Evaluation of walking activity and gait to identify physical and mental fatigue in neurodegenerative and immune disorders: preliminary insights from the IDEA-FAST feasibility study.

BACKGROUND: Many individuals with neurodegenerative (NDD) and immune-mediated inflammatory disorders (IMID) experience debilitating fatigue. Currently, assessments of fatigue rely on patient reported outcomes (PROs), which are subjective and prone to recall biases. Wearable devices, however, provide objective and reliable estimates of gait, an essential component of health, and may present objective evidence of fatigue. This study explored the relationships between gait characteristics derived from an inertial measurement unit (IMU) and patient-reported fatigue in the IDEA-FAST feasibility study. METHODS: Participants with IMIDs and NDDs (Parkinson's disease (PD), Huntington's disease (HD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (PSS), and inflammatory bowel disease (IBD)) wore a lower-back IMU continuously for up to 10 days at home. Concurrently, participants completed PROs (physical fatigue (PF) and mental fatigue (MF)) up to four times a day. Macro (volume, variability, pattern, and acceleration vector magnitude) and micro (pace, rhythm, variability, asymmetry, and postural control) gait characteristics were extracted from the accelerometer data. The associations of these measures with the PROs were evaluated using a generalised linear mixed-effects model (GLMM) and binary classification with machine learning. RESULTS: Data were recorded from 72 participants: PD = 13, HD = 9, RA = 12, SLE = 9, PSS = 14, IBD = 15. For the GLMM, the variability of the non-walking bouts length (in seconds) with PF returned the highest conditional R2, 0.165, and with MF the highest marginal R2, 0.0018. For the machine learning classifiers, the highest accuracy of the current analysis was returned by the micro gait characteristics with an intrasubject cross validation method and MF as 56.90% (precision = 43.9%, recall = 51.4%). Overall, the acceleration vector magnitude, bout length variation, postural control, and gait rhythm were the most interesting characteristics for future analysis. CONCLUSIONS: Counterintuitively, the outcomes indicate that there is a weak relationship between typical gait measures and abnormal fatigue. However, factors such as the COVID-19 pandemic may have impacted gait behaviours. Therefore, further investigations with a larger cohort are required to fully understand the relationship between gait and abnormal fatigue.

Fatigue-Related Changes of Daily Function: Most Promising Measures for the Digital Age.

Background: Fatigue is a prominent symptom in many diseases and is strongly associated with impaired daily function. The measurement of daily function is currently almost always done with questionnaires, which are subjective and imprecise. With the recent advances of digital wearable technologies, novel approaches to evaluate daily function quantitatively and objectively in real-life conditions are increasingly possible. This also creates new possibilities to measure fatigue-related changes of daily function using such technologies. Summary: This review examines which digitally assessable parameters in immune-mediated inflammatory and neurodegenerative diseases may have the greatest potential to reflect fatigue-related changes of daily function. Key Messages: Results of a standardized analysis of the literature reporting about perception-, capacity-, and performance-evaluating assessment tools indicate that changes of the following parameters: physical activity, independence of daily living, social participation, working life, mental status, cognitive and aerobic capacity, and supervised and unsupervised mobility performance have the highest potential to reflect fatigue-related changes of daily function. These parameters thus hold the greatest potential for quantitatively measuring fatigue in representative diseases in real-life conditions, e.g., with digital wearable technologies. Furthermore, to the best of our knowledge, this is a new approach to analysing evidence for the design of performance-based digital assessment protocols in human research, which may stimulate further systematic research in this area.

Identification of Fatigue and Sleepiness in Immune and Neurodegenerative Disorders from Measures of Real-World Gait Variability.

Current assessments of fatigue and sleepiness rely on patient reported outcomes (PROs), which are subjective and prone to recall bias. The current study investigated the use of gait variability in the "real world" to identify patient fatigue and daytime sleepiness. Inertial measurement units were worn on the lower backs of 159 participants (117 with six different immune and neurodegenerative disorders and 42 healthy controls) for up to 20 days, whom completed regular PROs. To address walking bouts that were short and sparse, four feature groups were considered: sequence-independent variability (SIV), sequence-dependant variability (SDV), padded SDV (PSDV), and typical gait variability (TGV) measures. These gait variability measures were extracted from step, stride, stance, and swing time, step length, and step velocity. These different approaches were compared using correlations and four machine learning classifiers to separate low/high fatigue and sleepiness.Most balanced accuracies were above 50%, the highest was 57.04% from TGV measures. The strongest correlation was 0.262 from an SDV feature against sleepiness. Overall, TGV measures had lower correlations and classification accuracies.Identifying fatigue or sleepiness from gait variability is extremely complex and requires more investigation with a larger data set, but these measures have shown performances that could contribute to a larger feature set.Clinical relevance- Gait variability has been repeatedly used to assess fatigue in the lab. The current study, however, explores gait variability for fatigue and daytime sleepiness in real-world scenarios with multiple gait-impacted disorders.

Technology acceptance of digital devices for home use: Qualitative results of a mixed methods study.

Objective: Digital devices have demonstrated benefits to patients with chronic and neurodegenerative diseases. But when patients use medical devices in their homes, the technologies have to fit into their lives. We investigated the technology acceptance of seven digital devices for home use. Methods: We conducted 60 semi-structured interviews with participants of a larger device study on their views on the acceptability of seven devices. Transcriptions were analysed using qualitative content analysis. Results: Based on the unified theory of acceptance and use of technology, we evaluated effort, facilitating conditions, performance expectancy and social influence of each device.In the effort category, five themes emerged: (a) the hassle to use the device; (b) its usability; (c) comfort; (d) disturbance to daily life; and (e) problems during usage. Facilitating conditions consisted of five themes: (a) expectations regarding a device; (b) quality of the instructions; (c) insecurities with usage; (d) possibilities of optimization; and (e) possibilities to use the device longer. Regarding performance expectancy, we identified three themes: (a) insecurities with the performance of a device; (b) feedback; and (c) motivation for using a device. In the social influence category, three themes emerged: (a) reactions of peers; (b) concerns with the visibility of a device; and (c) concerns regarding data privacy. Conclusions: We identify key factors that determine the acceptability of medical devices for home use from the participants' perspective. These include low effort of use, minor disruptions to their daily lives and good support from the study team.

Assessing fatigue and sleep in chronic diseases using physiological signals from wearables: A pilot study.

Problems with fatigue and sleep are highly prevalent in patients with chronic diseases and often rated among the most disabling symptoms, impairing their activities of daily living and the health-related quality of life (HRQoL). Currently, they are evaluated primarily via Patient Reported Outcomes (PROs), which can suffer from recall biases and have limited sensitivity to temporal variations. Objective measurements from wearable sensors allow to reliably quantify disease state, changes in the HRQoL, and evaluate therapeutic outcomes. This work investigates the feasibility of capturing continuous physiological signals from an electrocardiography-based wearable device for remote monitoring of fatigue and sleep and quantifies the relationship of objective digital measures to self-reported fatigue and sleep disturbances. 136 individuals were followed for a total of 1,297 recording days in a longitudinal multi-site study conducted in free-living settings and registered with the German Clinical Trial Registry (DRKS00021693). Participants comprised healthy individuals (N = 39) and patients with neurodegenerative disorders (NDD, N = 31) and immune mediated inflammatory diseases (IMID, N = 66). Objective physiological measures correlated with fatigue and sleep PROs, while demonstrating reasonable signal quality. Furthermore, analysis of heart rate recovery estimated during activities of daily living showed significant differences between healthy and patient groups. This work underscores the promise and sensitivity of novel digital measures from multimodal sensor time-series to differentiate chronic patients from healthy individuals and monitor their HRQoL. The presented work provides clinicians with realistic insights of continuous at home patient monitoring and its practical value in quantitative assessment of fatigue and sleep, an area of unmet need.

Fatigue in inflammatory rheumatic diseases: current knowledge and areas for future research.

Fatigue is a complex phenomenon and an important health concern for many people with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, primary Sjögren syndrome and systemic lupus erythematosus. Although some clinical trials have shown the benefits of cognitive behavioural therapy in fatigue management, the effect of this approach is relatively modest, and no curative treatment has been identified. The pathogenesis of fatigue remains unclear. Despite many challenges and limitations, a growing body of research points to roles for the immune system, the central and autonomic nervous systems and the neuroendocrine system in the induction and maintenance of fatigue in chronic diseases. New insights indicate that sleep, genetic susceptibility, metabolic disturbances and other biological and physiological mechanisms contribute to fatigue. Furthermore, understanding of the relationships between psychosocial factors and fatigue is increasing. However, the interrelationships between these diverse mechanisms and fatigue remain poorly defined. In this Review, we outline various biological, physiological and psychosocial determinants of fatigue in inflammatory rheumatic diseases, and propose mechanistic and conceptual models of fatigue to summarize current understanding, stimulate debate and develop further research ideas.

Autonomic Nervous System Dysfunction in Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune disease which primarily affects the exocrine glands, but can also affect other organs, including the nervous system. Many studies have reported evidence of autonomic nervous system (ANS) dysfunction in pSS which may contribute to a wide range of symptoms and functional burden. Symptoms of ANS dysfunction are common and widespread among patients with pSS and are associated with other features of the disease, particularly fatigue. Accumulating data on the inter-relationship between the ANS and the immune system via the vagus nerve have been reported. Vagus nerve stimulation (VNS) has also been associated with improvement in fatigue in patients with pSS. Taken together, these data suggest that the ANS may be a potential treatment target for pSS, in particularly those with fatigue being a predominant symptom. Future research to dissect the link between the ANS, immune dysregulation and clinical manifestations in pSS and to evaluate the potential of VNS as a therapy for pSS is warranted.

Improvement of Severe Fatigue Following Nuclease Therapy in Patients With Primary Sjögren's Syndrome: A Randomized Clinical Trial.

OBJECTIVE: To assess the safety and efficacy of RSLV-132, an RNase Fc fusion protein, in a phase II randomized, double-blind, placebo-controlled clinical trial in patients with primary Sjögren's syndrome (SS). METHODS: Thirty patients with primary SS were randomized to receive treatment with RSLV-132 or placebo intravenously once per week for 2 weeks, and then every 2 weeks for 12 weeks. Eight patients received placebo and 20 patients received RSLV-132 at a dose of 10 mg/kg. Clinical efficacy measures included the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Profile of Fatigue (ProF), and the Digit Symbol Substitution Test (DSST). RESULTS: Patients randomized to receive RSLV-132 experienced clinically meaningful improvements in the ESSPRI score (P = 0.27), FACIT-F score (P = 0.05), ProF score (P = 0.07), and DSST (P = 0.02) from baseline to day 99, whereas patients who received placebo showed no changes in any of these clinical efficacy measures. This improvement was significantly correlated with increased expression of selected interferon-inducible genes (Pearson's correlations, each P < 0.05). CONCLUSION: Administration of RSLV-132 improved severe fatigue, as determined by 4 independent patient-reported measures of fatigue, in patients with primary SS.

Denigration of general practice as a career choice: The students' perspective. A qualitative study.

BACKGROUND: General practice in the UK and other parts of the world is facing a recruitment crisis with insufficient numbers of medical students selecting it as a career choice. Denigration of general practice has been postulated as one of the contributing factors. AIM: To explore comments about general practice as a career made by clinical teachers from the medical student's perspective, and in doing so to further understand the current difficulties of recruiting into general practice. DESIGN & SETTING: A qualitative, explorative study of three focus groups of medical students from two medical schools in northern England. METHOD: A semi-structured interview format was utilised. The following four questions were posed to the participants about choosing general practice as a career: had they heard negative comments? Had they heard positive comments? Do they think comments influence student career decisions or is it a problem? Could they suggest any solutions to the issue? Results were analysed using thematic analysis. RESULTS: Students reported hearing both positive and negative comments about general practice as a career choice. They perceived the comments to potentially influence student career choice. Three underlying themes emerged: the individual (personal characteristics of students affecting the influence that comments have on them); the curriculum (presence and content of general practice teaching); and culture (in the medical school and profession). These were used to postulate a model that may explain how negative comments shape students' perceptions of general practice. CONCLUSION: Denigration of general practice is an ongoing problem within the medical profession and strategies to address it must be developed or recruitment to the specialty will continue to decline. This study suggests a model that can help to understand the complex relationship between different factors that result in negative comments being taken on board by medical students.

Symptomatic patients with P369S-R408Q mutations: familial Mediterranean fever or mixed auto-inflammatory syndrome?

A 51-year-old South African female of Ashkenazi Jewish descent was admitted with acute pleuritic chest pain, shortness of breath, fatigue and fever. She experienced vague abdominal and calf pains for 30 years. Her monozygotic twin was investigated independently for recurrent abdominal pain. Despite initially responding to antibiotics, treating suspected pneumonia, she developed recurrent fevers and pleuritic chest pain. After thorough investigation without significant findings, she re-attended days after discharge with similar symptoms. Familial Mediterranean fever (FMF) was suggested as she met diagnostic criteria and responded to colchicine, though FMF normally presents before 20 years old. Genetic testing showed no pathogenic mutations but heterozygous P369S and R408Q mutations. The significance of these mutations remains unclear, as they are found in asymptomatic patients, suggesting incomplete penetrance. She remains well, with full symptom resolution, but mixed auto-inflammatory syndrome may be a more appropriate diagnosis in symptomatic patients with both P369S and R408Q mutations.

Pain and depression are associated with both physical and mental fatigue independently of comorbidities and medications in primary Sjögren's syndrome.

Objectives: To report on fatigue in patients from the United Kingdom primary Sjögren's syndrome (pSS) registry identifying factors associated with fatigue and robust to assignable causes such as comorbidities and medications associated with drowsiness. Methods: From our cohort (n = 608), we identified those with comorbidities associated with fatigue, and those taking medications associated with drowsiness. We constructed dummy variables, permitting the contribution of these potentially assignable causes of fatigue to be assessed. Using multiple regression analysis, we modelled the relationship between Profile of Fatigue and Discomfort physical and mental fatigue scores and potentially related variables. Results: Pain, depression and daytime sleepiness scores were closely associated with both physical and mental fatigue (all p ≤ 0.0001). In addition, dryness was strongly associated with physical fatigue (p ≤ 0.0001). These effects were observed even after adjustment for comorbidities associated with fatigue or medications associated with drowsiness. Conclusions: These findings support further research and clinical interventions targeting pain, dryness, depression and sleep to improve fatigue in patients with pSS.This finding is robust to both the effect of other comorbidities associated with fatigue and medications associated with drowsiness.

Fatigue in primary Sjögren's syndrome (pSS) is associated with lower levels of proinflammatory cytokines: a validation study.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune rheumatic disease with symptoms including dryness, fatigue, and pain. The previous work by our group has suggested that certain proinflammatory cytokines are inversely related to patient-reported levels of fatigue. To date, these findings have not been validated. This study aims to validate this observation. Blood levels of seven cytokines were measured in 120 patients with pSS from the United Kingdom Primary Sjögren's Syndrome Registry and 30 age-matched healthy non-fatigued controls. Patient-reported scores for fatigue were classified according to severity and compared to cytokine levels using analysis of variance. The differences between cytokines in cases and controls were evaluated using Wilcoxon test. A logistic regression model was used to determine the most important identifiers of fatigue. Five cytokines, interferon-γ-induced protein-10 (IP-10), tumour necrosis factor-α (TNFα), interferon-α (IFNα), interferon-γ (IFN-γ), and lymphotoxin-α (LT-α) were significantly higher in patients with pSS (n = 120) compared to non-fatigued controls (n = 30). Levels of two proinflammatory cytokines, TNF-α (p = 0.021) and LT-α (p = 0.043), were inversely related to patient-reported levels of fatigue. Cytokine levels, disease-specific and clinical parameters as well as pain, anxiety, and depression were used as predictors in our validation model. The model correctly identifies fatigue levels with 85% accuracy. Consistent with the original study, pain, depression, and proinflammatory cytokines appear to be the most powerful predictors of fatigue in pSS. TNF-α and LT-α have an inverse relationship with fatigue severity in pSS challenging the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions.

Recent pharmacological advances in the management of gout.

Gout is the most common cause of inflammatory arthritis worldwide, and reports show that despite availability of therapies, management is still suboptimal. The new EULAR 2016 recommendations for the treatment of gout highlight the huge development in gout therapies, and the number of drugs being trialled only continues to increase. A clinical review of the evidence that underlies the recommendations from EULAR can reveal possible gaps in the literature and avenues for future research into gout therapies.