Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart.

B-cell lymphoma 2-associated athanogene-3 (Bag3) is expressed in all animal species, with Bag3 levels being most prominent in the heart, the skeletal muscle, the central nervous system, and in many cancers. Preclinical studies of Bag3 biology have focused on animals that have developed compromised cardiac function; however, the present studies were performed to identify the pathways perturbed in the heart even before the occurrence of clinical signs of dilatation and failure of the heart. These studies show that hearts carrying variants that knockout one allele of BAG3 have significant alterations in multiple cellular pathways including apoptosis, autophagy, mitochondrial homeostasis, and the inflammasome.

A Pilot Study of a Tablet-Based Emotion Regulation Intervention for Early Adolescents.

OBJECTIVE: This study examined the feasibility, acceptability, and preliminary outcomes of internet-based Talking About Risk and Adolescent Choices (iTRAC), a tablet intervention designed to promote emotion regulation (ER) skills among middle schoolers as a strategy for reducing risk behaviors. METHODS: Adolescents (12-14 years) were recruited from 3 urban US schools for advisory groups (n = 15), acceptability testing (n = 11), and pilot testing (n = 85). Youth advisory boards and expert panels tailored content, resulting in an animated intervention of instructional videos, games, and activities designed to teach ER strategies to young adolescents. Eighty-five adolescents were randomized to the 4-module digital iTRAC intervention or a wait-list control group. Adolescents and 1 parent completed baseline and 3-month follow-up questionnaires examining ER attitudes and behaviors; adolescents also completed behavioral tasks related to distress tolerance. RESULTS: Among those randomized to iTRAC, 88% completed all modules. Moderate effect sizes ( d ≥ 0.36) were found from baseline to follow-up on adolescents' beliefs in the controllability of emotions, awareness of emotions, self-efficacy for managing emotions, perceived access to ER strategies, and use of ER strategies. Parent measures of adolescent regulation showed mixed results. CONCLUSION: A digital intervention to enhance ER skills for youth in early adolescence was feasible and demonstrated promising indicators of impact on emotional competence. Increasing adolescents' awareness of and access to ER strategies could reduce decisions driven by transient emotions, which in turn may reduce engagement in risk behaviors and resultant negative health outcomes. This brief tablet-based intervention has the potential to be self-administered and used to increase emotional competency.

Training the next generation of behavioral medicine scientists to accelerate digital health.

We trace the evolution of digital health industry careers for behavioral medicine specialists. We discuss the current misalignment of career opportunities in the private sector with the predominant graduate education training model that emphasizes the pursuit of academic positions. We describe the potential risks to the profession and public health if the field does not adapt professional training models to be inclusive of private sector industry roles. Finally, we offer a series of recommendations aimed at trainees, faculty advisors, and training programs to better prepare trainees for meaningful careers in industry.

This commentary focuses on the career paths available for behavioral medicine scientists in the private sector digital health industry. Although this field has exciting and impactful career options, graduate training models have been slow to adapt to prepare graduates for these opportunities. We describe many actionable steps that trainees, advisors, and graduate programs can take to help training programs to evolve to prepare graduate for more diverse career paths.

Translational Potential of High-Resistance Inspiratory Muscle Strength Training.

Age-associated cardiovascular (CV) dysfunction increases the risk for CV diseases. Aerobic exercise training can improve CV function, but only a minority of adults meet aerobic exercise guidelines. High-resistance inspiratory muscle strength training is a time-efficient lifestyle intervention that may promote adherence and improve CV function. However, further investigation is needed to translate inspiratory muscle strength training into the public health domain.

Large-scale evaluation of a computer-based learning program to increase prison staff knowledge on geriatric and end-of-life care.

PURPOSE: The purpose of this study is to continue research and development of the ECAD-P learning system with an emphasis on developing a scalable unit for testing in a larger number of more diverse correctional settings. There are almost 2.3 million US persons incarcerated. Geriatric and end-of-life (EOL) care in corrections is not as equitable as care in the free world. Technological delivery of geriatric training to staff through computer-based learning (CBL) offers a novel approach to improve care and reduce disparities among those who are most vulnerable during confinement. DESIGN/METHODOLOGY/APPROACH: This mixed methods study built an interactive CBL for multidisciplinary staff to address EOL and geriatric issues in prisons. The CBL was iteratively built and tested prior to launching a full-scale evaluation using a pre/post-intervention design. FINDINGS: Evaluation of the CBL occurred at 7 sites (i.e. 6 state prisons and 1 prison health-care vendor). A total of 241 staff were recruited with 173 completing post-tests. Outcomes were knowledge acquisition regarding care for aging and dying incarcerated persons (i.e. cognitive measure) and attitudes, motivations and values for providing care (i.e. affective measure). Cognitive and affective post-tests were significantly better than at pre-test (all ps < 0.01). ANCOVAs revealed no significant differences for sex or ethnicity. ORIGINALITY/VALUE: Outcomes reveal that the CBL is acceptable, feasible and usable in corrections. Staff improved their knowledge after receiving the training. Correctional settings face increasing pressures to better address the health care and management needs of aged, chronically ill and dying incarcerated persons. This e-learning holds promise to contribute to better preparation of corrections staff to effectively care for these populations.

Vacteens.org: A Mobile Web app to Improve HPV Vaccine Uptake.

U.S. HPV vaccine uptake remains below the Healthy People 2030 goal of 80% series completion. Parental concerns and misinformation about the efficacy and safety of the Human Papillomavirus (HPV) vaccine remain, and may be addressed by digital interventions tailored to their concerns. Reported here are results from a small scale randomized trial testing a mobile web app for parents and their adolescent daughters (ages 11-14 years) encouraging HPV vaccination in New Mexico, an ethnically-diverse U.S. state. Methods: A clinic-cluster randomized trial where pediatric clinics (n = 9) were recruited and randomized, and parent-adolescent pairs (n = 82) within clinics received either the Vacteens.org/Vacunadolescente.org mobile web app or Usual and Customary (UC) HPV Vaccination information. Parents completed online surveys at baseline and 3-months. Daughters' HPV vaccine data were collected from the New Mexico State Immunization Information System 1 year post baseline. Results: Three month survey results found Vacteens.org/Vacunadolescente.org parents to have higher positive HPV vaccine beliefs, informed decision making, intent to vaccinate and vaccine confidence outcomes than UC parents. HPV vaccine data found higher first dose HPV vaccination (Pearson χ2 = 6.13, p = 0.013, Vacteens.org/Vacunadolescente.org group 59.4%, UC group 40.6%), and higher HPV vaccination series completion (Pearson χ2 = 6.49, p = 0.011, Vacteens.org/Vacunadolescente.org group 68.4%, UC group 31.6%). Conclusions: The small trial results showed the Vacteens.org/Vacunadolescente.org web app prompted positive vaccine-related attitudes and beliefs, and more HPV vaccination initiation and series completion. Mobile web apps can make decision-making tools for HPV vaccination widely available on digital platforms, reducing vaccine hesitancy, and confusion and increase HPV vaccine uptake.

Usability of a Technology-Based Bystander Bullying Intervention for Middle School Students in Rural, Low-Income Communities: Mixed Methods Study.

BACKGROUND: Students who are targets of bullying and who witness bullying are at high risk for negative mental health outcomes. Bystander training is essential to reduce bullying and the negative associated consequences for targets and bystanders. Resources necessary for program delivery, however, pose significant barriers for schools, particularly those in rural, low-income communities. Technology-based programs can reduce health disparities for students in these communities through cost-effective, easy-to-disseminate programming. OBJECTIVE: The aim of this study is to conduct usability testing of a bystander bullying web app prototype, STAC-T (technology-based STAC, which stands for the 4 bystander strategies Stealing the Show, Turning it Over, Accompanying Others, and Coaching Compassion) as an initial step in the development of a full-scale STAC-T intervention. Objectives include assessing usability and acceptability of the STAC-T prototype, understanding school needs and barriers to program implementation, and assessing differences in usability between school personnel and students. METHODS: A sample of 16 participants, including school personnel and students recruited from 3 middle schools in rural, low-income communities, completed usability testing followed by a qualitative interview. Descriptive statistics, 2-tailed independent sample t tests, and consensual qualitative research were used to assess usability and program satisfaction and to extract themes related to acceptability, feasibility, needs, barriers, and feedback for intervention development. RESULTS: Usability testing indicated that the app was easy to use, acceptable, and feasible. Both school personnel (mean rating 89.6, SD 5.1) and students (mean rating 91.8, SD 7.0) rated the app well above the standard cutoff score for above-average usability (ie, 68), and both school personnel (mean rating 5.83, SD 0.41) and students (mean rating 6.10, SD 0.57) gave the app high user-friendliness ratings (0-7 scale, with 7 as high user-friendliness). The overall ratings also suggested that school personnel and students were satisfied with the program. Of the 6 school personnel who said they would recommend the program, 1 (17%), 4 (66%), and 1 (17%) rated the program as 3, 4, and 5 stars, respectively; 80% (8/10) of students said they would recommend the program; and 60% (6/10) and 40% (4/10) rated the program as 4 stars and 5 stars, respectively. Qualitative data revealed that school personnel and students found the STAC-T app to be useful, user-friendly, and relevant, while providing feedback related to the importance of digital learning activities that engage the user. Data from school personnel also indicated positive perceptions regarding program feasibility and probability of program adoption, with the most significant barrier being cost, suggesting the importance of considering the financial resources available to schools in rural, low-income communities when setting the price point for the full-scale STAC-T intervention. CONCLUSIONS: This study provides support for the full-scale development of the STAC-T app and provides key information for revision to enhance used engagement. TRIAL REGISTRATION: ClinicalTrials.gov NCT04681495; https://clinicaltrials.gov/ct2/show/NCT04681495.

Inmates Care: Computer-Based Training for Geriatric and End-of-Life Care in Prisons.

The growing aged and dying incarcerated population increases demands on corrections health care. People who are incarcerated can assist in care delivery; however, currently, their training is typically face-to-face, home grown, and variable in content and duration. Six focus groups conducted with peer caregivers (PCs) (n = 12) and staff (n = 15) identified priority training topics. Three prototype modules (Standard Precautions; Loss and Grief; and Role of the Inmate Caregiver in the Final Hours) were developed in consultation with an advisory board. Face-to-face usability testing with (n = 20) PCs and staff confirmed contextual relevance and feasibility of the Inmates Care training. The mean system usability score for all participant segments was 86.5. Inmates Care holds promise to complement nurse-led training with a standardized e-training package.

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.

The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.

Technology-Based Bullying Intervention for Rural Schools: Perspectives on Needs, Challenges, and Design.

Bullying is a significant problem in the United States, with 26.7% of middle school students reporting bullying victimization. The majority of bullying programs are comprehensive, school-wide interventions that require significant resources for implementation, creating barriers and challenges for schools in rural and low-income communities. To increase access for these schools, we propose to translate a brief, bystander bullying intervention (STAC) into a technology-based format. Using consensual qualitative research (CQR), we aimed to understand the needs of school personnel and perceived challenges to program implementation to provide information on how to best serve middle schools in rural and low-income communities. We conducted interviews and focus groups with key school personnel at three middle schools in rural, low-income communities (N = 15). Participants indicated a strong interest in a technology-based bullying intervention and reported positive conditions for implementation including administrative support and technology-readiness. Participants identified program efficacy, flexibility of delivery, and parental involvement as important components of bullying prevention and identified implementation challenges, which included time, financial resources, and teacher buy-in. Perceived strengths of the STAC intervention included providing a clear definition of bullying, skills training and practice, and a certificate of completion. Feedback related to translating the intervention to a technology-based format included the use of virtual interaction and a hybrid virtual/in-person program, particularly for booster-sessions. Findings from this study support the need for the proposed technology-based STAC intervention and provide feedback on both the needs and challenges that need to be addressed for successful implementation in middle schools in rural and low-income communities.

Novel BAG3 Variants in African American Patients With Cardiomyopathy: Reduced ß-Adrenergic Responsiveness in Excitation-Contraction.

BACKGROUND: We reported 3 novel nonsynonymous single nucleotide variants of Bcl2-associated athanogene 3 (BAG3) in African Americans with heart failure (HF) that are associated with a 2-fold increase in cardiac events (HF hospitalization, heart transplantation, or death). METHODS AND RESULTS: We expressed BAG3 variants (P63A, P380S, and A479V) via adenovirus-mediated gene transfer in adult left ventricular myocytes isolated from either wild-type (WT) or cardiac-specific BAG3 haploinsufficient (cBAG3+/-) mice: the latter to simulate the clinical situation in which BAG3 variants are only found on 1 allele. Compared with WT myocytes, cBAG3+/- myocytes expressed approximately 50% of endogenous BAG3 levels and exhibited decreased [Ca2+]i and contraction amplitudes after isoproterenol owing to decreased L-type Ca2+ current. BAG3 repletion with WT BAG3 but not P380S, A479V, or P63A/P380S variants restored contraction amplitudes in cBAG3+/- myocytes to those measured in WT myocytes, suggesting excitation-contraction abnormalities partly account for HF in patients harboring these mutants. Because P63A is near the WW domain (residues 21-55) and A479V is in the BAG domain (residues 420-499), we expressed BAG3 deletion mutants (Δ1-61 and Δ421-575) in WT myocytes and demonstrated that the BAG but not the WW domain was involved in enhancement of excitation-contraction by isoproterenol. CONCLUSIONS: The BAG3 variants contribute to HF in African American patients partly by decreasing myocyte excitation-contraction under stress, and that both the BAG and PXXP domains are involved in mediating ß-adrenergic responsiveness in myocytes.

Barriers to and Strategies for Gaining Entry to Correctional Settings for Health Research.

Conducting research in corrections can contribute to improved individual and public health. Challenges to gaining entry to correctional settings to conduct research can impede research productivity, delay the launch of studies and inhibit researchers from proposing health research in corrections. The purpose of this paper is to share lessons learned from a large-scale corrections research project designed to develop computer-based learning modules to train front-line corrections personnel about geriatric and end-of-life care. Key lessons learned include the importance of building a team of experts, planning and punting, coordinating with institutional review boards and examining denied applications to inform future planning. To be effective in a correctional setting, leaders in nursing research and corrections nursing must work together within the contextual nature of prisons and jails to advance evidence-based practices for this vulnerable population. These lessons serve to establish best practices on how to access correctional settings and to enable more research in corrections.

Developing Computer-Based Learning on Care of Aged and Dying Incarcerated People.

INTRODUCTION: Corrections agencies are exploring ways to securely and cost-effectively increase access to high-quality, evidence-based educational programs for personnel. Technology-based instructional tools hold strong potential for continuing education. The Institute for Healthcare Improvement's Framework for Going to Full Scale was employed to guide a systematic approach. PURPOSE: The purpose of this article is to outline and describe the design and development of a media-rich interactive computer-based learning product, Enhancing Care for Aged and Dying in Prison, which addresses geriatric and end-of-life care issues in corrections. METHOD: Through an iterative process, the research team developed the computer-based educational program that included program and module-specific objectives in alignment with goals and priorities of the end users, detailed evidence-based content that was engaging and visually appealing, and assessments aimed at testing the user's knowledge. RESULTS: The Enhancing Care for Aged and Dying in Prison contains six modules, created under the careful guidance of the research team and the two advisory boards. Contents, including images and testimonials, were selected purposefully and strategically. Module objectives were developed in alignment with the goals and priorities of each module, and assessments tested user knowledge level pre/post module exposure. Completion of the training product advances the research and development necessary to further the goal of full-scale dissemination of the computer-based education. DISCUSSION/CONCLUSIONS: The goal of this program is to enhance care and improve quality of life for aged and dying inmates. Evidence-based training products are critical in preparing not only forensic nurses who work in corrections but also the broader group of correctional personnel in how to better meet the care needs of incarcerated persons.

Impact of Baseline Fatigue on a Physical Activity Intervention to Prevent Mobility Disability.

OBJECTIVES: Our aim was to examine the impacts of baseline fatigue on the effectiveness of a physical activity (PA) intervention to prevent major mobility disability (MMD) and persistent major mobility disability (PMMD) in participants from the Lifestyle Interventions and Independence for Elders (LIFE) study. DESIGN: Prospective cohort of individuals aged 65 years or older undergoing structured PA intervention or health education (HE) for a mean of 2.6 years. SETTING: LIFE was a multicenter eight-site randomized trial that compared the efficacy of a structured PA intervention with an HE program in reducing the incidence of MMD. PARTICIPANTS: Study participants (N = 1591) at baseline were 78.9 ± 5.2 years of age, with low PA and at risk for mobility impairment. MEASUREMENTS: Self-reported fatigue was assessed using the modified trait version of the Exercise-Induced Feelings Inventory, a six-question scale rating energy levels in the past week. Responses ranged from 0 (none of the time) to 5 (all of the time). Total score was calculated by averaging across questions; baseline fatigue was based on the median split: 2 or higher = more fatigue (N = 856) and lower than 2 = less fatigue (N = 735). Participants performed a usual-paced 400-m walk every 6 months. We defined incident MMD as the inability to walk 400-m at follow-up visits; PMMD was defined as two consecutive walk failures. Cox proportional hazard models quantified the risk of MMD and PMMD in PA vs HE stratified by baseline fatigue adjusted for covariates. RESULTS: Among those with higher baseline fatigue, PA participants had a 29% and 40% lower risk of MMD and PMMD, respectively, over the trial compared with HE (hazard ratio [HR] for MMD = .71; 95% confidence interval [CI] = .57-.90; P = .004) and PMMD (HR = .60; 95% CI = .44-.82; P = .001). For those with lower baseline fatigue, no group differences in MMD (P = .36) or PMMD (P = .82) were found. Results of baseline fatigue by intervention interaction was MMD (P = .18) and PMMD (P = .05). CONCLUSION: A long-term moderate intensity PA intervention was particularly effective at preserving mobility in older adults with higher levels of baseline fatigue. J Am Geriatr Soc 68:619-624, 2020.

Development of a mobile phone app to maintain physical activity in African American men: MobileMen.

BACKGROUND: African American men experience health disparities across a number of chronic diseases. mHealth technology is widely utilized to address lifestyle factors that contribute to these conditions. Participation of African American men in qualitative and quantitative studies of mHealth is low. Therefore, little is known regarding the acceptability of mHealth interventions and few interventions have been specifically developed for this population. The purpose of the current study is to describe the development of a smartphone application, MobileMen, to promote the maintenance of physical activity (PA) in African American men and to report on app feasibility when applied to the target population. METHODS: We used a mixed methods study design including formative research, user-centered design, and a feasibility study. Focus groups (n=26) were conducted to inform the acceptability of the app and desired features. Lab usability (n=19) was used to develop the app through an iterative process. A feasibility study was conducted to assess utilization of the app over a 1-month timeframe. Measures of usability and user-friendliness were collected during lab usability sessions. Satisfaction and app usage were collected following the feasibility study. RESULTS: The focus groups revealed that African American men use smartphone apps and that they are willing to utilize an app to maintain PA habits. The MobileMen app was subsequently developed and contained a dashboard, rewards, a learning component, a prompting system, and activity tracking. Scores increased between the first and last lab sessions for usability [5.0 (0.0) vs. 4.3 (1.0)] and user-friendliness [74.2 (17.0) vs. 70.6 (12.4)]. Participants reported acceptable satisfaction (mean values >3.5 on a 1-5 Likert scale) with most app components. CONCLUSIONS: African American men are willing to utilize mHealth to improve their health behavior, including PA. An initial version of the MobileMen app has been developed that is acceptable and user-friendly. However, there are several components requested by African American men could not be included in the current app but warrant future app development.

Role of Bcl2-associated Athanogene 3 in Turnover of Gap Junction Protein, Connexin 43, in Neonatal Cardiomyocytes.

Any pathological stress that impairs expression, turnover and phosphorylation of connexin 43 (Cx43), one of the major proteins of gap junctions, can adversely impact myocardial cell behavior, thus leading to the development of cardiac arrhythmias and heart failure. Our results in primary neonatal rat ventricular cardiomyocytes (NRVCs) show that impairment of the autophagy-lysosome pathway dysregulates degradation of Cx43, either by inhibiting lysosomal activity or suppressing the level of Bcl2-associated athanogene 3 (BAG3), a stress-induced pleiotropic protein that is involved in protein quality control (PQC) via the autophagy pathway. Inhibition of lysosomal activity leads to the accumulation of Cx43 aggregates and suppression of BAG3 significantly diminished turnover of Cx43. In addition, knock-down of BAG3 reduced the levels of Cx43 by dysregulating Cx43 protein stability. Under stress conditions, expression of BAG3 affected the state of Cx43 phosphorylation and its degradation. Furthermore, we found that BAG3 co-localized with the cytoskeleton protein, α-Tubulin, and depolymerization of α-Tubulin led to the intracellular accumulation of Cx43. These observations ascribe a novel function for BAG3 that involves control of Cx43 turnover under normal and stress conditions and potentially for optimizing communication of cardiac muscle cells through gap junctions.

Prior ß-blocker treatment decreases leukocyte responsiveness to injury.

Following injury, leukocytes are released from hematopoietic organs and migrate to the site of damage to regulate tissue inflammation and repair, however leukocytes lacking ß2-adrenergic receptor (ß2AR) expression have marked impairments in these processes. ß-blockade is a common strategy for the treatment of many cardiovascular etiologies, therefore the objective of our study was to assess the impact of prior ß-blocker treatment on baseline leukocyte parameters and their responsiveness to acute injury. In a temporal and ßAR isoform-dependent manner, chronic ß-blocker infusion increased splenic vascular cell adhesion molecule-1 (VCAM-1) expression and leukocyte accumulation (monocytes/macrophages, mast cells and neutrophils) and decreased chemokine receptor 2 (CCR2) expression, migration of bone marrow cells (BMC) and peripheral blood leukocytes (PBL), as well as infiltration into the heart following acute cardiac injury. Further, CCR2 expression and migratory responsiveness was significantly reduced in the PBL of patients receiving ß-blocker therapy compared to ß-blocker-naïve patients. These results highlight the ability of chronic ß-blocker treatment to alter baseline leukocyte characteristics that decrease their responsiveness to acute injury and suggest that prior ß-blockade may act to reduce the severity of innate immune responses.

Developing educational modules to enhance care of aged and dying inmates: Set-up phase.

The purpose of this article is to explain the strategies used in the "Set-up" phase of developing computer-based education on the care and management of incarcerated people who are older and/or dying. Public health nurses have an opportunity to support efforts in educating corrections staff to enhance health care for older and dying inmates. Such endeavors can promote social justice through inmates receiving evidence-based care that parallels that received by the community at large. "Set-up" is the first of four phases in the Institute for Healthcare Improvement's Framework for Going to Full Scale. Our design approach was threefold and included an environmental scan, a modified Delphi survey, and a usability study. An expert advisory board was consulted throughout the Set-up Phase. Participants for the Delphi Survey had expertise in geriatrics and corrections health care. Usability testing was conducted at two State Correctional Institutions. The Delphi Survey consisted of three Qualtrics surveys. Usability testing examined navigability; detected problems; observed time spent solving problems; identified problem severity; and developed recovery strategies. The Set-up established proof of concept, three prototype modules, and a specifications document to guide future programming. In addition, a Technology Niche Analyses® provided a preliminary commercialization plan (NIH, 2017). The Set-up phase has been instrumental in exposing the available infrastructure for dissemination of an educational product within corrections and may be a first step in addressing public health concerns on issues in aging. Commercial feasibility of the program and the need for continued research for Developing the Scalable Unit were established.