Efficacy of non-pharmacological interventions: a systematic review informing the 2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases

OBJECTIVE: To identify the best evidence on the efficacy of non-pharmacological interventions in reducing fatigue in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and to summarise their safety in the identified studies to inform European Alliance of Associations for Rheumatology recommendations for the management of fatigue in people with I-RMDs. METHODS: Systematic review of randomised controlled trials (RCTs) including adults with I-RMDs conducted according to the Cochrane Handbook. Search strategy ran in Medline, Embase, Cochrane Library, CINAHL Complete, PEDro, OTseeker and PsycINFO. Assessment of risk of bias, data extraction and synthesis were performed by two reviewers independently. Data were pooled in meta-analyses. RESULTS: From a total of 4150 records, 454 were selected for full-text review, 82 fulfilled the inclusion criteria and 55 RCTs were included in meta-analyses. Physical activity or exercise was efficacious in reducing fatigue in rheumatoid arthritis (RA) (standardised mean differences (SMD)=-0.23, 95% CI=-0.37 to -0.1), systemic lupus erythematosus (SLE) (SMD=-0.54, 95% CI=-1.07 to -0.01) and spondyloarthritis (SMD=-0.94, 95% CI=-1.23 to -0.66); reduction of fatigue was not significant in Sjögren's syndrome (SMD=-0.83, 95% CI=-2.13 to 0.47) and systemic sclerosis (SMD=-0.66, 95% CI=-1.33 to 0.02). Psychoeducational interventions were efficacious in reducing fatigue in RA (SMD=-0.32, 95% CI=-0.48 to -0.16), but not in SLE (SMD=-0.19, 95% CI=-0.46 to 0.09). Follow-up models in consultations (SMD=-0.05, 95% CI=-0.29 to 0.20) and multicomponent interventions (SMD=-0.20, 95% CI=-0.53 to 0.14) did not show significant reductions of fatigue in RA. The results of RCTs not included in the meta-analysis suggest that several other non-pharmacological interventions may provide a reduction of fatigue, with reassuring safety results. CONCLUSIONS: Physica activity or exercise and psychoeducational interventions are efficacious and safe for managing fatigue in people with I-RMDs

Objective and subjective measures of physical functioning in women with fibromyalgia: what type of measure is associated most clearly with subjective well-being?

To find modifiable factors that are related to subjective well-being would be valuable for improving interventions in fibromyalgia. Physical activity, sedentary behaviour, and physical fitness may represent potential areas to optimize treatment regimens. In fibromyalgia, there is a discordance between clinical observations and patient-reported outcomes (objective and subjective assessments). Therefore, the present study aims at analyzing the associations of objective and subjective evaluations of physical activity, sedentary behaviour, and physical fitness with subjective well-being and determine if and how objective and subjective associations differ In the most conservative multivariate analysis, we found independent associations of the objective measures of physical activity with positive affect and life satisfaction and sedentary behaviour with positive affect. No such relationship was seen with subjective measures of the same behaviours. Moreover, we observed that objective and subjective physical fitness evaluations were independent of each other related to subjective well-being. Independent associations of the objectivemeasures (but not the subjective assessments) of physical activity with positive affect and life satisfaction, and of sedentary behaviour with positive affect were observed. However, objective measures and subjective appraisals of physical fitness appear to be independently related to well-being,which should be consideredwhen developing physical exercise interventions for fibromyalgiaThis work was supported by the Spanish Ministry of Economy and Competitiveness [I+D+i DEP2010-15639, I+D+I DEP2013- 40908, and BES-2014–067612]; the Spanish Ministry of Education [FPU15/00002]. This study has been partially funded by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and by the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ERDF), ref. SOMM17/6107/ UGR. This research was supported (in part) by the Intramural Research program of the NIH, National Institute of Nursing Research

The effect of a high-fat diet on brain plasticity, inflammation and cognition in female ApoE4-knockin and ApoE-knockout mice

Apolipoprotein E4 (ApoE4), one of three common isoforms of ApoE, is a major risk factor for late-onset Alzheimer disease (AD). ApoE-deficient mice, as well as mice expressing human ApoE4, display impaired learning and memory functions and signs of neurodegeneration. Moreover, ApoE protects against high-fat (HF) diet induced neurodegeneration by its role in the maintenance of the integrity of the blood-brain barrier. The influence of a HF diet on the progression of AD-like cognitive and neuropathological changes was assessed in wild-type (WT), human ApoE4 and ApoE-knockout (ApoE-/-) mice to evaluate the modulatory role of ApoE in this process. From 12 months of age, female WT, ApoE4, and ApoE-/- mice were fed either a standard or a HF diet (19% butter, 0.5% cholate, 1.25% cholesterol) throughout life. At 15 months of age mice performed the Morris water maze, evaluating spatial learning and memory. ApoE-/- showed increased spatial learning compared to WT mice (p = 0.009). HF diet improved spatial learning in WT mice (p = 0.045), but did not affect ApoE4 and ApoE-/- mice. Immunohistochemical analyses of the hippocampus demonstrated increased neuroinflammation (CD68) in the cornu ammonis 1 (CA1) region in ApoE4 (p = 0.001) and in ApoE-/- (p = 0.032) mice on standard diet. HF diet tended to increase CD68 in the CA1 in WT mice (p = 0.052), while it decreased in ApoE4 (p = 0.009), but ApoE-/- remained unaffected. A trend towards increased neurogenesis (DCX) was found in both ApoE4 (p = 0.052) and ApoE-/- mice (p = 0.068). In conclusion, these data suggest that HF intake induces different effects in WT mice compared to ApoE4 and ApoE-/- with respect to markers for cognition and neurodegeneration. We propose that HF intake inhibits the compensatory mechanisms of neuroinflammation and neurogenesis in aged female ApoE4 and ApoE-/- mice

Efficacy of non-pharmacological interventions: a systematic review informing the 2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases

OBJECTIVE: To identify the best evidence on the efficacy of non-pharmacological interventions in reducing fatigue in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and to summarise their safety in the identified studies to inform European Alliance of Associations for Rheumatology recommendations for the management of fatigue in people with I-RMDs.  METHODS: Systematic review of randomised controlled trials (RCTs) including adults with I-RMDs conducted according to the Cochrane Handbook. Search strategy ran in Medline, Embase, Cochrane Library, CINAHL Complete, PEDro, OTseeker and PsycINFO. Assessment of risk of bias, data extraction and synthesis were performed by two reviewers independently. Data were pooled in meta-analyses.  RESULTS: From a total of 4150 records, 454 were selected for full-text review, 82 fulfilled the inclusion criteria and 55 RCTs were included in meta-analyses. Physical activity or exercise was efficacious in reducing fatigue in rheumatoid arthritis (RA) (standardised mean differences (SMD)=-0.23, 95% CI=-0.37 to -0.1), systemic lupus erythematosus (SLE) (SMD=-0.54, 95% CI=-1.07 to -0.01) and spondyloarthritis (SMD=-0.94, 95% CI=-1.23 to -0.66); reduction of fatigue was not significant in Sjögren's syndrome (SMD=-0.83, 95% CI=-2.13 to 0.47) and systemic sclerosis (SMD=-0.66, 95% CI=-1.33 to 0.02). Psychoeducational interventions were efficacious in reducing fatigue in RA (SMD=-0.32, 95% CI=-0.48 to -0.16), but not in SLE (SMD=-0.19, 95% CI=-0.46 to 0.09). Follow-up models in consultations (SMD=-0.05, 95% CI=-0.29 to 0.20) and multicomponent interventions (SMD=-0.20, 95% CI=-0.53 to 0.14) did not show significant reductions of fatigue in RA. The results of RCTs not included in the meta-analysis suggest that several other non-pharmacological interventions may provide a reduction of fatigue, with reassuring safety results.  CONCLUSIONS: Physica activity or exercise and psychoeducational interventions are efficacious and safe for managing fatigue in people with I-RMDs

Effects of early-life stress on peripheral and central mitochondria in male mice across ages

Exposure to early-life stress (ES) increases the vulnerability to develop metabolic diseases as well as cognitive dysfunction, but the specific biological underpinning of the ES-induced programming is unknown. Metabolic and cognitive disorders are often comorbid, suggesting possible converging underlying pathways. Mitochondrial dysfunction is implicated in both metabolic diseases and cognitive dysfunction and chronic stress impairs mitochondrial functioning. However, if and how mitochondria are impacted by ES and whether they are implicated in the ES-induced programming remains to be determined. ES was applied by providing mice with limited nesting and bedding material from postnatal day (P)2-P9, and metabolic parameters, cognitive functions and multiple aspects of mitochondria biology (i.e. mitochondrial electron transport chain (ETC) complex activity, mitochondrial DNA copy number, expression of genes relevant for mitochondrial function, and the antioxidant capacity) were studied in muscle, hypothalamus and hippocampus at P9 and late adulthood (10–12 months of age). We show that ES altered bodyweight (gain), adiposity and glucose levels at P9, but not in late adulthood. At this age, however, ES exposure led to cognitive impairments. ES affected peripheral and central mitochondria in an age-dependent manner. At P9, both muscle and hypothalamic ETC activity were affected by ES, while in hippocampus, ES altered the expression of genes involved in fission and antioxidant defence. In adulthood, alterations in ETC complex activity were observed in the hypothalamus specifically, whereas in muscle and hippocampus ES affected the expression of genes involved in mitophagy and fission, respectively. Our study demonstrates that ES affects peripheral and central mitochondria biology throughout life, thereby uncovering a converging mechanism that might contribute to the ES-induced vulnerability for both metabolic diseases and cognitive dysfunction, which could serve as a novel target for intervention.</p

Fatigue in Women with Fibromyalgia: A Gene-Physical Activity Interaction Study

Fatigue is a cardinal symptom in fibromyalgia. Fatigue is assumed to be the result of genetic susceptibility and environmental factors. We aimed at examining the role of genetic susceptibility for fatigue in southern Spanish women with fibromyalgia, by looking at single nucleotide polymorphisms in 34 fibromyalgia candidate-genes, at the interactions between genes, and at the gene-physical activity interactions. We extracted DNA from saliva of 276 fibromyalgia women to analyze gene-polymorphisms. Accelerometers registered physical activity and sedentary behavior. Fatigue was assessed with the Multidimensional Fatigue Inventory. Based on the Bonferroni's and False Discovery Rate values, we found that the genotype of the rs4453709 polymorphism (sodium channel protein type 9 subunit alpha, SCN9A, gene) was related to reduced motivation (AT carriers showed the highest reduced motivation) and reduced activity (AA carriers showed the lowest reduced activity). Carriers of the heterozygous genotype of the rs1801133 (methylene tetrahydrofolate reductase, MTHFR, gene) or rs4597545 (SCN9A gene) polymorphisms who were physically active reported lower scores on fatigue compared to their inactive counterparts. Highly sedentary carriers of the homozygous genotype of the rs7607967 polymorphism (AA/GG genotype; SCN9A gene) presented more reduced activity (a dimension of fatigue) than those with lower levels of sedentary behavior. Collectively, findings from the present study suggest that the contribution of genetics and gene-physical activity interaction to fatigue in fibromyalgia is modest

Comparison of blood lipids, lipoproteins, anthropometric measures, and resting and exercise cardiovascular responses in children, 6-7 years old

The purpose of this investigation was to determine sex differences and interrelationships in anthropometric, blood lipids and lipoproteins, steady rate and maximal bicycle ergometric measures in boys (N = 38) and girls (N= 28) ages 6 to 7 years. After adjusting for a significantly (P P -1 whereas no differences (P&gt; 0.05) existed in preexercise and maximal heart rates. Multiple regression analyses resulted in weak but significant (P P r = 0.46) was obtained for the girls. These data indicate that sex differences exist for selected ergometric, anthropometric, and blood lipid and lipoprotein measures as early as 6 years. Also, the association among blood lipid and lipoprotein measures may differ between boys and girls.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24221/1/0000480.pd

An Innovative Option for Venous Reconstruction After Pancreaticoduodenectomy: the Left Renal Vein

INTRODUCTION: Pancreatic ductal adenocarcinoma has a high mortality rate with limited treatment options. One option is pancreaticoduodenectomy, although complete resection may require venous resection. Pancreaticoduodenectomy with venous resection and reconstruction is becoming a more common practice with many choices for venous reconstruction. We describe the technique of using the left renal vein as a conduit for venous reconstruction during pancreaticoduodenectomy. METHODS: The technique for use of the left renal vein as an interposition graft for venous reconstruction during pancreaticoduodenectomy is described as well as outcomes for nine patients that have undergone the procedure. RESULTS: Nine patients, seven men, with a mean age of 57 years, have undergone the operation. There were eight interposition grafts and one patch graft. Mean operating time was 7.8 hours, and mean tumor size was 3.4 cm. Eight patients had node-positive disease, and six had involvement of the vein. Mean hospital stay was 14 days and perioperative morbidity included a superficial wound infection, delayed gastric emptying, ascites, and gastrointestinal bleeding in one patient each. Creatinine ranged from 0.8–1.1 mg/dl preoperatively and from 0.7–1.3 mg/dl at discharge. Mean follow-up was 6.8 months with normal creatinine values noted through the follow-up period. Two patients had died during follow-up from recurrent disease at 8.3 and 18.2 months after the operation. CONCLUSIONS: The left renal vein provides an additional choice for an autologous graft during pancreaticoduodenectomy with venous resection. The ease of harvesting the graft and maintenance of renal function distinguish its use

NET-RMDs study: networks of fatigue and pain in rheumatic and musculoskeletal diseases – protocol for an international cross-sectional study

Introduction Fatigue and pain are the main symptoms of rheumatic and musculoskeletal diseases (RMDs). Healthcare professionals have a primary role in helping patients to manage both these symptoms, which are part of a complex network of co-occurring factors including sleep problems, psychological distress, social support, body weight, diet, inactive lifestyle and disease activity. The patterns of relationships (networks) between these factors and these symptoms, fatigue and pain, are largely unknown. The current proposal aims to reveal them using network estimation techniques. We will also consider differences in networks for subgroups of people with (1) different RMDs and (2) different clusters (profiles) of biopsychosocial factors. Methods and analysis Adults with at least one RMD will be recruited to this online cross-sectional observational project. To provide a complete overview, a large sample size from different countries will be included. A brief online survey, using 0–10 numeric rating scales will measure, for the past month, levels of fatigue and pain as well as scores on seven biopsychosocial factors. These factors were derived from literature and identified by interviews with patients, health professionals and rheumatologists. Using this input, the steering committee of the project decided the factors to be measured giving priority to those that can be modified in self-management support in community health centres worldwide. Network estimation techniques are used to detect the complex patterns of relationships between these biopsychosocial factors, fatigue and pain; and how these differ for subgroups of people with different RMDs and profiles. Ethics and dissemination Ethical approval of national Institutional Review Boards was obtained. The online survey includes an information letter and informed consent form. The findings will be disseminated via conferences and publications in peer-reviewed scientific journals, while public media channels will be used to inform people with RMDs and other interested parties