Emilie Chazelle

Jean-François Chastang

Dr Isabelle Niedhammer
email: isabelle.niedhammer@inserm.fr

Psychosocial work factors and sleep problems: findings from the French national SIP survey

Keywords: psychosocial work factors, occupational factors, sleep problems, sleep disturbances, insufficient sleep duration, cross-sectional analyses, prospective analyses, doseresponse associations

Objectives This study aimed at exploring the cross-sectional and prospective associations between psychosocial work factors and sleep problems.

Methods

The study population consisted of a national representative sample of the French working population (SIP survey). The sample sizes were 7506 and 3555 for the crosssectional and prospective analyses. Sleep problems were defined by either sleep disturbances or insufficient sleep duration at least several times a week. Psychosocial work factors included classical (job strain model factors) and emergent factors (recognition, insecurity, role/ethical conflict, emotional demands, work-life imbalance, etc.). Occupational factors related to working time/hours and physical work environment were also included as well as covariates related to factors outside work. Statistical analyses were performed using weighted Poisson regression analysis.

Results

In the cross-sectional analyses, psychological demands, low social support, low recognition, emotional demands, perception of danger, work-life imbalance and night work were found to be associated with sleep problems. In the prospective analyses, psychological demands and night work were predictive of sleep problems. Using a less conservative method, more factors were found to be associated with sleep problems. Dose-response associations were observed showing that the more frequent the exposure to these factors, the higher the risk of sleep problems. No effect of repeated exposure was found on sleep problems.

Conclusion

Classical and emergent psychosocial work factors were associated with sleep problems. More prospective studies and prevention policies may be needed.

Introduction

Sleep disorders, and insomnia as one of the leading disorders, are very common diseases in Western countries. In European countries, the prevalence of people reporting at least one symptom of insomnia has been estimated to be 34.5% and 6.6% satisfied the DSM-IV requirement for positive and differential diagnosis in the general population [START_REF] Ohayon | Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the International Classification of Sleep Disorders (ICSD)[END_REF]. Sleep disorders have an important burden for health and a strong socioeconomic impact (Daley, Morin, LeBlanc, Gregoire & Savard, 2009). Indeed, sleep disorders have been found to be associated with mortality and various health outcomes such as cardiovascular diseases, and also with accidents including home, car and work accidents, and absenteeism (Akerstedt, Fredlund, Gillberg & Jansson, 2002a;[START_REF] Cappuccio | Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies[END_REF][START_REF] Daley | Insomnia and its relationship to health-care utilization, work absenteeism, productivity and accidents[END_REF][START_REF] Leger | Insomnia and accidents: cross-sectional study (EQUINOX) on sleep-related home, work and car accidents in 5293 subjects with insomnia from 10 countries[END_REF][START_REF] Schwartz | Insomnia and heart disease: a review of epidemiologic studies[END_REF][START_REF] Uehli | Sleep problems and work injuries: a systematic review and meta-analysis[END_REF].

The literature is seldom on potential occupational risk factors of sleep disorders; one exception may be working hours, especially night/shift work, and their impact on sleep (Akerstedt, Fredlund, Gillberg & Jansson, 2002b). The identification of occupational risk factors and prevention towards these factors may be crucial. Psychosocial work factors in association with sleep disorders have been studied rarely in the literature and mainly through the classical job strain model by Karasek [START_REF] Karasek | The Job Content Questionnaire (JCQ): an instrument for internationally comparative assessments of psychosocial job characteristics[END_REF], including psychological demands, decision latitude (or control) and social support, as well as the two combined situations, job strain (combination between high demands and low latitude) and iso-strain (combination between low support -isolation-and strain). A literature review using prospective and intervention studies on the associations between psychosocial work factors and sleep provided evidence for the associations of psychological demands and low control with poor sleep quality [START_REF] Van Laethem | Psychosocial work characteristics and sleep quality: a systematic review of longitudinal and intervention research[END_REF]. This review provided inconclusive results for other psychosocial work factors, the number of high-quality studies being insufficient.

Nevertheless, the authors of this review suggest that using all prospective studies (not only high-quality prospective studies), there may be moderate evidence for the effects of low social support, effort-reward imbalance and organizational injustice on sleep. Studies, that were not all prospective, found that low reward [START_REF] Eriksen | Work factors as predictors of poor sleep in nurses' aides[END_REF][START_REF] Fahlen | Effort-reward imbalance, sleep disturbances and fatigue[END_REF][START_REF] Kim | Association between job stress and insomnia in Korean workers[END_REF][START_REF] Kudielka | Effort-reword imbalance, overcommitment and sleep in a working population[END_REF], role conflict [START_REF] Eriksen | Work factors as predictors of poor sleep in nurses' aides[END_REF][START_REF] Knudsen | Job stress and poor sleep quality: Data from an American sample of full-time workers[END_REF], emotional demands [START_REF] Park | Organizational factors associated with work-related sleep problems in a nationally representative sample of Korean workers[END_REF], job insecurity [START_REF] Kim | Association between job stress and insomnia in Korean workers[END_REF][START_REF] Park | Organizational factors associated with work-related sleep problems in a nationally representative sample of Korean workers[END_REF] or work-family conflicts [START_REF] Lallukka | Conflicts between work and family life and subsequent sleep problems among employees from Finland, Britain, and Japan[END_REF][START_REF] Lallukka | Sleep complaints in middle-aged women and men: the contribution of working conditions and work-family conflicts[END_REF][START_REF] Park | Organizational factors associated with work-related sleep problems in a nationally representative sample of Korean workers[END_REF] were associated with sleep outcomes.

Methods

Study sample

The study was based on the data from the national representative SIP (Santé et Itinéraire Professionnel) survey, conducted by the French Ministries of Labour (DARES) and Health (DRESS), the French Centre for Employment Studies (CEE) and the French National Institute for Statistics and Economic Studies (INSEE). The main objective of the survey was to provide information about the occupational determinants of health in the national French population [START_REF] Coutrot | Parcours professionnel et état de santé[END_REF]. The SIP survey is a cohort study of a national representative sample of the French general population aged 20-74 years old in 2006.

The survey was based on a face-to-face questionnaire at respondent's home. The first interview took place in 2006 and the response rate was 76%, leading to an initial sample of 13648 people. The sample was followed up from 2006 to 2010 and interviewed again in 2010.

Previous studies by our team have already been published using these data [START_REF] Lassalle | Working conditions and psychotropic drug use: Cross-sectional and prospective results from the French national SIP study[END_REF]Malard, Chastang & Niedhammer, 2015a;[START_REF] Malard | Changes in psychosocial work factors in the French working population between 2006 and 2010[END_REF][START_REF] Murcia | Psychosocial work factors, major depressive and generalised anxiety disorders: Results from the French national SIP study[END_REF][START_REF] Murcia | Educational inequalities in major depressive and generalized anxiety disorders: results from the French national SIP study[END_REF][START_REF] Niedhammer | Psychosocial work factors and first depressive episode: retrospective results from the French national SIP survey[END_REF]Niedhammer, Malard & Chastang, 2015). The SIP survey was approved by the French Ethics Committees (CNIL and CNIS). -Classical factors: psychological demands, decision latitude, and social support at work as 3 proxies for the job strain model dimensions [START_REF] Karasek | The Job Content Questionnaire (JCQ): an instrument for internationally comparative assessments of psychosocial job characteristics[END_REF], -Emergent factors: recognition and job insecurity as two proxies of the sub-dimensions of reward (esteem and job insecurity) in the effort-reward imbalance model [START_REF] Siegrist | The measurement of effort-reward imbalance at work: European comparisons[END_REF] The associations between occupational factors and sleep problems, with adjustment for covariates, were studied using weighted Poisson regression analysis. Two types of models were performed: to study each factor separately with adjustment for covariates (models 1), and to study all factors simultaneously with adjustment for covariates (model 2). No collinearity was detected in these last models.

The binary variables of occupational factors were used first. In model 2, interaction terms between psychological demands and decision latitude were introduced to test Karasek's hypothesis of job strain. Interaction terms were also tested one by one in model 2 between gender and each factor to explore potential differences in the associations between genders.

To explore dose-response associations, analyses were performed using the frequency of follow-up whatever their working status in 2010 (and not only those who were working) was also performed.

The statistical analyses were performed using SAS and STATA.

Results

Description of the study sample

Among the 13648 people of the initial sample from the general population, 7506 people were working at the time of the interview in 2006. People with an organic sleep disorder (narcolepsy, bruxism, restless leg syndrome, obstructive or central sleep apnea, excessive daytime sleepiness) were not included (n=34). This sample of 7506 workers was used for the cross-sectional analysis. Among them, 6251 people were followed up in 2010 (follow-up rate: 83%). For the prospective analysis, people with sleep problems at baseline in 2006 (n=1932) and people who were not working at the time of the survey in 2010 (n=764) were excluded from the study. Thus, the study sample included 3555 workers for the prospective analysis (Figure 1). The description of the cross-sectional sample is provided in Table 1, and gender differences were observed for sleep problems, occupational factors and covariates. The prevalence of sleep problems was 27.66% for men and 33.73% for women, with a significant difference between genders. Sleep disturbances and insufficient sleep duration were strongly associated, confirming the interest of studying them together.

Cross-sectional analysis

In models 1, when each factor was studied separately, the frequency of exposure to occupational factors displayed significant linear associations with sleep problems, except job performance (Table 2). In model 2 with all factors studied simultaneously, the risk of sleep problems increased with the frequency of exposure to psychological demands, low social support, low recognition, emotional demands, perception of danger, work-life imbalance and night work. One interaction term with gender was significant: the association of psychological demands with sleep problems was stronger for men than for women.

Prospective analysis

Significant linear prospective associations were observed between the frequency of exposure to high psychological demands, low decision latitude, low recognition, ethical conflict, worklife imbalance and night work and sleep problems in models 1 (Table 3). The risk of sleep problems also increased with the frequency of exposure to biomechanical exposure and assembly-line work. In model 2, the risk of sleep problems increased with the frequency of exposure to psychological demands and night work. No interaction was found with gender.

Table 4 shows the results for the analysis of repeated exposure. As no significant interaction was found between exposure in 2006 and exposure in 2010, these interaction terms were not kept in the models (Table 4). No factor in 2006 was predictive of sleep problems in models 1 and 2 (one exception was low decision latitude). Almost all psychosocial work factors in 2010

were associated with sleep problems in models 1 (except decision latitude, social support, role conflict and job performance), and it was also the case in model 2 for psychological demands, emotional demands, work-life imbalance and night work with sleep problems. Biomechanical exposure also displayed a significant dose-response association with sleep problems.

Finally, no interaction term between psychological demands and decision latitude was found to be significant in both cross-sectional and prospective analyses.

Discussion

Main findings

In the cross-sectional analyses with all factors studied simultaneously, psychological demands, low social support, low recognition, emotional demands, perception of danger, work-life imbalance and night work displayed dose-response associations with sleep problems. In the prospective analyses with all factors explored together, psychological demands and night work were predictive of sleep problems with dose-response associations.

When each factor was studied separately (a less conservative method), more factors were found to be associated with sleep problems. Dose-response associations were observed

showing that the more frequent the exposure to some factors, the higher the risk of sleep problems. No effect of repeated exposure was found on sleep problems. Regarding the dimensions of the effort-reward imbalance model, low recognition as a proxy of esteem was associated with sleep problems in our study (except in models 2 in the prospective analysis). Previous studies [START_REF] Eriksen | Work factors as predictors of poor sleep in nurses' aides[END_REF][START_REF] Fahlen | Effort-reward imbalance, sleep disturbances and fatigue[END_REF][START_REF] Kim | Association between job stress and insomnia in Korean workers[END_REF][START_REF] Kudielka | Effort-reword imbalance, overcommitment and sleep in a working population[END_REF] showed a significant association between low reward and various sleep outcomes; only one of these studies had a prospective design [START_REF] Eriksen | Work factors as predictors of poor sleep in nurses' aides[END_REF]. Job insecurity was associated with sleep problems in models 1 in our cross-sectional analysis.

Two previous studies reported an association between job insecurity and sleep outcomes in cross-sectional samples of Korean workers [START_REF] Kim | Association between job stress and insomnia in Korean workers[END_REF][START_REF] Park | Organizational factors associated with work-related sleep problems in a nationally representative sample of Korean workers[END_REF].

Regarding emergent psychosocial work factors, we studied two factors related to role stressors, role conflict and ethical conflict, and they displayed significant associations with sleep problems in our models 1. Some rare studies explored role conflict in association with sleep outcomes and found that it was associated with poor sleep in a Norwegian prospective study among nurses' aides [START_REF] Eriksen | Work factors as predictors of poor sleep in nurses' aides[END_REF], and with difficulty initiating sleep and nonrestorative sleep in a American cross-sectional study [START_REF] Knudsen | Job stress and poor sleep quality: Data from an American sample of full-time workers[END_REF] but role conflict and role ambiguity were not associated with insomnia in a Japanese cross-sectional study among workers in a manufacturing company [START_REF] Nakata | Job stress, social support, and prevalence of insomnia in a population of Japanese daytime workers[END_REF]). Emotional demands and tensions with the public were associated with sleep problems in our cross-sectional analysis. These findings are in line with the results by Park et al. [START_REF] Park | Organizational factors associated with work-related sleep problems in a nationally representative sample of Korean workers[END_REF] who reported an association between emotional demands and work-related sleep problems in a cross-sectional sample of Korean workers. Work-life imbalance was found to be associated with sleep outcomes mostly in our cross-sectional analyses. Some rare studies found that work-life imbalance/conflicts were associated with sleep outcomes in cross-sectional samples of employees of the City of Helsinki [START_REF] Lallukka | Sleep complaints in middle-aged women and men: the contribution of working conditions and work-family conflicts[END_REF] and Korean workers [START_REF] Park | Organizational factors associated with work-related sleep problems in a nationally representative sample of Korean workers[END_REF], and in a prospective study using three British, Finnish and Japanese occupational cohorts [START_REF] Lallukka | Conflicts between work and family life and subsequent sleep problems among employees from Finland, Britain, and Japan[END_REF]. The factors of role stressors, emotional demands and work-life imbalance have been studied very rarely in association with sleep problems and would deserve more attention in future studies. Job performance and perception of danger were also studied in our study, but to our knowledge, no previous studies explored these factors.

Our study reported dose-response associations between exposure frequency and sleep

Strengths and limitations of the study

The strengths of the study may be underlined. The study was based on a large national representative sample of the French working population with satisfactory response and follow-up rates. Furthermore, as weights were included in all statistical analyses, nonresponse and attrition were corrected, and the results may be generalized to the whole working population. We observed gender differences in the prevalence of occupational factors, covariates and sleep problems, but found a very small number of differences in the associations between psychosocial work factors and sleep problems [START_REF] Niedhammer | How is sex considered in recent epidemiological publications on occupational risks?[END_REF]. A comparison was done between cross-sectional and prospective analyses. The cross-sectional analysis may provide information on the shortterm/acute effects of psychosocial work factors on sleep, although reverse causation may also be possible [START_REF] Magnusson Hanson | Cross-lagged relationships between workplace demands, control, support, and sleep problems[END_REF]. This analysis had a higher statistical power because of a larger sample size than the prospective analysis. The prospective analysis may provide information on the long-term and/or chronic effects of psychosocial work factors on sleep, makes clear the temporal sequence between exposure and outcome and possible the study of new cases of sleep problems. Psychosocial work factors were examined including both classical concepts and emergent factors understudied in the literature. We were able to provide information about dose-response associations, as the risk of sleep problems increased with the frequency of exposure to psychosocial work factors. Furthermore, sensitivity analyses also found doseresponse associations between exposure to psychosocial work factors and the frequency of sleep problems. Two types of models were performed allowing to study the associations between psychosocial work factors and sleep using two approaches, the first one exploring each factor separately, and the second one exploring all factors together, i.e. independently of each other. The second approach may be considered conservative as there may be complex interrelations between factors, some factors being causes or consequences of other factors, and may lead to overadjustment [START_REF] Rugulies | Do psychosocial work environment factors measured with scales from the Copenhagen Psychosocial Questionnaire predict register-based sickness absence of 3 weeks or more in Denmark?[END_REF]. Other occupational factors and major covariates, considered as well-known risk factors of sleep outcomes, were taken into account, and their results were consistent with the literature, reinforcing the validity of our study. In particular, night work and long working hours were found to be associated with sleep problems in agreement with previous studies (Akerstedt et al., 2002b;[START_REF] Dahlgren | Different levels of work-related stress and the effects on sleep, fatigue and cortisol[END_REF][START_REF] Nakashima | Association between long working hours and sleep problems in white-collar workers[END_REF][START_REF] Sekine | Work and family characteristics as determinants of socioeconomic and sex inequalities in sleep: The Japanese Civil Servants Study[END_REF][START_REF] Virtanen | Long working hours and sleep disturbances: the Whitehall II prospective cohort study[END_REF]. Sensitivity analyses were performed to check the robustness of the results and provided similar results.

Some limitations deserve to be mentioned. The study design was prospective but the 4-year period may be too long to study the impact of psychosocial work factors on sleep outcomes, and may lead to an underestimation of the associations observed. Indeed, other authors [START_REF] Akerstedt | Predicting changes in sleep complaints from baseline values and changes in work demands, work control, and work preoccupation--the WOLF-project[END_REF] suggested that the effects of exposure to psychosocial work factors on sleep may be shorter. A healthy worker effect may be suspected as workers developing sleep problems within the 4-year period may have left the labour market in 2010. A sensitivity analysis was performed including major changes in job and working conditions and long nonworking period(s) between 2006-2010 as additional covariates and the results were unchanged. Furthermore, a sensitivity analysis including all people at follow-up whatever their work status in 2010 (and not only those who were working) also provided similar results.

Psychosocial work factors were not measured using validated questionnaires, leading to potential imprecision in the variables used [START_REF] Fahlen | The Effort-Reward Imbalance model of psychosocial stress at the workplace -a comparison of ERI exposure assessment using two estimation methods[END_REF]. However, other authors underlined the interest and validity to construct proxies [START_REF] Karasek | Testing two methods to create comparable scale scores between the Job Content Questionnaire (JCQ) and JCQ-like questionnaires in the European JACE Study[END_REF]. Some psychosocial work factors may have been neglected as they were not available in the survey, and may be important in the association with sleep, such as organizational injustice [START_REF] Elovainio | Organizational justice and sleeping problems: The Whitehall II study[END_REF][START_REF] Kim | Association between job stress and insomnia in Korean workers[END_REF], threats and violence at work [START_REF] Eriksen | Work factors as predictors of poor sleep in nurses' aides[END_REF][START_REF] Park | Organizational factors associated with work-related sleep problems in a nationally representative sample of Korean workers[END_REF], or bullying [START_REF] Lallukka | Workplace bullying and subsequent sleep problems--the Helsinki Health Study[END_REF][START_REF] Nakata | Job stress, social support, and prevalence of insomnia in a population of Japanese daytime workers[END_REF]Niedhammer, David, Degioanni, Drummond, Philip & 143 occupational physicians, 2009). No validated instrument to measure sleep problems was used. Sleep disturbances and insufficient sleep duration were strongly associated and the separate analysis of these two variables provided very similar results compared to those of the combined outcome presented in the tables. A reporting bias may have occurred as both exposure and outcome were based on self-report, leading to a potential overestimation of the associations observed. Some covariates may be missing, such as consumption of psychoactive substances (tea, coffee or illicit drugs) or environmental factors (noise). The frequency variables of occupational factors were based on the initial coding for the factors with one item or on quartiles for the factors with more than one item RR associated with an increase of 1 unit of the frequency variables RR adjusted for gender, age, occupation, marital status, child under 3y, social support outside of work, and life events 1 Each occupational factor studied separately 2 All occupational factors studied simultaneously In bold: RR significant at 5% ***: p < 0.001, **: p < 0.01, *: p < 0.05 The two binary variables of exposure to each occupational factor in 2006 and 2010 were included simultaneously in the models The interaction terms between exposure in 2006 and 2010 were not included in these models (as they were non-significant) RR adjusted for gender, age, occupation, marital status, child under 3y, social support outside of work, and life events 1 Each occupational factor studied separately 2 All occupational factors studied simultaneously In bold: RR significant at 5% ***: p < 0.001, **: p < 0.01, *: p < 0.05

Conclusion

  These factors may be considered as emergent psychosocial work factors in association with sleep outcomes. As a substantial part of the studies were cross-sectional, included workers from specific populations (particular work sectors, companies or occupations) and/or explored a limited number of psychosocial work factors, the proof levels on the effects of psychosocial work factors, especially those that are not from the job strain model, on sleep need to be improved. The objectives of this study were to examine the associations of a large set of psychosocial work factors with sleep problems, taking well-known risk factors of sleep disorders into account. Innovative aspects of the study included the study of a large national representative sample of the working population, the analysis of cross-sectional and prospective data, the exploration of the job strain model factors and other understudied factors for the measurement of psychosocial work factors, and the study of frequency and duration of exposure. The study was designed as an etiological study aiming at exploring the associations of psychosocial work factors on the development of sleep problems.

  Sleep problems Sleep problems were assessed using two variables, sleep disturbances and insufficient sleep duration in 2006 and 2010. Sleep disturbances, i.e. difficulty initiating or maintaining sleep, or premature awakening, were assessed by the following item: 'Within the last twelve months, have you experienced sleep disturbances (difficulty falling asleep, night awakenings, premature awakening without being able to return to sleep): never/seldom, several times a month, several times a week, almost every day?' People who answered several times a week or almost every day were classified as cases of sleep disturbances. Sleep duration was assessed by the following item: 'Within the last twelve months, the number of your sleep hours during night has been: always/almost sufficient, insufficient several times a month, insufficient several times a week, insufficient almost every day?' People who answered having an insufficient number of sleep hours several times a week or almost every day were considered as having an insufficient sleep duration. People with either sleep disturbances or insufficient sleep duration at least several times a week were considered as cases of sleep problems in our analyses. The definition criteria of insomnia from the DSM-V reporting that 'the sleep difficulty occurs at least three nights a week' was followed to define the cases for sleep problems. Psychosocial work factors and other occupational factors (Appendix) Twelve psychosocial work factors were measured:

  2006) were multiplied by the inverse probability of being interviewed in 2010. Finally, a second marginal calibration on territorial unit, urban area, age×gender, education, nationality, and size of household was performed on the sample of individuals interviewed in 2006 and 2010 to be representative of the population of 2006. All analyses were performed including weights. A description of the study sample in 2006 was performed and a comparison was done between genders using Rao-Scott Chi-Square test. The associations between occupational factors and sleep problems were studied using crosssectional and prospective data among the total sample of men and women. The cross-sectional analyses were performed using the data of 2006 for all variables (occupational factors, covariates and sleep problems) among the sample of those who were working in 2006. The prospective analyses were performed using the data of 2006 (occupational factors and covariates) and 2010 (sleep problems) among the sample of those who were working in both 2006 and 2010 and were free of sleep problems in 2006.

  exposure and repeated exposure to occupational factors. The analysis of the frequency of exposure was done using the frequency variables as continuous variables and trend tests were performed to explore potential linear associations in both cross-sectional and prospective analyses. This analysis aimed at exploring whether the risk of sleep problems increased with the frequency of exposure. The prospective analysis of repeated exposure was performed using the exposures of 2006 and 2010 (binary variables) simultaneously and an interaction term between these two exposures was added to test whether the effect of exposure in 2010 was the same or different according to the values of the exposure in 2006. This analysis aimed at exploring whether repeated exposure in both 2006 and 2010 increased the risk further compared to the exposure in 2010 alone.Sensitivity analyses were performed including additional covariates that were: employment variables, job change and unemployment/inactivity periods between 2006 and 2010, overcommitment at work as a personality factor, health status, alcohol/tobacco consumption, and life events between 2006 and 2010. Finally, a sensitivity analysis including all people at

  problems. No impact of repeated exposure on sleep problems was observed in our study. Only a few studies explored the associations between changes in psychosocial work factors and sleep outcomes. Akerstedt et al. (Akerstedt, Nordin, Alfredsson, Westerholm & Kecklund, 2012) reported the effects of a change from low to high work demands and prolonged exposure to high demands on new cases of impaired sleep. De Lange et al. (de Lange, Kompier, Taris, Geurts, Beckers, Houtman et al. 2009) stated that cumulative exposure to a high-strain work environment (characterized by high job demands and low job control) was associated with elevated levels of sleep-related complaints.

  Our findings highlight the role of psychosocial work factors, including emergent factors, in sleep problems. These psychosocial work factors may have short-term effects on sleep, and for some of them long-term effects. Among these factors, some classical factors may be mentioned such as psychological demands, as well as emergent factors like emotional demands, low recognition and work-life imbalance. More prospective studies may be needed to confirm our results and prevention policies oriented towards new psychosocial work factors should be intensified. Appendix. List of the studied occupational factors and their items Classical psychosocial work factors: -psychological demands (3 items, work under pressure, too many things to do, and excessive amount of work) -decision latitude (2 items, freedom to decide how to do the work, and use of skills) -social support at work (1 item, good relationships with colleagues) Emergent psychosocial work factors: -recognition (1 item, fair feedback on the work done) -job insecurity (1 item, fear of job loss) -role conflict (1 item, not being able to work following best practices) -ethical conflict (1 item, exposure to unethical situations) -emotional demands (1 item, hiding feelings at work) -job performance (1 item, wage or promotion dependent on performance/productivity) -tensions with the public (1 item, tensions with users, students, patients, customers, etc.) -perception of danger at work (1 item, fear for his/her own safety or the safety of others) -work-life imbalance (1 item: work in line with family life). Working time/hours variables: -long working hours (1 item, ≥48h/week) -night work (1 item, work hours between 12-5am) -shift work (1 item, work on alternating shifts) -predictability of schedules (1 item, irregular hours difficult to predict) Other occupational exposures: -biomechanical exposure (3 items, manual materials handling, other biomechanical constraints, and vibrations) -physical exposure (2 items, loud noise and extreme temperatures) -chemical exposure (1 item, exposure to dust, fume, chemical products or germs) -assembly-line work or repetitive work under time constraint (1 item).

  /non-working)×age, urban area, size of household, occupation and economic activity was performed on the sample in 2006. Homogeneous response groups were formed based on characteristics in 2006 (work status, urban area, age, level of education, gender and self-reported health), and the probability of being interviewed in 2010 was

	Weights were calculated using marginal calibration and inverse probability weighting to
	, role conflict, ethical provide estimates representative of the population in 2006 (De Riccardis, 2012). Two sets of
	conflict, emotional demands, job performance, tensions with the public, perception of weights were used in the analyses: in the cross-sectional analysis, a first set of weights was
	danger at work and work-life imbalance. used to control for a potential bias related to non-response in 2006, and in the prospective
	analysis, a second set of weights was used to control for potential biases related to non-
	Although the focus was on psychosocial work factors, the study also included other response in 2006 and attrition in 2010. A marginal calibration on age, work status
	occupational factors that were: (working/unemployed
	-	Working time/hours variables: long working hours, night work, shift work and
		predictability of schedules.
	-	Occupational exposures of biomechanical, physical and chemical nature, and assembly-
		line work or repetitive work under time constraint.
	For all items, the response categories were always/often/sometimes/never. Items were
	summed when the factors included more than one item. Three measures of exposure were
	used:
	-	binary variables in 2006: exposed versus non-exposed using the median cut-offs,
	-	frequency variables in 2006: using the initial response categories,
		always/often/sometimes/never, for the factors with one item or quartiles for those with
		more than one item, and
	-	repeated exposure evaluated using the binary variables in 2006 and 2010 for each
		occupational factor.
	As the results were very close between binary and frequency variables, we chose to present
	the results of frequency variables only in our tables (except for the study of repeated
	exposures).
	Covariates
	The covariates, measured in 2006, included: age, occupational groups, marital status, presence
	of child(ren) <3 years old, social support outside work (2 items, instrumental and emotional
	support), life events during childhood i.e. before 18 years old (12 items) and life events within
	the four last years (4 items).
	Statistical methods

calculated for each group. Weights calculated by marginal calibration (for non-response in

  Comparison with the literatureRegarding the dimensions of the job strain model, psychological demands were associated with sleep problems in both cross-sectional and prospective analyses in our study. Our results are in agreement with previous findings as demonstrated by the strong evidence reported in the literature review by[START_REF] Van Laethem | Psychosocial work characteristics and sleep quality: a systematic review of longitudinal and intervention research[END_REF]. Low decision latitude was associated with sleep problems, especially in our models 1.[START_REF] Van Laethem | Psychosocial work characteristics and sleep quality: a systematic review of longitudinal and intervention research[END_REF] stated that there may be moderately strong evidence for the association between job control and sleep quality but also reported that a number of prospective studies did not find a significant effect of job control on sleep. Low social support was associated with sleep problems in our cross-sectional analyses. The review by[START_REF] Van Laethem | Psychosocial work characteristics and sleep quality: a systematic review of longitudinal and intervention research[END_REF] provided moderately strong evidence for the association between low social support and sleep quality. However, among the seven prospective studies reviewed, only one found a significant association and two others reported elements towards this association (for one outcome and not for all outcomes, and for maintenance of poor sleep quality).

Table 1

 1 Figure 1 Flow diagram for the cross-sectional and prospective study samples Description of the study sample according to sleep problems, covariates, and occupational factors in 2006

	13648 respondents
	in 2006
	5950 non-working people
	in 2006
	7698 working people
	in 2006
	158 non-working people at the
	time of the survey in 2006
	because of training, parental or
	sick leave
	7540 working people at the
	time of the survey in 2006
	34 with organic sleep disorders
	N=7506
	Cross-sectional study
	sample
	1255 non-respondents
	in 2010
	6251 respondents
	in 2010
	1932 with sleep problems
	in 2006
	4319 without sleep
	problems in 2006
	668 not working any more
	in 2010
	3651 working people
	in 2010
	96 non-working people at the
	time of the survey in 2010
	because of training, parental or
	sick leave
	N=3555
	Prospective study sample

Table 2

 2 Cross-sectional associations between occupational factors (frequency variables) and sleep problems in 2006: results of weighted Poisson regression analysis adjusted for covariates

	Men and women (N=7495)		Sleep problems
		RR 1	95% CI	RR 2	95% CI
	Psychosocial work factors
	High psychological demands	1.25***	1.20-1.30	1.10***	1.06-1.16
	Low decision latitude	1.07***	1.04-1.11	1.01	0.97-1.05
	Low social support	1.19***	1.13-1.25	1.08**	1.02-1.14
	Low recognition	1.16***	1.12-1.20	1.06**	1.02-1.11
	Job insecurity	1.14***	1.09-1.19	1.02	0.98-1.07
	Role conflict	1.15***	1.10-1.20	1.01	0.96-1.06
	Ethical conflict	1.23***	1.17-1.29	1.03	0.98-1.09
	Emotional demands	1.17***	1.13-1.21	1.08***	1.04-1.12
	Job performance	1.02	0.98-1.07	0.99	0.94-1.03
	Tensions with the public	1.18***	1.13-1.24	1.01	0.96-1.06
	Perception of danger	1.22***	1.16-1.28	1.06*	1.01-1.13
	Work life imbalance	1.30***	1.25-1.35	1.16***	1.11-1.21
	Working time variables
	Long working hours	1.13**	1.09-1.17	1.04	1.00-1.08
	Night work	1.18***	1.12-1.23	1.10***	1.04-1.16
	Shift work	1.04*	1.00-1.08	0.98	0.94-1.02
	Low predictability	1.11***	1.06-1.15	0.99	0.95-1.04
	Physical working conditions
	Biomechanical exposure	1.12***	1.08-1.16	1.02	0.98-1.06
	Physical exposure	1.11***	1.07-1.15	1.02	0.98-1.06
	Chemical exposure	1.09***	1.05-1.13	1.01	0.97-1.05
	Assembly-line work	1.08***	1.04-1.12	1.01	0.97-1.05
	The frequency variables of occupational factors were based on the initial coding for the factors with one item or on quartiles for the factors
	with more than one item
	RR associated with an increase of 1 unit of the frequency variables
	RR adjusted for gender, age, occupation, marital status, child under 3y, social support outside of work, and life events
	1 Each occupational factor studied separately 2 All occupational factors studied simultaneously
	In bold: RR significant at 5%
	***: p < 0.001, **: p < 0.01, *: p < 0.05

Table 3

 3 Prospective associations between occupational factors in 2006 (frequency variables) and sleep problems in 2010: results of weighted Poisson regression analysis adjusted for covariates

	Men and women (N=3550)		Sleep problems
		RR 1	95% CI	RR 2	95% CI
	Psychosocial work factors
	High psychological demands	1.14***	1.06-1.23	1.12*	1.03-1.21
	Low decision latitude	1.08**	1.02-1.15	1.04	0.98-1.12
	Low social support	1.01	0.89-1.14	0.93	0.81-1.06
	Low recognition	1.11**	1.04-1.19	1.07	0.99-1.16
	Job insecurity	1.08	0.98-1.19	1.02	0.92-1.12
	Role conflict	1.06	0.96-1.16	0.96	0.86-1.06
	Ethical conflict	1.16**	1.04-1.29	1.09	0.97-1.23
	Emotional demands	1.03	0.97-1.09	0.99	0.93-1.06
	Job performance	1.00	0.92-1.08	1.00	0.92-1.09
	Tensions with the public	1.04	0.94-1.15	0.97	0.87-1.08
	Perception of danger	1.10	0.99-1.22	1.03	0.92-1.16
	Work life imbalance	1.10*	1.00-1.22	1.03	0.93-1.15
	Working time variables
	Long working hours	1.00	0.92-1.09	0.98	0.89-1.07
	Night work	1.24***	1.13-1.34	1.23***	1.11-1.35
	Shift work	1.05	0.98-1.13	0.98	0.9-1.06
	Low predictability	0.99	0.91-1.07	0.94	0.86-1.03
	Physical working conditions
	Biomechanical exposure	1.07*	1.00-1.14	1.05	0.97-1.13
	Physical exposure	1.03	0.96-1.10	0.98	0.91-1.06
	Chemical exposure	1.02	0.95-1.10	0.97	0.89-1.06
	Assembly-line work	1.08*	1.00-1.16	1.03	0.95-1.11

Table 4

 4 Prospective associations between occupational factors in 2006 and 2010 and sleep problems in 2010: results of weighted Poisson regression analysis adjusted for covariates

	Men and women (N=3550)		Sleep problems
	RR (95% CI)	Exposure	Exposure	Exposure	Exposure
		in 2006 -RR 1	in 2010 -RR 1	in 2006 -RR 2	in 2010 -RR 2
	Psychosocial work factors
	High psychological demands	1.13 (0.96-1.32) 1.57*** (1.35-1.83) 1.16 (0.98-1.37) 1.31*** (1.11-1.54)
	Low decision latitude	1.21* (1.03-1.41)	1.13 (0.97-1.32)	1.20* (1.02-1.40)	1.00 (0.85-1.18)
	Low social support	0.96 (0.80-1.15)	1.17 (1.00-1.37)	0.91 (0.76-1.09)	1.01 (0.86-1.18)
	Low recognition	1.09 (0.93-1.28) 1.29** (1.11-1.50)	1.07 (0.90-1.26)	1.11 (0.95-1.30)
	Job insecurity	1.05 (0.88-1.26)	1.21* (1.02-1.44)	0.99 (0.83-1.18)	1.07 (0.90-1.27)
	Role conflict	0.99 (0.85-1.16)	1.12 (0.96-1.31)	0.92 (0.78-1.08)	0.93 (0.79-1.10)
	Ethical conflict	1.09 (0.93-1.28) 1.35*** (1.16-1.58) 1.06 (0.90-1.25)	1.15 (0.98-1.35)
	Emotional demands	0.94 (0.80-1.10) 1.56*** (1.33-1.82) 0.92 (0.78-1.07) 1.30*** (1.11-1.52)
	Job performance	1.07 (0.92-1.25)	0.91 (0.79-1.07)	1.05 (0.91-1.22)	0.87 (0.75-1.01)
	Tensions with the public	0.95 (0.81-1.12) 1.32*** (1.12-1.55) 0.91 (0.77-1.08)	1.07 (0.90-1.26)
	Perception of danger	0.98 (0.83-1.16) 1.40*** (1.19-1.64) 0.96 (0.81-1.13)	1.17 (1.00-1.38)
	Work life imbalance	1.02 (0.86-1.21)	1.45* (1.24-1.71)	1.01 (0.85-1.21)	1.22* (1.03-1.45)
	Working time variables
	Long working hours	0.92 (0.75-1.12)	1.27* (1.05-1.53)	0.87 (0.71-1.07)	1.07 (0.88-1.31)
	Shift work	1.02 (0.81-1.29)	1.17 (0.94-1.45)	0.88 (0.69-1.13)	0.96 (0.76-1.21)
	Low predictability	0.95 (0.79-1.14)	1.18 (0.99-1.40)	0.87 (0.72-1.05)	0.97 (0.81-1.16)
	Physical exposure	0.91 (0.76-1.08) 1.37*** (1.15-1.62) 0.88 (0.73-1.06)	1.08 (0.89-1.30)
	Chemical exposure	0.93 (0.77-1.12)	1.20* (1.00-1.44)	0.90 (0.74-1.09)	1.06 (0.88-1.29)
	Assembly-line work	1.10 (0.92-1.32)	1.16 (0.97-1.38)	1.06 (0.88-1.27)	1.00 (0.83-1.19)

Night work 1.08 (0.87-1.35) 1.52*** (1.24-1.86) 1.16 (0.92-1.44) 1.31* (1.06-1.61) Physical working conditions Biomechanical exposure 0.94 (0.79-1.12) 1.43*** (1.21-1.70) 0.91 (0.75-1.09) 1.27* (1.05-1.54)

Acknowledgements

The authors thank the members of the DARES, DREES, CEE and INSEE, and all the people who participated to the SIP survey and made this study possible.

Funding

French ministry of labour (DARES, grant no 2200727156).

Conflict of interest

The authors declare that they have no conflict of interest.


Larissa Valmy
email: larissa.valmy@ch-cayenne.fr

Barbara Gontier
email: gontierbarbara@gmail.com

Marie Claire Parriault
email: marie-claire.parriault@ch-cayenne.fr

Astrid Van Melle
email: astrid.van-melle@ch-cayenne.fr

Thomas Pavlovsky
email: thomas.pavlovsky@ch-cayenne.fr

Célia Basurko
email: c.basurko@free.fr

Claire Grenier
email: claire.grenier@croix-rouge.fr

Maylis Douine
email: maylis.douine@ch-cayenne.fr

Antoine Adenis
email: antoine.adenis@ch-cayenne.fr

Mathieu Nacher
email: mathieu.nacher@ch-cayenne.fr

Prevalence and predictive factors for renouncing medical care in poor populations of Cayenne, French Guiana

Keywords: Health care, renouncement, poor populations, logistic regression, Tree analysis, French Guiana

Background

Access to health care is a global public problem. In French Guiana, there exists social inequalities which are specially marked amongst immigrants who make up a third of the population. Health care inequalities are prevalent. The objective of this study was to determine factors associated with why health care amongst the poor population of Cayenne was renounced.

Study design

The study was cross sectional. It focused on knowledge, attitudes, practices and beliefs of the population living in poor neighborhoods of the Cayenne area.

Methods

Populations coming at the Red Cross mobile screening unit in poor urban areas of Cayenne were surveyed from July 2013 to June 2014. Structured questionnaires consisted of93 questions.Written informed consent was requested at the beginning of the questionnaire. The predictors for renouncing medical care were determined using logistic regression models and tree analysis.

Results

Twenty percent of persons had renounced care. Logistic regression showed that renouncement of health care wasnegativelyassociated with having noregular physician Adjusted Odds Ratio (AOR)=0.43 (95%CI=0.24-0.79) and positively associated withbeing embarrassed to ask certain questions AOR=6.81 (95%CI=3.98-11.65) and having been previously refused health care by a doctor . Tree analysis also showed that three of these variables were linked to renouncement, with feeling shy to ask certain questions as the first branching.

Conclusion

Healthcare mediation and welcoming staff may be simple solutions to the above problems which were underscored in our observations.

Although most people felt it was easy to see a doctor, one in five had renounced health care.

The variables identified by the models suggest vulnerable persons generally had previous negative encounters with the health system and felt unwanted or non eligible for healthcare.

Introduction Background

Health inequalities between countries and within countries remain salient [START_REF] Marmot | Social determinants of health inequalities[END_REF]. Both absolute and relative material standards matter, with the later having a greater importance [START_REF] Wilkinson | Socioeconomic determinants of health. Health inequalities: relative or absolute material standards?[END_REF][START_REF] Wagstaff | Poverty and health sector inequalities[END_REF].

Inequalities in income are paralleled by inequalities in health [START_REF] Van Doorslaer | Income-related inequalities in health: some international comparisons[END_REF]. Richer countries generally have better indicators than poorer countries, however, there is great heterogeneity [START_REF] Wilkinson | Social determinants of health: The solid facts[END_REF]. French Guiana has the highest GDP per capita on the South American continent, attracting numerous immigrants in search of a better life. Thus, a third of the population are immigrants, a great proportion of whom have no residence permit [START_REF]Projections de Population[END_REF]. The health system of French Guiana is French with modern facilities and the possibility of obtaining universal health insurance, including for illegal foreign citizens residing for more than 3 months on the territory. As for all French territories, mitigating health inequalities remains a major public health goal. There are great socio-sanitary differences between the various French regions, notably for French Guiana [START_REF] Thomas | Inégalités sociosanitaires dans les départements d'outre-mer: Analyses infra-régionales et comparaisons avec le niveau national[END_REF]. Previous studies in French Guiana have shown that undocumented immigrants reported a poorer health status [START_REF] Jolivet | Migrant health in French Guiana: are undocumented immigrants more vulnerable?[END_REF]. Studies have also shown that immigrants were tested later for HIV [START_REF] Nacher | Risk factors for late HIV diagnosis in French Guiana[END_REF], were more likely to interrupt follow up [START_REF] Nacher | Risk factors for follow-up interruption of HIV patients in French Guiana[END_REF], and, for cancer, had more advanced stages upon diagnosis [START_REF] Roue | Cervical cancer incidence in French Guiana: South American[END_REF]. The complexities of a poor immigrants' life, of the health care system and of the administrative requirements to access to rights, the lack of transport, and the refusal by some private practitioners to see patients with universal health insurance are all potential determinants of a sick patient to renounce toseea doctor [START_REF] Carde | Access to health care and racial discrimination[END_REF].

Objectives

We thus conducted a study in patients consulting the Red Cross screening truck in impoverished neighborhoods in Cayenne to determine how frequently persons had renounced healthcare and the variables that were most frequently associated with this.

Methods

Ethical aspects

The study protocol was approved by the Comitéd'Evaluation Ethique de l'Inserm (CEEI/IRB) (n°13-107) and the Commission Nationale Informatique et Liberté (CNIL) (authorisation n°1680353v0).

Study design

The study was cross-sectional. It was a descriptive and comparative knowledge, attitudes, practices, and beliefs study.

Setting

The study was conducted from from July 1 st , 2013 through June 30 th , 2014in poor neighborhoods of the Cayenne area. Neighborhoods were defined as « poor » if one of the following criteria were verified: neighborhood figuring in the City Hall list of « Contrats Urbains de Cohésion Sociale » (CUCS, urban contracts of social cohesion); spontaneous habitat zone (housing without building permits); neighborhoods without running water and/or electricity and/or municipal handling of waste and garbage.

Participants

The study population was poor populations.The surveyed population was adults, seeking free screening services at the Red Cross mobile screening unit (truck offering testing for HIV, diabetes, high blood pressure).

The surveyed areas are sensibly different from the rest of Cayenne and selected for this. They are mostly, but not exclusively inhabited, by immigrants. Given the small size of Cayenne, the surveyed areas are not very far from the health structures. However they are devoid of health structures, social facilities, and public transportation is often not available. The estimated population living in the surveyed areas was 46 000 relative to the 101 412 persons living in the greater Cayenne area.

Outcome criteria

The renouncement of care which was defined by answering yes to the question "Have you been ill or had pains and renounced care?". The answer to this question had no time framebut referred to French Guiana and thus represents a prevalence during the stay in French Guiana.

Inclusion criteria

Adults, over 18 years of age.

Non inclusion criteria

Person belonging to the study population refusing to participate, having previously participated, <18 years of age.

Sampling method

Samples were stratified by inclusion centers, with an equivalent proportion of persons relative to the estimated source population seen at each site.

The Red Cross mobile unit exists since 2012. It allows going towards populations in the poorest neighborhoods. Nurses are accompanied by health mediators from the local communities (DAAC, development, accompaniment, animation, cooperation). Twice a month a doctor is there to check vaccinations.

Data collection

The trained multilingual surveyors from the targeted communities asked all persons consulting the mobile unit. Written and oral information was given to all eligible persons. Written informed consent was requested at the beginning of the questionnaire. Persons accepting to participate to the study were interviewed face to face in their native language using a structured questionnaire that had been translated in local languages (Haitian Creole, Spanish, Portuguese, English, SrananTongo). The study was proposed to the first person arriving on site and then the second questionnaire was proposed when the surveyor had finished with the first person, and so on until the work day was finished.

Questionnaires were anonymous and numbered for each study site and according to their rank in passage that day. The questionnaires had 93 questions divided in5 parts:sociodemographic profile, health profile, health practices,attitudes, practices and knowledge on health mattersand health insurance. The EPICES score was calculated as described elsewhere [START_REF] Labbe | A new reliable index to measure individual deprivation: the EPICES score[END_REF].

The interview lasted up to 60 minutes. The initial questionnaire was devised by the Clinical Investigation Center and was reviewed and modified by the partners (Health insurance, municipalities NGOs Red Cross, Médecins du Monde, DAAC). It was pretested on 10 persons of the target population to optimize its comprehension and the perception. Patients were compensated for the time they gave the interviewer and were given a 5 euro voucher plus prevention material on diabetes, high blood pressure, HIV, and information about access to health insurance. Questionnaires were reviewed by the study coordinator, who then validated them if they were coherent.

Statistical methods

Data analysis was performed using R. Univariate analysis was performed then frequency distributions for each covariate were compared between those who had renounced health care and those that had not. Thematic logistic regression models considering significant variables (p<0.05) were computed for different set of questions: sociodemographic profile, health profile, medical practices, attitudes, attitudes, practices and knowledge on health matters and health insurance. Finally, the variables selected from these thematic multivariate models were added to a global logistic regression model. The goodness of fit test was used. The most parsimonious models were selected using Akaike's information criterion.

In addition CART analyses were performed using R [START_REF] Faraway | Extending the linear model with R: generalized linear, mixed effects and nonparametric regression models[END_REF][START_REF] De'ath | Classification and regression trees: a powerful yet simple technique for ecological data analysis[END_REF]. Classification And RegressionTree analysis is a non parametric multidimensional exploratory method. It is a segmentation method based on the construction of a decision tree. It aims to partition the sample using explanatory variables so that the obtained segments are as homogenous as possible regarding the dependent variable. It proceeds by successive iterations, the sample first being partitioned in homogenous sub-samples, each of which is then partitioned in homogenous sub samples, iteratively.In some cases, the trees obtained being too intricate, pruning is used to obtain a more parsimonious model.

Results

Between July 2013 and June 2014, a total of 546 questionnaires were filled.The refusal rate was zero. Table 1 provides a description of the study population stratified into 2 groups according healthcare renouncement.This table considers significant variables in the different sets of questions and other variables as age, gender, social vulnerability, income and perception ofhow easy it is to see a doctor. Table 2 presents the variables associated with healthcare renouncement and the p values.There were 51.8% of women. The average age was 37.0 (sd=12.9) in women and 35.6 (sd=13.7) in men.According to the EPICES score using the 30 threshold, 477 (87.4%) were socially precarious.Most of these persons came from foreign countries, 47% were foreign having some form of health insurance and additional 27% were foreign without insurance but were eligible to it as shown in Figure 1. Overall, 5% were foreigners not eligible for health insurance.

A significant proportion of persons had very low incomes for the standard of life of French Guiana (medical consultation costs: 23 Euro; net minimum wage: 1 137 Euros): 20% of patients earned less than 300 Euros per month, 35.2% less than 500 Euros, and 55% less than 800 Euros per month.

Overall, 113 persons (20.7%) had previously renounced health care whereas 433 had never done so (79.3%).Renouncement of care was more frequent in the precarious group (p=0.005).

Four hundred and three persons (73.8%) thought it was easy to see a doctor in Cayenne.

Among those that had never renounced care 75.8% though it was easy to see a doctor. Among those that had previously renounced for care still 66.4% thought it was easy to see a doctor.

For those having arrived in French Guiana for less than a year, 20 (18%) had renouncedwhereas 78 (69%) of those having arrived before 2013 had renounced,p=0.02 (see Table 2). Table3summarizes the differences between the two groups for different variables and shows adjusted odds ratios for thematic logistic regression models.For the sociodemographic variables, financial difficulties and being shy to ask certain questions or to go through medical or administrative appointments were significantly associated with the outcome. For the health profile, only the fact of having received dental care in the past 3 years was significant. For the medical practice and attitudes variables, having consulted the emergency ward in the past year, having a family physician and having been refused care by a doctor were significant predictors. For the variables pertaining to health insurance, having health insurance and understanding mail from health insurance were predictors.

Table 4shows the global model using the significant variables from each thematic logistic regression model. Among all the variables cited below, only being embarrassed to ask certain questions or to go through medical or administrative appointments, having a family physician and having been refused care by a doctorwere predictive of renouncement of care.

Figure 2shows that CART analysis identified feeling shy to ask certain questions or to go through medical or administrative appointments.CART analysis showed the2 paths associated withrenouncement of health care. The most salient one was feeling shy to ask certain questions or to go through medical or administrative appointments. The number shows the probability of healthcare renouncement and the one in brackets the proportion of observations in the leaf.

Discussion

Over 70% of the surveyed population, a vulnerable subset of the general population in Cayenne, declared it was easy to see a doctor in Cayenne. This was somewhat at odds with perceptions based on anecdotal reports. The context of health care setting at the time of the survey may have inflated the perception of the ease of contacting a doctor. In addition, the population showing up at the red cross bus may have represented a biased selection of persons least likely to renounce care thus leading to an underestimation of the main outcome. However, one in five persons had previously renounced care. In comparison, in France 15.4% of persons declared having renounced to care in 2008, and among those earning less than 870 Euros per month this proportion reached 24% [START_REF] Després | Le renoncement aux soins pour raisons financières:une approche économétrique[END_REF]. The association between low socio economic status and access to care is often observed but the proximal forces operating are not always explicit. The present study may offer some insights on perceptions or behaviors that may be of operational interest.A number of variables were independent predictors of renouncing care. In addition,the use of CART analysis was, to our knowledge,an original way to partition the population in homogenous groups regarding the main outcome. The most salient predictor was declaring feeling shy to ask certain questions or to go through medical or administrative appointments. Having previously been refused medical care was associated with increased likelihood of having renounced care. Having a family physician was associated with a lower probability of having renounced care. The above findings suggest that factors such as self esteem or knowledge of one's right to healthcare are possible determinants to target in order to access to care. Some persons being denied care may have generalized this experience to the health system as a whole either as a reluctance to be rejected again or as a belief that they were not entitled for health care [START_REF] Eshiett | Migrants and health: a cultural dilemma[END_REF].

Most of these persons were immigrants from countries where the authority and status of health professionals or administrative officers may have required the patients to be more submissive to authority. It may thus have taken some adjustment to be aware of one's rights and to learn how to navigate the health system [START_REF] Paasche-Orlow | The causal pathways linking health literacy to health outcomes[END_REF], as suggested by the fact that the most recent immigrants tended to renounce more frequently.A recent public health law suppressed the mandatory fee that patients without full coverage had to disburse. The future impact of this measure on renouncement of care is debatable but the present results suggest it may improve access.

Although, prior to the study variables such as fluency in French, transport means, employment, health insurance, residence permits were suspected determinants reported in the literature [START_REF] Bowen | Language Barriers in Access to Health Care for Health Canada[END_REF][START_REF] Legros | Health and access to care : for a more equal and easier access to health and care[END_REF], multivariate analyses did not retain them as significantly associated with the outcome. Perhaps in this urban area, there are a number of geographically accessible alternative offers of health care that buffer some of the difficulties of vulnerable patients.

However, beyond a simple contact with a physician, follow up may have been a more difficult problem than acute care for vulnerable patients, but we did not investigate this question. Given the broad cultural diversity in French Guiana, we predicted to find that some cultural differences would arise. Although Haitian nationals seemed to renounce more often, after multivariate analyses, nationality, a proxy to culture, was not retained, suggesting that socioeconomic determinants were the confounding variable behind specific "cultural" determinants.

Caution should be exercised when making inference from the results to all poor populations of Cayenne because thosethat never showed up at the Red Cross truck despite the health mediators' efforts may have represented a different subgroup less concerned by its health or unable to be present when the surveyors were on site. In addition, the surveyed areas were particularly known as poverty pockets but a number of other vulnerable persons live in other parts of town where the mix of determinants of renouncement may be different. However,and this was a deliberate choice, the surveyed population was globally very vulnerable and thus its attitudes, behaviors and practices are precious knowledge for health care actors in order to improve access to care in this population.

These results concern vulnerable populations living in a country with a universal health care system that is often presented as a model, but still struggles to achieve one of its priorities: to ensure that everyone has equal access to care. Therefore the present results may be very different from, and not applicable to, situations where persons do not have these access to health rights. As observed elsewhere, financial difficulties were linked to poverty [START_REF] Marmot | Social determinants of health inequalities[END_REF].

However, here it seemed "shyness" to interact with the system and prior refusal of care stressed that, beyond the perception of one's right to health care and perhaps one's status in society may be even more important psychosocial determinants [START_REF] Wilkinson | Socioeconomic determinants of health. Health inequalities: relative or absolute material standards?[END_REF] that presumably apply beyond the particular context of French Guiana.

Conclusion

Although these vulnerable populations reported that access to a physician was easy, 21% of the population declared having previously renounced health care. Shyness to ask andprior refusal of care were negatively associated with access to care whereas having a regular physician seemed like facilitating access to care after adjustment for confounding. Ensuring that all public servants remain cordial to make the health system more welcoming and familiar to vulnerable groups thus seems to be important to improve access to care in Cayenne. Health mediation, may also be an important response to reduce renouncement of health care [START_REF] Paskett | Patient navigation: an update on the state of the science[END_REF].

Figure

Figure 1 -

 1 Figure 1 -Descriptive analysis

Acknowledgment

The Project was funded by the Health Regional Agency (ARS).The authors would like to thank the reviewers for their valuable comments and suggestions to improve the quality of the paper.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

LV performed data analysis and interpretation, and prepared the manuscript.BGwas responsible for data collection.BG, MCP, AVM, TP, CB, CG and AA participated in the research design. CG and MD were involved in the final manuscript draft.MN initiated the study, provided guidance on data analyses,and was involved in the interpretation of data, manuscript writing and manuscript revision. All authors read and approved the final manuscript.

Description of the study population according to nationalities, access,eligibility and no 348 eligibilityto healthcare system -Results expressed as percentage -Others : Guinea Bissau, 349

Dominica and Peru 350

Additional file File 1 -STROBE Statement

Checklist of items that should be included in reports of cross-sectional studies.


Tristan Roué
email: tristan.roue@gmail.com

Av Du

Keywords: Breast cancer, Survival, Immigrant, South America

This study aimed to compare the relative survival of patients with invasive breast cancer between women from French Guiana (a French territory in South America) and metropolitan France. No study hadever compared survival of breast cancer on the basis of immigrant status in France. Our study underlined that access to care for migrants is challenging whichwgenerates health inequalities.

Background

The prognosis of breast cancer in French Guiana is worse than in France with 23 deaths per 100 incident cases against 17 per 100 in metropolitan France. This study aimed to compare relative survival of patients with invasive breast cancer (IBC) between women from French Guiana and metropolitan France and to determine risk factors influencing breast cancer survival in French Guiana.

Materials and methods

Data were collected from the Cancer registry of French Guiana. We comparedthe relative survival of women with IBC between French Guiana and metropolitan France. We used Cox's proportional hazard regression to evaluate the effect of prognostic factors on cancer-specific mortality in French Guiana.

Results

We included all 269 cases of IBC in women diagnosed in French Guiana between 2003 and 2009. The overall 5year relative survival rate of patients with IBC was 79% in French Guiana and 86% in metropolitan France. The place of birth (foreign country versus French territory), the tumor stage at the time of diagnosis, the mode of diagnosis (symptoms versus screening), the presence of hormone receptors in the tumor and the histologic type were the variables associated with survival differences. None of the other study variables were significantly associated with prognosis.

Conclusion

Access to care for migrants is challenging,which leads to health inequalities. Early detection through prevention programs is crucial to increaseIBC survival notably for foreign-born patients.

INTRODUCTION

Breast cancer is the most common type of cancer and the most common cause of cancer-related death in women worldwide. [START_REF] Parkin | Global cancer statistics[END_REF] Although breast cancer incidence is much higher in most developed countries than in many developing countries, mortality rates are proportionally higher in less developed regions of the world, notablyin South America. [START_REF] Schwartsmann | Breast cancer in South America: challenges to improve early detection and medical management of a public health problem[END_REF][START_REF]GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012[END_REF] French Guiana is a French territory located on the Guiana shield in South America.Despite a high GDP per capita close to that of France, the incidence of breast cancer in French Guiana is on par with the overall incidence in South America and markedly lower than in France. [START_REF] Roue | The epidemiology of breast cancer in French Guiana 2003-2006[END_REF] To reduce the burden of breast cancer and understand differences in cancer prognosis between different areas it is important to identify predictive factors for survival. Stage of disease at diagnosis is the most important prognostic factorforbreast cancer. [START_REF] Ruder | Estrogen and progesterone receptors in breast cancer patients. Epidemiologic characteristics and survival differences[END_REF][START_REF] Holleczek | Breast cancer survival in Germany: a population-based high resolution study from Saarland[END_REF] Overall, early detection, screening and therapeutic improvements havesignificantly reduced breast cancer mortality. [START_REF] Nystrom | Long-term effects of mammography screening: updated overview of the Swedish randomised trials[END_REF][START_REF] De Koning | Mammographic screening: evidence from randomised controlled trials[END_REF][START_REF] Autier | Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database[END_REF] Despite this evidence,studies in New Zealand and USAhave shownthat immigrant women were less likely than nonimmigrant women to report having had a mammogram in the past 2 years or to be diagnosed at an early stage of disease. [START_REF] Ryu | What factors explain disparities in mammography rates among Asian-American immigrant women? A population-based study in California. Women's health issues : official publication of the Jacobs Institute of Women[END_REF][START_REF] Consedine | The demographic, system, and psychosocial origins of mammographic screening disparities: prediction of initiation versus maintenance screening among immigrant and non-immigrant women[END_REF] In France, C. Rondet and colleagues, [START_REF] Rondet | Are immigrants and nationals born to immigrants at higher risk for delayed or no lifetime breast and cervical cancer screening? The results from a population-based survey in Paris metropolitan area in 2010[END_REF] showed that being a foreigner or of immigrant origin was a risk factor for being screened for cancer too late or never and that this gradient persisted after adjusting for socioeconomic characteristics. French Guiana attracts numerous immigrants from South America and the Caribbean who migrate in search of better socioeconomic opportunities. Thus, 30% of the population consists of immigrantsversus8% in metropolitan France. 13 Immigrants have access to health insurance, butin practice this may be somewhat complicated. Particularly, cases requiring specialized care are evacuated towards metropolitan France or Martinique for treatment.Immigrants mayexperience a number of informal barriers to hospital care related to language, unfamiliarity, and cultural factors in a socialised health-care system. [START_REF] Norredam | Cancer mortality does not differ between migrants and Danish-born patients[END_REF] It therefore seems important to study survival differences between immigrants and French-born patients.Indeed, in France no study has ever compared breast cancer survival between immigrant and French women. In the present study, we focussed on female breast cancer survival in French Guiana and aimed to determine whether different levels of breast cancer risk between metropolitan France and French Guiana, [START_REF] Roue | The epidemiology of breast cancer in French Guiana 2003-2006[END_REF] also implieddifferences in survival. Wedetermined risk factors influencing breast cancer survival in French Guiana taking the immigrant status into account.

MATERIALS AND METHODS

Ethical statement

This study used data from the Cancer Registry of French Guiana housed by the Regional Union of health care professionals (URPS). It has been officially certified by the Comité National des Registres (CNR) an emanation of the INSERM (National Institute for Medical Research) and the INVS (National Institute for Epidemiologic Surveillance and Alert, French CDC) in 2010 and 2012. Every three years the registry undergoes a quality audit by the Comité d'Evaluation des Registres. The registry has a scientific board and an ethical review board. The database has national regulatory approval by the Comission Nationale Informatique et Libertés (CNIL). All confidential information is encoded, protected by security systems and destroyed when no longer needed. No published results can allow the identification of patients. Participants gave written informed consent to the Cancer registry for the collection and use of their medical data.

Data source

Data coding strictly follows the procedures of the FRANCIM (Réseau Français des Registres de Cancer) & ENCR (European Network of Cancer Registries) network.

Study population and register linkages

This retrospective study was based on breast cancer cases diagnosed in persons living in French Guiana at the time of diagnosis from January 1 st , 2003 to December 31 st , 2009. The capture-recapture method was used to estimate the completeness of cancer registration. [START_REF] Der Heiden | Sata module to perform capture-recapture analysis for three sources with Goodnessof-fit based confidence intervals[END_REF] We estimated that 6 cases of breast cancer were missed between 2003 and 2009: completeness was estimated to be 96%.

Prognostic factors

The following socio-demographic factors were studied: age (<35 years [reference group], 35-49 years, 50-64 years, 65-74 years, ≥75 years); place of birth divided in two categories ("France" identifying patients born within all French regions [reference group] and "foreign country" defining patients born outside the Frenchterritory). In addition, information on thetumor were collected by the registry: tumor stage ("localized" T1-3N0M0 [reference group], "regional spread" T1-3N+M0, i.e. axillary lymph nodes that were positive for cancer on histological examination, "local spread" T4NxM0, "distant" M1); we could not distinguish mass screening from selective/opportunistic screening, thus themode of diagnosis was separated in two categories only (screening [reference group], diagnosis after symptoms); scarff-Bloom-Richardson (SBR) classification hadthree categories ("low" grade 1 [reference group], "intermediate" grade 2, "high" grade 3); histological type hadtwo categories (papillary-medullary-mucinous and tubular carcinoma [reference group], infiltrating duct carcinoma); hormone receptor status hadtwo categories because we could not distinguish both estrogen and progesterone in the data base ("positive" meant either estrogen or progesterone receptors were positive [reference group], "negative" meant both estrogen and progesterone receptors were negative); study period (2003-2005 [reference group], 2006-2009). HER2/neu expression was not available. The delays between the date of diagnosis and the date of first treatment were unknown for 36% of women, thusthis variable wasnot included in the analyses.

Follow-up

The breast cancer-specificsurvival was estimated byfollowing-up all cases untilDecember 31 st , 2013. The vital status of patients was checked regularly. The follow-up for the vital status can be done actively, through the RNIPP (Repertoire National d'Identification des Personnes Physiques) an emanation of the Insee (Institut national de la statistique et des études économiques), or passively, by matching death certificates at city hall.

Statistical analysis

For cancer cases net survival was the probability of survival in the hypothetical scenario where the studied cancer wasthe only possible cause of death. To compare breast cancer survival between French Guiana and metropolitan France, net survival durations were obtained using the new Pohar-Perme estimator of the net cumulative rate. [START_REF] Jooste | Unbiased estimates of long-term net survival of solid cancers in France[END_REF] Age-standardized net survival estimates were calculated using international cancer standard weights. [START_REF] Jooste | Unbiased estimates of long-term net survival of solid cancers in France[END_REF][START_REF] Corazziari | Standard cancer patient population for age standardising survival ratios[END_REF] We compared two estimates at a given time with a classical Z-test. Cause-specific survival isanother estimator of net survival. Cox proportional hazard models were used to estimate crude and adjusted mortality hazard ratios to compare breast cancer-specific survival according to prognostic factors. The underlying time scale was the time since diagnosis. The failure event was death due to breast cancer. Sixpatients without follow-up were excluded. No patients were notified with only a death certificate. Associated variables with p-values<0.05 in multivariate analyseswere considered statistically significant. Nonlinearity of continuous variables (age and study period) were assessed using a cubic spline term. [START_REF] Hess | Assessing time-by-covariate interactions in proportional hazards regression models using cubic spline functions[END_REF] The proportional hazards assumption for all the covariates was tested and validated by Schoenfeld residuals. Interactions between variables were also examined and considered if p<0.1 in multivariate analyses. To avoid loss of information and potentially biased estimates resulting from missing data in Cox analyses, we imputed missing values usingMultivariate Imputation by Chained Equation under missing-at-random (MAR) assumptions. [START_REF] Royston | Multiple imputation of missing values: further update of ice, with an emphasis on interval censoring[END_REF] All associated variables with p<0.2 in univariate analyses were also included in the series of chained equations. [START_REF] White | Multiple imputation using chained equations: Issues and guidance for practice[END_REF] All data analyses were performed using Stata/MP version 11.1 for Windows (StataCorp, USA).

RESULTS

Between 2003 and 2009, there were 275 new cases of breast cancer. Sixpatients without follow-up were excluded thus 269 patients were included in this study.The median age at diagnosis was 52 years (interquartile range: 44 -60 years), the youngest patient was 27 years old and the oldest was 94 years old. Table 1 presents patient and tumor characteristics. Overall, information on socio-demographic and tumor characteristics were available for 200 (74%) of the patients. Information on age, mode of diagnosis, tumor stage at diagnosis, SBR classification, histological type and hormone receptor status were available for 100%, 89.2%, 88.9%, 82.9%, 92.2% and 83.3% of the patients, respectively. The proportion of patient born outside France was 34.6%. These immigrants originated from Haiti (39%), Brazil (17%), Suriname (13%), Saint Lucia (7%), Guyana (7%), Anguilla (4%), Dominican Republic (3%), China (2%) and others countries (8%). Table 2 shows age-standardized 1, 3, 5-year net survival of invasive breast cancer patients in French Guiana and in metropolitan France. The age-standardized 1-year net survival of women with invasive breast cancer was not significantly different between French Guiana and metropolitan France. The 3-year net survival was 85% in French Guiana, compared to 91% for metropolitan France. This difference was most pronounced five years after the breast cancer diagnosis.The 5-year net survival was 79% in French Guiana versus86% in metropolitan France (p<0.05).Nevertheless, In French Guiana, the overall 5-year net survival rate of foreign-born patients and patients born on the French territory were respectively 62% and 87%. In French Guiana, women born on aFrench territory (including French Guiana) had the same survival rate as in metropolitan France (not shown in the table 2). Table 3 shows the hazard ratio (HR) of death by age, place of birth, mode of diagnosis, study period and tumor characteristics.A total of 65 women (24%) died before the 31 st December 2013 and 60 deaths were attributed to breast cancer. In univariate analyses (complete-cases only)all variables except study period were associated with mortality (p<0.25). In multivariate analyses (after imputation), place of birth, mode of diagnosis, tumor stage at diagnosis, histological type and hormone receptor status remained independently associated with breast cancerspecific survival (p<0.05). After adjusting for these factors, age and SBR classification were no longer associated with specific survival.

DISCUSSION AND CONCLUSIONS

This high resolution study presents survival data of breast cancer patients from French Guiana for the first time. The present study showed that the overall relative survival rate among women with invasive breast cancer in French Guiana was lower than among women in metropolitan France. Regression analysis revealed mode of diagnosis, tumor stage at diagnosis, histological type and hormone receptor status as independent prognostic factors associated with breast cancer-specific survival in French Guiana. The novel result of the present study was that there was a significant difference in breast cancer survival between women in French Guiana according to their immigrant status. Histological type and hormone receptor status are commonly prognostic factors of breast cancer with regard to disease recurrence and survival. [START_REF] Ruder | Estrogen and progesterone receptors in breast cancer patients. Epidemiologic characteristics and survival differences[END_REF][START_REF] Li | Risk of mortality by histologic type of breast cancer in the United States[END_REF] The main limitation is that we only had the combined hormone effects on survival. Nevertheless our study showed as in previous studies, [START_REF] Dunnwald | Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients[END_REF] that hormone receptor status was an independent prognostic factor of breast cancer survival. Clinical trials have shown that a large proportion of the survival advantage experienced by patients with hormone receptor-positive tumors compared to patients with hormone receptor-negative tumors may be due to the use of hormonal therapy. [START_REF] Dunnwald | Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients[END_REF][START_REF] Smith | Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others[END_REF] The mode of diagnosis was consistently associated with mortality among women diagnosed on the basis of clinical symptoms. Since 2004, mass organized screening was initiated throughout the French territory. All women aged 50-74 years are concerned by this every 2 years. As in other studies,the most important feature in the multivariate model was stage at diagnosis. [START_REF] Sant | Stage at diagnosis is a key explanation of differences in breast cancer survival across Europe[END_REF][START_REF] Sant | Differences in stage and therapy for breast cancer across Europe[END_REF] Unsurprisingly, early stage invasive breast cancer hada better prognosis than later stage cancer. Based on ethical and ideological considerations, the mortality of immigrants in France has been scarcely studied. [START_REF] Boulogne | Mortality differences between the foreign-born and locally-born population in France (2004-2007)[END_REF] Our study revealeda 1.80-fold difference in HR between women born in France and foreign born women after adjusting for stage at diagnosis and other prognostic factors.Moreover the difference in net survival between French Guiana and metropolitan France could in fact have reflectedthelower net survival rate among foreign-born patients in French Guiana than among patients born on the French territory. Indeed, in French Guiana, women born on the French territory had the same survival rate as in metropolitan France. Previous studies showed that immigrants who experience a language barrier are generally more stressed, which can lead to poorer health overall. [START_REF] Ding | Stress-associated poor health among adult immigrants with a language barrier in the United States. Journal of immigrant and minority health / Center for[END_REF][START_REF] Chen | Chinese female immigrants english-speaking ability and breast and cervical cancer early detection practices in the New York metropolitan area[END_REF] There is individual variation in psychosocial environments and McClintock et al., [START_REF] Mcclintock | Mammary cancer and social interactions: identifying multiple environments that regulate gene expression throughout the life span. The journals of gerontology[END_REF] showed that this individual variation could contribute to methylation of cancer genes that are part of the ontogeny of malignant disease throughthe failure of tissue-specific programmed cell death.Moreover,Women of African-ancestry tend to be diagnosedwith more aggressive types of breast cancer, such as ER-(estrogen receptor negative) and ER-/PR-/HER2-(estrogen receptor negative, progesterone receptor negative, HER2 expression negative) breast cancer than populations of European-ancestry. [START_REF] Long | Evaluating genome-wide association study-identified breast cancer risk variants in African-American women[END_REF] Genome-wide association studies have also identified a few differences in breast cancer risk variants between populations of European and African ancestry. [START_REF] Feng | A comprehensive examination of breast cancer risk loci in African American women[END_REF][START_REF] Olopade | Breast cancer genetics in African Americans[END_REF] These features should be considered particularly in French Guiana where almost one third of people were born outside France and hadan African-ancestry. One limitation of this paper is that we did not adjust the analyses based on HER2/neu expression becausesuch information was not available for most of the patients from the Registry database. This couldbe the focus of a future article becauseit deserves a thorough evaluation by itself.Another potential study limitation was that hormone receptor status, tumor histology and tumor grade were not assessed centrally becausethe data recorded by the cancer registry of French Guiana were derived from the review of clinical pathology reports from several hospitals. However, the proportions of the different hormone receptor status observed in our study were consistent with those reported in other studies. [START_REF] Bhikoo | Systematic review of breast cancer biology in developing countries (part 1): Africa, the middle East, eastern europe, Mexico, the Caribbean and South america[END_REF] Many reports suggest less surgery, radiation therapy, and hormone treatment and sometimes inappropriate treatments among African American patients when compared with Caucasian patients. [START_REF] Li | Differences in breast cancer stage, treatment, and survival by race and ethnicity[END_REF] However, since delay of first treatment, type of treatment was unknown for too many women in the present study, this represents another limitation of the results. This could have resulted in some confounders not being accounted for in the model. Despite somelimitations, the present study brings information on survival for clinically different subgroups of cancer patients. Thisimportant information on cancer survivalisof practical interest for health care planners and physicians. Our study underlines that access to care for migrants is challenging and leads tohealth inequalities. This observation comes at a moment when the French Ministry of Health has just released a Health law that places great emphasis on the reduction of health inequalities.Early detection through optimized prevention programs is crucial for increasing breast cancer survival, notably for foreign-born patients who represent a significant proportion of the population in French Guiana. The present results should thus stimulate further research to disentangle the main actionable determinants behind these survival differences.

CLINICAL PRACTICE POINTS

-Some studies showed that being of immigrant origin was a risk factor for being screened for cancer too late or never.

-However, based on ethical and ideological considerations, the mortality of immigrants in France has been scarcely studied.

-Our study showed a statistically significant difference in breast cancer survival between women in French Guiana according to their immigrant status.

-The data suggest that physicians and health care plannersshould consider targeting particular vulnerable subgroups of women for appropriate treatment, medical follow-up, and generally for culturally appropriate screening campaigns.

ACKNOWLEDGEMENTS

The authors thank Professor J.P. Droz for a critical reading of themanuscript.We certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.The present study was funded by the Health Regional Agency of French Guiana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: All authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.