Microparticles as BDMDAC (Quaternary Ammonium Compound) Carriers for Water Disinfection: A Layer-by-Layer Approach without Biocide Release.

This work studies the antimicrobial activity of benzyldimethyldodecyl ammonium chloride (BDMDAC)-coated microparticles with distinct morphological structures. Functionalized microparticles were prepared by the layer-by-layer (LbL) self-assembly technique on hydroxyapatite (Hap), calcium carbonate (CaCO3) and glass beads (GB) cores. All particles were characterized, before and after functionalization, by Fourier-Transform Infrared Spectroscopy (FTIR), Brunner-Emmett-Teller (BET) and Scanning Electron Microscopy (SEM) analyses. Antimicrobial activity was tested against planktonic Pseudomonas fluorescens. Planktonic bacteria were exposed to 100 mg/L, 200 mg/L and 400 mg/L of BDMDAC-coated microparticles for 240 min. This strategy promoted a complete bacteria reduction at 200 mg/L for Hap microparticles after 240 min. No release of biocide was detected through HPLC analyses during 2 weeks, suggesting that bacteria inactivation may be attributed to a contact killing mechanism.

2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases.

OBJECTIVES: Fatigue is prevalent in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and recognised as one of the most challenging symptoms to manage. The existence of multiple factors associated with driving and maintaining fatigue, and the evidence about what improves fatigue has led to a multifaceted approach to its management. However, there are no recommendations for fatigue management in people with I-RMDs. This lack of guidance is challenging for those living with fatigue and health professionals delivering clinical care. Therefore, our aim was to develop EULAR recommendations for the management of fatigue in people with I-RMDs. METHODS: A multidisciplinary taskforce comprising 26 members from 14 European countries was convened, and two systematic reviews were conducted. The taskforce developed the recommendations based on the systematic review of evidence supplemented with taskforce members' experience of fatigue in I-RMDs. RESULTS: Four overarching principles (OAPs) and four recommendations were developed. OAPs include health professionals' awareness that fatigue encompasses multiple biological, psychological and social factors which should inform clinical care. Fatigue should be monitored and assessed, and people with I-RMDs should be offered management options. Recommendations include offering tailored physical activity and/or tailored psychoeducational interventions and/or, if clinically indicated, immunomodulatory treatment initiation or change. Patient-centred fatigue management should consider the individual's needs and preferences, their clinical disease activity, comorbidities and other psychosocial and contextual factors through shared decision-making. CONCLUSIONS: These 2023 EULAR recommendations provide consensus and up-to-date guidance on fatigue management in people with I-RMDs.

Mast cells impair melanoma cell homing and metastasis by inhibiting HMGA1 secretion.

Metastatic disease is the major cause of death from cancer. From the primary tumour, cells remotely prepare the environment of the future metastatic sites by secreted factors and extracellular vesicles. During this process, known as pre-metastatic niche formation, immune cells play a crucial role. Mast cells are haematopoietic bone marrow-derived innate immune cells whose function in lung immune response to invading tumours remains to be defined. We found reduced melanoma lung metastasis in mast cell-deficient mouse models (Wsh and MCTP5-Cre-RDTR), supporting a pro-metastatic role for mast cells in vivo. However, due to evidence pointing to their antitumorigenic role, we studied the impact of mast cells in melanoma cell function in vitro. Surprisingly, in vitro co-culture of bone-marrow-derived mast cells with melanoma cells showed that they have an intrinsic anti-metastatic activity. Mass spectrometry analysis of melanoma-mast cell co-cultures secretome showed that HMGA1 secretion by melanoma cells was significantly impaired. Consistently, HMGA1 knockdown in B16-F10 cells reduced their metastatic capacity in vivo. Importantly, analysis of HMGA1 expression in human melanoma tumours showed that metastatic tumours with high HMGA1 expression are associated with reduced overall and disease-free survival. Moreover, we show that HMGA1 is reduced in the nuclei and enriched in the cytoplasm of melanoma metastatic lesions when compared to primary tumours. These data suggest that high HMGA1 expression and secretion from melanoma cells promote metastatic behaviour. Targeting HMGA1 expression intrinsically or extrinsically by mast cells actions reduce melanoma metastasis. Our results pave the way to the use of HMGA1 as anti-metastatic target in melanoma as previously suggested in other cancer types.

Characterization of plasma circulating small extracellular vesicles in patients with metastatic solid tumors and newly diagnosed brain metastasis.

Nearly 40% of the advanced cancer patients will present brain metastases during the course of their disease, with a 2-year life expectancy of less than 10%. Immune system impairment, including the modulation of both STAT3 and PD-L1, is one of the hallmarks of brain metastases. Liquid biopsy could offer several advantages in brain metastases management, such as the possibility of noninvasive dynamic monitoring. Extracellular vesicles (EVs) have been recently proposed as novel biomarkers especially useful in liquid biopsy due to their secretion in biofluids and their role in cell communication during tumor progression. The main aim of this work was to characterize the size and protein cargo of plasma circulating EVs in patients with solid tumors and their correlation with newly diagnosed brain metastases, in addition to their association with other relevant clinical variables. We analyzed circulating EVs in the plasma of 123 patients: 42 patients with brain metastases, 50 without brain metastases and 31 healthy controls. Patients with newly diagnosed brain metastases had a lower number of circulating EVs in the plasma and a higher protein concentration in small EVs (sEVs) compared to patients without brain metastases and healthy controls. Interestingly, melanoma patients with brain metastases presented decreased STAT3 activation and increased PD-L1 levels in circulating sEVs compared to patients without central nervous system metastases. Decreased STAT3 activation and increased PD-L1 in plasma circulating sEVs identify melanoma patients with brain metastasis.

Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism.

Secreted extracellular vesicles (EVs) influence the tumor microenvironment and promote distal metastasis. Here, we analyzed the involvement of melanoma-secreted EVs in lymph node pre-metastatic niche formation in murine models. We found that small EVs (sEVs) derived from metastatic melanoma cell lines were enriched in nerve growth factor receptor (NGFR, p75NTR), spread through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Remarkably, sEVs enhanced lymphangiogenesis and tumor cell adhesion by inducing ERK kinase, nuclear factor (NF)-κB activation and intracellular adhesion molecule (ICAM)-1 expression in lymphatic endothelial cells. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased lymph node metastasis and extended survival in pre-clinical models. Furthermore, NGFR expression was augmented in human lymph node metastases relative to that in matched primary tumors, and the frequency of NGFR+ metastatic melanoma cells in lymph nodes correlated with patient survival. In summary, we found that NGFR is secreted in melanoma-derived sEVs, reinforcing lymph node pre-metastatic niche formation and metastasis.

Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis.

Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not completely defined. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in mouse melanoma lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth, and metastasis. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.

TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics.

Long noncoding RNAs (lncRNAs) are regulatory molecules which have been traditionally considered as "non-coding". Strikingly, recent evidence has demonstrated that many non-coding regions, including lncRNAs, do in fact contain small-open reading frames that code for small proteins that have been called microproteins. Only a few of them have been characterized so far, but they display key functions in a wide variety of cellular processes. Here, we show that TUNAR lncRNA encodes an evolutionarily conserved microprotein expressed in the nervous system that we have named pTUNAR. pTUNAR deficiency in mouse embryonic stem cells improves their differentiation potential towards neural lineage both in vitro and in vivo. Conversely, pTUNAR overexpression impairs neuronal differentiation by reduced neurite formation in different model systems. At the subcellular level, pTUNAR is a transmembrane protein that localizes in the endoplasmic reticulum and interacts with the calcium transporter SERCA2. pTUNAR overexpression reduces cytoplasmatic calcium, consistent with a possible role of pTUNAR as an activator of SERCA2. Altogether, our results suggest that our newly discovered microprotein has an important role in neural differentiation and neurite formation through the regulation of intracellular calcium. From a more general point of view, our results provide a proof of concept of the role of lncRNAs-encoded microproteins in neural differentiation.

Efficacy of psychological interventions on psychological outcomes in coronary artery disease: systematic review and meta-analysis.

BACKGROUND: The benefits of cognitive-behavioral treatment (CBT) and positive psychology therapy (PPT) in patients with cardiovascular disease are still not well defined. We assessed the efficacy of CBT and PPT on psychological outcomes in coronary artery disease (CAD) patients. METHODS: Randomized controlled trials evaluating CBT or PPT in CAD patients published until May 2018 were systematically analyzed. Primary outcomes were depression, stress, anxiety, anger, happiness, and vital satisfaction. Random effects meta-analyses using the inverse variance method were performed. Effects were expressed as standardized mean difference (SMD) or mean differences (MD) with their 95% confidence intervals (CIs); risk of bias was assessed with the Cochrane tool. RESULTS: Nineteen trials were included (n = 1956); sixteen evaluated CBT (n = 1732), and three PPT (n = 224). Compared with control groups, depressive symptoms (13 trials; SMD -0.80; 95% CI -1.33 to -0.26), and anxiety (11 trials; SMD -1.26; 95% CI -2.11 to -0.41) improved after the PI, and depression (6 trials; SMD -2.08; 95% CI -3.22 to -0.94), anxiety (5 trials; SMD -1.33; 95% CI -2.38 to -0.29), and stress (3 trials; SMD -3.72; 95% CI -5.91 to -1.52) improved at the end of follow-up. Vital satisfaction was significantly increased at follow-up (MD 1.30, 0.27, 2.33). Non-significant effects on secondary outcomes were found. Subgroup analyses were consistent with overall analyses. CONCLUSION: CBT and PPT improve several psychological outcomes in CAD patients. Depression and anxiety improved immediately after the intervention while stress and vital satisfaction improve in the mid-term. Future research should assess the individual role of CBT and PPT in CAD populations.

Anxiety, Reinforcement Sensitivity and Social Context in Accepting the Experience of Pain Among Rheumatoid Arthritis Patients.

Background: Acceptance has become one of the most widely studied processes regarding chronic pain because of its ability to influence participants' adaptation and coping responses. Leading researchers have found relationships between variables such as anxiety, reinforcement sensitivity, and the responses of the participants' environment to their behavior and acceptance. In contrast, few studies have been found that investigate the variables that predict the acceptance of pain. This study has set out to explore the relationships between pain-related anxiety, sensitivity to contingencies, and the punishment responses of significant people toward pain behaviors regarding pain acceptance. Methods: With a view to fulfilling this purpose, a cohort of 62 participants with rheumatoid arthritis was chosen, and the subjects were assessed through the following self-report measures: Chronic Pain Acceptance Questionnaire, CPAQ; Pain Anxiety Symptoms Scale, PASS-20; The Sensitivity to Punishment and Sensitivity to Reward Questionnaire, SPSRQ, and The West Haven-Yale Multidimensional Pain Inventory, WHYMPI. The study's initial objectives were achieved by means of a stepwise multiple linear regression analysis. Results: The linear regression analyses revealed a negative and significant correlation between anxiety, reinforcement sensitivity, and the significant persons' responses to pain behaviors and pain acceptance. Conclusion: The results suggest that the identification of these variables might be important for addressing these participants' pain. Finally, the discussion focuses on our findings' implications as regards their use in clinical practice.

Apert syndrome: Cranial procedures and brain malformations in a series of patients.

BACKGROUND: Apert syndrome is one of the most severe craniofacial disorders. This study aims to describe the craniofacial surgeries and central nervous system malformations of a cohort of children with Apert syndrome treated in the past 20 years and to compare these data with previously published data. METHODS: Retrospective analysis of a series of patients with Apert syndrome treated between 1999 and 2019 in our hospital. Information was analyzed regarding craniofacial procedures, hydrocephalus and presence of shunts, Chiari malformation Type 1, and other brain malformations such as corpus callosum and septum pellucidum anomalies. RESULTS: Thirty-seven patients were studied. Ventriculoperitoneal shunt prevalence was 24.3%, and 8.1% of patients required decompressive surgery for Chiari malformation. All of them needed at least one cranial vault remodeling procedure. The median age for this procedure was 8 months. In 69.7% of patients, the first cranial vault intervention was performed in the fronto-orbital region. In 36.4% of patients, a midface advancement had been performed at the time of this review, although this proportion was very dependent on the follow-up period and the age of the patients. The median age for the midface advancement procedure was 5.25 years. Anomalies of the corpus callosum and the septum pellucidum were reported in 43.2% and 59.5% of patients, respectively. CONCLUSION: Apert syndrome is a type of syndromic craniosynostosis, and patients usually require one or more cranial and facial surgeries. In comparison with other syndromic craniosynostosis types, Apert syndrome less frequently requires a VP shunt or treatment for a Chiari malformation.

The influence of secreted factors and extracellular vesicles in ovarian cancer metastasis.

Ovarian cancer cells mainly metastasise within the peritoneal cavity, the lethal consequence of tumour progression in this cancer type. Classically, changes in tumour cells, such as epithelial to mesenchymal transition, involve the down-regulatinon of E-cadherin, activation of extracellular proteases and integrin-mediated adhesion. However, our current understanding of ovarian tumour progression suggests the implication of both intrinsic and extrinsic factors. It has been proposed that ovarian cancer metastases are a consequence of the crosstalk between cancer cells and the tumour microenvironment by soluble factors and extracellular vesicles. Characterisation of the alterations in both the tumour cells and the surrounding microenvironment has emerged as a new research field to understand ovarian cancer metastasis. In this mini review, we will summarise the most recent findings, focusing our attention on the role of secreted factors and extracellular vesicles in ovarian cancer metastasis.

Emotional affection on a sustained attention task: The importance the aging process and depression.

Chronic pain is a complex experience that has now become a major public health issue. This has prompted many researchers to study attention, understanding it to be a crucial factor that allows altering the experience of pain, while attributing considerable importance to sustained attention. Accordingly, the main studies in this field stress the importance of emotion regulation processes and emotions on the perception of painful stimuli and attentional processes themselves. Nevertheless, only a handful of studies have been found that directly study the relationship between these variables. Within this context, this article sets out to analyse emotional regulation processes, emotional variables (depression and anxiety), the experience of pain, and age on the ability to maintain the vigilance response in a sample of patients with chronic pain. This involved selecting a sample of 49 patients with rheumatoid arthritis and examining their performance in an ad-hoc sustained attention test. With a view to complying with the study's main purpose, the participants were also assessed through the use of the following self-report measures: the Beck Depression Inventory (BDI-I); the Hospital Anxiety and Depression Scale (HADS); the McGill Pain Questionnaire, and the Difficulties in Emotion Regulation Scale (DERS). Linear regression analyses revealed a significant impact of the aging process on the performance times in the attention task. Likewise, age and depression recorded a significant correlation with the mistakes made during the task. These results suggest that higher depression levels and an older age might be related to a worse adaptation to pain management techniques based on attention processes, such as mindfulness.

The Impact of Cognitive Anxiety and the Rating of Pain on Care Processes in a Vigilance Task: The Important Part Played by Age.

Chronic pain is a serious public health problem that has grown exponentially in recent years, which is why it has received the attention of numerous researchers. Most of the studies in the field of chronic pain have focused on care as a mediating variable on the perception of painful stimuli and emotions. Nevertheless, there are very few studies that have gone in the opposite direction. This study's aim is therefore to analyse the impact of emotional variables (anxiety and depression), the rating of pain, and age on vigilance processes in a sample of patients with chronic pain. To do so, the attentional performance of a cohort of 52 patients with chronic pain was measured through the use of a modified dot-probe task. Furthermore, all the participants were evaluated using the following self-report measures: Beck's Depression Inventory-II (BDI-II), the McGill Pain Questionnaire, and the Pain Anxiety Symptoms Scale-20 (PASS-20). Stepwise multiple linear regression analysis revealed a significant negative correlation between the pain rating index and the number of mistakes the participants made during the attention test. There was also a positive and significant correlation with age and another negative and significant correlation with cognitive anxiety regarding the overall performance times during the undertaking of the experimental task. These results point to the importance of a more in-depth understanding of the impact that the emotional variables and other variables such as age have on attentional processes and the rating of pain. Finally, the discussion focuses on the implications these results could have for clinical practice or for future research studies in this field.

Emotional regulation processes: influence on pain and disability in fibromyalgia patients.

OBJECTIVES: Fibromyalgia (FM) is a chronic syndrome characterised by widespread musculoskeletal pain associated with other symptoms, including psychological distress. While negative mood (anxiety, depression, and anger) has been widely explored in FM, few studies have investigated emotional dysregulation. Our purpose was to evaluate problems in the processes of emotional regulation and to explore their influence on the severity of pain and disability. METHODS: Emotional regulations, anxiety, depression, anger, pain and disability were evaluated in 47 FM patients and 47 healthy subjects. Regression analyses were performed to evaluate the role that emotional regulation processes have on pain severity and disability of FM patients. RESULTS: Results showed that although FM patients do not differ in terms of the attention paid to their emotional states, FM patients had greater difficulties in the emotional regulation process. In addition, emotional rejection and interference are two variables that influence the pain severity and disability. CONCLUSIONS: FM patients need to be trained in strategies for regulating their emotions, in order to achieve a reduction in negative mood states, as well as their impact in pain and disability.

Ivabradine in acute heart failure: Effects on heart rate and hemodynamic parameters in a randomized and controlled swine trial.

BACKGROUND: Acute heart failure patients could benefit from heart rate reduction, as myocardial consumption and oxidative stress are related to tachycardia. Ivabradine could have a clinical role attenuating catecholamine-induced tachycardia. The aim of this study was to evaluate hemodynamic effects of ivabradine in a swine model of acute heart failure. METHODS: Myocardial infarction was induced by 45 min left anterior descending artery balloon occlusion in 18 anesthetized pigs. An infusion of dobutamine and noradrenaline was maintained aiming to preserve adequate hemodynamic support, accompanied by fluid administration to obtain a pulmonary wedged pressure ≥ 18 mmHg. After reperfusion, rhythm and hemodynamic stabilization, the animals were randomized to 0.3 mg/kg ivabradine intravenously (n = 9) or placebo (n = 9). Hemodynamic parameters were observed over a 60 min period. RESULTS: Ivabradine was associated with a significant reduction in heart rate (88.4 ± 12.0 bpm vs. 122.7 ± 17.3 bpm after 15 min of ivabradine/placebo infusion, p < 0.01) and an increase in stroke volume (68.8 ± 13.7 mL vs. 52.4 ± 11.5 mL after 15 min, p = 0.01). There were no significant differences in systemic or pulmonary arterial pressure, or significant changes in pulmonary capillary pressure. However, after 15 min, cardiac output was significantly reduced with ivabradine (-5.2% vs. +15.0% variation in ivabradine/placebo group, p = 0.03), and central venous pressure increased (+4.2% vs. -19.7% variation, p < 0.01). CONCLUSIONS: Ivabradine reduces heart rate and increases stroke volume without modifying systemic or left filling pressures in a swine model of acute heart failure. However, an excessive heart rate reduction could lead to a decrease in cardiac output and an increase in right filling pressures. Future studies with specific heart rate targets are needed.

Validation of a Quality of Life Instrument in Spanish Patients With Rheumatic Diseases: The Rosser Classification System.

OBJECTIVE: The aim of this study was to assess the reliability and validity of the Spanish version of the Rosser classification system for disease states in patients with musculoskeletal disorders. METHODS: Our study was based on a questionnaire validation design. Patients were attended at an outpatient rheumatology clinic at Hospital Clínico San Carlos, Madrid, Spain. The Rosser classification system was completed by the physician from the research team (PMQ) and by the patient (HMQ). Criterion standards: The EuroQol-5D for the HMQ and the physician global estimate (DOCGL) for the PMQ. Internal consistency reliability was assessed using Cronbach α. Test-retest reliability and interobserver reliability were analyzed using the intraclass correlation coefficient. The criterion validity between HMQ and EuroQol-5D and between PMQ and DOCGL was assessed using the Spearman correlation coefficient. RESULTS: The full analysis was based on 4 samples of patients (104 to 266 patients), most of whom were middle-aged women. For HMQ, Cronbach α was 0.70. Test-retest reproducibility was 0.7. With respect to criterion validity, significant correlations in the expected direction were observed. For PMQ, Cronbach α was 0.70, indicating excellent intraobserver and interobserver reliability. With respect to criterion validity, strong correlations were observed between the PMQ and the DOCGL. CONCLUSIONS: The Rosser classification system showed satisfactory reliability and suitable criterion validity for patients with musculoskeletal disorders. The instrument seems to be suitable for clinical decision making and research.

Expert recommendations on the psychological needs of patients with rheumatoid arthritis.

OBJECTIVE: To establish feasible and practical recommendations for the management of the psychological needs of patients with rheumatoid arthritis (RA) from the moment of diagnosis through the course of the disease. METHODS: A nominal group meeting was held with an RA expert team including rheumatologists and psychologists, at which a guided discussion addressed the most important psychological and emotional needs in RA. Based on the comments collected, and a literature review, a matrix document of recommendations for telematics discussion was prepared, as well as a Delphi survey to test agreement with these recommendations. Agreement was defined if at least 80% of participants voted ≥ 7 (from 1, totally disagree to 10, totally agree). For each recommendation, the level of evidence and grading of recommendations was established following the Oxford criteria, and the degree of agreement through the Delphi. RESULTS: Thirteen recommendations were established, addressing several key processes: (1) identification of psychological problems and needs in patients with RA, and a guideline for their management in daily practice; (2) communication with patients; (3) referral criteria to mental health professionals. CONCLUSIONS: These recommendations are intended to help health care professionals openly address the psychological aspects of patients in daily practice to follow and treat them properly.

The influence of tumour-derived extracellular vesicles on local and distal metastatic dissemination.

Extracellular vesicles (EVs) are key mediators of intercellular communication that have been ignored for decades. Tumour cells benefit from the secretion of vesicles as they can influence the behaviour of neighbouring tumour cells within the tumour microenvironment. Several studies have shown that extracellular vesicles play an active role in pre-metastatic niche formation and importantly, they are involved in the metastatic organotropism of different tumour types. Tumour-derived EVs carry and transfer molecules to recipient cells, modifying their behaviour through a process defined as "EV-driven education". EVs favour metastasis to sentinel lymph nodes and distal organs by reinforcing angiogenesis, inflammation and lymphangiogenesis. Hence, in this review we will summarize the main mechanisms by which tumour-derived EVs regulate lymph node and distal organ metastasis. Moreover, since some cancers metastasize through the lymphatic system, we will discuss recent discoveries about the presence and function of tumour EVs in the lymph. Finally, we will address the potential value of tumour EVs as prognostic biomarkers in liquid biopsies, specially blood and lymphatic fluid, and the use of these tools as early detectors of metastases.

Tumour-adipose tissue crosstalk: fuelling tumour metastasis by extracellular vesicles.

During metastasis, tumour cells must communicate with their microenvironment by secreted soluble factors and extracellular vesicles. Different stromal cell types (e.g. bone marrow-derived cells, endothelial cells and fibroblasts) influence the growth and progression of tumours. In recent years, interest has extended to other cell types in the tumour microenvironment such as adipocytes and adipose tissue-derived mesenchymal stem cells. Indeed, obesity is becoming pandemic in some developing countries and it is now considered to be a risk factor for cancer progression. However, the true impact of obesity on the metastatic behaviour of tumours is still not yet fully understood. In this 'Perspective' article, we will discuss the potential influence of obesity on tumour metastasis, mainly in melanoma, breast and ovarian cancer. We summarize the main mechanisms involved with special attention to the role of extracellular vesicles in this process. We envisage that besides having a direct impact on tumour cells, obesity systemically preconditions the tumour microenvironment for future metastasis by favouring the formation of pro-inflammatory niches.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.

The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: validation in six countries.

Objective: To evaluate the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ), the revised Bristol Rheumatoid Arthritis Numerical Rating Scales (BRAF-NRS V2) and the Rheumatoid Arthritis Impact of Disease (RAID) scale in six countries. Methods: We surveyed RA patients in France, Germany, The Netherlands, Spain, Sweden and the UK, including the HAQ, 36-item Short Form Health Survey (SF-36) and potential revisions of the BRAF-NRS coping and Spanish RAID coping items. Factor structure and internal consistency were examined by factor analysis and Cronbach's α and construct validity by Spearman's correlation. Results: A total of 1276 patients participated (76% female, 25% with a disease duration <5 years, median HAQ 1.0). The original BRAF-MDQ four-factor structure and RAID single-factor structure were confirmed in every country with ⩾66% of variation in items explained by each factor and all item factor loadings of 0.71-0.98. Internal consistency for the BRAF-MDQ total and subscales was a Cronbach's α of 0.75-0.96 and for RAID, 0.93-0.96. Fatigue construct validity was shown for the BRAF-MDQ and BRAF-NRS severity and effect scales, correlated internally with SF-36 vitality and with RAID fatigue (r = 0.63-0.93). Broader construct validity for the BRAFs and RAID was shown by correlation with each other, HAQ and SF-36 domains (r = 0.46-0.82), with similar patterns in individual countries. The revised BRAF-NRS V2 Coping item had stronger validity than the original in all analyses. The revised Spanish RAID coping item performed as well as the original. Conclusion: Across six European countries, the BRAF-MDQ identifies the same four aspects of fatigue, and along with the RAID, shows strong factor structure and internal consistency and moderate-good construct validity. The revised BRAF-NRS V2 shows improved construct validity and replaces the original.