The objective of this analysis was to systematically review the evidence for virtual reality (VR) therapy in an adult post-stroke population in both custom built virtual environments (VE) and ...commercially available gaming systems (CG).
MEDLINE, CINAHL, EMBASE, ERIC, PSYCInfo, DARE, PEDro, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews were systematically searched from the earliest available date until April 4, 2013. Controlled trials that compared VR to conventional therapy were included. Population criteria included adults (>18) post-stroke, excluding children, cerebral palsy, and other neurological disorders. Included studies were reported in English. Quality of studies was assessed with the Physiotherapy Evidence Database Scale (PEDro).
Twenty-six studies met the inclusion criteria. For body function outcomes, there was a significant benefit of VR therapy compared to conventional therapy controls, G = 0.48, 95% CI = 0.27, 0.70, and no significant difference between VE and CG interventions (P = 0.38). For activity outcomes, there was a significant benefit of VR therapy, G = 0.58, 95% CI = 0.32, 0.85, and no significant difference between VE and CG interventions (P = 0.66). For participation outcomes, the overall effect size was G = 0.56, 95% CI = 0.02, 1.10. All participation outcomes came from VE studies.
VR rehabilitation moderately improves outcomes compared to conventional therapy in adults post-stroke. Current CG interventions have been too few and too small to assess potential benefits of CG. Future research in this area should aim to clearly define conventional therapy, report on participation measures, consider motivational components of therapy, and investigate commercially available systems in larger RCTs.
Prospero CRD42013004338.
Patient nonadherence with therapy is a major barrier to rehabilitation. Recovery is often limited and requires prolonged, intensive rehabilitation that is time-consuming, expensive, and difficult. We ...review evidence for the potential use of video games in rehabilitation with respect to the behavioral, physiological, and motivational effects of gameplay. In this Special Interest article, we offer a method to evaluate effects of video game play on motor learning and their potential to increase patient engagement with therapy, particularly commercial games that can be interfaced with adapted control systems. We take the novel approach of integrating research across game design, motor learning, neurophysiology changes, and rehabilitation science to provide criteria by which therapists can assist patients in choosing games appropriate for rehabilitation. Research suggests that video games are beneficial for cognitive and motor skill learning in both rehabilitation science and experimental studies with healthy subjects. Physiological data suggest that gameplay can induce neuroplastic reorganization that leads to long-term retention and transfer of skill; however, more clinical research in this area is needed. There is interdisciplinary evidence suggesting that key factors in game design, including choice, reward, and goals, lead to increased motivation and engagement. We maintain that video game play could be an effective supplement to traditional therapy. Motion controllers can be used to practice rehabilitation-relevant movements, and well-designed game mechanics can augment patient engagement and motivation in rehabilitation. We recommend future research and development exploring rehabilitation-relevant motions to control games and increase time in therapy through gameplay.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A61) for more insights from the authors.
Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, as ...in the treatment of HIV (e.g., lopinavir/ritonavir) and more recently COVID-19 (Paxlovid or nirmatrelvir/ritonavir). Despite its clinical importance, the exact mechanism of ritonavir-mediated CYP3A4 inactivation is still not fully understood. Nonetheless, ritonavir is clearly a potent mechanism-based inactivator, which irreversibly blocks CYP3A4. Here, we discuss four fundamentally different mechanisms proposed for this irreversible inactivation/inhibition, namely the (I) formation of a metabolic-intermediate complex (MIC), tightly coordinating to the heme group; (II) strong ligation of unmodified ritonavir to the heme iron; (III) heme destruction; and (IV) covalent attachment of a reactive ritonavir intermediate to the CYP3A4 apoprotein. Ritonavir further appears to inactivate CYP3A4 and CYP3A5 with similar potency, which is important since ritonavir is applied in patients of all ethnicities. Although it is currently not possible to conclude what the primary mechanism of action in vivo is, it is unlikely that any of the proposed mechanisms are fundamentally wrong. We, therefore, propose that ritonavir markedly inactivates CYP3A through a mixed set of mechanisms. This functional redundancy may well contribute to its overall inhibitory efficacy.
Human motor behavior is highly goal directed, requiring the central nervous system to coordinate different aspects of motion generation to achieve the motion goals. The concept of motor synergies ...provides an approach to quantify the covariation of joint motions and of muscle activations, i.e., elemental variables, during a task. To analyze goal-directed movements, factorization methods can be used to reduce the high dimensionality of these variables while accounting for much of the variance in large data sets. Three factorization methods considered in this paper are principal component analysis (PCA), nonnegative matrix factorization (NNMF), and independent component analysis (ICA). Bilateral human reaching data sets are used to compare the methods, and advantages of each are presented and discussed. PCA and NNMF had a comparable performance on both EMG and joint motion data and both outperformed ICA. However, NNMF's nonnegativity condition for activation of basis vectors is a useful attribute in identifying physiologically meaningful synergies, making it a more appealing method for future studies. A simulated data set is introduced to clarify the approaches and interpretation of the synergy structures returned by the three factorization methods.
Literature on comparing factorization methods in identifying motor synergies using numerically generated, simulation, and muscle activation data from animal studies already exists. We present an empirical evaluation of the performance of three of these methods on muscle activation and joint angles data from human reaching motion: principal component analysis, nonnegative matrix factorization, and independent component analysis. Using numerical simulation, we also studied the meaning and differences in the synergy structures returned by each method. The results can be used to unify approaches in identifying and interpreting motor synergies.
This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as ...first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated.
Patients received cetuximab (400 mg/m(2) initial dose followed by 250 mg/m(2)/wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1, plus leucovorin 200 mg/m(2) and fluorouracil as a 400 mg/m(2) bolus followed by a 600 mg/m(2) infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233).
The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated.
KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.
The X-ray free-electron laser has opened a new era for photon science, improving the X-ray brightness by ten orders of magnitude over previously available sources. Similar to an optical laser, the ...spectral and temporal structure of the radiation pulses can be tailored to the specific needs of many experiments by accurately manipulating the lasing medium, that is, the electron beam. Here we report the generation of mJ-level two-colour hard X-ray pulses of few femtoseconds duration with an XFEL driven by twin electron bunches at the Linac Coherent Light Source. This performance represents an improvement of over an order of magnitude in peak power over state-of-the-art two-colour XFELs. The unprecedented intensity and temporal coherence of this new two-colour X-ray free-electron laser enable an entirely new set of scientific applications, ranging from X-ray pump/X-ray probe experiments to the imaging of complex biological samples with multiple wavelength anomalous dispersion.
•Mission-oriented innovation policy may create new innovation pathways.•These pathways lead to rapid diffusion & learning by doing, using & interacting.•Dominant design can come before radical ...technological experimentation.•Classic design pathways are reversed.•There is a risk of early lock-in if there is no room for experimentation & variety.
A new era of transformative and mission-oriented innovation policy has arisen due to the urgency of grand societal challenges, such as climate change. This new era requires a massive restructuring of societies, industries and consumption and will depend on, in part, new technologies and a high degree of coordination between the industry, civil society and government. These new forms of innovation policy may seriously alter classic innovation dynamics. This is indeed the case in offshore wind, in which a specific institutional architecture has led to a rapidly formed dominant design that emerged early in the technology’s development. Radical experimentation, normally expected at the beginning of technological development, only began to emerge after 20 years of diffusion. This trend reverses classic innovation pathways. This paper empirically demonstrates this reversed innovation trend and then proposes a new innovation dynamic founded in a new era of grand societal challenges. It then proceeds to illustrate how The Netherlands has promoted and embedded a rapidly formed dominant design through an analysis of its offshore wind innovation system based on 31 interviews. It concludes that well-positioned incumbents and a specific innovation system architecture have created this trend, a notion applicable to a broader socio-technical system context. A rapidly formed dominant design and quick diffusion are critical to ensuring countries meet their climate pledges, but may risk early lock-in if there is no room for experimentation. We propose that governments ensure sufficient attention to variety and experimentation in innovation systems while maintaining a focus on rapid diffusion.
During standing balance, vestibular signals encode head movement and are transformed into coordinates that are relevant to maintaining upright posture of the whole body. This transformation must ...account for head-on-body orientation as well as the muscle actions generating the postural response. Here, we investigate whether this transformation is dependent upon a muscle's ability to stabilize the body along the direction of a vestibular disturbance. Subjects were braced on top of a robotic balance system that simulated the mechanics of standing while being exposed to an electrical vestibular stimulus that evoked a craniocentric vestibular error of head roll. The balance system was limited to move in a single plane while the vestibular error direction was manipulated by having subjects rotate their head in yaw. Vestibular-evoked muscle responses were greatest when the vestibular error was aligned with the balance direction and decreased to zero as the two directions became orthogonal. This demonstrates that muscles respond only to the component of the error that is aligned with the balance direction and thus relevant to the balance task, not to the cumulative afferent activity, as expected for vestibulospinal reflex loops. When we reversed the relationship between balancing motor commands and associated vestibular sensory feedback, the direction of vestibular-evoked ankle compensatory responses was also reversed. This implies that the nervous system quickly reassociates new relationships between vestibular sensory signals and motor commands related to maintaining balance. These results indicate that vestibular-evoked muscle activity is a highly flexible balance response organized to compensate for vestibular disturbances.
The postural corrections critical to standing balance and navigation rely on transformation of sensory information into reference frames that are relevant for the required motor actions. Here, we demonstrate that the nervous system transforms vestibular sensory signals of head motion according to a muscle's ability to stabilize the body along the direction of a vestibular-evoked disturbance. By manipulating the direction of the imposed vestibular signal relative to a muscle's action, we show that the vestibular contribution to muscle activity is a highly flexible and organized balance response. This study provides insight into the neural integration and central processing associated with transformed vestibulomotor relationships that are essential to standing upright.
To investigate whether the compensatory trunk movements of stroke survivors observed during reaching tasks can be decreased by force and visual feedback, and to examine whether one of these feedback ...modalities is more efficacious than the other in reducing this compensatory tendency.
Randomized crossover trial.
University research laboratory.
Community-dwelling older adults (N=15; 5 women; mean age, 64±11y) with hemiplegia from nontraumatic hemorrhagic or ischemic stroke (>3mo poststroke), recruited from stroke recovery groups, the research group's website, and the community.
In a single session, participants received augmented feedback about their trunk compensation during a bimanual reaching task. Visual feedback (60 trials) was delivered through a computer monitor, and force feedback (60 trials) was delivered through 2 robotic devices.
Primary outcome measure included change in anterior trunk displacement measured by motion tracking camera. Secondary outcomes included trunk rotation, index of curvature (measure of straightness of hands' path toward target), root mean square error of hands' movement (differences between hand position on every iteration of the program), completion time for each trial, and posttest questionnaire to evaluate users' experience and system's usability.
Both visual (-45.6% 45.8 SD change from baseline, P=.004) and force (-41.1% 46.1 SD, P=.004) feedback were effective in reducing trunk compensation. Scores on secondary outcome measures did not improve with either feedback modality. Neither feedback condition was superior.
Visual and force feedback show promise as 2 modalities that could be used to decrease trunk compensation in stroke survivors during reaching tasks. It remains to be established which one of these 2 feedback modalities is more efficacious than the other as a cue to reduce compensatory trunk movement.
X-ray free-electron lasers, with pulse durations ranging from a few to several hundred femtoseconds, are uniquely suited for studying atomic, molecular, chemical and biological systems. ...Characterizing the temporal profiles of these femtosecond X-ray pulses that vary from shot to shot is not only challenging but also important for data interpretation. Here we report the time-resolved measurements of X-ray free-electron lasers by using an X-band radiofrequency transverse deflector at the Linac Coherent Light Source. We demonstrate this method to be a simple, non-invasive technique with a large dynamic range for single-shot electron and X-ray temporal characterization. A resolution of less than 1 fs root mean square has been achieved for soft X-ray pulses. The lasing evolution along the undulator has been studied with the electron trapping being observed as the X-ray peak power approaches 100 GW.
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