Improving public health by improving clinical trial guidelines and their application.

Evidence generated from randomized controlled trials forms the foundation of cardiovascular therapeutics and has led to the adoption of numerous drugs and devices that prolong survival and reduce morbidity, as well as the avoidance of interventions that have been shown to be ineffective or even unsafe. Many aspects of cardiovascular research have evolved considerably since the first randomized trials in cardiology were conducted. In order to be large enough to provide reliable evidence about effects on major outcomes, cardiovascular trials may now involve thousands of patients recruited from hundreds of clinical sites in many different countries. Costly infrastructure has developed to meet the increasingly complex organizational and operational requirements of these clinical trials. Concerns have been raised that this approach is unsustainable, inhibiting the reliable evaluation of new and existing treatments, to the detriment of patient care. These issues were considered by patients, regulators, funders, and trialists at a meeting of the European Society of Cardiology Cardiovascular Roundtable in October 2015. This paper summarizes the key insights and discussions from the workshop, highlights subsequent progress, and identifies next steps to produce meaningful change in the conduct of cardiovascular clinical research.

Low-grade inflammation may moderate the effect of behavioral treatment for chronic pain in adults.

The purpose of the present pilot study was to explore the moderating role of basal inflammation on the effects of behavioral pain treatment in 41 patients with long-standing pain. Baseline pro-inflammatory status moderated behavioral treatment outcomes: higher pre-treatment levels of Tumor Necrosis Factor (TNF)-α and Interleukin (IL)-6 were related to less improvement in pain intensity, psychological inflexibility and in mental health-related quality of life. The treatment outcomes improved in the subgroup that had low levels of pro-inflammatory cytokines at baseline, while the subjects with higher pro-inflammatory status did not. Altogether, results indicate that low-grade inflammation may influence the behavioral treatment outcomes and provide a possible explanation of the heterogeneity in treatment response.

CS1, a controlled-release formulation of valproic acid, for the treatment of patients with pulmonary arterial hypertension: Rationale and design of a Phase 2 clinical trial.

Although rare, pulmonary arterial hypertension (PAH) is associated with substantial morbidity and a median survival of approximately 7 years, even with treatment. Current medical therapies have a primarily vasodilatory effect and do not modify the underlying pathology of the disease. CS1 is a novel oral, controlled-release formulation of valproic acid, which exhibits a multi-targeted mode of action (pulmonary pressure reduction, reversal of vascular remodeling, anti-inflammatory, anti-fibrotic, and anti-thrombotic) and therefore potential for disease modification and right ventricular modeling in patients with PAH. A Phase 1 study conducted in healthy volunteers indicated favorable safety and tolerability, with no increased risk of bleeding and significant reduction of plasminogen activator inhibitor 1. In an ongoing randomized Phase 2 clinical trial, three doses of open-label CS1 administered for 12 weeks is evaluating the use of multiple outcome measures. The primary endpoint is safety and tolerability, as measured by the occurrence of adverse events. Secondary outcome measures include the use of the CardioMEMS™ HF System, which provides a noninvasive method of monitoring pulmonary artery pressure, as well as cardiac magnetic resonance imaging and echocardiography. Other outcomes include changes in risk stratification (using the REVEAL 2.0 and REVEAL Lite 2 tools), patient reported outcomes, functional capacity, 6-min walk distance, actigraphy, and biomarkers. The pharmacokinetic profile of CS1 will also be evaluated. Overall, the novel design and unique, extensive clinical phenotyping of participants in this trial will provide ample evidence to inform the design of any future Phase 3 studies with CS1.

The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms.

BACKGROUND: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations. METHODS: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (ß-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-ß-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0-10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions. RESULTS AND CONCLUSIONS: Only ß-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-ß-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-ß-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation.

Background: Chronic sickness behavior is implicated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain but the level of subjective sickness behavior in these conditions has not been investigated or compared to other clinical and non-clinical samples, or to the level in experimental inflammation. Furthermore, the relationship between sickness behavior and self-rated health and functioning is not known in patients with ME/CFS and chronic pain. The aim of the present study was to investigate how sickness behavior in patients with chronic conditions differs from that in individuals with experimental acute sickness, primary care patients, the general population and healthy subjects. In addition, we wanted to explore how sickness behavior is related to self-rated health and health-related functioning. Methods: Sickness behavior was quantified using the sickness questionnaire (SicknessQ). Self-ratings were collected at one time-point in 6 different samples. Levels of sickness behavior in patients with ME/CFS (n â€‹= â€‹38) and patients with chronic pain (n â€‹= â€‹190) were compared to healthy subjects with lipopolysaccharide(LPS)-induced inflammation (n â€‹= â€‹29), primary care patients (n â€‹= â€‹163), individuals from the general population (n â€‹= â€‹155) and healthy subjects (n â€‹= â€‹48), using linear regression. Correlations and moderated regression analyses were used to investigate associations between sickness behavior and self-rated health and health-related functioning in ME/CFS, chronic pain and the general population. Results: LPS-injected individuals (M â€‹= â€‹16.3), patients with ME/CFS (M â€‹= â€‹16.1), chronic pain (M â€‹= â€‹16.1) and primary care patients (M â€‹= â€‹10.7) reported significantly higher SicknessQ scores than individuals from the general population (M â€‹= â€‹5.4) and healthy subjects (M â€‹= â€‹3.6) all p's â€‹< â€‹0.001). In turn, LPS-injected individuals, patients with ME/CFS and chronic pain reported significantly higher SicknessQ scores than primary care patients (p's â€‹< â€‹0.01). Higher levels of sickness behavior were associated with poorer self-rated health and health-related functioning (p's â€‹< â€‹0.01), but less so in patients with ME/CFS and chronic pain than in individuals from the general population. Conclusions: Patients with ME/CFS and chronic pain report similar high levels of sickness behavior; higher than primary care patients, and comparable to levels in experimental inflammation. Further study of sickness behavior in ME/CFS and chronic pain populations is warranted as immune-to-brain interactions and sickness behavior may be of importance for functioning as well as in core pathophysiological processes in subsets of patients.

Infants' and toddlers' remembering and forgetting of a stressful medical procedure.

OBJECTIVE: To examine whether a distressing medical procedure leaves lasting impressions in young children's memories. METHODS: Children 12- to 78-weeks old (N = 172) received inhalation treatment through a face mask or underwent other interventions at a pediatric emergency department. They were randomized to be presented with neutral cues and cues from the inhalation 1 week or 6 months after the target event. Children's reactions at cue presentation were scored from videotapes. RESULTS: Across the age span tested, children treated with inhalation showed higher distress than controls when presented with cues from inhalation 1 week, but not 6 months after target treatment. CONCLUSIONS: Stress during medical procedures in preverbal children may develop as a result of prior experience of such procedures. These memories typically seem to fade within 6 months.

Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17.

Coronary artery disease (CAD) is a leading cause of death world-wide, and most cases have a complex, multifactorial aetiology that includes a substantial heritable component. Identification of new genes involved in CAD may inform pathogenesis and provide new therapeutic targets. The PROCARDIS study recruited 2,658 affected sibling pairs (ASPs) with onset of CAD before age 66 y from four European countries to map susceptibility loci for CAD. ASPs were defined as having CAD phenotype if both had CAD, or myocardial infarction (MI) phenotype if both had a MI. In a first study, involving a genome-wide linkage screen, tentative loci were mapped to Chromosomes 3 and 11 with the CAD phenotype (1,464 ASPs), and to Chromosome 17 with the MI phenotype (739 ASPs). In a second study, these loci were examined with a dense panel of grid-tightening markers in an independent set of families (1,194 CAD and 344 MI ASPs). This replication study showed a significant result on Chromosome 17 (MI phenotype; p = 0.009 after adjustment for three independent replication tests). An exclusion analysis suggests that further genes of effect size lambda(sib) > 1.24 are unlikely to exist in these populations of European ancestry. To our knowledge, this is the first genome-wide linkage analysis to map, and replicate, a CAD locus. The region on Chromosome 17 provides a compelling target within which to identify novel genes underlying CAD. Understanding the genetic aetiology of CAD may lead to novel preventative and/or therapeutic strategies.

Can exposure and acceptance strategies improve functioning and life satisfaction in people with chronic pain and whiplash-associated disorders (WAD)? A randomized controlled trial.

Although 14% to 42% of people with whiplash injuries end up with chronic debilitating pain, there is still a paucity of empirically supported treatments for this group of patients. In chronic pain management, there is increasing consensus regarding the importance of a behavioural medicine approach to symptoms and disability. Cognitive behaviour therapy has proven to be beneficial in the treatment of chronic pain. An approach that promotes acceptance of, or willingness to experience, pain and other associated negative private events (e.g. fear, anxiety, and fatigue) instead of reducing or controlling symptoms has received increasing attention. Although the empirical support for treatments emphasizing exposure and acceptance (such as acceptance and commitment therapy) is growing, there is clearly a need for more outcome studies, especially randomized controlled trials. In this study, participants (N = 21) with chronic pain and whiplash-associated disorders were recruited from a patient organization and randomized to either a treatment or a wait-list control condition. Both groups continued to receive treatment as usual. In the experimental condition, a learning theory framework was applied to the analysis and treatment. The intervention consisted of a 10-session protocol emphasizing values-based exposure and acceptance strategies to improve functioning and life satisfaction by increasing the participants' abilities to behave in accordance with values in the presence of interfering pain and distress (psychological flexibility). After treatment, significant differences in favor of the treatment group were seen in pain disability, life satisfaction, fear of movements, depression, and psychological inflexibility. No change for any of the groups was seen in pain intensity. Improvements in the treatment group were maintained at 7-month follow-up. The authors discuss implications of these findings and offer suggestions for further research in this area.

Exposure and acceptance in the rehabilitation of adolescents with idiopathic chronic pain - a pilot study.

For chronic pain of unclear origin (idiopathic), pharmacological therapy is often insufficient. Psychological treatment strategies have been developed and evaluated for adults with chronic pain. However, few such studies are seen with youths, and to date there is limited empirical evidence regarding the effectiveness of psychological treatment for generalized musculoskeletal pain syndromes in adolescents. Acceptance and commitment therapy (ACT) is a development of cognitive behaviour therapy emphasizing exposure and acceptance. In this pilot study, 14 adolescents referred to the pain treatment service due to chronic debilitating pain were treated using an ACT-based approach. It was hypothesized that avoidance of pain and related stimuli was central to the disability seen among these patients, and that exposure and acceptance strategies could increase functioning and decrease pain. In contrast to emphasizing reductions in pain and distress, the treatment objective was to improve functioning by increasing the patient's ability to act in line with personal values in the presence of negative thoughts, emotions or bodily sensations. Following treatment, and retained at 3- and 6-month follow-up, improvements in functional ability, school attendance, catastrophizing and pain (i.e., intensity and interference) were seen. The outcome of this pilot study indicates that exposure and acceptance can been useful in the rehabilitation of adolescents with chronic debilitating pain. Randomized controlled studies are needed to empirically evaluate the effectiveness of this approach.

Exploring Changes in Valued Action in the Presence of Chronic Debilitating Pain in Acceptance and Commitment Therapy for Youth - A Single-Subject Design Study.

Objective: The objective of the study was to improve the understanding of processes of change in Acceptance and Commitment Therapy for youth with chronic debilitating pain by exploring the relation between individual change patterns in pain intensity and valued activities. Method: A single-subject design across three adolescents suffering from longstanding debilitating pain was utilized. Pain intensity and participation in valued activities were rated daily. Visual analysis of the graphed data was performed to evaluate the effects of the intervention, and the relationship between pain intensity and values-based activity. Results: The graphed data illustrated that pain levels did not decrease from the baseline period to the follow-up period. In contrast, compared to baseline ratings values oriented behaviors increased from the start of treatment to the follow-up period. Conclusion: Results illustrate that increases in values-based behavior may occur without corresponding decreases in pain, and warrant further research on change processes in ACT for youth suffering from chronic pain.

Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study.

BACKGROUND: Limited prospective epidemiological data are available on the relation between exposure to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and hepatitis A virus (HAV), individually or as a total pathogen score, and human cardiovascular (CV) disease. METHODS AND RESULTS: We analyzed enrollment sera from 3168 Canadian patients in the Heart Outcomes Prevention Evaluation (HOPE) study for antibodies to C pneumoniae, H pylori, CMV, and HAV and measured the relation between serostatus and 494 adjudicated trial outcomes of myocardial infarction, stroke, or CV death over 4.5 years of follow-up. CV events were associated with CMV serostatus (covariate-adjusted hazard ratio [HR], 1.24; 95% CI, 1.01, 1.53). Neither C pneumoniae IgG (adjusted HR, 0.87; 95% CI, 0.68, 1.10), C pneumonia IgA (adjusted HR, 1.10; 95% CI, 0.90, 1.34), H pylori IgG (HR, 0.99; 95% CI, 0.82, 1.19), nor HAV IgG (HR, 1.01; 95% CI, 0.83, 1.24) predicted CV events. Total pathogen score was associated with CV events (adjusted HR for 4 versus 1 or 0=1.41; 95% CI, 1.02, 1.96). CONCLUSIONS: Exposure to CMV but not to C pneumoniae, H pylori, or HAV was associated with a slight excess risk of subsequent myocardial infarction, stroke, or CV death in HOPE study patients, and total pathogen score based on these infections predicted a small increased hazard of CV events.

Efficacy and Cost-effectiveness of Acceptance and Commitment Therapy and Applied Relaxation for Longstanding Pain: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: To date, few studies have compared Acceptance and Commitment Therapy (ACT) for longstanding pain with established treatments. Only 1 study has evaluated the cost-effectiveness of ACT. The aim of the current study was to evaluate the efficacy and cost-effectiveness of ACT and applied relaxation (AR) for adults with unspecific, longstanding pain. MATERIALS AND METHODS: On the basis of the inclusion criteria 60 consecutive patients received 12 weekly group sessions of ACT or AR. Data were collected pretreatment, midtreatment, and posttreatment, as well as at 3- and 6-month follow-up. Growth curve modeling was used to analyze treatment effects on pain disability, pain intensity, health-related quality of life (physical domain), anxiety, depression, and acceptance. RESULTS: Significant improvements were seen across conditions (pretreatment to follow-up assessment) on all outcome measures. Pain disability decreased significantly in ACT relative to AR from preassessment to postassessment. A corresponding decrease in pain disability was seen in AR between postassessment and 6-month follow-up. Pain acceptance increased only in ACT, and this effect was maintained at 6-month follow-up. Approximately 20% of the participants achieved clinically significant change after treatment. Health economic analyses showed that ACT was more cost-effective than AR at post and 3-month follow-up assessment, but not at 6-month follow-up. DISCUSSION: More studies investigating moderators and mediators of change are needed. The present study is one of few that have evaluated the cost-effectiveness of ACT and AR and compared ACT with an established behavioral intervention, and the results provide additional support for behavioral interventions for longstanding pain.

A family with abdominal aortic aneurysms.

This investigation focused on 7 siblings to 2 brothers with abdominal aortic aneurysm (AAA), with respect to AAA, Chlamydia pneumoniae (CP) serology, serum cholesterol, and smoking habits. Five male and 4 female siblings were included. All siblings underwent ultrasonography, and surgical specimens from the aorta were prepared for immunohistochemical (IHC) analysis. Blood was obtained from all living siblings and serum cholesterol level was analyzed. Serologic analysis was done by microimmunofluorescence (MIF). Smoking habits were recorded. In addition to the 2 known siblings with AAA, 2 other brothers with AAA were found. Four of 8 siblings had IgG 1/512 or greater and 7 of 8 had IgA 1/64 or greater. Two of 3 were positive for CP in IHC obtained from aortic specimens. Two of 8 had hypercholesterolemia; 7 of 9 were smokers. C. pneumoniae as well as smoking seems to be important in the pathogenesis of AAA in this small cohort; however, larger patient cohorts are needed.

Cognitive Behavioral Therapy increases pain-evoked activation of the prefrontal cortex in patients with fibromyalgia.

Interventions based on Cognitive Behavioral Therapy (CBT) are widely used to treat chronic pain, but the brain mechanisms responsible for these treatment effects are poorly understood. The aim of this study was to validate the relevance of the cortical control theory in response to an exposure-based form of CBT, Acceptance and Commitment Therapy, in patients with chronic pain. Forty-three female patients diagnosed with fibromyalgia syndrome were enrolled in a randomized, 12-week, waiting-list controlled clinical trial (CBT n=25; controls n=18). CBT was administered in groups of six patients during 12 weekly sessions. Functional magnetic resonance imaging (fMRI) during pressure-evoked pain was assessed before and after treatment or the 12-week period. Self-report questionnaires of depression and anxiety were administered pre- and posttreatment as well as 3 months following end of treatment. Patients treated with CBT reported larger improvement of fibromyalgia on the Patient Global Impression of Change measure, and improved depression and anxiety symptoms, compared to the waiting-list controls. However, there were no effects on clinical pain or pain sensitivity measures. An analysis of fMRI scans revealed that CBT led to increased activations in the ventrolateral prefrontal/lateral orbitofrontal cortex; regions associated with executive cognitive control. We suggest that CBT changes the brain's processing of pain through an altered cerebral loop between pain signals, emotions, and cognitions; leading to increased access to executive regions for reappraisal of pain. Our data thereby support our hypothesis about the activation of a cortical control mechanism in response to CBT treatment in chronic pain.

Mediators of change in acceptance and commitment therapy for pediatric chronic pain.

Even though psychological interventions are well established in the treatment of pediatric chronic pain, there is a clear need for further development, especially with severely disabled patients. However, optimizing effectiveness in psychological treatments for pain requires clarification of the mechanisms of action. Studies addressing change processes are scarce, however, particularly in relation to pediatric chronic pain. Acceptance and Commitment Therapy (ACT), as an extension of traditional cognitive behavior therapy, is essentially aimed at improving functioning by increasing the ability to act effectively in the presence of pain and distress, that is, psychological flexibility. ACT has shown promising results for both adult and pediatric chronic pain. In the present study, the mediators of change in an ACT-oriented treatment for pediatric chronic pain were examined using a bootstrapped cross product of coefficients approach. Pain interference and depression were used as outcome variables. Six different variables relevant to theories underlying ACT and cognitive behavior therapy were included in the analyses as possible mediators of change: pain impairment beliefs, pain reactivity, self-efficacy, kinesiophobia, catastrophizing, and pain intensity. Results illustrated that pain impairment beliefs and pain reactivity were the only variables that significantly mediated the differential effects of treatment on outcomes at follow-up. Also, these 2 mediators were shown to independently predict effects in outcome variables at follow-up while controlling for earlier effects in outcome, but only for the ACT condition. Although tentative, the pattern of results suggests that variables consistent with psychological flexibility mediate the effects of ACT-based interventions to improve functioning in patients with chronic debilitating pain.