Public feedback on a proposed statewide virtual translational research community.

INTRODUCTION: Researchers have explored using the internet and social media to recruit participants to specific research projects. Less systematic work has been done to inform the engagement of large populations in virtual communities to advance clinical and translational science. We report on our first step to use social media to engage Minnesota residents by studying the willingness of participants to engage in a virtual (Facebook) community about the concepts of health and health-related research. METHODS: Data were collected at the 2018 Minnesota State Fair using a cross-sectional, 46-item survey with assessment including sociodemographics and willingness to engage in a Facebook group for health-related research. Quantitative analysis included univariate, bivariate, and multivariate analyses. Content analysis was used to generate themes from open-ended survey responses. RESULTS: Five hundred people completed the survey; after data cleaning, 418 participant responses informed this report. A majority were younger than age 50 (73%), female (66%), and married/partnered (54%). Overall, 46% of participants agreed/strongly agreed they are willing to join the Facebook group. Multivariate logistic regression identified social media use over the past 6 months as the sole variable independently associated with willingness to join the Facebook group (once a day vs. never or rarely OR = 1.82 (0.86, 3.88), several hours a day vs. never or rarely OR = 2.17 (1.17, 4.02, overall p-value 0.048). CONCLUSION: Facebook holds potential for reaching a broader community, democratizing access to and engagement with clinical and translational research. Social media infrastructure and content could be disseminated to other institutions with Clinical and Translational Science Awards.

Community Engagement in Academic Health Centers: A Model for Capturing and Advancing Our Successes.

Community engagement (CE) has come to the forefront of academic health centers' (AHCs) work because of two recent trends: the shift from a more traditional 'treatment of disease' model of health care to a population health paradigm (Gourevitch, 2014), and increased calls from funding agencies to include CE in research activities (Bartlett, Barnes, & McIver, 2014). As defined by the Centers for Disease Control and Prevention, community engagement is "the process of working collaboratively with and through groups of people affiliated by geographic proximity, special interest, or similar situations to address issues affecting the well-being of those people" (Centers for Disease Control and Prevention (CDC), 1997, p. 9). AHCs are increasingly called on to communicate details of their CE efforts to key stakeholders and to demonstrate their effectiveness. The population health paradigm values preventive care and widens the traditional purview of medicine to include social determinants of patients' health (Gourevitch, 2014). Thus, it has become increasingly important to join with communities in population health improvement efforts that address behavioral, social, and environmental determinants of health (Michener, et al., 2012; Aguilar-Gaxiola, et al., 2014; Blumenthal & Mayer, 1996). This CE can occur within multiple contexts in AHCs (Ahmed & Palermo, 2010; Kastor, 2011) including in education, clinical activities, research, health policy, and community service.

Patient vs. Community Engagement: Emerging Issues.

BACKGROUND: The value proposition of including patients at each step of the research process is that patient perspectives and preferences can have a positive impact on both the science and the outcomes of comparative effectiveness research. How to accomplish engagement and the extent to which approaches to community engagement inform strategies for effective patient engagement need to be examined to address conducting and accelerating comparative effectiveness research. OBJECTIVES: To examine how various perspectives and diverse training lead investigators and patients to conflicting positions on how best to advance patient engagement. RESEARCH DESIGN: Qualitative methods were used to collect perspectives and models of engagement from a diverse group of patients, researchers and clinicians. The project culminated with a workshop involving these stakeholders. The workshop used a novel approach, combining World Café and Future Search techniques, to compare and contrast aspects of patient engagement and community engagement. SUBJECTS: Participants included patients, researchers, and clinicians. MEASURES: Group and workshop discussions provided the consensus on topics related to patient and community engagement. RESULTS: Participants developed and refined a framework that compares and contrasts features associated with patient and community engagement. CONCLUSIONS: Although patient and community engagement may share a similar approach to engagement based on trust and mutual benefit, there may be distinctive aspects that require a unique lexicon, strategies, tactics, and activities.

Project Career: An individualized postsecondary approach to promoting independence, functioning, and employment success among students with traumatic brain injuries.

BACKGROUND: Project Career is a five-year interdisciplinary demonstration project funded by NIDILRR. It provides technology-driven supports, merging Cognitive Support Technology (CST) evidence-based practices and rehabilitation counseling, to improve postsecondary and employment outcomes for veteran and civilian undergraduate students with traumatic brain injury (TBI). GOAL: Provide a technology-driven individualized support program to improve career and employment outcomes for students with TBI. OBJECTIVES: Project staff provide assessments of students' needs relative to assistive technology, academic achievement, and career preparation; provide CST training to 150 students; match students with mentors; provide vocational case management; deliver job development and placement assistance; and maintain an electronic portal regarding accommodation and career resources. METHODS: Participating students receive cognitive support technology training, academic enrichment, and career preparatory assistance from trained professionals at three implementation sites. Staff address cognitive challenges using the 'Matching Person with Technology' assessment to accommodate CST use (iPad and selected applications (apps)). JBS International (JBS) provides the project's evaluation. RESULTS: To date, 117 students participate with 63% report improved life quality and 75% report improved academic performance. CONCLUSION: Project Career provides a national model based on best practices for enabling postsecondary students with TBI to attain academic, employment, and career goals.

Qualitative case studies of professional-level workers with traumatic brain injuries: A contextual approach to job accommodation and retention.

BACKGROUND: Traumatic brain injury (TBI) is a multi-systemic disability that causes a wide range of difficulties with personal and social functioning. METHODS: Four individuals with TBI participated in an evaluation of barriers to their continued employment following graduation from college. A trained interviewer completed the Work Experience Survey (WES) in teleconsultation sessions with each participant. RESULTS: Researchers applied a qualitative case study research design. Participants reported a wide range of difficulties in performing essential functions of their jobs (3 to 24) that have the potential to significantly affect their productivity. Career mastery problems reflected outcomes associated with TBI such as 'believing that others think I do a good job' and 'having the resources (e.g., knowledge, tools, supplies, and equipment) needed to do the job.' Indicative of their wish to continue their current employment, participants reported high levels of job satisfaction. CONCLUSIONS: The WES is a cost-effective needs assessment tool to aid health and rehabilitation professionals in providing on-the-job supports to workers with TBI.

Sweet Is the Memory of Past Troubles: NK Cells Remember.

Natural killer (NK) cells are important in host defense against tumors and microbial pathogens. Recent studies indicate that NK cells share many features with the adaptive immune system, and like B cells and T cells, NK cells can acquire immunological memory. Here, we review evidence for NK cell memory and the molecules involved in the generation and maintenance of these self-renewing NK cells that provide enhanced protection of the host.

Project Career: A qualitative examination of five college students with traumatic brain injuries.

BACKGROUND: Project Career is an interprofessional five-year development project designed to improve the employment success of undergraduate college and university students with traumatic brain injury (TBI). The case study information was collected and synthesized by the project's Technology and Employment Coordinators (TECs) at each of the project's three university sites. The project's evaluation is occurring independently through JBS International, Inc. OBJECTIVE: Five case studies are presented to provide an understanding of student participants' experiences within Project Career. Each case study includes background on the student, engagement with technology, vocational supports, and interactions with his/her respective TEC. METHODS: A qualitative analysis from the student's case notes is provided within each case study, along with a discussion of the overall qualitative analysis. RESULTS: Across all five students, the theme Positive Outcomes was mentioned most often in the case notes. Of all the different type of challenges, Cognitive Challenges were most often mentioned during meetings with the TECs, followed by Psychological Challenges, Physical Challenges, Other Challenges, and Academic Challenges, respectively. CONCLUSION: Project Career is providing academic enrichment and career enhancement that may substantially improve the unsatisfactory employment outcomes that presently await students with TBI following graduation.

Activities and interim outcomes of a multi-site development project to promote cognitive support technology use and employment success among postsecondary students with traumatic brain injuries.

BACKGROUND: This article describes the activities and interim outcomes of a multi-site development project called Project Career, designed to promote cognitive support technology (CST) use and employment success for college and university students with traumatic brain injuries (TBIs). OBJECTIVES: To obtain early intervention results from participants in Project Career's first 18 months of operation. METHODS: Fifty-six students with TBI have participated to date across three implementation sites in Massachusetts, Ohio, and West Virginia, with 25 of these participants being military veterans. Descriptive analyses provide information regarding the participants, the barriers they face due to their TBI in obtaining a post-secondary education, and the impact services provided by Project Career have had to date in ameliorating those difficulties. Inferential statistical analyses provide preliminary results regarding program effectiveness. RESULTS: Preliminary results indicate the program is encouraging students to use CST strategies in the form of iPads and cognitive enhancement applications (also known as 'apps'). Significant results indicate participants are more positive, independent, and social; participants have a more positive attitude toward technology after six months in the program; and participants reported significantly improved experiences with technology during their first six months in the program. CONCLUSION: Participating students are actively preparing for their careers after graduation through a wide range of intensive vocational supports provided by project staff members.

Cutting edge: NKG2C(hi)CD57+ NK cells respond specifically to acute infection with cytomegalovirus and not Epstein-Barr virus.

CMV induces the expansion of a unique subset of human NK cells expressing high levels of the activating CD94-NKG2C receptor that persist after control of the infection. We investigated whether this subset is CMV specific or is also responsive to acute infection with EBV. We describe a longitudinal study of CMV(-) and CMV(+) students who were acutely infected with EBV. The NKG2C(hi) NK subset was not expanded by EBV infection. However, EBV infection caused a decrease in the absolute number of immature CD56(bright)CD16(-) NK cells in the blood and, in CMV(+) individuals, induced an increased frequency of mature CD56(dim)NKG2A(+)CD57(+) NK cells in the blood that persisted into latency. These results provide further evidence that NKG2C(+) NK cells are CMV specific and suggest that EBV infection alters the repertoire of NK cells in the blood.

Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci.

Recent thymic emigrants (RTEs) are the youngest T cells in the lymphoid periphery and exhibit phenotypic and functional characteristics distinct from those of their more mature counterparts in the naive peripheral T cell pool. We show in this study that the Il2 and Il4 promoter regions of naive CD4(+) RTEs are characterized by site-specific hypermethylation compared with those of both mature naive (MN) T cells and the thymocyte precursors of RTEs. Thus, RTEs do not merely occupy a midpoint between the thymus and the mature T cell pool, but represent a distinct transitional T cell population. Furthermore, RTEs and MN T cells exhibit distinct CpG DNA methylation patterns both before and after activation. Compared with MN T cells, RTEs express higher levels of several enzymes that modify DNA methylation, and inhibiting methylation during culture allows RTEs to reach MN T cell levels of cytokine production. Collectively, these data suggest that the functional differences that distinguish RTEs from MN T cells are influenced by epigenetic mechanisms and provide clues to a mechanistic basis for postthymic maturation.

Natural killer cells: walking three paths down memory lane.

Immunological memory has traditionally been regarded as a unique feature of the adaptive immune response, mediated in an antigen-specific manner by T and B lymphocytes. All other hematopoietic cells, including natural killer (NK) cells, are classified as innate immune cells, which have been considered short-lived but can respond rapidly against pathogens in a manner not thought to be driven by antigen. Interestingly, NK cells have recently been shown to survive long term after antigen exposure and subsequently mediate antigen-specific recall responses. In this review, we address the similarities between, and the controversies surrounding, three major viewpoints of NK memory that have arisen from these recent studies: (i) mouse cytomegalovirus (MCMV)-induced memory; (ii) cytokine-induced memory; and (iii) liver-restricted memory cells.

Molecular definition of the identity and activation of natural killer cells.

Using whole-genome microarray data sets of the Immunological Genome Project, we demonstrate a closer transcriptional relationship between NK cells and T cells than between any other leukocytes, distinguished by their shared expression of genes encoding molecules with similar signaling functions. Whereas resting NK cells are known to share expression of a few genes with cytotoxic CD8(+) T cells, our transcriptome-wide analysis demonstrates that the commonalities extend to hundreds of genes, many encoding molecules with unknown functions. Resting NK cells demonstrate a 'preprimed' state compared with naive T cells, which allows NK cells to respond more rapidly to viral infection. Collectively, our data provide a global context for known and previously unknown molecular aspects of NK cell identity and function by delineating the genome-wide repertoire of gene expression of NK cells in various states.

Post-thymic maturation: young T cells assert their individuality.

T cell maturation was once thought to occur entirely within the thymus. Now, evidence is mounting that the youngest peripheral T cells in both mice and humans comprise a distinct population from their more mature, yet still naive, counterparts. These cells, termed recent thymic emigrants (RTEs), undergo a process of post-thymic maturation that can be monitored at the levels of cell phenotype and immune function. Understanding this final maturation step in the process of generating useful and safe T cells is of clinical relevance, given that RTEs are over-represented in neonates and in adults recovering from lymphopenia. Post-thymic maturation may function to ensure T cell fitness and self tolerance.

Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage.

After intrathymic development, T cells exit the thymus and join the peripheral T-cell pool. Such recent thymic emigrants (RTEs) undergo both phenotypic and functional maturation during the first 3 weeks they reside in the periphery. Using a well-controlled in vitro polarization scheme, we now show that CD4(+) RTEs are defective in T-helper (Th) type 0 (Th0), Th1, Th17, and regulatory T-cell lineage commitment, with dampened cytokine production and transcription factor expression. In contrast, CD4(+) RTES are biased toward the Th2 lineage both in vitro and in vivo, with more robust interleukin-4, interleukin-5, and interleukin-13 production than their mature naive counterparts. Coculture experiments demonstrate that mature naive T cells influence neighboring RTEs in their Th responses. In adoptive hosts, CD4(+) RTEs drive production of the Th2-associated antibody isotype immunoglobulin G1 and mediate airway inflammatory disease. This bias in RTEs likely results from dampened negative regulation of the Th2 lineage by diminished levels of T-bet, a key Th1 transcription factor. CD4(+) RTEs thus represent a transitional population with a distinct interpretation of, and response to, immunologic cues. These characteristics may be beneficial during the postthymic maturation period by leading to the avoidance of inappropriate immune responses, particularly in lymphopenic neonates and adults.

Uneven colonization of the lymphoid periphery by T cells that undergo early TCR{alpha} rearrangements.

A sparse population of thymocytes undergoes TCRalpha gene rearrangement early in development, before the double-positive stage. The potential of these cells to contribute to the peripheral T cell pool is unknown. To examine the peripheral T cell compartment expressing a repertoire biased to early TCR gene rearrangements, we developed a mouse model in which TCRalpha rearrangements are restricted to the double-negative stage of thymocyte development. These mice carry floxed RAG2 alleles and a Cre transgene driven by the CD4 promoter. As expected, conventional T cell development is compromised in such Cre(+) RAG2(fl/fl) mice, and the TCRalphabeta(+) T cells that develop are limited in their TCRalpha repertoire, preferentially using early rearranging Valpha genes. In the gut, the Thy-1(+)TCRalphabeta(+) intraepithelial lymphocyte (IEL) compartment is surprisingly intact, whereas the Thy-1(-)TCRalphabeta(+) subset is almost completely absent. Thus, T cells expressing a TCRalpha repertoire that is the product of early gene rearrangements can preferentially populate distinct IEL compartments. Despite this capacity, Cre(+) RAG2(fl/fl) T cell progenitors cannot compete with wild-type T cell progenitors in mixed bone marrow chimeras, suggesting that in normal mice, there is only a small contribution to the peripheral T cell pool by cells that have undergone early TCRalpha rearrangements. In the absence of wild-type competitors, aggressive homeostatic proliferation in the IEL compartment can promote a relatively normal Thy-1(+) TCRalphabeta(+) T cell pool from the limited population derived from Cre(+) RAG2(fl/fl) progenitors.

Postthymic maturation influences the CD8 T cell response to antigen.

Complete T cell development requires postthymic maturation, and we investigated the influence of this ontological period on the CD8 T cell response to infection by comparing responses of mature CD8 T cells with those of recent thymic emigrants (RTEs). When activated with a noninflammatory stimulus or a bacterial or viral pathogen, CD8 RTEs generated a lower proportion of cytokine-producing effector cells and long-lived memory precursors compared with their mature counterparts. Although peripheral T cell maturation is complete within several weeks after thymic egress, RTE-derived memory cells continued to express inappropriate levels of memory cell markers and display an altered pattern of cytokine production, even 8 weeks after infection. When rechallenged, RTE-derived memory cells generated secondary effector cells that were phenotypically and functionally equivalent to those generated by their mature counterparts. The defects at the effector and memory stages were not associated with differences in the expression of T cell receptor-, costimulation-, or activation-associated cell surface markers yet were associated with lower Ly6C expression levels at the effector stage. This work demonstrates that the stage of postthymic maturation influences cell fate decisions and cytokine profiles of stimulated CD8 T cells, with repercussions that are apparent long after cells have progressed from the RTE compartment.

Cost of workplace accommodations for individuals with disabilities: with or without personal assistance services.

BACKGROUND: This study compared the expense associated with use of personal assistance services (PAS) for individuals with disabilities to the expense incurred by individuals with disabilities who did not use PAS. The intent of this investigation was to assess the disability accommodation costs and benefits of PAS and non-PAS cases. METHODS: The study uses 1,182 follow-up telephone surveys and 24 telephone interviews of employers who had previously contacted the Job Accommodation Network (JAN) to discuss disability-related accommodations for an employee or potential employee that were conducted from January 2004 through December 2006. The survey included 69 employers who had considered PAS. The surveys were conducted by the University of Iowa's Law, Health Policy, and Disability Center, which contacted employers who had previously contacted JAN for consultation on workplace accommodations. The interviews were conducted by the International Center for Disability Information at West Virginia University. RESULTS: Key findings point to the costs associated with PAS cases and with cases not involving PAS accommodations. As reported by the employers, the median "one-time cost" of accommodations (not $0) for non-PAS cases was $500. The median "one-time cost" of accommodations (not $0) for PAS cases was $1,850. When $0 cost of accommodations on PAS cases was factored in with "one-time cost" of accommodations for PAS cases, the median cost was $0. For non-PAS cases of accommodations, when $0 cost of accommodations was considered, the outcome was a median cost of $0. The annual cost for PAS accommodations was a median cost of $8,000 in comparison to $2,000 for non-PAS. The median dollar amount estimates of direct benefits were $1,600 for PAS accommodations, similar to $1,500 for non-PAS. The most frequently mentioned benefits from PAS accommodations were (a) increased productivity, (b) increased diversity, (c) retention of a valued employee, (d) improved interactions with co-workers, (e) increased overall company morale, and (f) increased overall company productivity. CONCLUSIONS: The findings heighten awareness of the cost and benefits aspects associated with PAS for people with disabilities. Many non-PAS accommodations cost nothing to the employer (e.g., changing the work schedule, moving the individual to another location). When dollar cost was involved, the costs for PAS accommodations were more than three times greater than non-PAS accommodations.

Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1.

We developed an in vitro method for isolating and expanding autologous CD4+ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1. We infused these cells into a patient with refractory metastatic melanoma who had not undergone any previous conditioning or cytokine treatment. We show that the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.

BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas-mediated cell death.

Microorganisms with pathogen-associated molecular patterns (PAMP) activate B cells directly by binding to TLR and also indirectly by inducing APC to release cytokines such as BAFF that promote B cell survival. We found that murine B cells activated concomitantly with LPS (TLR-4 ligand) and BAFF are protected from spontaneous apoptosis, but are more susceptible to Fas/CD95-mediated cell death. This increased susceptibility to Fas-induced apoptosis is associated with a dramatic coordinated up-regulation of Fas/CD95 and IRF-4 expression through a mechanism mediated, at least in part, by inhibition of the MEK/ERK pathway. Up-regulation of Fas/CD95 by BAFF is restricted to B cells activated through TLR-4, but not through TLR-9, BCR or CD40. TLR ligands differ in the BAFF family receptors (R) they induce on B cells: BAFF-R is increased by the TLR4 ligand, LPS, but not by the TLR9 ligand, CpG-containing oligodeoxynucleotides, which, in contrast, strongly up-regulates transmembrane activator and CAML interactor (TACI). This suggests the up-regulation of Fas by BAFF is mediated by BAFF-R and not by TACI. Consistently, APRIL, which binds to TACI and B cell maturation antigen but not BAFF-R, did not enhance Fas expression on LPS-activated B cells. Increased susceptibility to Fas-mediated killing of B cells activated with LPS and BAFF may be a fail-safe mechanism to avoid overexpansion of nonspecific or autoreactive B cells.