Age-matched Healthy Adults Research Articles

Influence of vibrotactile random noise on the smoothness of the grasp movement in patients with chemotherapy-induced peripheral neuropathy.

Patients with chemotherapy-induced peripheral neuropathy (CIPN) often suffer from sensorimotor dysfunction of the distal portion of the extremities (e.g., loss of somatosensory sensation, numbness/tingling, difficulty typing on a keyboard, or difficulty buttoning/unbuttoning a shirt). The present study aimed to reveal the effects of subthreshold vibrotactile random noise stimulation on sensorimotor dysfunction in CIPN patients without exacerbating symptoms. Twenty-five patients with CIPN and 28 age-matched healthy adults participated in this study. To reveal the effects of subthreshold vibrotactile random noise stimulation on sensorimotor function, participants were asked to perform a tactile detection task and a grasp movement task during random noise stimulation delivered to the volar and dorsal wrist. We set three intensity conditions of the vibrotactile random noise: 0, 60, and 120% of the sensory threshold (Noise 0%, Noise 60%, and Noise 120% conditions). In the tactile detection task, a Semmes-Weinstein monofilament was applied to the volar surface of the tip of the index finger using standard testing measures. In the grasp movement task, the distance between the thumb and index finger was recorded while the participant attempted to grasp a target object, and the smoothness of the grasp movement was quantified by calculating normalized jerk in each experimental condition. The experimental data were compared using two-way repeated-measures analyses of variance with two factors: experimental condition (Noise 0, 60, 120%) × group (Healthy controls, CIPN patients). The tactile detection threshold and the smoothness of the grasp movement were only improved in the Noise 60% condition without exacerbating numbness/tingling in CIPN patients and healthy controls. The current study suggested that the development of treatment devices using stochastic resonance can improve sensorimotor function for CIPN patients.

Periodontal Disease in Association with Myocardial Infarction with Non-Obstructive Coronary Arteries and Microvascular Coronary Artery Disease

BackgroundThe relationship between periodontitis and myocardial infarction with non-obstructive coronary arteries (MINOCA) and microvascular angina has not been previously investigated. Hence, the present study aimed to elucidate the association between periodontitis in patients with angina despite non-obstructive coronary artery disease (CAD). In addition, we compared the prevalence of periodontitis in the age-matched general population with no CVD or CV risk factors. MethodsThis prospective observational study included patients diagnosed with MINOCA by screening electronic records of all the ACS patients (n=103,955) from January 2018 to December 2021. All patients diagnosed with MINOCA were enrolled as group 1 and age-matched controls with no CAD were labelled as group 2. Those with recent periodontal treatment and endocarditis prophylaxis were excluded. Univariate and multivariate regression analyses were performed to determine independent predictors of MINOCA and severe periodontitis. ResultsThe study population comprised 6,237 patients with MINOCA (group 1) and 6,000 age-matched healthy adults (group 2) who had no major cardiovascular events. Female gender (odds ratio [OR]: 1.04, 95% confidence interval [CI]: [0.93 – 1.59], p=0.004), diabetes mellitus (OR: 0.25, [0.05 – 0.63], p=0.02), peripheral arterial disease (OR: 0.78, [0.63 – 0.91], p=0.001), dyslipidaemia (OR: 1.45, [0.47 – 2.93], p=0.015), smoking, moderate (OR: 5.42, [1.91 – 22.69], p=0.04) and severe periodontitis (OR: 2.58, [1.72 – 3.26], p=0.027) were independent predictors of MINOCA. ConclusionThe present study, for the first time, demonstrated an independent association between moderate to severe periodontitis and the increased incidence of MINOCA among the general population.

Radiological Changes of Paraspinal Muscles: A Comparative Study of Patients with Isthmic Spondylolisthesis, Patients with Degenerative Lumbar Spondylolisthesis, and Healthy Subjects

To investigate the differences, correlations, and clinical significance of the paraspinal muscles among patients with isthmic spondylolisthesis (IS), degenerative lumbar spondylolisthesis (DLS), and age-matched healthy subjects. This study involved 159 age-matched patients with L4 anterior spondylolisthesis. The patients were divided into the IS group (n = 81) and DLS group (n = 78). Eighty-four age-matched healthy adults were enrolled as the control group. The cross-sectional area (CSA) of paraspinal muscles (multifidus [MF], erector spinae [ES], and psoas [PS]) and the relative CSA of the paraspinal muscles (paraspinal muscle CSA/vertebral CSA) were measured in the IS group, DLS group, and control group. The degree of fat infiltration was simultaneously observed. There was no significant difference in age or sex among the three groups. The relative CSA of the MF and PS was higher in control group than in IS and DLS groups (p < 0.05). The relative CSA of ES was higher in IS and control groups than in DLS group (p < 0.05). The relative CSA of total paraspinal muscles decreased in the order of control group > IS group > DLS group (p < 0.05). Logistic regression analysis showed that the relative CSA of MF, and the degree of fat infiltration of ES were independent protective factors for IS (odds ratio < 1, p < 0.05). The relative CSA of MF was an independent protective factor for DLS (odds ratio < 1, p < 0.05), whereas BMI and the degree of fat infiltration of MF were independent risk factor for DLS (odds ratio > 1, p < 0.05). Compared with the control group, patients with IS and DLS showed varying degrees of degeneration, and the degree of degeneration in patients with DLS was more severe at the same age. Lower fat infiltration and higher paraspinal muscle CSA are protective factors for IS and DLS, whereas the higher BMI is risk factor for DLS.

Comparison of material properties of heel pad between adults with and without type 2 diabetes history: An in-vivo investigation during gait.

ObjectiveThis study was aimed to compare the material properties of heel pad between diabetes patients and healthy adults, and investigate the impact of compressive loading history and length of diabetes course on the material properties of heel pad.MethodsThe dual fluoroscopic imaging system (DFIS) and dynamic foot-ground contact pressure-test plate were used for measuring the material properties, including primary thickness, peak strain, peak stress, stiffness, viscous modulus and energy dissipation ratio (EDR), both at time zero and following continuous loading. Material properties between healthy adults and DM patients were compared both at time zero and following continuous weight bearing. After then, comparison between time-zero material properties and properties following continuous loading was performed to identify the loading history-dependent biomechanical behaviour of heel pad. Subgroup-based sensitivity analysis was then conducted to investigate the diabetes course (<10 years vs. ≥10 years) on the material properties of heel pad.ResultsTen type II DM subjects (20 legs), aged from 59 to 73 (average: 67.8 ± 4.9), and 10 age-matched healthy adults (20 legs), aged from 59 to 72 (average: 64.4 ± 3.4), were enrolled. Diabetes history was demonstrated to be associated with significantly lower primary thickness (t=3.18, p=0.003**), higher peak strain (t=2.41, p=0.021*), lower stiffness (w=283, p=0.024*) and lower viscous modulus (w=331, p<0.001***) at time zero, and significantly lower primary thickness (t=3.30, p=0.002**), higher peak strain (w=120, p=0.031*) and lower viscous modulus (t=3.42, p=0.002**) following continuous loading. The continuous loading was found to be associated with significantly lower primary thickness (paired-w=204, p<0.001***) and viscous modulus (paired-t=5.45, p<0.001***) in healthy adults, and significantly lower primary thickness (paired-w=206, p<0.001***) and viscous modulus (paired-t=7.47, p<0.001***) in diabetes group. No any significant difference was found when conducting the subgroup analysis based on length of diabetes course (<10 years vs. ≥10 years), but the regression analysis showed that the length of diabetes history was positively associated with the peak strain, at time zero (r=0.506, p<0.050) and following continuous loading (r=0.584, p<0.010).ConclusionsDiabetes patients were found to be associated with decreased primary thickness and viscous modulus, and increased peak strain, which may contribute to the vulnerability of heel pad to injury and ulceration. Pre-compression history-dependent behaviour is observable in soft tissue of heel pad, with lowered primary thickness and viscous modulus.

Novel imaging markers for altered cerebrovascular morphology in aging, stroke, and Alzheimer's disease.

Altered brain vasculature is a key phenomenon in several neurologic disorders. This paper presents a quantitative assessment of the anatomical variations in the Circle of Willis (CoW) andvascular morphology in healthy aging, acute ischemic stroke (AIS) and Alzheimer's Disease (AD). We used our novel automatic method to segment and extract geometric features of the cerebral vasculature from MR angiography scans of 175 healthy subjects, which were used to create a probabilistic atlas of cerebrovasculature and to study normal aging and intersubject variations in CoW anatomy. Subsequently, we quantified and analyzed vascular alterations in 45AIS and 50 AD patients, two prominent cerebrovascular and neurodegenerative disorders. In the sampled cohort, we determined that the CoW is fully formed in only 35% of healthy adults and found significantly (p&lt;.05) increased tortuosity and fractality, with increasing age and also with disease in both AIS and AD. We also found significantly lower vessel length, volume, and number of branches in AIS patients, as expected. The AD cerebral vessels exhibited significantly smaller diameter and more complex branching patterns, compared to age-matched healthy adults. These changes were significantly heightened (p&lt;.05) among healthy, early onset mild AD, and moderate/severe dementia groups. Although our study does not include longitudinal data due to paucity of such datasets, the specific geometric features and quantitative comparisons demonstrate the potential for using vascular morphology as a noninvasive imaging biomarker for neurologic disorders.

Compensatory Responses During Slip-Induced Perturbation in Patients With Knee Osteoarthritis Compared With Healthy Older Adults: An Increased Risk of Falls?

Background: Functional impairment of the knee joint affected by osteoarthritis and loss of muscle strength leads to a significant increase in the number of falls. Nevertheless, little is known about strategies for coping with gait perturbations in patients with knee osteoarthritis (KOA). Thus, this study aimed to examine the compensatory strategies of patients with KOA in response to a backward slip perturbation compared with healthy older adults. Methods: An automated perturbation program was developed by using D-Flow software based on the Gait Real-time Analysis Interactive Lab, and an induced backward slip perturbation was implemented on nine patients with severe KOA (68.89 ± 3.59 years) and 15 age-matched healthy older adults (68.33 ± 3.29 years). Step length, gait speed, range of motion, vertical ground reaction forces, lower extremity joint angles, and joint moments were computed and analyzed. Results: Compared with older adults, patients with KOA had significantly lower step length, gait speed, and vertical ground reaction forces in both normal walking and the first recovery step following backward slip perturbations. Inadequate flexion and extension of joint angles and insufficient generation of joint moments predispose patients with KOA to fall. Hip extension angle and flexion moment, knee range of motion, and vertical ground reaction forces are key monitoring variables. Conclusion: The risk of falls for patients with KOA in response to backward slip perturbations is higher. Patients with KOA should focus not only on quadriceps muscle strength related to knee range of motion but also on improving hip extensor strength and activation through specific exercises. Targeted resistance training and perturbation-based gait training could be better options.

Spatiotemporal, kinematic and kinetic assessment of the effects of a foot drop stimulator for home-based rehabilitation of patients with chronic stroke: a randomized clinical trial

BackgroundGait disability affects the daily lives of patients with stroke in both home and community settings. An abnormal foot–ankle position can cause instability on the supporting surface and negatively affect gait. Our research team explored the ability of a portable peroneal nerve-targeting electrical stimulator to improve gait ability by adjusting the foot–ankle position during walking in patients with chronic stroke undergoing home-based rehabilitation.MethodsThis was a double-blinded, parallel-group randomized controlled trial. Thirty-one patients with chronic stroke and ankle–foot motor impairment were randomized to receive 3 weeks of gait training, which involved using the transcutaneous peroneal nerve stimulator while walking (tPNS group; n = 16, mean age: 52.25 years), or conventional home and/or community gait training therapy (CT group; n = 15, mean age: 54.8 years). Functional assessments were performed before and after the 3-week intervention. The outcome measures included spatiotemporal gait parameters, three-dimensional kinematic and kinetic data on the ankle–foot joint, and a clinical motor and balance function assessment based on the Fugl–Meyer Assessment of Lower Extremity (FMA-LE) and Berg Balance scales (BBS). Additionally, 16 age-matched healthy adults served as a baseline control of three-dimensional gait data for both trial groups.ResultsThe FMA-LE and BBS scores improved in both the tPNS groups (p = 0.004 and 0.001, respectively) and CT groups (p = 0.034 and 0.028, respectively) from before to after training. Participants in the tPNS group exhibited significant differences in spatiotemporal gait parameters, including double feet support, stride length, and walking speed of affected side, and the unaffected foot off within a gait cycle after training (p = 0.043, 0.017, 0.001 and 0.010, respectively). Additionally, the tPNS group exhibited significant differences in kinematic parameters, such as the ankle angle at the transverse plane (p = 0.021) and foot progression angle at the frontal plane (p = 0.009) upon initial contact, and the peak ankle joint angle at the transverse plane (p = 0.023) and foot progression angle (FPA) at the frontal and transverse planes (p = 0.032 and 0.046, respectively) during gait cycles after 3 weeks of training.ConclusionsUse of a portable tPNS device during walking tasks appeared to improve spatiotemporal gait parameters and ankle and foot angles more effectively than conventional home rehabilitation in patients with chronic stroke. Although guidelines for home-based rehabilitation training services and an increasing variety of market devices are available, no evidence for improvement of motor function and balance was superior to conventional rehabilitation.Trial registration Chictr, ChiCTR2000040137. Registered 22 November 2020, https://www.chictr.org.cn/showproj.aspx?proj=64424

Electroencephalography Microstate Alterations in Otogenic Vertigo: A Potential Disease Marker.

ObjectivesA huge population, especially the elderly, suffers from otogenic vertigo. However, the multi-modal vestibular network changes, secondary to periphery vestibular dysfunction, have not been fully elucidated. We aim to identify potential microstate electroencephalography (EEG) signatures for otogenic vertigo in this study.Materials and MethodsPatients with recurrent otogenic vertigo and age-matched healthy adults were recruited. We performed 256-channel EEG recording of all participants at resting state. Neuropsychological questionnaires and vestibular function tests were taken as a measurement of patients’ symptoms and severity. We clustered microstates into four classes (A, B, C, and D) and identified their dynamic and syntax alterations of them. These features were further fed into a support vector machine (SVM) classifier to identify microstate signatures for vertigo.ResultsWe compared 40 patients to 45 healthy adults, finding an increase in the duration of Microstate A, and both the occurrence and time coverage of Microstate D. The coverage and occurrence of Microstate C decreased significantly, and the probabilities of non-random transitions between Microstate A and D, as well as Microstate B and C, also changed. To distinguish the patients, the SVM classifier, which is built based on these features, got a balanced accuracy of 0.79 with a sensitivity of 0.78 and a specificity of 0.8.ConclusionThere are several temporal dynamic alterations of EEG microstates in patients with otogenic vertigo, especially in Microstate D, reflecting the underlying process of visual-vestibular reorganization and attention redistribution. This neurophysiological signature of microstates could be used to identify patients with vertigo in the future.

Long-term biopsychosocial issues and health-related quality of life in young adolescents and adults treated for childhood Complex Regional Pain Syndrome, type 1.

Treatment for childhood Complex Regional Pain Syndrome (CRPS) is associated with long-term recovery. The present study aimed to investigate the long-term biopsychosocial status and quality of life in young adolescents and adults after the treatment of childhood CRPS. A 4year follow-up of individuals with childhood-CRPS, type 1 (n=22; age:12years (years) [median] at treatment and 17years at follow-up) was completed. Biopsychosocial status and quality of life were assessed with structured interviews, using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the Strengths and Difficulties Questionnaire (SDQ), the Pediatric Pain Coping Inventory (PPCI), and the Pediatric Quality of Life Inventory (PedsQL). Comparisons were made with normative samples of age-matched controls. CRPS at follow-up was still present in seven out of 22, and non-CRPS pain symptoms were found in 12 out of 22 individuals. Signs of mental health pain-related problems, including phobias and obsessive-compulsive disorder, were observed in ten out of 19 individuals. Mental well-being, social functioning, and quality of life (SDQ and PedsQL) were independent of pain status (p>0.05). Adaptive pain coping strategies were utilized regardless of pain status (PPCI). Social functioning (p<0.01) and the quality of life (p=0.01) were attenuated and statistically significantly poorer than healthy age-matched young adults but better than for fibromyalgia subjects. A subset of individuals treated for childhood-CRPS, type 1 experiences long-term consequences of persistent pain, a decrease in quality of life indicators, and demonstrates significant psychosocial issues. Childhood-CRPS is suggested to be associated with long-term psychosocial consequences and poorer quality of life than found in age-related healthy peers. Subjects treated for childhood CRPS may need a longer clinical follow-up attempting to preclude relapse of CRPS and non-CRPS pain.

Short term priming effect of brain-actuated muscle stimulation using bimanual movements in stroke

ObjectiveBrain-computer interface triggered-functional electrical stimulation (BCI-FES) is an emerging neurorehabilitation therapy post stroke, mostly for the affected hand. We explored the feasibility of a bimanual BCI-FES and its short-term priming effects, i.e. stimuli-induced behaviour change. We compared EEG parameters between unimanual and bimanual movements and differentiated the effect of age from the effect of stroke. MethodsTen participants with subacute stroke, ten age-matched older healthy adults, and ten younger healthy adults underwent unimanual and bimanual BCI-FES sessions. Delta alpha ratio (DAR) and brain symmetry index (BSI) were derived from the pre- and post- resting-state EEG. Event-related desynchronization (ERD) and laterality index were derived from movement- EEG. ResultsParticipants were able to control bimanual BCI-FES. ERD was predominantly contralateral for unimanual movements and bilateral for bimanual movements. DAR and BSI only changed in healthy controls. Baseline values indicated that DAR was affected by stroke while BSI was affected by both age and stroke. ConclusionsBimanual BCI control offers a larger repertoire of movements, while causing the same short-term changes as unimanual BCI-FES. Prolonged practice may be required to achieve a measurable effect on DAR and BSI for stroke. SignificanceBimanual BCI-FES is feasible in people affected by stroke.

Peripheral inflammatory cytokines and motor symptoms in persons with Parkinson's disease

BackgroundMany of the motor symptoms of Parkinson's disease (PD) impact quality of life and are not fully ameliorated by current pharmacological and surgical treatments. A better understanding of the pathophysiology underlying these symptoms is needed. Previous research has suggested that inflammation may play a significant role in PD pathophysiology and progression, but there is limited research exploring how inflammation directly relates to motor symptoms in PD. Thus, the purpose of this study was to evaluate associations between peripheral immune inflammatory markers and motor symptoms of PD, specifically, tremor, bradykinesia, and postural and gait instability. We hypothesized that peripheral inflammatory cytokines would predict the severity of motor symptoms in persons with PD, and that there will be higher levels of peripheral inflammatory cytokine markers in persons with PD when compared to age-matched healthy older adults. MethodsTwenty-six participants with PD and fourteen healthy older adults completed the study. For participants with PD, the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) was recorded and scored by two Movement Disorders Neurologists masked to the study. A blood sample was collected from both participants with PD and the healthy older adults. Through the MILLIPLEX® map High Sensitivity Human Cytokine Kit, key inflammation-related markers were analyzed (TNF-α, IFN-γ, IL-1β, IL-8, IL-2, IL-7, IL-5, IL-13, IL, 4, IL-10 IL-12p70, GM-CSF, and IL-6). ResultsResults revealed significantly higher levels of IL-6 in persons with PD when compared to healthy older adults (p ​= ​0.005). Moreover, results revealed that higher levels of IL-4 (p ​= ​0.011) and lower levels of IFNγ (p ​= ​0.003) significantly predicted more severe tremor in persons with PD. No other associations between the peripheral inflammation markers and other motor symptoms were observed. ConclusionsOverall, these results are consistent with a growing body of literature that implicates inflammatory cytokines in the PD, and further suggests that inflammatory cytokines, or lack thereof, may be associated with tremor in persons with PD.

Comparison of quality of life (QoL) in survivors of testicular nonseminomatous germ cell tumor (NSGCT) with age-matched controls using EORTC QLQ-C30 questionnaire.

413 Background: Testicular NSGCT is typically diagnosed in young males, and is a highly curable cancer. Data pertaining to the quality of life of testicular NSGCT survivors are limited. Methods: Patients aged 18 or more years with a diagnosis of testicular NSGCT treated in a large tertiary care centre in New Delhi, India between January 2015 and July 2019 were eligible to participate. Patients had to be disease free for at least two years for QoL assessment using EORTC QLQ-C30 questionnaire. Raw scores were transformed as per the EORTC scoring manual. Controls were healthy age-matched adults recruited from the patient accompanying population. Results: We identified 55 survivors and 100 controls. Median age was 32 (range, 18-65) years and 58.2% of patients stage III disease, while the rest were equally divided in stage I and II. Chemotherapy was administered in 94% patients, while 25% had retroperitoneal lymph node resection for residual disease and relapse occurred in 11%, who were treated with salvage chemotherapy and resection of the residual disease. Emotional, social and global scores were significantly lower in survivors as compared to controls. Among symptom scales, fatigue, pain, dyspnoea, insomnia, appetite loss, and financial difficulty were significantly increased in patients as compare to survivors (Table). On a multivariate analysis, neither stage of disease nor treatment were found to be associated significantly with QOL scores. Conclusions: Survivors of testicular NSGCT have lower emotional, social and global functioning and a higher symptom burden. Since NSGCT affects young males, aggressive measures may be needed to improve the QoL in such patients.[Table: see text]

Personalized Connectome-Based Modeling in Patients with Semi-Acute Phase TBI: Relationship to Acute Neuroimaging and 6 Month Follow-Up.

Following traumatic brain injury (TBI), cognitive impairments manifest through interactions between microscopic and macroscopic changes. On the microscale, a neurometabolic cascade alters neurotransmission, while on the macroscale diffuse axonal injury impacts the integrity of long-range connections. Large-scale brain network modeling allows us to make predictions across these spatial scales by integrating neuroimaging data with biophysically based models to investigate how microscale changes invisible to conventional neuroimaging influence large-scale brain dynamics. To this end, we analyzed structural and functional neuroimaging data from a well characterized sample of 44 adult TBI patients recruited from a regional trauma center, scanned at 1–2 weeks postinjury, and with follow-up behavioral outcome assessed 6 months later. Thirty-six age-matched healthy adults served as comparison participants. Using The Virtual Brain, we fit simulations of whole-brain resting-state functional MRI to the empirical static and dynamic functional connectivity of each participant. Multivariate partial least squares (PLS) analysis showed that patients with acute traumatic intracranial lesions had lower cortical regional inhibitory connection strengths than comparison participants, while patients without acute lesions did not differ from the comparison group. Further multivariate PLS analyses found correlations between lower semiacute regional inhibitory connection strengths and more symptoms and lower cognitive performance at a 6 month follow-up. Critically, patients without acute lesions drove this relationship, suggesting clinical relevance of regional inhibitory connection strengths even when traumatic intracranial lesions were not present. Our results suggest that large-scale connectome-based models may be sensitive to pathophysiological changes in semi-acute phase TBI patients and predictive of their chronic outcomes.

The ERG1A K+ Channel Is More Abundant in Rectus abdominis Muscle from Cancer Patients Than that from Healthy Humans.

Background: The potassium channel encoded by the ether-a-gogo-related gene 1A (erg1a) has been detected in the atrophying skeletal muscle of mice experiencing either muscle disuse or cancer cachexia and further evidenced to contribute to muscle deterioration by enhancing ubiquitin proteolysis; however, to our knowledge, ERG1A has not been reported in human skeletal muscle. Methods and Results: Here, using immunohistochemistry, we detect ERG1A immunofluorescence in human Rectus abdominis skeletal muscle sarcolemma. Further, using single point brightness data, we report the detection of ERG1A immunofluorescence at low levels in the Rectus abdominis muscle sarcolemma of young adult humans and show that it trends toward greater levels (10.6%) in healthy aged adults. Interestingly, we detect ERG1A immunofluorescence at a statistically greater level (53.6%; p < 0.05) in the skeletal muscle of older cancer patients than in age-matched healthy adults. Importantly, using immunoblot, we reveal that lower mass ERG1A protein is 61.5% (p < 0.05) more abundant in the skeletal muscle of cachectic older adults than in healthy age-matched controls. Additionally, we report that the ERG1A protein is detected in a cultured human rhabdomyosarcoma line that may be a good in vitro model for the study of ERG1A in muscle. Conclusions: The data demonstrate that ERG1A is detected more abundantly in the atrophied skeletal muscle of cancer patients, suggesting it may be related to muscle loss in humans as it has been shown to be in mice experiencing muscle atrophy as a result of malignant tumors.

Kinect-based rapid movement training to improve balance recovery for stroke fall prevention: a randomized controlled trial

BackgroundFalls are more prevalent in stroke survivors than age-matched healthy older adults because of their functional impairment. Rapid balance recovery reaction with adequate range-of-motion and fast response and movement time are crucial to minimize fall risk and prevent serious injurious falls when postural disturbances occur. A Kinect-based Rapid Movement Training (RMT) program was developed to provide real-time feedback to promote faster and larger arm reaching and leg stepping distances toward targets in 22 different directions.ObjectiveTo evaluate the effectiveness of the interactive RMT and Conventional Balance Training (CBT) on chronic stroke survivors’ overall balance and balance recovery reaction.MethodsIn this assessor-blinded randomized controlled trial, chronic stroke survivors were randomized to receive twenty training sessions (60-min each) of either RMT or CBT. Pre- and post-training assessments included clinical tests, as well as kinematic measurements and electromyography during simulated forward fall through a “lean-and-release” perturbation system.ResultsThirty participants were recruited (RMT = 16, CBT = 14). RMT led to significant improvement in balance control (Berg Balance Scale: pre = 49.13, post = 52.75; P = .001), gait control (Timed-Up-and-Go Test: pre = 14.66 s, post = 12.62 s; P = .011), and motor functions (Fugl-Meyer Assessment of Motor Recovery: pre = 60.63, post = 65.19; P = .015), which matched the effectiveness of CBT. Both groups preferred to use their non-paretic leg to take the initial step to restore stability, and their stepping leg’s rectus femoris reacted significantly faster post-training (P = .036).ConclusionThe RMT was as effective as conventional balance training to provide beneficial effects on chronic stroke survivors’ overall balance, motor function and improving balance recovery with faster muscle response.Trial registration: The study was registered at Clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT03183635, NCT03183635) on 12 June 2017.

Abstract P152: Low Memory Recall And High Common Carotid Artery Flow Pulsatility In Non-Dialysis Chronic Kidney Disease Patients

A significant proportion of patients with non-dialysis chronic kidney disease (CKD) present with mild-to-moderate deficits in the cognitive domains of executive function and episodic memory. Excess blood flow pulsatility is damaging to the microvasculature of high-flow, low-resistance organs like the brain and may contribute to the cognitive deficits prevalent among CKD patients. We tested the hypothesis that patients with moderate-to-severe non-dialysis CKD have excess flow pulsatility along their carotid and cerebral vasculature that is associated with deficits in executive function and episodic memory. We recruited 10 non-dialysis CKD patients (age=68±8 yrs; estimated glomerular filtration rate, eGFR=36±18 mL/min/1.73 m 2 ) and 7 healthy age-matched adults (age=65±5 yrs; eGFR=81±17 mL/min/1.73 m 2 ). Global cognitive function was assessed with the Montreal Cognitive Assessment (MoCA). Executive function and episodic memory were assessed using the NIH Toolbox Flanker Inhibitory Control and Attention Test and California Verbal Learning Test III, respectively, and reported as standardized scores (mean=100, SD=15). Pulsatility index [(systolic blood velocity - diastolic blood velocity)/ mean blood velocity] was measured in the common carotid (CCA), internal carotid (ICA), and middle cerebral arteries (MCA) via Doppler and transcranial Doppler ultrasound. Compared to healthy adults, CKD patients did not differ in total brain blood flow (p=0.42) but had lower MoCA (CKD=26±3, Healthy=29±1; p=0.01) and memory recall scores (CKD=92±21, Healthy=110±9; p=0.05). CKD patients did not differ from our healthy control group in executive function (CKD=91±10, Healthy=90±11; p=0.80) but did produce a mean score that was 0.6 SD lower than the NIH Toolbox reference sample. CKD patients had a higher pulsatility index in the CCA (CKD=2.3±0.5, Healthy=1.9±0.3; p=0.05) but not in the ICA (p=0.68) or MCA (p=0.57). CCA pulsatility index was strongly and inversely associated with episodic memory recall scores (r=-0.64, p&lt;0.01, n=17). This data suggests that although the higher CCA flow pulsatility in non-dialysis CKD patients does not appear to be transmitted to the cerebrovasculature, it nevertheless may still be contributing to memory impairments.

Acceptance of immersive head-mounted display virtual reality in stroke patients

BackgroundAs virtual reality (VR) has become more accessible, it has increasingly come into focus for clinical application. Therapy with VR shows potential as an engaging, effective, and economic way to improve cognitive abilities following a stroke. ObjectivesWhile application of VR in clinical settings appears promising, its widespread use will crucially depend on acceptance of immersive head mounted display virtual reality (HMD-VR) systems when used in different patient groups. This study aimed to investigate acceptance of HMD-VR in stroke patients compared to a control group of healthy age-matched adults. MethodsThe attitude towards HMD-VR, as one of the most important predictors of technology acceptance within the technology acceptance model framework, was assessed in 20 stroke patients and 20 age-matched healthy adults. Further HMD-VR acceptance related measures concerned self-reported user experience, computer self-efficacy and cybersickness (see also Huygelier et al., 2019). Additionally, performance measures for memory span and speed were recorded in two VR-tasks. ResultsBoth groups showed positive attitude above the neutral point of the scale and reported positive user experience in the VR-setting. Self-reported cybersickness was at modest levels and comparable in both groups. Controls had higher and more homogeneous scores in user experience, and performed notably faster in the VR-task while there were no significant differences in memory-span. ConclusionThe study results suggest that treatment provided by immersive HMD-VR is tolerated by older adults, including those who have had strokes. This was the case without prior acquaintance with the VR-device or -software, and it was neither hindered by negative attitudes towards VR, nor cybersickness.

Wnt5a Induces ROR1 to Complex with DOCK2 and Promote Proliferation of Chronic Lymphocytic Leukemia Cells

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic protein expressed on chronic lymphocytic leukemia (CLL) B cells, but not on virtually all normal adult tissues. Studies have found that high-level leukemia-cell expression of ROR1 associated with enhanced leukemia-cell proliferation, aggressive disease, and shorter overall survival compared to that of patients with CLL cells that had low-to-negligible expression of ROR1 (Cui B. et al., Blood, 128:2931, 2016). Analysis of ROR1-immune precipitates of CLL-cell lysates via mass spectrometry and immunoblot analyses revealed that ROR1 was associated with DOCK2 (Dedicator of Cytokinesis 2) in freshly isolated CLL cells. DOCK2 is a member of the DOCK-A subfamily of guanine exchange factors (GEFs) specific for Rac1 and Rac2 (Rac1/2) that is expressed primarily in leukocytes, including CLL B cells. DOCK proteins differ from other GEFs in that they do not possess the canonical tandem Dbl-homology (DH) and Pleckstrin-homology (PH) domains that elicit nucleotide exchange. Instead DOCK2 possess a DOCK homology region 2 (DHR2) domain, which mediates Rac activation by stabilizing Rac in its nucleotide-free state. DOCK2 also contains a N-terminal SH3 domain. We found that ROR1 dissociated from DOCK2 in CLL cells cultured in serum-free medium, unless the cells were stimulated with exogenous Wnt5a, which we found present at high-levels in the plasma of CLL patients relative to that of age-matched healthy adults. Wnt5a could induce ROR1 to complex with DOCK2 and cause activation of Rac1/2; this effect could be inhibited by silencing DOCK2 in primary CLL cells. Furthermore, these effects of Wnt5a on CLL cells also could be completely blocked by treatment of the CLL cells with cirmtuzumab, a humanized anti-ROR1 mAb, which is undergoing clinical evaluation in patients with CLL. We find that silencing DOCK2 specifically impaired the capacity of Wnt5a to enhance CXCL12-directed migration or CLL-cell proliferation in vitro. We corroborated these findings using the CLL-cell-line MEC1, which also expresses DOCK2, but does not express ROR1. MEC1 cells can be transduced to express ROR1 or various mutant forms of ROR1, allowing us to examine the structure-function relationships required for ROR1-DOCK2 interactions. We confirmed that DOCK2 complexes with ROR1 in response to Wnt5a in MEC1-ROR1 cells. We generated truncated forms of ROR1 and found the cytoplastmic proline-rich domain (PRD) of ROR1 was required for ROR1 to complex with DOCK2 and activate Rac1/2 upon stimulation with Wnt5a. We next introduced single amino-acid substitutions of proline (P) to alanine (A) in the ROR1-PRD at positions 784, 808, 826, or 841 in potential SH3-binding sites. In contrast to wild-type ROR1, or other ROR1P==>A mutants, ROR1P(808)A had impaired capacity to recruit DOCK2 to ROR1 in response to Wnt5a. Moreover, unlike MEC1 cells transfected with wild-type ROR1 or ROR1 with P->A substitutions at positions 784, 826, or 841, MEC1 cells transfected to express ROR1P(808)A did not have a growth advantage over that of MEC1 cells that do not express ROR1. This study reveals that the recruitment of DOCK2 may be critical for the capacity of Wnt5a to enhance CLL proliferation, which may contribute to the observed increased tendency for disease progression in CLL patients who have leukemia cells that express high-levels of ROR1. DisclosuresKipps:Oncternal: Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

Wnt5a Induces ROR1 to Bind and Activate Cortactin, Which Functions in Planar Cell Polarity and Migration of Chronic Lymphocytic Leukemia Cells

Studies have revealed a dynamic trafficking of chronic lymphocytic leukemia cells (CLL) between the blood and lymphoid compartments. Targeted therapies that impair chemokine-receptor signaling, such as ibrutinib, disrupt the capacity of leukemia cells to re-enter lymphoid compartments, precluding CLL cells from receiving growth/survival signals from the accessory cells within the lymphoid-tissue microenvironment, thereby causing attrition in the leukemia-cell population over time in a patient undergoing such targeted therapy. Studying the signaling pathways and intracellular proteins that influence/govern leukemia-cell migration may identify additional agents that can further disrupt CLL-cell trafficking and potentially enhance the therapeutic activity of drugs such as ibrutinib. Factoring in leukemia-cell migration may be the cytoskeletal protein cortactin (also called EMS1), which possesses a SH3 domain and a F-actin-binding domain, allowing it link cell-surface receptor-complexes to the actin cytoskeleton. Upon tyrosine phosphorylation, cortactin is activated, thereby facilitating RhoGTPase activation and polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery, which is required for planar cell polarity, lamellipodia formation, invadopodia formation, cell migration, and endocytosis. We find cortactin abundantly is expressed in CLL B cells. Moreover, in freshly isolated CLL cells, we find that cortactin associates with ROR1, an evolutionarily conserved, oncoembryonic surface-protein expressed on many cancers, including CLL. Culture of CLL cells in serum-free medium results in the dissociation/inactivation of the ROR1-cortactin complex unless the leukemia cells are stimulated with the ligand for ROR1, namely Wnt5a, which, relative to the plasma of age-matched healthy adults, is present at high levels in the plasma of patients with CLL, including patients undergoing therapy with ibrutinib. Moreover, we find that Wnt5a induces ROR1 to complex with cortactin, which then undergoes tyrosine phosphorylation at Y421, recruit ARHGEF1, and activate RhoA, thereby enhancing/enabling leukemia-cell migration. These effects of Wnt5a on CLL cells could not be inhibited by ibrutinib, but could be blocked by cirmtuzumab, a humanized, high-affinity monoclonal antibody specific for ROR1 that is undergoing clinical evaluation in patients with CLL. We corroborated these findings using the CLL cell line MEC1, which also expresses cortactin, but does not express ROR1. MEC1 cells can be transduced to express ROR1 or various mutant forms of ROR1, allowing us to examine the structure-function relationships required for ROR1-cortactin complex formation. We confirmed that cortactin complexes with ROR1 and undergoes activation in response to Wnt5a in MEC1-ROR1 cells. We generated truncated forms of ROR1 and found the cytoplasmic proline-rich domain (PRD) of ROR1 was required for ROR1 to complex with cortactin upon stimulation with Wnt5a. We next introduced single amino-acid substitutions of proline (P) to alanine (A) in the ROR1-PRD at positions 784, 808, 826, 841, or 850 in potential SH3-binding sites. In contrast to wild-type ROR1, or other ROR1P==>A mutants, ROR1P(841)A had impaired capacity to recruit cortactin to ROR1 in response to Wnt5a. Moreover, Wnt5a could not induce cells expressing ROR1P(841)A to phosphorylate cortactin, and was not able to enhance MEC1-ROR1-cell F-actin polymerization. Collectively, these studies reveal that cortactin plays an important role in Wnt5a-enhanced CLL cell migration/F-actin polymerization via a ROR1-dependent signaling pathway that cannot be inhibited by ibrutinib or other inhibitors of BTK. DisclosuresKipps:AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Oncternal: Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Wnt5a Can Induce Activation of Rac1 and Proliferation in Mantle Cell Lymphoma Via a ROR1-Dependent, but BTK-Independent, Signaling Pathway

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL). This is underscored by the clinical effectiveness of an inhibitor of Bruton's tyrosine kinase (BTK), ibrutinib, which can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, particularly in patients with MCL. This suggests that ancillary pathways contribute to the growth/survival of MCL/CLL that are independent of BCR-signaling and/or inhibition of BTK. Studies have found that Wnt5a can promote activation of Rho GTPase Rac1 to enhance CLL-cell proliferation and survival via a ROR1-dependent,but BTK-independent pathway (Yu J, et al., Leukemia 31:1333, 2017). Furthermore, Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab, a humanized anti-ROR1 mAb, which significantly could enhance the capacity of ibrutinib to clear CLL cells in vivo . MCL cells also express ROR1. Moreover, we find that the median level of ROR1 on primary MCL cells is higher than that on CLL cells; the median absolute mean fluorescence intensity of ROR1 (ROR1 DMFI) on MCL (87.5 ± 18.5 (S.D.), N = 8) was significantly higher than the median ROR1 DMFI on CLL cells (38.5 ± 18.5 (S.D.), N = 1567; (Cui B, et al., Blood 128:2931, 2016)). We also found that the plasma of patients with MCL had high levels of Wnt5a that were comparable to those found in patients with CLL; in contrast Wnt5a was virtually undetectable in the plasma of age-matched healthy adults. We cultured primary MCL cells of different patients with ibrutinib, cirmtuzumab, or both ibrutinib and cirmtuzumab for 2 h, and then stimulated the cells with exogenous Wnt5a for 30 min. In parallel, the same MCL cells were cultured without exogenous Wnt5a. We found that Wnt5a induced Rac1 activation in the primary MCL cells. Cirmtuzumab, but not ibrutinib, could inhibit the capacity of Wnt5a to induce primary MCL cells to activate Rac1. We induced proliferation of MCL cells by co-culturing MCL cells with HeLa cells expressing CD154 (HeLaCD154) and recombinant interleukin (IL)-4 and IL-10. Addition of exogenous Wnt5a to co-cultures of MCL cells with HeLaCD154 cells and IL-4/10 significantly enhanced the proportion of dividing MCL entering S/G2 and the numbers of cell divisions over time. Treatment of the MCL cells with cirmtuzumab, but not ibrutinib, blocked Wnt5a-enhanced survival and proliferation of MCL cells from each of 3 different patients. This study demonstrates that Wnt5a can induce Rac1 activation, which leads to enhanced proliferation and survival of primary MCL cells via a ROR1-dependent signaling pathway that can be blocked by cirmtuzumab. On the other hand, this signaling pathway cannot be blocked by ibrutinib, even at concentrations that completely inhibit BTK or BCR-signaling. This implies that cirmtuzumab and ibrutinib may have additive, if not synergistic, activity in the treatment of patients with MCL. DisclosuresKipps:Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Oncternal: Research Funding.