Quality of Life in Children and Adolescents with Neurofibromatosis Type 1: A Single-Center Observational Study.

This article obtains an overview of the health status of children and adolescents with neurofibromatosis type 1 (NF1) with a focus on the clinical course of the disease, neuropsychodiagnostic findings, and their impact on quality of life (QoL). In this observational study, data were collected from 24 children and adolescents with NF1 who were cared for at the University Hospital in Innsbruck, Austria, from 2008 to 2022. Data were collected every 6 to 12 months from routine check-ups, including clinical features and imaging findings. Results of neuropsychodiagnostic tests and the KINDL questionnaire to assess QoL were included. Of 24 patients, 15 underwent a neuropsychological examination. Attention performance was examined in 11 of them. Eight of 11 (72%) showed an attention deficit. Assessment for specific developmental disorders showed visual-spatial difficulties in 12/15 (80%) patients. The KINDL questionnaire values ranged from 58.22 to 97.92 (0 stands for reduced QoL, 100 for very good QoL). Patients with scoliosis had a lower range of QoL (56.33-73.96). No trend in QoL was observed in children and adolescents with plexiform neurofibromas, below-average intelligence or optic gliomas. NF1 patients show very different clinical courses. Regular neuropsychological assessment especially with regard to visual-spatial skills and attention deficits is necessary to offer appropriate support, promote children's development, and thus improve their QoL.

Retrospective Analysis of Vision Rehabilitation for Veterans With Traumatic Brain Injury-Related Vision Dysfunction.

INTRODUCTION: Traumatic brain injury (TBI) can trigger vision-based sequelae such as oculomotor and accommodative abnormalities, visual-vestibular integrative dysfunction, visual field loss, and photosensitivity. The need for diagnosis and management of TBI-related vision impairment has increased because of the increasing frequencies of combat warfighters returning from Iraq and Afghanistan with TBIs. The purpose of this research was to learn the sequelae of rehabilitation service delivery to veterans with TBI-related visual dysfunction after they are diagnosed. To accomplish this, we investigated vision rehabilitation assessments and interventions provided to veterans with TBI-related visual dysfunction at the Department of Veterans Affairs (VA) specialty polytrauma facilities for the 2 years following their injury. The research questions asked what assessments, interventions, and prescribed assistive devices were provided by VA specialty clinics (e.g., occupational therapy, polytrauma, and blind rehabilitation) and how service delivery was affected by demographic and clinical variables. MATERIALS AND METHODS: A retrospective design was used to analyze VA data using natural language processing of unstructured clinician notes and logistic regression of structured data. Participants included 350 veterans with TBI who received rehabilitation at one of the five VA Polytrauma Rehabilitation Centers (Tampa, FL; Richmond, VA; Minneapolis, MN; San Antonio, TX; and Palo Alto, CA) between 2008 and 2017 and who were administered the 2008 congressionally mandated "Traumatic Brain Injury Specific Ocular Health and Visual Functioning Exam." The outcome variables were vision assessments, interventions, and prescribed assistive technology discovered via natural language processing of clinician notes as well as the vision rehabilitation specialty clinics providing the clinical care (polytrauma, occupational therapy, outpatient blind rehabilitation, inpatient blind rehabilitation, optometry, and low vision) extracted from VA structured administrative data. RESULTS: Veterans receiving rehabilitation for TBI-related vision dysfunction were most frequently assessed for saccades, accommodation, visual field, and convergence. Intervention was provided most frequently for eye-hand coordination, saccades, accommodation, vergence, and binocular dysfunction. Technology provided included eyeglasses, wheelchair/scooter, walker/cane, aids for the blind, and computer. There was an overlap in the services provided by specialty clinics. Services available and delivered were significantly associated with the comorbidities of each patient and the specialty clinics available at each VA Polytrauma Rehabilitation Center. CONCLUSIONS: The delivery of patient services should be driven by the needs of veterans and not by system-level factors such as the availability of specific vision rehabilitation services at specific locations. Traditional low vision and blind rehabilitation programs were not designed to treat the comorbidities and symptoms associated with TBI. To address this challenge, blind rehabilitation and neurologic recovery cross training is needed. Our findings document how five VA Polytrauma Rehabilitation Centers implemented this training in 2008. The next step is to extend and standardize this new paradigm to community care, where these post-deployment patients now reside.

Veterans with Traumatic Brain Injury-related Ocular Injury and Vision Dysfunction: Recommendations for Rehabilitation.

SIGNIFICANCE: We know the prevalence of traumatic brain injury (TBI)-related vision impairment and ocular injury symptoms. Lacking is an understanding of health care utilization to treat these symptoms. Utilization knowledge is important to structuring access to treatment, identifying clinical training needs, and providing evidence of the effectiveness of treatment. PURPOSE: This article reports rehabilitation, glasses/contacts, and imaging/photography/video recommendations made by optometrists and ophthalmologists as part of the Department of Veterans Affairs-mandated Performance of Traumatic Brain Injury Specific Ocular Health and Visual Functioning Examination administered to veterans with TBI at Department of Veterans Affairs polytrauma specialty facilities. METHODS: Using a retrospective design, natural language processing, and descriptive and regression statistics, data were analyzed for 2458 Operation Enduring Freedom/Operation Iraqi Freedom veterans who were administered the mandated examination between 2008 and 2017. RESULTS: Of the 2458 veterans, vision rehabilitation was recommended for 24%, glasses/contacts were recommended for 57%, and further imaging/photography/video testing was recommended for 58%. Using key words in the referral, we determined that 37% of veterans were referred to blind rehabilitation, 16% to occupational therapy, and 3% to low-vision clinics. More than 50% of the referrals could have been treated by blind rehabilitation, occupational therapy, or low-vision clinics. Rehabilitation referrals were significantly associated with younger age, floaters, photosensitivity, double vision, visual field and balance deficits, dizziness, and difficulty reading. In comparison, prescriptions for glasses and contacts were associated with older age, photosensitivity, blurred vision, decreased visual field and night vision, difficulty reading, and dry eye. Imaging/photography/video testing was associated with floaters, photosensitivity, and headache. CONCLUSIONS: Findings delineate service delivery models available to veterans with TBI-related vision impairment. The challenge these data address is the lack of clear paths from diagnosis of TBI to identification of vision dysfunction deficits to specialized vision rehabilitation, and finally to community reintegration and community based-vision rehabilitation.

Veterans with Traumatic Brain Injury-related Ocular Injury and Vision Dysfunction: Vision Rehabilitation Utilization.

SIGNIFICANCE: Visual dysfunction is frequently associated with traumatic brain injury (TBI). Although evidence regarding the prevalence of symptoms of this population has been published, little is known about health care utilization. A retrospective review of the data derived from the Department of Veterans Affairs (VA)-mandated "Traumatic Brain Injury Specific Ocular Health and Visual Functioning Examination for Polytrauma Rehabilitation Center Patients" provided a unique opportunity to investigate vision rehabilitation utilization. PURPOSE: The purpose of this study was to understand (a) the frequency of vision rehabilitation follow-up visits at 6, 12, and 24 months; (b) the association between follow-up and demographic, comorbidity, and severity of TBI covariates as well as ocular and visual symptoms, geographic access, and evaluating facility; and (c) why some veterans did not follow up with recommendations. METHODS: Retrospective and survey designs were used. The sample included 2458 veterans who served in the Operation Enduring Freedom/Operation Iraqi Freedom conflicts and received care at one of the five VA Polytrauma Rehabilitation Centers between January 1, 2008, and December 31, 2017. Quantitative and qualitative descriptive analyses and stepwise logistic regression were performed. RESULTS: About 60% of veterans followed up with recommended vision rehabilitation with visits equally split between VA Polytrauma Rehabilitation Centers and community VA facilities. For each 10-year increase in age, there was a corresponding reduction of 12% in the odds of follow-up. Veterans with decreased visual field had 50% greater odds of follow-up than those who did not. Veterans with difficulty reading had 59% greater odds of follow-up than those who did not. Those who had a double vision had 45% greater odds of follow-up than those who did not. CONCLUSIONS: Our findings suggest that the need for vision rehabilitation may extend as long as 2 years after TBI. Access to vision rehabilitation is complicated by the paucity of available neuro-optometric services.

Sustained acoustic medicine for the treatment of musculoskeletal injuries: a systematic review and meta-analysis.

BACKGROUND: Musculoskeletal injuries account for 10 million work-limited days per year and often lead to both acute and/or chronic pain, and increased chances of re-injury or permanent disability. Conservative treatment options include various modalities, nonsteroidal anti-inflammatory drugs, and physical rehabilitation programs. Sustained Acoustic Medicine is an emerging prescription home-use mechanotransductive device to stimulate cellular proliferation, increase microstreaming and cavitation in situ, and to increase tissue profusion and permeability. This research aims to summarize the clinical evidence on Sustained Acoustic Medicine and measurable outcomes in the literature. METHODS: A systematic literature review was conducted using PubMed, EBSCOhost, Academic Search Complete, Google Scholar and ClinicalTrials.gov to identify studies evaluating the effects of Sustained Acoustic Medicine on the musculoskeletal system of humans. Articles identified were selected based on inclusion criteria and scored on the Downs and Black checklist. Study design, clinical outcomes and primary findings were extracted from included studies for synthesis and meta-analysis statistics. RESULTS: A total of three hundred and seventy-two participants (372) were included in the thirteen clinical research studies reviewed including five (5) level I, four (4) level II and four (4) level IV studies. Sixty-seven (67) participants with neck and back myofascial pain and injury, one hundred and fifty-six (156) participants with moderate to severe knee pain and radiographically confirmed knee osteoarthritis (Kellgren-Lawrence grade II/III), and one hundred forty-nine (149) participants with generalized soft-tissue injury of the elbow, shoulder, back and ankle with limited function. Primary outcomes included daily change in pain intensity, change in Western Ontario McMaster Osteoarthritis Questionnaire, change in Global Rate of Change, and functional outcome measures including dynamometry, grip strength, range-of-motion, and diathermic heating (temperature measurement). CONCLUSION: Sustained Acoustic Medicine treatment provides tissue heating and tissue recovery, improved patient function and reduction of pain. When patients failed to respond to physical therapy, Sustained Acoustic Medicine proved to be a useful adjunct to facilitate healing and return to work. As a non-invasive and non-narcotic treatment option with an excellent safety profile, Sustained Acoustic Medicine may be considered a good therapeutic option for practitioners.

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.

Using a Post Fall Assessment Simulation to Examine Nurse Thought Processes.

The prevalence of injurious falls is high in the Veterans Health Administration (VHA) and a major patient safety issue. The VHA is embracing technology such as simulation to improve patient care. Little is known regarding nurse thought processes while undergoing a post fall assessment simulation in the VHA. This article examines the benefit of using an evidence-based post fall simulation to improve nurse assessment skills while providing opportunity for practice without harm to patients.

Steroid-responsive meningitis-arteritis in dogs in Germany: Are there epidemiological or clinical factors influencing recurrence rate?

OBJECTIVE: Steroid-responsive meningitis arteritis (SRMA) is one of the most common inflammatory diseases of the central nervous system in dogs. The present study examined breed and sex predisposition factors based on the population of dogs in Germany as well as epidemiological and clinical factors regarding the relapse rate of SRMA. MATERIAL AND METHODS: Data of 153 dogs with SRMA (SRMA) were analysed retrospectively in this multicentre study. It was investigated whether some dog breeds that suffer from SRMA were disproportionately more often (n ≥ 5) represented when compared to the total population of dogs in Germany. Furthermore it was examined which sex is affected more often. Data provided by "Verband für das deutsche Hundewesen" (VDH) and "Tasso e. V." was used as reference data of the total population. The following factors were investigated with regard to the occurrence of one or more relapses: signalment; body weight; age at first presentation; time period between last vaccination and onset of clinical signs; clinical signs and timepoint of the first SRMA manifestation; results of cerebrospinal fluid (CSF) analysis at first presentation (nucleated cell count and differentiation, protein concentration); immunglobulin A and C-reactive protein (CRP) concentrations in serum and CSF; immunosuppressive medication; follow-up data including response to therapy, occurrence of relapses and mortality including reasons, i. e. due to the disease, therapy or euthanasia. RESULTS: The breed had a statistically significant influence on the development of SRMA (p < 0.05). Beagles and Boxers were affected more often by SRMA than other breeds in relation to the total population in Germany. Relapses occurred in 29.4 % of the 153 dogs of this study. In contrast to the development of SRMA, in which male dogs have a significantly increased risk of developing SRMA (p < 0.05), female dogs are more likely to relapse (p = 0.02). Patients on prednisolone monotherapy had fewer relapses than those with prednisolone and azathioprine in combination (p < 0.05). Younger age (p = 0.071) und lower CRP concentrations (p = 0.081) at first presentation were tentatively associated with a higher incidence of relapses. CONCLUSION: The determined breed and sex predispositions support the diagnosis of SRMA arteritis and confirm previous observations. This study allows a more accurate explanation to owners about the risk of relapse.

Virtual Reality as a Therapy Adjunct for Fear of Movement in Veterans With Chronic Pain: Single-Arm Feasibility Study.

BACKGROUND: Virtual reality (VR) has demonstrated efficacy for distraction from pain-related thoughts and exposure to feared movements. Little empirical VR research has focused on chronic pain management. OBJECTIVE: The purpose of this study was to examine the feasibility of VR as an adjunctive intervention for Veterans with chronic pain. We designed a hierarchy ranging from low-intensity pain distraction to high-intensity movement-based exposure for this purpose. VR apps were mapped onto the hierarchy. METHODS: Sixteen Veterans receiving inpatient chronic pain rehabilitation participated in daily VR sessions over a 3-week period. Trajectories across the distraction-to-exposure hierarchy and Veteran-reported intensity ratings were described and evaluated over time. Minimum clinically important differences (MCIDs), pre-post effect sizes, and 95% confidence intervals were examined for fear of movement using the Fear of Daily Activities Questionnaire (FDAQ) and Pain Outcomes Questionnaire-VA (POQ-VA; fear scale). This approach was applied to secondary outcomes: POQ-VA (pain intensity, interference, negative affect), Pain Catastrophizing Scale, and Patient-Specific Functioning Scale (PSFS). Session attendance, completion, and VR experiences were described. RESULTS: Ten of 14 Veterans (71%) who participated in three or more VR sessions completed the distraction-to-exposure hierarchy. Only three trajectories emerged more than once. Due to high completion rates, Veterans that completed the hierarchy could self-select nonhierarchy apps. Veterans rated all hierarchy levels (low, medium, high) near medium intensity. Self-selected activities were rated as high intensity. For kinesiophobia, six Veterans (38%) exceeded the MCID on the FDAQ and a small effect size improvement was observed (Cohen d=-0.35). The confidence interval (95% CI -0.71 to 0.01) indicated the possibility of a null effect. The POQ-VA fear scale yielded no effect (Cohen d=0.06, 95% CI -0.43 to 0.54). For secondary outcomes, Veterans exceeding MCID were calculated with complete data: pain intensity (1/15, 7%), pain catastrophizing (5/14, 36%), and patient-specific functioning (10/15, 67%). Effect sizes were large for patient-specific functioning (Cohen d=1.14, 95% CI 0.50-1.78), medium for mobility interference (Cohen d=-0.56, 95% CI -0.96 to -0.16), and small for pain intensity (Cohen d=-0.40, 95% CI -0.69 to -0.12) and catastrophizing (Cohen d=-0.41, 95% CI -0.79 to -0.02). No effects were observed for interference in daily activities (Cohen d=0.10, 95% CI -0.27 to 0.47) and negative affect (Cohen d=0.07, 95% CI -0.26 to 0.40). Veterans attended 85.2% (98/108) of VR sessions and completed 95% (93/96) of sessions attended. Twenty-minute sessions were rated as too short. No significant adverse events were reported. CONCLUSIONS: Findings support the feasibility of VR as an adjunct for Veterans with chronic pain. However, the hierarchy will require modification, as evidenced by homogeneous intensity ratings. Veteran-selected activities presented the highest intensity ratings, largest outcome effect size (PSFS), and MCID. This highlights the important role of utilizing Veteran stakeholders in hierarchy modification, design of VR interventions, and outcome selection.

Amputees' Attitudes Toward Participation in Amputee Support Groups and the Role of Virtual Technology in Supporting Amputees: Survey Study.

BACKGROUND: Acquiring information about and living with an amputation (or limb differential) is a lifelong endeavor. Although medical institutions address the immediate medical needs of amputees, information regarding how to live life as an amputee is provided from numerous sources, one of which is amputee support groups. OBJECTIVE: This study aimed at understanding why amputees join support groups, leave support groups, and possibly return to support groups as well as how technology, specifically virtual reality, might play a role in supporting patients' needs. The results are intended to provide data for support groups, to increase their impact on amputee participants. METHODS: A 38-item online survey was developed based on the findings of a previous randomized trial. The survey was administered between April and September 2018 and divided into four sections: Demographics, Limb Loss History, Amputee Support Group Participation, and Technology Usage. Items used multiple-choice, drop-down menu, check-box formats with explanation boxes for open-ended responses. Descriptive analyses were performed for both qualitative (open-ended questions) and quantitative data. RESULTS: Of the 59 amputees enrolled, 54 completed the survey. All the respondents were aged 20-39 years, and nearly half of the older respondents thought audio and video teleconferencing or avatar-based technology would increase participation in support groups. The results suggest that an early goal for amputees who join support groups is to focus on regaining mobility and functionality in order to return to their normal life. Once achieved, the goal transitions to one of social connection with other amputees, although there is a caveat: Simply being an amputee may not provide sufficient connections for developing long-term social relationships. The strongest reason for joining a support group was to learn about living with an amputation, followed by networking and learning new skills. CONCLUSIONS: The results suggest four key takeaways regarding amputee participation in support groups: (1) the needs of participants in amputee support groups change over time; (2) meeting content needs to be relevant to agendas primarily driven by participants; (3) support group participation is also driven by the desire to increase functionality by developing skills, become familiar with prosthetic technology, have more than amputation in common with other participants, and participate at the designated meeting time and location; and (4) the use of technology should support patients' needs.

Immune-Deficient Pfp/Rag2-/- Mice Featured Higher Adipose Tissue Mass and Liver Lipid Accumulation with Growing Age than Wildtype C57BL/6N Mice.

Aging is a risk factor for adipose tissue dysfunction, which is associated with inflammatory innate immune mechanisms. Since the adipose tissue/liver axis contributes to hepatosteatosis, we sought to determine age-related adipose tissue dysfunction in the context of the activation of the innate immune system fostering fatty liver phenotypes. Using wildtype and immune-deficient mice, we compared visceral adipose tissue and liver mass as well as hepatic lipid storage in young (ca. 14 weeks) and adult (ca. 30 weeks) mice. Adipocyte size was determined as an indicator of adipocyte function and liver steatosis was quantified by hepatic lipid content. Further, lipid storage was investigated under normal and steatosis-inducing culture conditions in isolated hepatocytes. The physiological age-related increase in body weight was associated with a disproportionate increase in adipose tissue mass in immune-deficient mice, which coincided with higher triglyceride storage in the liver. Lipid storage was similar in isolated hepatocytes from wildtype and immune-deficient mice under normal culture conditions but was significantly higher in immune-deficient than in wildtype hepatocytes under steatosis-inducing culture conditions. Immune-deficient mice also displayed increased inflammatory, adipogenic, and lipogenic markers in serum and adipose tissue. Thus, the age-related increase in body weight coincided with an increase in adipose tissue mass and hepatic steatosis. In association with a (pro-)inflammatory milieu, aging thus promotes hepatosteatosis, especially in immune-deficient mice.

Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3.

Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains.

China Electricity Generation Greenhouse Gas Emission Intensity in 2030: Implications for Electric Vehicles.

Electrification of transportation offers clear national energy security benefits but unclear climate benefits. With the current heterogeneity of grid electricity mix in China, greenhouse gas (GHG) benefits of battery electric vehicles (BEVs) vary dramatically with location. Currently, compared to baseline conventional gasoline vehicles, BEVs in north and northeastern Chinese provinces have very modest (∼10-20%) well-to-wheel (WTW) GHG benefits, whereas BEVs in southern provinces have substantial benefits (∼50%). With the expected transition to a more renewable electricity mix documented here, regional effects will largely disappear and the benefits of BEVs will be substantial (∼60-70% lower than current internal combustion engine vehicles (ICEVs) and ∼10-40% lower than 2030 advanced hybrid electric vehicles (HEVs)) across the whole of China by 2030. GHG emissions from BEVs in Chinese cities (Beijing, Shanghai, Chongqing, and Pearl River Delta) and United States cities and regions (New York; Washington, DC; Chicago; New England; Texas; and California) in 2015 and 2030 are evaluated and compared. BEVs in Chinese cities will still have substantially higher WTW GHG emissions than those in New York, New England, and California in 2030.

SPR-Measured Dissociation Kinetics of PROTAC Ternary Complexes Influence Target Degradation Rate.

Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming a target/PROTAC/ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation of a method to directly determine binding parameters for ternary complex kinetics has been reported, and it remains to be addressed whether tuning the kinetics of PROTAC ternary complexes may be an effective strategy to improve the efficiency of targeted protein degradation. Here, we develop an SPR-based assay to quantify the stability of PROTAC-induced ternary complexes by measuring for the first time the kinetics of their formation and dissociation in vitro using purified proteins. We benchmark our assay using four PROTACs that target the bromodomains (BDs) of bromodomain and extraterminal domain proteins Brd2, Brd3, and Brd4 to the von Hippel-Lindau E3 ligase (VHL). We reveal marked differences in ternary complex off-rates for different PROTACs that exhibit either positive or negative cooperativity for ternary complex formation relative to binary binding. The positively cooperative degrader MZ1 forms comparatively stable and long-lived ternary complexes with either Brd4BD2 or Brd2BD2 and VHL. Equivalent complexes with Brd3BD2 are destabilized due to a single amino acid difference (Glu/Gly swap) present in the bromodomain. We observe that this difference in ternary complex dissociative half-life correlates to a greater initial rate of intracellular degradation of Brd2 and Brd4 relative to Brd3. These findings establish a novel assay to measure the kinetics of PROTAC ternary complexes and elucidate the important kinetic parameters that drive effective target degradation.

A virtual reality intervention for fear of movement for Veterans with chronic pain: protocol for a feasibility study.

BACKGROUND: A key concern for people with chronic pain is experiencing increased pain and/or re-injury. Consequently, individuals with chronic pain can develop a maladaptive fear of movement that leads to adverse functional consequences. A primary goal of chronic pain rehabilitation is re-engagement in feared movements through exposure. This is often challenging since safe movement can be uncomfortable. Virtual environments provide a promising opportunity to safely and gradually expose Veterans to movements that are avoided in the real world. The current study will utilize multiple virtual reality (VR) applications (APPs) of varying the intensity levels ranging from passive distraction from pain to active exposure to feared movement. The primary aims of this pilot are to examine VR as an adjunctive nonpharmacological intervention to assist with the adoption and implementation of skills to decrease fear of movement and increase overall functioning among Veterans with chronic pain. Second, to build a hierarchy of VR APPs to assist in gradual exposure to feared movements. METHODS: This study will be conducted in the Chronic Pain Rehabilitation Program (CPRP) at the James A. Haley Veterans Hospital, a unique inpatient program within the VA system. Participants will include up to 20 Veterans who receive a VR intervention as part of their physical therapy. A rating form containing qualitative and quantitative experiences will be administered following each VR session to assess feasibility and to provide descriptive information for the proposed hierarchy. Effect sizes will be calculated from intake and discharge measures for the primary outcome fear of movement and secondary pain and functional outcomes. DISCUSSION: This study will inform the feasibility of a randomized controlled trial examining the clinical utility of using VR to reduce fear of movement and increase function among Veterans with chronic pain. VR has the advantage of being easily implemented both within VA healthcare settings as well as in Veterans' own residences, where engagement in ongoing self-management approaches is often most challenging. Presumably, VR that is matched to patient needs, progresses in intensity, immerses Veterans in the applications, and is perceived positively by Veterans, will result in positive functional outcomes.

Association of Admission Functional Status and Assistive Device Provision for Veterans Poststroke: A Retrospective Study.

OBJECTIVES: The aims of the study were (a) to provide knowledge about the provision of assistive devices in practice and (b) to describe the challenges of standardizing device provision. DESIGN: This is a retrospective study using Department of Veteran Affairs National Prosthetic Patient Database and other administrative databases. The cohort included all veterans treated by the Veterans Health Administration for stroke during fiscal years 2007-2008. Descriptive methods were used to analyze data with emphasis on inspecting relationships between device provision and motor and cognitive function using Functional Independence Measure scores. RESULTS: A total of 8374 veterans treated for stroke and receiving at least one assistive device are included. Individuals who received standard or caregiver controlled wheelchairs tended to be older, and those who received ultralight or caregiver controlled wheelchairs had a higher proportion of Hispanics than the overall cohort. Veterans who received any type of wheelchair had lower motor, cognitive, and total functioning scores than the cohort as a whole. Veterans who received canes had the highest functioning. Veteran patients who received patient lifts and beds had lower cognitive scores compared with the overall cohort. CONCLUSIONS: Functional status can provide some objectivity to the largely subjective assistive device provision decision-making process; however, many other factors must be considered simultaneously, complicating efforts to standardize provision.

Assessment of the hepatocytic differentiation ability of human skin-derived ABCB5+ stem cells.

The continuously decreasing willingness for liver donation aggravates treatment of end-stage liver diseases requiring organ transplantation as the only curative strategy. Cell therapy approaches using human hepatocytes or stem cell-derived hepatocyte-like cells may be a therapeutic option out of this dilemma. ABCB5-positive mesenchymal stromal cells from human skin featured promising potential to treat immune-mediated diseases. Since most of chronic liver diseases involve exaggerating immune mechanisms, it was the aim to demonstrate in this study, whether ABCB5+ stem cells may serve as a resource to generate hepatocytic cells for application in liver cell transplantation. Using an established single-step protocol, which had been successfully applied to differentiate mesenchymal stromal cells into the hepatocytic lineage, ABCB5+ skin-derived stem cells did not gain significant characteristics of hepatocytes. Yet, upon culture in hepatocytic differentiation medium, ABCB5+ stem cells secreted immunomodulatory and anti-fibrotic factors as well as proteins, which may prompt hepatic morphogenesis besides others. Hepatic transplantation of ABCB5+ stem cells, which had been prior cultured in hepatocytic differentiation medium, did not cause any obvious deterioration of liver architecture suggesting their safe application. Thus, human ABCB5+ skin-derived stem cells secreted putative hepatotropic factors after culture in hepatocytic differentiation medium.

Mammalian MSC from selected species: Features and applications.

Mesenchymal stromal/stem cells (MSC) are promising candidates for cellular therapy of different diseases in humans and in animals. Following the guidelines of the International Society for Cell Therapy, human MSC may be identified by expression of a specific panel of cell surface markers (CD105+, CD73+, CD90+, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-). In addition, multiple differentiation potential into at least the osteogenic, adipogenic, and chondrogenic lineage is a main criterion for MSC definition. Human MSC and MSC of a variety of mammals isolated from different tissues meet these criteria. In addition to the abovementioned, they express many more cell surface markers. Yet, these are not uniquely expressed by MSC. The gross phenotypic appearance like marker expression and differentiation potential is similar albeit not identical for MSC from different tissues and species. Similarly, MSC may feature different biological characteristics depending on the tissue source and the isolation and culture procedures. Their versatile biological qualities comprising immunomodulatory, anti-inflammatory, and proregenerative capacities rely largely on the migratory and secretory capabilities of MSC. They are attracted to sites of tissue lesion and secrete factors to promote self-repair of the injured tissue. This is a big perspective for clinical MSC applications in both veterinary and human medicine. Phase I/II clinical trials have been initiated to assess safety and feasibility of MSC therapies in acute and chronic disease settings. Yet, since the mode of MSC action in a specific disease environment is still unknown at large, it is mandatory to unravel the response of MSC from a given source onto a specific disease environment in suitable animal models prior to clinical applications. © 2017 International Society for Advancement of Cytometry.

Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6.

The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.

Family Caregiver Training Program (FCTP): A Randomized Controlled Trial.

OBJECTIVE: The purpose of this study was to examine the effectiveness of the Family Caregiver Training Program (FCTP) for caregivers of people with dementia. METHOD: A random assignment control group research design with a 3-mo follow-up was implemented. RESULTS: Thirty-six family caregivers of people with dementia demonstrated an increase in activity of daily living (ADL) knowledge (p < .001) and maintenance of that knowledge 3 mo posttest. Caregiver confidence, regardless of group assignment, improved; however, it was not maintained. Burden, depression, and occupational performance and satisfaction remained unchanged for the intervention group; however, physical health as it pertained to quality of life improved 3 mo posttest (p < .001). CONCLUSION: Findings demonstrate that the FCTP can effectively provide knowledge to family caregivers on how to assist people with dementia with ADLs. Even when standard care was provided, there was limited information on ADLs that family caregivers faced daily.