A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

BACKGROUND: Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. METHODS: We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. RESULTS: We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. CONCLUSIONS: Our results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases

Randomized controlled trial of an internet-based self-guided hand exercise program to improve hand function in people with systemic sclerosis: the Scleroderma Patient-centered Intervention Network Hand Exercise Program (SPIN-HAND) trial

BACKGROUND: Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. Functional impairment of hands is common. The Scleroderma Patient-centered Intervention Network (SPIN)-HAND trial compared effects of offering access to an online self-guided hand exercise program to usual care on hand function (primary) and functional health outcomes (secondary) in people with SSc with at least mild hand function limitations. METHODS: The pragmatic, two-arm, parallel-group cohort multiple randomized controlled trial was embedded in the SPIN Cohort. Cohort participants with Cochin Hand Function Scale (CHFS) scores ≥ 3 and who indicated interest in using the SPIN-HAND Program were randomized (3:2 ratio) to an offer of program access or to usual care (targeted N = 586). The SPIN-HAND program consists of 4 modules that address (1) thumb flexibility and strength; (2) finger bending; (3) finger extension; and (4) wrist flexibility and strength. The primary outcome analysis compared CHFS scores 3 months post-randomization between participants offered versus not offered the program. Secondary outcomes were CHFS scores 6 months post-randomization and functional health outcomes (Patient-Reported Outcomes Measurement Information System profile version 2.0 domain scores) 3 and 6 months post-randomization. RESULTS: In total, 466 participants were randomized to intervention offer (N = 280) or usual care (N = 186). Of 280 participants offered the intervention, 170 (61%) consented to access the program. Of these, 117 (69%) viewed at least one hand exercise instruction video and 77 (45%) logged into the program website at least 3 times. In intent-to-treat analyses, CHFS scores were 1.2 points lower (95% CI − 2.8 to 0.3) for intervention compared to usual care 3 months post-randomization and 0.1 points lower (95% CI − 1.8 to 1.6 points) 6 months post-randomization. There were no statistically significant differences in other outcomes. CONCLUSION: The offer to use the SPIN-HAND Program did not improve hand function. Low offer uptake, program access, and minimal usage among those who accessed the program limited our ability to determine if using the program would improve function. To improve engagement, the program could be tested in a group format or as a resource to support care provided by a physical or occupational therapist. TRIAL REGISTRATION: NCT03419208. Registered on February 1, 2018

Patterns of patient-reported symptoms and association with sociodemographic and systemic sclerosis disease characteristics: a scleroderma Patient-centered Intervention Network (SPIN) Cohort cross-sectional study

Background: Systemic sclerosis is a heterogenous disease in which little is known about patterns of patient-reported symptom clusters. We aimed to identify classes of individuals with similar anxiety, depression, fatigue, sleep disturbance, and pain symptoms and to evaluate associated sociodemographic and disease-related characteristics. Methods: This multi-centre cross-sectional study used baseline data from Scleroderma Patient-centered Intervention Network Cohort participants enrolled from 2014 to 2020. Eligible participants completed the PROMIS-29 v2.0 measure. Latent profile analysis was used to identify homogeneous classes of participants based on patterns of anxiety, depression, fatigue, sleep disturbance, and pain scores. Sociodemographic and disease-related characteristics were compared across classes. Findings: Among 2212 participants, we identified five classes, including four classes with “Low” (565 participants, 26%), “Normal” (651 participants, 29%), “High” (569 participants, 26%), or “Very High” (193 participants, 9%) symptom levels across all symptoms. Participants in a fifth class, “High Fatigue/Sleep/Pain and Low Anxiety/Depression” (234 participants, 11%) had similar levels of fatigue, sleep disturbance, and pain as in the “High” class but low anxiety and depression symptoms. There were significant and substantive trends in sociodemographic characteristics (age, education, race or ethnicity, marital or partner status) and increasing disease severity (diffuse disease, tendon friction rubs, joint contractures, gastrointestinal symptoms) across severity-based classes. Disease severity and sociodemographic characteristics of “High Fatigue/Sleep/Pain and Low Anxiety/Depression” class participants were similar to the “High” severity class. Interpretation: Most people with systemic sclerosis can be classified by levels of patient-reported symptoms, which are consistent across symptoms and highly associated with sociodemographic and disease-related variables, except for one group which reports low mental health symptoms despite high levels of other symptoms and substantial disease burden. Studies are needed to better understand resilience in systemic sclerosis and to identify and facilitate implementation of cognitive and behavioural strategies to improve coping and overall quality of life. Funding: National Institute of Nursing Research (F31NR019007), Canadian Institutes of Health Research, Arthritis Society Canada, the Lady Davis Institute for Medical Research, the Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclérodermie Québec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland

Pain levels and associated factors in the Scleroderma Patient-centered Intervention Network (SPIN) cohort: a multicentre cross-sectional study

Background: Pain is an important and detrimental feature of systemic sclerosis but is often overlooked or deprioritised in research and clinical care. Raynaud's phenomenon, arthritis, and cutaneous ulcers are among the commonly reported disease manifestations of systemic sclerosis that could be associated with pain. We aimed to assess levels of pain intensity and interference and to evaluate disease factors associated with pain intensity and interference. Methods: In this multicentre cross-sectional study, participants from the Scleroderma Patient-centered Intervention Network cohort who completed pain intensity and interference measures (Patient Reported Outcomes Information System-29 profile, version 2·0) as part of baseline assessments were included. Patients were recruited from 46 centres in Australia, Canada, France, Mexico, Spain, the UK, and the USA between April 15, 2014, and Jan 7, 2020. Eligible patients included those aged 18 years or older who met the criteria for systemic sclerosis devised by the American College of Rheumatology and the European League Against Rheumatism. Associations of pain intensity and pain interference with systemic sclerosis-related variables and overlap syndromes, controlling for sociodemographic variables, were assessed with multiple linear regression. Continuous independent variables were standardised. Findings: Among 2157 participants with systemic sclerosis (268 [12%] males and 1889 [88%] females), 1870 (87%) reported mild, moderate, or severe pain (defined as ≥1 on a 0 to 10 scale), and 815 (38%) reported moderate or severe pain (defined as ≥5). Moreover, 757 (35%) participants reported moderate or severe pain interference. Greater pain intensity was independently associated with female sex (0·58 points [95% CI 0·26–0·90]), non-White race or ethnicity (0·50 points [0·21–0·79]), fewer years in formal education (0·30 points per SD [0·19–0·41]), country (reference: USA; Canada: 0·29 points [0·01–0·57] and UK: 0·58 points [0·21–0·95]), greater body-mass index (0·35 points per SD [0·24–0·45]); joint contractures (0·67 points [0·39–0·94]), digital ulcers (0·33 points [0·10–0·55]), gastrointestinal involvement (0·66 points [0·33–0·98]), skin involvement (measured using modified Rodnan skin score; 0·22 points per SD [0·10–0·35]), rheumatoid arthritis (0·96 points [0·50–1·43]), and Sjögren's syndrome (0·42 points [0·01–0·83]). Pain interference results were similar. Interpretation: Pain is common among people with systemic sclerosis. Controlling for sociodemographic variables, greater pain was associated with multiple systemic sclerosis-related manifestations, including joint contractures, digital ulcers, gastrointestinal involvement, skin involvement, and the presence of overlap syndromes. Health-care providers should work with patients to address pain, including identifying and addressing systemic sclerosis manifestations associated with their pain, and supporting behavioural approaches to minimise impact on function and quality of life. Funding: Canadian Institutes of Health Research, Arthritis Society, The Lady Davis Institute for Medical Research of the Jewish General Hospital, Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclérodermie Québec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland

Evaluation of Measurement Properties and Differential Item Functioning in the English and French Versions of the University of California, Los Angeles, Loneliness Scale-6: A Scleroderma Patient-Centered Intervention Network (SPIN) Study

Objective: Loneliness has been associated with poorer health-related quality of life but has not been studied in patients with systemic sclerosis (SSc). The current study was undertaken to examine and compare the psychometric properties of the English and French versions of the University of California, Los Angeles, Loneliness Scale-6 (ULS-6) in patients with SSc during the COVID-19 pandemic. Methods: This study used baseline cross-sectional data from 775 adults enrolled in the Scleroderma Patient-Centered Intervention Network (SPIN) COVID-19 Cohort. Reliability and validity of ULS-6 scores overall and between languages were evaluated using confirmatory factor analysis (CFA), differential item functioning (DIF) through the multiple-indicator multiple-cause (MIMIC) model, omega/alpha calculation, and correlations of hypothesized convergent relationships. Results: CFA for the total sample supported the single-factor structure (comparative fit index [CFI] 0.96, standardized root mean residual [SRMR] 0.03), and all standardized factor loadings for items were large (0.60–0.86). The overall MIMIC model with language as a covariate fit well (CFI 0.94, SRMR 0.04, root mean square error of approximation 0.11). Statistically significant DIF was found for 3 items across language (βitem2 = 0.14, P < 0.001; βitem4 = –0.07, P = 0.01; βitem6 = 0.13, P < 0.001), but these small differences were without practical measurement implications. Analyses demonstrated high internal consistency with no language-based convergent validity differences. Conclusion: Analyses demonstrated evidence of acceptable reliability and validity of ULS-6 scores in English- and French-speaking adults with SSc. DIF analysis supported use of the ULS-6 to examine comparative experiences of loneliness without adjusting for language

A Genome Scan for Positive Selection in Thoroughbred Horses

Thoroughbred horses have been selected for exceptional racing performance resulting in system-wide structural and functional adaptations contributing to elite athletic phenotypes. Because selection has been recent and intense in a closed population that stems from a small number of founder animals Thoroughbreds represent a unique population within which to identify genomic contributions to exercise-related traits. Employing a population genetics-based hitchhiking mapping approach we performed a genome scan using 394 autosomal and X chromosome microsatellite loci and identified positively selected loci in the extreme tail-ends of the empirical distributions for (1) deviations from expected heterozygosity (Ewens-Watterson test) in Thoroughbred (n = 112) and (2) global differentiation among four geographically diverse horse populations (FST). We found positively selected genomic regions in Thoroughbred enriched for phosphoinositide-mediated signalling (3.2-fold enrichment; P<0.01), insulin receptor signalling (5.0-fold enrichment; P<0.01) and lipid transport (2.2-fold enrichment; P<0.05) genes. We found a significant overrepresentation of sarcoglycan complex (11.1-fold enrichment; P<0.05) and focal adhesion pathway (1.9-fold enrichment; P<0.01) genes highlighting the role for muscle strength and integrity in the Thoroughbred athletic phenotype. We report for the first time candidate athletic-performance genes within regions targeted by selection in Thoroughbred horses that are principally responsible for fatty acid oxidation, increased insulin sensitivity and muscle strength: ACSS1 (acyl-CoA synthetase short-chain family member 1), ACTA1 (actin, alpha 1, skeletal muscle), ACTN2 (actinin, alpha 2), ADHFE1 (alcohol dehydrogenase, iron containing, 1), MTFR1 (mitochondrial fission regulator 1), PDK4 (pyruvate dehydrogenase kinase, isozyme 4) and TNC (tenascin C). Understanding the genetic basis for exercise adaptation will be crucial for the identification of genes within the complex molecular networks underlying obesity and its consequential pathologies, such as type 2 diabetes. Therefore, we propose Thoroughbred as a novel in vivo large animal model for understanding molecular protection against metabolic disease

How to engage stakeholders in research: design principles to support improvement

Abstract Background: Closing the gap between research production and research use is a key challenge for the health research system. Stakeholder engagement is being increasingly promoted across the board by health research funding organisations, and indeed by many researchers themselves, as an important pathway to achieving impact. This opinion piece draws on a study of stakeholder engagement in research and a systematic literature search conducted as part of the study. Main body: This paper provides a short conceptualisation of stakeholder engagement, followed by ‘design principles’ that we put forward based on a combination of existing literature and new empirical insights from our recently completed longitudinal study of stakeholder engagement. The design principles for stakeholder engagement are organised into three groups, namely organisational, values and practices. The organisational principles are to clarify the objectives of stakeholder engagement; embed stakeholder engagement in a framework or model of research use; identify the necessary resources for stakeholder engagement; put in place plans for organisational learning and rewarding of effective stakeholder engagement; and to recognise that some stakeholders have the potential to play a key role. The principles relating to values are to foster shared commitment to the values and objectives of stakeholder engagement in the project team; share understanding that stakeholder engagement is often about more than individuals; encourage individual stakeholders and their organisations to value engagement; recognise potential tension between productivity and inclusion; and to generate a shared commitment to sustained and continuous stakeholder engagement. Finally, in terms of practices, the principles suggest that it is important to plan stakeholder engagement activity as part of the research programme of work; build flexibility within the research process to accommodate engagement and the outcomes of engagement; consider how input from stakeholders can be gathered systematically to meet objectives; consider how input from stakeholders can be collated, analysed and used; and to recognise that identification and involvement of stakeholders is an iterative and ongoing process. Conclusion: It is anticipated that the principles will be useful in planning stakeholder engagement activity within research programmes and in monitoring and evaluating stakeholder engagement. A next step will be to address the remaining gap in the stakeholder engagement literature concerned with how we assess the impact of stakeholder engagement on research us

Validation of the social interaction anxiety scale in scleroderma: A scleroderma patientcentered intervention network cohort study

INTRODUCTION: Individuals with visible differences due to medical conditions, such as systemic sclerosis (SSc; scleroderma), have reported difficulty navigating social situations because of issues such as staring, invasive questions, and rude comments. Fears or anxiety linked to situations in which a person interacts with others is known as social interaction anxiety. However, there exists no validated measurement tool to examine social interaction anxiety in rheumatologic conditions. METHODS: The present study examines the reliability (internal consistency) and validity (structural and convergent) of the Social Interaction Anxiety Scale-6 (SIAS-6) in a sample of 802 individuals with SSc, and compares these psychometric properties across limited and diffuse subtypes of the disease. Multi-group confirmatory factor analysis was used to examine the factor structure of the SIAS-6 in patients with both limited and diffuse SSc. RESULTS: A one-factor structure was found to fit well for individuals with SSc with both limited and diffuse disease. The measure demonstrated strong internal consistency reliability and convergent validity with relevant measures in expected magnitudes and directions. CONCLSUION: The SIAS-6 is a psychometrically robust measure that can confidently be used in SSc populations to examine social interaction anxiety. Moreover, scores can meaningfully be compared between patients with limited and diffuse disease

Randomized feasibility trial of the Scleroderma patient-centered intervention network hand exercise program (SPIN-HAND): Study protocol

BACKGOUND: Significant functional impairment of the hands is nearly universal in systemic sclerosis (SSc, scleroderma). Hand exercises may improve hand function, but developing, testing and disseminating rehabilitation interventions in SSc is challenging. The Scleroderma Patient-centered Intervention Network (SPIN) was established to address this issue and has developed an online hand exercise program to improve hand function for SSc patients (SPIN-HAND). The aim of the proposed feasibility trial is to evaluate the feasibility of conducting a full-scale randomized controlled trial (RCT) of the SPIN-HAND intervention. DESIGN AND METHODS: The SPIN-HAND feasibility trial will be conducted via the SPIN Cohort. The SPIN Cohort was developed as a framework for embedded pragmatic trials using the cohort multiple RCT design. In total, 40 English-speaking SPIN Cohort participants with at least mild hand function limitations (Cochin Hand Function Scale ≥3) and an indicated interest in using an online hand-exercise intervention will be randomized with a 1:1 ratio to be offered to use the SPIN-HAND program or usual care for 3 months. The primary aim is to evaluate the trial implementation processes, required resources and management, scientific aspects, and participant acceptability and usage of the SPIN-HAND program. DISCUSSION: The SPIN-HAND exercise program is a self-help tool that may improve hand function in patients with SSc. The SPIN-HAND feasibility trial will ensure that trial methodology is robust, feasible, and consistent with trial participant expectations. The results will guide adjustments that need to be implemented before undertaking a full-scale RCT of the SPIN-HAND program. TRIAL REGISTRATION: ClinicalTrials.gov IDENTIFIER: NCT03092024