Brain-derived neurotrophic factor (BDNF) epigenomic modifications and brain-related phenotypes in humans: A systematic review.

Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.

Symptom Cluster Profiles Among Adults with Insomnia and Heart Failure.

OBJECTIVE/BACKGROUND: Both heart failure (HF) and insomnia are associated with high symptom burden that may be manifested in clustered symptoms. To date, studies of insomnia have focused only on its association with single symptoms. The purposes of this study were to: (1) describe daytime symptom cluster profiles in adults with insomnia and chronic HF; and (2) determine the associations between demographic and clinical characteristics, insomnia and sleep characteristics and membership in symptom cluster profiles. PARTICIPANTS: One hundred and ninety-five participants [M age 63.0 (SD12.8); 84 (43.1%) male; 148 (75.9%) New York Heart Association Class I/II] from the HeartSleep study (NCT0266038), a randomized controlled trial of the sustained effects of cognitive behavioral therapy for insomnia (CBT-I). METHODS: We analyzed baseline data, including daytime symptoms (fatigue, pain, anxiety, depression, dyspnea, sleepiness) and insomnia (Insomnia Severity Index), and sleep characteristics (Pittsburgh Sleep Quality Index, wrist actigraphy). We conducted latent class analysis to identify symptom cluster profiles, bivariate associations, and multinomial regression. RESULTS: We identified three daytime symptom cluster profiles, physical (N = 73 participants; 37.4%), emotional (N = 12; 5.6%), and all-high symptoms (N = 111; 56.4%). Body mass index, beta blockers, and insomnia severity were independently associated with membership in the all-high symptom profile, compared with the other symptom profile groups. CONCLUSIONS: Higher symptom burden is associated with more severe insomnia in people with stable HF. There is a need to understand whether treatment of insomnia improves symptom burden as reflected in transition from symptom cluster profiles reflecting higher to lower symptom burden.

Trajectory of self-care in people with stable heart failure and insomnia after two self-care interventions.

OBJECTIVE: To describe (1) self-care trajectories among adults with heart failure (HF) and insomnia over 1-year; (2) the extent to which trajectories varied between cognitive behavioral therapy for insomnia (CBT-I) or HF self-care intervention; and (3) the associations between self-care trajectories and clinical and demographic characteristics, sleep, symptoms and stress, and functional performance. METHODS: We conducted secondary analysis of data from a randomized controlled trial of the effects of CBT-I compared with HF self-care education among adults with stable HF and insomnia. We used the Self-Care of Heart Failure Index v6.2. The analytic approaches included t-tests, group-based trajectory modeling, ANOVA, and chi-square. RESULTS: We included 175 participants (M age=63.0 (12.9) years, White, N = 100]. We found four self-care trajectories: Low self-care (N = 47, 26.8%); Moderate self-care (N = 68, 38.9%): Adequate self-care (N = 42, 24.0%); and Optimal self-care (N = 18, 10.3%). There was no difference in self-care trajectories between interventions. The low self-care group had the most severe baseline fatigue, anxiety, and perceived stress, and lowest cognitive abilities. CONCLUSION: Both interventions prevented declining self-care. Future research is needed to determine the most efficacious intervention to improve self-care trajectories. PRACTICE IMPLICATIONS: Healthcare providers should provide ongoing self-care support for those with persistently low and moderate self-care.

CE: Pain and Mental Health Symptoms After Traumatic Orthopedic Injury.

ABSTRACT: This article highlights the need to screen survivors of traumatic orthopedic injuries for postinjury symptoms associated with stressor-related disorders such as acute stress disorder and posttraumatic stress disorder, including pain, sleep disturbances, anxiety, and depression. The authors discuss the presentation of these postinjury symptoms, the instruments used to screen for each, the various pharmacological and nonpharmacological treatments, and the nursing implications for managing postinjury symptoms in traumatic orthopedic injury survivors.

Symptom cluster profiles following traumatic orthopaedic injuries.

BACKGROUND: Millions of Americans experience traumatic orthopaedic injuries (TOIs) annually. Post-injury symptoms of acute stress disorder (ASD), anxiety, depression, pain, and sleep disturbance are common. Symptoms often present in clusters. Symptom cluster profiles phenotypically characterize TOI survivors' experiences with clustered symptoms. Expression of brain-derived neurotrophic factor (BDNF) may contribute to the biological underpinnings of symptom cluster profile membership. METHODS: We recruited hospitalized TOI survivors within 72 hours of injury. We measured symptoms of ASD with the Acute Stress Disorder Scale and symptoms of anxiety, depression, pain, and sleep disturbance with Patient-Reported Outcomes Measurement Information System (PROMIS) short forms. We measured serum BDNF concentrations with enzyme-linked immunosorbent assay (ELISA) and identified rs6265 genotypes with TaqMan real-time PCR. We performed latent profile analysis to identify the symptom cluster profiles. We identified the variables associated with symptom cluster profile membership with unadjusted and adjusted multinomial logistic regression. RESULTS: We identified 4 symptom cluster profiles characterized by symptom severity that we labelled Physical Symptoms Only, and Mild, Moderate, and Severe Psychological Distress. Age, self-identified Black race, resilience, and serum BDNF concentrations were associated with lower odds, and female sex with higher odds, of being in the Psychological Distress clusters. Clinical characteristics and rs6265 genotypes were not associated with symptom cluster profile membership. CONCLUSION: TOI survivors experience distinct symptom cluster profiles. Sociodemographic characteristics and serum BDNF concentrations, not clinical characteristics, were associated with symptom cluster profile membership. These findings support comprehensive symptom screening and treatment for all TOI survivors and further evaluating BDNF as a biomarker of post-injury symptom burden.

Sleep Characteristics, Mood, Somatic Symptoms, and Self-Care Among People With Heart Failure and Insomnia.

BACKGROUND: Almost 50% of people with heart failure (HF) experience chronic insomnia and must perform self-care to manage their day-to-day healthcare needs. Understanding multifactorial influences on self-care, including demographic, clinical, and sleep characteristics, and mood and somatic symptoms will help identify people at highest risk for poor self-care. However, past research focused only on the associations of single symptoms and self-care. Multivariate approaches are needed to account for the synergistic associations of self-care with sleep, mood, and somatic symptoms among people with HF. OBJECTIVES: The aims of the study were to (a) evaluate the levels of self-care maintenance and self-care confidence among people with stable HF and chronic insomnia; (b) identify the clinical and demographic correlates of self-care maintenance and confidence among people with stable HF and chronic insomnia; and (c) identify the associations between sleep characteristics, mood and somatic symptoms, and self-care maintenance and confidence among people with stable HF and chronic insomnia. METHODS: We utilized a cross-sectional design with 195 adult participants who had chronic HF and insomnia. We assessed for symptoms of anxiety; depression; dyspnea; fatigue; stress; insomnia severity; and sleep disturbance, impairment, and quality. Self-care was measured using the Self-Care for Heart Failure Index v6.2. We used generalized linear models to test the associations between the demographic and clinical factors and self-care maintenance and confidence; exploratory and confirmatory factor analysis to identify the factor structure underlying the symptoms; and structural equation modeling to test the combined associations of the demographic and clinical factors and latent factors with self-care maintenance and confidence. RESULTS: Self-care maintenance, confidence, and management were inadequate in most participants. We identified three latent factors among the nine symptoms: "sleep characteristics," "mood," and "somatic symptoms." In the structural equation model, "sleep characteristics," White race, and having a left ventricular ejection fraction of <45 were associated with self-care maintenance. Age was negatively associated with self-care confidence. DISCUSSION: Poor sleep characteristics negatively influence the ability of people with HF and insomnia to perform self-care behaviors. Knowledge of the associations among age, left ventricular ejection fraction, and race with self-care will help clinicians and future researchers identify those at risk for poor self-care.

A Systematic Review of Risk Factors for Suicide Among Persons Living with HIV (1996-2020).

Persons living with HIV (PWH) are at elevated risk for suicide. We conducted a systematic literature review following PRISMA-P guidelines to examine risk factors associated with suicide as a cause of morbidity among PWH. We searched six electronic databases using search terms (suicide, suicide attempt, self-harm, self-injurious behavior, HIV, AIDS, PWH). We focused on factors that were specific to HIV infection (CD4 count, HIV-1 RNA, and antiretroviral therapy [ART]). The initial search yielded N = 2657 studies. Eligible studies included suicide as an outcome, quantitative study design, and publication in peer-reviewed journals from 1996 through 2020. Fourteen studies met inclusion criteria. PWH share risk factors for suicide found in the general population: psychiatric illness, previous suicide attempt, drug and alcohol misuse. PWH also have HIV-specific risk factors for suicide. HIV diagnosis in the past two years and transmission related to injection drug use were associated with increased risk; HIV-1 RNA, ART, and AIDS-defining illness were not.

RESUMEN: Las personas viviendo con VIH (PVV) tienen riesgo elevado de suicidio. Realizamos un examen sistemático de la bibliografía, siguiendo las pautas PRISMA-P para examinar los factores de riesgo asociados con suicidio como la causa de morbilidad entre PVV. Realizamos búsquedas en seis bases de datos electrónicas mediante el uso de términos de búsqueda (suicidio, intento de suicidio, autolesiones, comportamiento autolesivo, VIH, AIDS). Nos hemos centrado en factores que eran específicos de la infección por VIH (recuento de CD4, ARN del VIH-1 y la terapia antirretroviral). La búsqueda inicial arrojó N = 2657 estudios. Los estudios seleccionados según criterio incluyeron muerte por suicidio, que el diseño del estudio fuera cuantitativo, y la publicación haya sido entre 1996 y 2020. 14 estudios cumplieron estos criterios de inclusión para el estudio. PVV comparten los mismos factores de riesgo de suicidio que se encuentran en la población general: enfermedad psiquiátrica, intento previo de suicidio, abuso de drogas y alcohol. PVV también poseen factores de riesgo de suicidio propios del VIH. El diagnóstico de VIH en los últimos dos años y la transmisión relacionada con el uso de drogas inyectables se asociaron con un mayor riesgo; mientras que el ARN del VIH-1, la terapia antirretroviral y las enfermedades definidas del SIDA no fueron asociadas con un mayor riesgo de suicidio.

Cognitive behavioral therapy for insomnia has sustained effects on insomnia, fatigue, and function among people with chronic heart failure and insomnia: the HeartSleep Study.

STUDY OBJECTIVES: Insomnia is common among adults with chronic heart failure (HF) and associated with daytime symptoms and decrements in function. The purpose of this randomized controlled trial (RCT) was to evaluate the sustained effects over one year of CBT-I (Healthy Sleep: HS) compared with HF self-management education (Healthy Hearts; attention control: HH) on insomnia severity, sleep characteristics, symptoms, and function among people with stable HF. The primary outcomes were insomnia severity, actigraph-recorded sleep efficiency, and fatigue. METHODS: We randomized adults with stable HF with preserved or reduced ejection fraction who had at least mild insomnia (Insomnia severity index >7) in groups to HS or HH (4 sessions/8 weeks). We obtained wrist actigraphy and measured insomnia severity, self-reported sleep characteristics, symptoms (fatigue, excessive daytime sleepiness, anxiety, depression), and six-minute walk distance at baseline, within one month of treatment, and at 6 and 12 months. We used general linear mixed models (GLMM) and generalized estimating equations (GEE) to evaluate the effects. RESULTS: The sample included 175 participants (M age = 63 ± 12.9 years; 43% women; 18% Black; 68% New York Heart Association Class II or II; 33%; LVEF < 45%) randomized to HS (n = 91) or HH (n = 84). HS had sustained effects on insomnia severity, sleep quality, self-reported sleep latency and efficiency, fatigue, excessive daytime sleepiness, and six-minute walk distance at 12 months. CONCLUSIONS: CBT-I produced sustained improvements in insomnia, fatigue, daytime sleepiness, and objectively measured physical function among adults with chronic HF, compared with a robust HF self-management program that included sleep hygiene education. CLINICAL TRIAL INFORMATION: Insomnia Self-Management in Heart Failure; https://clinicaltrials.gov/ct2/show/NCT02660385; NCT02660385.

Anxiety Symptoms After Orthopedic Injury: A Systematic Review.

BACKGROUND: Millions of Americans are injured each year, with 75% suffering orthopedic injuries. Those with orthopedic injury often experience postinjury symptoms, such as anxiety, that negatively influence long-term outcomes. The purpose of this systematic review was to evaluate (1) the prevalence of anxiety symptoms chronologically in relation to time of orthopedic injury, (2) the associations of anxiety symptoms with other symptoms in individuals with orthopedic injury, and (3) the associations between anxiety symptoms and functional performance and mental health outcomes in individuals with orthopedic injury. METHODS: The databases CINAHL, Ovid MEDLINE, Ovid PsycInfo, Ovid Embase, ProQuest, and ClinicalTrials.gov were searched on June 25, 2020. Studies were selected for review if (1) participants were 16 years or older, (2) the prevalence of anxiety symptoms was listed, (3) anxiety symptoms were assessed using a validated instrument, (4) the study was published in English, and (5) more than 50% of the participants suffered orthopedic injury to the appendicular skeleton or pelvic ring. RESULTS: Anxiety symptoms were present in 11.5%-55.9% of individuals up to 10 years after orthopedic injury and often co-occurred with those of depression, pain, and posttraumatic stress disorder to negatively influence functional performance and mental health outcomes. CONCLUSIONS: Anxiety symptoms post-orthopedic injury are highly prevalent and persistent. Anxiety symptoms are associated with other distressing symptoms and influence long-term outcomes. These findings highlight the need to screen for and treat anxiety symptoms following orthopedic injury and may help in designing future self-management interventions.

Symptom cluster profiles following traumatic orthopedic injuries: A protocol.

Traumatic injuries affect millions of Americans annually, resulting in $671 billion in healthcare costs and lost productivity. Postinjury symptoms, like pain, sleep disturbance, anxiety, depression, and stressor-related disorders are highly prevalent following traumatic orthopedic injuries (TOI) and may contribute to negative long-term outcomes. Symptoms rarely present in isolation, but in clusters of two or more symptoms that co-occur to affect health in aggregate. Identifying symptom cluster profiles following TOI may identify those at highest risk for negative outcomes. Dysregulation of brain-derived neurotrophic factor (BDNF) is a potential biological mechanism responsible for symptom cluster profile membership after TOI and may be targeted in future precision-health applications. The purpose of this paper is to present the protocol of a cross-sectional study designed to identify symptom cluster profiles and measure the extent to which the BDNF val66met mutation and serum concentration of BDNF are associated with membership in symptom cluster profiles. We plan to recruit 150 TOI survivors within the first 72 h of injury. The study aims are to (1) describe TOI survivors' membership in symptom cluster profiles, indicated by pain, sleep disturbance, and symptoms of anxiety, depression, and stressor-related disorders, immediately following a TOI; (2) examine associations between demographic and clinical factors and symptom cluster profile membership among TOI survivors; (3) test the hypothesis that low serum concentrations of BDNF are associated with membership among symptom cluster profiles following TOI; and (4) test the hypothesis that the presence of the val66met mutation on one or both alleles of the BDNF gene is associated with membership among symptom cluster profiles following TOI.

Are Geriatric Patients Who Sustain High-Energy Traumatic Injury Likely to Return to Functional Independence?

OBJECTIVES: To evaluate physical function and return to independence of geriatric trauma patients, to compare physical function outcomes of geriatric patients who sustained high-energy trauma with that of those who sustained low-energy trauma, and to identify predictors of physical function outcomes. DESIGN: Retrospective. SETTING: Urban Level I trauma center. PATIENTS: Study group of 216 patients with high-energy trauma and comparison group of 117 patients with low-energy trauma. INTERVENTION: Injury mechanism (high- vs. low-energy mechanism). MAIN OUTCOME MEASUREMENT: Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF) patient-reported outcome measure, and change in living situation and mobility. RESULTS: Physical function outcomes and return to independence differed between patients with high-energy and low-energy injuries. High-energy geriatric trauma patients had significantly higher PROMIS PF scores compared with low-energy geriatric trauma patients (PROMIS PF score 42.2 ± 10.4 vs. 24.6 ± 10.4, P < 0.001). High-energy geriatric trauma patients were able to ambulate outdoors without an assistive device in 67% of cases and were living independently 74% of the time in comparison with 28% and 45% of low-energy geriatric trauma patients, respectively (P < 0.001, P < 0.001). Multivariate linear regression analysis demonstrated that low-energy mechanism injury was independently associated with a 13.2 point reduction in PROMIS PF score (P < 0.001). CONCLUSIONS: Geriatric patients greater than 1 year out from sustaining a high-energy traumatic injury seem to be functioning within the expected range for their age, whereas low-energy trauma patients seem to be functioning substantially worse than both age-adjusted norms and their high-energy cohorts. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Is prescribed lower extremity weight-bearing status after geriatric lower extremity trauma associated with increased mortality?

OBJECTIVES: Evaluate whether mortality after discharge is elevated in geriatric fracture patients whose lower extremity weight-bearing is restricted. DESIGN: Retrospective cohort study SETTING: Urban Level 1 trauma center PATIENTS/PARTICIPANTS: 1746 patients >65 years of age INTERVENTION: Post-operative lower extremity weight-bearing status MAIN OUTCOME MEASURE: Mortality, as determined by the Social Security Death Index RESULTS: Univariate analysis demonstrated that patients who were weight-bearing as tolerated on bilateral lower extremities (BLE) had significantly higher 5-year mortality compared to patients with restricted weight-bearing on one lower extremity and restricted weight-bearing on BLE (30%, 21% and 22% respectively, p < 0.001). Cox regression analysis controlling for variables including age, Charlson Comorbidity Index, Injury Severity Scale, combined UE/LE injury, injury mechanism (high vs low), sex, BMI and GCS demonstrated that, in comparison to patients who were weight bearing as tolerated on BLE, restricted weight-bearing on one lower extremity had a hazard ratio (HR) of 0.97 (95% confidence interval 0.78 to 1.20, p = 0.76) and restricted weight-bearing in BLE had a HR of 0.91 (95% confidence interval 0.60 to 1.36, p = 0.73). CONCLUSIONS: In geriatric patients, prescribed weight-bearing status did not have a statistically significant association with mortality after discharge, when controlling for age, sex, body mass index, medical comorbidities, Injury Severity Scale (ISS), mechanism of injury, nonoperative treatment and admission GCS. This remained true in when the analysis was restricted to operative injuries only.

Survivorship After High-Energy Geriatric Trauma.

OBJECTIVES: To evaluate in-hospital, 1-year, and 5-year survivorship of geriatric patients after high-energy trauma, to compare survivorship of geriatric patients who sustained high-energy trauma with that of those who sustained low-energy trauma, and to identify predictors for mortality. DESIGN: Retrospective. SETTING: Urban Level I trauma center. PATIENTS: Study group of 1849 patients with high-energy trauma and comparison group of 761 patients with low-energy trauma. INTERVENTION: Each patient was observed from the time of index admission through the end of the study period or until death or readmission. MAIN OUTCOME MEASUREMENT: Long-term survivorship based on the Social Security Death Index. RESULTS: Survivorship between patients with high-energy and low-energy injuries was statistically significant. Among patients who sustained high-energy injuries, in-hospital mortality was 8%, 1-year mortality was 15%, and 5-year mortality was 25%. Among patients who sustained low-energy injuries, in-hospital mortality was 3%, 1-year mortality was 23%, and 5-year mortality was 40%. Low-energy mechanism of injury was an independent predictor for 1-year and 5-year mortality, even when controlling for Charlson Comorbidity Index (CCI), Injury Severity Score (ISS), age, sex, body mass index (BMI), and admission Glasgow Coma Scale (GCS) score. CONCLUSIONS: Geriatric patients with high-energy injuries and those with low-energy injuries seem to represent different patient populations, and low-energy mechanism seems to be a marker for frailty. High-energy mechanism was associated with lower long-term mortality rates, even when controlling for CCI, ISS, age, sex, BMI and admission GCS score. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.