Study protocol for a three-arm randomized controlled trial investigating the effectiveness, cost-utility, and physiological effects of a fully self-guided digital Acceptance and Commitment Therapy for Spanish patients with fibromyalgia.

Objective: Fibromyalgia (FM) is a prevalent pain syndrome with significant healthcare and societal costs. The aim of the SMART-FM-SP study is to determine the effectiveness, cost-utility, and physiological effects in patients with FM of a digital intervention (STANZA®) currently marketed in the United States, which delivers smartphone-based, fully self-guided Acceptance and Commitment Therapy (Digital ACT) for treating FM-related symptoms. Methods: A single-site, parallel-group, superiority, randomized controlled trial (RCT) will be conducted, including a total of 360 adults diagnosed with FM. Individuals will be randomly allocated (1:1:1) to treatment as usual (TAU), to TAU plus 12 weeks of treatment with Digital ACT, or to TAU plus 12 weeks of treatment with digital symptom tracking (i.e. FibroST). Participants will be assessed at baseline, post-treatment, and 6-month follow-up. An intention-to-treat analysis using linear mixed models will be computed to analyze the effects of Digital ACT on functional impairment (primary outcome), as measured by the Fibromyalgia Impact Questionnaire Revised at 6 months from the inception of the treatment. Secondary outcomes include impression of change, symptoms of distress, pain catastrophising, quality of life, cost-utility, and selected biomarkers (cortisol and cortisone, immune-inflammatory markers, and FKBP5 gene polymorphisms). The role of ACT-related processes of change will be tested with path analyses. Conclusions: This study is the first RCT that tests Digital ACT for Spanish patients with FM. Results will be important not only for patients and clinicians, but also for policy makers by examining the cost-utility of the app in a public healthcare context.

Economic Evaluation of Videoconference Group Acceptance and Commitment Therapy and Behavioral Activation Therapy for Depression Versus Usual Care Among Adults With Chronic Low Back Pain Plus Comorbid Depressive Symptoms.

Chronic pain and depression are frequently comorbid conditions associated with significant health care and social costs. This study examined the cost-utility and cost-effectiveness of videoconference-based group forms of Acceptance and Commitment Therapy (ACT) and Behavioral Activation Therapy for Depression (BATD), as a complement to treatment-as-usual (TAU), for patients with chronic low back pain (CLBP) plus depressive symptoms, compared to TAU alone. A trial-based economic evaluation (n = 234) was conducted from a governmental and health care perspective with a time horizon of 12 months. Primary outcomes were the Brief Pain Inventory-Interference Scale (BPI-IS) and Quality Adjusted Life Year. Compared to TAU, ACT achieved a significant reduction in total costs (d = .47), and BATD achieved significant reductions in indirect (d = .61) and total costs (d = .63). Significant improvements in BPI-IS (d = .73 and d = .66, respectively) and Quality Adjusted Life Year scores (d = .46 and d = .28, respectively) were found in ACT and BATD compared to TAU. No significant differences in costs and outcomes were found between ACT and BATD. In the intention-to-treat analyses, from the governmental and health care perspective, no significant differences in cost reduction and incremental effects were identified in the comparison between ACT, BATD, and TAU. However, in the complete case analysis, significant incremental effects of ACT (∆BPI-IS = -1.57 and -1.39, respectively) and BATD (∆BPI-IS = -1.08 and -1.04, respectively) compared with TAU were observed. In the per-protocol analysis, only the significant incremental effects of ACT (∆BPI-IS = -1.68 and -1.43, respectively) compared to TAU were detected. In conclusion, ACT and BATD might be efficient options in the management of CLBP plus comorbid depression symptoms as compared to usual care. However, no clear difference was found in the comparison between the 2 active therapies regarding cost-effectiveness or cost-utility. PERSPECTIVE: The economic evaluation of psychological therapies for the management of complex conditions can be used in decision-making and resource allocation. This study provides evidence that ACT and BATD are more effective and involve a greater reduction in costs than usual care in the management of CLBP plus comorbid depressive symptoms. TRIAL NUMBER: NCT04140838.

Effectiveness of an online multicomponent program (FATIGUEWALK) for chronic fatigue syndrome: A randomized controlled trial.

OBJECTIVE: This study aimed to evaluate the effectiveness of an online multicomponent intervention called FATIGUEWALK (FaW) compared to treatment as usual (TAU) in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). METHOD: FaW included pain neuroscience education, therapeutic exercise, cognitive restructuring, and mindfulness training. A total of 428 patients with CFS/ME were randomized into two study arms: online FaW plus TAU versus TAU alone. A single-blinded randomized controlled trial was conducted. Validated patient-reported outcome measures of fatigue, pain, anxiety, depression, and physical function were collected at baseline and posttreatment, following the FaW intervention, which lasted 12 weeks. RESULTS: Statistically significant improvements (with small-to-moderate effect sizes) were observed in online FaW versus TAU alone with respect to multidimensional aspects of fatigue (Cohen's d ranging from 0.25 to 0.73) and most secondary outcomes (pain and fatigue intensity, depressive and anxious symptomatology, functional impairment, kinesiophobia, physical functioning). The absolute risk reduction in FaW versus TAU was 19%, 95% confidence interval (CI) [12.19, 25.80] with number needed to treat = 6, 95% CI [3.9, 8.2]. Overall, similar clinical improvements were observed in sensitivity analyses including a subgroup of patients without comorbidity with fibromyalgia (n = 70). CONCLUSIONS: This is the first study to assess the short-term effectiveness of an online multicomponent intervention added to TAU, compared to TAU alone, for the management of CFS/ME. Further trials, including active control groups with an equivalent treatment dose, and assessing the long-term effectiveness of the online FaW, are warranted. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Efficacy of Videoconference Group Acceptance and Commitment Therapy (ACT) and Behavioral Activation Therapy for Depression (BATD) for Chronic Low Back Pain (CLBP) Plus Comorbid Depressive Symptoms: A Randomized Controlled Trial (IMPACT Study).

This study examined the efficacy of adding a remote, synchronous, group, videoconference-based form of acceptance and commitment therapy (ACT) or behavioral activation therapy for depression (BATD) to treatment-as-usual (TAU) in 234 patients with chronic low back pain (CLBP) plus comorbid depressive symptoms. Participants were randomly assigned to ACT, BATD, or TAU. Compared to TAU, ACT produced a significant reduction in pain interference at posttreatment (d = .64) and at follow-up (d = .73). BATD was only superior to TAU at follow-up (d = .66). A significant reduction in pain catastrophizing was reported by patients assigned to ACT and BATD at posttreatment (d = .45 and d = .59, respectively) and at follow-up (d = .59, in both) compared to TAU. Stress was significantly reduced at posttreatment by ACT in comparison to TAU (d = .69). No significant between-group differences were found in depressive or anxiety symptoms. Clinically relevant number needed to treat (NNT) values for reduction in pain interference were obtained at posttreatment (ACT vs TAU = 4) and at follow-up (ACT vs TAU = 3; BATD vs TAU = 5). In both active therapies, improvements in pain interference at follow-up were significantly related to improvements at posttreatment in psychological flexibility. These findings suggest that new forms of cognitive-behavioral therapy are clinically useful in improving pain interference and pain catastrophizing. Further research on evidence-based change processes is required to understand the therapeutic needs of patients with chronic pain and comorbid conditions. TRIAL NUMBER: NCT04140838. PERSPECTIVE: Group videoconference-based ACT and BATD showed greater efficacy than TAU for reducing pain interference and pain catastrophizing in patients with CLBP plus clinically relevant depression. Psychological flexibility appeared to be the main contributor to treatment effects for both ACT and BATD.

A systematic review of cognitive behavioral therapy-based interventions for comorbid chronic pain and clinically relevant psychological distress.

Objective: Chronic pain frequently co-occurs with clinically relevant psychological distress. A systematic review was conducted to identify the efficacy of cognitive behavioral therapy-based interventions for patients with these comorbid conditions. Methods: The systematic search was carried out in Medline, PsycINFO, Web of Science, and Scopus up to March 18th, 2023. Four reviewers independently conducted screenings, extraction, and quality assessment. Results: Twelve randomized controlled trials and one non-randomized controlled trial involving 1,661 participants that examined the efficacy of Cognitive Behavioral Therapy (nine studies), Mindfulness-based Interventions (three studies), Acceptance and Commitment Therapy (one study), and Behavioral Activation Therapy for Depression (one study) were included. Compared to treatment as usual, six out of eight studies of traditional Cognitive Behavioral Therapy reported significant differences in the reduction of depressive symptoms at post-treatment (d from 1.31 to 0.18) and four out of six at follow-up (d from 0.75 to 0.26); similarly, five out of six reported significant differences in the reduction of anxiety symptoms at post-treatment (d from 1.08 to 0.19) and three out of four at follow-up (d from 1.07 to 0.27). Overall, no significant differences between traditional Cognitive Behavioral Therapy and treatment as usual were reported at post-treatment and follow-up in the studies exploring pain intensity and pain catastrophizing. Conclusion: The available evidence suggests that traditional Cognitive Behavioral Therapy may produce significant benefits for the improvement of depression, anxiety, and quality of life, but not for pain intensity and pain catastrophizing. More evidence is needed to determine the effects of MBI, ACT, and BATD. Systematic review registration: PROSPERO, CRD42021219921.

Effectiveness, cost-utility and physiological underpinnings of the FIBROWALK multicomponent therapy in online and outdoor format in individuals with fibromyalgia: Study protocol of a randomized, controlled trial (On&Out study).

Introduction: The On&Out study is aimed at assessing the effectiveness, cost-utility and physiological underpinnings of the FIBROWALK multicomponent intervention conducted in two different settings: online (FIBRO-On) or outdoors (FIBRO-Out). Both interventions have proved to be efficacious in the short-term but there is no study assessing their comparative effectiveness nor their long-term effects. For the first time, this study will also evaluate the cost-utility (6-month time-horizon) and the effects on immune-inflammatory biomarkers and Brain-Derived Neurotrophic Factor (BDNF) levels of both interventions. The objectives of this 6-month, randomized, controlled trial (RCT) are 1) to examine the effectiveness and cost-utility of adding FIBRO-On or FIBRO-Out to Treatment-As-Usual (TAU) for individuals with fibromyalgia (FM); 2) to identify pre-post differences in blood biomarker levels in the three study arms and 3) to analyze the role of process variables as mediators of 6-month follow-up clinical outcomes. Methods and analysis: Participants will be 225 individuals with FM recruited at Vall d'Hebron University Hospital (Barcelona, Spain), randomly allocated to one of the three study arms: TAU vs. TAU + FIBRO-On vs. TAU + FIBRO-Out. A comprehensive assessment to collect functional impairment, pain, fatigue, depressive and anxiety symptoms, perceived stress, central sensitization, physical function, sleep quality, perceived cognitive dysfunction, kinesiophobia, pain catastrophizing, psychological inflexibility in pain and pain knowledge will be conducted pre-intervention, at 6 weeks, post-intervention (12 weeks), and at 6-month follow-up. Changes in immune-inflammatory biomarkers [i.e., IL-6, CXCL8, IL-17A, IL-4, IL-10, and high-sensitivity C-reactive protein (hs-CRP)] and Brain-Derived Neurotrophic Factor will be evaluated in 40 participants in each treatment arm (total n = 120) at pre- and post-treatment. Quality of life and direct and indirect costs will be evaluated at baseline and at 6-month follow-up. Linear mixed-effects regression models using restricted maximum likelihood, mediational models and a full economic evaluation applying bootstrapping techniques, acceptability curves and sensitivity analyses will be computed. Ethics and dissemination: This study has been approved by the Ethics Committee of the Vall d'Hebron Institute of Research. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and various community engagement activities. Trial registration number NCT05377567 (clinicaltrials.gov).

Immune-inflammatory and hypothalamic-pituitary-adrenal axis biomarkers are altered in patients with non-specific low back pain: A systematic review.

This systematic review aimed to investigate immune-inflammatory and hypothalamic-pituitary-adrenal (HPA) axis biomarkers in individuals with non-specific low back pain (NSLBP) compared to healthy control. The search was performed in five databases until 4 November 2021. Two reviewers independently conducted screenings, data extraction, risk of bias, and methodological quality assessment of 14 unique studies. All studies reported the source of the fluid analyzed: nine studies used serum, two used plasma, one used serum and plasma, and two studies used salivary cortisol. We found preliminary and limited evidence (only one study for each biomarker) of increased levels in growth differentiation factor 15 (GDF-15), interleukin-23 (IL-23), transforming growth factor-beta (TGF-ß), and soluble tumor necrosis factor receptor 1 (sTNF-R1) in NSLBP. Inconsistent and limited evidence was identified for interleukin-10 (IL-10). Although C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels appear to increase in NSLBP, only one study per each biomarker reported statistically significant differences. Interleukin-1 beta (IL-1ß), interleukin-17 (IL-17), interferon gamma (IFN-γ), and high-sensitivity CRP (hsCRP) showed no significant differences. Regarding cortisol, one study showed a significant increase and another a significant decrease. More robust evidence between GDF-15, IL-23, TGF-ß, and sTNF-R1 with NSLBP is needed. Moreover, contrary to the findings reported in previous studies, when comparing results exclusively with healthy control, insufficient robust evidence for IL-6, TNF-α, and CRP was found in NSLBP. In addition, cortisol response (HPA-related biomarker) showed a dysregulated functioning in NSLBP, with incongruent evidence regarding its directionality. Therefore, our effort is to find adjusted evidence to conclude which immune-inflammatory and HPA axis biomarkers are altered in NSLBP and how much their levels are affected. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020176153, identifier CRD42020176153.

Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost-utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study).

INTRODUCTION: There is evidence that low-dose naltrexone (LDN; <5.0 mg/day) reduces pain and improves the quality of life of people with fibromyalgia syndrome (FMS). However, no randomised controlled trials with long-term follow-ups have been carried out. The INNOVA study will evaluate the add-on efficacy, safety, cost-utility and neurobiological effects of LDN for reducing pain in patients with FMS, with a 1-year follow-up. METHODS AND ANALYSIS: A single-site, prospective, randomised, double-blinded, placebo-controlled, parallel design phase III trial will be performed. Eligibility criteria include being adult, having a diagnosis of FMS and experiencing pain of 4 or higher on a 10-point numerical rating scale. Participants will be randomised to a LDN intervention group (4.5 mg/day) or to a placebo control group. Clinical assessments will be performed at baseline (T0), 3 months (T1), 6 months (T2) and 12 months (T3). The primary endpoint will be pain intensity. A sample size of 60 patients per study arm (120 in total), as calculated prior to recruitment for sufficient power, will be monitored between January 2022 and August 2024. Assessment will also include daily ecological momentary evaluations of FMS-related symptoms (eg, pain intensity, fatigue and sleep disturbance), and side effects via ecological momentary assessment through the Pain Monitor app during the first 3 months. Costs and quality-adjusted life years will be also calculated. Half of the participants in each arm will be scanned with MRI at T0 and T1 for changes in brain metabolites related to neuroinflammation and central sensitisation. Inflammatory biomarkers in serum will also be measured. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and community engagement activities. TRIAL REGISTRATION NUMBER: NCT04739995.

Do humor styles predict clinical response to the MINDSET (MINDfulneSs & EducaTion) program? A pilot study in patients with fibromyalgia / ¿Los estilos de humor predicen la respuesta clínica al programa MINDSET (MINDfulneSs & EducaTion)? Un estudio piloto en pacientes con fibromialgia

Background and aim: Humor has been described as an effective coping strategy for dealing with chronic pain conditions; likewise, coping strategies predict some clinical outcomes after cognitive-behavioral therapy and mindfulness-based interventions. The present study aims to preliminarily explore the role of humor styles in predicting clinical changes after the multicomponent intervention (MINDSET) that combines mindfulness and psychoeducation for fibromyalgia (FM) patients. Material and methods: A subsample of 35 patients with FM of the EUDAIMON study, a randomized controlled trial, was used for the present study; linear regressions and Spearman's correlations were computed. Results: Affiliative humor and positive/negative ratio humor styles had a unique predictive effect on self-reported clinical changes. Significant correlations between humor styles with functional impact and mindfulness facets were observed. Conclusions: Some humor styles may imply a better disposition in patients to learn and implement the concepts and resources that the intervention offered.(AU)

Antecedentes y objetivo: El humor se considera una estrategia de afrontamiento efectiva para afrontar enfermedades crónicas; asimismo, las estrategias de afrontamiento pueden predecir cambios clínicos experimentados tras intervenciones cognitivo-conductuales y basadas en mindfulness. El presente estudio explora el rol de los estilos de humor en la predicción de cambios clínicos tras una intervención multicomponente (MINDSET, mindfulness+psicoeducación) para pacientes con fibromialgia. Materiales y métodos: En este estudio participaron 35 pacientes con fibromialgia, una submuestra del ensayo controlado y aleatorizado del estudio EUDAIMON. Se realizaron regresiones lineales y correlaciones de Spearman. Resultados: El humor afiliativo y la ratio de estilos positivos/negativos mostraron un efecto predictor en cambios clínicos auto-reportados. Se observaron correlaciones significativas entre estilos de humor, impacto funcional y facetas de mindfulness. Conclusiones: Algunos estilos de humor pueden implicar una mejor predisposición en los pacientes para aprender y aplicar los recursos que la intervención ofrece.(AU)

Persistent Pulmonary Hypertension in Corrected Valvular Heart Disease: Hemodynamic Insights and Long-Term Survival.

Background The determinants and consequences of pulmonary hypertension after successfully corrected valvular heart disease remain poorly understood. We aim to clarify the hemodynamic bases and risk factors for mortality in patients with this condition. Methods and Results We analyzed long-term follow-up data of 222 patients with pulmonary hypertension and valvular heart disease successfully corrected at least 1 year before enrollment who had undergone comprehensive hemodynamic and imaging characterization as per the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. Median (interquartile range) mean pulmonary pressure was 37 mm Hg (32-44 mm Hg) and pulmonary artery wedge pressure was 23 mm Hg (18-26 mm Hg). Most patients were classified either as having combined precapillary and postcapillary or isolated postcapillary pulmonary hypertension. After a median follow-up of 4.5 years, 91 deaths accounted for 4.21 higher-than-expected mortality in the age-matched population. Risk factors for mortality were male sex, older age, diabetes mellitus, World Health Organization functional class III and higher pulmonary vascular resistance-either measured by catheterization or approximated from ultrasound data. Higher pulmonary vascular resistance was related to diabetes mellitus and smaller residual aortic and mitral valve areas. In turn, the latter correlated with prosthetic nominal size. Six-month changes in the composite clinical score and in the 6-minute walk test distance were related to survival. Conclusions Persistent valvular heart disease-pulmonary hypertension is an ominous disease that is almost universally associated with elevated pulmonary artery wedge pressure. Pulmonary vascular resistance is a major determinant of mortality in this condition and is related to diabetes mellitus and the residual effective area of the corrected valve. These findings have important implications for individualizing valve correction procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00862043.

Do humor styles predict clinical response to the MINDSET (MINDfulneSs & EducaTion) program? A pilot study in patients with fibromyalgia.

BACKGROUND AND AIM: Humor has been described as an effective coping strategy for dealing with chronic pain conditions; likewise, coping strategies predict some clinical outcomes after cognitive-behavioral therapy and mindfulness-based interventions. The present study aims to preliminarily explore the role of humor styles in predicting clinical changes after the multicomponent intervention (MINDSET) that combines mindfulness and psychoeducation for fibromyalgia (FM) patients. MATERIAL AND METHODS: A subsample of 35 patients with FM of the EUDAIMON study, a randomized controlled trial, was used for the present study; linear regressions and Spearman's correlations were computed. RESULTS: Affiliative humor and positive/negative ratio humor styles had a unique predictive effect on self-reported clinical changes. Significant correlations between humor styles with functional impact and mindfulness facets were observed. CONCLUSIONS: Some humor styles may imply a better disposition in patients to learn and implement the concepts and resources that the intervention offered.

Mindfulness-Based Program Plus Amygdala and Insula Retraining (MAIR) for the Treatment of Women with Fibromyalgia: A Pilot Randomized Controlled Trial.

The lack of highly effective treatments for fibromyalgia (FM) represents a great challenge for public health. The objective of this parallel, pilot randomized controlled trial (RCT) was two-fold: (1) to analyze the clinical effects of mindfulness plus amygdala and insula retraining (MAIR) compared to a structurally equivalent active control group of relaxation therapy (RT) in the treatment of FM; and (2) to evaluate its impact on immune-inflammatory markers and brain-derived neurotrophic factor (BDNF) in serum. A total of 41 FM patients were randomized into two study arms: MAIR (intervention group) and RT (active control group), both as add-ons of treatment as usual. MAIR demonstrated significantly greater reductions in functional impairment, anxiety, and depression, as well as higher improvements in mindfulness, and self-compassion at post-treatment and follow-up, with moderate to large effect sizes. Significant decreases in pain catastrophizing and psychological inflexibility and improvements in clinical severity and health-related quality of life were found at follow-up, but not at post-treatment, showing large effect sizes. The number needed to treat was three based on the criteria of ≥50% Fibromyalgia Impact Questionnaire (FIQ) reduction post-treatment. Compared to RT, the MAIR showed significant decreases in BDNF. No effect of MAIR was observed in immune-inflammatory biomarkers (i.e., TNF-α, IL-6, IL-10, and hs-CRP). In conclusion, these results suggest that MAIR, as an adjuvant of treatment-as-usual (TAU), appears to be effective for the management of FM symptoms and for reducing BDNF levels in serum.

Efficacy, cost-utility and physiological effects of Acceptance and Commitment Therapy (ACT) and Behavioural Activation Treatment for Depression (BATD) in patients with chronic low back pain and depression: study protocol of a randomised, controlled trial including mobile-technology-based ecological momentary assessment (IMPACT study).

INTRODUCTION: The IMPACT study focuses on chronic low back pain (CLBP) and depression symptoms, a prevalent and complex problem that represents a challenge for health professionals. Acceptance and Commitment Therapy (ACT) and Brief Behavioural Activation Treatment for Depression (BATD) are effective treatments for patients with persistent pain and depression, respectively. The objectives of this 12 month, multicentre, randomised, controlled trial (RCT) are (i) to examine the efficacy and cost-utility of adding a group-based form of ACT or BATD to treatment-as-usual (TAU) for patients with CLBP and moderate to severe levels of depressive symptoms; (ii) identify pre-post differences in levels of some physiological variables and (iii) analyse the role of polymorphisms in the FKBP5 gene, psychological process measures and physiological variables as mediators or moderators of long-term clinical changes. METHODS AND ANALYSIS: Participants will be 225 patients with CLBP and moderate to severe depression symptoms recruited at Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain) and Hospital del Mar (Barcelona, Spain), randomly allocated to one of the three study arms: TAU vs TAU+ACT versus TAU+BATD. A comprehensive assessment to collect clinical variables and costs will be conducted pretreatment, post-treatment and at 12 months follow-up, being pain interference the primary outcome measure. The following physiological variables will be considered at pretreatment and post-treatment assessments in 50% of the sample: immune-inflammatory markers, hair cortisol and cortisone, serum cortisol, corticosteroid-binding globulin and vitamin D. Polymorphisms in the FKBP5 gene (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916) will be analysed at baseline assessment. Moreover, we will include mobile-technology-based ecological momentary assessment, through the Pain Monitor app, to track ongoing clinical status during ACT and BATD treatments. Linear mixed-effects models using restricted maximum likelihood, and a full economic evaluation applying bootstrapping techniques, acceptability curves and sensitivity analyses will be computed. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu and Hospital del Mar. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and various community engagement activities. TRIAL REGISTRATION NUMBER: NCT04140838.

A Delphi consensus on the management of oral anticoagulation in patients with non-valvular atrial fibrillation in Spain: ACOPREFERENCE study.

OBJECTIVE: To evaluate the level of agreement between cardiologists regarding the management of oral anticoagulation (OAC) in patients with non-valvular atrial fibrillation (NVAF) in Spain. MATERIALS AND METHODS: A two-round Delphi study was performed using an online survey. In round 1, panel members rated their level of agreement with the questionnaire items on a 9-point Likert scale. Item selection was based on acceptance by ≥66.6% of panellists and the agreement of the scientific committee. In round 2, the same panellists evaluated those items that did not meet consensus in round 1. RESULTS: A total of 238 experts participated in round 1; of these, 217 completed the round 2 survey. In round 1, 111 items from 4 dimensions (Thromboembolic and bleeding risk evaluation for treatment decision-making: 18 items; Choice of OAC: 39 items; OAC in specific cardiology situations: 12 items; Patient participation and education: 42 items) were evaluated. Consensus was reached for 92 items (83%). Over 80% of the experts agreed with the use of DOACs as the initial anticoagulant treatment when OAC is indicated. Panellists recommended the use of DOACs in patients at high risk of thromboembolic complications (CHA2DS2-VASc ≥3) (83%), haemorrhages (HAS-BLED ≥3) (89%) and poor quality of anticoagulation control (SAMe-TT2R2 >2) (76%), patients who fail to achieve an optimal therapeutic range after 3 months on VKA treatment (93%), and those who are to undergo cardioversion (80%). Panellists agreed that the efficacy and safety profile of each DOAC (98%), the availability of a specific reversal agent (72%) and patient's preference (85%) should be considered when prescribing a DOAC. A total of 97 items were ultimately accepted after round 2. CONCLUSIONS: This Delphi panel study provides expert-based recommendations that may offer guidance on clinical decision-making for the management of OAC in NVAF. The importance of patient education and involvement has been highlighted.

The Bed Nucleus of the Stria Terminalis as a Brain Correlate of Psychological Inflexibility in Fibromyalgia.

This study explored the brain structural correlates of psychological flexibility (PF) as measured with the Psychological Inflexibility in Pain Scale (PIPS) in patients with fibromyalgia (FM). Structural magnetic resonance imaging data from 47 FM patients were used to identify Gray Matter Volume (GMV) alterations related to PIPS scores. Brain GMV clusters related to PIPS were then correlated with clinical and cognitive variables to further explore how emerged brain clusters were intertwined with FM symptomatology. Longitudinal changes in PIPS-related brain clusters values were assessed by studying pre-post data from 30 patients (15 allocated to a mindfulness-based stress reduction (MBSR) program and 15 to treatment-as-usual). Changes in PIPS-related brain clusters were also explored in participants showing greater/lower longitudinal changes in PIPS scores. PIPS scores were positively associated with GMV in a bilateral cluster in the ventral part of the bed nucleus of the stria terminalis (BNST). Significant associations between BNST cluster with functional impairment, depressive symptomatology, perceived stress and the nonjudging mindfulness facet were observed. Participants reporting greater pre-post increases in PIPS scores showed greater increases in BNST cluster values. These findings contribute to the understanding on the neurobiological bases of PF in FM and encourage further explorations of the role of the BNST in chronic pain.

Peripheral immune aberrations in fibromyalgia: A systematic review, meta-analysis and meta-regression.

The objective was to identify immune alterations in patients with fibromyalgia syndrome (FMS) compared to healthy controls (HC) using meta-analysis and meta-regression. Six electronic databases were searched for suitable original articles investigating immune biomarkers in FMS in comparison to HC. We extracted outcomes and variables of interest, such as mean and SD of peripheral blood immune biomarkers, age or sex. A random-effects model with restricted maximum-likelihood estimator was used to compute effect sizes (standardized mean difference and 95% CI, Hedges' g) and meta-analysis, group meta-analysis and meta-regressions were conducted. Forty-three papers were included in this systematic review, of which 29 were suitable for meta-analysis. Interleukin (IL)-6 (g = 0.36 (0.09-0.63); I2 = 85.94; p = 0.01), IL-4 (g = 0.50 (0.03-0.98); I2 = 81.87; p = 0.04), and IL-17A (g = 0.53 (0.00-1.06); I2 = 87.15; p = 0.05), were significantly higher in FMS compared to HC while also combinations of cytokines into relevant phenotypes were significantly upregulated including M1 macrophage (g = 0.23 (0.03-0.43); I2 = 77.62; p = 0.02), and immune-regulatory (g = 0.40 (0.09-0.72); I2 = 84.81; p = 0.01) phenotypes. Heterogeneity levels were very high and subgroup and meta-regression analyses showed that many covariates explained part of the heterogeneity including medication washout, sex, time of blood sampling and exclusion of patients with major depressive disorder. In conclusion, FMS is accompanied by a disbalance between upregulated pro-inflammatory (M1 and Th-17) and immune-regulatory cytokines although effect sizes are small-to-moderate. Based on our results we provide specific methodological suggestions for future research, which should assess Th-1, Th-17, chemokines, and Th-2 phenotypes while controlling for possible confounding variables specified in this study.

Patients With Fibromyalgia Reporting Severe Pain but Low Impact of the Syndrome: Clinical and Pain-Related Cognitive Features.

BACKGROUND: Fibromyalgia (FM) is a prevalent and highly disabling chronic pain syndrome. However, differences among patients regarding how pain impacts on daily life are remarkable. The main aim of this study was to identify clinical and pain-related cognitive variables characterizing patients reporting high adaptability despite experiencing severe chronic pain. METHODS: Two hundred and eighty-three Spanish patients with FM with high levels of pain were classified into 2 groups: (1) those reporting low impact of the syndrome, and (2) those with moderate-to-high impact. Perceived stress, anxiety, and depressive symptoms along with pain catastrophizing, psychological inflexibility, and perceived control over pain were evaluated. Differences in sociodemographics, years with FM, past/current major depressive disorder comorbidity, and health-related economic costs (ie, medications, use of medical services, lost productivity due to sick leave) were also assessed. Stepwise logistic regression analyses predicting group membership from clinical variables and pain-related cognitive processes as predictors were performed. RESULTS: Lower stress, anxiety, and depressive symptoms, along with reduced pain catastrophism, psychological inflexibility, and perceived control over pain, were found in the low-impact group. Significant predictors of group membership (low-impact vs. moderate-to-high impact) in regression analyses were "cognitive fusion" (psychological inflexibility), "helplessness" (pain catastrophizing), and depressive symptomatology, together with pain intensity and other FM symptoms. CONCLUSIONS: The present study provides further evidence on resilience resources in chronic pain by identifying some variables (ie, reduced depressive symptomatology, pain catastrophizing, and psychological inflexibility) differentially characterizing a profile of patients with FM who are especially able to adapt to high levels of pain.

Machine Learning to Understand the Immune-Inflammatory Pathways in Fibromyalgia.

Fibromyalgia (FM) is a chronic syndrome characterized by widespread musculoskeletal pain, and physical and emotional symptoms. Although its pathophysiology is largely unknown, immune-inflammatory pathways may be involved. We examined serum interleukin (IL)-6, high sensitivity C-reactive protein (hs-CRP), CXCL-8, and IL-10 in 67 female FM patients and 35 healthy women while adjusting for age, body mass index (BMI), and comorbid disorders. We scored the Fibromyalgia Severity Score, Widespread Pain Index (WPI), Symptom Severity Scale (SSS), Hospital Anxiety (HADS-A), and Depression Scale and the Perceived Stress Scale (PSS-10). Clinical rating scales were significantly higher in FM patients than in controls. After adjusting for covariates, IL-6, IL-10, and CXCL-8 were lower in FM than in HC, whereas hs-CRP did not show any difference. Binary regression analyses showed that the diagnosis FM was associated with lowered IL-10, quality of sleep, aerobic activities, and increased HADS-A and comorbidities. Neural networks showed that WPI was best predicted by quality of sleep, PSS-10, HADS-A, and the cytokines, while SSS was best predicted by PSS-10, HADS-A, and IL-10. Lowered levels of cytokines are associated with FM independently from confounders. Lowered IL-6 and IL-10 signaling may play a role in the pathophysiology of FM.

A randomized controlled efficacy trial of mindfulness-based stress reduction compared with an active control group and usual care for fibromyalgia: the EUDAIMON study.

Fibromyalgia (FM) syndrome represents a great challenge for clinicians and researchers because the efficacy of currently available treatments is limited. This study examined the efficacy of mindfulness-based stress reduction (MBSR) for reducing functional impairment as well as the role of mindfulness-related constructs as mediators of treatment outcomes for people with FM. Two hundred twenty-five participants with FM were randomized into 3 study arms: MBSR plus treatment-as-usual (TAU), FibroQoL (multicomponent intervention for FM) plus TAU, and TAU alone. The primary endpoint was functional impact (measured with the Fibromyalgia Impact Questionnaire Revised), and secondary outcomes included "fibromyalginess," anxiety and depression, pain catastrophising, perceived stress, and cognitive dysfunction. The differences in outcomes between groups at post-treatment assessment (primary endpoint) and 12-month follow-up were analyzed using linear mixed-effects models and mediational models through path analyses. Mindfulness-based stress reduction was superior to TAU both at post-treatment (large effect sizes) and at follow-up (medium to large effect sizes), and MBSR was also superior to FibroQoL post-treatment (medium to large effect sizes), but in the long term, it was only modestly better (significant differences only in pain catastrophising and fibromyalginess). Immediately post-treatment, the number needed to treat for 20% improvement in MBSR vs TAU and FibroQoL was 4.0 (95% confidence interval [CI] = 2.1-6.5) and 5.0 (95% CI = 2.7-37.3). An unreliable number needed to treat value of 9 (not computable 95% CI) was found for FibroQoL vs TAU. Changes produced by MBSR in functional impact were mediated by psychological inflexibility and the mindfulness facet acting with awareness. These findings are discussed in relation to previous studies of psychological treatments for FM.

Immune-inflammatory pathways and clinical changes in fibromyalgia patients treated with Mindfulness-Based Stress Reduction (MBSR): A randomized, controlled clinical trial.

Fibromyalgia (FM) is a highly prevalent and disabling syndrome characterized by chronic widespread musculoskeletal pain and a broad range of cognitive and affective symptoms. Up to now, the pathogenesis of FM is unknown although a peripheral and central sensitization involving an imbalance on immune biomarkers appears to have a relevant role in its aetiology. The aim of this study was to extend previous clinical findings of Mindfulness-Based Stress Reduction (MBSR) to both its impact on clinical symptomatology and immune biomarkers (IL-6, CXCL8, IL-10 and hs-CRP), and also to explore the role of biomarkers as predictors of efficacy. METHODS: A total of 70 female patients with FM were randomly assigned to two treatment modalities, namely Treatment as Usual (TAU) plus MBSR (n = 35) or TAU alone (n = 35). This study is embedded within a larger RCT (n = 225) that includes three study arms (TAU; TAU plus MBSR; and TAU plus the psychoeducative intervention FibroQoL), and a 12-month follow-up (clinical trial registration: NCT02561416). Blood cytokine assays and clinical assessment were conducted at baseline and post-treatment. Treatment effects were analysed using linear mixed models with intention to treat and per protocol analyses. In order to evaluate the balance between pro- and anti-inflammatory pathways, ratios of pro-inflammatory IL-6, CXCL8 and hs-CRP with the anti-inflammatory cytokine IL-10 were calculated (i.e. IL-6/IL-10, CXCL8/IL10 and hs-CRP/IL-10). RESULTS: The results show that MBSR is an efficacious intervention to reduce clinical severity of patients with FM. MBSR also prevents the tendency of IL-10 to decrease as observed in the TAU group. Higher levels of baseline CXCL8 levels attenuate the beneficial effect of MBSR practice on clinical symptomatology, including pain, energy, stiffness or quality of sleep. Furthermore, higher baseline IL-6/IL-10 and CXCL8/IL-10 ratios were associated with less improvement in psychological inflexibility following MBSR treatment. DISCUSSION: Our results show that mindfulness training has clinical efficacy in patients with FM. The results suggest that MBSR has significant immune regulatory effects in FM patients, while immune-inflammatory pathways may in part predict the clinical efficacy of MBSR. These cytokines and chemokines may be adequate biomarkers to monitor responsivity to MBSR.