Pain, Return to Community Status, and 90-Day Mortality Among Hospitalized Patients With Heart Failure.

BACKGROUND: Pain is common among patients with heart failure but has not been examined with short-term discharge outcomes. The purpose was to examine whether pain at discharge predicts return to community status and 90-day mortality among hospitalized patients with heart failure. METHODS: Data from medical records of 2169 patients hospitalized with heart failure were analyzed in this retrospective cohort study. The independent variable was a diagnosis of pain at discharge. Outcomes were return to community status (yes/no) and 90-day mortality. Logistic regression was used to address aims. Covariates included age, gender, race, vital signs, comorbid symptoms, comorbid conditions, cardiac devices, and length of stay. RESULTS: The sample had a mean age of 66.53 years, and was 57.4% women and 55.9% Black. Of 2169 patients, 1601 (73.8%) returned to community, and 117 (5.4%) died at or before 90 days. Patients with pain returned to community less frequently (69.6%) compared with patients without pain (75.2%), which was a statistically significant relationship (odds ratio, 0.74; 95% confidence interval, 0.57-0.97; P = .028). Other variables that predicted return to community status included age, comorbid conditions, dyspnea, fatigue, systolic blood pressure, and length of stay. Pain did not predict increased 90-day mortality. Variables that predicted mortality included age, liver disease, and systolic blood pressure. CONCLUSION: Patients with pain were less likely to return to community but did not have higher 90-day mortality. Pain in combination with other symptoms and comorbid conditions may play a role in mortality if acute pain versus chronic pain can be stratified in a future study.

Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype.

Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.

Pain and Heart Failure During Transport by Emergency Medical Services and Its Associated Outcomes: Hospitalization, Mortality, and Length of Stay.

BACKGROUND: Over 22% of patients with heart failure (HF) are transported by emergency medical services (EMSs) for a primary complaint of pain. The relationship between a primary complaint of pain on hospitalization status, mortality, or length of stay following transport by EMS is understudied. OBJECTIVES: The objective of this study was to determine whether a primary complaint of pain during EMS transport predicted hospitalization status, mortality, or inpatient length of stay. METHODS: In this retrospective longitudinal cohort study, data were analyzed from electronic health records of 3539 patients with HF. Descriptive statistics and multivariate logistic and linear regression analyses were used to achieve study objectives. RESULTS: Demographics were mean age 64.83 years (standard deviation [SD] = 14.58); gender 57.3% women, 42.7% men; self-reported race 56.2% black, 43.2% white, and 0.7% other. Of 3539 patients, 2346 (66.3%) were hospitalized, 149 (4.2%) died, and the mean length of stay was 6.02 (SD = 7.55) days. A primary complaint of pain did not predict increased odds of in-hospital mortality but did predict 39% lower odds of hospitalization (p < .001), and 26.7% shorter length of stay (p < .001). Chest pain predicted 49% lower odds of hospitalization (p < .001) and 34.1% (p < .001) shorter length of stay, whereas generalized pain predicted 45% lower odds of hospitalization (p = .044) following post-hoc analysis. CONCLUSIONS: A primary complaint of chest pain predicted lower odds of hospitalization and shorter length of stay, possibly due to established treatment regimens. Additional research is needed to examine chronic pain rather than a primary complaint of pain.

Computerized Cognitive Training and 24-Month Mortality in Heart Failure.

BACKGROUND: Cognitive dysfunction predicts mortality in heart failure (HF). Computerized cognitive training (CCT) has shown preliminary efficacy in improving cognitive function. However, the relationship between CCT and mortality is unclear. Aims were to evaluate (1) long-term efficacy of CCT in reducing 24-month mortality and (2) age, HF severity, global cognition, memory, working memory, depressive symptoms, and health-related quality of life as predictors of 24-month mortality among patients with HF. METHODS: In this prospective longitudinal study, 142 patients enrolled in a 3-arm randomized controlled trial were followed for 24 months. Logistic regression was used to achieve the aims. RESULTS: Across 24 months, 16 patients died (CCT, 8.3%; control groups, 12.8%). Computerized cognitive training did not predict 24-month mortality (odds ratio [OR], 0.65). Older age (OR, 1.08), worse global cognition (OR, 0.73), memory (OR, 0.81), and depressive symptoms (OR, 1.10) at baseline predicted 24-month mortality. CONCLUSIONS: Efficacious interventions are needed to improve global cognition, memory, and depressive symptoms and reduce mortality in HF.

Spectral flow cytometry identifies distinct nonneoplastic plasma extracellular vesicle phenotype in glioblastoma patients.

Background: Glioblastoma (GBM) is the most common malignant brain tumor and has a poor prognosis. Imaging findings at diagnosis and in response to treatment are nonspecific. Developing noninvasive assays to augment imaging would be helpful. Plasma extracellular vesicles (EVs) are a promising biomarker source for this. Here, we develop spectral flow cytometry techniques that demonstrate differences in bulk plasma EV phenotype between GBM patients and normal donors that could serve as the basis of a liquid biopsy. Methods: Plasma EVs were stained for EV-associated tetraspanins (CD9/CD63/CD81), markers indicating cell of origin (CD11b/CD31/CD41a/CD45), and actin/phalloidin (to exclude cell debris). EVs were analyzed using spectral flow cytometry. Multiparametric analysis using t-distributed stochastic neighbor embedding (t-SNE) and self-organizing maps on flow cytometry data (FlowSOM) was performed comparing GBM and normal donor (ND) plasma EVs. Results: Size exclusion chromatography plus spectral-based flow cytometer threshold settings enriched plasma EVs while minimizing background noise. GBM patients had increased CD9+, CD63+, CD81+, and myeloid-derived (CD11b+) EVs. Multiparametric analysis demonstrated distinct surface marker expression profiles in GBM plasma EVs compared to ND EVs. Fifteen plasma EV sub-populations differing in size and surface marker expression were identified, six enriched in GBM patients and two in normal donors. Conclusions: Multiparametric analysis demonstrates that GBM patients have a distinct nonneoplastic plasma EV phenotype compared to ND. This simple rapid analysis can be performed without purifying tumor EVs and may serve as the basis of a liquid biopsy.

The Impact of a Mobile Support Group on Distress and Physical Activity in Breast Cancer Survivors: Randomized, Parallel-Group, Open-Label, Controlled Trial.

BACKGROUND: While mobile health apps have demonstrated their potential in revolutionizing health behavior changes, the impact of a mobile community built on these apps on the level of physical activity and mental well-being in cancer survivors remains unexplored. OBJECTIVE: In this randomized controlled trial, we examine the effects of participation in a mobile health community specifically designed for breast cancer survivors on their physical activity levels and mental distress. METHODS: We performed a single-center, randomized, parallel-group, open-label, controlled trial. This trial enrolled women between 20 and 60 years of age with stage 0 to III breast cancer, an Eastern Cooperative Oncology Group performance status of 0, and the capability of using their own smartphone apps. From January 7, 2019, to April 17, 2020, a total of 2,616 patients were consecutively screened for eligibility after breast cancer surgery. Overall, 202 patients were enrolled in this trial, and 186 patients were randomly assigned (1:1) to either the intervention group (engagement in a mobile peer support community using an app for tracking steps; n=93) or the control group (using the app for step tracking only; n=93) with a block size of 10 without stratification. The mobile app provides a visual interface of daily step counts, while the community function also provides rankings among its members and regular notifications encouraging physical activity. The primary end point was the rate of moderate to severe distress for the 24-week study period, measured through an app-based survey using the Distress Thermometer. The secondary end point was the total weekly steps during the 24-week period. RESULTS: After excluding dropouts, 85 patients in the intervention group and 90 patients in the control group were included in the analysis. Multivariate analyses showed that patients in the intervention group had a significantly lower degree of moderate to severe distress (B=-0.558; odds ratio 0.572; P<.001) and a higher number of total weekly step counts (B=0.125; rate ratio 1.132; P<.001) during the 24-week period. CONCLUSIONS: Engagement in a mobile app-based patient community was effective in reducing mental distress and increasing physical activity in breast cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov NCT03783481; https://classic.clinicaltrials.gov/ct2/show/NCT03783481.

Perceived Facilitators and Barriers to Treatment Fidelity in Computerized Cognitive Training Interventions.

BACKGROUND: Computerized cognitive training (CCT) interventions may have an important role in improving cognition among patients with heart failure. Ensuring treatment fidelity of CCT interventions is an essential part of testing their efficacy. OBJECTIVE: The aim of this study was to describe facilitators of and barriers to treatment fidelity perceived by CCT intervenors while delivering the interventions to patients with heart failure. METHODS AND RESULTS: A qualitative descriptive study was completed with 7 intervenors who delivered CCT interventions in 3 studies. Directed content analysis revealed 4 main themes of perceived facilitators: (1) training for intervention delivery, (2) supportive work environment, (3) prespecified implementation guide, and (4) confidence and awareness. Three main themes were identified as perceived barriers: (1) technical issues, (2) logistic barriers, and (3) sample characteristics. CONCLUSION: This study is novel because it was one of the few studies focused on the intervenors' perceptions rather than the patients' perception of using CCT interventions. Beyond the treatment fidelity recommendations, this study found new components that might help the future investigators in designing and implementing CCT interventions with high treatment fidelity.

Differential Gene Expression Among Patients With Heart Failure Experiencing Pain.

BACKGROUND: Chronic pain is frequently experienced by patients with heart failure (HF) and is associated with higher mortality, higher symptom burden, and worsened health-related quality of life. However, the genomic mechanisms underlying chronic pain in HF are understudied. Building an understanding of the mechanistic underpinnings of pain may inform novel interventions. OBJECTIVE: The objective was to identify genes associated with pain from messenger RNA sequence data collected from patients with HF with and without pain. METHODS: The current study analyzed data from 40 patients with HF previously enrolled in a clinical trial. Pain presence was measured using the Health Utilities Index Mark-3. Genes were tested for differential expression using DESeq2, and differentially expressed genes were analyzed for protein-protein interaction (PPI) and relevant ontological pathways using Metascape. Genes located within the core of the PPI network were considered key in disease-relevant biological pathways. Differentially expressed genes within this PPI network were reviewed in existing literature to narrow down candidate genes of interest. These target genes of interest were reanalyzed in a second sample of 24 patients with HF using validation quantitative polymerase chain reaction. RESULTS: A total of 334 genes (279 upregulated, 55 downregulated) were differentially expressed between patients with and without pain in the primary sample of 40. These genes were largely aligned with neutrophil degranulation pathways. Seven genes of interest were identified from a core network of 15 co-expressed genes in the PPI network and existing literature. Three of these seven genes, matrix metallopeptidase 8 ( MMP8 ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and neutrophil defensin 3 ( DEFA3 ), were upregulated in patients with pain versus without pain in both the primary and validation samples. All seven genes of interest are involved in immune, inflammatory, and atherosclerotic processes. DISCUSSION: These results identify potential genes that may play a mechanistic role in chronic pain in HF. Further research is needed to evaluate these potential genes among clearly delineated pain phenotypes.

Evaluating depressive symptoms, BDNF Val66Met, and APOE-ε4 as moderators of response to computerized cognitive training in heart failure.

BACKGROUND: Depressive symptoms, brain-derived neurotrophic factor (BDNF) Val66Met, and apolipoprotein (APOE)-ε4 may moderate response to computerized cognitive training (CCT) interventions among patients with heart failure (HF). OBJECTIVES: The purpose of this study was to examine moderators of intervention response to CCT over 8 months among patients with HF enrolled in a 3-arm randomized controlled trial. Outcomes were memory, serum BDNF, working memory, instrumental activities of daily living (IADLs), and health-related quality of life (HRQL). METHODS: 256 patients with HF were randomized to CCT, computerized crossword puzzles active control, and usual care control groups for 8 weeks. Data were collected at enrollment, baseline, 10 weeks, and 4 and 8 months. Mixed effects models were computed to evaluate moderators. RESULTS: As previously reported, there were no statistically significant group by time effects in outcomes among the 3 groups over 8 months. Tests of moderation indicated that depressive symptoms and presence of BDNF Val66Met and APOE-ε4 were not statistically significant moderators of intervention response in outcomes of delayed recall memory, serum BDNF, working memory, IADLs, and HRQL. In post hoc analysis evaluating baseline global cognitive function, gender, age, and HF severity as moderators, no significant effects were found. HF severity was imbalanced among groups (P = .049) which may have influenced results. CONCLUSIONS: Studies are needed to elucidate biological mechanisms of cognitive dysfunction in HF and test novel interventions to improve memory, serum BDNF, working memory, IADLs and HRQL. Patients may need to be stratified or randomized by HF severity within intervention trials.

Use of heparin to rescue immunosuppressive monocyte reprogramming by glioblastoma-derived extracellular vesicles.

OBJECTIVE: The profound immunosuppression found in glioblastoma (GBM) patients is a critical barrier to effective immunotherapy. Multiple mechanisms of tumor-mediated immune suppression exist, and the induction of immunosuppressive monocytes such as myeloid-derived suppressor cells (MDSCs) is increasingly appreciated as a key part of this pathology. GBM-derived extracellular vesicles (EVs) can induce the formation of MDSCs. The authors sought to identify the molecular consequences of these interactions in myeloid cells in order to identify potential targets that could pharmacologically disrupt GBM EV-monocyte interaction as a means to ameliorate tumor-mediated immune suppression. Heparin-sulfate proteoglycans (HSPGs) are a general mechanism by which EVs come into association with their target cells, and soluble heparin has been shown to interfere with EV-HSPG interactions. The authors sought to assess the efficacy of heparin treatment for mitigating the effects of GBM EVs on the formation of MDSCs. METHODS: GBM EVs were collected from patient-derived cell line cultures via staged ultracentrifugation and cocultured with monocytes collected from apheresis cones from healthy blood donors. RNA was isolated from EV-conditioned and unconditioned monocytes after 72 hours of coculture, and RNA-sequencing analysis performed. For the heparin treatment studies, soluble heparin was added at the time of EV-monocyte coculture and flow cytometry analysis was performed 72 hours later. After the initial EV-monocyte coculture period, donor-matched T-cell coculture studies were performed by adding fluorescently labeled and stimulated T cells for 5 days of coculture. RESULTS: Transcriptomic analysis of GBM EV-treated monocytes demonstrated downregulation of several important immunological and metabolic pathways, with upregulation of the pathways associated with synthesis of cholesterol and HSPG. Heparin treatment inhibited association between GBM EVs and monocytes in a dose-dependent fashion, which resulted in a concomitant reduction in MDSC formation (p < 0.01). The authors further demonstrated that reduced MDSC formation resulted in a partial rescue of immune suppression, as measured by effects on activated donor-matched T cells (p < 0.05). CONCLUSIONS: The authors demonstrated that GBM EVs induce broad but reproducible reprogramming in monocytes, with enrichment of pathways that may portend an immunosuppressive phenotype. The authors further demonstrated that GBM EV-monocyte interactions are potentially druggable targets for overcoming tumor-mediated immune suppression, with heparin inhibition of EV-monocyte interactions demonstrating proof of principle.

Glioblastoma may evade immune surveillance through primary cilia-dependent signaling in an IL-6 dependent manner.

Glioblastoma is the most common, malignant primary brain tumor in adults and remains universally fatal. While immunotherapy has vastly improved the treatment of several solid cancers, efficacy in glioblastoma is limited. These challenges are due in part to the propensity of glioblastoma to recruit tumor-suppressive immune cells, which act in conjunction with tumor cells to create a pro-tumor immune microenvironment through secretion of several soluble factors. Glioblastoma-derived EVs induce myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs) from myeloid precursors leading to systemic and local immunosuppression. This process is mediated by IL-6 which contributes to the recruitment of tumor-associated macrophages of the M2 immunosuppressive subtype, which in turn, upregulates anti-inflammatory cytokines including IL-10 and TGF-ß. Primary cilia are highly conserved organelles involved in signal transduction and play critical roles in glioblastoma proliferation, invasion, angiogenesis, and chemoradiation resistance. In this perspectives article, we provide preliminary evidence that primary cilia regulate intracellular release of IL-6. This ties primary cilia mechanistically to tumor-mediated immunosuppression in glioblastomas and potentially, in additional neoplasms which have a shared mechanism for cancer-mediated immunosuppression. We propose potentially testable hypotheses of the cellular mechanisms behind this finding.

State of the Science: The Relevance of Symptoms in Cardiovascular Disease and Research: A Scientific Statement From the American Heart Association.

Symptoms of cardiovascular disease drive health care use and are a major contributor to quality of life. Symptoms are of fundamental significance not only to the diagnosis of cardiovascular disease and appraisal of response to medical therapy but also directly to patients' daily lives. The primary purpose of this scientific statement is to present the state of the science and relevance of symptoms associated with cardiovascular disease. Symptoms as patient-reported outcomes are reviewed in terms of the genesis, manifestation, and similarities or differences between diagnoses. Specifically, symptoms associated with acute coronary syndrome, heart failure, valvular disorders, stroke, rhythm disorders, and peripheral vascular disease are reviewed. Secondary aims include (1) describing symptom measurement methods in research and application in clinical practice and (2) describing the importance of cardiovascular disease symptoms in terms of clinical events and other patient-reported outcomes as applicable.

Superinduction of immunosuppressive glioblastoma extracellular vesicles by IFN-γ through PD-L1 and IDO1.

Background: Glioblastoma (GBM), the most common primary brain tumor, has a median survival of 15-16 months. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. GBMs express the interferon-gamma (IFN-γ)-responsive immunosuppressive molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1). Extracellular vesicles (EVs) have also been implicated in GBM-mediated immunosuppression, in part through PD-L1. We therefore sought to determine if GBM IFN-γ exposure increased GBM EV-mediated immunosuppression and mechanisms underlying this. Methods: Human GBM-derived cells were cultured in the presence/absence of IFN-γ. EVs were harvested. PD-L1, IDO1, and EV-associated protein expression was assessed. GBM EVs (+/-IFN-γ) were cultured with healthy donor monocytes. Immunosuppressive myeloid-derived suppressor cell (MDSC) and nonclassical monocyte (NCM) frequency was determined. Impact of GBM (+/-IFN-γ) EV-treated monocytes on CD3/CD28-mediated T cell proliferation was assessed. The impact of PD-L1 and IDO1 knockdown in GBM EVs in this system was evaluated. Results: IFN-γ exposure increased PD-L1 and IDO1 expression in GBM cells and EVs without altering EV size or frequency. IFN-γ-exposed GBM EVs induced more MDSC and NCM differentiation in monocytes and these monocytes caused more T cell inhibition than IFN-γ-naive GBM EVs. PD-L1 and/or IDO1 knockdown in GBM cells abrogated the immunosuppressive effects of IFN-γ-exposed GBM EVs on monocytes. Conclusions: IFN-γ exposure such as might occur during an antitumor immune response results in superinduction of GBM EVs' baseline immunosuppressive effects on monocytes. These effects are mediated by increased PD-L1 and IDO1 expression in GBM EVs. These data highlight mechanisms of GBM EV-mediated immunosuppression and identify therapeutic targets (PD-L1, IDO1) to reverse these effects.

Virtual reality cognitive intervention for heart failure: CORE study protocol.

Introduction: Heart failure (HF) is a prevalent, serious chronic illness that affects 6.5 million adults in the United States. Among patients with HF, the prevalence of attention impairment is reported to range from 15% to 27%. Although attention is fundamental to human activities including HF self-care, cognitive interventions for patients with HF that target improvement in attention are scarce. The COgnitive intervention to Restore attention using nature Environment (CORE) study aims to test the preliminary efficacy of the newly developed Nature-VR, a virtual reality-based cognitive intervention that is based on the restorative effects of nature. Nature-VR development was guided by Attention Restoration Theory. The target outcomes are attention, HF self-care, and health-related quality of life (HRQoL). Our exploratory aims examine the associations between attention and several putative/established HF biomarkers (eg, oxygen saturation, brain-derived neurotrophic factor, apolipoprotein E, dopamine receptor, and dopamine transporter genes) as well as the effect of Nature-VR on cognitive performance in other domains (ie, global cognition, memory, visuospatial, executive function, and language), cardiac and neurological events, and mortality. Methods: This single-blinded, two-group randomized-controlled pilot study will enroll 74 participants with HF. The Nature-VR intervention group will view three-dimensional nature pictures using a virtual reality headset for 10 minutes per day, 5 days per week for 4 weeks (a total of 200 minutes). The active comparison group, Urban-VR, will view three-dimensional urban pictures using a virtual reality headset to match the Nature-VR intervention in intervention dose and delivery mode, but not in content. After baseline interviews, four follow-up interviews will be conducted to assess sustained effects of Nature-VR at 4, 8, 26, and 52 weeks. Discussion: The importance and novelty of this study consists of using a first-of-its kind, immersive virtual reality technology to target attention and in investigating the health outcomes of the Nature-VR cognitive intervention among patients with HF.

Randomized Controlled Trial of a Cognitive Intervention to Improve Memory in Heart Failure.

BACKGROUND: The objective of this 3-arm randomized controlled trial was to evaluate the efficacy of computerized cognitive training (CCT) in improving primary outcomes of delayed-recall memory and serum brain-derived neurotrophic factor (BDNF) levels; and the secondary outcomes were working memory, instrumental activities of daily living (IADLs) and health-related quality of life (HRQL) in patients with heart failure (HF). METHODS AND RESULTS: Patients (n = 256) were randomly assigned to 8 weeks of CCT using BrainHQ, computerized crossword puzzles active control intervention, and usual care. All patients received weekly nurse-enhancement interventions. Data were collected at enrollment and baseline visits and at 10 weeks and 4 and 8 months. In mixed effects models, there were no statistically significant group or group-by-time differences in outcomes. There were statistically significant differences over time in all outcomes in all groups. Patients improved over time on measures of delayed-recall memory, working memory, IADLs, and HRQL and had decreased serum BDNF. CONCLUSIONS: CCT did not improve outcomes compared with the active control intervention and usual care. Nurse-enhancement interventions may have led to improved outcomes over time. Future studies are needed to test nurse-enhancement interventions in combination with other cognitive interventions to improve memory in persons with HF.

Characterizing Pain Leading to Emergency Medical Services Activation in Heart Failure.

BACKGROUND: Pain is a common but understudied symptom among patients with heart failure (HF) transported by emergency medical services (EMS). The aims were to determine explanatory factors of a primary complaint of pain and pain severity, and characterize pain among patients with HF transported by EMS. METHODS: Data from electronic health records of patients with HF transported by EMS within a midwestern United States county from 2009 to 2017 were analyzed. Descriptive statistics, χ 2 , analysis of variance, and logistic and multiple linear regression analyses were used. RESULTS: The sample (N = 4663) was predominantly women (58.1%) with self-reported race as Black (57.7%). The mean age was 64.2 ± 14.3 years. Pain was the primary complaint in 22.2% of the sample, with an average pain score of 6.8 ± 3.1 out of 10. The most common pain complaint was chest pain (68.1%). Factors associated with a primary pain complaint were younger age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.96-0.97), history of myocardial infarction (OR, 1.96; 95% CI, 1.55-2.49), and absence of shortness of breath (OR, 0.67; 95% CI, 0.58-0.77). Factors associated with higher pain severity were younger age ( b = -0.05, SE = 0.013), being a woman ( b = 1.17, SE = 0.357), and White race ( b = -1.11, SE = 0.349). CONCLUSIONS: Clinical and demographic factors need consideration in understanding pain in HF during EMS transport. Additional research is needed to examine these factors to improve pain management and reduce transports due to pain.

911 Calls for Emergency Medical Services in Heart Failure: A Descriptive Qualitative Study.

BACKGROUND: Heart failure (HF) is a common condition leading to activation of emergency medical services (EMS). OBJECTIVE: The aim of this study was to describe reasons given by persons with HF, family members, or other caregivers for requesting EMS activation during 911 calls. METHODS: In this descriptive qualitative study, a content analysis was performed on transcribed audio files of 383 EMS requests involving 383 persons with HF in the community. RESULTS: One hundred forty-seven calls (38.4%) were placed by the family members, 75 (19.6%) were placed by the patients, 56 (14.6%) were placed by healthcare workers or personnel from living facilities, and the remaining calls (n = 105, 27.4%) were placed by others (eg, friends, neighbors, officers). Three broad categories of symptoms, signs, and events were identified as the reasons for an EMS request. Frequently reported symptoms were breathing problems (55.4%), chest pain (18.3%), and other pain (eg, head, extremities) (16.7%). Signs included decreased consciousness (15.4%), swelling (5.7%), and bleeding (5.0%). The reported events involved falls (8.1%), heart attack (6.3%), hypoxic episodes (6.0%), stroke (5.2%), and post-hospital-discharge complications (4.7%). In most calls (74.9%), multiple reasons were reported and a combination of symptoms, signs, and events were identified. Heart failure diagnosis was mentioned in fewer than 10% of the calls. CONCLUSIONS: Overall, symptoms and signs of HF exacerbation were common reasons to activate 911 calls. Falls were frequently reported. Under the duress of the emergent situations surrounding the 911 call, callers rarely mentioned the existence of HF. Interventions are needed to guide patients with HF and their family members to promote the management of HF to reduce EMS activation as well as to activate EMS quickly for acute changes in HF conditions.

Testing influences of APOE and BDNF genes and heart failure on cognitive function.

BACKGROUND: Apolipoprotein E (APOE) ε2, ε4 and brain-derived neurotrophic factor (BDNF) Val66Met alleles have been associated with cognition. Associations of these alleles with cognition in heart failure (HF) and influences of HF across the cognitive spectrum (i.e., cognitively normal to Alzheimer's dementia [AD]) remain unexplored. OBJECTIVES: To investigate influences of APOE ε2, ε4, BDNF Met and HF on cognition among participants across the cognitive spectrum. METHODS: Genetic association study using national databases (N = 7,166). RESULTS: APOE ε2 frequencies were similar across the cognitive spectrum among participants with HF. APOE ε4 frequency was lower among participants with HF and AD than non-HF participants with AD. BDNF Met frequencies did not differ across the spectrum. HF was associated with worse attention and language. In the HF subsample, ε4 was associated with worse memory. CONCLUSION: Associations between APOE and cognition may differ in HF but need to be tested in a larger sample.

Plasma extracellular vesicles as a source of biomarkers in traumatic brain injury.

OBJECTIVE: The objective of this study was to isolate extracellular vesicles (EVs) from plasma in a cohort of patients with traumatic brain injury (TBI) and analyze their contents for novel biomarkers that could prove useful for rapid diagnosis and classification of brain injury during initial evaluation. METHODS: Plasma EVs were isolated by serial ultracentrifugation from patients with TBI (n = 15) and healthy controls (n = 5). Samples were obtained from the TRACK-TBI biorepository (2010-present). Size and concentration were determined by nanoparticle tracking. Glial fibrillary acidic protein (GFAP) concentration was determined in EV protein. EV RNA was isolated and deep sequencing of short noncoding RNA was performed. RESULTS: Plasma EVs are physically similar but contained approximately 10 times more GFAP in TBI patients with altered consciousness than patients and controls with normal consciousness. Eleven highly differentially expressed microRNAs (miRNAs) were identified between these groups. Genes targeted by these miRNAs are highly associated with biologically relevant cellular pathways, including organismal injury, cellular development, and organismal development. Multiple additional coding and noncoding RNA species with potential biomarker utility were identified. CONCLUSIONS: Isolating plasma EVs in patients with TBI is feasible. Increased GFAP concentration-a validated plasma TBI marker-in EVs from TBI patients with altered consciousness, along with differential expression of multiple miRNAs targeting TBI-relevant pathways, suggests that EVs may be a useful source of TBI biomarkers. Additional evaluation in larger patient cohorts is indicated.

An Integrative Review of Brain-Derived Neurotrophic Factor and Serious Cardiovascular Conditions.

BACKGROUND: There is emerging evidence that supports a role for brain-derived neurotrophic factor (BDNF) in the risk and presence of serious cardiovascular conditions. However, few existing literature reviews methodically describe empirical findings regarding this relationship. OBJECTIVES: The purpose of this integrative review was to (a) evaluate BDNF (serum/plasma BDNF levels, BDNF Val66Met genotype) among humans at risk for or with serious cardiovascular conditions and (b) investigate the relationship between BDNF and risk/presence of serious cardiovascular conditions in humans. METHODS: An integrative review was conducted. Articles in English included human subjects, a measure of BDNF levels or BDNF gene, serious cardiovascular conditions, and quantitative data analyses. The search resulted in 475 unique titles, with the final sample including 35 articles representing 30 studies. Articles that received "good" or "fair" ratings (n = 31) using the National Heart, Lung, and Blood Institute Study Quality Assessment Tools were included for synthesis. RESULTS: The retrieved articles were largely nonexperimental, with sample sizes ranging from 20 to 5,510 participants. Overall, BDNF levels were lower in patients with chronic heart failure and stroke, but higher in patients with unstable angina and recent myocardial infarction. Lower BDNF levels were associated with higher incidence of cardiovascular events in patients with a prior history of serious cardiovascular conditions and decreased cardiovascular risk in healthy samples. For BDNF genotype, on average, 36.3% of participants had Met alleles. The frequency of the BDNF Met allele varied across race/ethnicity and cardiovascular conditions and in terms of association with serious cardiovascular condition incidence/risk. DISCUSSION: These findings indicate an emerging area of science. Future investigation is needed on serious cardiovascular condition phenotypes in relationship to BDNF in the same study conditions. Results also suggest for use of standardized BDNF measurement across studies and additional investigation in cardiovascular inflammatory processes that affect BDNF. Moreover, within specific populations, the frequency of Met alleles may be too low to be detected in sample sizes normally found in these types of studies.