but significantly different in most simple neurons. These observations suggest that simple and complex VOTS neurons constitute distinctive vestibular pathways where complex neurons, exhibiting a novel spatiotemporal filtering mechanism in processing otolith-related signals, are well suited to drive tilt-related responses, whereas simple neurons probably mediate pure translation related responses.

Eye-pursuit and reafferent head movement signals carried by pursuit neurons in the caudal part of the frontal eye fields during head-free pursuit.

Eye and head movements are coordinated during head-free pursuit. To examine whether pursuit neurons in frontal eye fields (FEF) carry gaze-pursuit commands that drive both eye-pursuit and head-pursuit, monkeys whose heads were free to rotate about a vertical axis were trained to pursue a juice feeder with their head and a target with their eyes. Initially the feeder and target moved synchronously with the same visual angle. FEF neurons responding to this gaze-pursuit were tested for eye-pursuit of target motion while the feeder was stationary and for head-pursuit while the target was stationary. The majority of pursuit neurons exhibited modulation during head-pursuit, but their preferred directions during eye-pursuit and head-pursuit were different. Although peak modulation occurred during head movements, the onset of discharge usually was not aligned with the head movement onset. The minority of neurons whose discharge onset was so aligned discharged after the head movement onset. These results do not support the idea that the head-pursuit-related modulation reflects head-pursuit commands. Furthermore, modulation similar to that during head-pursuit was obtained by passive head rotation on stationary trunk. Our results suggest that FEF pursuit neurons issue gaze or eye movement commands during gaze-pursuit and that the head-pursuit-related modulation primarily reflects reafferent signals resulting from head movements.

Application of a novel actigraphy algorithm to detect movement and sleep/wake patterns in children with autism spectrum disorder.

OBJECTIVE: Actigraphy is a non-intrusive method of recording rest/activity cycles as well as a surrogate for sleep/wake activity. Standard actigraphy analysis is limited in ascribing discrete movement events to wake status during sleep. We applied a novel algorithm to overnight actigraphy data recorded simultaneously with video polysomnography-electroencephalography (video PSG-EEG) to determine its ability to define movement and sleep/wake patterns in children with autism spectrum disorder (ASD) and age-comparable typically developing (TD) controls. METHODS: A previously published novel algorithm uses mathematical endpoints to analyze actigraphy data without assumptions about sleep/wake status, and smooths data using moving windows of increasing length. Nighttime activity level "S" events (S1-S5) determined by this algorithm (n = 273) were identified in 15 children ages 3-10 years (nine with ASD and six TD) who wore an AW2 Spectrum Actiwatch (Philips Respironics) while undergoing simultaneous video PSG-EEG. Data were analyzed to identify the time each activity level "S" event occurred, video movement events (movements captured by video and scored based on level of severity), and sleep/wake status defined by PSG-EEG. The relationships among activity level "S" events, video movement events, and sleep/wake status were analyzed statistically. RESULTS: Activity level "S" events, the presence and severity of video movement events, and sleep-wake status, were significantly associated. These associations were present in both participants with ASD and those who were typically developing. CONCLUSION: This actigraphy algorithm shows promise for detecting nighttime movements and sleep/wake status and warrants further study in larger datasets of neurotypical children and those with neurodevelopmental disorders.

Verification, analytical validation, and clinical validation (V3): the foundation of determining fit-for-purpose for Biometric Monitoring Technologies (BioMeTs).

Digital medicine is an interdisciplinary field, drawing together stakeholders with expertize in engineering, manufacturing, clinical science, data science, biostatistics, regulatory science, ethics, patient advocacy, and healthcare policy, to name a few. Although this diversity is undoubtedly valuable, it can lead to confusion regarding terminology and best practices. There are many instances, as we detail in this paper, where a single term is used by different groups to mean different things, as well as cases where multiple terms are used to describe essentially the same concept. Our intent is to clarify core terminology and best practices for the evaluation of Biometric Monitoring Technologies (BioMeTs), without unnecessarily introducing new terms. We focus on the evaluation of BioMeTs as fit-for-purpose for use in clinical trials. However, our intent is for this framework to be instructional to all users of digital measurement tools, regardless of setting or intended use. We propose and describe a three-component framework intended to provide a foundational evaluation framework for BioMeTs. This framework includes (1) verification, (2) analytical validation, and (3) clinical validation. We aim for this common vocabulary to enable more effective communication and collaboration, generate a common and meaningful evidence base for BioMeTs, and improve the accessibility of the digital medicine field.

A systematic review of feasibility studies promoting the use of mobile technologies in clinical research.

Mobile technologies, such as smart phone applications, wearables, ingestibles, and implantables, are increasingly used in clinical research to capture study endpoints. On behalf of the Clinical Trials Transformation Initiative, we aimed to conduct a systematic scoping review and compile a database summarizing pilot studies addressing mobile technology sensor performance, algorithm development, software performance, and/or operational feasibility, in order to provide a resource for guiding decisions about which technology is most suitable for a particular trial. Our systematic search identified 275 publications meeting inclusion criteria. From these papers, we extracted data including the medical condition, concept of interest captured by the mobile technology, outcomes captured by the digital measurement, and details regarding the sensors, algorithms, and study sample. Sixty-seven percent of the technologies identified were wearable sensors, with the remainder including tablets, smartphones, implanted sensors, and cameras. We noted substantial variability in terms of reporting completeness and terminology used. The data have been compiled into an online database maintained by the Clinical Trials Transformation Initiative that can be filtered and searched electronically, enabling a user to find information most relevant to their work. Our long-term goal is to maintain and update the online database, in order to promote standardization of methods and reporting, encourage collaboration, and avoid redundant studies, thereby contributing to the design and implementation of efficient, high-quality trials.

Advancing the Use of Mobile Technologies in Clinical Trials: Recommendations from the Clinical Trials Transformation Initiative.

Mobile technologies offer the potential to reduce the costs of conducting clinical trials by collecting high-quality information on health outcomes in real-world settings that are relevant to patients and clinicians. However, widespread use of mobile technologies in clinical trials has been impeded by their perceived challenges. To advance solutions to these challenges, the Clinical Trials Transformation Initiative (CTTI) has issued best practices and realistic approaches that clinical trial sponsors can now use. These include CTTI recommendations on technology selection; data collection, analysis, and interpretation; data management; protocol design and execution; and US Food and Drug Administration submission and inspection. The scientific principles underpinning the clinical trials enterprise continue to apply to studies using mobile technologies. These recommendations provide a framework for including mobile technologies in clinical trials that can lead to more efficient assessment of new therapies for patients.

Prefrontal neurons coding suppression of specific saccades.

The prefrontal cortex has been implicated in the suppression of unwanted behavior, based upon observations of humans and monkeys with prefrontal lesions. Despite this, there has been little direct neurophysiological evidence for a mechanism that suppresses specific behavior. In this study, we used an oculomotor delayed match/nonmatch-to-sample task in which monkeys had to remember a stimulus location either as a marker of where to look or as a marker of where not to look. We found a group of neurons in both the frontal eye field and the caudal prefrontal cortex that carried signals selective for the forbidden stimulus. The activity of these "don't look" neurons correlated with the monkeys' success or failure on the task. These results demonstrate a frontal signal that is related to the active suppression of one action while the subject performs another.

Detection of Nocturnal Scratching Movements in Patients with Atopic Dermatitis Using Accelerometers and Recurrent Neural Networks.

Atopic dermatitis is a chronic inflammatory skin condition affecting both children and adults and is associated with pruritus. A method for objectively quantifying nocturnal scratching events could aid in the development of therapies for atopic dermatitis and other pruritic disorders. High-resolution wrist actigraphy (three-dimensional accelerometer sensors sampled at 20 Hz) is a noninvasive method to record movement. This paper presents an algorithm to detect nocturnal scratching events based on actigraphy data. The twofold process consists of segmenting the data into "no motion," "single handed motion," and "both handed motion" followed by discriminating motion segments into scratching and other motion using a bidirectional recurrent neural network classifier. The performance was compared against manually scored infrared video data collected from 24 subjects (6 healthy controls and 18 atopic dermatitis patients) demonstrating an score of 0.68 and a rank correlation of 0.945. The algorithm clearly outperformed a published reference method based on wrist actigraphy ( score of 0.09 and a rank correlation of 0.466). The results suggest that scratching movements can be discriminated from other nocturnal movements accurately.

Assurance of Myeloid Growth Factor Administration in an Infusion Center: Pilot Quality Improvement Initiative.

PURPOSE: Four incident reports involving missed doses of myeloid growth factors (MGFs) triggered the need for an outcome-driven initiative. From March 1, 2015, to February 29, 2016, at University of California Irvine Health Chao Infusion Center, 116 of 3,300 MGF doses were missed (3.52%), including pegfilgrastim, filgrastim, and sargramostim. We hypothesized that with the application of Lean Six Sigma methodology, we would achieve our primary objective of reducing the number of missed MGF doses to < 0.5%. METHODS: This quality improvement initiative was conducted at Chao Infusion Center as part of a Lean Six Sigma Green Belt Certification Program. Therefore, Lean Six Sigma principles and tools were used throughout each phase of the project. Retrospective and prospective medical record reviews and data analyses were performed to evaluate the extent of the identified problem and impact of the process changes. Improvements included systems applications, practice changes, process modifications, and safety-net procedures. RESULTS: Preintervention, 24 missed doses (20.7%) required patient supportive care measures, resulting in increased hospital costs and decreased quality of care. Postintervention, from June 8, 2016, to August 7, 2016, zero of 489 MGF doses were missed after 2 months of intervention ( P < .001). Chao Infusion Center reduced missed doses from 3.52% to 0%, reaching the goal of < 0.5%. CONCLUSION: The establishment of simplified and standardized processes with safety checks for error prevention increased quality of care. Lean Six Sigma methodology can be applied by other institutions to produce positive outcomes and implement similar practice changes.

A novel actigraphy data analysis tool and its application to identifying the optimal threshold value in three subject populations.

Most actigraphy devices use different analysis methods and a non-standardized threshold value to estimate sleep/wake status and identify rest intervals. To address limitations of these approaches, a new algorithm was developed that makes no assumptions about sleep/wake status, objectively selects an optimal threshold for different populations, and provides mathematical endpoints to more fully describe the activity patterns of subjects. The optimal threshold (cts min(-1)) is defined as the value that maximizes the duration of the rest period while minimizing the inclusion of epochs from the active period. This value is identified as the beginning of a plateau region of a rest duration versus threshold value graph. Application of this new algorithm to data from 56 healthy adults, 6 healthy children, and 14 children with autism spectrum disorder (ASD) showed that the three groups had different optimal threshold values (35, 40, and 45 cts min(-1) for adults, children and ASD respectively). The rest periods of healthy children was longer than that of adults (8.5 ± 0.5 versus 6.3 ± 0.9 h, p < 0.001). Healthy children also had less activity during the rest periods than adults (10.5 ± 1.8 versus 15.1 ± 11.8 cts min(-1)) and ASD children (12.0 ± 2.2 cts min(-1)) but these differences were not statistically significant. However, the distributions of their activity values during rest periods as measured by skewness and kurtosis were significantly greater than that of healthy adults (skewness: 7.3 ± 0.9 versus 6.2 ± 0.9, p < 0.01, kurtosis: 83.3 ± 16.5 versus 52.8 ± 14.4, p < 0.001) and of ASD children (skewness: 6.4 ± 0.6. p < 0.05, kurtosis: 57.7 ± 12.8, p < 0.001). These findings are consistent with more restful sleep patterns which would have mostly low levels of activity with few large values. The new analysis tool may be helpful in standardizing actigraphy data analyses while providing new insights into activity patterns.

Epithelial lining fluid solute concentrations in chronic obstructive lung disease patients and normal subjects.

The exhaled breath condensate (EBC) method represents a new, noninvasive way to detect inflammatory and metabolic markers in the fluid that covers the airways [epithelial lining fluid (ELF)]. However, respiratory droplets represent only a very small and variable fraction of the EBC, most (approximately 99.99%) of which is water vapor. Our objective was to show that ELF concentrations could be calculated from EBC values by using any of three dilutional indicators (urea, total cations, and conductivity) in nine normal and nine chronic obstructive lung disease (COPD) subjects. EBC concentrations of Na(+), K(+), Ca(2+), Mg(2+), total cations, urea, and conductivity varied over a 10-fold range among individuals, but concentrations of these constituents (except Ca(2+)) remained well correlated (r(2) = 0.44-0.83, P < 0.001). Dilution (D) of respiratory droplets in water vapor was calculated by dividing plasma concentrations of the dilutional indicators by EBC concentrations. Estimates of D were not significantly different among these indicators, and urea D averaged 10,800 +/- 2,100 (SE) in normal and 12,600 +/- 3,300 in COPD subjects. Although calculated Na(+) concentrations in the ELF were less than one-half those in plasma, and concentrations of K(+), Ca(2+), and Mg(2+) exceeded those in plasma, total cation concentrations in ELF were not significantly different from those in plasma, indicating that ELF is isotonic in both normal and COPD subjects. EBC amylase concentrations (measured with an ultrasensitive procedure) indicated that saliva represented <10% of the respiratory (ELF) droplets in all but three samples. Dilutional and salivary markers are essential for interpretation of EBC studies.

Current approaches and future directions to understanding control of head movement.

This chapter reviews four key issues that must be addressed to advance our knowledge of control of head movement by the central nervous system (CNS). (1) Researchers must consider how the CNS utilizes the multiple muscle patterns that can produce the same head movement in carrying out tasks in an optimal way. (2) More attention must be paid to the dynamics of neck muscle activation that are required to implement head movements and show they are produced by CNS circuits. (3) Research is required to determine how the multiple pathways that impinge upon neck motor centers are utilized in a variety of tasks including eye-head gaze shifts, smooth head tracking, head stabilization and manipulating objects with the head. These pathways include corticospinal, vestibulospinal, reticulospinal (three subdivisions), fastigiospinal, tectospinal and interstitiospinal tracts. (4) Further analysis is needed to understand how vestibular signals are modulated during each of the above-mentioned tasks. This ambitious agenda is justified by the fact that the head-neck motor system is an ideal model for understanding issues of complex motor control.

An Enantioselective Synthesis of Cis Perhydroisoquinoline LY235959.

A novel synthesis of NMDA receptor antagonist LY235959 (1) has been achieved in 13% overall yield and 17 steps from (R)-pantolactone (7). Highlights of the synthesis include (a) use of a chiral auxiliary controlled asymmetric Diels-Alder reaction to provide the desired absolute and relative stereochemistry at C-4a, C-6, and C-8a, (b) an efficient alkylation of hindered iodide 13 using a novel amide benzophenone imine, (c) oxidative ring opening of the [2.2.2] bicyclic system to simultaneously functionalize the molecule for intramolecular cyclization and phosphonate introduction, and (d) an increased understanding of how the C-3 stereochemistry may be controlled by thermodynamic equilibration. Synthesis of epimer 20 in high overall yield makes this synthetic route attractive for future development efforts.

Comparison of actigraphy and polysomnography to assess effects of zolpidem in a clinical research unit.

OBJECTIVE: This study sought to compare devices that use actigraphy for measuring sleep endpoints in the clinical research unit (CRU) and home environment. The abilities of polysomnography (PSG) and actigraphy monitors to detect drug effects in a CRU were also investigated. METHODS: Eleven healthy subjects were recruited and monitored with PSG for four consecutive nights in a CRU after receiving no treatment (night 1, N1), and then placebo or 5 mg day(-1) or 10 mg day(-1) zolpidem in a randomised, cross-over design. Subjects wore two devices that use actigraphy (a Respironics® Actiwatch® on the wrist and a BodyMedia® Sensewear® Armband on the upper-arm) on the non-dominant arm for five nights at home and four nights in the CRU during PSG. RESULTS: Wake after sleep onset (WASO) and total sleep time (TST) measured by PSG and estimates of WASO by the Actiwatch decreased significantly with 5mg but not 10mg of zolpidem versus placebo. Direct activity (counts/min) with the Actiwatch decreased in response to zolpidem (both 5 and 10 mg day(-1)) versus placebo. Armband recordings of direct activity were similar to the Actiwatch but not significantly different versus placebo. Both actigraphy device estimates of TST were approximately 1h longer in CRU versus home. Agreement between actigraphy estimates of TST and WASO and PSG values of TST and WASO were closer during nights with zolpidem treatment. CONCLUSIONS: PSG can detect the effects of zolpidem on sleep in a CRU setting. Actigraphy can provide useful assessment of sleep, but direct activity endpoints may be more effective than estimates of TST and WASO.

A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome.

OBJECTIVE: This study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS). METHODS: This six-arm, double-blind, placebo-controlled, dose-response study randomized patients (N=137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose-response was characterized using an exponential decay model, which estimates the maximal effect (E(max)) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety. RESULTS: The separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED(50)) and 90% (ED(90)) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related. CONCLUSIONS: In this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.