Portable Touchscreen Assessment of Motor Skill: A Registered Report of the Reliability and Validity of EDNA MoTap.

Portable and flexible administration of manual dexterity assessments is necessary to monitor recovery from brain injury and the effects of interventions across clinic and home settings, especially when in-person testing is not possible or convenient. This paper aims to assess the concurrent validity and test-retest reliability of a new suite of touchscreen-based manual dexterity tests (called EDNA™MoTap) that are designed for portable and efficient administration. A minimum sample of 49 healthy young adults will be conveniently recruited. The EDNA™MoTap tasks will be assessed for concurrent validity against standardized tools (the Box and Block Test [BBT] and the Purdue Pegboard Test) and for test-retest reliability over a 1- to 2-week interval. Correlation coefficients of r > .6 will indicate acceptable validity, and intraclass correlation coefficient (ICC) values > .75 will indicate acceptable reliability for healthy adults. The sample were primarily right-handed (91%) adults aged 19 and 34 years (M = 24.93, SD = 4.21, 50% female). The MoTap tasks did not demonstrate acceptable validity, with tasks showing weak-to-moderate associations with the criterion assessments. Some outcomes demonstrated acceptable test-retest reliability; however, this was not consistent. Touchscreen-based assessments of dexterity remain relevant; however, there is a need for further development of the EDNA™MoTap task administration.

Home-based (virtual) rehabilitation improves motor and cognitive function for stroke patients: a randomized controlled trial of the Elements (EDNA-22) system.

BACKGROUND: Home-based rehabilitation of arm function is a significant gap in service provision for adult stroke. The EDNA-22 tablet is a portable virtual rehabilitation-based system that provides a viable option for home-based rehabilitation using a suite of tailored movement tasks, and performance monitoring via cloud computing data storage. The study reported here aimed to compare use of the EDNA system with an active control (Graded Repetitive Arm Supplementary Program-GRASP training) group using a parallel RCT design. METHODS: Of 19 originally randomized, 17 acute-care patients with upper-extremity dysfunction following unilateral stroke completed training in either the treatment (n = 10) or active control groups (n = 7), each receiving 8-weeks of in-home training involving 30-min sessions scheduled 3-4 times weekly. Performance was assessed across motor, cognitive and functional behaviour in the home. Primary motor measures, collected by a blinded assessor, were the Box and Blocks Task (BBT) and 9-Hole Pegboard Test (9HPT), and for cognition the Montreal Cognitive Assessment (MoCA). Functional behaviour was assessed using the Stroke Impact Scale (SIS) and Neurobehavioural Functioning Inventory (NFI). RESULTS: One participant from each group withdrew for personal reasons. No adverse events were reported. Results showed a significant and large improvement in performance on the BBT for the more-affected hand in the EDNA training group, only (g = 0.90). There was a mild-to-moderate effect of training on the 9HPT for EDNA (g = 0.55) and control (g = 0.42) groups, again for the more affected hand. In relation to cognition, performance on the MoCA improved for the EDNA group (g = 0.70). Finally, the EDNA group showed moderate (but non-significant) improvement in functional behaviour on the SIS (g = 0.57) and NFI (g = 0.49). CONCLUSION: A short course of home-based training using the EDNA-22 system can yield significant gains in motor and cognitive performance, over and above an active control training that also targets upper-limb function. Intriguingly, these changes in performance were corroborated only tentatively in the reports of caregivers. We suggest that future research consider how the implementation of home-based rehabilitation technology can be optimized. We contend that self-administered digitally-enhanced training needs to become part of the health literacy of all stakeholders who are impacted by stroke and other acquired brain injuries. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) Number: ACTRN12619001557123. Registered 12 November 2019, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378298&isReview=true.

Elements virtual rehabilitation improves motor, cognitive, and functional outcomes in adult stroke: evidence from a randomized controlled pilot study.

BACKGROUND: Virtual reality technologies show potential as effective rehabilitation tools following neuro-trauma. In particular, the Elements system, involving customized surface computing and tangible interfaces, produces strong treatment effects for upper-limb and cognitive function following traumatic brain injury. The present study evaluated the efficacy of Elements as a virtual rehabilitation approach for stroke survivors. METHODS: Twenty-one adults (42-94 years old) with sub-acute stroke were randomized to four weeks of Elements virtual rehabilitation (three weekly 30-40 min sessions) combined with treatment as usual (conventional occupational and physiotherapy) or to treatment as usual alone. Upper-limb skill (Box and Blocks Test), cognition (Montreal Cognitive Assessment and selected CogState subtests), and everyday participation (Neurobehavioral Functioning Inventory) were examined before and after inpatient training, and one-month later. RESULTS: Effect sizes for the experimental group (d = 1.05-2.51) were larger compared with controls (d = 0.11-0.86), with Elements training showing statistically greater improvements in motor function of the most affected hand (p = 0.008), and general intellectual status and executive function (p ≤ 0.001). Proportional recovery was two- to three-fold greater than control participants, with superior transfer to everyday motor, cognitive, and communication behaviors. All gains were maintained at follow-up. CONCLUSION: A course of Elements virtual rehabilitation using goal-directed and exploratory upper-limb movement tasks facilitates both motor and cognitive recovery after stroke. The magnitude of training effects, maintenance of gains at follow-up, and generalization to daily activities provide compelling preliminary evidence of the power of virtual rehabilitation when applied in a targeted and principled manner. TRIAL REGISTRATION: this pilot study was not registered.

Ambient Protection of Few-Layer Black Phosphorus via Sequestration of Reactive Oxygen Species.

Few-layer black phosphorous (BP) has emerged as a promising candidate for next-generation nanophotonic and nanoelectronic devices. However, rapid ambient degradation of mechanically exfoliated BP poses challenges in its practical deployment in scalable devices. To date, the strategies employed to protect BP have relied upon preventing its exposure to atmospheric conditions. Here, an approach that allows this sensitive material to remain stable without requiring its isolation from the ambient environment is reported. The method draws inspiration from the unique ability of biological systems to avoid photo-oxidative damage caused by reactive oxygen species. Since BP undergoes similar photo-oxidative degradation, imidazolium-based ionic liquids are employed as quenchers of these damaging species on the BP surface. This chemical sequestration strategy allows BP to remain stable for over 13 weeks, while retaining its key electronic characteristics. This study opens opportunities to practically implement BP and other environmentally sensitive 2D materials for electronic applications.

Medicinal chemistry approaches to avoid aldehyde oxidase metabolism.

Aldehyde oxidase (AO) is a molybdenum-containing enzyme distributed throughout the animal kingdom and capable of metabolising a wide range of aldehydes and N-heterocyclic compounds. Although metabolism by this enzyme in man is recognised to have significant clinical impact where human AO activity was not predicted by screening in preclinical species, there is very little reported literature offering real examples where drug discoverers have successfully designed away from AO oxidation. This article reports on some strategies adopted in the Pfizer TLR7 agonist programme to successfully switch off AO metabolism that was seen principally in the rat.

Upper-limb virtual rehabilitation for traumatic brain injury: a preliminary within-group evaluation of the elements system.

AIM: The aim of this study was to assess the efficacy of the Elements virtual reality (VR) system for rehabilitation of upper-limb function in patients with traumatic brain injury (TBI). METHODS: Using a within-group design, patients were tested three times, each 4 weeks apart: Pre-intervention 1 and 2 and Post-intervention. During intervention, participants received 12 1-hour training sessions over 4 weeks in addition to their usual care. Five males and four females aged 18-48 years with severe TBI were recruited. The Elements system consisted of a 100-cm tabletop LCD, camera tracking system, tangible user interfaces (i.e. graspable objects of basic shape) and software. The system provided two modes of interaction with augmented feedback: goal-directed and exploratory. Upper-limb performance was assessed using system-rated measures (movement speed, accuracy and efficiency) and standardized tests. RESULTS: Planned comparisons revealed little change in performance over the pre-test period apart from an increase in movement speed. There were significant training effects, with large effect sizes on all measures except the nuts-and-bolts task. CONCLUSIONS: These preliminary findings support the results of an early case study of the Elements system, further demonstrating that VR training is a viable adjunct to conventional physical therapy in facilitating motor learning in patients with TBI.

Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms.

PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min⁻¹ kg⁻¹ for PF-184298, and 5 to >20 mL min⁻¹ kg⁻¹ for PF-4776548. A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction. A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298. A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.

Discovery of a highly potent series of TLR7 agonists.

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.

Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection.

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.

Upper limb virtual rehabilitation for traumatic brain injury: initial evaluation of the elements system.

PRIMARY OBJECTIVE: To evaluate the effectiveness of a tabletop virtual-reality (VR) based upper-limb rehabilitation system (called Elements) for promoting movement skill in patients with TBI. RESEARCH DESIGN: An ABA case study design with multiple baselines was employed. Baseline performance in this design is contrasted against the results during the treatment phase. RESEARCH METHODS: Three patients with TBI participated in 12 1-hour sessions of VR-based training. The VR system consisted of a 42-inch tabletop LCD, camera tracking system and tangible user interface. The system requires participants to move an object to cued locations while receiving augmented movement feedback to reinforce speed, trajectory and placement. Upper limb performance was assessed using these three system-measured variables and standardized tests. Trends in the time-sequence plots for each patient were assessed by sight inspection of smoothed data and then by statistical analyses. RESULTS: Participants demonstrated improvements on movement accuracy, efficiency and bimanual dexterity and mixed improvement on speed and other measures of movement skill. CONCLUSION: Taken together, the findings demonstrate that the Elements system shows promise in facilitating motor learning in these TBI patients. Larger scale trials are now deemed a viable step in further validating the system.

Pharmacokinetic-pharmacodynamic modeling of alpha interferon response induced by a Toll-like 7 receptor agonist in mice.

Recombinant alpha interferon (IFN-alpha) is used in the treatment of hepatitis C virus (HCV)-infected patients but is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-alpha and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-alpha as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.

Localisation of melanin-concentrating hormone receptor 1 in rat brain and evidence that sleep parameters are not altered despite high central receptor occupancy.

The present study describes the optimisation of an autoradiography assay that provides a means to measure the in vitro potency of melanin-concentrating hormone receptor 1 (MCH(1)) antagonists in native tissues and their ex vivo receptor occupancy. Initial localisation studies demonstrated that the MCH(1) receptor radioligand [(125)I]-S36057 bound to rat caudate putamen with specific binding of consistently >60%. In vitro, the MCH(1) receptor antagonists GW3430, SNAP-94847 and 4'-{[1-(cyclopropylmethyl)piperidin-4-ylidene] [5-fluoro-6-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}biphenyl-3-carbonitrile (referred to as Compound A) exhibited concentration dependent inhibition of the specific binding of [(125)I]-S36057, with a rank order of affinity of SNAP-94847>Compound A>GW3430. In an ex vivo occupancy assay, Compound A dosed orally to rats caused a concentration dependent inhibition of the specific binding of [(125)I]-S36057 to rat caudate putamen. The occupancy reached 87+/-11% at 30 mg/kg and the estimated ED(50) was 9.3 mg/kg, which was equivalent to a free plasma concentration of 40 nM. As MCH has been reported to play a role in the regulation of the sleep cycle, the effect of Compound A on sleep parameters was investigated. However Compound A, at exposures that achieved near maximal receptor occupancy, failed to demonstrate any effects on the sleep/wake pattern in telemetered rats. We conclude that our ex vivo receptor occupancy assay is suitable for selecting centrally penetrant MCH(1) receptor antagonists and that, despite high levels of receptor occupancy, the selective MCH(1) receptor antagonist Compound A failed to elicit any changes in sleep electroencephalogram (EEG) parameters.

Development of a micro-turbulent flow chromatography focus mode method for drug quantitation in discovery bioanalysis.

An online turbulent flow chromatography method coupled to tandem mass spectrometry (TFC-MS/MS) has been developed within our bioanalytical group, suited to the analysis of mid to late stage discovery compounds. A dual column configuration utilising isocratic focusing of the analyte upon the analytical column maintained an excellent peak shape for a large proportion of compounds encountered and enabled consistent quantitation to sub-nanogram concentrations (<15 pg on column). Furthermore, the low sample injection volume coupled with rapid column washing using basic and acidic mobile phases, has proved advantageous in removing sample carryover and also the overall exposure to biological material; favourable for good system robustness. All the data discussed were generated with a method cycle time of 5 min providing accurate quantitation (acceptance criteria based upon FDA method validation guidelines) with multiple analytes and biological matrices.