Flore Duranton

Anneke Kramer

Ilan Szwarc

Brian Bieber

Nathalie Gayrard

Bernard Jover

Fernando Vetromile

Ziad A Massy

Christian Combe

Francesca Tentori

Kitty J Jager

Marie-Françoise Servel

Dr Àngel Argilés
email: argiles@rd-n.org

GEOGRAPHICAL VARIATIONS IN BLOOD PRESSURE LEVEL AND SEASONALITY IN HEMODIALYSIS PATIENTS

Keywords: renal dialysis, blood pressure, seasons, weather, geography, longitudinal studies

Seasons and climate influence the regulation of blood pressure (BP) in the general population and in hemodialysis patients. It is unknown if this phenomenon varies across the world. Our objective was to estimate BP seasonality in hemodialysis patients from different geographical locations. Patients from 7 European countries (Spain, Italy, France, Belgium, Germany, United Kingdom, Sweden) participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) on years 2007-2011 were studied. Factors influencing pre-and post-dialysis systolic (SBP) and diastolic BP (DBP) levels were analyzed by mixed models. There were 9655 patients (median age 68; 59% male) from 263 facilities, seen every four months during a median duration of 1.3 year. Pre-and post-dialysis SBP increased by a mean estimate and 95% confidence interval of 5.1 [3.7 ; 6.4] and 4.4 [2.9 ; 5.9] mmHg for each 10°-increase in latitude (1111km to the North). In the longitudinal analysis, pre-dialysis SBP was lower in summer and higher in winter (difference: 1.7 [1.3 ; 2.2] mmHg), with greater differences in southern locations (P interaction =0.04). Pre-dialysis SBP was inversely associated with outdoor temperature (-0.8 [-1.0 ; -0.5] mmHg/7.2°C), with steeper slopes in southern locations (P interaction =0.005). Results were similar for pre-dialysis DBP. In conclusion, there is a geographical and seasonal gradient of blood pressure in European hemodialysis patients.

There is a need to consider these effects when evaluating and treating blood pressure in this population and potentially in others.

INTRODUCTION

Cardiovascular diseases are the main cause of mortality worldwide and their impact is increasing. [START_REF] Lozano | Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study[END_REF] While age-specific cardiovascular mortality rates decreased in the past decades, the number of cases is increasing as a consequence of population growth and aging. [START_REF] Lozano | Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study[END_REF] Hypertension is a major cause of cardiovascular diseases and its treatment remains a challenge for modern medicine. [START_REF] Kotchen | Ushering Hypertension Into a New Era of Precision Medicine[END_REF] Blood pressure (BP) level is conditioned by genetic as well as environmental factors and follows cyclic patterns of various periods corresponding to days (circadian rhythm) and years (seasonal cycle). [START_REF] Parati | Assessment and management of bloodpressure variability[END_REF] These patterns are clinically important as they may interfere with the diagnosis of hypertension and may have utility as indicators of a patient's cardiovascular status. In addition, cyclic patterns are likely to affect the actual cardiovascular risk that patients are exposed to.

Hypertension is very common in hemodialysis (HD) patients, in whom the prevalence often exceeds 90% at the moment of dialysis initiation. [START_REF] Ok | Controversies and problems of volume control and hypertension in haemodialysis[END_REF] In this population, BP level is closely monitored and adjusted mainly through correction of volume overload and use of BPlowering medications. Still, analyzing change in BP over a 4-year period, we observed a clear seasonal pattern with higher BP in winter and lower BP in summer. [START_REF] Argilés | Seasonal changes in blood pressure in patients with endstage renal disease treated with hemodialysis[END_REF] This phenomenon was later confirmed in other studies across the world, but not all. [START_REF] Tozawa | Seasonal blood pressure and body weight variation in patients on chronic hemodialysis[END_REF][START_REF] Spósito | Seasonal variations of blood pressure and overhydration in patients on chronic hemodialysis[END_REF][START_REF] Cheung | Seasonal variations in clinical and laboratory variables among chronic hemodialysis patients[END_REF][START_REF] Usvyat | Seasonal variations in mortality, clinical, and laboratory parameters in hemodialysis patients: a 5-year cohort study[END_REF][START_REF] Guinsburg | Seasonal variations in mortality and clinical indicators in international hemodialysis populations from the MONDO registry[END_REF][START_REF] Fine | Lack of seasonal variation in blood pressure in patients on hemodialysis in a North American center[END_REF] The seasonal change in BP is correlated with several climatic parameters namely external temperature, humidity, rainfall and daylight span, suggesting that BP level and seasonality would vary across locations with different climates. [START_REF] Argilés | Seasonal changes in blood pressure in patients with endstage renal disease treated with hemodialysis[END_REF][START_REF] Spósito | Seasonal variations of blood pressure and overhydration in patients on chronic hemodialysis[END_REF][START_REF] Argilés | Seasonal modifications in blood pressure are mainly related to interdialytic body weight gain in dialysis patients[END_REF] There are supportive results from the general population, in whom geographical gradients in BP and hypertension were observed (higher BP in populations closer to the poles). [START_REF] Elford | Migration and geographic variations in blood pressure in Britain[END_REF][START_REF] Rostand | Ultraviolet Light May Contribute to Geographic and Racial Blood Pressure Differences[END_REF] Across independent samples from the general population across the world, BP seasonality was reported to follow a geographic trend. [START_REF] Barnett | The effect of temperature on systolic blood pressure[END_REF] However, it is not known if such a geographic trend can be observed for within-patient BP seasonal change in HD 5/28 patients. The presence of seasonal variations in this closely monitored population would confirm a strong influence of external factors on BP levels.

The objectives of our study were to assess seasonality (effect of season or climate exposure) and the influence of location (country or latitude) on pre-and post-dialysis BP level in HD patients, as well as their interaction. We analyzed data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) to answer these questions. The DOPPS is a longitudinal observational study designed to describe dialysis practice and patient characteristics and outcome across the world, using nationally representative samples of HD facilities and patients. [START_REF] Young | The Dialysis Outcomes and Practice Patterns Study (DOPPS): An international hemodialysis study[END_REF][START_REF] Pisoni | The Dialysis Outcomes and Practice Patterns Study (DOPPS): design, data elements, and methodology[END_REF] The study of the European subset is the focus of a collaboration entitled EURODOPPS, between the DOPPS and the European Renal Association -European Dialysis and Transplant Association (ERA-EDTA). EURODOPPS consists in longitudinal data from a large population of HD patients living in a wide geographical area with different climates.

METHODS

Study population

The DOPPS is an international prospective study of adult HD patients. This study considered prevalent HD patients (dialysis vintage ≥ 6 months) from 7 European countries (Spain, Italy, France, Belgium, Germany, United Kingdom, Sweden) participating in DOPPS phases 3 and 4 (2005-2011). Study approval was obtained by a central institutional review board and local ethics committees. Informed patient consent was obtained in accordance with local requirements.

An average of 30 patients were randomly enrolled from dialysis facilities treating 20 patients or more, randomly selected by strata of region and facility type (dialysis organization size, rural/urban, free-standing/hospital-based) according to the frequency of facilities within each stratum. An algorithm was developed to randomly select 20 to 40 prevalent patients by facility, depending on facility size. Replenishment strategies were used during follow-up: patients who died or departed the facility were replaced on the facility's anniversary of study start (DOPPS 3) or every four months (DOPPS 4) via random selection among new patients.

Case-mix details and comorbidities were collected at study entry. Every four months, laboratory values, BP, weight, dialysis prescription and BP-lowering medications were extracted from patient records. Pre-and post-dialysis systolic BP (SBP) and diastolic BP (DBP) were measured immediately before and after the dialysis session preferably in sitting position by trained professionals (nurses or nephrologists). BP measurement was performed according to local clinical practice. Intradialytic weight loss was calculated as the difference between pre-and post-dialysis weights, expressed in percent of post-dialysis weight.

Although re-sampling of patients across phases could occur, populations or facilities from different phases were considered independent. We defined baseline as the first observation of initially sampled patients and replenishment patients from each facility and phase.

Geographical and seasonal exposures

Meteorological records over the years 2005-2011 were obtained from the national weather institutes of Belgium, France, and United Kingdom, the Global Historical Climatology Network Monthly and Daily Databases and the European Climate Assessment & Dataset of Monthly Indices. [START_REF]Météo en Belgique : Archive des stations[END_REF][19][START_REF]Climate Historic -Met Office[END_REF][START_REF] Menne | An Overview of the Global Historical Climatology Network-Daily Database[END_REF][START_REF] Menne | Global Historical Climatology Network -Daily[END_REF][START_REF]Global Historical Climatology Network monthly mean temperature data set, version 3[END_REF][START_REF]European Climate Assessment & Dataset[END_REF][START_REF] Lawrimore | An overview of the Global Historical Climatology Network monthly mean temperature data set, version 3[END_REF] Monthly mean of daily minimum, maximum and mean outdoor temperature, monthly cumulative sunshine duration and monthly cumulative rainfall (normalized by square-root transformation) were available for all seven countries. Monthly mean of daily mean humidity was available in Belgium, Germany and Spain. Monthly mean of daily maximum wind speed (normalized by logarithm transformation) was available in France, Germany and Spain. Monthly mean of daily mean atmospheric pressure was available in Belgium, Germany, Spain and Sweden. Dialysis units were matched to the closest meteorological station based on geographical coordinates, and climate records were matched to clinical observations based on the month of the year. Geographical exposure of patients was defined as the country of the dialysis unit or the latitude of the matched meteorological station. Latitudes are set to 0° at the equator and 90° at the poles. We considered an increase in latitude of 10° (i.e. 1111km to the North in the Northern Hemisphere) as the unit of change. Exposure to seasons was based on the month of observation as: Winter (December, January and February), Spring (March, April and May), Summer (June, July and August), and Autumn (September, October, November).

Statistical analysis

Our objective was to test the association of seasonality and location (and their interaction) with pre-and post-dialysis BP level. The dataset consisted of repeated measures of BP nested within patients and dialysis facilities. We modeled BP level using mixed models with seasonality (season or climate), location (country or latitude) and their interaction seasonality×location as fixed effects. The hierarchical structure was accounted for by allowing random intercepts at the patient and facility levels. The DOPPS phase, time from the start of the phase, and the interactions time×phase, time×country, time×country×phase were included to control for differences in baseline BP level and longitudinal trends in BP ("unadjusted model"). The adjusted model additionally included baseline patient characteristics (age, gender, dialysis vintage, body mass index (BMI), smoking, comorbidities) and baseline dialysis prescription (vascular access, blood flow, weekly hours of dialysis, dialysate sodium) as fixed effects. Models of BP were not adjusted for diagnosis of hypertension and use of antihypertensive therapies at baseline. Indeed, we were interested in BP estimates irrespective of the prevalence of hypertension. Concerning antihypertensive therapies, although it would have been interesting to control for the BP-lowering effect, we observed that the number of medication types was in fact associated with higher blood pressure (data not shown), highlighting selection bias rather than treatment effect.

Stratified analyses were performed to test the robustness of pre-dialysis SBP results from the adjusted model in relevant subgroups (gender, age, baseline diagnosis of hypertension, number of BP-lowering therapies, dialysis duration and dialysate sodium concentration, mean SBP during follow-up, and tertiles of intradialytic weight loss and post-dialysis BMI).

Results are expressed as mean ± standard deviation (SD), median and interquartile range (IQR) and estimates and 95% confidence intervals [CI]. An alpha level of 0.05 was used for all statistical tests and all P-values are two-sided. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

The study included 9655 patients and over 50 000 observations (Figure S1). The median follow-up was 1.3 (0.7 ; 2.3) years and there was an average of 5.4 ± 2.5 observations per patient. Patients were dialyzed in 263 facilities corresponding to 121 meteorological stations across 7 European countries (figure 1A). Patients from different countries displayed differences in baseline characteristics, including pre-dialysis and post-dialysis BP (table 1). In mixed models, BP level was significantly associated with countries or latitude, in the way that patients from northern locations had higher pre-and post-dialysis BP (figure 1B). For each 10°-increase in latitude, pre-dialysis SBP and DBP increased by 5.1 [3.7 ; 6.4] Pre-dialysis BP was significantly associated with seasons, while post-dialysis BP was not (figure 2A and2B). On average, pre-dialysis SBP was 1.7 [1.3 ; 2.2] mmHg lower in summer compared to winter and for pre-dialysis DBP, the difference was of 0.8 [0.5 ; 1.0] mmHg. The seasonal difference in pre-dialysis SBP differed among countries (figure 2C, P<0.001). The effect was the highest in Italy and lowest in Belgium, where it was null. The seasonal effect was attenuated in northern locations, as indicated by the significant interaction of season with latitude (table 2, figure 2C). Results were similar after adjusting for patient and dialysis characteristics (table S1).

All climate parameters varied with seasons and countries (table S2). Pre-dialysis SBP was closely and inversely related to outdoor temperature with a lower effect in the north (figure 3, table 2). Accounting for patient and dialysis characteristics, the average difference per 10°C was the greatest in United Kingdom (-2.1 mmHg), but taking into account the temperature range, the greatest difference was observed in Italy (-3.9 mmHg for a change from the 10 th to the 90 th percentile), figure 3. Results were similar with minimum and maximum outdoor temperatures (data not shown). Sunshine duration was similarly associated with lower predialysis SBP, although to a lower extent (table 2). In contrast, we did not observe any association between post-dialysis SBP and seasons, outdoor temperature or sunshine duration (data not shown), suggesting that the dialysis-induced modifications overcome any other influential factors of BP tested in the present study. Pre-dialysis SBP was associated with wind speed and rainfall in a latitude-dependent manner (table 2). Greater rainfall was associated with lower pre-dialysis SBP in northern locations and higher SBP in southern places. While wind speed was not significantly associated with SBP at an average European latitude (50°), greater wind speed was significantly associated with higher pre-dialysis SBP in the south. Pre-dialysis SBP was higher in humid periods; it was not associated with atmospheric pressure (table 2). Results were globally similar with DBP (table S1).

In subgroup analyses, we observed that the rise in pre-dialysis SBP from Summer to Winter was greater in female patients (figure 4). It was also greater in patients without hypertension, with lower mean follow-up SBP or at times where fewer BP-lowering drugs were prescribed (figure 4). The seasonal change was greater when larger intradialytic weight loss (≥ 2.5%) was reported. In contrast, longer dialysis sessions (> 12 h/week) were associated with smaller BP seasonality. The seasonal change was not apparently affected by age, BMI or dialysate sodium concentration.

DISCUSSION

In a large population of European HD patients, we observed international differences in preand post-dialysis BP, even when controlling for differences in patients and dialysis characteristics. Interestingly, we identified for the first time a North-South gradient of BP in HD patients with higher levels near the pole. Mean pre-dialysis SBP was more than 10 mmHg higher in UK compared to Spain. The reasons for this are certainly multi-factorial and probably include differences in environmental, genetic and cultural background, physical activity and medical handling. Similar BP gradients are present in the general population, [START_REF] Rostand | Ultraviolet Light May Contribute to Geographic and Racial Blood Pressure Differences[END_REF][START_REF] Cabrera | Associations of Blood Pressure With Geographical Latitude, Solar Radiation, and Ambient Temperature: Results From the Chilean Health Survey, 2009-2010[END_REF] but it is surprising that it remained in HD patients whose BP is both closely monitored and strongly influenced by dialysis procedures. A clinical impact of geographical disparities of BP on public health is expected. In observational studies of HD patients, the risk of cardiovascular mortality is associated with both lower and higher BP level. [START_REF] Zager | U" curve association of blood pressure and mortality in hemodialysis patients[END_REF][START_REF] Robinson | Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study[END_REF][START_REF] Duranton | Early changes in body weight and blood pressure are associated with mortality in incident dialysis patients[END_REF] Low BP is a sign of cardiac dysfunction associated with short-term mortality. [START_REF] Ok | Controversies and problems of volume control and hypertension in haemodialysis[END_REF] In contrast, elevated BP is directly related to mortality and pharmacological BP reductions improve the cardiovascular risk. [START_REF] Heerspink | Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials[END_REF][START_REF] Charra | Survival as an index of adequacy of dialysis[END_REF] In the past years, in Germany, BP decreased while the use of antihypertensive therapies and polymedication increased. [START_REF] Sarganas | Trends in Antihypertensive Medication Use and Blood Pressure Control Among Adults With Hypertension in Germany[END_REF] This likely explains the relatively low BP observed in German HD patients in our study, despite a high prevalence of hypertension. The North-South gradients of BP and mortality could be blunted by public health initiatives. [START_REF] Van Dijk | Effect of general population mortality on the north-south mortality gradient in patients on replacement therapy in Europe[END_REF][START_REF] Vartiainen | Thirty-five-year trends in cardiovascular risk factors in Finland[END_REF] In accordance with results from single-center studies and an international registry of HD patients, we confirmed at the individual level that pre-dialysis BP was significantly lower in summer compared to winter. [START_REF] Argilés | Seasonal changes in blood pressure in patients with endstage renal disease treated with hemodialysis[END_REF][START_REF] Spósito | Seasonal variations of blood pressure and overhydration in patients on chronic hemodialysis[END_REF][START_REF] Guinsburg | Seasonal variations in mortality and clinical indicators in international hemodialysis populations from the MONDO registry[END_REF][START_REF] Broers | Season affects body composition and estimation of fluid overload in haemodialysis patients: variations in body composition; a survey from the European MONDO database[END_REF] That these results were observed in patients whose BP is frequently monitored for a tight control suggests a considerable effect of seasonality, whether it is direct or mediated by other factors. For the first time, we reported that the magnitude of the seasonal effect varied between countries and with latitude in HD patients. Seasonality was less pronounced at the pole, in agreement with observations from the general population. [START_REF] Barnett | The effect of temperature on systolic blood pressure[END_REF]

12/28

The magnitude of seasonal changes was around 2 mmHg for pre-dialysis SBP and 1 mmHg for DBP. This is in line with methodologically comparable literature, [START_REF] Usvyat | Seasonal variations in mortality, clinical, and laboratory parameters in hemodialysis patients: a 5-year cohort study[END_REF][START_REF] Broers | Season affects body composition and estimation of fluid overload in haemodialysis patients: variations in body composition; a survey from the European MONDO database[END_REF] while other studies reported peak-to-peak amplitudes up to 12 mmHg. [START_REF] Argilés | Seasonal changes in blood pressure in patients with endstage renal disease treated with hemodialysis[END_REF][START_REF] Spósito | Seasonal variations of blood pressure and overhydration in patients on chronic hemodialysis[END_REF] The size of the effect that we reported was probably blunted by the limited time frequency of data collection. In 59 HD patients, we observed that SBP varied by 6 to 9 mmHg between extreme months (i.e., May and November) while the estimate of seasonal change (from summer to winter) was 3 mmHg (unpublished data). Likewise, we can expect in the present study that mean change in SBP between extreme months could be two-or three-fold higher than the reported seasonal change. Nonetheless, there were geographical disparities in seasonality, with average seasonal change in SBP ranging from 3 mmHg in Italy to null in Belgium. This is not the first time that a lack of seasonality is reported. [START_REF] Fine | Lack of seasonal variation in blood pressure in patients on hemodialysis in a North American center[END_REF] This could be explained by a seasonal adjustment of BP medical handling or other factors.

Climate is expected to be responsible for seasonal patterns. With regards to BP, the influence of climate may occur through temperature-induced vasoconstriction and dilation, UV-related vitamin D synthesis, climate-or exercise-related perspiration and changes in dietary and water intake. [START_REF] Rostand | Ultraviolet Light May Contribute to Geographic and Racial Blood Pressure Differences[END_REF] We observed that increasing outdoor temperatures were consistently associated with lower pre-dialysis BP. Both outdoor and indoor temperatures have been shown to influence the level of BP. [START_REF] Barnett | The effect of temperature on systolic blood pressure[END_REF] Low temperatures have a direct effect on vasoconstriction, while high temperatures trigger sweating to evacuate body heat. BP displays an acute response to ambient temperature (within minutes to hours), in addition to a persistent effect maintained over weeks. [START_REF] Modesti | Season, temperature and blood pressure: a complex interaction[END_REF] For the first time, we report in HD patients a greater effect of outdoor temperature on BP in southern locations. Longer sunshine duration was also associated with lower pre-dialysis BP although it is mainly the result of its tight link with outdoor temperature. In a warm and humid climate, a limitation of sweating occurs despite elevated body temperature, due to skin saturation in water. [START_REF] Gisolfi | Work-heat tolerance of distance runners[END_REF] Compared to dry conditions, a reduced sweating rate results in higher BP, more importantly in HD patients with limited urinary water output. This is consistent with the direct association between humidity and BP level that we observed in the present study and in a previous work. [START_REF] Argilés | Seasonal modifications in blood pressure are mainly related to interdialytic body weight gain in dialysis patients[END_REF] Wind may also influence BP by promoting sweating in hot and humid environments. This is in contrast with the observed association between windy episodes and higher BP in southern locations. Maximum wind speed recorded over the month may well not be a relevant measure of wind exposure.

Interestingly, we found that patients with greater intra-dialytic weight loss were more sensitive to seasons, supporting the view that over-hydration allows a greater leeway to change. Nonetheless, hydration-independent mechanisms should not be undermined as suggested by the simultaneous increase in extracellular water content and decrease in BP in summer recently reported. [START_REF] Broers | Season affects body composition and estimation of fluid overload in haemodialysis patients: variations in body composition; a survey from the European MONDO database[END_REF] The understanding and correction of BP seasonality is of utmost clinical value. On the one hand, seasonality may interfere with the assessment of mid-term longitudinal trends in BP, hence improperly reflecting the efficacy of BP-lowering strategies. On the other hand, HD patients suffer from excess mortality in winter, potentially related to the higher BP in winter. [START_REF] Usvyat | Seasonal variations in mortality, clinical, and laboratory parameters in hemodialysis patients: a 5-year cohort study[END_REF][START_REF] Guinsburg | Seasonal variations in mortality and clinical indicators in international hemodialysis populations from the MONDO registry[END_REF][START_REF] Heerspink | Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials[END_REF] In older individuals, a 3 mmHg-decrease in SBP is associated with a 12% reduction in cardiovascular mortality. [START_REF] Lewington | Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies[END_REF] Finally, BP variability itself is associated with cardiovascular morbi-mortality. [START_REF] Parati | Assessment and management of bloodpressure variability[END_REF] Given the high cardiovascular risk of dialyzed patients, a moderate effect on blood pressure can represent a consequent gain in life-years overall.

Seasonal variations in BP could be avoided by adapting dialysis prescription and antihypertensive therapies, preferably in winter in order to minimize BP, provided that it is acceptable for patients.

Our study has some limitations. Data collection was not specifically designed for the purpose, preventing to precisely estimate the magnitude of seasonal change. Still, the study was based 14/28 on large nationally-representative populations of European HD patients which warrants the validity of regional BP estimates and the robustness of geographical trends. Of note, these trends may not be maintained beyond temperate areas. [START_REF] Guinsburg | Seasonal variations in mortality and clinical indicators in international hemodialysis populations from the MONDO registry[END_REF] Secondly, the measurement of BP was not standardized but taken according to usual practice. Although this could affect observed international differences, it is unlikely to influence within-patient and within-center change in BP. Finally, the relevance of our results should not be minimized by the reported effect size, which does not reflect existing inter-individual variability. Some patients may be insensitive to seasons, while others probably face important seasonal changes. For instance, BP seasonality was smaller in patients with elevated BP or receiving many BP-lowering therapies. Finally, although this study was performed in HD patients, there is strong evidence that results in the general population would be comparable. [START_REF] Rostand | Ultraviolet Light May Contribute to Geographic and Racial Blood Pressure Differences[END_REF][START_REF] Barnett | The effect of temperature on systolic blood pressure[END_REF] Footnote: Countries are ordered from South to North. Values are mean ± SD, median (IQR) or percentages. All P-values for differences between countries are < 0.05.

Figure legends

Figure 1 :

 1 Figure 1: Geographical distribution of facilities (A) and facility average in pre-dialysis systolic blood pressure (SBP) by latitude (B). Locations are represented by meteorological stations, one point may represent several facilities. Pre-dialysis SBP was 5.1 [3.7 ; 6.4] mmHg higher per 10°increase in latitude, P < 0.001 (unadjusted mixed model).

Figure 2 :

 2 Figure 2: Mean SBP (solid line) and DBP (dashed line) by season (A and B) and magnitude of seasonal differences in pre-dialysis SBP by country (C). Pre-dialysis SBP and DBP increased from Summer to Winter by 1.7 [1.3 ; 2.2] and 0.8 [0.5 ; 1.0] mmHg. There was no difference in postdialysis BP (SBP: 0.0 [-0.4 ; 0.5]; DBP: 0.1 [-0.2 ; 0.3] mmHg). The seasonal change in SBP decreased by 0.8 [0.1 ; 1.5] mmHg for a 10°-increase in latitude (P = 0.04). Estimates and 95% CI from unadjusted mixed models. Win: winter, Sp: spring, Sum: summer, Aut: Autumn.

Figure 3 :

 3 Figure 3: Mean pre-dialysis SBP level by outdoor temperature by country. Temperature isdisplayed from the 10th to the 90th percentile of each country. The effect of temperature was significant (P < 0.001) and associated with the country (P interaction = 0.004). Estimates from mixed models adjusting for baseline patient and dialysis characteristics.

Figure 4 :

 4 Figure 4: Subgroup analysis of seasonal change in SBP. Estimates and 95% CI for the change in SBP from Summer to Winter at a latitude of 50° obtained from mixed models adjusting for baseline patient and dialysis characteristics with the exception of the grouping variable. BPL drug: blood pressure lowering drug.

  Figure 1

Figure 2 27/ 28

 228 Figure 2

  Figure 3

  and 1.7 [0.8 ; 2.6] mmHg. Adjusting on patients and dialysis characteristics did not affect results. In Germany, SBP was lower than expected based on its northern location (observed, 133 [131 ; 135] mmHg; estimated at a latitude of 51°, 139 [138 ; 140] mmHg).

Table 1 . Patients characteristics at baseline by country

 1

	Chacteristics	Spain	Italy	France	Germany	Belgium	United Kingdom	Sweden
	Number of patients	1571	1384	1401	1556	1246	1144	1353
	Age (year)	64.0 ± 15.6	66.1 ± 13.7	65.4 ± 15.2	64.8 ± 14.3	68.5 ± 13.6	61.5 ± 15.6	64.8 ± 14.2
	Gender (% Male)	59%	59%	58%	59%	57%	58%	65%
	Years on dialysis	2.0 (0.8 ; 5.4) 2.7 (0.8 ; 6.7) 2.3 (0.8 ; 5.9) 2.0 (0.8 ; 5.1) 1.7 (0.8 ; 4.2) 2.3 (0.8 ; 5.7) 1.8 (0.8 ; 4.9)
	BMI (kg/m²)	25.2 ± 4.5	24.8 ± 5.1	25.3 ± 5.6	26.5 ± 5.2	25.7 ± 5.1	26.3 ± 5.4	25.9 ± 6.0
	Laboratory values
	Serum albumin (g/L)	38 ± 5	38 ± 6	37 ± 5	40 ± 6	38 ± 5	38 ± 5	35 ± 5
	Serum sodium (mEq/L)	138 ± 4	138 ± 4	137 ± 3	139 ± 3	138 ± 4	137 ± 3	139 ± 3
	Serum potassium (mEq/L)	5.3 ± 0.8	5.3 ± 0.9	4.9 ± 0.8	5.2 ± 0.8	4.9 ± 0.7	5.0 ± 0.8	4.8 ± 0.7
	Blood pressure (mmHg)
	Pre-dialysis SBP	133 ± 23	134 ± 23	139 ± 25	133 ± 21	139 ± 24	143 ± 25	140 ± 27
	Pre-dialysis DBP	71 ± 13	72 ± 13	72 ± 15	72 ± 12	71 ± 14	74 ± 15	74 ± 14
	Post-dialysis SBP	126 ± 23	129 ± 24	132 ± 25	127 ± 21	132 ± 23	132 ± 25	135 ± 27
	Post-dialysis DBP	69 ± 13	71 ± 13	70 ± 15	70 ± 12	69 ± 13	69 ± 14	72 ± 14
	Number of BPL drug types
	(%)
	0	40%	40%	24%	10%	28%	34%	17%
	1-3	56%	55%	70%	68%	69%	59%	68%
	≥ 4	4%	5%	6%	22%	3%	7%	15%
	Dialysis parameters
	Blood flow (mL/min)	353 ± 50	302 ± 47	326 ± 47	293 ± 48	330 ± 75	332 ± 61	330 ± 52
	Dialysis duration (hr/week)	12.0 ± 2.3	11.5 ± 1.8	12.0 ± 1.9	13.3 ± 2.3	12.0 ± 2.0	11.3 ± 1.7	13.0 ± 2.4
	Dialysis duration (min/session)	233 ± 33	227 ± 24	241 ± 33	265 ± 44	241 ± 37	228 ± 31	254 ± 37
	Intradialytic weight loss (% of post-dialysis weight)	3.1 ± 1.4	3.7 ± 1.5	3.4 ± 1.5	2.6 ± 1.6	2.7 ± 1.5	2.4 ± 1.3	2.7 ± 1.5
	Dialysate Sodium concentration (mEq/L)	140 ± 1	141 ± 2	141 ± 2	138 ± 2	140 ± 2	138 ± 1	139 ± 2
	Vascular access (%)
	Arteriovenous fistula	67%	78%	75%	79%	56%	70%	55%
	Synthetic graft	8%	4%	8%	8%	3%	5%	10%
	Catheter	26%	19%	17%	13%	41%	25%	34%

Table 1 . Patients characteristics at baseline by country (continued).

 1

	Chacteristics	Spain	Italy	France	Germany	Belgium	United Kingdom	Sweden
	Cardiovascular
	comorbidities (% yes)
	Hypertension	86%	74%	87%	92%	82%	70%	84%
	Congestive heart failure	36%	18%	34%	34%	36%	16%	30%
	Coronary heart disease	33%	34%	39%	57%	49%	39%	46%
	Peripheral vascular disease	31%	30%	40%	34%	35%	19%	28%
	Cerebrovascular disease	16%	16%	15%	20%	22%	14%	18%
	Other CVD	41%	30%	38%	40%	47%	22%	39%
	Non cardiovascular
	comorbidities (% yes)
	Diabetes	31%	28%	35%	40%	38%	28%	41%
	Psychiatric disorders	20%	14%	12%	13%	17%	12%	14%
	Lung disease	18%	14%	13%	13%	19%	7%	9%
	Cancer	15%	15%	16%	16%	19%	14%	17%
	Neurologic disease	12%	11%	11%	17%	15%	8%	10%
	Recurrent cellulitis	8%	8%	8%	12%	12%	6%	12%
	Smoking status (%)
	Active	11%	12%	13%	17%	15%	16%	13%
	Former	33%	28%	31%	20%	29%	20%	33%
	Non Smoker	49%	45%	48%	51%	43%	42%	42%
	Unknown	7%	15%	8%	12%	13%	22%	12%

PERSPECTIVES

For the first time, analyzing data from over 9500 patients, we showed that BP level was lower in HD patients living in southern European countries. This effect may be surprising given the fact that dialyzed patients are frequently hypertensive and that their BP is strongly influenced by medical procedures (dialysis, antihypertensive therapies). This particularly relevant in the context of international comparisons of health status and outcome. The reasons for this remain to be confirmed, but differences in climate, diet, lifestyle and medical strategies could be involved.

In addition, we confirmed the presence of BP seasonality in a large cohort of nationally representative samples and found that BP displayed greater seasonal changes in southern places. Seasonality was explained by climate, and most importantly by outdoor temperature.

For the same change in outdoor temperature, the change in SBP was greater in southern locations. Preventing the winter rise of BP could limit the excess winter mortality. BP seasonality should be taken into account by clinicians when defining BP goals and antihypertensive strategies.  BP seasonality varies with latitude: it is larger in patients from southern locations.

Sources of

What Is Relevant?

 Transient increases in BP and high BP variability increase the risk of cardiovascular disease.

 BP seasonality could be prevented.

Summary

In southern places, BP is lower and displays greater seasonal changes. This may affect the diagnosis of hypertension and the risk of adverse outcome.


Christian Duval

Thomas Schucker

Thomas Sch Ücker

Gravitational birefringence of light at cosmological scales

The Fedorov-Imbert effect

Considering the boundary between air (or vacuum) and a glass plate as a discontinuous electric field, Fedorov 1 and Imbert 2 predicted that photons of a given polarisation follow a discontinuous trajectory with an offset of the order of a wave length as shown in Figure 1. Note that the infinite gradient of the electric field induces an infinite speed of light along the dotted line. The offset of photons of the opposite polarisation is in the opposite direction. Therefore photons of different polarisations follow different trajectories, an effect called birefringence or also Spin Hall Effect of Light.

of the physical field, namely the refractive index in this case. Quite a large number of articles following these references have, since then, been published in this rapidly evolving subject in optics; see, e.g., [?] for an up-to-date overview. At this stage, it should be emphasized that the SHEL, originally studied from a theoretical perspective, has lately been observed experimentally using techniques of Weak Quantum Measurement [?, ?] that are well adapted to wavelengths in the nanometer range. Hence the subject rests on strong theoretical and also experimental bases. It is noteworthy that the SHEL was shown to admit, rather unexpectedly, a fullfledged description [?, ?] in terms of symplectic geometry based on the generic coadjoint orbits of the Euclidean group E(3) with "built-in" Berry connection. This formalism was then used to derive the equations of motion of photons in arbitrary inhomogeneous [?], anisotropic [?] optical media, as well as polarized classical light rays in inhomogeneous media [?]. The crux of the theory was the occurrence, via plain gravitational minimal coupling, of a spin-curvature coupling term responsible for an anomalous velocity. It is this specific geometrical standpoint, conveniently adapted to general relativity (GR), that we will espouse in the present work.

+ + + + + + 3 3 3 3 3 3 • •
With the advantage of our previous experience with SHEL, our purpose will therefore be two-fold. We will first set up a purely geometric (and classical) formalism to describe the motion of spinning massless particles in GR. They are governed by highly non-linear ordinary di↵erential equations presented in Section ?? and specialized to the setting of This effect was observed for the first time 10 years ago 3,4 using techniques of weak quantum measurement.

Adding spin to geodesics

Gravitational fields with gradient also induce birefringence of light. To see this we must generalize the geodesics, which describe trajectories of point-like test particles without spin in a gravitational field. The gravitational field is encoded in the Christoffel symbols of a pseudo-Riemannian metric.

Let X µ (τ ) be the trajectory of a massless spinless particle with 4-velocity dX µ /dτ and 4-momentum P µ (τ ). Its equations of motion (geodesics) read in first order formalism,

d dτ X µ = P µ , (1)
D dτ P µ = 0, (2)
with D/dτ denoting the covariant derivative with respect to the Christoffel symbols. The equations of motion have one conserved quantity, P µ P µ = m 2 = 0. Note that the massless limit is delicate; by the equivalence principle the geodesics for massive particles do not depend on this positive mass m and the limit m → 0 cannot be continuous.

In the seventies spin was added to the massless particle 5,6,7,[START_REF] Saturnini | Un modèle de particules à spin de masse nulle dans le champ de gravitation[END_REF] in the form of the antisymmetric spin tensor S µν (τ ) coupled to the gradient of the gravitational field encoded in the Riemann tensor.

d dτ X µ = P µ + 2 S µ ν R ν βρσ S ρσ P β R αβρσ S αβ S ρσ , (3)
D dτ P µ = -s -det(R α βρσ S ρσ ) R αβρσ S αβ S ρσ P µ , (4)
D dτ S µν = P µ d dτ X ν -P ν d dτ X µ , (5)
where s is the "scalar spin" defined by

-1 2 S µ ν S ν µ =: s 2 . (6)
Let us anticipate that upon a 3+1 split X = ( x, t), the scalar spin becomes the projection of the spin 3-vector s onto the 3-moment p (or the highest and lowest weight of the spin representation).

Photons have s = ±h.

In presence of spin, we have three more conserved quantities, the scalar spin s and

P µ d dτ X µ = 0, S µ ν P ν = 0. (7)
The equations of motion (3 -5) for the massless particle with spin have three delicate properties:

• They are ill defined in Minkowski space because of the vanishing Riemann tensor.

• The limit of vanishing spin is delicate as for the limit of vanishing mass in the case of geodesics.

• We are confronted with super-luminal propagation velocities as in the Fedorov-Imbert effect.

Note also that all four conserved quantities are valid for an arbitrary metric, they do not derive from isometries via Emmy Noether's theorem. A self-contained derivation of the equations of motion from the massive Mathisson-Papapetrou-Dixon equations can be found in the appendix of reference 9 .

The example of the Robertson-Walker metric

In 1976 Saturnini 8 has analyzed the equations of motion (3 -5) for the Schwarzschild metric.

Here we consider flat Robertson-Walker metrics [START_REF] Duval | [END_REF] .

Because of the many vector products in the computations we use Euclidean coordinates x and cosmic time t and write the line element as -a(t) 2 d x 2 + dt 2 , with positive scale factor a > 0, that we also suppose increasing, a > 0. Thanks to Emmy Noether's theorem for the six Killing vectors for translations ∂/∂ x and rotations x ∧ ∂/∂ x and the conformal Killing vector a(t) ∂/∂t, the equations of motion reduce drastically and can be solved by a Runge-Kutta algorithm. Figure 2 shows a typical result in the ΛCDM model. For a given polarisation, s = h, the trajectory of the photon is the helix. The dashed line is the trajectory of a 'photon' without spin, (x 1 (t), 0, 0). The transverse spin s ⊥ e at emission time t e is indicated by the short arrow at the left. The opposite polarisation, s = -h, produces the same helix but of opposite chirality. The spin s precesses around the center of the helix with the same variable instantaneous period as the period of the helix. Let us denote this period by T helix (t). We also want to compute the position of the center x center (t) of the helix and its radius R helix (t). To this end we linearize the equations of motion in the parameter | s e | λ e /(2π h a e ), λ e being the wavelength at emission. For a Lyman α photon of redshift 2.4 this parameter is of the order of 10 -34 , well justifying the linear approximation. It yields:

T helix (t) ∼ a(t) a e λ e 1 + q(t)
with q := -a a (t)/a (t) 2 . (8)

x center (t) ∼    x 1 (t) 0 -λe 2π ae 1 -a e x 1 (t)    , R helix (t) ∼ a(t) a e λ e 2π . (9)
Note that in this approximation the projection of the helix on the null geodesic coincides with this geodesic at all times. To be concrete, consider a z = 2.4 Lyman α photon engaged in a race with a fictitious mass-and spinless competitor travelling at the speed of light. Both competitors are emitted by the same source at the same time, the race lasts 3 • 10 9 light years and they arrive simultaneously in our telescope. However, they arrive with a transverse offset of the order of 10 -7 meter. To achieve this remarkable draw, the photon on its helix has to travel at roughly √ 2 times the speed of light during the entire race. Said differently, the superluminal propagation in the equations of motion (3 -5) does violate causality, but only at the tiny scale of the order of a wave length. For a quantum of solace, note that the support of the Feynman propagator of the Dirac operator in Minkowski space leaks out of the light-cone [START_REF] Scharf | Finite quantum electrodynamics[END_REF] . However this leakage is damped exponentially and also there, causality violation is extremely tiny.

Robertson-Walker metrics with curvature give similar results as computed in reference 11 . There you also find an unsuccessful attempt on finding spin effects in the Hubble diagram of supernovae.

Conclusions and questions

• The gravitational field of an expanding universe produces birefringence of light.

• This birefringence carries information on the acceleration of the universe.

• Of course the main question is: Can this birefringence be measured?

In 1976 Saturnini 8 has shown that the gravitational field of a static, spherical mass produces birefringence of light.

• How does birefringence in the Schwarzschild solution interfere with lensing? Einstein predicted gravitational waves in 1916. They were observed in 2015. Concerning birefringence, three questions are immediate:

• Does the gravitational field of a gravitational wave also produce birefringence of light?

• If yes, what information is carried by this birefringence?

• Can this birefringence be measured in interferometers with polarized laser beams?

Taking due account of its spin, the photon propagates through an expanding universe on a helix. Did Feynman already know about this when he chose to represent the photon propagator by a curly line?

Figure 1 :

 1 Figure 1: The Fedorov-Imbert e↵ect for reflection: A plane glass surface (represented by the rectangle) reflects an incoming, circularly polarized light beam. The dashed lines indicate the orthogonal projections of incoming and reflected light beams onto the glass surface. The dotted line (between the blobs) is the o↵set between the reflected beam and a hypothetical reflected beam of spinless photons (not shown in the figure). The o↵set is of the order of the wavelength of the light beam.

Figure 1 -

 1 Figure 1 -The Fedorov (1955) Imbert (1972) effect for reflection: A plane glass surface reflects an incoming, circularly polarized light beam. The dashed lines indicate the orthogonal projections of incoming and reflected light beams onto the glass surface. The dotted line (between the blobs) is the offset between incoming and reflected beams. It is of the order of the wavelength of the light beam.

Figure 2 -

 2 Figure 2 -The trajectory of photons, x(t), in a flat Robertson-Walker universe in comoving coordinates is the helix. The dashed line is the null geodesic. The transverse spin s ⊥ e at emission time te is indicated by the short arrow at the left.

Acknowledgments

As always, it is a pleasure to thank Vera de Sá-Varanda, Jacques Dumarchez and their team for their warm and efficient hospitality.


Orianne Dumas
email: orianne.dumas@inserm.fr

Aleta S Wiley

Catherine Quinot

Raphaëlle Varraso

Jan-Paul Zock

Paul K Henneberger

Frank E Speizer

Nicole Le Moual

Carlos A Camargo

Occupational exposure to disinfectants and asthma control in U.S. nurses

Take home message

Frequent use of disinfectants is associated with poor asthma control in nurses.

INTRODUCTION

To achieve and maintain asthma control is the primary target of asthma management international guidelines [START_REF] Papaioannou | Control of asthma in real life: still a valuable goal?[END_REF]. However, population-based studies in Europe and in the U.S. have shown that asthma control is suboptimal in 40-50% of adult patients, with even higher rates among women [START_REF] Braido | Determinants and impact of suboptimal asthma control in Europe: The International Cross-Sectionnal And Longitudinal Assessment On Asthma Control (LIAISON) study[END_REF][START_REF] Fuhlbrigge | The status of asthma control in the U.S. adult population[END_REF]. While asthma management recommendations mainly focus on treatment, identification and avoidance of exposures contributing to poor asthma control are recognized as important steps in disease management [START_REF] Papaioannou | Control of asthma in real life: still a valuable goal?[END_REF]. Nevertheless, few epidemiological studies have focused on determinants of asthma control among adults [START_REF] Papaioannou | Control of asthma in real life: still a valuable goal?[END_REF][START_REF] Schatz | Predictors of asthma control: what can we modify?[END_REF].

Workplace exposures contribute to poor asthma control and severe exacerbations [START_REF] Moual | Occupational exposures and uncontrolled adult-onset asthma in the European Community Respiratory Health Survey II[END_REF][START_REF] Boulet | Asthma control in the workplace[END_REF], and their reduction has been suggested as one of the public health interventions likely to have the greatest effect in improvement of respiratory health [START_REF] Beasley | Risk factors for asthma: is prevention possible ?[END_REF]. A substantial part of workrelated asthma cases have been identified in the healthcare industry, which is one of the largest employment sectors in the U.S. and in Europe [START_REF] Wiszniewska | Occupational allergy: respiratory hazards in healthcare workers[END_REF][START_REF] White | Asthma in Health Care Workers: 2008 and 2010 Behavioral Risk Factor Surveillance System Asthma Call-back Survey[END_REF]. Increased risk of asthma symptoms/exacerbations among healthcare workers is believed to be related in large part to exposure to cleaning products and disinfectants [START_REF] Wiszniewska | Occupational allergy: respiratory hazards in healthcare workers[END_REF][START_REF] Arif | Association between cleaning-related chemicals and workrelated asthma and asthma symptoms among healthcare professionals[END_REF][START_REF] Siracusa | Asthma and exposure to cleaning products -a European Academy of Allergy and Clinical Immunology task force consensus statement[END_REF][START_REF] Gonzalez | Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds[END_REF]. Although some of the chemicals contained in these products (e.g., bleach, quaternary ammonium compounds [quats], ammonia) have been associated with current asthma or asthma symptoms/exacerbations [START_REF] Arif | Association between cleaning-related chemicals and workrelated asthma and asthma symptoms among healthcare professionals[END_REF][START_REF] Gonzalez | Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds[END_REF][START_REF] Dumas | Occupational exposure to cleaning products and asthma in hospital workers[END_REF][START_REF] Arif | Occupational exposures and asthma among nursing professionals[END_REF], results from epidemiological studies are limited or inconsistent regarding most specific agents. This question is of particular importance in healthcare settings as work-related asthma prevention strategies, usually based on avoidance of the harmful agent(s), need to be implemented in accordance with infection control guidelines regarding disinfection procedures, to protect patients from infections [START_REF] Quinn | Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention[END_REF].

The Nurses' Health Study II (NHSII) is a large, ongoing, prospective study of U.S. female nurses. In 2014, we initiated a case-control study on asthma nested within the NHSII, to study occupational determinants of asthma. In a recent publication, we address the challenge of assessing exposure to a wide range of disinfectants in this population, for which we developed a Job-Task-Exposure Matrix (JTEM) [START_REF] Quinot | Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses[END_REF]. In the present paper, we investigated the association between occupational exposure to cleaning/disinfection tasks and specific agents, and asthma control.

MATERIAL AND METHODS

Population

The NHSII began in 1989 when 116,430 female registered nurses from 15 U.S. states, aged 25-44 years, completed a questionnaire on their medical history and lifestyle characteristics [START_REF] Camargo | Prospective study of body mass index, weight change, and risk of adult-onset asthma in women[END_REF][START_REF] Moual | Are operating room nurses at higher risk of severe persistent asthma? The Nurses' Health Study[END_REF][START_REF] Dumas | Asthma history, job type and job changes among US nurses[END_REF]. Follow-up questionnaires have been sent every 2 years since. In 2014, 10,618 participants who ever reported physician-diagnosed asthma in biennial questionnaires and were in a nursing job in 2011 were invited to complete two questionnaires, one on occupational exposures and one on asthma (Figure 1, response rate: 80%). This investigation was approved by the Institutional Review Board at the Brigham and Women's Hospital, (Boston, MA).

Asthma

Participants who reported asthma in biennial questionnaires were categorized on the basis of supplemental asthma questionnaires according to validated case definitions, as described previously [START_REF] Camargo | Prospective study of body mass index, weight change, and risk of adult-onset asthma in women[END_REF][START_REF] Moual | Are operating room nurses at higher risk of severe persistent asthma? The Nurses' Health Study[END_REF][START_REF] Dumas | Asthma history, job type and job changes among US nurses[END_REF]. We selected participants who reiterated on the supplemental questionnaire that a physician had diagnosed her as having asthma, and who reported use of any asthma medication in the past year [START_REF] Camargo | Prospective study of body mass index, weight change, and risk of adult-onset asthma in women[END_REF]. Sensitivity analyses were conducted using a more stringent asthma definition, based on the latter criteria and additional report of use of a prescribed long-term preventive medication (ie, inhaled corticosteroids, cromolyn sodium, nedocromil, salmeterol, theophylline) in the past year. Among them, asthma control was defined using the Asthma Control Test score (range 5-25), based on five questions on activity limitations, frequency of symptoms, and frequency of use of quick-relief medication in the past four weeks [START_REF] Schatz | Asthma Control Test: Reliability, validity, and responsiveness in patients not previously followed by asthma specialists[END_REF].

Exposure to disinfectants

Information on general disinfection tasks (frequency of use of disinfectants to clean surfaces/medical instruments, use of spray) was collected in the occupational questionnaire [START_REF] Arif | Association between cleaning-related chemicals and workrelated asthma and asthma symptoms among healthcare professionals[END_REF][START_REF] Donnay | Under-estimation of self-reported occupational exposure by questionnaire in hospital workers[END_REF], as described previously [START_REF] Quinot | Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses[END_REF]. These questions also were asked in the 2013 main questionnaire, i.e., before and independently of the 2014-2015 asthma sub-study (Figure 1).

Exposure to seven major disinfectants/cleaning products (formaldehyde, glutaraldehyde, hypochlorite bleach, hydrogen peroxide, alcohol, quats, and enzymatic cleaners) was evaluated by a nurse-specific JTEM. The JTEM was designed using information collected by questionnaire in a random sample of NHSII participants without asthma (n=9,073), as described in details elsewhere [START_REF] Quinot | Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses[END_REF] and in online supplement. The JTEM assigned exposure level (low, medium, or high) based on combinations of types of nursing jobs and general disinfection tasks ("job-task" axis).

Exposure to eight other products with lower exposure prevalence (orthophtalaldehyde, peracetic acid, acetic acid, ammonia, phenolics, ethylene oxide, chloramine T and "green" products) was not evaluated by the JTEM but by self-report [START_REF] Quinot | Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses[END_REF]. Results regarding these eight products are presented in online supplement.

Analyses

Associations between exposure to disinfectants and asthma control were evaluated by logistic regressions. Asthma control (outcome) was classified into four categories (25: controlled; 20-24: partly controlled; 16-19: poorly controlled; ≤15: very poorly controlled) and considered either as a categorical variable or as an ordinal variable. Disinfection tasks were studied using dichotomous variables (task performed 1-3 or 4-7 days/week vs. never or <1 day/week). Exposure to specific disinfectants according to JTEM was studied using 3level variables (low, medium, or high exposure level). First, we studied exposure to each disinfectant separately. Then, as nurses were classified as exposed to several products, we studied exposure to combinations of several specific products evaluated by JTEM, for the products found associated with asthma control when studied separately. Analyses were adjusted for age, smoking status, body mass index (BMI), race (white vs. other) and ethnicity (Hispanic vs. other). A two-sided P<0.05 was considered statistically significant. Analyses were run using SAS V.9 (SAS Institute, Cary, NC, USA).

RESULTS

Of the 8,524 participants who returned both questionnaires on asthma and occupation, 6,833 were still in a nursing job in 2014-2015 (Figure 1). Among them, n=4,237 reported use of any asthma medication in the past year. Participants with missing data for ACT questions (n=135) were excluded. This yielded a population of 4,102 women eligible for analysis.

Participants were on average 58 years of age and 70% were never smokers. Regarding cleaning/disinfection tasks, 46% of the nurses reported weekly use of disinfectants to clean surfaces, 19% to clean medical instruments, and 19% reported weekly use of sprays. Weekly use of disinfectants was associated with younger age (P=0.001), but no significant difference was observed regarding smoking status, BMI, race, or ethnicity. The ACT score ranged from 7 to 25 (median: 23, Q1-Q3: 21-25). Asthma was controlled in 32% of nurses, partly controlled in 50%, poorly controlled in 12% and very poorly controlled in 6%. Women with poor asthma control were more often current or ex-smoker and had a higher BMI (Table 1).

Description of each of the ACT score components in the study population is presented in Table 2.

Cleaning/disinfection tasks and asthma control

In multivariable models (Table 3), weekly use of disinfectants to clean medical instruments was associated with poorly and very poorly controlled asthma (odds ratio [OR], 95% Confidence Interval [CI]: 1.37, 1.05-1.79 and 1.88, 1.38-2.56, respectively; P-trend<0.001), but no association was observed for the use of disinfectants to clean surfaces.

Associations were similar in participants with childhood-onset and adult-onset asthma (age at onset <18 vs. ≥18 years, P interaction=0.92) and with or without atopy (defined by report of ever having had hay fever, seasonal allergy or allergic rhinitis, P interaction=0.76). Weekly use of spray was also associated with poorer asthma control (Table 3, P-trend=0.002), in particular sprays used for surface cleaning/disinfection, patient care, and air-refreshing sprays (Supplementary Table E1). When examining frequency of cleaning/disinfection tasks (Supplementary Table E2), associations with poor asthma control were generally stronger among nurses with the highest frequency of use (4-7 days/week). However, for spray use, significant associations were observed even among nurses with infrequent use (<1 day/week).

We found similar results in sensitivity analyses (a) studying associations between disinfection tasks reported in the 2013 main questionnaire and asthma control evaluated in 2014-2015, (Supplementary Table E3), and (b) using a more stringent asthma definition (Supplementary Table E4).

Use of a face mask or other respiratory protection devices when working with disinfectant was reported by 5% of the participants overall, but was more frequent (P=0.03) among women with poorer asthma control. Use of latex gloves (24%) was not associated with asthma control. No significant difference in the association between use of disinfectants to clean instruments and poorer asthma control (P interaction ≥0.40) was observed according to use of respiratory protection devices or to use of latex gloves (Supplementary Figure E1).

Specific disinfectants/cleaning products evaluated by the JTEM and asthma control

In multivariable models, using JTEM estimates, high level of exposure to formaldehyde (P-trend=0.02), glutaraldehyde (P-trend=0.02), hypochlorite bleach (P-trend=0.02), hydrogen peroxide (P-trend=0.01) and enzymatic cleaners (P-trend<0.001) were significantly associated with poorer asthma control (Figure 2); quats (P-trend=0.14) and alcohol (P-trend=0.12) were not. More detailed results for each category of asthma control are presented in Supplementary Table E5.

Nurses generally were classified as exposed to several products (i.e., we did not identify subgroups of nurses with exposure to a single product). Based on this observation, we studied a combination of specific products evaluated by JTEM (Table 4). In this analysis, no associations with asthma control were observed among nurses exposed (i) to hypochlorite bleach or hydrogen peroxide but not to the other products; or (ii) to aldehydes (formaldehyde or glutaraldehyde) but not to the other products. In contrast, a significant increased risk of poorer asthma control was observed (P-trend=0.05) among nurses exposed to hypochlorite bleach/hydrogen peroxide and aldehydes; and among those further exposed to enzymatic cleaners (P-trend=0.001). The latter exposure combination was observed in participants employed in various nursing jobs (emergency room, operating room, outpatient or community, other hospital nursing or nursing outside hospital), and among them, most (83%) reported weekly use of disinfectants to clean medical instruments.

In addition, we further examined the associations between exposure to alcohol and quats and asthma control (a) among nurses not exposed to high level of any of the other five products, and (b) among all nurses, in multivariable models further adjusted for the other five products (combined). In both analyses, the absence of association between exposure to alcohol or quats and asthma control was confirmed, with ORs close to the null and P-trends >0.30.

DISCUSSION

In this study of 4,102 U.S. nurses with asthma, disinfections tasks, in particular disinfection of medical instruments, were associated with poor asthma control. We found increased risks of poor asthma control associated with exposure to glutaraldehyde, formaldehyde, enzymatic cleaners, hypochlorite bleach and hydrogen peroxide, in particular for nurses exposed to several of these products. Exposure to quats and alcohol were not associated with poor asthma control.

To our knowledge, this is the first time that asthma control has been studied in relation to occupational exposure to disinfectants among a large cohort of healthcare workers. Asthma was well-characterized in this population of nurses; a previous validation study in NHSII indeed confirmed 95% of the nurses' reports of doctor-diagnosed asthma. [START_REF] Camargo | Prospective study of body mass index, weight change, and risk of adult-onset asthma in women[END_REF] Moreover, we evaluated asthma control using a standardized and validated definition (ACT) [START_REF] Papaioannou | Control of asthma in real life: still a valuable goal?[END_REF][START_REF] Cloutier | Asthma outcomes: Composite scores of asthma control[END_REF], integrating the main domains of asthma control (symptoms, use of rescue therapy, sleep interference, activity limitations). Many studies on work-related asthma have focused on distinguishing risk factors for occupational asthma (i.e., new-onset asthma caused by occupational exposure) and work-exacerbated asthma (worsening of a pre-existing asthma) [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF]. In the current study, the association between use of disinfectants and poor asthma control was similar among nurses with childhood-onset (i.e., pre-existing) and adult-onset (i.e., potentially caused by occupational exposures) asthma. Although the distinction between occupational and work-exacerbated asthma is important for legal considerations (workers' compensation), it may be less relevant from a public health perspective as both occupational and work-exacerbated asthma have long-term socio-economic and health consequences [START_REF] Lemière | Work-exacerbated asthma and occupational asthma: Do they really differ?[END_REF].

To minimize risk of exacerbations and accelerated lung function decline in workers, experts have called for research on occupational exposures contributing to poor asthma control [START_REF] Boulet | Asthma control in the workplace[END_REF].

Our results are consistent with a few recent studies showing that exposure to occupational asthmagens [START_REF] Moual | Occupational exposures and uncontrolled adult-onset asthma in the European Community Respiratory Health Survey II[END_REF][START_REF] Marincu | Rates and predictors of uncontrolled bronchial asthma in elderly patients from western Romania[END_REF][START_REF] Lindström | Middle-Aged Men With Asthma Since Youth[END_REF], and in particular cleaning agents [START_REF] Moual | Occupational exposures and uncontrolled adult-onset asthma in the European Community Respiratory Health Survey II[END_REF][START_REF] Dumas | Cleaning and asthma characteristics in women[END_REF], are associated with uncontrolled asthma. Mechanisms by which disinfectants and cleaning products impact respiratory health remain unclear and require further research [START_REF] Siracusa | Asthma and exposure to cleaning products -a European Academy of Allergy and Clinical Immunology task force consensus statement[END_REF]. Some products (e.g. enzyme-based products) have sensitizing potential, but most agents are assumed to act as respiratory irritants [START_REF] Siracusa | Asthma and exposure to cleaning products -a European Academy of Allergy and Clinical Immunology task force consensus statement[END_REF], and may cause injury of the airway epithelium, oxidative stress and long-lasting neurogenic inflammation [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Dumas | Occupational exposures and fluorescent oxidation products in 723 adults of the EGEA study[END_REF]. Regardless of the exact mechanisms, our results support the need to consider occupation and potential exposure to disinfectants in clinical practice to improve management of patients with asthma [START_REF] Boulet | Asthma control in the workplace[END_REF][START_REF] Lemière | Outcome of work-related asthma exacerbations in Quebec and Ontario[END_REF].

Identifying the specific tasks and agents associated with poor asthma control is of particular importance to improve asthma management among healthcare workers. We found that medical instrument disinfection was associated with poor asthma control, pointing toward a role of high-level disinfectants used on critical or semi-critical items [START_REF] Quinn | Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention[END_REF]. We did not find evidence of an association between use of disinfectants to clean surface and asthma control, although this type of task has been associated with increased risk of physician-diagnosed asthma in a study of healthcare workers in Texas [START_REF] Arif | Occupational exposures and asthma among nursing professionals[END_REF]. Few epidemiological studies have investigated the relationship between specific cleaning agents and disinfectants and asthma outcomes in healthcare workers [START_REF] Arif | Association between cleaning-related chemicals and workrelated asthma and asthma symptoms among healthcare professionals[END_REF][START_REF] Gonzalez | Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds[END_REF][START_REF] Dumas | Occupational exposure to cleaning products and asthma in hospital workers[END_REF], and they were limited in terms of number/variety of specific products studied and attempt to control for correlated exposures. In the current study, although we could not fully study the independent effect of each chemical -because we did not find subgroups of nurses with exposure to a single product -we attempted to identify combinations of exposures associated with greater risk of poor asthma control. We found particularly increased risk among nurses with exposure to aldehydes (formaldehyde or glutaraldehyde), hypochlorite bleach or hydrogen peroxide, and enzymatic cleaners, based on JTEM estimates. Formaldehyde has been known as an asthmagen for long [START_REF] Chan-Yeung | Aetiological agents in occupational asthma[END_REF].

Glutaraldehyde and hydrogen peroxide also have been suggested as agents implicated in occupational asthma among healthcare workers in a smaller study in Canada [START_REF] Dimich-Ward | Respiratory health survey of respiratory therapists[END_REF] or case reports in France and in the U.S. [START_REF] Cristofari-Marquand | Asthma caused by peracetic acid-hydrogen peroxide mixture[END_REF][START_REF] Hawley | Respiratory Symptoms and Skin Irritation Among Hospital Workers Using a New Disinfection Product -Pennsylvania, 2015. US Department of Health and Human Services/Centers for Disease Control and Prevention Morbidity & Mortality[END_REF]. Associations between the use of hypochlorite bleach and asthma outcomes have been reported in European studies [START_REF] Siracusa | Asthma and exposure to cleaning products -a European Academy of Allergy and Clinical Immunology task force consensus statement[END_REF]. Enzymatic products are used to clean items before high level disinfection or sterilization. A role of enzymatic cleaners in asthma among healthcare workers was suspected based on case reports in healthcare settings [START_REF] Adisesh | Occupational asthma and rhinitis due to detergent enzymes in healthcare[END_REF], and earlier reports in the detergent industry [START_REF] Cullinan | An outbreak of asthma in a modern detergent factory[END_REF] in the U.K. We believe this is the first time these agents have been implicated in an epidemiological study.

Finally, a strong association between exposure to quats and physician-diagnosed asthma has been reported in a study of 543 French healthcare workers [START_REF] Gonzalez | Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds[END_REF], in contrast with our results.

Exposure to quats is particularly difficult to evaluate [START_REF] Donnay | Under-estimation of self-reported occupational exposure by questionnaire in hospital workers[END_REF]. In our study, although we integrated information collected on products' brand names and review of the corresponding safety date sheets, as recommended [START_REF] Gonzalez | Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds[END_REF], when creating the JTEM, exposure to quats may still be under-estimated. However, any trend for an association between exposure to quats and poor asthma control disappeared after controlling for exposure to other products.

Besides the active ingredients, specific types of tasks and products' application procedures may influence respiratory health effects and are interesting targets for interventions [START_REF] Quinn | Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention[END_REF]. Spraying has been associated with increased risk of asthma or respiratory symptoms, likely because of the higher potential for inhalation exposure when using sprays [START_REF] Dumas | Occupational exposure to cleaning products and asthma in hospital workers[END_REF]. Consistently, we found in the current study that use of spray was associated with poor asthma control.

Major strengths of our study included the large sample size and the use, for the first time, of a nurse-specific JTEM. Most existing studies on the relationship between the use of specific cleaning/disinfecting products and asthma relied on self-reported exposures, raising the issue of both non-differential and differential misclassification bias, potentially leading to bias either toward or away from the null [START_REF] Donnay | Under-estimation of self-reported occupational exposure by questionnaire in hospital workers[END_REF]. Use of job-exposure matrices (JEM) is generally favored in occupational epidemiology for exposure assessment in large populations [START_REF] Loomis | Towards population-wide exposure assessment[END_REF]. Because nursing jobs are heterogeneous (i.e., nurses with the same job title may perform different tasks), we showed that taking into account disinfection tasks (within job variability) in exposure assessment by creating a JTEM provides better exposure estimates than a JEM, i.e. reduces exposure misclassification [START_REF] Quinot | Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses[END_REF]. In the present study, we observed associations between exposure to several products, as evaluated by the JTEM, and asthma control.

However, as we used questionnaires to evaluate disinfection tasks, some of our results may be subject to differential misclassification bias (i.e. differential recall of exposure according to asthma outcomes, possibly leading to spurious associations). To address this question, we performed a sensitivity analysis studying prospectively the associations between disinfection tasks in 2013 and asthma control in 2014-2015, and found similar results, suggesting that differential misclassification bias is not likely a major explanation for our findings regarding disinfection tasks. Potential for recall bias in the association between self-reported cleaning/disinfection tasks and asthma has been formally evaluated in the Texas healthcare workers study; although the author warn against the possibility of such bias, only a slight effect was reported [START_REF] Delclos | Occupational exposures and asthma in health-care workers: comparison of self-reports with a workplace-specific job exposure matrix[END_REF]. Finally, other studies where evaluation of disinfectant exposure was based on expert assessment (i.e., independent of participants' recall), have reported associations with current or physician-diagnosed asthma [START_REF] Gonzalez | Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds[END_REF][START_REF] Dumas | Occupational exposure to cleaning products and asthma in hospital workers[END_REF].

The cross-sectional design of our study also prevents addressing the question of a healthy worker effect, i.e. a tendency of workers with asthma history or more severe asthma to avoid or leave jobs involving harmful exposures such as disinfectants. Such an effect has been suggested in a previous analysis of this cohort of women who have been in nursing jobs for several decades [START_REF] Dumas | Asthma history, job type and job changes among US nurses[END_REF], and may cause underestimation of some associations in the current study. However, it is notable that we observed strong positive associations between exposure to several disinfectants and poor asthma control despite a potential healthy worker effectwhich typically bias associations toward the null [START_REF] Dumas | Asthma history, job type and job changes among US nurses[END_REF]. In future studies, assessing the association between disinfectant exposures and asthma control among healthcare workers at an earlier career stage, and the impact of exposure duration, would be of particular interest.

Finally, in our study, exposure to eight specific disinfectants could not be evaluated using the JTEM as exposure prevalence was too low (<10% with weekly exposures in all nursing job types) to create such estimates [START_REF] Quinot | Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses[END_REF], which was a limitation. However, we evaluated risks associated with exposure to major disinfectants and cleaning agents used in healthcare settings [START_REF] Henn | Precautionary practices of healthcare workers who disinfect medical and dental devices using high-level disinfectants[END_REF]. Our results also confirmed that latex exposure was no longer the major concerns for respiratory health among healthcare workers, as suggested in the last years [START_REF] Wiszniewska | Occupational allergy: respiratory hazards in healthcare workers[END_REF], most likely because of the reduction of use of powdered latex gloves.

In our study, the use of respiratory protection devices when handling disinfectants was limited -in accordance with a previous report [START_REF] Henn | Precautionary practices of healthcare workers who disinfect medical and dental devices using high-level disinfectants[END_REF] -although it was more frequent among nurses with poor asthma control. Even with more than 4,000 nurses, because of low numbers, we could not determine whether use of respiratory protection devices had an impact on the association between disinfectants use and asthma control. However, use of personal protective equipment is generally not considered as the most effective measure of work-related asthma prevention. Elimination of hazardous substances and replacement with safer alternatives is preferred [START_REF] Quinn | Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention[END_REF]. In accordance with earlier reports, we found that many chemicals in healthcare settings may have an impact on respiratory health, including products (e.g., hydrogen peroxide) used as alternative to known asthmagens (e.g. aldehydes) [START_REF] Henn | Precautionary practices of healthcare workers who disinfect medical and dental devices using high-level disinfectants[END_REF]. Our result thus support the investigation of emerging non-chemical technologies for disinfection (e.g., steam, ultraviolet light) as a potential alternative to chemical disinfection [START_REF] Quinn | Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention[END_REF], and further research on green cleaning, integrating health risk reduction among the products' standards [START_REF] Garza | Traditional and environmentally preferable cleaning product exposure and health symptoms in custodians[END_REF].

The U.S. has more than 3 million registered nurses, and over 12 million workers are employed in the healthcare industry [41]; in Europe, healthcare worker represent ~10% of the workforce [START_REF] Wiszniewska | Occupational allergy: respiratory hazards in healthcare workers[END_REF]. We found that the use of several specific disinfectants in nurses was associated with poor to very poor asthma control. Our findings highlight the urgency of integrating occupational health considerations to guidelines for cleaning and disinfection in healthcare [START_REF] Quinn | Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention[END_REF]; they suggest targets for future efforts to improve asthma management in a large group of workers. In NHSII, the active follow-up rate (number of person-years in the cohort when participants are censored after their last questionnaire response) from 1989 to 2013 was 86% of the potential person-years. * Women with asthma invited to complete the surveys were selected among women who reported physician-diagnosed asthma in biennial questionnaires, but only recent respondents (i.e., who returned 2013 or 2015 questionnaires) were invited. The first invite to complete the survey was sent by email to participants with email address (85%) and by regular mail to participants without email address (15%). After this first attempt (including two email reminders for women with email address), all non-respondents received up to two more invites by regular mail. † Non-respondents were significantly younger and were more often current smokers, obese and nonwhite than respondents. Non-respondents reported higher use of disinfectants in 2011 (weekly use of disinfectants to clean surfaces: 47%) than respondents (43%). ‡ Participants who reiterated on the supplemental questionnaire that a physician had diagnosed her as having asthma, and reported use of any asthma medication in the past year. § Participants with missing data for Asthma Control Test score questions did not differ from included participants for age, smoking status, BMI, race, ethnicity, or self-reported use of disinfectants. NHSII: Nurses' Health Study II.

Figure 2.

Associations between exposure to specific disinfectants/cleaning products evaluated by the JTEM and asthma control. Results are presented as odds ratio (OR) and 95% confidence intervals (CI) for a decrease in Asthma Control Test score category (25: controlled; 20-24: partly controlled; 16-19: poorly controlled; ≤15: very poorly controlled), analyzed as an ordinal variable (ordinal logistic regression), and adjusted for age, smoking status, body mass index, race and ethnicity. Associations presented compare high exposure level vs. low exposure level, for each product; no association was observed when comparing medium to low exposure level. JTEM -Job-Task-Exposure Matrix. score was based on responses to five questions (components) on activity limitations, frequency of symptoms, and frequency of use of quick-relief medication in the last four weeks. Each question was scored using a 5-point scale (1: poor control to 5: good control). Scores for each question are then summed to give the ACT score (range 5-25). Results presented as percentage of participants with a score ≤3 for a given component: activity limitations (asthma keep from getting as much done at work, school or at home), "some of the time" to "all of the time"; shortness of breath, "3-6 times/week" to "more than once daily"; woken up by asthma symptoms at night -"once/week" to "every night"; use ß-agonist inhaler "2 times/week" to "3+ times daily"; self-rated asthma control, "Somewhat controlled" to "Not controlled at all".

Figure 1 .

 1 Figure 1. Flow-chart of the study population.In NHSII, the active follow-up rate (number of person-years in the cohort when participants are censored after their last questionnaire response) from 1989 to 2013 was 86% of the potential person-years. * Women with asthma invited to complete the surveys were selected among women who reported physician-diagnosed asthma in biennial questionnaires, but only recent respondents (i.e., who returned 2013 or 2015 questionnaires) were invited. The first invite to complete the survey was sent by email to participants with email address (85%) and by regular mail to participants without email address (15%). After this first attempt (including two email reminders for women with email address), all non-respondents received up to two more invites by regular mail. † Non-respondents were significantly younger and were more often current smokers, obese and nonwhite than respondents. Non-respondents reported higher use of disinfectants in 2011 (weekly use of disinfectants to clean surfaces: 47%) than respondents (43%). ‡ Participants who reiterated on the supplemental questionnaire that a physician had diagnosed her as having asthma, and reported use of any asthma medication in the past year. § Participants with missing data for Asthma Control Test score questions did not differ from included participants for age, smoking status, BMI, race, ethnicity, or self-reported use of disinfectants. NHSII: Nurses' Health Study II.

Table 1 .

 1 Characteristics of the participants according to asthma control, among 4,102 nurses with asthma Body Mass Index. * In 2013 (main Nurse's Health Study II questionnaire). Missing values for smoking status: n=5; BMI: 37.

		Asthma Control Test score
	25	20-24	16-19	≤15	P

Table 2 .

 2 Description of Asthma Control Test score components, among 4,102 nurses with asthma

	Asthma Control Test score

Acknowledgments

The Nurses' Health Study II is coordinated at the Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA. We would like to thank the participants and staff of the Nurses' Health Study II for their valuable contributions. In particular, we would like to thank Lisa Abramovitz, Krislyn Boggs, Charlotte Marsh, Chidiogo Onwuakor and Christina Staffiere for their help with data cleaning and management. We also thank Francine Kauffmann for her participation in the study conception.

Funding: Centers for Disease Control and Prevention R01 OH-10359; National Institutes of Health UM1 CA176726; Hubert Curien Partnerships for French-Dutch cooperation, French Ministry of Higher Education and Research and OCW Dutch Ministry (Ministerie van Onderwijs, Cultuur en Wetenschap) PHC Van Gogh 33653RF. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n. PCOFUND-GA-2013-609102, through the PRESTIGE programme coordinated by Campus France. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.