The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

Pre-analytical processing of plasma and serum samples for combined proteome and metabolome analysis.

Metabolomic and proteomic analyses of human plasma and serum samples harbor the power to advance our understanding of disease biology. Pre-analytical factors may contribute to variability and bias in the detection of analytes, especially when multiple labs are involved, caused by sample handling, processing time, and differing operating procedures. To better understand the impact of pre-analytical factors that are relevant to implementing a unified proteomic and metabolomic approach in a clinical setting, we assessed the influence of temperature, sitting times, and centrifugation speed on the plasma and serum metabolomes and proteomes from six healthy volunteers. We used targeted metabolic profiling (497 metabolites) and data-independent acquisition (DIA) proteomics (572 proteins) on the same samples generated with well-defined pre-analytical conditions to evaluate criteria for pre-analytical SOPs for plasma and serum samples. Time and temperature showed the strongest influence on the integrity of plasma and serum proteome and metabolome. While rapid handling and low temperatures (4°C) are imperative for metabolic profiling, the analyzed proteomics data set showed variability when exposed to temperatures of 4°C for more than 2 h, highlighting the need for compromises in a combined analysis. We formalized a quality control scoring system to objectively rate sample stability and tested this score using external data sets from other pre-analytical studies. Stringent and harmonized standard operating procedures (SOPs) are required for pre-analytical sample handling when combining proteomics and metabolomics of clinical samples to yield robust and interpretable data on a longitudinal scale and across different clinics. To ensure an adequate level of practicability in a clinical routine for metabolomics and proteomics studies, we suggest keeping blood samples up to 2 h on ice (4°C) prior to snap-freezing as a compromise between stability and operability. Finally, we provide the methodology as an open-source R package allowing the systematic scoring of proteomics and metabolomics data sets to assess the stability of plasma and serum samples.

Improvement of Apraxia With Augmented Reality: Influencing Pantomime of Tool Use via Holographic Cues.

Background: Defective pantomime of tool use is a hall mark of limb apraxia. Contextual information has been demonstrated to improve tool use performance. Further, knowledge about the potential impact of technological aids such as augmented reality for patients with limb apraxia is still scarce. Objective: Since augmented reality offers a new way to provide contextual information, we applied it to pantomime of tool use. We hypothesize that the disturbed movement execution can be mitigated by holographic stimulation. If visual stimuli facilitate the access to the appropriate motor program in patients with apraxia, their performance should improve with increased saliency, i.e., should be better when supported by dynamic and holographic cues vs. static and screen-based cues. Methods: Twenty one stroke patients and 23 healthy control subjects were randomized to mime the use of five objects, presented in two Environments (Screen vs. Head Mounted Display, HMD) and two Modes (Static vs. Dynamic) resulting in four conditions (ScreenStat, ScreenDyn, HMDStat, HMDDyn), followed by a real tool demonstration. Pantomiming was analyzed by a scoring system using video recordings. Additionally, the sense of presence was assessed using a questionnaire. Results: Healthy control participants performed close to ceiling and significantly better than patients. Patients achieved significantly higher scores with holographic or dynamic cues. Remarkably, when their performance was supported by animated holographic cues (e.g., striking hammer), it did not differ significantly from real tool demonstration. As the sense of presence increases with animated holograms, so does the pantomiming. Conclusion: Patients' performance improved with visual stimuli of increasing saliency. Future assistive technology could be implemented upon this knowledge and thus, positively impact the rehabilitation process and a patient's autonomy.

The impact of visuospatial perception on distance judgment and depth perception in an Augmented Reality environment in patients after stroke: an exploratory study.

BACKGROUND: Augmented Reality (AR)-based interventions are applied in neurorehabilitation with increasing frequency. Depth perception is required for the intended interaction within AR environments. Until now, however, it is unclear whether patients after stroke with impaired visuospatial perception (VSP) are able to perceive depth in the AR environment. METHODS: Different aspects of VSP (stereovision and spatial localization/visuoconstruction) were assessed in 20 patients after stroke (mean age: 64 ± 14 years) and 20 healthy subjects (HS, mean age: 28 ± 8 years) using clinical tests. The group of HS was recruited to assess the validity of the developed AR tasks in testing stereovision. To measure perception of holographic objects, three distance judgment tasks and one three-dimensionality task were designed. The effect of impaired stereovision on performance in each AR task was analyzed. AR task performance was modeled by aspects of VSP using separate regression analyses for HS and for patients. RESULTS: In HS, stereovision had a significant effect on the performance in all AR distance judgment tasks (p = 0.021, p = 0.002, p = 0.046) and in the three-dimensionality task (p = 0.003). Individual quality of stereovision significantly predicted the accuracy in each distance judgment task and was highly related to the ability to perceive holograms as three-dimensional (p = 0.001). In stroke-survivors, impaired stereovision had a specific deterioration effect on only one distance judgment task (p = 0.042), whereas the three-dimensionality task was unaffected (p = 0.317). Regression analyses confirmed a lacking impact of patients' quality of stereovision on AR task performance, while spatial localization/visuoconstruction significantly prognosticated the accuracy in distance estimation of geometric objects in two AR tasks. CONCLUSION: Impairments in VSP reduce the ability to estimate distance and to perceive three-dimensionality in an AR environment. While stereovision is key for task performance in HS, spatial localization/visuoconstruction is predominant in patients. Since impairments in VSP are present after stroke, these findings might be crucial when AR is applied for neurorehabilitative treatment. In order to maximize the therapy outcome, the design of AR games should be adapted to patients' impaired VSP.  Trial registration: The trial was not registered, as it was an observational study.

Exercise Therapy Teamwork in German Rehabilitation Settings: Results of a National Survey Using Mixed Methods Design.

A key prerequisite for implementing biopsychosocial exercise therapy concepts as parts of multimodal rehabilitation programs is interprofessional teamwork. Based on a nationwide survey of exercise therapy using a mixed methods design, it is of interest to determine to what extent there are links between team-related processes (e.g., interprofessional exchange) and structural features of the exercise therapy departments (e.g., department size) and the individual rating of interprofessional teamwork. The first part of the study involved a questionnaire-based survey, where exercise therapy heads of 1146 rehabilitation facilities were contacted. In the second part of the study, 58 exercise therapy heads held discussions in six focus groups. The results from both parts showed that interprofessional teamwork was rated positively overall. Team meetings were seen as the central platform for exchange. However, particularly in larger facilities, the hierarchical position of medical management and lacking resources were negatively associated with interprofessional exchange. The results affirm empirically that a more binding provision of adequate structural and organizational conditions, such as sufficient time slots for liaising on content, are essential for effective teamwork. This would facilitate and improve the promotion of physical activity in multimodal rehabilitation programs.

The "Beam-Me-In Strategy" - remote haptic therapist-patient interaction with two exoskeletons for stroke therapy.

BACKGROUND: We present a robot-assisted telerehabilitation system that allows for haptic interaction between therapist and patient over distance. It consists of two arm therapy robots. Attached to one robot the therapists can feel on their own arm the limitations of the patient's arm which is attached to the other robot. Due to the exoskeleton structure of the robot, movements can be performed in the three-dimensional space. METHODS: Fifteen physical and occupational therapists tested this strategy, named "Beam-Me-In", while using an exoskeleton robot connected to a second exoskeleton robot in the same room used by the study experimenter. Furthermore, the therapists assessed the level of impairment of recorded and simulated arm movements. They quantified four typical impairments of stroke patients: reduced range of motion (active and passive), resistance to passive movement, a lack of ability to fractionate a movement, and disturbed quality of movement. RESULTS: On a Likert Scale (0 to 5 points) therapists rated the "Beam-Me-In" strategy as a very useful medium (mode: 4 points) to evaluate a patient's progress over time. The passive range of motion of the elbow joint was assessed with a mean absolute error of 4.9∘ (absolute precision error: 6.4∘). The active range of motion of the elbow was assessed with a mean absolute error of 4.9∘ (absolute precision error: 6.5∘). The resistance to passive movement (i.e. modified Tardieu Scale) and the lack of ability to fractionate a movement (i.e. quantification of pathological muscle synergies) was assessed with an inter-rater reliability of 0.930 and 0.948, respectively. CONCLUSIONS: The "Beam-Me-In" strategy is a promising approach to complement robot-assisted movement training. It can serve as a platform to assess and identify abnormal movement patterns in patients. This is the first application of remote three-dimensional haptic assessmen t applied to telerehabilitation. Furthermore, the "Beam-Me-In" strategy has a potential to overcome barriers for therapists regarding robot-assisted telerehabilitation.

What is the impact of user affect on motor learning in virtual environments after stroke? A scoping review.

PURPOSE: The purported affective impact of virtual reality (VR) and active video gaming (AVG) systems is a key marketing strategy underlying their use in stroke rehabilitation, yet little is known as to how affective constructs are measured or linked to intervention outcomes. The purpose of this scoping review is to 1) explore how motivation, enjoyment, engagement, immersion and presence are measured or described in VR/AVG interventions for patients with stroke; 2) identify directional relationships between these constructs; and 3) evaluate their impact on motor learning outcomes. METHODS: A literature search was undertaken of VR/AVG interventional studies for adults post-stroke published in Medline, PEDro and CINAHL databases between 2007 and 2017. Following screening, reviewers used an iterative charting framework to extract data about construct measurement and description. A numerical and thematic analytical approach adhered to established scoping review guidelines. RESULTS: One hundred fifty-five studies were included in the review. Although the majority (89%; N = 138) of studies described at least one of the five constructs within their text, construct measurement took place in only 32% (N = 50) of studies. The most frequently described construct was motivation (79%, N = 123) while the most frequently measured construct was enjoyment (27%, N = 42). A summative content analysis of the 50 studies in which a construct was measured revealed that constructs were described either as a rationale for the use of VR/AVGs in rehabilitation (76%, N = 38) or as an explanation for intervention results (56%, N = 29). 38 (76%) of the studies proposed relational links between two or more constructs and/or between any construct and motor learning. No study used statistical analyses to examine these links. CONCLUSIONS: Results indicate a clear discrepancy between the theoretical importance of affective constructs within VR/AVG interventions and actual construct measurement. Standardized terminology and outcome measures are required to better understand how enjoyment, engagement, motivation, immersion and presence contribute individually or in interaction to VR/AVG intervention effectiveness.

An augmented reality approach for ADL support in Alzheimer's disease: a crossover trial.

BACKGROUND: Dementia of the Alzheimer's type can impair the performance of activities of daily living and therefore severely impact independent living. Assistive technologies can support such patients when carrying out daily tasks. METHODS: In this crossover study, we used an augmented reality approach using a Microsoft HoloLens to support patients in a tea making task. During task execution, subjects received three-dimensional dynamic holograms of the sub-steps necessary to complete the task. Ten patients suffering from Alzheimer's disease were tested and post-hoc semi-structured interviews were conducted to assess usability. RESULTS: The patients committed errors when executing the task with and without holographic assistance. No differences in success rates or error frequencies were observed (psuccess = .250, perrors = .887). Patients revealed prolonged trial durations (Glass' Δ = 1.475) when wearing the augmented reality headset. A model of multiple linear regression (R2adjusted = .958) revealed an influence of the errors in the control condition and a moderation by the errors in the experimental condition. Patients with more severe problems in the natural performance of the task showed lower increases in trial durations when wearing the HoloLens. CONCLUSIONS: We assume that the application was a secondary task requesting its own resources and impairing performance on its own. The regression suggests however that the given assistance was compensating these additional costs in patients with stronger needs of support. Interview data on usability revealed an overall positive feedback towards the application although the hardware was considered uncomfortable and too large. We conclude that the approach proved feasible and the acceptability was overall high, although advances in hardware and the patient-interface are necessary to assist patients suffering from Alzheimer's disease in daily activities. TRIAL REGISTRATION: DRKS, DRKS00014870. Registered 11 June 2018 - Retrospectively registered, TrialID = DRKS00014870 .

Exercise therapy in medical rehabilitation: Study protocol of a national survey at facility and practitioner level with a mixed method design.

BACKGROUND: The importance of physical activity and the orientation of exercise therapy in rehabilitation has changed for many chronic health conditions. Exercise therapy is the most applied therapy form within multidisciplinary rehabilitation programs for almost all chronic health conditions. Despite the scientifically discussed need to refine exercise therapy, there is relatively little knowledge of how exercise therapy is actually conducted. This study protocol describes the methodological procedure used in the project "Exercise therapy in medical rehabilitation: a survey at facility and practitioner level", which aims to take a national survey of exercise therapy in rehabilitation practice in Germany. METHODS: The project was implemented using an explanatory sequential mixed method design. Quantitative and qualitative methods were integrated in two consecutive project phases. Phase 1 used a standardized, quantitative written survey of the heads of exercise therapy departments to compile a national overview of concepts and process features of exercise therapy of individual rehabilitation facilities. Phase 2 recorded individual perspectives and opinions concerning exercise therapy goals, content and methods and current developments in the rehabilitation context (e.g., physical activity promotion, interdisciplinarity, standardization) of exercise therapy practitioners. Over the course of two one-and-a-half day workshops, central themes were introduced and prepared with standardized written individual surveys from Phase 1 and combined with qualitative surveys using facilitated group discussions (focus groups in mixed methods design). DISCUSSION: The project generates a comprehensive picture of exercise therapy in medical rehabilitation at facility level and inserts further information at the practitioner level into this context. The chosen methodology of a mixed method design combines the perspective of the facility with that of the practitioner, thus allowing for a complex and multifaceted description of the status quo in exercise therapy practice and makes it possible to identify facilitators and barriers for the refinement of exercise therapy in specific everyday rehabilitation. These findings form the basis for the systematic development of quality exercise therapy in rehabilitation, in particular in terms of the refinement, implementation and dissemination of biopsychosocial concepts of exercise therapy.

The impact of unilateral brain damage on weight perception, sensorimotor anticipation, and fingertip force adaptation.

Damage to the left parietal cortex can lead to apraxia - a selective deficit in tool use and action planning. There is conflicting evidence as to whether this disorder affects more fundamental motor parameters, such as applying the appropriate forces to lift objects based upon how heavy they look. Here we examined how individuals with left and right-lateralized brain damage lift and perceive the weight of objects of the same mass which vary in their size and material properties. No clear differences emerged between the groups in terms of how visual material properties affected their perceptions of object weight or their initial application of grip and load forces. There was, however, some evidence that unilateral brain injury impaired the use of size cues for the parameterization of grip forces.