Economic evaluation of digitally enabled aged and neurological rehabilitation care in the Activity and MObility UsiNg Technology (AMOUNT) trial.

OBJECTIVE: To investigate the trial-based cost-effectiveness of the addition of a tailored digitally enabled exercise intervention to usual care shown to be clinically effective in improving mobility in the Activity and MObility UsiNg Technology (AMOUNT) rehabilitation trial compared to usual care alone. DESIGN: Economic evaluation alongside a pragmatic randomized controlled trial. PARTICIPANTS: 300 people receiving inpatient aged and neurological rehabilitation were randomized to the intervention (n = 149) or usual care control group (n = 151). MAIN MEASURES: Incremental cost effectiveness ratios were calculated for the additional costs per additional person demonstrating a meaningful improvement in mobility (3-point in Short Physical Performance Battery) and quality-adjusted life years gained at 6 months (primary analysis). The joint probability distribution of costs and outcomes was examined using bootstrapping. RESULTS: The mean cost saving for the intervention group at 6 months was AU$2286 (95% Bootstrapped cost CI: -$11,190 to $6410) per participant; 68% and 67% of bootstraps showed the intervention to be dominant (i.e. more effective and cost saving) for mobility and quality-adjusted life years, respectively. The probability of the intervention being cost-effective considering a willingness to pay threshold of AU$50,000 per additional person with a meaningful improvement in mobility or quality-adjusted life year gained was 93% and 77%, respectively. CONCLUSIONS: The AMOUNT intervention had a high probability of being cost-effective if decision makers are willing to pay AU$50,000 per meaningful improvement in mobility or per quality-adjusted life year gained, and a moderate probability of being cost-saving and effective considering both outcomes at 6 months post randomization.

Digitally enabled aged care and neurological rehabilitation to enhance outcomes with Activity and MObility UsiNg Technology (AMOUNT) in Australia: A randomised controlled trial.

BACKGROUND: Digitally enabled rehabilitation may lead to better outcomes but has not been tested in large pragmatic trials. We aimed to evaluate a tailored prescription of affordable digital devices in addition to usual care for people with mobility limitations admitted to aged care and neurological rehabilitation. METHODS AND FINDINGS: We conducted a pragmatic, outcome-assessor-blinded, parallel-group randomised trial in 3 Australian hospitals in Sydney and Adelaide recruiting adults 18 to 101 years old with mobility limitations undertaking aged care and neurological inpatient rehabilitation. Both the intervention and control groups received usual multidisciplinary inpatient and post-hospital rehabilitation care as determined by the treating rehabilitation clinicians. In addition to usual care, the intervention group used devices to target mobility and physical activity problems, individually prescribed by a physiotherapist according to an intervention protocol, including virtual reality video games, activity monitors, and handheld computer devices for 6 months in hospital and at home. Co-primary outcomes were mobility (performance-based Short Physical Performance Battery [SPPB]; continuous version; range 0 to 3; higher score indicates better mobility) and upright time as a proxy measure of physical activity (proportion of the day upright measured with activPAL) at 6 months. The dataset was analysed using intention-to-treat principles. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000936628). Between 22 September 2014 and 10 November 2016, 300 patients (mean age 74 years, SD 14; 50% female; 54% neurological condition causing activity limitation) were randomly assigned to intervention (n = 149) or control (n = 151) using a secure online database (REDCap) to achieve allocation concealment. Six-month assessments were completed by 258 participants (129 intervention, 129 control). Intervention participants received on average 12 (SD 11) supervised inpatient sessions using 4 (SD 1) different devices and 15 (SD 5) physiotherapy contacts supporting device use after hospital discharge. Changes in mobility scores were higher in the intervention group compared to the control group from baseline (SPPB [continuous, 0-3] mean [SD]: intervention group, 1.5 [0.7]; control group, 1.5 [0.8]) to 6 months (SPPB [continuous, 0-3] mean [SD]: intervention group, 2.3 [0.6]; control group, 2.1 [0.8]; mean between-group difference 0.2 points, 95% CI 0.1 to 0.3; p = 0.006). However, there was no evidence of a difference between groups for upright time at 6 months (mean [SD] proportion of the day spent upright at 6 months: intervention group, 18.2 [9.8]; control group, 18.4 [10.2]; mean between-group difference -0.2, 95% CI -2.7 to 2.3; p = 0.87). Scores were higher in the intervention group compared to the control group across most secondary mobility outcomes, but there was no evidence of a difference between groups for most other secondary outcomes including self-reported balance confidence and quality of life. No adverse events were reported in the intervention group. Thirteen participants died while in the trial (intervention group: 9; control group: 4) due to unrelated causes, and there was no evidence of a difference between groups in fall rates (unadjusted incidence rate ratio 1.19, 95% CI 0.78 to 1.83; p = 0.43). Study limitations include 15%-19% loss to follow-up at 6 months on the co-primary outcomes, as anticipated; the number of secondary outcome measures in our trial, which may increase the risk of a type I error; and potential low statistical power to demonstrate significant between-group differences on important secondary patient-reported outcomes. CONCLUSIONS: In this study, we observed improved mobility in people with a wide range of health conditions making use of digitally enabled rehabilitation, whereas time spent upright was not impacted. TRIAL REGISTRATION: The trial was prospectively registered with the Australian New Zealand Clinical Trials Register; ACTRN12614000936628.

Physiological Replication of the Human Glomerulus Using a Triple Culture Microphysiological System.

The function of the glomerulus depends on the complex cell-cell/matrix interactions and replication of this in vitro would aid biological understanding in both health and disease. Previous models do not fully reflect all cell types and interactions present as they overlook mesangial cells within their 3D matrix. Herein, the development of a microphysiological system that contains all resident renal cell types in an anatomically relevant manner is presented. A detailed transcriptomic analysis of the contributing biology of each cell type, as well as functionally appropriate albumin retention in the system, is demonstrated. The important role of mesangial cells is shown in promoting the health and maturity of the other cell types. Additionally, a comparison of the incremental advances that each individual cell type brings to the phenotype of the others demonstrates that glomerular cells in simple 2D culture exhibit a state more reflective of the dysfunction observed in human disease than previously recognized. This in vitro model will expand the capability to investigate glomerular biology in a more translatable manner by the inclusion of the important mesangial cell compartment.

Integrating community participation in the transition of older adults from hospital to home: a scoping review.

INTRODUCTION: Benefits of community participation and physical activity for the health and wellbeing of older adults are well documented. This review aims to answer the question; "How is community participation considered for older adults in the transition from hospital to home?" MATERIALS AND METHODS: This scoping review searched key databases using subject headings and keywords. Two independent reviewers selected studies based on a systematic procedure. Inclusion criteria were adults aged ≥60 years, transitioning from hospital to home, reporting on community participation, inclusive of leisure activities, social activities, and physical activity. RESULTS: Of 2206 initial unique articles, 19 met inclusion criteria. Articles covered a range of diagnoses, most frequently stroke, hip replacement, or fracture. Numerous measures of community participation were reported, identifying "low" and "reduced" community participation in ten studies. Measures of physical activity, health-related quality of life, sleep quality, and loneliness were variable. Five studies reported interventions and four reported improved components of community participation. Numerous barriers to community participation were identified, with recommendations for future transition care services considered. CONCLUSION: There are considerable barriers to promoting community participation in transition care services for older people. Older adults need information to prepare for returning home from hospital and to regain valued leisure and social activities for health-related quality of life.IMPLICATIONS FOR REHABILITATIONCommunity participation is an important component of healthy ageing which health professionals should consider beyond discharge.Levels of mobility and endurance should be considered in terms of facilitating community participation for older adults.Transition care services should provide adequate information to prepare individuals expectations of returning home following hospital stay, whilst attempting to maintain valued leisure and social activities.

Location monitoring of physical activity and participation in community dwelling older people: a scoping review.

Background: Community participation and physical activity are important for the health of older adults. This review aimed to identify studies which have measured physical activity and community participation in older adults using Global positioning systems.Materials and methods: This scoping review searched key databases using predetermined subject headings and keywords. Two independent reviewers selected studies based on a systematic procedure following current guidelines. Inclusion criteria for studies were: participants aged over 50 years living independently in the community that reported on physical activity and/or participation inclusive of physical and social activity, and including a quantitative measure of location. All searches were limited to English. The primary review question was; "What studies have monitored the location of physical activity in an older population?" with secondary enquiries investigating the types of global positioning system devices, barriers and facilitators for activity and community participation.Results: The search returned 3723 articles (following duplicate removal) and 45 met the inclusion criteria. Studies from 12 countries published over a 12-year period were included. Participants were mainly healthy (n = 23) followed by having a cognitive impairment (n = 10). There were 14 different global positioning system devices used, assessing a variety of outcomes (n = 24). Seventeen studies identified facilitators and barriers to participation and physical activity in an older population. The most common facilitators were safety, weather and access to multi-purpose facilities. The most common barriers were weather, safety, low income/high deprivation areas and use of motor vehicles.Conclusion: This scoping review identified a variety of locational monitoring of older people using global positioning devices. Global positioning systems are a valuable tool to obtain accurate activity locations of older people. There is a need for clear guidelines regarding the use of global positioning system devices and specified outcomes in primary research to enable comparison across studies.Implications for rehabilitationPhysical activity and community participation are vital for healthy ageing.The environment can act as a facilitator or barrier to physical activity and community participation for older adults.Interventions need to target facilitators (weather, safety, facility access and social components) to maximize physical activity and community participation in older people.Interventions should be designed to reduce the barriers (weather, safety, low income and motor vehicle dependency) that prevent older adults from actively participating in their community.

Activity and MObility UsiNg Technology (AMOUNT) rehabilitation trial - description of device use and physiotherapy support in the post-hospital phase.

PURPOSE: To describe device use and physiotherapy support in the post-hospital phase of the AMOUNT rehabilitation trial. METHODS: We performed an evaluation of the support required for device use by participants randomised to the intervention group who received digitally-enabled rehabilitation in the post-hospital phase (n = 144). Intervention, additional to standard rehabilitation, utilised eight digital devices (virtual reality videogames, activity monitors and handheld computer devices) to improve mobility and increase physical activity. Participants were taught to use devices during inpatient rehabilitation and were then discharged home to use the devices for the remainder of the 6-month trial. Physiotherapist-participant contact occurred every 1-2 weeks using a health coaching approach, including technology support when required. Intervention datasheets were audited, and descriptive statistics used to report device use and support required. RESULTS: Participants (mean (SD) age 70 (18) years; 49% neurological health conditions) used an average of 2 (SD 1) devices (98% used an activity monitor). Eight percent of physiotherapy contact included technology support with 30% provided remotely. Support addressed 845 issues categorised under initial set-up and instruction (27%), education and training (31%), maintenance (23%) and trouble-shooting (19%). CONCLUSION: Digital devices can be used for home-based rehabilitation, but ongoing technology support is essential. Clinical Trials Registry: ACTRN12614000936628IMPLICATIONS FOR REHABILITATIONDigital device use at home to support long-term management of health conditions is likely to become increasingly important as the need for rehabilitation increases and rehabilitation resources become more limited.Technology support for set-up and ongoing device use is a critical enabler of home-based digital interventions.Health professionals delivering home-based digital interventions require sufficient training and equipment and may need to vary the mode (e.g., home visit vs. telephone or video conference) depending on the technology support required.

How Commercially Available Virtual Reality-Based Interventions Are Delivered and Reported in Gait, Posture, and Balance Rehabilitation: A Systematic Review.

OBJECTIVE: Virtual reality (VR) technologies are increasingly used in physical rehabilitation; however, it is unclear how VR interventions are being delivered, and, in particular, the role of the therapist remains unknown. The purpose of this study was to systematically evaluate how commercially available VR technologies are being implemented in gait, posture, and balance rehabilitation, including justification, content, procedures, and dosage of the intervention and details of the therapist role. METHODS: Five databases were searched between 2008 and 2018. Supervised interventional trials with >10 adult participants using commercially available VR technologies to address mobility limitations were independently selected by 2 authors. One author extracted reported intervention characteristics into a predesigned table and assessed methodological quality, which was independently verified by a second author. A total of 29 studies were included. RESULTS: Generally, minimal clinical reasoning was provided to justify technology or activity selection, with recreational systems and games used most commonly (n = 25). All but 1 study used a single interventional technology. When explicitly described, the intervention was delivered by a physical therapist (n = 14), a therapist assistant (n = 2), both (n = 1), or an occupational therapist (n = 1). Most studies reported supervision (n = 12) and safeguarding (n = 8) as key therapist roles, with detail of therapist feedback less frequently reported (n = 4). Therapist involvement in program selection, tailoring, and progression was poorly described. CONCLUSION: Intervention protocols of VR rehabilitation studies are incompletely described and generally lack detail on clinical rationale for technology and activity selection and on the therapist role in intervention design and delivery, hindering replication and translation of research into clinical practice. Future studies utilizing commercially available VR technologies should report all aspects of intervention design and delivery and consider protocols that allow therapists to exercise clinical autonomy in intervention delivery. IMPACT STATEMENT: The findings of this systematic review have highlighted that VR rehabilitation interventions targeting gait, posture, and balance are primarily delivered by physical therapists, whose most reported role was supervision and safeguarding. There was an absence of detail regarding complex clinical skills, such as tailoring of the intervention and reasoning for the choice of technology and activity. This uncertainty around the role of the therapist as an active ingredient in VR-based rehabilitation hinders the development of implementation guidelines. To inform the optimal involvement of therapists in VR rehabilitation, it is essential that future studies report on all aspects of VR intervention design and delivery.

Heparin-based hydrogels induce human renal tubulogenesis in vitro.

Dialysis or kidney transplantation is the only therapeutic option for end stage renal disease. Accordingly, there is a large unmet clinical need for new causative therapeutic treatments. Obtaining robust models that mimic the complex nature of the human kidney is a critical step in the development of new therapeutic strategies. Here we establish a synthetic in vitro human renal tubulogenesis model based on a tunable glycosaminoglycan-hydrogel platform. In this system, renal tubulogenesis can be modulated by the adjustment of hydrogel mechanics and degradability, growth factor signaling, and the presence of insoluble adhesion cues, potentially providing new insights for regenerative therapy. Different hydrogel properties were systematically investigated for their ability to regulate renal tubulogenesis. Hydrogels based on heparin and matrix metalloproteinase cleavable peptide linker units were found to induce the morphogenesis of single human proximal tubule epithelial cells into physiologically sized tubule structures. The generated tubules display polarization markers, extracellular matrix components, and organic anion transport functions of the in vivo renal proximal tubule and respond to nephrotoxins comparable to the human clinical response. The established hydrogel-based human renal tubulogenesis model is thus considered highly valuable for renal regenerative medicine and personalized nephrotoxicity studies. STATEMENT OF SIGNIFICANCE: The only cure for end stage kidney disease is kidney transplantation. Hence, there is a huge need for reliable human kidney models to study renal regeneration and establish alternative treatments. Here we show the development and application of an in vitro human renal tubulogenesis model using heparin-based hydrogels. To the best of our knowledge, this is the first system where human renal tubulogenesis can be monitored from single cells to physiologically sized tubule structures in a tunable hydrogel system. To validate the efficacy of our model as a drug toxicity platform, a chemotherapy drug was incubated with the model, resulting in a drug response similar to human clinical pathology. The established model could have wide applications in the field of nephrotoxicity and renal regenerative medicine and offer a reliable alternative to animal models.

Macromolecular crowding for tailoring tissue-derived fibrillated matrices.

Tissue-derived fibrillated matrices can be instrumental for the in vitro reconstitution of multiphasic extracellular microenvironments. However, despite of several advantages, the obtained scaffolds so far offer a rather narrow range of materials characteristics only. In this work, we demonstrate how macromolecular crowding (MMC) - the supplementation of matrix reconstitution media with synthetic or natural macromolecules in ways to create excluded volume effects (EVE) - can be employed for tailoring important structural and biophysical characteristics of kidney-derived fibrillated matrices. Porcine kidneys were decellularized, ground and the obtained extracellular matrix (ECM) preparations were reconstituted under varied MMC conditions. We show that MMC strongly influences the fibrillogenesis kinetics and impacts the architecture and the elastic modulus of the reconstituted matrices, with diameters and relative alignment of fibrils increasing at elevated concentrations of the crowding agent Ficoll400, a nonionic synthetic polymer of sucrose. Furthermore, we demonstrate how MMC modulates the distribution of key ECM molecules within the reconstituted matrix scaffolds. As a proof of concept, we compared different variants of kidney-derived fibrillated matrices in cell culture experiments referring to specific requirements of kidney tissue engineering approaches. The results revealed that MMC-tailored matrices support the morphogenesis of human umbilical vein endothelial cells (HUVECs) into capillary networks and of murine kidney stem cells (KSCs) into highly branched aggregates. The established methodology is concluded to provide generally applicable new options for tailoring tissue-specific multiphasic matrices in vitro. STATEMENT OF SIGNIFICANCE: Tissue-derived fibrillated matrices can be instrumental for the in vitro reconstitution of multiphasic extracellular microenvironments. However, despite of several advantages, the obtained scaffolds so far offer a rather narrow range of materials characteristics only. Using the kidney matrix as a model, we herein report a new approach for tailoring tissue-derived fibrillated matrices by means of macromolecular crowding (MMC), the supplementation of reconstitution media with synthetic or natural macromolecules. MMC-modulation of matrix reconstitution is demonstrated to allow for the adjustment of fibrillation kinetics and nano-architecture, fiber diameter, alignment, and matrix elasticity. Primary human umbilical vein endothelial cells (HUVEC) and murine kidney stem cells (KSC) were cultured within different variants of fibrillated kidney matrix scaffolds. The results showed that MMC-tailored matrices were superior in supporting desired morphogenesis phenomena of both cell types.

Effect of affordable technology on physical activity levels and mobility outcomes in rehabilitation: a protocol for the Activity and MObility UsiNg Technology (AMOUNT) rehabilitation trial.

INTRODUCTION: People with mobility limitations can benefit from rehabilitation programmes that provide a high dose of exercise. However, since providing a high dose of exercise is logistically challenging and resource-intensive, people in rehabilitation spend most of the day inactive. This trial aims to evaluate the effect of the addition of affordable technology to usual care on physical activity and mobility in people with mobility limitations admitted to inpatient aged and neurological rehabilitation units compared to usual care alone. METHODS AND ANALYSIS: A pragmatic, assessor blinded, parallel-group randomised trial recruiting 300 consenting rehabilitation patients with reduced mobility will be conducted. Participants will be individually randomised to intervention or control groups. The intervention group will receive technology-based exercise to target mobility and physical activity problems for 6 months. The technology will include the use of video and computer games/exercises and tablet applications as well as activity monitors. The control group will not receive any additional intervention and both groups will receive usual inpatient and outpatient rehabilitation care over the 6-month study period. The coprimary outcomes will be objectively assessed physical activity (proportion of the day spent upright) and mobility (Short Physical Performance Battery) at 6 months after randomisation. Secondary outcomes will include: self-reported and objectively assessed physical activity, mobility, cognition, activity performance and participation, utility-based quality of life, balance confidence, technology self-efficacy, falls and service utilisation. Linear models will assess the effect of group allocation for each continuously scored outcome measure with baseline scores entered as a covariate. Fall rates between groups will be compared using negative binomial regression. Primary analyses will be preplanned, conducted while masked to group allocation and use an intention-to-treat approach. ETHICS AND DISSEMINATION: The protocol has been approved by the relevant Human Research Ethics Committees and the results will be disseminated widely through peer-reviewed publication and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12614000936628. Pre-results.

Immunotherapy with injectable hydrogels to treat obstructive nephropathy.

Hydrogels are gaining attention as injectable vehicles for delivery of therapeutics for a range of applications. We describe self-assembling and injectable Dock-and-Lock hydrogels for local delivery of interleukin-10 (IL-10) to abate the progression of inflammation and fibrosis that leads to chronic kidney disease. As monitored with a fluorescent tag, hydrogels degraded within a few days in vitro and matched IL-10 release profiles; however, hydrogels remained in the kidney for up to 30 days in vivo. A unilateral ureteral obstruction (UUO) mouse model was used to investigate in vivo outcomes after hydrogel injection and IL-10 delivery. Eight groups were investigated (7, 21, 35 days, n = 4): healthy, sham, healthy injected with mouse serum albumin (MSA), healthy + hydrogel, UUO, UUO + IL-10, UUO + hydrogel, UUO + hydrogel/IL-10. 15 µL of IL-10, hydrogel, or hydrogel/IL-10 was injected under the renal capsule 3 days after the UUO. Immunohistochemistry (IHC) was performed on paraffin sections to identify macrophages and apoptotic cells and trichrome staining was used to evaluate fibrosis. There were no significant differences in inflammatory markers between all control groups. With hydrogel delivery, macrophage infiltration and apoptosis were significantly reduced at days 21 and 35 compared to untreated animals. By day 35, IL-10 delivery via hydrogel reduced macrophage infiltration and apoptosis more than IL-10 injection alone. Fibrosis was decreased by day 35 in all treatment groups. This work supports the use of hydrogel delivery of IL-10 to treat chronic kidney disease.

Tunable hydrogel-microsphere composites that modulate local inflammation and collagen bulking.

Injectable biomaterials alone may alter local tissue responses, including inflammatory cascades and matrix production (e.g. stimulatory dermal fillers are used as volumizing agents that induce collagen production). To expand upon the available material compositions and timing of presentation, a tunable hyaluronic acid (HA) and poly(lactide-co-glycolide) (PLGA) microsphere composite system was formulated and assessed in subcutaneous and cardiac tissues. HA functionalized with hydroxyethyl methacrylate (HeMA) was used as a precursor to injectable and degradable hydrogels that carry PLGA microspheres (~50 µm diameter) to tissues, where the HA hydrogel degradation (~20 or 70 days) and quantity of PLGA microspheres (0-300 mgml(-1)) are readily varied. When implanted subcutaneously, faster hydrogel degradation and more microspheres (e.g. 75 mgml(-1)) generally induced more rapid tissue and cellular interactions and a greater macrophage response. In cardiac applications, tissue bulking may be useful to alter stress profiles and to stabilize the tissue after infarction, limiting left ventricular (LV) remodeling. When fast degrading HeMA-HA hydrogels containing 75 mgml(-1) microspheres were injected into infarcted tissue in sheep, LV dilation was limited and the thickness of the myocardial wall and the presence of vessels in the apical infarct region were increased ~35 and ~60%, respectively, compared to empty hydrogels. Both groups decreased volume changes and infarct areas at 8 weeks, compared to untreated controls. This work illustrates the importance of material design in expanding the application of tissue bulking composites to a range of biomedical applications.