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After more than a decade of electronic cigarette (E-cig) use in the United States, uncertainty persists regarding E-cig use and long-term cardiopulmonary disease risk. As all E-cigs use propylene glycol and vegetable glycerin (PG-VG) and generate abundant saturated aldehydes, mice were exposed by inhalation to PG-VG–derived aerosol, formaldehyde (FA), acetaldehyde (AA), or filtered air. Biomarkers of exposure and cardiopulmonary injury were monitored by mass spectrometry (urine metabolites), radiotelemetry (respiratory reflexes), isometric myography (aorta), and flow cytometry (blood markers). Acute PG-VG exposure significantly affected multiple biomarkers including pulmonary reflex (decreased respiratory rate, −50%), endothelium-dependent relaxation (−61.8 ± 4.2%), decreased WBC (−47 ± 7%), and, increased RBC (+6 ± 1%) and hemoglobin (+4 ± 1%) versus air control group. Notably, FA exposure recapitulated the prominent effects of PG-VG aerosol on pulmonary irritant reflex and endothelial dysfunction, whereas AA exposure did not. To attempt to link PG-VG exposure with FA or AA exposure, urinary formate and acetate levels were measured by GC-MS. Although neither FA nor AA exposure altered excretion of their primary metabolite, formate or acetate, respectively, compared with air-exposed controls, PG-VG aerosol exposure significantly increased post-exposure urinary acetate but not formate. These data suggest that E-cig use may increase cardiopulmonary disease risk independent of the presence of nicotine and/or flavorings. This study indicates that FA levels in tobacco product-derived aerosols should be regulated to levels that do not induce biomarkers of cardiopulmonary harm. There remains a need for reliable biomarkers of exposure to inhaled FA and AA.NEW & NOTEWORTHY Use of electronic cigarettes (E-cig) induces endothelial dysfunction (ED) in healthy humans, yet the specific constituents in E-cig aerosols that contribute to ED are unknown. Our study implicates formaldehyde that is formed in heating of E-cig solvents (propylene glycol, PG; vegetable glycerin, VG). Exposure to formaldehyde or PG-VG–derived aerosol alone stimulated ED in female mice. As ED was independent of nicotine and flavorants, these data reflect a “universal flaw” of E-cigs that use PG-VG. [ABSTRACT FROM AUTHOR]

Electronic nicotine delivery systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol, and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and "respiratory braking"—biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or FA (5 ppm). Short-term exposures to PG: VG and FA-induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N - 1,3-thiazolidine-4-carboxylic acid, TCA; N - 1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h). 13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0 to 3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS. [ABSTRACT FROM AUTHOR]

Patients presenting for treatment of chronic pain often believe that pain reduction must be achieved before returning to normal functioning. However, treatment programs for chronic pain typically take a rehabilitative approach, emphasizing decreasing pain-related disability first with the expectation that pain reduction will follow. This information is routinely provided to patients, yet no studies have systematically examined the actual trajectories of pain and disability in a clinical care setting. In this study of youth with chronic pain (N = 94, 8 to 18 years), it was hypothesized that 1) functional disability and pain would decrease over the course of psychological treatment for chronic pain and 2) functional disability would decrease more quickly than pain intensity. Participants received cognitive behavioral therapy (CBT) for pain management (M = 5.6 sessions) plus standard medical care. The Functional Disability Inventory and a Numeric Rating Scale of average pain intensity were completed by the child at every CBT session. Hierarchical linear modeling was conducted to examine the longitudinal trajectories of disability and pain. Standardized estimates of the slopes of change were obtained to test differences in rates of change between pain and disability. Results showed an overall significant decline in functional disability over time. Although pain scores reduced slightly from pretreatment to posttreatment, the longitudinal decline over treatment was not statistically significant. As expected, the rate of change of disability was significantly more rapid than pain. Evidence for variability in treatment response was noted, suggesting the need for additional research into individual trajectories of change in pediatric pain treatment. [ABSTRACT FROM AUTHOR]

Abstract: Pain behaviors provide meaningful information about adolescents in chronic pain, enhancing their verbal report of pain intensity with information about the global pain experience. Caregivers likely consider these expressions when making judgments about their adolescents’ medical or emotional needs. Current validated measures of pain behavior target acute or procedural pain and young or non-verbal children, while observation systems may be too cumbersome for clinical practice. The objective of this research was to design and evaluate the Adolescent Pain Behavior Questionnaire (APBQ), a parent-report measure of adolescent (11–19years) pain expressions. This paper provides preliminary results on reliability and validity of the APBQ. Parent-adolescent dyads (N =138) seen in a multidisciplinary pain management clinic completed the APBQ and questionnaires assessing pain characteristics, quality of life, functional disability, depressive symptoms, and pain catastrophizing. Principal components analysis of the APBQ supported a single component structure. The final APBQ scale contained 23 items with high internal consistency (α =0.93). No relationship was found between parent-reported pain behaviors and adolescent-reported pain intensity. However, significant correlations were found between parent-reported pain behaviors and parent- and adolescent-reported functional disability, pain catastrophizing, depressive symptoms, and poorer quality of life. The assessment of pain behaviors provides qualitatively different information than solely recording pain intensity and disability. It has clinical utility for use in behavioral treatments seeking to reduce disability, poor coping, and distress. [Copyright &y& Elsevier]

Although crotonaldehyde (CR) is an abundant α,β-unsaturated aldehyde in mainstream cigarette smoke (MCS), the cardiovascular toxicity of inhaled CR is largely unexplored. Thus, male C57BL/6 J mice were exposed acutely (1 h, 6 h, and 4d) and chronically (12 weeks) to CR (at levels relevant to MCS; 1 and 3 ppm), and cardiovascular and systemic outcomes were measured in vivo and in vitro. Diastolic blood pressure was decreased (hypotension) by both acute and chronic CR exposure. Vascular toxicity of inhaled CR was quantified in isolated aorta in response to agonists of contraction (phenylephrine, PE) and relaxation (acetylcholine, ACh; sodium nitroprusside, SNP). Although no change in contractility was observed, ACh-induced relaxations were augmented after both acute and chronic CR exposures whereas SNP-induced relaxation was enhanced only following 3 ppm CR exposure. Because CR is a known agonist of the transient receptor potential ankyrin 1 (TRPA1) channel, male TRPA1-null mice were exposed to air or CR (4d, 1 ppm) and aortic function assessed in vitro. CR exposure had no effect on TRPA1-null aortic function indicating a role of TRPA1 in CR effects in C57BL/6 J mice. Notably, CR exposure (4d, 1 ppm) had no effect on aortic function in female C57BL/6 J mice. This study shows that CR inhalation exposure induces real-time and persistent vascular changes that promote hypotension—a known risk factor for stroke. Because of continued widespread exposures of humans to combustion-derived CR (environmental and tobacco products), CR may be an important cardiovascular disease risk factor. Unlabelled Image • HPMMA is the primary urinary metabolite of crotonaldehyde exposure in mice. • Acute and chronic inhalation exposure of mice to crotonaldehyde (1 ppm) led to hypotension. • Acute and chronic inhalation exposure of mice to crotonaldehyde enhanced aortic relaxations. • Aortic dysfunction induced by crotonaldehyde exposure in mice was TRPA1-dependent. [ABSTRACT FROM AUTHOR]

Abstract: The primary objective of this study was to estimate a clinically significant and quantifiable change in functional disability to identify treatment responders in a clinical trial of cognitive-behavioral therapy (CBT) for youth with juvenile fibromyalgia (JFM). The second objective was to examine whether baseline functional disability (Functional Disability Inventory), pain intensity, depressive symptoms (Children’s Depression Inventory), coping self-efficacy (Pain Coping Questionnaire), and parental pain history predicted treatment response in disability at 6-month follow-up. Participants were 100 adolescents (11–18years of age) with JFM enrolled in a recently published clinical trial comparing CBT to a fibromyalgia education (FE) intervention. Patients were identified as achieving a clinically significant change in disability (ie, were considered treatment responders) if they achieved both a reliable magnitude of change (estimated as a ⩾7.8-point reduction on the FDI) using the Reliable Change Index, and a reduction in FDI disability grade based on established clinical reference points. Using this rigorous standard, 40% of patients who received CBT (20 of 50) were identified as treatment responders, compared to 28% who received FE (14 of 50). For CBT, patients with greater initial disability and higher coping efficacy were significantly more likely to achieve a clinically significant improvement in functioning. Pain intensity, depressive symptoms, and parent pain history did not significantly predict treatment response. Estimating clinically significant change for outcome measures in behavioral trials sets a high bar but is a potentially valuable approach to improve the quality of clinical trials, to enhance interpretability of treatment effects, and to challenge researchers to develop more potent and tailored interventions. [Copyright &y& Elsevier]

Juvenile-onset fibromyalgia (JFM) is typically diagnosed in adolescence and characterized by widespread pain and marked functional impairment. The long-term impact of JFM into adulthood is poorly understood. The objectives of this study were to describe physical and psychosocial outcomes of youth diagnosed with JFM in early adulthood (∼8-year follow-up), examine longitudinal trajectories of pain and depressive symptoms from adolescence to young adulthood, and examine the impact of pain and depressive symptoms on physical functioning over time. Participants were 97 youth with JFM enrolled in a prospective longitudinal study in which pain symptoms, and physical and psychosocial functioning were assessed at 4 time points over approximately 8 years. At the time 4 follow-up (Mage = 24.2 years), the majority continued to suffer from pain and impairment in physical, social, and psychological domains. However, trajectories of pain and emotional symptoms showed varying patterns. Longitudinal analysis using growth mixture modeling revealed 2 pain trajectories (Steady Improvement and Rapid Rebounding Improvement), whereas depressive symptoms followed 3 distinct trajectories (Low-Stable, Improving, and Worsening). Membership in the Worsening Depressive symptoms group was associated with poorer physical functioning over time (P < 0.001) compared with the Low-Stable and Improving groups. This study offers evidence that although JFM symptoms persist for most individuals, pain severity tends to decrease over time. However, depressive symptoms follow distinct trajectories that indicate subgroups of JFM. In particular, JFM patients with worsening depressive symptoms showed decreasing physical functioning and may require more intensive and consistent intervention to prevent long-term disability. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pediatric functional abdominal pain disorders are common, costly, and disabling. Clinical anxiety is highly prevalent and is associated with increased pain and functional disability. Thus, a psychological screening process is recommended but is infrequently used in current practice. METHODS: A screening process for patient-reported anxiety (Screen for Child Anxiety and Related Disorders), functional disability (Functional Disability Inventory), and pain levels was implemented in a large gastroenterology division within a major medical center. Quality improvement methods and traditional analytic approaches were used to test the feasibility and outcomes of routine screening in patients ages 8 to 18 with abdominal pain. RESULTS: Screening rates increased from <1% to >80%. A total of 1291 patients who reported having abdominal pain completed the screening during the first 6 months. Clinically significant anxiety (43.1%), at least moderate disability (45%), and elevated pain (61.5%) were common in children with abdominal pain. The presence of clinically significant anxiety corresponded with higher pain and pain-related disability. Twenty-one percent of youth had clinical elevations in all 3 areas. In such instances, medical providers received an automated prompt to tailor care, including to consider a psychological referral. After the project implementation, psychological referral rates increased from 8.3 per 1000 patients to 15.2 per 1000 patients. CONCLUSIONS: Systematic screening for anxiety, pain, and pain-related disability as a routine part of medical care can be reliably implemented with clinically meaningful results. Future directions include examining the role of anxiety over the long-term and reducing clinician burden. [ABSTRACT FROM AUTHOR]

Objective Juvenile fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder in children and adolescents for which there are no evidence-based treatments. The objective of this multisite, single-blind, randomized clinical trial was to test whether cognitive-behavioral therapy (CBT) was superior to fibromyalgia (FM) education in reducing functional disability, pain, and symptoms of depression in juvenile FMS. Methods Participants were 114 adolescents (ages 11-18 years) with juvenile FMS. After receiving stable medications for 8 weeks, patients were randomized to either CBT or FM education and received 8 weekly individual sessions with a therapist and 2 booster sessions. Assessments were conducted at baseline, immediately following the 8-week treatment phase, and at 6-month followup. Results The majority of patients (87.7%) completed the trial per protocol. Intent-to-treat analyses showed that patients in both groups had significant reductions in functional disability, pain, and symptoms of depression at the end of the study, and CBT was significantly superior to FM education in reducing the primary outcome of functional disability (mean baseline to end-of-treatment difference between groups 5.39 [95% confidence interval 1.57, 9.22]). Reduction in symptoms of depression was clinically significant for both groups, with mean scores in the range of normal/nondepressed by the end of the study. Reduction in pain was not clinically significant for either group (<30% decrease in pain). There were no study-related adverse events. Conclusion In this controlled trial, CBT was found to be a safe and effective treatment for reducing functional disability and symptoms of depression in adolescents with juvenile FMS. [ABSTRACT FROM AUTHOR]

Abstract: The Functional Disability Inventory (FDI) is a well-established and commonly used measure of physical functioning and disability in youth with chronic pain. Further validation of the measure has been called for, in particular, examination of the clinical utility and factor structure of the measure. To address this need, we utilized a large multicenter dataset of pediatric patients with chronic pain who had completed the FDI and other measures assessing pain and emotional functioning. Clinical reference points to allow for interpretation of raw scores were developed to enhance clinical utility of the measure, and exploratory factor analysis was performed to examine its factor structure. Participants included 1300 youth ages 8 to 18 years (mean=14.2 years; 76% female) with chronic pain. Examination of the distribution of FDI scores and validation with measures of depressive symptoms and pain intensity yielded 3 distinct categories of disability: No/Minimal Disability, Moderate Disability, and Severe Disability. Factor analysis of FDI scores revealed a 2-factor solution representing vigorous Physical Activities and non-physically strenuous Daily Activities. The 3-level classification system and factor structure were further explored via comparison across the 4 most commonly encountered pain conditions in clinical settings (head, back, abdominal, and widespread pain). Our findings provide important new information regarding the clinical utility and validity of the FDI. This will greatly enhance the interpretability of scores for research and clinical use in a wide range of pediatric pain conditions. In particular, these findings will facilitate use of the FDI as an outcome measure in future clinical trials. Clinical reference points and a preliminary factor structure for the Functional Disability Inventory (FDI) increase the clinical and research utility of the measure. [Copyright &y& Elsevier]

Objectives. Currently, there are no prospective studies exploring the prognosis of patients with juvenile primary FM syndrome (JPFS) or their physical, emotional and social outcomes as they enter the early adult years. The primary objective of this study was to assess long-term outcomes of a paediatric sample of clinically referred JPFS patients and their matched healthy controls.Methods. Participants were 48 youths (current mean age = 19 years) diagnosed with JPFS in childhood or adolescence and 43 healthy controls matched in age, gender and race. The average length of follow-up was 3.67 years (range 2–6 years). Participants completed online (web-based) self-report questionnaires about current pain and physical symptoms, health status, anxiety, depressive symptoms and current and past treatments.Results. Results showed that 62.5% of participants in the JPFS group continued to experience widespread pain and 60.4% reported having all the cardinal features of FM syndrome (including widespread pain, poor sleep and fatigue) at follow-up. The JPFS group reported significantly lower scores on all measures of health status and physical functioning compared with healthy controls and significantly greater symptoms of anxiety and depression.Conclusion. The results of this controlled follow-up study demonstrate that symptoms of FM appear to be chronic in a majority of clinically referred JPFS patients and the associated physical and emotional impairment can also be persistent. Implications for treatment and the need for further prospective longitudinal studies are discussed. [ABSTRACT FROM PUBLISHER]

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Exposure to air pollution, specifically particulate matter of diameter ≤2.5 μm (PM 2.5), is a well-established risk factor for CVD. However, the contribution of gaseous pollutant exposure to CVD risk is less clear. To examine the vascular effects of exposure to individual volatile organic compounds (VOCs) and mixtures of VOCs. We measured urinary metabolites of acrolein (CEMA and 3HPMA), 1,3-butadiene (DHBMA and MHBMA3), and crotonaldehyde (HPMMA) in 346 nonsmokers with varying levels of CVD risk. On the day of enrollment, we measured blood pressure (BP), reactive hyperemia index (RHI – a measure of endothelial function), and urinary levels of catecholamines and their metabolites. We used generalized linear models for evaluating the association between individual VOC metabolites and BP, RHI, and catecholamines, and we used Bayesian Kernel Machine Regression (BKMR) to assess exposure to VOC metabolite mixtures and BP. We found that the levels of 3HPMA were positively associated with systolic BP (0.98 mmHg per interquartile range (IQR) of 3HPMA; CI: 0.06, 1.91; P = 0.04). Stratified analysis revealed an increased association with systolic BP in Black participants despite lower levels of urinary 3HPMA. This association was independent of PM 2.5 exposure and BP medications. BKMR analysis confirmed that 3HPMA was the major metabolite associated with higher BP in the presence of other metabolites. We also found that 3HPMA and DHBMA were associated with decreased endothelial function. For each IQR of 3HPMA or DHBMA, there was a −4.4% (CI: −7.2, −0.0; P = 0.03) and a −3.9% (CI: −9.4, −0.0; P = 0.04) difference in RHI, respectively. Although in the entire cohort the levels of several urinary VOC metabolites were weakly associated with urinary catecholamines and their metabolites, in Black participants, DHBMA levels showed strong associations with urinary norepinephrine and normetanephrine levels. Exposure to acrolein and 1,3-butadiene is associated with endothelial dysfunction and may contribute to elevated risk of hypertension in participants with increased sympathetic tone, particularly in Black individuals. • Volatile organic compounds (VOCs) are major components of environmental pollution. • Exposure to VOCs is associated with high blood pressure and endothelial dysfunction. • Exposure to VOCs is also associated with increased levels of catecholamines. • Black participants were more susceptible to vascular changes in response to exposure. • Exposure to VOCs may be a significant risk factor in the development of heart disease. [ABSTRACT FROM AUTHOR]

Juvenile-onset fibromyalgia (JFM) is a chronic debilitating pain condition that negatively impacts physical, social and academic functioning. Cognitive-behavioral therapy (CBT) is beneficial in reducing functional disability among adolescents with JFM but has only a modest impact on pain reduction and does not improve physical exercise participation. This randomized controlled trial (RCT) aims to test whether a novel intervention that combines CBT with specialized neuromuscular exercise training (the Fibromyalgia Integrative Training program for Teens "FIT Teens") is superior to CBT alone or a graded aerobic exercise (GAE) program. This 3-arm multi-site RCT will examine the efficacy of the FIT Teens intervention in reducing functional disability (primary outcome) and pain intensity (secondary outcome), relative to CBT or GAE. All interventions are 8-weeks (16 sessions) in duration and are delivered in small groups of 4–6 adolescents with JFM. A total of 420 participants are anticipated to be enrolled across seven sites with approximately equal allocation to each treatment arm. Functional disability and average pain intensity in the past week will be assessed at baseline, post-treatment and at 3-, 6-, 9- and 12-month follow-up. The 3-month follow-up is the primary endpoint to evaluate treatment efficacy; longitudinal assessments will determine maintenance of treatment gains. Changes in coping, fear of movement, biomechanical changes and physical fitness will also be evaluated. This multi-site RCT is designed to evaluate whether the combined FIT Teens intervention will have significantly greater effects on disability and pain reduction than CBT or GAE alone for youth with JFM. Clinical trials.gov registration: NCT 03268421. [ABSTRACT FROM AUTHOR]