Immersive Virtual Reality to Improve Outcomes in Veterans With Stroke: Protocol for a Single-Arm Pilot Study.

BACKGROUND: Over the last decade, virtual reality (VR) has emerged as a cutting-edge technology in stroke rehabilitation. VR is defined as a type of computer-user interface that implements real-time simulation of an activity or environment allowing user interaction via multiple sensory modalities. In a stroke population, VR interventions have been shown to enhance motor, cognitive, and psychological recovery when utilized as a rehabilitation adjunct. VR has also demonstrated noninferiority to usual care therapies for stroke rehabilitation. OBJECTIVE: The proposed pilot study aims to (1) determine the feasibility and tolerability of using a therapeutic VR platform in an inpatient comprehensive stroke rehabilitation program and (2) estimate the initial clinical efficacy (effect size) associated with the VR platform using apps for pain distraction and upper extremity exercise for poststroke neurologic recovery. METHODS: This study will be conducted in the Comprehensive Integrated Inpatient Rehabilitation Program at the James A Haley Veterans' Hospital. Qualitative interviews will be conducted with 10 clinical staff members to assess the feasibility of the VR platform from the clinician perspective. A prospective within-subject pretest-posttest pilot design will be used to examine the tolerability of the VR platform and the clinical outcomes (ie, upper extremity neurologic recovery, hand dexterity, pain severity) in 10 veteran inpatients. A VR platform consisting of commercially available pain distraction and upper extremity apps will be available at the participants' bedside for daily use during their inpatient stay (approximately 4-6 weeks). Clinician interviews will be analyzed using qualitative descriptive analysis. Cohen d effect sizes with corresponding 95% CIs will be calculated for upper extremity neurologic recovery, hand dexterity, and pain. The proportion of participants who achieve minimal clinically important difference after using the VR platform will be calculated for each clinical outcome. RESULTS: This study was selected for funding in August 2020. Institutional review board approval was received in October 2020. The project start date was December 2020. The United States Department has issued a moratorium on in-person research activities secondary to COVID-19. Data collection will commence once this moratorium is lifted. CONCLUSIONS: Our next step is to conduct a large multi-site clinical trial that will incorporate the lessons learned from this pilot feasibility study to test the efficacy of a VR intervention in inpatient rehabilitation and transition to home environments. When VR is used in patients' rooms, it serves to provide additional therapy and may reduce clinician burden. VR also presents an opportunity similar to home-based practice exercises. VR can be implemented in both clinical settings and people's own homes, where engagement in ongoing self-management approaches is often most challenging. This unique experience offers the potential for seamless transition from inpatient rehabilitation to the home. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/26133.

The Management of Stroke Rehabilitation: A Synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

Description: In June 2019, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved an update of the joint clinical practice guideline for rehabilitation after stroke. This synopsis summarizes the key recommendations from this guideline. Methods: In February 2018, the VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included clinical stakeholders and stroke survivors and conformed to the National Academy of Medicine (formerly the Institute of Medicine) tenets for trustworthy clinical practice guidelines. The guideline panel identified key questions, systematically searched and evaluated the literature, and developed 2 algorithms and 42 key recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Stroke survivors and their family members were invited to share their perspectives to further inform guideline development. Recommendations: The guideline recommendations provide evidence-based guidance for the rehabilitation care of patients after stroke. The recommendations are applicable to health care providers in both primary care and rehabilitation. Key features of the guideline are recommendations in 6 areas: timing and approach; motor therapy; dysphagia; cognitive, speech, and sensory therapy; mental health therapy; and other functions, such as returning to work and driving.

Degradable Copolymer Nanoparticles from Radical Ring-Opening Copolymerization between Cyclic Ketene Acetals and Vinyl Ethers.

2-Methylene-1,3-dioxepane (MDO) and different vinyl ether (VE) monomers were successfully copolymerized by free-radical radical ring-opening copolymerization (rROP) to yield P(MDO- co-VE) copolymers with Mn = 7 000-13 000 g·mol-1 and high molar fractions of MDO ( FMDO = 0.7-0.9). By using VE derivatives of different aqueous solubilities or by grafting PEG chains onto the copolymers by "click" chemistry via azide-containing VE units, hydrophobic, amphiphilic and water-soluble copolymers were obtained. The different copolymers were then formulated into nanoparticles by nanoprecipitation using Pluronics for hydrophobic copolymers, without surfactant for amphiphilic copolymers, or blended with PMDO for water-soluble copolymers. Most of the copolymers led to nanoparticles with average diameters in the 130-250 nm with narrow particle size distributions and satisfying colloidal stability for a period of at least 1-2 weeks and up to 6 months. The copolymers were successfully degraded under accelerated, hydrolytic or enzymatic conditions. Hydrophobic copolymers led to degradation kinetics in PBS similar to that of PCL and complete degradation (-95% in Mn decrease) was observed in the presence of enzymes (lipases). Preliminary cytotoxicity assays were performed on endothelial cells (HUVEC) and macrophages (J774.A1) and revealed high cell viabilities at 0.1 mg·mL-1.

Degradable polymer prodrugs with adjustable activity from drug-initiated radical ring-opening copolymerization.

Degradable polymer prodrugs based on gemcitabine (Gem) as an anticancer drug were synthesized by 'drug-initiated' nitroxide-mediated radical ring-opening copolymerization (NMrROP) of methacrylic esters and 2-methylene-4-phenyl-1,3-dioxolane (MPDL). Different structural parameters were varied to determine the best biological performances: the nature of the monomer [i.e., oligo(ethylene glycol) methacrylate (OEGMA) or methyl methacrylate (MMA)], the nature of the Gem-polymer linker (i.e., amide or amide and diglycolate) and the MPDL content in the copolymer. Depending on the nature of the methacrylate monomer, two small libraries of water-soluble copolymer prodrugs and nanoparticles were obtained (M n ∼10 000 g mol-1, D = 1.1-1.5), which exhibited tunable hydrolytic degradation under accelerated conditions governed by the MPDL content. Drug-release profiles in human serum and in vitro anticancer activity on different cell lines enabled preliminary structure-activity relationships to be established. The cytotoxicity was independently governed by: (i) the MPDL content - the lower the MPDL content, the greater the cytotoxicity; (ii) the nature of the linker - the presence of a labile diglycolate linker enabled a greater Gem release compared to a simple amide bond and (iii) the hydrophilicity of the methacrylate monomer-OEGMA enabled a greater anticancer activity to be obtained compared to MMA-based polymer prodrugs. Remarkably, the optimal structural parameters enabled reaching the cytotoxic activity of the parent (free) drug.

Telechelic polymers from reversible-deactivation radical polymerization for biomedical applications.

The main strategies for the design of telechelic polymers synthesized by reversible-activation radical polymerization for biomedical applications are covered spanning from drug delivery and targeting to theranostics and sensing.

Radical Copolymerization of Vinyl Ethers and Cyclic Ketene Acetals as a Versatile Platform to Design Functional Polyesters.

Free-radical copolymerization of cyclic ketene acetals (CKAs) and vinyl ethers (VEs) was investigated as an efficient yet simple approach for the preparation of functional aliphatic polyesters. The copolymerization of CKA and VE was first predicted to be quasi-ideal by DFT calculations. The theoretical prediction was experimentally confirmed by the copolymerization of 2-methylene-1,3-dioxepane (MDO) and butyl vinyl ether (BVE), leading to rMDO =0.73 and rBVE =1.61. We then illustrated the versatility of this approach by preparing different functional polyesters: 1) copolymers functionalized by fluorescent probes; 2) amphiphilic copolymers grafted with poly(ethylene glycol) (PEG) side chains able to self-assemble into PEGylated nanoparticles; 3) antibacterial films active against Gram-positive and Gram-negative bacteria (including a multiresistant strain); and 4) cross-linked bioelastomers with suitable properties for tissue engineering applications.

Rehospitalization in the First Year Following Veteran and Service Member TBI: A VA TBI Model Systems Study.

OBJECTIVE: To determine the incidence and causes of rehospitalization following military or Veteran traumatic brain injury (TBI). SETTING: Department of Veterans Affairs (VA) Veterans Health Administration Polytrauma Rehabilitation Centers (VHA PRCs). PARTICIPANTS: Consecutive sample of VHA TBI Model System participants (N = 401). DESIGN: Prospective observational cohort study. MAIN MEASURES: Number and type of rehospitalizations in first year post-TBI. RESULTS: Forty-one percent of 401 participants were rehospitalized. Rehospitalization status was associated with greater injury severity and receipt of TBI while active duty. Of those rehospitalized, 30% had 2 or more readmissions. Participants experiencing multiple rehospitalizations (2+) were more likely to have sustained their TBI during deployment than those with none or single rehospitalization. This group also sustained more severe injuries and spent more time in VA PRC inpatient rehabilitation. Common reasons for rehospitalization included inpatient rehabilitation (33%), unspecified (26%), orthopedic (10%), seizures (8%), infection (8%), and psychiatric (7%). CONCLUSION: This is the first study examining military and Veteran rehospitalization following TBI requiring inpatient rehabilitation at a VA PRC. Findings indicate frequent rehospitalizations in the first year postinjury, suggesting the need for preventive models of health maintenance following inpatient rehabilitation discharge. Greater surveillance of those with deployment-related TBI or active duty at the time of injury and greater TBI severity may be warranted.

Radical Ring-Opening Copolymerization of Cyclic Ketene Acetals and Maleimides Affords Homogeneous Incorporation of Degradable Units.

Radical copolymerization of donor-acceptor (D-A) monomer pairs has served as a versatile platform for the development of alternating copolymers. However, due to the use of conventional radical polymerization, the resulting copolymers have generally been limited to nondegradable vinyl polymers. By combining radical D-A copolymerization with radical ring-opening polymerization (rROP), we have synthesized an alternating copolymer with a high incorporation of degradable backbone units. Copolymerization of N-ethyl maleimide (NEtMI) with the cyclic ketene acetal (CKA) 2-methylene-4-phenyl-1,3-dioxolane (MPDL) was demonstrated to proceed in an alternating fashion, and controlled polymerization was achieved using reversible addition-fragmentation chain transfer (RAFT) polymerization. Spontaneous copolymerization, in the absence of an exogenous initiating source, occurred when the mixture of monomers was heated, presumably due to the large electron disparity between the comonomers. Chain-extension with styrene afforded well-defined P(MPDL-alt-NEtMI)-b-polystyrene copolymers, and degradation of the homopolymers and block copolymers showed complete breakdown of the alternating copolymer.

Osmium Atoms and Os2 Molecules Move Faster on Selenium-Doped Compared to Sulfur-Doped Boronic Graphenic Surfaces.

We deposited Os atoms on S- and Se-doped boronic graphenic surfaces by electron bombardment of micelles containing 16e complexes [Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-diselenate/dithiolate)] encapsulated in a triblock copolymer. The surfaces were characterized by energy-dispersive X-ray (EDX) analysis and electron energy loss spectroscopy of energy filtered TEM (EFTEM). Os atoms moved ca. 26× faster on the B/Se surface compared to the B/S surface (233 ± 34 pm·s(-1) versus 8.9 ± 1.9 pm·s(-1)). Os atoms formed dimers with an average Os-Os distance of 0.284 ± 0.077 nm on the B/Se surface and 0.243 ± 0.059 nm on B/S, close to that in metallic Os. The Os2 molecules moved 0.83× and 0.65× more slowly than single Os atoms on B/S and B/Se surfaces, respectively, and again markedly faster (ca. 20×) on the B/Se surface (151 ± 45 pm·s(-1) versus 7.4 ± 2.8 pm·s(-1)). Os atom motion did not follow Brownian motion and appears to involve anchoring sites, probably S and Se atoms. The ability to control the atomic motion of metal atoms and molecules on surfaces has potential for exploitation in nanodevices of the future.

Precious metal carborane polymer nanoparticles: characterisation of micellar formulations and anticancer activity.

We report the encapsulation of highly hydrophobic 16-electron organometallic ruthenium and osmium carborane complexes [Ru/Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolate)] ( and ) in Pluronic® triblock copolymer P123 core-shell micelles. The spherical nanoparticles and , dispersed in water, were characterized by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and synchrotron small-angle X-ray scattering (SAXS; diameter ca. 15 and 19 nm, respectively). Complexes and were highly active towards A2780 human ovarian cancer cells (IC(50) 0.17 and 2.50 µM, respectively) and the encapsulated complexes, as and nanoparticles, were less potent (IC(50) 6.69 µM and 117.5 µM, respectively), but more selective towards cancer cells compared to normal cells.

Descriptive characteristics and rehabilitation outcomes in active duty military personnel and veterans with disorders of consciousness with combat- and noncombat-related brain injury.

OBJECTIVE: To report the injury and demographic characteristics, medical course, and rehabilitation outcome for a consecutive series of veterans and active duty military personnel with combat- and noncombat-related brain injury and disorder of consciousness (DOC) at the time of rehabilitation admission. DESIGN: Retrospective study. SETTING: Rehabilitation center. PARTICIPANTS: From January 2004 to October 2009, persons (N=1654) were admitted to the Polytrauma Rehabilitation System of Care. This study focused on the N=122 persons admitted with a DOC. Participants with a DOC were primarily men (96%), on active duty (82%), ≥12 years of education, and a median age of 25. Brain injury etiologies included mixed blast trauma (24%), penetrating (8%), other trauma (56%), and nontrauma (13%). Median initial Glasgow Coma Scale score was 3, and rehabilitation admission Glasgow Coma Scale score was 8. Individuals were admitted for acute neurorehabilitation approximately 51 days postinjury with a median rehabilitation length of stay of 132 days. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Recovery of consciousness and the FIM instrument. RESULTS: Most participants emerged to regain consciousness during neurorehabilitation (64%). Average gains ± SD on the FIM cognitive and motor subscales were 19 ± 25 and 7 ± 8, respectively. Common medical complications included spasticity (70%), dysautonomia (34%), seizure occurrence (30%), and intracranial infection (22%). Differential outcomes were observed across etiologies, particularly for those with blast-related brain injury etiology. CONCLUSIONS: Despite complex comorbidities, optimistic outcomes were observed. Individuals with severe head injury because of blast-related etiologies have different outcomes and comorbidities observed. Health-services research with a focus on prevention of comorbidities is needed to inform optimal models of care, particularly for combat injured soldiers with blast-related injuries.

Do rehospitalization rates differ among injury severity levels in the NIDRR Traumatic Brain Injury Model Systems program?

OBJECTIVE: To compare the rate and nature of rehospitalization in a cohort of patients enrolled in the National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems (TBIMS) who have disorders of consciousness (DOC) at the time of rehabilitation admission with those in persons with moderate or severe traumatic brain injury (TBI) but without DOC at rehabilitation admission. DESIGN: Prospective observational study. SETTING: Inpatient rehabilitation within TBIMS with annual follow-up. PARTICIPANTS: Of 9028 persons enrolled from 1988 to 2009 (N=9028), 366 from 20 centers met criteria for DOC at rehabilitation admission and follow-up data, and another 5132 individuals met criteria for moderate (n=769) or severe TBI (n=4363). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants and/or their family members completed follow-up data collection including questions about frequency and nature of rehospitalizations at 1 year postinjury. For the subset of participants with DOC, additional follow-up was conducted at 2 and 5 years postinjury. RESULTS: The DOC group demonstrated an overall 2-fold increase in rehospitalization in the first year postinjury relative to those with moderate or severe TBI without DOC. Persons with DOC at rehabilitation admission have a higher rate of rehospitalization across several categories than persons with moderate or severe TBI. CONCLUSIONS: Although the specific details of rehospitalization are unknown, greater injury severity resulting in DOC status on rehabilitation admission has long-term implications. Data highlight the need for a longitudinal approach to patient management.

Longitudinal outcome of patients with disordered consciousness in the NIDRR TBI Model Systems Programs.

Few studies address the course of recovery from prolonged disorders of consciousness (DOC) after severe traumatic brain injury (TBI). This study examined acute and long-term outcomes of persons with DOC admitted to acute inpatient rehabilitation within the National Institute on Disability and Rehabilitation Research (NIDRR) TBI Model Systems Programs (TBIMS). Of 9028 persons enrolled from 1988 to 2009, 396 from 20 centers met study criteria. Participants were primarily male (73%), Caucasian (67%), injured in motor vehicle collision (66%), with a median age of 28, and emergency department Glasgow Coma Scale (GCS) score of 3. Participant status was evaluated at acute rehabilitation admission and discharge and at 1, 2, and 5 years post-injury. During inpatient rehabilitation, 268 of 396 (68%) regained consciousness and 91 (23%) emerged from post-traumatic amnesia (PTA). Participants demonstrated significant improvements on GCS (z=16.135, p≤0.001) and Functional Independence Measure (FIM) (z=15.584, p≤0.001) from rehabilitation admission (median GCS=9; FIM=18) to discharge (median GCS=14; FIM=43). Of 337 with at least one follow-up visit, 28 (8%) had died by 2.1 years (mean) after discharge. Among survivors, 66 (21%) improved to become capable of living without in-house supervision, and 63 demonstrated employment potential using the Disability Rating Scale (DRS). Participants with follow-up data at 1, 2, and 5 years post-injury (n=108) demonstrated significant improvement across all follow-up evaluations on the FIM Cognitive and Supervision Rating Scale (p<0.01). Significant improvements were observed on the DRS and FIM Motor at 1 and 2 years post-injury (p<0.01). Persons with DOC at the time of admission to inpatient rehabilitation showed functional improvement throughout early recovery and in years post-injury.