Thomas Davergne
email: thomas.davergne@gmail.com

Rikke H Moe
email: rikmoe@gmail.com

Bruno Fautrel
email: bruno.fautrel@aphp.fr

Laure Gossec
email: laure.gossec@gmail.com

Affiliations

Laure Combourieu

Maude Barreau

Simone Birnbaum

Noémie Duclos

Timothee Gillot

Matthieu Guemann

Development and initial validation of a questionnaire to assess facilitators and barriers to physical activity for patients with rheumatoid arthritis, axial spondyloarthritis or psoriatic arthritis

Keywords: , 4 tables, 2 figures Motivation, Physical activity, Spondylitis, Ankylosing, Arthritis, Rheumatoid, Arthritis, Psoriatic, Surveys and Questionnaires

    Development and initial validation of a questionnaire to assess facilitators and barriers to physical activity for patients with rheumatoid arthritis, axial spondyloarthritis and/or psoriatic arthritis

Introduction

Axial spondyloarthritis (axSpA), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are the most prevalent inflammatory rheumatic diseases, representing 2% of the general population [START_REF] Feld | Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison[END_REF][START_REF] Schett | Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment[END_REF]. They share common characteristics such as inflammation, pain and fatigue, systemic manifestations and can potentially lead to structural changes in joint or spine with loss of function [START_REF] Feld | Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison[END_REF][START_REF] Gossec | Reporting of patient-perceived impact of rheumatoid arthritis and axial spondyloarthritis over 10 years: a systematic literature review[END_REF].

According to the World Health Organization (WHO), physical inactivity (lack of physical activity) has been identified as the fourth leading risk factor for global mortality [START_REF]Global health risks: Mortality and burden of disease attributable to selected major risks[END_REF]. Patients with these 3 inflammatory arthritis (IA) i.e., RA, SpA or PsA, are more prone to physical inactivity than the general population [START_REF] O'dwyer | Physical activity guidelines: is the message getting through to adults with rheumatic conditions?[END_REF]. For example, only a quarter of axSpA patients met the recommended level of physical activity (PA) [START_REF] O'dwyer | Physical activity guidelines: is the message getting through to adults with rheumatic conditions?[END_REF] and PA objectively measured by a tracker revealed that RA patients performed 200 minutes of PA per week less than healthy subjects [START_REF] Barker | Physical activity of UK adults with chronic disease: crosssectional analysis of accelerometer-measured physical activity in 96 706 UK Biobank participants[END_REF].

Patients with IA derive specific benefits from regular PA. These include, in particular, reduction of pain intensity and risk of cardiovascular diseases [START_REF] Geenen | EULAR recommendations for the health professional's approach to pain management in inflammatory arthritis and osteoarthritis[END_REF][START_REF] Peters | EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis[END_REF]. For example in AxSpA, increased PA leads to improved physical function and reduced fatigue and disease-related activity [START_REF] Regnaux | Exercise programmes for ankylosing spondylitis[END_REF]. Thus, PA is a key component of clinical practice guidelines for the management of these rheumatic conditions [START_REF] Peters | EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis[END_REF][START_REF] Heijde D Van Der | 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis[END_REF][START_REF] Wendling | 2018 update of French Society for Rheumatology (SFR) recommendations about the everyday management of patients with spondyloarthritis[END_REF].

Increasing PA is a challenge [START_REF] Niedermann | Barriers and facilitators of vigorous cardiorespiratory training in axial Spondyloarthritis: Surveys among patients, physiotherapists, rheumatologists[END_REF]. Lifestyle changes (such as PA levels) should be addressed by a global approach and by taking into account behavioural barriers to increase chances of success [START_REF] Knittle | Targeting motivation and self-regulation to increase physical activity among patients with rheumatoid arthritis: a randomised controlled trial[END_REF].

Regarding PA, barriers and facilitators have been identified [START_REF] Sechrist | Development and psychometric evaluation of the exercise benefits/barriers scale[END_REF]. Barriers appear to be mostly related to psychological status, and facilitators are linked in part to social support [START_REF] Sechrist | Development and psychometric evaluation of the exercise benefits/barriers scale[END_REF][START_REF] Coste | Perceived barriers to and facilitators of physical activity in people with knee osteoarthritis: Development of the Evaluation of the Perception of Physical Activity questionnaire[END_REF]. Questionnaires can be used to assess barriers and facilitators, which could be useful in developing interventions tailored to the patient's needs, and thus more likely to be successful. Such a questionnaire could be also valuable in the process of implementing physical activity recommendations [START_REF] Osthoff | EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis[END_REF].

For the general population and for people with osteoarthritis, questionnaires have been developed to assess barriers and facilitators to PA [START_REF] Sechrist | Development and psychometric evaluation of the exercise benefits/barriers scale[END_REF][START_REF] Coste | Perceived barriers to and facilitators of physical activity in people with knee osteoarthritis: Development of the Evaluation of the Perception of Physical Activity questionnaire[END_REF]. However, barriers in IA may be different due to the specific burden of the disease, including pain and fatigue, but also structural damage possibly leading to joint or spine functional impairment [START_REF] Gossec | Reporting of patient-perceived impact of rheumatoid arthritis and axial spondyloarthritis over 10 years: a systematic literature review[END_REF].Furthermore, patients with IA may have erroneous beliefs regarding PA [START_REF] Niedermann | Barriers and facilitators of vigorous cardiorespiratory training in axial Spondyloarthritis: Surveys among patients, physiotherapists, rheumatologists[END_REF]. To our knowledge, no questionnaire assessing perceived barriers and facilitators to PA has been validated for patients with IA.

The aim of this work was to elaborate a self-administered questionnaire to identify the perceived barriers and facilitators to PA in people with IA, and to validate the questionnaire in terms of psychometric properties.

Methods

The study was developed according to COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) and Outcome Measures in Rheumatology (OMERACT) [START_REF] Boers | OMERACT Filter 2.1: Elaboration of the Conceptual Framework for Outcome Measurement in Health Intervention Studies[END_REF][START_REF] Mokkink | COSMIN Study Design checklist for Patient-reported outcome measurement instruments[END_REF].

Several phases were performed, to generate, select and score items for the questionnaire, then to assess the psychometric properties of this questionnaire and to finalise the questionnaire and assess its reliability. These steps are shown in Figure 1.

Phase 1: Systematic review of barriers and facilitators to physical activity

The first step aimed to inform the choice of barriers and facilitators. Given the more abundant literature in RA, we chose to concentrate the systematic review on barriers and facilitators to PA for RA patients. The search was performed in Medline, Web of Science and the grey literature, as well as bibliography of included studies and related studies, from inception to January 2019. Key search terms were exercise [MeSH], barriers [Title/Abstract], facilitators [Title/Abstract] and Arthritis, Rheumatoid [MeSH]. All qualitative reports of barriers and facilitators in RA, published in English were collected. A thematic synthesis was applied to extract main barriers and facilitators to PA, which were selected when reported at least in 2 publications, then grouped by theme by the experts.

Phase 2: Identification of the questionnaire items

First, each main barrier and facilitator from the systematic review was formulated using the patients' verbatim where possible. Items were presented at either barriers, facilitators or either one of those categories. This preliminary wording was then assessed for face validity, and reworded where needed, by 11 experts in rheumatology or physiotherapy. Finally, the preliminary questionnaire was tested by 14 patients with IA through cognitive debriefing, and the items were reworded if needed [START_REF] Hewlett | Translating patient reported outcome measures: methodological issues explored using cognitive interviewing with three rheumatoid arthritis measures in six European languages[END_REF]. For this, consecutive outpatients were contacted from one tertiary care hospital in France. They were aged above 18, with definite RA based on the ACR/EULAR classification criteria of rheumatoid arthritis [START_REF] Aletaha | Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative[END_REF],

or axSpA based on the Assessment of SpondyloArthritis international Society classification criteria [START_REF] Rudwaleit | The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection[END_REF] with no restriction for co-morbidities and were able to read and write in French language. At that step, items were developed simultaneously in English and French and the quality of the cross-cultural validity was tested using the usual translation and back-translation procedure [START_REF] Chen | Translation and back-translation in qualitative nursing research: methodological review[END_REF]. The following steps were carried out using the French version.

Phase 3: Scoring

Based on the cognitive debriefing, we chose to first ask for impact of each item on PA (yes/no), then to rate the impact on PA on a numeric scale ranging from 0 (no impact) to 10 (maximal impact). Rating the impact is important since other authors have demonstrated that the presence or absence of an item is not enough to discriminate between active and inactive participants, and that the extent to which the items impact PA should be noted [START_REF] Brittain | General and Arthritis-Specific Barriers to Moderate Physical Activity in Women With Arthritis[END_REF]. Items which can be considered as either barriers or facilitators are rated from -10 to 10, items which are barriers only are rated from -10 to 0, and items which are facilitators only are rated from 0 to 10. This scoring has been used previously [START_REF] Brittain | General and Arthritis-Specific Barriers to Moderate Physical Activity in Women With Arthritis[END_REF]. When an item was indicated as not affecting physical activity, it was scored at 0.

Phase 4: Evaluation of the psychometric properties and finalisation of the IFAB

To assess the items and different versions of the Inflammatory arthritis Facilitators And Barriers questionnaire (IFAB), several analyses were performed.

Study design

A prospective observational study was conducted in a single tertiary care centre in Paris, France. A longitudinal observation was used in a subset of patients for reliability. The validation study was accepted by the ethics committee (CPP Sud-Est III, France, EudraCT 2019-A01413-54, methodology MR03 for non-interventional study). Participant informed consent was collected before inclusion.

Population

All patients who satisfied the inclusion criteria, seen in outpatient visits from November 2019 to January 2020 were asked to participate. The inclusion criteria were: age above 18; definite IA confirmed by the rheumatologist: axSpA (referring to the Assessment of SpondyloArthritis international Society classification criteria [START_REF] Rudwaleit | The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection[END_REF]), RA (referring to the international classification criteria of RA [START_REF] Aletaha | Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative[END_REF]) or PsA (referring to the ClASsification of Psoriatic ARthritis (CASPAR) criteria [START_REF] Taylor | Classification criteria for psoriatic arthritis: Development of new criteria from a large international study[END_REF]); agreement to participate and informed consent; ability to read and write in the language of participating country. There were no restrictions for comorbidities; however, bed-ridden patients were excluded.

Instruments administered

The participants completed self-administered questionnaires: the newly-developed IFAB questionnaire, the Modified Health Assessment Questionnaire (mHAQ) to assess functional status [START_REF] White | Measures of adult general functional status: SF-36 Physical Functioning Subscale (PF-10), Health Assessment Questionnaire (HAQ), Modified Health Assessment Questionnaire (MHAQ), Katz Index of Independence in activities of daily living, Functional Independence Measure (FIM), and Osteoarthritis-Function-Computer Adaptive Test (OA-Function-CAT)[END_REF], the Fear-Avoidance Beliefs Questionnaire subscale for PA (FABQ-PA) to assess patients' fear avoidance and beliefs about PA [START_REF] Staerkle | Longitudinal validation of the Fear-Avoidance Beliefs Questionnaire (FABQ) in a Swiss-German sample of low back pain patients[END_REF], the Tampa Scale for Kinesiophobia (TSK) to assess the subjective rating of kinesiophobia or fear of movement [START_REF] Swinkels-Meewisse | Psychometric properties of the Tampa Scale for kinesiophobia and the fear-avoidance beliefs questionnaire in acute low back pain[END_REF] and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) to assess disease activity for patients with AxSpA [START_REF] Zochling | Measures of symptoms and disease status in ankylosing spondylitis: Ankylosing Spondylitis Disease Activity Score (ASDAS), Ankylosing Spondylitis Quality of Life Scale (ASQoL), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Global Score (BAS-G), Bath Ankylosing Spondylitis Metrology Index (BASMI), Dougados Functional Index (DFI), and Health Assessment Questionnaire for the Spondylarthropathies (HAQ-S)[END_REF] (online supplementary Table 1). In RA, disease activity was assessed by the physician through the Disease Activity Score 28 (DAS28) [START_REF] Bentley | A modified rheumatoid arthritis disease activity score without acute-phase reactants (mDAS28) for epidemiological research[END_REF]. Disease duration, level of pain and patient global assessment were also collated. Finally, the steering committee developed two numeric rating scale global questions related to PA as follows: "when I think about the PA I want to do, I feel held back and limited" and "when I think about the PA I want to do, I feel supported and encouraged" Reliability was explored by test-retest one week after the first completion, which is long enough to prevent recall of the 14 items questionnaire, and short enough to ensure that patients remain stage, including without onset of flare. The second completion concerned only the IFAB in the same format, and was filled in from home. Only patient with stable condition between the two assessment were included. Patients who expressed a change in conditions were excluded of the analysis of reliability.

Number of expected patients for reliability was 30 to achieve an adequate sample size.

All questionnaires were administered in French, using the French versions.

Analysis of psychometric properties and choice of the final IFAB items

Based on the validation study, the steering committee finalized the questionnaire: the objective was to aim for brevity (to enhance feasibility) without losing content validity, leading to possible deletion of some questions. The selection of the most relevant items for the final IFAB was based on correlation against legacy measures, correlation between each item and the total score (Spearman's rho coefficient greater than 0.5, with P < 0.05), clinical relevance (modifiable items were preferred), and reliability of each item (intraclass correlation coefficient, ICC > 0.5). Construct validity of each item and of several versions of the IFAB questionnaire were assessed against each of the legacy questionnaires. The hypotheses included: for convergent validity, correlation between the IFAB and the individual items and the legacy questionnaires assessing related concepts (mHAQ, FABQ-PA, TSK); and for divergent validity, absence of correlation with BASDAI, DAS28, level of pain, patient global assessment and disease duration. A correlation between the IFAB and the two simple questions related to PA was also expected. Reliability was assessed on the sub-set of patients with stable symptoms since the first completion.

The distribution of the scores was evaluated for the questionnaire score and items by the mean, standard deviation, range and median. Floor and ceiling effects were investigated for the questionnaire score and items (accepted maximum for both: 15%). Internal consistency and feasibility were also analysed. Respondent acceptability was considered satisfactory for a frequency of missing data < 15% on the retest. Feasibility was also tested by measuring the duration of completion on 10 participants.

Statistical analyses

For assessment of psychometric properties, a sample size of 60 patients was aimed for validity, and 30 patients for reliability, as proposed by COSMIN, without a formal calculation of power [START_REF] Mokkink | COSMIN Study Design checklist for Patient-reported outcome measurement instruments[END_REF].

Statistical analyses were performed using R version 3.5.1. Continuous data were presented as mean (standard deviation (SD)) and discrete data were presented as median [interquartile range]. Normality was assessed visually before using means (SD) and parametric tests. There was no imputation of missing data. Convergent and divergent validity were assessed by Spearman's correlations, considered very small if < 0.30, small if 0.30 to 0.50, moderate if 0.50 to 0.70 and strong if > 0.70 [START_REF] Chen | Translation and back-translation in qualitative nursing research: methodological review[END_REF].

ICC was based on the two-way random effect model, and coefficients > 0.70 were considered satisfactory. Internal consistency of the questionnaire was determined by Cronbach's α, and ≥ 0.70 was considered as satisfactory [START_REF] Tavakol | Making sense of Cronbach's alpha[END_REF].

Results

Systematic review of barriers and facilitators to physical activity

Of 89 references, 10 (11.2%) studies were qualitative reports in RA and were analysed: 3 (49 patients) were focus groups and 7 (99 patients) were individual interviews [START_REF] Thomas | Keeping physically active with rheumatoid arthritis: semistructured interviews to explore patient perspectives, experiences and strategies[END_REF][START_REF] Larkin | It might hurt, but still it's good': People with rheumatoid arthritis beliefs and expectations about physical activity interventions[END_REF][START_REF] Greysen | A Qualitative Study Exploring Community Yoga Practice in Adults with Rheumatoid Arthritis[END_REF][START_REF] Withall | Physical activity engagement in early rheumatoid arthritis: a qualitative study to inform intervention development[END_REF][START_REF] Wang | People's Perceptions and Beliefs about their Ability to Exercise with Rheumatoid Arthritis: A Qualitative Study[END_REF][START_REF] Loeppenthin | Physical activity maintenance in patients with rheumatoid arthritis: a qualitative study[END_REF][START_REF] Law | Perceptions of the effects of exercise on joint health in rheumatoid arthritis patients[END_REF][START_REF] Crowley | Barriers to Exercise in Rheumatoid Arthritis -a Focus Group Study[END_REF][START_REF] Swärdh | Views on Exercise Maintenance: Variations Among Patients With Rheumatoid Arthritis[END_REF][START_REF] Kamwendo | Physical activity in the life of the patient with rheumatoid arthritis[END_REF] (Online supplementary Figure 1). In all, 148 patients participated: weighted mean age 57.9 years (standard deviation, SD 3.6, range of means 50.0-63.5 years), weighted mean disease duration 13.5 years (SD 5.7, range 6.9-21.0). Barriers and facilitators to PA were reported for general PA in 6 studies and for supervised exercises (e.g. exercise program led by physiotherapist) in 4 studies. Overall, 7 categories of barriers (mean 3.4 (SD 1.9) per study) and 8 categories of facilitators (mean 3.7 (SD 2.1) per study) were reported (Table 1). These could be grouped in 4 major themes psychological status, social support, disease, or environmental factors. The 3 most reported categories of barriers were symptoms of RA (8/10 studies), beliefs, fears and loss of motivation (7/10) and lack of support, exercise knowledge, confidence and conflict in advice from healthcare (4/10). The 3 most reported categories of facilitators were group socialization and social support (8/10), positive beliefs, knowledge about benefits of PA (5/10) and positive emotions and experiences of PA (5/10).

Identification of the questionnaire items

The main themes were reworded into short items and face validity was confirmed by the expert committee. Cognitive debriefing with 14 IA patients led to slight rewordings. The preliminary IFAB questionnaire contained 14 items: 6 considered as either barriers or facilitators, 4 items as barriers only and 4 items as facilitators only (online Supplementary Table 2).

Psychometric properties of the questionnaire

Characteristics of participants included in the validation study

The study included 63 patients (26 (41%) RA, 24 (38%) axSpA, 13 (21%) PsA), with mean age 52.8 (SD 16.5) years, mean disease duration 12.5 (SD 12.3) years and 53% of women (Table 2 and online Supplementary Figure 2). Disease activity was moderate (mean DAS28 3.8 (SD 1.1), median 3.7 [interquartile range 3.1;4.3], mean BASDAI 3.1 (SD 1.4), median 3.1 [1.9;3.9]) and 73% received a biological treatment (Table 2).

Final version of the questionnaire

Based on the results and the pre-defined criteria, the decision was taken to reduce the questionnaire from 14 items to 10 items (Table 3 and (online Supplementary Table 2). In the final questionnaire, 4 items can be considered either as barriers or facilitators, 3 items as barriers only and 3 items as facilitators only (Table 3 and4). The score of the final list of items can vary between -70 and 70 (Figure 1). The items are related to: psychological status (N=6), social support (N=2), disease (N=1), or environmental factors (N=1) (Table 3).

Concurrent validity and internal consistency

Main psychometric properties are shown in Table 4 and online Supplementary Table 3. Convergent validity was partly satisfied, with correlation between the IFAB total score and the mHAQ (rho=-0.24, p<0.05), but no correlation with TSK and FABQ-PA. Divergent validity was satisfied (online Supplementary Table 3). The questionnaire score had a significant positive correlation with the single questions related to the feeling of support and encouragement (rho=0.32, p<0.05) and a significant negative correlation with the feeling of limitation (rho=-0.29, p<0.05) as expected. The internal consistency of the final version of the questionnaire was good (Cronbach α values= 0.69).

Data completeness and score distribution

The proportion of missing values ranged from 0 to 6% for items and was 12% for the final score at retest (Table 3).

For use in practice, the questionnaire is available online Supplementary Table 4 in English, and from the authors in French. We propose that in case of one missing item, that item is replaced by the value 0; in case of 2 or more missing items, the questionnaire cannot be scored.

The distribution of items considered as barrier or facilitator only was not normal (Table 4). Floor and ceiling effect were noted when patients were not affected by a barrier (range, 42-73%) or facilitator (range 24-53%). This reflects the fact that not all barriers/facilitators affect all patients, which was expected. In the validation study, there were no floor/ceiling effects for the global score. The completion time was < 5 minutes.

Reliability

Of the 48 participants who were asked to complete the questionnaires for the test-retest analysis, 32

were analysed (Online Supplementary Figure 2). The ICC of the IFAB questionnaire was satisfactory (0.78 [95% confidence interval, 0.59; 0.88]) (Table 4).

Discussion

In this study, we have developed an easy to use questionnaire to assess barriers and facilitators to PA for patients with IA. The proposed IFAB questionnaire has 10 items, with a score from -70 to 70, higher scores indicating higher levels of facilitation and lower levels of barriers. This questionnaire appears to be feasible, reliable and to have satisfactory internal consistency. This questionnaire may guide targeted interventions to increase PA level of patients with IA.

Other questionnaires have been developed to assess barriers to PA in the general population [START_REF] Sechrist | Development and psychometric evaluation of the exercise benefits/barriers scale[END_REF] or other disabled populations such as osteoarthritis [START_REF] Coste | Perceived barriers to and facilitators of physical activity in people with knee osteoarthritis: Development of the Evaluation of the Perception of Physical Activity questionnaire[END_REF], mobility impairments [START_REF] Vasudevan | Development of the Barriers to Physical Activity Questionnaire for People with Mobility Impairments[END_REF], stroke population [START_REF] Drigny | Development and Validation of a Questionnaire to Assess Barriers to Physical Activity After Stroke: The Barriers to Physical Activity After Stroke Scale[END_REF] or coronary artery disease [START_REF] Joussain | Barriers to physical activity in coronary artery disease patients: Development and validation of a new scale[END_REF]. In these questionnaires, the number of items used to assess barriers varied from 11 to 63. Only one recently-published questionnaire (the EPPA questionnaire) assessed facilitators of PA [START_REF] Coste | Perceived barriers to and facilitators of physical activity in people with knee osteoarthritis: Development of the Evaluation of the Perception of Physical Activity questionnaire[END_REF]. Seven out of ten barriers and facilitators of the EPPA questionnaire were also assessed in the IFAB questionnaire, indicating an expected overlap. However, the EPPA questionnaire is applicable to osteoarthritis, not IA. When comparing with a theoretical framework of behaviour change developed by Canes in 2012, we observed that the IFAB questionnaire covers 7 out of the 14 possible domains (knowledge, beliefs about the capabilities, beliefs about consequences, reinforcement, intentions, environmental factors and resources and social influence) [START_REF] Cane | Validation of the theoretical domains framework for use in behaviour change and implementation research[END_REF]. This shows the potential interest of the IFAB questionnaire to examine different aspects of the areas of behaviour change.

PA is highly recommended for the IA population, but not performed sufficiently [START_REF] Barker | Physical activity of UK adults with chronic disease: crosssectional analysis of accelerometer-measured physical activity in 96 706 UK Biobank participants[END_REF]. There's been a growing interest patient reported outcomes; the Food and Drug Administration underlines their importance and encourages their use [START_REF] Speight | FDA guidance on patient reported outcomes[END_REF]. This study applied recommended methodology for the IFAB questionnaire development and validation. The current questionnaire can be both used for research and clinical practice as it takes less than 5 minutes to complete and has little missing data. This questionnaire has the potential to identify perceptions towards PA in order to address barriers such as mistaken beliefs, and encourage facilitators. It may be useful to implement such a questionnaire during patient education to increase awareness of barriers and facilitators or in clinical trials evaluating PA level to observe the relationship between perceived facilitators and barriers and PA levels. The question remains on how to interpret IFAB scores. In the present study, the median of the score was 3 (range -70 to 70), with a first quartile value (defining the lower 25% of the group) at -5.

It might be interesting to propose a targeted intervention to patients with the lower scores, for example negative scores or scores below -5. Patients with PsA may face additional barriers, such as social discomfort due to concomitant skin disease. Published literature on barriers and facilitators associated with participation in physical activity among people with PsA is limited [START_REF] Geenen | EULAR recommendations for the health professional's approach to pain management in inflammatory arthritis and osteoarthritis[END_REF]. Given the lack of specific knowledge, physical activity considerations for this population should be based on available knowledge about RA patients. In this study, the mean score in IFAB questionnaire in PsA patients was 4.7 (14.9) and was not statistically different from the score in patients with RA and axial SpA (7.0 (17.1)

and 4.7 (21.1) respectively).

Cultural environment is important to consider when assessing barriers and facilitators. Different aspects of the IFAB questionnaire, such as social environment and psychological status, can be influenced by culture and habits [START_REF] Jia | The roles of health culture and physical environment in workplace health promotion: a two-year prospective intervention study in China[END_REF]. The questionnaire was validated only in France. However, the systematic review performed to develop the questionnaire included studies conducted in various countries. Moreover, experts involved for the face validity came from different countries (France, Norway and England). The questionnaire was developed both in English and French following a validated translation and cross-cultural adaptation process [START_REF] Beaton | Guidelines for the Process of Cross-Cultural Adaptation of Self-Report Measures[END_REF]. The culture of PA can change from country to country and from year to year [START_REF] Weinberg | Motivation for youth participation in sport and physical activity: relationships to culture, self-reported activity levels, and gender[END_REF]. Policies and regulations vary across the world. Through national prevention plans, increasing numbers of people are aware of the recommendations to perform PA [START_REF] O'dwyer | Physical activity guidelines: is the message getting through to adults with rheumatic conditions?[END_REF]. The popularity of a sport evolves over the years as shown nowadays by the growing interest in running or fitness. Technology is more and more developed and used to promote and track PA and the image of an athletic body is more and more valued [START_REF] Davergne | Use of wearable activity trackers to improve physical activity behavior in rheumatic and musculoskeletal diseases: A systematic review and meta-analysis[END_REF]. The physical environment is also being adapted to allow regular PA, e.g. through the installation of biking lanes or recreational programs in parks. In addition, the cost of activities tends to decrease. As a consequence, it is possible that this questionnaire will have to be updated in the future.

This study has strengths and weaknesses. The generation of themes was based on a systematic literature review of barriers and facilitators to PA for patients; however, the review concerned RA only, due to the more extensive literature in this population. Recently, similar barriers and facilitators have been evidenced in patients with AxSpA [START_REF] Niedermann | Barriers and facilitators of vigorous cardiorespiratory training in axial Spondyloarthritis: Surveys among patients, physiotherapists, rheumatologists[END_REF] and to our knowledge barriers and facilitators to PA have not been studied in patients with PsA. Cognitive debriefing was applied to improve the understandability of items by patients. Cognitive debriefing is an important step and generally underused [START_REF] Hewlett | Translating patient reported outcome measures: methodological issues explored using cognitive interviewing with three rheumatoid arthritis measures in six European languages[END_REF]. The development process of the questionnaire involved a variety of experts, including physiotherapists, which is rarely the case. The assessment of psychometric properties was complete, including internal consistency, construct validity, data completeness and reliability [START_REF] Mokkink | COSMIN Study Design checklist for Patient-reported outcome measurement instruments[END_REF]. Many questionnaires applied in rheumatology have not undertaken such a complete psychometric assessment [START_REF] Mokkink | COSMIN Study Design checklist for Patient-reported outcome measurement instruments[END_REF]. The sample size of patients to assess the validity of the questionnaire (n=63) was low but is considered by COSMIN as adequate [START_REF] Mokkink | COSMIN Study Design checklist for Patient-reported outcome measurement instruments[END_REF]. The sample size for reliability may be considered as low (n=32) [START_REF] Mokkink | COSMIN Study Design checklist for Patient-reported outcome measurement instruments[END_REF]. However, proper statistical analysis was used (ICC) and reliability was satisfactory [START_REF] Mokkink | COSMIN Study Design checklist for Patient-reported outcome measurement instruments[END_REF]. No analysis of differential effect in different diseases was carried out. However, all the 3 IA diseases were represented and levels of pain and functional status were equivalent among IA diseases (data not shown). The absence of correlation between the IFAB and questionnaires assessing fear avoidance/beliefs about PA and kinesiophobia was unexpected. However, the IFAB questionnaire assesses several dimensions and some of these are not related to fears (avoidance or kinesiophobia), such as social support or level of symptoms. We believe the global nature of the IFAB could explain the lack of correlations. Furthermore, construct validity showed some correlation with functional status, which was expected and strengthens the face validity of the IFAB questionnaire.

In conclusion, this short questionnaire may be useful to assess barriers and facilitators in order to increase PA in IA patients. Further studies should assess the relation between IFAB scores and objective PA, and assess the efficacy of interventions to improve PA, based on the IFAB score. This questionnaire could be used to design intervention with bigger chance of success and to help implement physical activity recommendations. Note: preprint is available here: https://www.researchsquare.com/article/rs-32149/v1 Items which can be considered as either barriers or facilitators are rated from -10 to 10, items which are barriers only are rated from -10 to 0, and items which are facilitators only are rated from 0 to 10.

The score of the final questionnaire can vary between -70 and 70. The reliability of some items was low (ICC <0.5). This can be explained by a change of state of the patient between test and retest or a lack of understanding of the item itself. However, we needed to retain these items since they were clinically important to assess and since the reliability of the whole questionnaire was satisfactory.

Supplementary table 3: Correlation between IFAB and the legacy questionnaires, Spearman's rho (p values)

14 .

 14 Confidence on how to exercise safely 5. Presence or absence of support and/or advice from healthcare professionals 6. Contact and proximity with others during physical activity* * Items were deleted from the final IFAB as follows: item 3 (low clinical relevance, low reliability), item 6 (low clinical relevance, low reliability), item 9 (low clinical relevance, low correlation with other questionnaire, low reliability, low correlation with IFAB), item 13 (1 patient misunderstanding).

Table 1 : Systematic review of barriers and facilitators to physical activity in patients with RA

 1

	Major themes	Barriers			N	Facilitators	N
					studies*		studies*
	Disease	Symptoms of RA		8	Stable symptoms and	3
						effective medication
	Psychological	Negative beliefs and fears (fear of	7	Positive	beliefs,	5
	status	increase of symptoms), loss of		knowledge	about
		motivation				benefits of PA
						Positive emotions and	5
						experiences of PA
	Environmental	Bad weather			3	Heat, warm climate,	2
	context					exercise in warm water
		Inaccessible facilities		2	Convenient	setting:	4
						community or gym
						setting, outside hospital
		Lack of time			2
	Social support	Fear of contact with others	3	External	monitoring,	3
						adherence	support
						(e.g., reminders)
		Lack of support or exercise	4	Group	socialization,	8
		knowledge	from	healthcare		social support
		providers, or conflict in advice
		from healthcare providers
						Support	from	3
						healthcare	providers
						(advice, empathy)
	*The N refers to the number of studies (of 10 studies) referring to the concept

Table 2 : Characteristics of 63 patients with inflammatory arthritis participating in the validation of the IFAB questionnaire

 2

	Characteristic

Table 3 : The 10 items of the IFAB questionnaire to assess barriers and facilitators to physical activity

 3

	Barriers or facilitators*	Facilitators			Barriers
	1. Level of symptoms (pain,	5. A belief that physical	8. Knowledge of benefits of
	fatigue, lack of mobility)	activity	will	make	physical activity for health
		symptoms worse
	2. Weather conditions				9. Knowledge of benefits of
		6. Lack of motivation	physical activity for mood
	3. Presence or absence of
	support from others (friends,	7. Lack of knowledge on	10. Confidence on how to
	family)	which exercises to do	exercise safely
		and how much
	4. Presence or absence of
	support and/or advice from
	healthcare professionals
	*These items can be either a barrier or a facilitator.

Table 4 : Performance of the IFAB items and final IFAB questionnaire

 4 Missing data in the questionnaire at retest $Floor and ceiling effects are the % of patients with a minimal or maximal value for the item, which reflects the item is assessed as not being a barrier or a facilitator.

	Item or final IFAB	Score, mean	Range	Missing	Floor/cei	Intraclass	Correlation with
	(range of possible	(SD) [median]	(min;max)	values at	ling	Correlation	IFAB: rho (p
	values)			retest (%)*	effect	coefficient	value)
					(%)$	(95%
						confidence
						interval)
	Item 1 (-10;10)	-3.2 (3.9) [-4]	(-10;7)	0	2/0	0.65	0.43 (0.01)
						(0.42;0.81)
	Item 2 (-10;10)	-2.7 (3.7) [0]	(-10;7)	0	2/0	0.49	0.33 (<0.001)
						(0.18;0.72)
	Item 3 (-10;10)	0.0 (5.1) [0]	(-10;10)	3	2/8	0.60	0.57 (<0.001)
						(0.33;0.79)
	Item 4 (-10;10)	1.9 (4.2) [0]	(-6;10)	3	0/7	0.34	0.56 (<0.001)
						(0.03;0.62)
	Item 5 (-10;0)	2.3 (3.7) [0]	(-10;0)	0	2/73	0.01 (-	0.36 (0.01)
						0.33;0.35)
	Item 6 (-10;0)	1.9 (4.3) [-3]	(-10;0)	3	7/42	0.62	0.37 (0.01)
						(0.36;0.80)
	Item 7 (-10;0)	-1.6 (2.7) [0]	(-10;0)	3	2/71	0.61	0.29 (0.04)
						(0.35;0.79)
	Item 8 (0;10)	-3.6 (3.7) [6]	(0;10)	3	24/9	0.51	0.66 (<0.001)
						(0.21;0.73)
	Item 9 (0;10)	-2.4 (3.2) [5]	(0;10)	6	25/15	0.71	0.64 (<0.001)
						(0.50;0.86)
	Item 10 (0;10)	-1.5 (2.7) [0]	(0;10)	3	53/6	0.59	0.53 (<0.001)
						(0.31;0.78)
	Global IFAB score	5.1 (3.6) [3]	(-29;57)	13	0/0	0.79 (0.59;	-
	(-70;70)					0.88)
	The items are detailed in Table 3.

*

Distribution of the IFAB questionnaire in 63 patients

	Supplementary
	Footnote
	X axis: IFAB total score
	Y Axis: % of patients

Table 2 : Items of barriers and facilitators to physical activity included in the initial version of the IFAB questionnaire

 2

	Barriers or facilitators	Facilitators	Barriers
	1. Level of symptoms (pain,	7. A belief that physical activity	11.Knowledge of benefits of
	fatigue, lack of mobility)	will make symptoms worse	physical activity for health
	2. Weather conditions	8. Lack of motivation	12. Knowledge of benefits of
			physical activity for mood
	3. Presence or absence of activity	9. Lack of time*	13. External reminders (e.g.:
	facilities (e.g., green area for		from	health	professionals,
	walking, gym …)*		calendars…)*
	4. Presence or absence of support	10. Lack of knowledge on
	from others (friends, family)	which exercises to do and how
		much

  : modified Health Assessment Questionnaire; FABQ: Fear and beliefs questionnaire; TSK: Tampa Scale of Kinesiophobia; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; DAS28: Disease Activity Score 28; PGA: patient global assessment; PA: Physical activity; *global questions related to PA

	Item	MHAQ FABQ TSK	BASD	DAS2	Disease	Pain	PGA Barriers	Suppor
	s				AI	8	duration			to PA*	t of PA*
	Item	-0.50	-0.14	0.25	-0.54	0.00	-0.23	-0.56	0.31	-0.37	0.26
	1	(0.00)	(0.29)	(0.05)	(0.05)	(0.98)	(0.08)	(0.00)	(0.02)	(0.00)	(0.04)
	Item	-0.13	0.04	0.09	0.15	0.07	0.01	-0.15	0.25	-0.10	0.20
	2	(0.33)	(0.77)	(0.47)	(0.49)	(0.68)	(0.96)	(0.25)	(0.05)	(0.42)	(0.11)
	Item	0,05	0.13	0.18	0.01	-0.30	0.16	0.17	0.10	0.04	0.33
	3	(0.69)	(0.35)	(0.16)	(0.97)	(0.09)	(0.22)	(0.21)	(0.48)	(0.77)	(0.01)
	Item	0.21	0.08	-0.06	0.31	0.11	0.22	0.25	-0.06	0.22	0.16
	4	(0.11)	(0.53)	(0.64)	(0.12)	(0.55)	(0.09)	(0.05)	(0.65)	(0.08)	(0.20)
	Item	-0.43	-0.23	0.28	-0.45	-0.09	-0.29	-0.36	0.07	-0.28	0.04
	5	(0.00)	(0.07)	(0.03)	(0.02)	(0.63)	(0.02)	(0.00)	(0.65)	(0.03)	(0.74)
	Item	-0.27	-0.08	0.06	-0.45	0.31	-0.33	-0.16	0.09	-0.25	0.03
	6	(0.05)	(0.52)	(0.66)	(0.02)	(0.08)	(0.01)	(0.22)	(0.62)	(0.05)	(0.84)
	Item	-0.27	-0.14	0.21	-0.01	-0.23	0.01	-0.14	0.14	-0.17	0.11
	7	(0.03)	(0.28)	(0.11)	(0.95)	(0.20)	(0.94)	(0.28)	(0.52)	(0.19)	(0.38)
	Item	-0.10	0.05	0.20	0.02	0.06	-0.02	0.16	0.07	-0.10	0.27
	8	(0.45)	(0.72)	(0.13)	(0.91)	(0.73)	(0.87)	(0.22)	(0.30)	(0.44)	(0.04)
	Item	-0.05	0.11	0.08	-0.05	0.08	-0.06	0.13	0.17	-0.18	0.31
	9	(0.70)	(0.40)	(0.54)	(0.80)	(0.66)	(0.65)	(0.33)	(0.30)	(0.40)	(0.02)
	Item	-0.27	-0.11	-0.03	-0.31	0.22	-0.31	0.02	-0.07	-0.11	0.12
	10	(0.13)	(040.)	(0.79)	(013.)	(0.24)	(0.01)	(0.88)	(0.60)	(0.39	(0.35)
	IFAB -0.24	-0.12	0.19	-0.21	0.12	-0.23	-0.05	0.19	-0.29	0.32
		(0.05)	(0.40)	(0.19)	(0.32)	(0.56)	(0.11)	(0.71)	(0.19)	(0.04)	(0.02)

mHAQ

This work was supported by Eli Lilly France, Sandoz France and the French society of Physiotherapy through unrestricted grants. The funders played no role in the design of the study, data collection and analysis, the decision to publish, or the preparation of the manuscript Davergne, Rikke H Moe, Bruno Fautrel and The validation study was accepted by the ethics committee (CPP Sud-Est III, France, EudraCT 2019-A01413-54, methodology MR03 for non-interventional study).

Availability of data and material:

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability:

The codes use in R software during the current study are available from the corresponding author on reasonable request.

Used to quantify functional status [START_REF] White | Measures of adult general functional status: SF-36 Physical Functioning Subscale (PF-10), Health Assessment Questionnaire (HAQ), Modified Health Assessment Questionnaire (MHAQ), Katz Index of Independence in activities of daily living, Functional Independence Measure (FIM), and Osteoarthritis-Function-Computer Adaptive Test (OA-Function-CAT)[END_REF]. This subscale contains 8 items regarding daily activity, scored from 0 ("without any difficulty") to 3

("unable to do"). The final score range from 0 to 3 (worse functional status) and is calculated by adding all scored items together (at least 6 of the 8 items are required) and dividing by the total number of items answered to obtain the final score.

Fear-Avoidance Beliefs

Questionnaires subscale for PA (FABQ-PA)

Used to assess patient's fear avoidance and beliefs about PA [START_REF] Staerkle | Longitudinal validation of the Fear-Avoidance Beliefs Questionnaire (FABQ) in a Swiss-German sample of low back pain patients[END_REF]. The FABQ-PA is a 4 item questionnaire scored from 0 to 24 where the higher scores indicate the highest degree of fear and avoidance beliefs.

The Tampa Scale for Kinesiophobia (TSK)

Used to assess the subjective rating of kinesiophobia or fear of movement [START_REF] Swinkels-Meewisse | Psychometric properties of the Tampa Scale for kinesiophobia and the fear-avoidance beliefs questionnaire in acute low back pain[END_REF]. The TSK is a self-completed 17 item questionnaire and the range of scores is from 17 to 68 where the higher scores indicate an increasing degree of kinesiophobia.

Bath Ankylosing

Spondylitis Disease

Activity Index (BASDAI)

Used to assess disease activity for patients with axSpA (0-10 with higher score indicating higher disease activity) [START_REF] Zochling | Measures of symptoms and disease status in ankylosing spondylitis: Ankylosing Spondylitis Disease Activity Score (ASDAS), Ankylosing Spondylitis Quality of Life Scale (ASQoL), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Global Score (BAS-G), Bath Ankylosing Spondylitis Metrology Index (BASMI), Dougados Functional Index (DFI), and Health Assessment Questionnaire for the Spondylarthropathies (HAQ-S)[END_REF].

Disease Activity Score

(DAS28)

Was used to assess disease activity for patients with RA or PsA (0.96-8.47 with higher score indicating higher disease activity) [START_REF] Bentley | A modified rheumatoid arthritis disease activity score without acute-phase reactants (mDAS28) for epidemiological research[END_REF] Supplementary Table 4

. Final IFAB and scoring

Please take few moments to think about all the physical activity you did in the previous month: walking, jogging, gardening, other kind of sport… Now, think about all the things that have encouraged you, and all the things that prevented you form doing physical activity in the previous month. This questionnaire has 10 items. It aims to collect all the things that have encouraged you or prevented you from doing physical activity in the previous month.

Please indicate for each item if it has rather encouraged you, prevented you, or had no impact on your physical activity in the previous month (only one answer). If needed, rate the importance.

A: Items that may have encouraged me or prevented me from doing physical activity in the last month.

1. Level of symptoms (pain, fatigue, lack of mobility)  rather prevented me from doing physical activity in the previous month  rather encouraged to do physical activity in the previous month  had no impact on my physical activity in the previous month 2. Weather conditions  rather prevented me from doing physical activity in the previous month  rather encouraged to do physical activity in the previous month  had no impact on my physical activity in the previous month 3. Presence or absence of support from others (friends, family)  rather prevented me from doing physical activity in the previous month  rather encouraged to do physical activity in the previous month  had no impact on my physical activity in the previous month 4. Presence or absence of support and/or advice from healthcare professionals  rather prevented me from doing physical activity in the previous month  rather encouraged to do physical activity in the previous month  had no impact on my physical activity in the previous month B: Items that may have prevented me from doing physical activity in the last month. 5. A belief that physical activity will make symptoms worse  rather prevented me from doing physical activity in the previous month  had no impact on my physical activity in the previous month 6. Lack of motivation  rather prevented me from doing physical activity in the previous month  had no impact on my physical activity in the previous month 7. Lack of knowledge on which exercises to do and how much  rather prevented me from doing physical activity in the previous month  had no impact on my physical activity in the previous month C: Items that may have encouraged me from doing physical activity in the last month. 8. Knowledge of benefits of physical activity for health  rather encouraged to do physical activity in the previous month  had no impact on my physical activity in the previous month 9. Knowledge of benefits of physical activity for mood  rather encouraged to do physical activity in the previous month  had no impact on my physical activity in the previous month


MD Martin Dres
email: martin.dres@aphp.fr

PhD Alexandre Demoule

Monitoring diaphragm function in the ICU

Keywords: Diaphragm, electrical activity, thickening fraction, excursion, mechanical ventilation

This article reviews the clinical problem of diaphragm function in critically ill patients and describes recent advances in bedside monitoring of diaphragm function.

Recent findings

Diaphragm weakness, a consequence of diaphragm dysfunction and atrophy, is a common condition in the intensive care unit and is associated with serious clinical consequences. Bedside diaphragm function monitoring can now be performed by means of two approaches: diaphragm electrical activity and diaphragm ultrasound. The use of ultrasound to assess diaphragm structure (thickness, thickening) and mobility (caudal displacement) appears to be feasible and reproducible, but no large-scale "real-life" study is available. Diaphragm ultrasound can also be used to evaluate diaphragm muscle stiffness by means of shear wave elastography and strain by means of speckle tracking, both of which are correlated with diaphragm function in healthy subjects. Electrical activity of the diaphragm is correlated with diaphragm function during brief airway occlusion, but the repeatability of these measurements exhibits high within-subject variability.

Summary

Mechanical ventilation is involved in the pathogenesis of diaphragm dysfunction, which is associated with severe adverse events. Although the use of ultrasound and diaphragm electrical activity recording could potentially facilitate monitoring of diaphragm function in order to deliver diaphragm-protective ventilation, no guidelines concerning the use of these modalities have yet been published. The weaning process, assessment of patient-ventilator synchrony and evaluation of diaphragm function may be the most clinically relevant indications for these techniques.

Introduction

Careful and safe use of mechanical ventilation is a major issue in the intensive care unit (ICU). Mechanical ventilation certainly helps patients to overcome the most severe forms of acute respiratory failure, but, in the meantime, also produces unintended harmful effects.

One such harmful effect, diaphragm atrophy and dysfunction resulting from ventilatorinduced respiratory muscle disuse, has become an issue of major concern. Diaphragm atrophy and dysfunction are commonly observed in mechanically ventilated patients [START_REF] Vivier | Atrophy of Diaphragm and Pectoral Muscles in Critically Ill Patients[END_REF][START_REF] Goligher | Mechanical Ventilation-induced Diaphragm Atrophy Strongly Impacts Clinical Outcomes[END_REF][START_REF] Dres | Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients[END_REF] and are associated with difficult and prolonged weaning [START_REF] Dres | Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients[END_REF], prolonged duration of mechanical ventilation (3), ventilator-associated complications (re-intubation, tracheostomy) (2) and mortality [START_REF] Dres | Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients[END_REF]. However, significant technological and physiological progress has been made, allowing bedside monitoring of diaphragm function. Like all muscles, the diaphragm contracts, shortens, thickens, stiffens and finally generates a pressure inside the thorax that allows alveolar ventilation, the ultimate goal of breathing. Diaphragm function can now be evaluated at the bedside by means of several approaches [START_REF] Laveneziana | ERS statement on respiratory muscle testing at rest and during exercise[END_REF]. Transmission of respiratory drive can be recorded by monitoring the electrical activity of the diaphragm (EAdi). It is also possible to directly visualize by the thickening of the diaphragm by ultrasound and more recently, it has been reported that diaphragm ultrasound can be used to evaluate diaphragm stiffness and deformation (strain). Of note, the reference technique to investigate diaphragm function is phrenic nerve magnetic stimulation, but it can only be performed in expert centres, which explains the growing interest in diaphragm ultrasound and EAdi recording as potential bedside substitutes. In the present review, we will discuss recent evidence highlighting the clinical issues related to diaphragm dysfunction in the ICU and the potential importance of diaphragm function monitoring. Finally, the latest developments on diaphragm function monitoring will be described before discussing translation of recent knowledge into clinical practice.

Why diaphragm function monitoring is important in the ICU?

Diaphragm dysfunction is a common condition

A landmark study published by Levine et al. demonstrated rapid disuse-induced atrophy of diaphragm fibers in brain-dead adult donors exposed to several hours of mechanical ventilation [START_REF] Levine | Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans[END_REF]. This observation is consistent with a core of animal studies and more recent ultrasound-based analysis demonstrating the impact of ventilator-induced diaphragm disuse on diaphragm atrophy (6) and dysfunction. ICU patients are exposed to several other risk factors of diaphragm dysfunction in addition to mechanical ventilationinduced disuse (i.e. sepsis, critical illness severity) making it difficult to determine the specific contribution of mechanical ventilation to the development of diaphragm dysfunction [START_REF] Dres | Critical illness-associated diaphragm weakness[END_REF]. Regardless of the risk factors involved, various studies have reported a high prevalence of diaphragm dysfunction in the ICU, as more than two-thirds of mechanically ventilated patients are diagnosed with diaphragm dysfunction at the time of the first weaning attempt [START_REF] Dres | Critical illness-associated diaphragm weakness[END_REF].

Diaphragm dysfunction is a major concern

Diaphragm dysfunction has major implications for ICU patients. Firstly, as the diaphragm is a major determinant of the load/capacity respiratory balance, diaphragm dysfunction may increase the risk of weaning failure and subsequently prolong the duration of mechanical ventilation. Importantly, a recent study has suggested that diaphragm function is predominantly a key determinant for the outcome of the spontaneous breathing trial rather than the outcome of extubation. Secondly, diaphragm dysfunction has been associated with complications such as reintubation, tracheostomy and prolonged ventilation (2), and postoperative complications [START_REF] Spadaro | Point of Care Ultrasound to Identify Diaphragmatic Dysfunction after Thoracic Surgery[END_REF][START_REF] Moury | Diaphragm thickening in cardiac surgery: a perioperative prospective ultrasound study[END_REF]. It is also associated with ICU mortality [START_REF] Dres | Critical illness-associated diaphragm weakness[END_REF].

Diaphragm-ventilator interaction

Under certain circumstances, patients may struggle against the ventilator, which generates asynchrony. In turn, asynchrony may be associated with discomfort, dyspnea and poor prognosis. However, detection of asynchrony is not an easy task for clinicians. While visual inspection of airway pressure, volume and flow waveforms allows the detection of gross asynchronies, this method is not sufficiently reliable and sensitive. The reference method is based on the use of an esophageal catheter to visualize mismatches between changes in pleural pressure and changes in airway pressure and flow waveforms. Diaphragm contraction plays a crucial role in changes in pleural pressure, suggesting that monitoring diaphragm function simultaneously with the breathing pattern could facilitate the detection of patient-ventilator asynchrony [START_REF] Soilemezi | Understanding Patient-Ventilator Asynchrony Using Diaphragmatic Ultrasonography[END_REF].

What is diaphragm function and how can it be monitored in the ICU?

The diaphragm is a musculotendinous structure stretched between the thorax and the abdomen, making direct examination impossible (Figure 1). Bedside investigation of diaphragm function requires costly equipment and involves semi-invasive approaches. For these reasons, apart from research purposes, diaphragm function monitoring has rarely been performed in clinical practice in recent years. However, things have changed with the emergence of techniques such as diaphragm ultrasound and recording of the electrical activity of the diaphragm by means of a dedicated esophageal catheter. Before describing these techniques, we will discuss the definition of diaphragm function and the reference method used to diagnose diaphragm dysfunction.

Pressure-generating capacity

The physiological function of the diaphragm is to shorten and produce a force.

Although this force cannot be measured directly, the capacity of the diaphragm to generate a pressure can be measured. When the diaphragm contracts, it descends towards the abdomen, which simultaneously generates increased abdominal pressure and decreased thoracic pressure, resulting in a transdiaphragmatic pressure (Pdi). The maximum Pdi, which is the Pdi generated by a forced inspiratory effort, is considered to be the most physiological approach to assessment of diaphragm function. However, ICU patients are generally unable to produce maximum effort due to lack of cooperation induced by sedation or delirium. To overcome this issue, it has been proposed to measure Pdi in response to supramaximal bilateral magnetic phrenic nerve stimulation (Pdi,twitch). While Pdi in response to magnetic stimulation is not a substitute for maximum Pdi, it has the advantage of being independent of the patient's cooperation and is able to provide standardized measurements. As measuring transdiaphragmatic pressure requires both esophageal and gastric balloons, it is acceptable to exclusively use changes in tracheal pressure during magnetic phrenic nerve stimulation (Ptr,stim) to evaluate diaphragm function. A Ptr,stim less than -11 cmH 2 O is used to define diaphragm dysfunction in the ICU (Table 1).

Diaphragm ultrasound

Over the last 10 years, diaphragm ultrasound has been increasingly used in the ICU and several studies have been published on this topic in adults [START_REF] Vetrugno | Ultrasound Imaging for Diaphragm Dysfunction: A Narrative Literature Review[END_REF] and children [START_REF] Johnson | Muscle atrophy in mechanically-ventilated critically ill children[END_REF][START_REF] Ng | Reliability of bedside ultrasound of limb and diaphragm muscle thickness in critically ill children[END_REF][START_REF] Glau | Progressive Diaphragm Atrophy in Pediatric Acute Respiratory Failure[END_REF].

When the diaphragm contracts, it shortens, thickens, displaces and stiffens. Ultrasound can measure diaphragm thickness, thickening and displacement (also called excursion) (Figure 1).

For reasons of feasibility, diaphragm ultrasound is mainly performed on the right hemidiaphragm via two approaches: subcostal and intercostal (Figure 2). The subcostal approach visualizes caudal displacement of the hemi-diaphragm. Measurement of the excursion of the right hemi-diaphragm is associated with high intra-and inter-observer reliability [START_REF] Boussuges | Diaphragmatic motion studied by m-mode ultrasonography: methods, reproducibility, and normal values[END_REF]. The lower limit of normal is greater than 3.6 cm in women and greater than 4.7 cm in men during maximum inspiratory effort [START_REF] Boussuges | Diaphragmatic motion studied by m-mode ultrasonography: methods, reproducibility, and normal values[END_REF]. In healthy subjects, there is a moderate correlation between diaphragm excursion and markers of pressure-generating capacity [START_REF] Spiesshoefer | Noninvasive Prediction of Twitch Transdiaphragmatic Pressure: Insights from Spirometry, Diaphragm Ultrasound, and Phrenic Nerve Stimulation Studies[END_REF]. In mechanically ventilated patients, diaphragm excursion is poorly correlated with markers of pressuregenerating capacity (pressure-time product of transdiaphragmatic pressure, transdiaphragmatic pressure, twitch pressure), but has been associated with weaning outcome (the greater the excursion, the better the outcome) [START_REF] Dres | Diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications[END_REF]. In contrast, diaphragm thickness is not correlated with either markers of pressure-generating capacity or weaning outcome [START_REF] Dres | Diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications[END_REF].

Diaphragm ultrasound can detect a decrease in diaphragm thickness, suggesting diaphragm atrophy ( 2), but increased thickness has also been reported [START_REF] Goligher | Mechanical Ventilation-induced Diaphragm Atrophy Strongly Impacts Clinical Outcomes[END_REF] although the significance of this observation remains unclear. A remarkable observation on the relationship between histological diaphragm atrophy and pulmonary function tests was recently reported in patients with amyotrophic lateral sclerosis [START_REF] Guimarães-Costa | Human diaphragm atrophy in amyotrophic lateral sclerosis is not predicted by routine respiratory measures[END_REF]. The authors failed to demonstrate any significant correlation between markers of pressure-generating capacity and severity of diaphragm atrophy [START_REF] Guimarães-Costa | Human diaphragm atrophy in amyotrophic lateral sclerosis is not predicted by routine respiratory measures[END_REF]. These findings suggest that atrophy is only one of several markers of diaphragm dysfunction.

Changes in thickness between expiration and inspiration can be used to determine the diaphragm thickening fraction, defined as the difference between end-inspiratory and endexpiratory diaphragm thickness over the end-expiratory diaphragm thickness, expressed as a percentage. Measurement of diaphragm thickening fraction is less reproducible than measurement of diaphragm thickness [START_REF] Goligher | Measuring diaphragm thickness with ultrasound in mechanically ventilated patients: feasibility, reproducibility and validity[END_REF]. There is a poor correlation between diaphragm thickening fraction and diaphragm function [START_REF] Dres | Diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications[END_REF] because thickening is a one-dimensional parameter, whereas diaphragm contraction results from active three-dimensional displacement of muscle volume [START_REF] Laveneziana | ERS statement on respiratory muscle testing at rest and during exercise[END_REF]. The correlation between diaphragm thickening fraction and markers of pressure-generating capacity is therefore only moderate, ranging from r 2 =0.28 in healthy subjects [START_REF] Goligher | Measuring diaphragm thickness with ultrasound in mechanically ventilated patients: feasibility, reproducibility and validity[END_REF] to rho=0.87 in mechanically ventilated patients [START_REF] Dubé | Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications[END_REF]. This wide range indicates a limited validity of diaphragm thickening fraction to quantify diaphragm effort. Of note, the validity of TFdi to estimate diaphragm effort has been recently questioned in a study in which TFdi remained unchanged in healthy subjects exposed to a stepwise threshold inspiratory loading protocol from 0 to 50% of maximum inspiratory pressure [START_REF] Oppersma | Functional assessment of the diaphragm by speckle tracking ultrasound during inspiratory loading[END_REF]. However, the poor intra-operator reproducibility coefficient (85%) in this study could explained the lack of change in TFdi during the protocol. In the ICU, diaphragm thickening fraction (and diaphragm excursion) should be measured, whenever possible, with the lowest ventilatory assistance and ideally under continuous positive airway pressure set to zero or via a T-tube to avoid underestimation of diaphragm thickening fraction and excursion. A cut-off < 29% for diaphragm thickening fraction has been associated with diaphragm dysfunction in mechanically ventilated patients [START_REF] Dubé | Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications[END_REF] and cut-off values for predicting successful weaning (success of the spontaneous breathing trial and/or extubation success) range between 25% and 35% [START_REF] Dres | Diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications[END_REF][START_REF] Dres | Diaphragm function and weaning from mechanical ventilation: an ultrasound and phrenic nerve stimulation clinical study[END_REF][START_REF] Eltrabili | Evaluation of Diaphragmatic Ultrasound Indices as Predictors of Successful Liberation From Mechanical Ventilation in Subjects With Abdominal Sepsis[END_REF][START_REF] Qing | Using twitch tracheal airway pressure, negative inhale forced pressure, and Medical Research Council score to guide weaning from mechanical ventilation[END_REF]. A study comparing diaphragm ultrasound and phrenic nerve stimulation showed that both methods accurately predicted weaning outcome [START_REF] Dres | Diaphragm function and weaning from mechanical ventilation: an ultrasound and phrenic nerve stimulation clinical study[END_REF]. However, discordant results have been reported for the performance of diaphragm thickening fraction to predict weaning outcome. One study reported that diaphragm thickening fraction measured before starting the weaning trial was significantly higher in patients who failed the weaning trial compared to patients who had passed the weaning trial with no other between-group differences until the end of the trial [START_REF] Rittayamai | The evolution of diaphragm activity and function determined by ultrasound during spontaneous breathing trials[END_REF]. The maximum diaphragm thickening fraction and maximum excursion were also similar in both groups before starting the weaning trial [START_REF] Rittayamai | The evolution of diaphragm activity and function determined by ultrasound during spontaneous breathing trials[END_REF]. In contrast, other authors have observed a lower diaphragm thickening fraction in patients who subsequently failed the weaning trial [START_REF] Dres | Diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications[END_REF]. Another study that enrolled patients who had successfully passed the weaning trial reported no difference in terms of diaphragm thickening fraction or diaphragm excursion between patients successfully extubated and those who failed extubation [START_REF] Vivier | Inability of diaphragm ultrasound to predict extubation failure: a multicenter study[END_REF]. Altogether, these findings emphasize the importance of standardizing the use of diaphragm ultrasound during weaning. Such standardization could take into account the timing of the measurement (before or during the weaning trial), the patient population of interest (those at highest risk of weaning failure), the conditions of ventilation (unassisted ventilation may be preferred) and the measurements (tidal or during maximum effort depending on the level of patient cooperation). Some authors have suggested combining an ultrasound-derived index with the breathing pattern [START_REF] Spadaro | Can diaphragmatic ultrasonography performed during the T-tube trial predict weaning failure? The role of diaphragmatic rapid shallow breathing index[END_REF][START_REF] Palkar | Diaphragm Excursion-Time Index: A New Parameter Using Ultrasonography to Predict Extubation Outcome[END_REF]. Spadaro et al. observed that the ratio of diaphragm excursion over respiratory rate performed better than the rapid shallow breathing index, diaphragm excursion alone and maximum inspiratory pressure to predict weaning outcome [START_REF] Spadaro | Can diaphragmatic ultrasonography performed during the T-tube trial predict weaning failure? The role of diaphragmatic rapid shallow breathing index[END_REF]. Other authors have sought to evaluate the performance of changes in the excursion-time index (a product of diaphragm excursion and inspiratory time) between assist-control mode and spontaneous breathing trial to predict extubation outcome [START_REF] Palkar | Diaphragm Excursion-Time Index: A New Parameter Using Ultrasonography to Predict Extubation Outcome[END_REF]. In this study, a decrease in excursion-time index less than 3.8% between assist-control mode and spontaneous breathing trial had a sensitivity of 79.2% and a specificity of 75% to predict successful extubation [START_REF] Palkar | Diaphragm Excursion-Time Index: A New Parameter Using Ultrasonography to Predict Extubation Outcome[END_REF].

In another study, diaphragm ultrasound was used to identify patients presenting to the emergency room with acute exacerbation of chronic obstructive pulmonary disease to predict the risk of non-invasive ventilation failure [START_REF] Marchioni | Ultrasound-assessed diaphragmatic impairment is a predictor of outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease undergoing noninvasive ventilation[END_REF]. Patients with diaphragm dysfunction, defined by a diaphragm thickening fraction < 20% on tidal ventilation, were found to be more likely to fail noninvasive ventilation (risk ratio= 4.4; p < 0.001) [START_REF] Marchioni | Ultrasound-assessed diaphragmatic impairment is a predictor of outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease undergoing noninvasive ventilation[END_REF].

Apart from classical ultrasound-derived indices, longitudinal shortening of the diaphragm (strain) can also be measured by speckle tracking [START_REF] Oppersma | Functional assessment of the diaphragm by speckle tracking ultrasound during inspiratory loading[END_REF] and diaphragm stiffness can be measured by shear wave elastography (Figure 3) [START_REF] Chino | Diaphragmatic shear modulus at various submaximal inspiratory mouth pressure levels[END_REF]. A moderate to strong correlation between strain and isometric contractions has been demonstrated in skeletal muscles [START_REF] Frich | Musculoskeletal application and validation of speckle-tracking ultrasonography[END_REF].

Preliminary findings indicate a strong correlation between strain and transdiaphragmatic pressure (r 2 = 0.72 (P < 0.0001) [START_REF] Oppersma | Functional assessment of the diaphragm by speckle tracking ultrasound during inspiratory loading[END_REF]. Shear wave elastography is an ultrasound-based imaging technique that noninvasively measures shear wave velocity propagating in a target tissue and shear wave velocity is directly correlated with stiffness index (shear modulus) [START_REF] Bachasson | Diaphragm shear modulus reflects transdiaphragmatic pressure during isovolumetric inspiratory efforts and ventilation against inspiratory loading[END_REF].

Because of the strong linear relationship between muscle shear modulus and active muscle force, ultrasound shear wave elastography provides an index of change of individual muscle force. A strong correlation (r 2 > 0.95) between submaximal inspiratory mouth pressure and diaphragm shear modulus is observed in healthy subjects [START_REF] Chino | Diaphragmatic shear modulus at various submaximal inspiratory mouth pressure levels[END_REF] and a strong correlation is observed between transdiaphragmatic pressure and shear modulus during isovolumetric inspiratory effort against closed airways (r = 0.82) and during ventilation (r = 0.70) against inspiratory loading [START_REF] Bachasson | Diaphragm shear modulus reflects transdiaphragmatic pressure during isovolumetric inspiratory efforts and ventilation against inspiratory loading[END_REF]. Diaphragm strain and diaphragm shear modulus may be able to provide complementary data in the evaluation of diaphragm function but no study in ICU patients has yet been published.

Diaphragm electrical activity

Diaphragm electrical activity can be measured by surface electromyography (EMG) or multi-array esophageal electrodes. The main advantage of monitoring diaphragm function by surface EMG is that it is continuous and noninvasive, but it is frequently contaminated by the electrocardiogram or neighboring muscle activity and it is subject to power and electromagnetic interferences. Multi-array esophageal electrodes can facilitate recording of the electrical activity of the diaphragm by using a dedicated nasogastric feeding tube, allowing continuous monitoring of EAdi. However, EAdi values are difficult to interpret, as only very limited data concerning "normal" values are currently available. A recent study reported a broad range of median EAdi peaks in spontaneously breathing healthy subjects (from 5 V to 30 V), but usually around 15 V (33). Interestingly, surface EMG of the diaphragm correlates very well with EAdi after averaging breaths into deciles [START_REF] Bellani | Measurement of Diaphragmatic Electrical Activity by Surface Electromyography in Intubated Subjects and Its Relationship With Inspiratory Effort[END_REF]. EAdi can be interpreted together with the breathing pattern in order to evaluate the transformation of drive (EAdi) into pressure or tidal volume (VT) (neuromechanical coupling). A strong correlation has been reported between EAdi and transdiaphragmatic pressure (Pdi), notably during end-expiratory occlusion, suggesting that the neuromechanical efficiency ratio (Pdi/EAdi) could be useful to estimate inspiratory effort on breath-by-breath analysis [START_REF] Bellani | Estimation of Patient's Inspiratory Effort From the Electrical Activity of the Diaphragm[END_REF].

Similar findings have also been recently reported in children [START_REF] Essouri | Relationship Between Diaphragmatic Electrical Activity and Esophageal Pressure Monitoring in Children[END_REF]. However, the repeatability of the measurements of the neuromechanical efficiency ratio recently has been questioned, as these measurements currently exhibit marked within-subject variability [START_REF] Jansen | Estimation of the diaphragm neuromuscular efficiency index in mechanically ventilated critically ill patients[END_REF]. This poor repeatability could potentially constitute a major limitation and clinicians must use several measurements to select occlusions with the lowest variability in order to estimate inspiratory muscle effort from EAdi [START_REF] Jansen | Estimation of the diaphragm neuromuscular efficiency index in mechanically ventilated critically ill patients[END_REF]. The transformation of EAdi into VT can also be studied by calculating the neuroventilatory efficiency index (VT/EAdi). The VT/EAdi ratio can allow early distinction between patients likely to pass or fail the spontaneous breathing trial [START_REF] Dres | Diaphragm electromyographic activity as a predictor of weaning failure[END_REF].

Lastly, the patient-ventilator breath contribution (PVBC) index can be used to determine the respective contribution of the patient and the ventilator to total inspiratory VT. This index is calculated as the ratio of inspiratory VT/EAdi during unassisted breaths (no pressure support) over the same ratio during assisted breaths (with pressure support). A higher PVBC index indicates a higher contribution of the patient. Once again, poor reliability has been reported

for measurements of the PVBC index using the currently available methods [START_REF] Jonkman | Monitoring patient-ventilator breath contribution in the critically ill during neurally adjusted ventilatory assist: reliability and improved algorithms for bedside use[END_REF]. However, after using a new algorithm for EAdi matching between assisted and unassisted breaths (in order to select assisted and unassisted breaths displaying similar EAdi), the authors significantly improved the reliability of the measurements [START_REF] Jonkman | Monitoring patient-ventilator breath contribution in the critically ill during neurally adjusted ventilatory assist: reliability and improved algorithms for bedside use[END_REF].

What are the indications for diaphragm function monitoring?

Taking into account both the effects of excessive ventilatory assistance on the risk of diaphragm dysfunction and the effects of insufficient ventilatory assistance on the risk of patient self-inflicted lung injury [START_REF] Grieco | Patient self-inflicted lung injury: implications for acute hypoxemic respiratory failure and ARDS patients on non-invasive support[END_REF], the main objective of diaphragm function monitoring would be to closely tailor the appropriate level of assistance to the patient's needs and comfort. Some strategies designed to protect the lungs and mitigate the effects of diaphragm disuse have been proposed, but they now need to be tested before they can be generalized [START_REF] Schepens | Lung-and Diaphragm-protective Ventilation in Acute Respiratory Distress Syndrome: Rationale and Challenges[END_REF]. In particular, ultrasound may be useful to monitor diaphragm function together with airway or esophageal pressure recordings to assess patient-ventilator asynchrony [START_REF] Soilemezi | Understanding Patient-Ventilator Asynchrony Using Diaphragmatic Ultrasonography[END_REF]. A possible application of diaphragm ultrasound in this context could be monitoring of patients with acute respiratory distress syndrome treated by deep sedation or neuromuscular blocking agents to ensure that they do not exhibit hidden asynchronies. However, in order to be clinically relevant, this type of monitoring would need to be displayed continuously, which would require further technological improvements before it can be used in a clinical decision support system [START_REF] Spadaro | An open-loop, physiological model based decision support system can reduce pressure support while acting to preserve respiratory muscle function[END_REF]. Another application of diaphragm monitoring would be the weaning from mechanical ventilation [START_REF] Dres | Diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications[END_REF]. Diaphragm monitoring could be particularly useful in patients presenting difficult and prolonged weaning and could help to diagnose diaphragm dysfunction that can interfere with the weaning process, but it could also be used as a predictor of extubation failure in order to implement appropriate preventive strategies. Lastly, diaphragm function monitoring could be used to evaluate inspiratory effort in order to titrate the level of ventilator assistance in patients requiring prolonged weaning. Normal ranges of inspiratory effort would need to be available before this technique could be used in routine clinical practice.

Conclusion

Key bullet points

 Diaphragm dysfunction is common in the ICU and is associated with prolonged duration of mechanical and respiratory complications.

 Diaphragm ultrasound and diaphragm electrical activity recording are useful to monitor the diaphragm function at the bedside.

 Diaphragm monitoring may be used to tailor the ventilator settings in order to provide a diaphragm protective ventilationbetween over and under diaphragm use.

  Monitoring diaphragm function in the ICU could help physicians to more clearly understand the interaction between the patient's effort and the ventilator. It could participate in the ventilator setting decision-making process. Ultimately, diaphragm function monitoring could be very useful in patients with difficult and prolonged weaning by predicting weaning failure and diagnosing diaphragm dysfunction. Future research into diaphragm monitoring in the ICU must investigate the correlation (and its determinants) between standard markers of diaphragm function and ultrasound-derived indices and electrical activity. The reproducibility of clinical measurements must also be improved. Standardization in the form of specific good practice guidelines for diaphragm ultrasound and electrical activity recording in mechanically ventilated patients is also necessary.

Figure 1 .

 1 Figure 1. Panel A is a schematic representation of the diaphragm (in red) and phrenic nerves

Figure 2 .

 2 Figure 2. Description of diaphragm ultrasound intercostal and subcostal windows.

Figure 3 .

 3 Figure 3. Shear wave elastography on the right hemi-diaphragm via the intercostal approach.

Figure 1 .

 1 Figure 1.

Figure 3 .

 3 Figure 3.

Table 1 .

 1 Diaphragm function monitoring techniquesIntercostal approach between the 8 th and 10 th intercostal space. It is calculated as the ratio of (Ti-Te)/Te and expressed as %. Ptr,stim, change in tracheal pressure induced by magnetic phrenic nerve stimulation, Peso, esophageal pressure; Pga, gastric pressure; EMG, electromyogram; ICU, intensive care unit; ECG, electrocardiogram; Tins, inspiratory time; Ti, diaphragm inspiratory thickness; Te, diaphragm expiratory thickness.

	Description	Advantages	Limitations	Normal values

Damien Bachasson (Institut de from Hamilton, personal fees and non-financial support from Fisher & Paykel, grants from the French Ministry of Health, personal fees from Getinge, grants and personal fees from Respinor, grants and non-financial support from Lungpacer.