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Background. Up to 85% of people with chronic stroke experience somatosensory impairment, which contributes to poor sensorimotor control and non-use of the affected limb. Neurophysiological mechanisms suggest motor rehabilitation may improve tactile sense post-stroke, however, somatosensory recovery has rarely been reported in controlled trials. Objective. To compare the effect of four upper limb motor rehabilitation programs on the recovery of tactile sensation in adults with chronic stroke. Methods. Adults with chronic stroke and mild or moderate upper extremity hemiparesis ( n = 167) were enrolled in a multi-site randomized controlled trial. Participants completed three weeks of gaming therapy, gaming therapy with additional telerehabilition, Constraint-Induced Movement therapy, or traditional rehabilitation. Here, we report the results of a secondary outcome, tactile sensation, measured with monofilaments, before and after treatment, and 6 months later. Results. A mixed-effects general linear model revealed similar positive change in tactile sensitivity regardless of the type of training. On average, participants were able to detect a stimulus that was 32% and 33% less after training and at 6-month follow-up, respectively. One-third of participants experienced recategorization of their level of somatosensory impairment (e.g., regained protective sensation) following training. Poorer tactile sensation at baseline was associated with greater change. Conclusions. About one-third of individuals with mild/moderate chronic hemiparesis experience sustained improvements in tactile sensation following motor rehabilitation, regardless of the extent of tactile input in the rehabilitation program. Potential for sensory improvement is an additional motivator for those post-stroke. Characteristics of those who improve and mechanisms of improvement are important future questions. Clinicaltrials.gov NCT02631850.

Background: Integrating behavioral intervention into motor rehabilitation is essential for improving paretic arm use in daily life. Demands on therapist time limit adoption of behavioral programs like Constraint-Induced Movement (CI) therapy, however. Self-managed motor practice could free therapist time for behavioral intervention, but there remains insufficient evidence of efficacy for a self-management approach., Methods: This completed, parallel, five-site, pragmatic, single-blind trial established the comparative effectiveness of using in-home gaming self-management as a vehicle to redirect valuable therapist time towards behavioral intervention. Community-dwelling adults with post-stroke (>6 months) mild/moderate upper extremity hemiparesis were randomized to receive one of 4 different interventions over a 3-week period: 5 h of behaviorally-focused intervention plus gaming self-management (Self-Gaming), the same with additional behaviorally-focused telerehabilitation (Tele-Gaming), 5 h of Traditional motor-focused rehabilitation, or 35 h of CI therapy. Primary outcomes assessed everyday arm use (Motor Activity Log Quality of Movement, MAL) and motor speed/function (Wolf Motor Function Test, WMFT) immediately before treatment, immediately after treatment, and 6 months later. Intent-to-treat analyses were implemented with linear mixed-effects models on data gathered from March 15, 2016 to November 21, 2019. ClinicalTrials.gov, NCT02631850., Results: Of 193 enrolled participants, 167 began treatment and were analyzed, 150 (90%) completed treatment, and 115 (69%) completed follow-up. Tele-Gaming and Self-Gaming produced clinically meaningful MAL gains that were 1·0 points (95% CI 0·8 to 1·3) and 0·8 points (95% CI 0·5 to 1·0) larger than Traditional care, respectively. Self-Gaming was less effective than CI therapy (-0·4 points, 95% CI -0·6 to -0·2), whereas Tele-Gaming was not (-0·2 points, 95% CI -0·4 to 0·1). Six-month retention of MAL gains across all groups was 57%. All had similar clinically-meaningful WMFT gains; six-month retention of WMFT gains was 92%., Interpretation: Self-managed motor-gaming with behavioral telehealth visits has outcomes similar to in-clinic CI therapy. It addresses most access barriers, requiring just one-fifth as much therapist time that is redirected towards behavioral interventions that enhance the paretic arm's involvement in daily life., Funding: PCORI, NIH., Competing Interests: Drs. Gauthier, Borstad, Lowes, and Crawfis co-founded Games That Move You, PBC to commercialize the gaming technology utilized in this research; conflict management plans were put in place through The Ohio State University prior to conducting this trial to ensure research integrity., (© 2021 The Author(s).)

The derivation of hepatocytes from human induced pluripotent stem cells (hiPSC) is of great interest for applications in pharmacological research. However, full maturation of hiPSC-derived hepatocytes has not yet been achieved in vitro. To improve hepatic differentiation, co-cultivation of hiPSC with human umbilical vein endothelial cells (HUVEC) during hepatic differentiation was investigated in this study. In the first step, different culture media variations based on hepatocyte culture medium (HCM) were tested in HUVEC mono-cultures to establish a suitable culture medium for co-culture experiments. Based on the results, two media variants were selected to differentiate hiPSC-derived definitive endodermal (DE) cells into mature hepatocytes with or without HUVEC addition. DE cells differentiated in mono-cultures in the presence of those media variants showed a significant increase ( p < 0.05) in secretion of α-fetoprotein and in activities of cytochrome P450 (CYP) isoenzymes CYP2B6 and CYP3A4 as compared with cells differentiated in unmodified HCM used as control. Co-cultivation with HUVEC did not further improve the differentiation outcome. Thus, it can be concluded that the effect of the used medium outweighed the effect of HUVEC co-culture, emphasizing the importance of the culture medium composition for hiPSC differentiation., Competing Interests: The authors declare no conflict of interest.

Background: Constraint-Induced Movement therapy (CI therapy) is shown to reduce disability, increase use of the more affected arm/hand, and promote brain plasticity for individuals with upper extremity hemiparesis post-stroke. Randomized controlled trials consistently demonstrate that CI therapy is superior to other rehabilitation paradigms, yet it is available to only a small minority of the estimated 1.2 million chronic stroke survivors with upper extremity disability. The current study aims to establish the comparative effectiveness of a novel, patient-centered approach to rehabilitation utilizing newly developed, inexpensive, and commercially available gaming technology to disseminate CI therapy to underserved individuals. Video game delivery of CI therapy will be compared against traditional clinic-based CI therapy and standard upper extremity rehabilitation. Additionally, individual factors that differentially influence response to one treatment versus another will be examined., Methods: This protocol outlines a multi-site, randomized controlled trial with parallel group design. Two hundred twenty four adults with chronic hemiparesis post-stroke will be recruited at four sites. Participants are randomized to one of four study groups: (1) traditional clinic-based CI therapy, (2) therapist-as-consultant video game CI therapy, (3) therapist-as-consultant video game CI therapy with additional therapist contact via telerehabilitation/video consultation, and (4) standard upper extremity rehabilitation. After 6-month follow-up, individuals assigned to the standard upper extremity rehabilitation condition crossover to stand-alone video game CI therapy preceded by a therapist consultation. All interventions are delivered over a period of three weeks. Primary outcome measures include motor improvement as measured by the Wolf Motor Function Test (WMFT), quality of arm use for daily activities as measured by Motor Activity Log (MAL), and quality of life as measured by the Quality of Life in Neurological Disorders (NeuroQOL)., Discussion: This multi-site RCT is designed to determine comparative effectiveness of in-home technology-based delivery of CI therapy versus standard upper extremity rehabilitation and in-clinic CI therapy. The study design also enables evaluation of the effect of therapist contact time on treatment outcomes within a therapist-as-consultant model of gaming and technology-based rehabilitation., Trial Registration: Clinicaltrials.gov, NCT02631850 .

The hepatic differentiation of human induced pluripotent stem cells (hiPSC) holds great potential for application in regenerative medicine, pharmacological drug screening, and toxicity testing. However, full maturation of hiPSC into functional hepatocytes has not yet been achieved. In this study, we investigated the potential of a dynamic three-dimensional (3D) hollow fiber membrane bioreactor technology to improve the hepatic differentiation of hiPSC in comparison to static two-dimensional (2D) cultures. A total of 100 × 10(6) hiPSC were seeded into each 3D bioreactor (n = 3). Differentiation into definitive endoderm (DE) was induced by adding activin A, Wnt3a, and sodium butyrate to the culture medium. For further maturation, hepatocyte growth factor and oncostatin M were added. The same differentiation protocol was applied to hiPSC maintained in 2D cultures. Secretion of alpha-fetoprotein (AFP), a marker for DE, was significantly (p < 0.05) higher in 2D cultures, while secretion of albumin, a typical characteristic for mature hepatocytes, was higher after hepatic differentiation of hiPSC in 3D bioreactors. Functional analysis of multiple cytochrome P450 (CYP) isoenzymes showed activity of CYP1A2, CYP2B6, and CYP3A4 in both groups, although at a lower level compared to primary human hepatocytes (PHH). CYP2B6 activities were significantly (p < 0.05) higher in 3D bioreactors compared with 2D cultures, which is in line with results from gene expression. Immunofluorescence staining showed that the majority of cells was positive for albumin, cytokeratin 18 (CK18), and hepatocyte nuclear factor 4-alpha (HNF4A) at the end of the differentiation process. In addition, cytokeratin 19 (CK19) staining revealed the formation of bile duct-like structures in 3D bioreactors similar to native liver tissue. The results indicate a better maturation of hiPSC in the 3D bioreactor system compared to 2D cultures and emphasize the potential of dynamic 3D culture systems in stem cell differentiation approaches for improved formation of differentiated tissue structures.

Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.