Abstract
Aims
We aimed to determine whether treatment with sildenafil improves outcomes of patients with persistent pulmonary hypertension (PH) after correction of valvular heart disease (VHD).
...Methods and results
The sildenafil for improving outcomes after valvular correction (SIOVAC) study was a multricentric, randomized, parallel, and placebo-controlled trial that enrolled stable adults with mean pulmonary artery pressure ≥ 30 mmHg who had undergone a successful valve replacement or repair procedure at least 1 year before inclusion. We assigned 200 patients to receive sildenafil (40 mg three times daily, n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure (HF), change in functional class, and patient global self-assessment. Only 27 patients receiving sildenafil improved their composite clinical score, as compared with 44 patients receiving placebo; in contrast 33 patients in the sildenafil group worsened their composite score, as compared with 14 in the placebo group odds ratio 0.39; 95% confidence interval (CI) 0.22–0.67; P < 0.001. The Kaplan–Meier estimates for survival without admission due to HF were 0.76 and 0.86 in the sildenafil and placebo groups, respectively (hazard ratio 2.0, 95% CI = 1.0–4.0; log-rank P = 0.044). Changes in 6-min walk test distance, natriuretic peptides, and Doppler-derived systolic pulmonary pressure were similar in both groups.
Conclusion
Treatment with sildenafil in patients with persistent PH after successfully corrected VHD is associated to worse clinical outcomes than placebo. Off-label usage of sildenafil for treating this source of left heart disease PH should be avoided.
The trial is registered with ClinicalTrials.gov, number NCT00862043.
•Levels of IL-6, IL-4 and IL-17 are slightly upregulated in fibromyalgia (FMS).•Immune-inflammatory and the compensatory (IRS/CIRS) phenotypes are also upregulated.•Research in immune-inflammatory in ...FMS needs to evaluate cofounding variables.•Immune-inflammatory studies in FMS need to focus on a wider spectrum of biomarkers.
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.
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 greater than or equal to66.6% 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 (CHA.sub.2 DS.sub.2 -VASc greater than or equal to3) (83%), haemorrhages (HAS-BLED greater than or equal to3) (89%) and poor quality of anticoagulation control (SAMe-TT.sub.2 R.sub.2 >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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mortality from acute coronary syndrome has fallen but a substantial number of chronic patients remain symptomatic. The present study was designed to determine the clinical characteristics and ...therapeutic treatment of patients with stable angina and its impact on their quality of life.
A cross-sectional, multicenter, observational study of 2039 patients with stable angina attended in outpatient clinics was performed. Data were collected on clinical variables and on the subjective perception of the severity of angina and the resulting limitations. Patients completed questionnaires on their perception of severity and quality of life.
We analyzed data on 2024 patients; 73% were men (mean age 68 10 years). Some 50.3% were asymptomatic (<1 angina attack per week in the previous 4 weeks), 39.2% reported 1-3 attacks per week and 10.5% reported >3 attacks per week; 66% had previously undergone revascularization, and 59% of these developed recurrent angina. Patients rated the severity of their condition higher than did their physicians (4.5 2.5 vs 4.3 2.3; P=.002). Physicians’ and patients’ perceptions of the repercussions of angina showed little concordance (kappa<0.3). The patients believed their condition was much more severe, more debilitating, and had a greater negative impact on their quality of life.
A high proportion of patients with stable angina remains symptomatic and their quality of life is impaired. Their perception of the condition is worse than that of their physicians.
La mortalidad por cardiopatía isquémica aguda se ha reducido, pero los pacientes crónicos persisten sintomáticos en una proporción importante. Se pretende conocer las características clínicas y la terapéutica del paciente con angina estable y el impacto de esta enfermedad en la calidad de vida.
Estudio observacional, multicéntrico y de corte transversal, sobre 2.039 pacientes con angina estable en control ambulatorio. Además de variables clínicas, el investigador recogió su valoración subjetiva sobre la gravedad de la angina y la limitación causada por ella. Los pacientes contestaron sobre percepción de gravedad y calidad de vida con cuestionarios específicos.
Se analizó a 2.024 pacientes. El 73% eran varones (media de edad, 68±10 años). El 50,3% estaba asintomático (menos de una crisis de angina por semana en las últimas 4 semanas), el 39,2% había tenido entre una y tres crisis por semana, y el 10,5% declaró más de tres crisis por semana. El 66% había sido revascularizado, y de ellos el 59% volvía a tener angina. Los pacientes puntuaron la gravedad de la enfermedad más que los médicos (4,5±2,5 frente a 4,3±2,3; p=0,002). Las percepciones del médico y del paciente sobre la repercusión de la angina tuvieron poca concordancia (índice kappa<0,3), pues los pacientes consideraron que su enfermedad era más grave, más invalidante y con mayor disminución de la calidad de vida.
Persiste una elevada proporción de pacientes sintomáticos y con reducción de la calidad de vida. La percepción del paciente sobre la enfermedad es peor que la del médico.
•Mindfulness-Based Stress Reduction reduced fibromyalgia severity.•Unlikeusual care, mindfulness achieves to maintain IL-10 levels.•Higher baseline levels of CXCL8 buffered the effect of mindfulness ...on severity.•Immune regulatory ratios were related to changes in psychological inflexibility.
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.
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).
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.
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.
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.
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.
Objetivo: Este estudio tuvo como objetivo evaluar la efectividad de una intervención multicomponente en línea llamada FATIGUEWALK (FaW) en comparación con el tratamiento habitual (TAU, por sus siglas en inglés) en pacientes con síndrome de fatiga crónica/encefalomielitis miálgica (CFS/ME, por sus siglas en inglés). Método: FaW incluyó educación en neurociencia del dolor, ejercicio terapéutico, reestructuración cognitiva y entrenamiento de atención plena. Un total de 428 pacientes con CFS/ME fueron asignados aleatoriamente a dos grupos de estudio: FaW en línea más TAU versus TAU solo. Se llevó a cabo un estudio controlado aleatorio (ECA) simple ciego. Se recopilaron medidas de resultado validadas informadas por los pacientes de fatiga, dolor, ansiedad, depresión y función física al inicio y después del tratamiento, después de la intervención FaW, que duró 12 semanas. Resultados: Se observaron mejoras estadísticamente significativas (con tamaños de efecto pequeños a moderados) en FaW en línea versus TAU solo con respecto a los aspectos multidimensionales de la fatiga (la d de Cohen oscila entre 0.25 y 0.73) y la mayoría de los resultados secundarios (intensidad de dolor y la fatiga, depresión y ansiedad sintomatológica, deterioro funcional, kinesiofobia, funcionamiento físico). La reducción del riesgo absoluto en FaW versus TAU fue del 19% (IC del 95% = 12.19, 25.80) con número necesario a tratar (NNT) = 6 (IC del 95% = 3.9-8.2). En general, se observaron mejoras clínicas similares en los análisis de sensibilidad que incluyeron un subgrupo de pacientes sin comorbilidad con fibromialgia (n = 70). Conclusiones: Este es el primer estudio que evalúa la efectividad a corto plazo de una intervención multicomponente en línea agregada a TAU, en comparación con TAU sola, para el tratamiento del CFS/ME. Se justifican ensayos adicionales, que incluyan grupos de control activo con una dosis de tratamiento equivalente y que evalúen la eficacia a largo plazo del FaW en línea.
Public Significance StatementThe FATIGUEWALK (FaW) program is a video-based multicomponent treatment for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). This trial strongly suggests that FaW is an effective treatment for improving fatigue and psychological and physical comorbid impairment in CFS/ME patients, both with and without fibromyalgia. This study highlights the importance of online and multicomponent interventions for CFS/ME treatment.
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.
Soft polymers such as the investigated polyurethane, characterized by low Young's moduli and prone to high shear deflection, are frequently applied in pneumatic cylinders. Their performance and ...lifetime without external lubrication are highly determined by the friction between seal and shaft and the wear rate. FEM simulation has established itself as a tool in seal design processes but requires input values for friction and wear depending on material, load, and velocity. This paper presents a tribological test configuration for long stroke, reciprocating movement, allowing the generation of data which meet the requirements of input parameters for FEM simulations without the geometrical influences of specific seal profiles. A numerical parameter study, performed with an FEM model, revealed the most eligible sample geometry as a flat, disc-shaped sample of the polymer glued on a stiff sample holder. At the same time, the study illustrates that the sensitivity of the contact pressure distribution to Poisson's ratio and CoF can be minimized by the developed and verified setup. It ensures robust, reliable, and repeatable experimental results with uniform contact pressures and constant contact areas to be used in databases and FEM simulations of seals, enabling upscaling from generically shaped samples to complex seal profiles.
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-β), 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-1β), 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-β, 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.
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