Multisystem afflictions in former National Football League players.

BACKGROUND: The long-term health consequences of participation in American style football (ASF) are not well understood. METHODS: We conducted a retrospective cohort study of men who had played in the NFL after 1960. Participants were studied using a standardized self-administered questionnaire designed to determine both the exposure history to ASF and the prevalence of chronic pain, sleep apnea, cardiometabolic disease, and neurocognitive impairment. Logistic regression and negative binomial regression models were used to assess associations between age, ethnicity, body-mass index during professional football career, field position, and football career duration with individual and multiple afflictions. RESULTS: In this cohort of former NFL players (n = 3745), approximately one quarter of the eligible former players (27%) reported two or more medical afflictions (chronic pain, cardiometabolic disease, sleep apnea, or neurocognitive impairment). Career duration was significantly associated with an increase in the number of comorbidities. Age, race, and body-mass index were associated with all affliction categories, other than neurocognitive impairment, which was similarly prevalent in middle-aged players and older players. Earlier age when first playing the sport was protective against cardiometabolic affliction. CONCLUSIONS: Former NFL players report significant combinations of cross-system afflictions. Future work will be required to determine mechanistic underpinnings. However, attention to the whole player, rather than specific organ systems seems critical to improve long-term health outcomes in former ASF professional athletes.

The Football Players' Health Study at Harvard University: Design and objectives.

The Football Players Health Study at Harvard University (FPHS) is a unique transdisciplinary, strategic initiative addressing the challenges of former players' health after having participated in American style football (ASF). The whole player focused FPHS is designed to deepen understanding of the benefits and risks of participation in ASF, identify risks that are potentially reversible or preventable, and develop interventions or approaches to improve the health and wellbeing of former players. We are recruiting and following a cohort of former professional ASF players who played since 1960 (current n = 3785). At baseline, participants complete a self-administered standardized questionnaire, including initial reporting of exposure history and physician-diagnosed health conditions. Additional arms of the initiative are addressing targeted studies, including promising primary, secondary, and tertiary interventions; extensive in-person clinical phenotyping, and legal and ethical concerns of the play. This paper describes the components of the FPHS studies undertaken and completed thus far, as well as those studies currently underway or planned for the near future. We present our initiatives herein as a potential paradigm of one way to proceed (acknowledging that it is not the only way). We share what we have learned so that it may be useful to others, particularly in regard to trying to make professional sports meet the needs of multiple stakeholders ranging from players to owners, to fans, and possibly even to parents making decisions for their children.

IL-21 can supplement suboptimal Lck-independent MAPK activation in a STAT-3-dependent manner in human CD8(+) T cells.

Although both MHC class II/CD8α double-knockout and CD8ß null mice show a defect in the development of MHC class I-restricted CD8(+) T cells in the thymus, they possess low numbers of high-avidity peripheral CTL with limited clonality and are able to contain acute and chronic infections. These in vivo data suggest that the CD8 coreceptor is not absolutely necessary for the generation of Ag-specific CTL. Lack of CD8 association causes partial TCR signaling because of the absence of CD8/Lck recruitment to the proximity of the MHC/TCR complex, resulting in suboptimal MAPK activation. Therefore, there should exist a signaling mechanism that can supplement partial TCR activation caused by the lack of CD8 association. In this human study, we have shown that CD8-independent stimulation of Ag-specific CTL previously primed in the presence of CD8 coligation, either in vivo or in vitro, induced severely impaired in vitro proliferation. When naive CD8(+) T cells were primed in the absence of CD8 binding and subsequently restimulated in the presence of CD8 coligation, the proliferation of Ag-specific CTL was also severely hampered. However, when CD8-independent T cell priming and restimulation were supplemented with IL-21, Ag-specific CD8(+) CTL expanded in two of six individuals tested. We found that IL-21 rescued partial MAPK activation in a STAT3- but not STAT1-dependent manner. These results suggest that CD8 coligation is critical for the expansion of postthymic peripheral Ag-specific CTL in humans. However, STAT3-mediated IL-21 signaling can supplement partial TCR signaling caused by the lack of CD8 association.

Individual and cumulative health afflictions are associated with greater impairment in physical and mental function in former professional American style football players.

BACKGROUND: Former American style football players (ASF players) have recognized health concerns associated with prior sport participation. It remains unknown whether categorizations of current health conditions, referred to in this report as afflictions (conceptually framed as neurocognitive, cardiovascular, cardiometabolic, sleep apnea, and chronic pain) are associated with physical and mental function. OBJECTIVE: To evaluate the association of afflictions to physical and mental function. It was hypothesized that former National Football League players with any affliction would have worse function compared to unafflicted participants. It was anticipated that multiple afflictions would result in cumulative loss of function. DESIGN: Cross-sectional retrospective design. SETTING: Academic medical multisite hospital system. PARTICIPANTS: A total of 3913 of 15,611 former ASF players who played professionally from 1960 to 2019 (response rate 25%). Assessment of Risk Factors Self-report survey. MAIN OUTCOME MEASURES: Each participant completed the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale and Physical Function questionnaires. Responses were used to generate two physical function and one mental function subscale scores. Raw scores were converted to T-scores categorized as impaired (T-score < 40) or unimpaired (T-score ≥ 40). Primary analyses measured the association of affliction to function (impaired or unimpaired). RESULTS: After adjusting for confounders (age, race, position, number of seasons, age of first exposure to football, alcohol use, smoking history, and current body mass index), each affliction was associated with reduced physical function on the Global physical function subscale (risk ratio [RR] = 1.23-2.45, all P < .005), physical function scale (RR = 1.24-2.75, all P < .01), and mental function scale (RR = 1.34-2.87, all P < .001), except that cardiovascular affliction was not associated with mental function (RR = 1.15, P = .15). The lowest functional measures were observed in those afflicted by chronic pain. Cumulative afflictions were associated with worse function. CONCLUSIONS: Afflictions are associated with cumulative reduction of function. Research evaluating how afflictions interact may help elucidate mechanisms for illness and develop interventions to optimize function.

A panel of human cell-based artificial APC enables the expansion of long-lived antigen-specific CD4+ T cells restricted by prevalent HLA-DR alleles.

Many preclinical experiments have attested to the critical role of CD4(+) T cell help in CD8(+) cytotoxic T lymphocyte (CTL)-mediated immunity. Recent clinical trials have demonstrated that reinfusion of CD4(+) T cells can induce responses in infectious diseases and cancer. However, few standardized and versatile systems exist to expand antigen-specific CD4(+) T(h) for clinical use. K562 is a human erythroleukemic cell line, which lacks expression of HLA class I and class II, invariant chain and HLA-DM but expresses adhesion molecules such as intercellular adhesion molecule-1 and leukocyte function-associated antigen-3. With this unique immunologic phenotype, K562 has been tested in clinical trials of cancer immunotherapy. Previously, we created a K562-based artificial antigen-presenting cell (aAPC) that generates ex vivo long-lived HLA-A2-restricted CD8(+) CTL with a central/effector memory phenotype armed with potent effector function. We successfully generated a clinical version of this aAPC and conducted a clinical trial where large numbers of anti-tumor CTL are reinfused to cancer patients. In this article, we shifted focus to CD4(+) T cells and developed a panel of novel K562-derived aAPC, where each expresses a different single HLA-DR allele, invariant chain, HLA-DM, CD80, CD83 and CD64; takes up soluble protein by endocytosis and processes and presents CD4(+) T-cell peptides. Using this aAPC, we were able to determine novel DR-restricted CD4(+) T-cell epitopes and expand long-lived CD4(+) T-cells specific for multiple antigens without growing bystander Foxp3(+) regulatory T cells. Our results suggest that K562-based aAPC may serve as a translatable platform to generate both antigen-specific CD8(+) CTL and CD4(+) T(h).

Development of a COVID-19 Application Ontology for the ACT Network.

Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that that are critical to COVID-19 research. The ontology contains over 50,000 concepts in the domains of diagnosis, procedures, medications, and laboratory tests. In particular, it has computational phenotypes to characterize the course of illness and outcomes, derived terms, and harmonized value sets for SARS-CoV-2 laboratory tests. The ontology was deployed and validated on the ACT COVID-19 network that consists of nine academic health centers with data on 14.5M patients. This ontology, which is freely available to the entire research community on GitHub at https://github.com/shyamvis/ACT-COVID-Ontology, will be useful for harmonizing EHRs for COVID-19 research beyond the ACT network.

Development of a Coronavirus Disease 2019 (COVID-19) Application Ontology for the Accrual to Clinical Trials (ACT) network.

Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that are critical to COVID-19 research. The ontology contains over 50 000 concepts in the domains of diagnosis, procedures, medications, and laboratory tests. In particular, it has computational phenotypes to characterize the course of illness and outcomes, derived terms, and harmonized value sets for severe acute respiratory syndrome coronavirus 2 laboratory tests. The ontology was deployed and validated on the ACT COVID-19 network that consists of 9 academic health centers with data on 14.5M patients. This ontology, which is freely available to the entire research community on GitHub at https://github.com/shyamvis/ACT-COVID-Ontology, will be useful for harmonizing EHRs for COVID-19 research beyond the ACT network.

Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells.

Interleukin (IL)-7 is essential for normal T cell development. Previously, we have shown that IL-7 increases viability and proliferation of T cell acute lymphoblastic leukemia (T-ALL) cells by up-regulating Bcl-2 and down-regulating the cyclin-dependent kinase inhibitor p27kip1. Here, we examined the signaling pathways via which IL-7 mediates these effects. We investigated mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)-Akt (protein kinase B) pathways, which have active roles in T cell expansion and have been implicated in tumorigenesis. IL-7 induced activation of the MEK-Erk pathway in T-ALL cells; however, inhibition of the MEK-Erk pathway by the use of the cell-permeable inhibitor PD98059, did not affect IL-7-mediated viability or cell cycle progression of leukemic cells. IL-7 induced PI3K-dependent phosphorylation of Akt and its downstream targets GSK-3, FOXO1, and FOXO3a. PI3K activation was mandatory for IL-7-mediated Bcl-2 up-regulation, p27kip1 down-regulation, Rb hyperphosphorylation, and consequent viability and cell cycle progression of T-ALL cells. PI3K signaling was also required for cell size increase, up-regulation of CD71, expression of the glucose transporter Glut1, uptake of glucose, and maintenance of mitochondrial integrity. Our results implicate PI3K as a major effector of IL-7-induced viability, metabolic activation, growth and proliferation of T-ALL cells, and suggest that PI3K and its downstream effectors may represent molecular targets for therapeutic intervention in T-ALL.

Outcome of alloanergized haploidentical bone marrow transplantation after ex vivo costimulatory blockade: results of 2 phase 1 studies.

We report the outcomes of 24 patients with high-risk hematologic malignancies or bone marrow failure (BMF) who received haploidentical bone marrow transplantation (BMT) after ex vivo induction of alloantigen-specific anergy in donor T cells by allostimulation in the presence of costimulatory blockade. Ninety-five percent of evaluable patients engrafted and achieved full donor chimerism. Despite receiving a median T-cell dose of 29 x10(6)/kg, only 5 of 21 evaluable patients developed grade C (n = 4) or D (n = 1) acute graft-versus-host disease (GVHD), with only one attributable death. Twelve patients died from treatment-related mortality (TRM). Patients reconstituted T-cell subsets and immunoglobulin levels rapidly with evidence of in vivo expansion of pathogen-specific T cells in the early posttransplantation period. Five patients reactivated cytomegalovirus (CMV), only one of whom required extended antiviral treatment. No deaths were attributable to CMV or other viral infections. Only 1 of 12 evaluable patients developed chronic GVHD. Eight patients survive disease-free with normal performance scores (median follow-up, 7 years). Thus, despite significant early TRM, ex vivo alloanergization can support administration of large numbers of haploidentical donor T cells, resulting in rapid immune reconstitution with very few viral infections. Surviving patients have excellent performance status and a low rate of chronic GVHD.

Identification of an evolutionarily conserved transcriptional signature of CD8 memory differentiation that is shared by T and B cells.

After Ag encounter, naive lymphocytes differentiate into populations of memory cells that share a common set of functions including faster response to Ag re-exposure and the ability to self-renew. However, memory lymphocytes in different lymphocyte lineages are functionally and phenotypically diverse. It is not known whether discrete populations of T and B cells use similar transcriptional programs during differentiation into the memory state. We used cross-species genomic analysis to examine the pattern of genes up-regulated during the differentiation of naive lymphocytes into memory cells in multiple populations of human CD4, CD8, and B cell lymphocytes as well as two mouse models of memory development. We identified and validated a signature of genes that was up-regulated in memory cells compared with naive cells in both human and mouse CD8 memory differentiation, suggesting marked evolutionary conservation of this transcriptional program. Surprisingly, this conserved CD8 differentiation signature was also up-regulated during memory differentiation in CD4 and B cell lineages. To validate the biologic significance of this signature, we showed that alterations in this signature of genes could distinguish between functional and exhausted CD8 T cells from a mouse model of chronic viral infection. Finally, we generated genome-wide microarray data from tetramer-sorted human T cells and showed profound differences in this differentiation signature between T cells specific for HIV and those specific for influenza. Thus, our data suggest that in addition to lineage-specific differentiation programs, T and B lymphocytes use a common transcriptional program during memory development that is disrupted in chronic viral infection.

Scale-up of the Accrual to Clinical Trials (ACT) network across the Clinical and Translational Science Award Consortium: a mixed-methods evaluation of the first 18 months.

INTRODUCTION: The Clinical and Translational Science Award (CTSA) Program is a Consortium of nearly 60 academic medical research centers across the USA and a natural network for evaluating the spread and uptake of translational research innovation across the Consortium. METHODS: Dissemination of the Accrual to Clinical Trials (ACT) Network, a federated clinical informatics data network for population-based cohort discovery, began January 2018 across the Consortium. Diffusion of innovation theory guided dissemination design and evaluation. Mixed-methods assessed the spread and uptake across the Consortium through July 1, 2019 (n = 48 CTSAs). Methods included prospective time activity tracking (Kaplan-Meier curves), and survey and qualitative interviews. RESULTS: Within 18 months, nearly 80% of CTSAs had joined the data network and two-thirds of CTSAs achieving technical readiness had initiated launch to local clinical investigators. Over 10,000 ACT Network queries are projected for 2019; and by 2020, nearly all CTSAs will have joined the network. Median time-from-technical-readiness-to-local-launch was 154 days (interquartile range: 87-225 days]. Quality improvement processes reduced time-to-launch by 35.2% (64 days, p = 0.0036). Lessons learned include: (1) conceptualize dissemination as two-stage adoption demonstrating value for both CTSA hub service providers and clinical investigators; (2) include institutional trial into dissemination strategies so CTSA hubs can refine internal workflows and gather local user feedback endorsement; (3) embrace designing-for-dissemination during technology development; and (4) sustain adaptive dissemination and customer relationship management to keep CTSA hubs and users engaged. CONCLUSIONS: Scale-up and spread of the ACT Network provides lessons learned for others disseminating innovation across the CTSA Consortium. The Network is primed for embedded implementation research.

Self-Reported Cognitive Function and Mental Health Diagnoses among Former Professional American-Style Football Players.

Clinical practice strongly relies on patients' self-report. Former professional American-style football players are hesitant to seek help for mental health problems, but may be more willing to report cognitive symptoms. We sought to assess the association between cognitive symptoms and diagnosed mental health problems and quality of life among a cohort of former professional players. In a cross-sectional design, we assessed self-reported cognitive function using items from the Quality of Life in Neurological Disorders (Neuro-QOL) Item Bank. We then compared mental health diagnoses and quality of life, assessed by items from the Patient-Reported Outcome Measurement Information System (PROMIS®), between former professional players reporting daily problems in cognitive function and former players not reporting daily cognitive problems. Of the 3758 former professional players included in the analysis, 40.0% reported daily problems due to cognitive dysfunction. Former players who reported daily cognitive problems were more likely to also report depression (18.0% vs. 3.3%, odds ratio [OR] = 6.42, 95% confidence interval [CI] [4.90-8.40]) and anxiety (19.1% vs. 4.3%, OR = 5.29, 95% CI [4.14-6.75]) than those without daily cognitive problems. Further, former players reporting daily cognitive problems were more likely to report memory loss and attention deficit(/hyperactivity) disorder and poorer general mental health, lower quality of life, less satisfaction with social activities and relationships, and more emotional problems. These findings highlight the potential of an assessment of cognitive symptoms for identifying former players with mental health, social, and emotional problems.

Dissociation of its opposing immunologic effects is critical for the optimization of antitumor CD8+ T-cell responses induced by interleukin 21.

PURPOSE: Interleukin 21 (IL-21) is a promising new cytokine, which is undergoing clinical testing as an anticancer agent. Although IL-21 provides potent stimulation of CD8(+) T cells, it has also been suggested that IL-21 is immunosuppressive by counteracting the maturation of dendritic cells. The dissociation of these two opposing effects may enhance the utility of IL-21 as an immunotherapeutic. In this study, we used a cell-based artificial antigen-presenting cell (aAPC) lacking a functional IL-21 receptor (IL-21R) to investigate the immunostimulatory properties of IL-21. EXPERIMENTAL DESIGN: The immunosuppressive activity of IL-21 was studied using human IL-21R(+) dendritic cells. Antigen-specific CD8(+) T cells stimulated with human cell-based IL-21R(-)aAPC were used to isolate the T-cell immunostimulatory effects of IL-21. The functional outcomes, including phenotype, cytokine production, proliferation, and cytotoxicity were evaluated. RESULTS: IL-21 limits the immune response by maintaining immunologically immature dendritic cells. However, stimulation of CD8(+) T cells with IL-21R(-) aAPC, which secrete IL-21, results in significant expansion. Although priming in the presence of IL-21 temporarily modulated the T-cell phenotype, chronic stimulation abrogated these differences. Importantly, exposure to IL-21 during restimulation promoted the enrichment and expansion of antigen-specific CD8(+) T cells that maintained IL-2 secretion and gained enhanced IFN-gamma secretion. Tumor antigen-specific CTL generated in the presence of IL-21 recognized tumor cells efficiently, demonstrating potent effector functions. CONCLUSIONS: IL-21 induces opposing effects on antigen-presenting cells and CD8(+) T cells. Strategic application of IL-21 is required to induce optimal clinical effects and may enable the generation of large numbers of highly avid tumor-specific CTL for adoptive immunotherapy.

Cyclin D1-specific cytotoxic T lymphocytes are present in the repertoire of cancer patients: implications for cancer immunotherapy.

PURPOSE: Cyclin D1, a key cell cycle regulator, is overexpressed in multiple types of cancer. Such tumor-associated genes may be useful targets for cancer immunotherapy. Nevertheless, it had previously been suggested that efficient T cells recognizing cyclin D1-derived epitopes are absent from the repertoire because of thymic deletion. We attempted to induce autologous CTL from healthy donors and patients with cyclin D1-overexpressing tumors using a highly efficient T-cell expansion system based on CD40-activated B cells as antigen-presenting cells. EXPERIMENTAL DESIGN: Cyclin D1-derived, HLA-A*0201-restricted epitopes were predicted by multiple computer algorithms, screened in HLA-A2-binding assays, and used for T-cell stimulation. The generated CTL lines and clones were analyzed by IFN-gamma enzyme-linked immunosorbent spot assay or cytolysis assay. RESULTS: After screening, at least two naturally processed and presented HLA-A*0201-binding cyclin D1 epitopes were identified. CTL specific for these epitopes could be successfully generated from HLA-A2(+) donors. T cells efficiently recognized target cells pulsed with the cognate peptide and cyclin D1-expressing tumor cell lines in an HLA-A*0201-restricted manner. More importantly, HLA-A*0201-matched, primary cyclin D1(+) tumor cells were efficiently recognized by cyclin D1-specific CTL. These CTL could be generated from patients with mantle cell lymphoma and cyclin D1(+) colon cancer. CONCLUSIONS: These results underscore that cyclin D1 needs to be considered as a target for broad-based antitumor immunotherapy.

CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans.

PURPOSE: CpG oligodeoxynucleotides (CpG-ODN) are being investigated as cancer vaccine adjuvants because they mature plasmacytoid dendritic cells (PDC) into potent antigen-presenting cells. CpG-ODN also induce PDC to secrete chemokines that alter lymphocyte migration. Whether CpG-ODN TLR signals enhance antigen-specific immunity and/or trafficking in humans is unknown. EXPERIMENTAL DESIGN: We conducted a phase I study of CpG-ODN (1018 ISS) given as a vaccine adjuvant with granulocyte-macrophage colony-stimulating factor (GM-CSF) to induce T-cell immunity to a peptide vaccine from the tumor-associated antigen hTERT. RESULTS: The adjuvant effect was limited; only 1 of 16 patients showed a high-frequency hTERT-specific tetramer CD8(+) T-cell response. However, CpG-ODN induced marked, transient peripheral blood lymphopenia. Biopsies showed dense lymphocytic infiltration at the vaccine site clustered around activated PDC. In vitro, CpG-ODN-treated PDC induced T-cell migration, showing that CpG-ODN stimulation of human PDC was sufficient to chemoattract T cells. CONCLUSIONS: Our results show that (a) CpG-ODN with GM-CSF may not be an effective adjuvant strategy for hTERT peptide vaccines but (b) GM-CSF/CpG-ODN causes a PDC-mediated chemokine response that recruits T-cell migration to the peripheral tissues. These findings suggest a novel therapeutic role for targeted injections of CpG-ODN to direct lymphocyte migration to specific sites such as the tumor bed.

Mortality Among Professional American-Style Football Players and Professional American Baseball Players.

Importance: Studies of American-style football players have suggested lower overall mortality rates compared with general populations, but with possibly increased neurodegenerative mortality. However, comparisons with general populations can introduce bias. This study compared mortality between US National Football League (NFL) and US Major League Baseball (MLB) players, a more appropriate comparison group of professional athletes. Objective: To compare all-cause and cause-specific mortality between NFL and MLB players. Design, Setting, and Participants: In this retrospective cohort study, the setting was US mortality from January 1, 1979, through December 31, 2013. The dates of analysis were January 2016 to April 2019. Participants were 3419 NFL and 2708 MLB players with at least 5 playing seasons. Exposures: Participation in the NFL compared with the MLB. Main Outcomes and Measures: Vital status and causes of death from the National Death Index from 1979 through 2013 were obtained. Cox proportional hazards regression models using age as the timescale were used to calculate hazard ratios (HRs) and 95% CIs to examine all-cause and cause-specific mortality among NFL players compared with MLB players, adjusted for race and decade of birth. Results: By the end of follow-up, there were 517 deaths (mean [SD] age, 59.6 [13.2] years) in the NFL cohort and 431 deaths (mean [SD] age, 66.7 [12.3] years) in the MLB cohort. Cardiovascular and neurodegenerative conditions, respectively, were noted as underlying or contributing causes in 498 and 39 deaths in the NFL and 225 and 16 deaths in the MLB. Compared with MLB players, NFL players had significantly elevated rates of all-cause (HR, 1.26; 95% CI, 1.10-1.44), cardiovascular disease (HR, 2.40; 95% CI, 2.03-2.84), and neurodegenerative disease (HR, 2.99; 95% CI, 1.64-5.45) mortality. Comparing hypothetical populations of 1000 NFL and 1000 MLB players followed up to age 75 years, there would be an excess 21 all-cause deaths among NFL players, as well as 77 and 11 more deaths with underlying or contributing causes that included cardiovascular and neurodegenerative conditions, respectively. Conclusions and Relevance: This study found that NFL players had elevated all-cause, cardiovascular, and neurodegenerative mortality rates compared with MLB players, although the absolute number of excess neurodegenerative deaths was still small. Factors that vary across these sports (eg, body habitus and head trauma) as opposed to those common across sports (eg, physical activity) could underlie the differences.

Association of Concussion Symptoms With Testosterone Levels and Erectile Dysfunction in Former Professional US-Style Football Players.

Importance: Small studies suggest that head trauma in men may be associated with low testosterone levels and sexual dysfunction through mechanisms that likely include hypopituitarism secondary to ischemic injury and pituitary axonal tract damage. Athletes in contact sports may be at risk for pituitary insufficiencies or erectile dysfunction (ED) because of the high number of head traumas experienced during their careers. Whether multiple symptomatic concussive events are associated with later indicators of low testosterone levels and ED is unknown. Objective: To explore the associations between concussion symptom history and participant-reported indicators of low testosterone levels and ED. Design, Setting, and Participants: This cross-sectional study of former professional US-style football players was conducted in Boston, Massachusetts, from January 2015 to March 2017. Surveys on past football exposures, demographic factors, and current health conditions were sent via electronic and postal mail to participants within and outside of the United States. Analyses were conducted in Boston, Massachusetts; the data analysis began in March 2018 and additional analyses were performed through June 2019. Of the 13 720 male former players eligible to enroll who were contacted, 3506 (25.6%) responded. Exposures: Concussion symptom score was calculated by summing the frequency with which participants reported 10 symptoms, such as loss of consciousness, disorientation, nausea, memory problems, and dizziness, at the time of football-related head injury. Main Outcomes and Measures: Self-reported recommendations or prescriptions for low testosterone or ED medication served as indicators for testosterone insufficiency and ED. Results: In 3409 former players (mean [SD] age, 52.5 [14.1] years), the prevalence of indicators of low testosterone levels and ED was 18.3% and 22.7%, respectively. The odds of reporting low testosterone levels or ED indicators were elevated for previously established risk factors (eg, diabetes, sleep apnea, and mood disorders). Models adjusted for demographic characteristics, football exposures, and current health factors showed a significant monotonically increasing association of concussion symptom score with the odds of reporting the low testosterone indicator (highest vs lowest quartile, odds ratio, 2.39; 95% CI, 1.79-3.19; P < .001). The ED indicator showed a similar association (highest quartile vs lowest, odds ratio, 1.72; 95% CI, 1.30-2.27; P < .001). Conclusions and Relevance: Concussion symptoms at the time of injury among former football players were associated with current participant-reported low testosterone levels and ED indicators. These findings suggest that men with a history of head injury may benefit from discussions with their health care clinicians regarding testosterone deficiency and sexual dysfunction.

Exposure to American Football and Neuropsychiatric Health in Former National Football League Players: Findings From the Football Players Health Study.

BACKGROUND: Former American football players have a higher prevalence of cognitive impairment than that of the US general population. It remains unknown what aspects of playing football are associated with neuropsychiatric outcomes. HYPOTHESIS: It was hypothesized that seasons of professional football, playing position, and experience of concussions were associated with cognition-related quality of life (QOL) and indicators of depression and anxiety. STUDY DESIGN: Descriptive epidemiology study. METHODS: The authors examined whether seasons of professional football, playing position, and experience of concussions, as measured by self-report of 10 symptoms, were associated with cognition-related QOL and indicators of depression and anxiety in a cross-sectional survey conducted 2015 to 2017. Cognition-related QOL was measured by the short form of the Quality of Life in Neurological Disorders: Applied Cognition-General Concerns. The Patient Health Questionnaire-4 measured depression and anxiety symptoms. Of 13,720 eligible men with apparently valid contact information, 3506 players returned a questionnaire at the time of this analysis (response rate = 25.6%). RESULTS: Seasons of professional play (risk ratio [RR] per 5 seasons = 1.19, 95% CI = 1.06-1.34) and playing position were associated with cognition-related QOL. Each 5 seasons of play was associated with 9% increased risk of indicators of depression at borderline statistical significance (P = .05). When compared with former kickers, punters, and quarterbacks, men who played any other position had a higher risk of poor cognition-related QOL, depression, and anxiety. Concussion symptoms were strongly associated with poor cognition-related QOL (highest concussion quartile, RR = 22.3, P < .001), depression (highest quartile, RR = 6.0, P < .0001), and anxiety (highest quartile, RR = 6.4, P < .0001), even 20 years after last professional play. CONCLUSION: The data suggest that seasons of play and playing position in the NFL are associated with lasting neuropsychiatric health deficits. Additionally, poor cognition-related QOL, depression, and anxiety appear to be associated with concussion in the long term.

Long-lived antitumor CD8+ lymphocytes for adoptive therapy generated using an artificial antigen-presenting cell.

PURPOSE: Antitumor lymphocytes can be generated ex vivo unencumbered by immunoregulation found in vivo. Adoptive transfer of these cells is a promising therapeutic modality that could establish long-term antitumor immunity. However, the widespread use of adoptive therapy has been hampered by the difficulty of consistently generating potent antitumor lymphocytes in a timely manner for every patient. To overcome this, we sought to establish a clinical grade culture system that can reproducibly generate antigen-specific cytotoxic T lymphocytes (CTL). EXPERIMENTAL DESIGN: We created an off-the-shelf, standardized, and renewable artificial antigen-presenting cell (aAPC) line that coexpresses HLA class I, CD54, CD58, CD80, and the dendritic cell maturation marker CD83. We tested the ability of aAPC to generate tumor antigen-specific CTL under optimal culture conditions. The number, phenotype, effector function, and in vitro longevity of generated CTL were determined. RESULTS: Stimulation of CD8(+) T cells with peptide-pulsed aAPC generated large numbers of functional CTL that recognized a variety of tumor antigens. These CTLs, which possess a phenotype consistent with in vivo persistence, survived ex vivo for prolonged periods of time. Clinical grade aAPC(33), produced under current Good Manufacturing Practices guidelines, generated sufficient numbers of CTL within a short period of time. These CTL specifically lysed a variety of melanoma tumor lines naturally expressing a target melanoma antigen. Furthermore, antitumor CTL were easily generated in all melanoma patients examined. CONCLUSIONS: With clinical grade aAPC(33) in hand, we are now poised for clinical translation of ex vivo generated antitumor CTL for adoptive cell transfer.

Relation of Anterior Cruciate Ligament Tears to Potential Chronic Cardiovascular diseases.

We have enrolled a cohort of former National Football League players (n = 3,506) who played since 1960 to assess potential long term health consequences associated with participating in the sport. Each participant has completed a self-administered questionnaire including reporting of physician-diagnosed health conditions. One of the early assessments was to evaluate whether anterior cruciate ligament (ACL) tears were associated with later life co-morbidities, including cardiovascular effects. We used Cox proportional hazards to estimate hazard ratios (HR) for joint replacement surgeries, myocardial infarction, sleep apnea, arthritis, dementia, and stroke by history of ACL tear during their professional career. For additional outcomes without date of occurrence reported we used logistic regression to estimate odds ratios adjusted for potential confounding variables in all models. After adjusting for covariates, former National Football League players who tore their ACL had approximately a twofold increase in muscular skeletal co-morbidities, including knee joint replacement and arthritis, compared with those without ACL tears. In addition, those with a history of ACL tears also had more than a 50% increased risk of myocardial infarction (HR 1.52; 95% confidence interval 0.97 to 2.38) and a slight increase in sleep apnea (HR 1.15; 95% confidence interval 0.96 to 1.38). ACL tears sustained by athletes may increase the risk of co-morbidities beyond the musculoskeletal system. As there are more than 100,000 ACL reconstructions annually in the United States, our findings could have widespread public health importance if these findings generalize to a population beyond professional football players. In conclusion, enhanced screening for other risk factors for these conditions in patients who have torn their ACL might identify those who could most benefit from prevention strategies.