Wenjuan Wei
email: wenjuan.wei@cstb.fr

Sutharsini Sivanantham

Laeticia Malingre

Olivier Ramalho

Corinne Mandin

Predicting the rate constants of semivolatile organic compounds with hydroxyl radicals and ozone in indoor air

Keywords: SVOCs, reactivity, QSAR model, machine learning, regression, random forest

Semivolatile organic compounds (SVOCs) in air can react with hydroxyl radicals (OH), nitrate radicals (NO3) and ozone (O3). Two questions regarding SVOC reactivity with OH, NO3 and O3 in the gas and particle phases remain to be addressed: according to the existing measurements in the literature, which are the most reactive SVOCs in air, and how can the SVOC reactivity in the gas and particle phases be predicted? In the present study, a literature review of the second-order rate constant (k) was carried out to determine the SVOC reactivity with OH, NO3 and O3 in the

INTRODUCTION

Indoor semivolatile organic compounds (SVOCs) can originate from indoor sources, including various materials and consumer products containing SVOCs, and from outdoor sources, including organic matter combustion and the use of agrochemical products [START_REF] Weschler | Semivolatile organic compounds in indoor environments[END_REF]. Among the SVOCs, many phthalates, organochlorines, brominated flame retardants, polycyclic aromatic hydrocarbons (PAHs) and pesticides have endocrine-disrupting properties [START_REF] De Coster | Endocrine-disrupting chemicals: Associated disorders and mechanisms of action[END_REF]. Since SVOCs are present in gas and sorbed phases, including material surfaces, airborne particles and settled dust, their removal from indoor environments is difficult [START_REF] Weschler | Semivolatile organic compounds in indoor environments[END_REF].

The reaction of SVOCs with oxidants including hydroxyl radicals (OH), nitrate radicals (NO3) and ozone (O3) in outdoor air is the primary SVOC degradation process in the atmosphere [START_REF] Wang | Predicting rate constants of hydroxyl radical reactions with organic pollutants: Algorithm, validation, applicability domain, and mechanistic interpretation[END_REF]. Indoor OH, NO3 and O3 can come from outdoor air through ventilation and infiltration and indoor sources such as cleaning agents and electronic equipment [START_REF] Weschler | Indoor Chemistry[END_REF]. A study of 72 SVOCs frequently detected in French dwellings showed that the pseudo-first-order reaction rate constants of some PAHs and pesticides in indoor air with OH, NO3 and O3 were of the same order or magnitude as the typical air change rate (0.56 h -1 ) in the indoor environment [START_REF] Wei | Reactivity of Semivolatile Organic Compounds with Hydroxyl Radicals, Nitrate Radicals, and Ozone in Indoor Air[END_REF]. This result suggests that SVOC reactivity is comparable with air change in terms of indoor SVOC removal. Therefore, reactivity may play an important role in transfer and fate of some SVOCs indoors.

The SVOC/oxidant reaction rate constant in the air can be measured in environmental chambers under controlled temperature, humidity and pressure conditions [START_REF] Liu | Kinetic studies of heterogeneous reactions of particulate phosmet and parathion with NO3 radicals[END_REF][START_REF] Mattei | Heterogeneous atmospheric degradation of pesticides by ozone: Influence of relative humidity and particle type[END_REF] graphite, azelaic acid, aluminum oxide, silicon dioxide and iron(III) oxide. The data quality of the selected studies was verified, i.e., QA/QC processes were followed in these studies, and the standard deviations of the measured k values, if provided, were < 30%. Moreover, if several k values were measured in different studies for the same reaction at the same temperature and relative humidity, the median value was used in the present work. The present work did not use any duplicated values for the same reaction at the same temperature and relative humidity for the model development to not assign extra weights to certain compounds.

Calculation of the variables that predict reactivity

Several descriptors were found to influence the indoor transport and oxidation of SVOCs [START_REF] Cheng | A Quantitative-Structure-Activity-Relationship (QSAR) model for the reaction rate constants of organic compounds during the ozonation process at different temperatures[END_REF][START_REF] Li | Quantitative structure-activity relationship models for predicting reaction rate constants of organic contaminants with hydrated electrons and their mechanistic pathways[END_REF][START_REF] Wang | Predicting rate constants of hydroxyl radical reactions with organic pollutants: Algorithm, validation, applicability domain, and mechanistic interpretation[END_REF][START_REF] Wei | Reactivity of Semivolatile Organic Compounds with Hydroxyl Radicals, Nitrate Radicals, and Ozone in Indoor Air[END_REF][START_REF] Yang | Rate constants of hydroxyl radical oxidation of polychlorinated biphenyls in the gas phase: A singledescriptor based QSAR and DFT study[END_REF]. The descriptors can be classified into three groups and include 2 environmental descriptors (i.e., air temperature and relative humidity), 12 quantum chemical descriptors (e.g., polarizability and dipole moment), 13 molecular descriptors (e.g., number of carbon atoms and atomic van der Waals volume) and 6 physical property descriptors (e.g., water solubility and Henry's law constant). A list of these descriptors is provided in Table 1.

The environmental descriptors were obtained from the literature together with the second-order rate constants. The former specifies the environmental conditions under which the second-order rate constants were measured. The quantum chemical descriptors were calculated using two software programs, i.e., Avogadro and Gaussian. The structures of the 90 SVOCs were drawn using Avogadro (application version: 1.2.0; library version: 1.2.0;Open Babel version: 2.3.90;Qt version: 4.8.6). The structure of each compound was automatically optimized using the Merck molecular force field (MMFF94) and the steepest descent algorithm. The Gaussian input was then generated to perform optimization and frequency calculations using the B3LYP/ 6-31G(d,p) functional and basis sets (C. Li et al., 2014;[START_REF] Yang | Rate constants of hydroxyl radical oxidation of polychlorinated biphenyls in the gas phase: A singledescriptor based QSAR and DFT study[END_REF]. Gaussian 09 W (version 9.0, revision C.01) was used to calculate the values of the selected quantum chemical descriptors.

The molecular descriptors were obtained from the MOLE DB database [START_REF] Ballabio | Introduction to MOLE db -On-line Molecular descriptors database[END_REF], and the physical property descriptors were obtained using EPI software (U.S. Environmental Protection Agency and Syracuse Research Corporation). When both the measured and predicted values were available in the EPI software, the present study chose the measured values for further model development. Both MOLE DB and EPI use the chemical CAS number as the input.

Development of the predictive models

The QSAR models were developed following the Organization for Economic Cooperation and Development (OECD, 2007) guidelines. Before the statistical analyses were performed, the distributions of the k values and 33 descriptors were investigated, and logarithm transformation was applied to k, the octanol/water partition coefficient (Kow), vapor pressure (VP), water solubility (WS), Henry's law constant (HC) and octanol/gas partition coefficient (Koa) to reduce data skewness.

The reactivity of SVOCs with OH, NO3 and O3 in the gas and particle phases was studied.

QSAR model development started with the reactivity of SVOCs with OH in the gas phase because 47 k values were obtained from the literature, which allowed testing multiple statistical models and identifying high-performance models. Preselection of descriptive variables among the 33 descriptors was performed prior to developing the QSAR models using (1) the Spearman correlation test to identify the descriptors significantly correlated with log10k (p-value ≤ 0.05), including whether their relationship is linear, and (2) the standardized principal component analysis (PCA) to classify the significant descriptors that were identified in the Spearman test and to identify the most representative descriptor of each class to avoid multicollinearity issues in developing the QSAR models. The descriptors selected by the Spearman test only and then by PCA constituted the first and second sets of descriptive variables for developing the QSAR models, respectively. Overall, the preselection of descriptive variables aimed to meet the principle of parsimony [START_REF] Vandekerckhove | Model comparison and the principle of parsimony[END_REF].

Eight statistical models frequently used in environmental studies (Wei et al., 2019b) were first selected to study SVOC/OH reactivity in the gas phase, including multiple linear regression (MLR), partial least squares (PLS), LASSO regression, ridge regression, elasticnet regression, bagging, random forest and gradient boosting. For PLS, LASSO, ridge and elasticnet regressions, the variables were standardized before fitting the models, and the computed regression coefficients were then reverse standardized. Decision trees and their bootstrap aggregations (bagging, boosting and random forest) are based on thresholds and are not sensitive to the scales of variables. Thus, the data were not standardized for these models. The basic MLR model, without data standardization, was built for the purpose of comparisons among models.

RStudio (version 1.1.383) and R packages including "stats", "pls", "plsdepot", "glmnet", "adabag", "randomForest" and "gbm" were used to develop the statistical models. The data were split into two sets: 60% for training and 40% for testing (external validation). Internal validation using the leave-one-out cross-validation method was applied in the training process. The data split allowed both sets to contain enough data (28 SVOCs in the training set and 19 SVOCs in the testing set) to calculate performance metrics. The R 2 , adjusted R 2 , root mean square error (RMSE) and Q 2 values were adopted as performance metrics to evaluate the prediction performance of the models. R 2 and the adjusted R 2 only allow internal validation, whereas RMSE and Q 2 allow both internal and external validations (Q 2 LOO: leave-one-out cross-validation, Q 2 EXT: external validation). High R 2 and Q 2 values and a low RMSE value indicate a high model performance [START_REF] Chin | The partial least squares approach for structural equation modeling[END_REF]. High-performance models to predict SVOC/OH reaction rate constants were identified and then applied to the other sets of SVOC/oxidant reactivity values containing 14 to 32 values. Since these reactivity sets did not contain enough data for both training and testing, all the data were used for training, and the models were validated internally using the leave-one-out cross-validation method.

RESULTS AND DISCUSSION

Second-order rate constants

The second-order rate constants obtained from the literature are summarized in Tables S1 -S6 in the Supporting Information (SI). The k values for the reaction with OH in the gas phase were obtained for compounds including PAHs, PCBs, organophosphates, dioxins, and certain pesticides (e.g., carbamates, thiocarbamates, dinitroanilines and lindane). The log10k values varied between -12.43 and -9.52. PAHs and organophosphates were more reactive than dioxins and PCBs. The reactivity of pesticides was dependent on the chemical family. The k values for the reaction with OH in the particle phase were acquired for compounds including PAHs, DEHP and two pesticides (pyrifenox and terbuthylazine). The log10k values varied between -13.59 and -10.74. DEHP, terbuthylazine and pyrifenox were more reactive than PAHs. For the same PAHs, such as pyrene and fluoranthene, the k values for the gas-phase reactions were higher than those for the particle-phase reactions by two orders of magnitude at the same air temperature and relative humidity. This occurs because gas-phase SVOCs react directly with gas-phase OH, and particle-phase SVOCs may react with OH radicals that are sorbed onto particles [START_REF] Socorro | Heterogeneous reactions of ozone with commonly used pesticides adsorbed on silica particles[END_REF]. The k values for the reaction with NO3 in the gas phase were obtained for compounds including PAHs, dibenzothiophene and certain pesticides (e.g., carbamates, thiocarbamates and dichlorvos). The log10k values varied between -14.04 and -11.26. PAHs were more reactive than the other SVOCs. The k values for the reaction with NO3 in the particle phase were acquired for compounds including PAHs and certain pesticides (e.g., pyrethroids, organophosphates and carbamates). The log10k values varied between -12.36 and -11.00. Among the pesticides, the pyrethroids and organophosphates were more reactive than the carbamates. The k values for the reaction with O3 in the gas phase were obtained for compounds including PAHs, dioxins, certain pesticides (e.g., thiocarbamates, ethalfluralin, dichlorvos and propachlor) and PAHs were more reactive than dioxins and pesticides.

The k values for the reaction with O3 in the particle phase were acquired for compounds including PAHs, certain pesticides (e.g., dicarboximide fungicides, carbamates, pyrethroids, phenylpyrazoles and dinitroanilines) and DEHP. The log10k values varied between -18.98 and -14.68. Among the pesticides, carbamates and pyrethroids were more reactive than phenylpyrazoles and dinitroanilines.

Predictive model for SVOC/OH reactions

The Spearman test and PCA were performed to preselect descriptive variables for developing the QSAR models. The Spearman test and PCA results for the SVOC/OH reaction in the gas phase are listed in Tables S7 andS8 in the SI. The Spearman test revealed that 20 descriptors were significantly correlated with the log10k value (p-value ≤ 0.05). The first set of descriptive variables for developing the QSAR models consisted of 9 descriptors (EHOMO, Ds, TE, MM, ELUMO-EHOMO, (ELUMO-EHOMO) 2 , nX, RE and nH) with correlation coefficients for the Spearman test ≥ 0.5. Although relative humidity also had a correlation coefficient ≥ 0.5, it was not used as a descriptive variable because most of the log10k values were obtained in dry air (RH = 0). Among the 20 descriptors identified by the Spearman test, 6 (EHOMO, nH, µ, α, log10VP and BP) were representative of the PCA axes based on their axis contributions and on the descriptor types, i.e., quantum chemical descriptors, molecular descriptors, and physical property descriptors. Thus, the 6 descriptors were used as the second set of descriptive variables for developing the QSAR models. Since log10VP, α and µ were found to be correlated, only α was retained in the third set of descriptive variables (EHOMO, nH, α and BP) for parsimony.

The QSAR models developed for predicting log10k for the SVOC/OH reactions in the gas phase are listed in Table 2 andFigure 1. Among the regression models, the MLR, LASSO and elasticnet regressions were used to perform a second selection of input descriptive variables. The most effective models in terms of the performance metrics of the training (R 2 ≥ 0.72, adjusted R 2 ≥ 0.68, RMSE ≤ 0.39, and Q 2 ≥ 0.59) and testing (RMSE ≤ 0.39 and Q 2 ≥ 0.66) datasets adopted three descriptive variables, i.e., nH, EHOMO and BP, and similar between the training and testing sets, indicating that these models were robust and not overfitted. Although the above three models can address nonlinear problems, the models cannot be visualized using simple equations. This black-box effect makes these three models more difficult in terms of understanding and interpretation compared to the five linear models.

Nevertheless, they were developed to compare the performance between the linear and nonlinear models in predicting SVOC reactivity. Since the LASSO regression and random forest models were the most effective linear and nonlinear models, respectively, among the eight statistical models in predicting log10k for the SVOC/OH reactions in the gas phase, the two methods were further used to develop predictive models for the other reactions.

For the SVOC/OH reactions in the particle phase, the Spearman test identified 15 descriptors that were significantly correlated with log10k (correlation coefficient ≥ 0.5), which were then used as the first set of descriptive variables for developing the QSAR models (Table S9 in the SI).

Among them, five descriptors (i.e., chi, log10VP, Qxx, BELm2 and ELUMO) were selected using PCA as the second set of descriptive variables for parsimony. Since the dataset of SVOC/OH reactions in the particle phase contained only 20 SVOCs, all the data were used for model training with internal validation (Table 3 andFigure The random forest model was tested despite its black-box effect for a performance comparison between the linear and nonlinear models. The random forest model also had good performance (R 2 = 0.87, adjusted R 2 = 0.82, RMSE = 0.36, and Q 2 = 0.52) in predicting log10k using five descriptive variables. The R 2 values were higher and the RMSE value was lower than those of the LASSO model, indicating that the random forest model had a higher prediction accuracy than the LASSO model. However, the random forest model had a lower Q 2 value than that of the LASSO model, indicating that the observed log10k values were not reconstructed as well by the random forest model according to the leave-one-out cross-validation method. The Q²LOO values of the leave-one-out cross-validation were higher than 0.5 for the selected LASSO and random forest models, indicating that the models were robust.

Predictive model for SVOC/O3 reactions

For SVOC/O3 reactions in the gas phase, only 14 k values were acquired from the literature. No descriptor was identified as being significantly correlated with log10k. Therefore, no QSAR model could be developed based on these data. For SVOC/O3 reactions in the particle phase, 32 k values were obtained from the literature. Because of the limited number of the k values, they were all used for model training with internal validation to reduce the risk of overfitting and chance correlation, and model testing (external validation) was not performed. Descriptors were preselected using the Spearman test, which identified 18 descriptors that were significantly correlated with log10k (correlation coefficient ≥ 0.5) as the first set of descriptive variables (Table S10 in the SI). Three descriptors (Ds, chi and nO) were further selected using PCA as the second set of descriptive variables for parsimony. The performance of the LASSO and random forest models is summarized in Table 4 andFigure 3. The most effective LASSO model (R 2 = 0.73, adjusted R 2 = 0.62, RMSE = 0.60, and Q 2 = 0.38) adopted nine descriptive variables for prediction, and the equation is as follows:

log10k = -1.592 -2.720 × chi -0.297 × nN -0.041 × T -0.059 × BIC1 + 6.872 × EHOMO - 0.014 × Qzz -0.002 × MM -0.004 × RH -0.033 × nH (7)
The random forest models using both 18 and 3 descriptive variables had high R 2 and Q 2 values and low RMSE values, indicating that these random forest models could predict log10k better than the LASSO model. Nevertheless, the Q²LOO value was lower than 0.5 for the LASSO model, indicating that the model may be overfitted.

Overall, LASSO and random forest methods select variables to optimize the number of explanatory variables regarding the number of observations. The random forest model was built on bootstrap samples. This method reduces the risk of overfitting and makes the model robust.

The LASSO regression method prevents overfitting by shrinking large regression coefficients (OECD, 2007).

Predictive model for SVOC/NO3 reactions

For SVOC/NO3 reactions in the gas phase, only eight k values were found in the literature, which was not enough to train a statistical model. For SVOC/NO3 reactions in the particle phase, the correlation between the log10k values and the descriptors was evaluated using the Spearman test.

However, no variable was significantly correlated with log10k (p-value > 0.05). Although the dataset contained only 18 SVOCs, it indicated that the 33 descriptors used in the present study may not be the most relevant descriptors for predicting log10k for SVOC/NO3 reactions in the particle phase.

Limitations and perspectives of the study

Compared to QSAR models using a large number of descriptive variables for predicting the reactivity of organic compounds (Öberg, 2005), the present work intended to have a limited number of selected variables because using a large number of descriptors with a small dataset of observations can lead to a high risk of overfitting and chance correlation for QSAR models [START_REF] Hutter | Determining the Degree of Randomness of Descriptors in Linear Regression Equations with Respect to the Data Size[END_REF][START_REF] Topliss | Chance correlations in structure-activity studies using multiple regression analysis[END_REF][START_REF] Tropsha | Best Practices for QSAR Model Development, Validation, and Exploitation[END_REF]. Since the number of observations in the present study, i.e., the measured 2 nd -order rate constants for SVOCs, are limited in the literature, using selected descriptors is necessary to avoid obtaining misleading correlations by chance. Therefore, the present work chose several representative descriptors based on reactivity studies in the literature [START_REF] Cheng | A Quantitative-Structure-Activity-Relationship (QSAR) model for the reaction rate constants of organic compounds during the ozonation process at different temperatures[END_REF][START_REF] Li | Quantitative structure-activity relationship models for predicting reaction rate constants of organic contaminants with hydrated electrons and their mechanistic pathways[END_REF][START_REF] Wang | Predicting rate constants of hydroxyl radical reactions with organic pollutants: Algorithm, validation, applicability domain, and mechanistic interpretation[END_REF][START_REF] Wei | Reactivity of Semivolatile Organic Compounds with Hydroxyl Radicals, Nitrate Radicals, and Ozone in Indoor Air[END_REF][START_REF] Yang | Rate constants of hydroxyl radical oxidation of polychlorinated biphenyls in the gas phase: A singledescriptor based QSAR and DFT study[END_REF] to encompass four measurement and molecular aspects: the experimental environment, quantum chemical properties, molecular properties and physical properties.

The present work identified the most relevant descriptive variables for predicting the SVOC/oxidant reaction rate constants in the gas and particle phases. For SVOC/OH reactions in the gas phase, nH, EHOMO and BP were the most relevant descriptors. nH is relevant because SVOC/OH reactions proceed mainly by OH addition to the aromatic rings for PAHs [START_REF] Atkinson | Mechanisms of the gas-phase reactions of aromatic hydrocarbons and PAHs with OH and NO3 radicals[END_REF] and PCBs [START_REF] Dang | Theoretical perspectives on the mechanism and kinetics of the OH radical-initiated gas-phase oxidation of PCB126 in the atmosphere[END_REF] and by hydrogen abstraction or addition for phthalates [START_REF] Li | Reaction pathway and oxidation mechanisms of dibutyl phthalate by persulfate activated with zero-valent iron[END_REF]. EHOMO has also been found by several studies as a relevant descriptor of the reactivity of organic compounds [START_REF] Cabañas | Reaction of the NO3 radical with some thiophenes: Kinetic study and a correlation between rate constant and EHOMO[END_REF][START_REF] Wang | Predicting rate constants of hydroxyl radical reactions with organic pollutants: Algorithm, validation, applicability domain, and mechanistic interpretation[END_REF]. BP is a representative physical property of chemical compounds and is correlated with many other physical properties, such as the solubility, activity coefficient and partition coefficient of organic compounds [START_REF] Hilal | Prediction of the Solubility, Activity Coefficient and Liquid/Liquid Partition Coefficient of Organic Compounds[END_REF]Wei et al., 2019a). The study by Yang et al. showed that the gasphase PCB/OH reaction rate constant can be predicted by a single descriptor, i.e., polarizability [START_REF] Yang | Rate constants of hydroxyl radical oxidation of polychlorinated biphenyls in the gas phase: A singledescriptor based QSAR and DFT study[END_REF]. Although polarizability was also identified by the Spearman test as being significantly correlated with the log10k value, the correlation coefficient was < 0.5. This is probably because the dataset in the present work includes not only PCBs but also PAHs, pesticides and phthalates.

The QSAR model in the present work for predicting the gas-phase SVOC/OH reaction rate constant was compared with other QSAR models developed for PCBs [START_REF] Yang | Rate constants of hydroxyl radical oxidation of polychlorinated biphenyls in the gas phase: A singledescriptor based QSAR and DFT study[END_REF] and organic compounds [START_REF] Wang | Predicting rate constants of hydroxyl radical reactions with organic pollutants: Algorithm, validation, applicability domain, and mechanistic interpretation[END_REF]. Although the three QSAR models were trained using different statistical methods and descriptive variables, the log10k values predicted using the model in the present work (Eq. 3) and that of Yang et al. were consistent in terms of PCB reactivity predictions (Figure 4). The k values predicted by the present work and by Yang et al.

differed from the measured values within one order of magnitude (Figure 4). However, the k values predicted by the model of Wang et al. differed from the measured data by three orders of magnitude (Figure 4). This difference is probably because the model of Wang et al. was trained using organic compound data, including not only PAHs but also volatile organic compounds (VOCs) [START_REF] Wang | Predicting rate constants of hydroxyl radical reactions with organic pollutants: Algorithm, validation, applicability domain, and mechanistic interpretation[END_REF]. The comparison results indicate that the QSAR models developed based on data including various VOCs may present significant uncertainties in SVOC reactivity predictions.

Overall, statistical modeling relies on existing data. The QSAR models developed in the present work are currently based on a database of 139 k values for 90 SVOCs including some PAHs, PCBs, dioxins, phthalates and pesticides belonging to different chemical families. The model performance for predicting these SVOC families was verified through internal and/or external validations. To the best of our knowledge, they are the first models dedicated to address the SVOC reactivity in both the gas and particle phases. Nevertheless, supplementary measurement data will be needed to further validate the models before applying them to other SVOC families, such as polybrominated diphenyl ethers and organophosphates. The framework of the method allows the models to be easily updated if more field measurement data are available in the future.

The selected statistical methods, LASSO and random forest, allow modeling on small datasets with high dimensions, i.e., many variables. The random forest method is based on a random mechanism that makes the model robust: at each iteration, a random bootstrap sample is selected, explanatory variables are selected, and a new model is built; at the end of the algorithm, all the models are aggregated. Thus, the variances in estimators are reduced by the average aggregation technique, and the risk of overfitting is reduced by bootstrapping and selecting variables.

Moreover, the decision trees are based on thresholds; thus, the random forest models are not sensitive to the scales of variables [START_REF] Hastie | The elements of statistical learning: data mining, inference, and prediction[END_REF]. LASSO is a regression method that prevents overfitting by shrinking large regression coefficients. It also selects variables to handle multicollinearity and provides sparse models [START_REF] Hastie | Statistical learning with sparsity: the lasso and generalizations[END_REF][START_REF] Tibshirani | Regression Shrinkage and Selection Via the Lasso[END_REF].

CONCLUSIONS

A literature review of k values obtained from measurements was carried out to provide an overview of the SVOC reactivity in the gas and particle phases with OH, NO3 and O3. Based on the literature data, QSAR models were developed to predict the k value using quantum chemical, molecular, physical property and environmental descriptors. Among eight statistical models, the LASSO and random forest models were identified as the most effective linear and nonlinear models, respectively, with the highest performance for predicting the gas-phase SVOC/OH

INTRODUCTION

For several decades now, migration has been in constant increase in Europe. In 2017 alone, 2.4 million people migrated to Europe [1].

As recommended by the World Health Organization (WHO), it is of extreme importance that all host countries make sure to give equitable access to health care services to these new waves of people [2]. Prevention of vaccine-preventable diseases is one of the priorities but many studies show low seroprotection rates in migrants [START_REF] Jablonka | Tetanus and diphtheria immunity in refugees in Europe in 2015[END_REF][START_REF] Chironna | Immunity to diphtheria among refugees in southern Italy[END_REF][START_REF] Mipatrini | Vaccinations in migrants and refugees: a challenge for European health systems. A systematic review of current scientific evidence[END_REF][START_REF] Hübschen | IgG antibody prevalence suggests high immunization needs in newcomers to Luxembourg[END_REF][START_REF] Skull | Incomplete immunity and missed vaccination opportunities in East African immigrants settling in Australia[END_REF]. Supporting these findings are the occurrences of vaccine-preventable epidemics, measles in particular [START_REF] Jones | Measles outbreak in a refugee settlement in Calais, France: January to February 2016[END_REF][START_REF] Werber | Large measles outbreak introduced by asylum seekers and spread among the insufficiently vaccinated resident population, Berlin, October 2014 to[END_REF], registered in refugee camps.

However, migrants still face barriers to health care access. Moreover, vaccination catch-up is difficult because:

-Few people have proof of their previous vaccinations (neither vaccination card or any other written documentation) [START_REF] Williams | Measles among migrants in the European Union and the European Economic Area[END_REF][START_REF] Mipatrini | Vaccinations in migrants and refugees: a challenge for European health systems, 2017. A systematic review of current scientific evidence[END_REF],

-The vaccination may have started in a transit country and been interrupted, with no proof, -Vaccine schedules and catch-up approaches vary between the native, transit and host countries.

In Europe, for an adult with unknown status, many countries [START_REF] Koch | Recommendations of the Standing Committee on Vaccination (STIKO) at the Robert Koch Institute[END_REF][START_REF] Greenbook | The UK immunisation schedule[END_REF][START_REF]I controlli alla frontiera. La frontiera dei controlli. Controlli sanitari all'arrivo e percorsi di tutela per i migranti ospiti nei centri di accoglienza[END_REF][START_REF]Calendrier des vaccinations et recommandations[END_REF][START_REF] Pottie | Evidencebased clinical guidelines for immigrants and refugees[END_REF] recommend a complete vaccine catch-up without serological testing: three doses of diphtheria, tetanus and poliomyelitis (dT-IPV) are generally administered at month 0 (M0), M2 and M8-12, with the first one containing the pertussis valence (dTacp-IPV).

In France, the independent committee INFOVAC [START_REF] France | Rattrapage des vaccinations chez l'enfant et l'adulte[END_REF] and the High Authority in Health (HAS) recommend an alternative strategy with the realization of a tetanus serology 4-8 weeks after a first dose of dTacp-IPV. The catch-up process would then be based on the result. If the concentration of antibodies against tetanus is ≤ 0.1 UI/ml, a total vaccine catch-up is recommended; if the concentration is between 0.1 UI/mL and 1 UI/ml, one dose of the vaccine is needed as this result would reflect a short-term protection; a concentration of antibodies is ≥ 1 UI/ml reflects a long-term protection against tetanus and no supplementary vaccination is needed.

In the USA, the Centre for Disease Control and Prevention (CDC) [START_REF]General Best Practice Guidelines for Immunization: Special Situations[END_REF] recommends tetanus serological testing before catch-up vaccination or after one dose of dTacp-IPV for the vaccination of adopted and migrant children.

These alternative strategies are based on the postulate that the tetanus serology reflects the diphtheria, poliomyelitis and pertussis serologies as these vaccines are generally administered concomitantly during childhood.

Serology allows the catch-up process to be adapted to the immunity of each person; not everyone will need to be fully re-immunized. However, it raises the cost of the vaccine catchup, as well as increases the risk of missing catch-up by setting it back to a future consultation while waiting for the serological results.

Many studies were conducted on wounded patients in emergency rooms to assess their tetanus immunity status with the use of a rapid finger prick test [START_REF] Elkharrat | Evaluation of a bedside immunotest to predict individual anti-tetanus seroprotection: a prospective concordance study of 1018 adults in an emergency department[END_REF][START_REF] Colombet | Diagnosis of tetanus immunization status: multicenter assessment of a rapid biological test[END_REF][START_REF] Hatamabadi | Tetanus Quick Stick as an applicable and cost-effective test in assessment of immunity status[END_REF][START_REF] Stubbe | Seroprotection against tetanus in patients attending an emergency department in Belgium and evaluation of a bedside immunotest[END_REF][START_REF] Bock | Évaluation du tétanos quick stick ® pour la détermination de l'immunité antitétanique aux urgences[END_REF][START_REF] Cavenaile | Évaluation d'un test rapide immunochromatographique comme aide à la prophylaxie antitétanique dans un service d'urgences[END_REF][START_REF] Ardelean-Jaby | Évaluation du test sanguin « Tétanos Quick Stick » (TQS) en situation d'urgence. EM-Consulte[END_REF]. It demonstrated that this test, which is positive when IgG is ≥ 0.1 UI/ml in serum or is ≥ 0.2 UI/ml in total blood, had a good sensibility (85.3-86%), specificity (94-100%) and a good positive predictive value (92.1%-100%) but sometimes insufficient negative predictive value. Moreover, it was appreciated for its simplicity of use (as a capillary sugar blood test), its rapidity (the result is obtained in 10 minutes), its help in overcoming non-contributory anamnesis and in saving costs, especially by decreasing the need to use human immunoglobulins and unnecessary vaccine doses.

Few studies in France have assessed its interest in the vaccine catch-up of migrants as a substitute for serology [START_REF] Seve | Quel schéma vaccinal pour la population migrante en France : schéma complet ou rappel ? Intérêt du tétanos quick test[END_REF][START_REF] Roye | Etude de la couverture vaccinale des migrants originaires d'Europe de l'Est consultant à la PASS[END_REF][START_REF] Sylvain | Intérêt de l'utilisation du Tétanos Quick Stick comme aide au rattrapage vaccinal chez les migrants arrivant en France[END_REF].

The goal of the study was to evaluate whether the use of rapid tetanus immunotest could improve the vaccination catch-up in migrants coming in health care services as the PASS, as compared to the immediate vaccine catch-up strategy.

To that aim, we conducted a prospective interventional study using the Tétanos Quick Stick® (TQS®) as a tool to assess the tetanus immunity status in a migrant population seeking care in a large free health care centre in Paris. The secondary aim was to study the factors associated with an immunoprotection against tetanus and the costs that could be saved by using the TQS® test.

MATERIALS AND METHODS

Conduct of the study

We conducted a monocentric prospective study at the Permanence d'Accès aux Soins de Santé (PASS) of the Hôtel-Dieu university hospital located in the centre of Paris (France). The "PASS" structures were created in 1998 and aimed at delivering free primary care consultations to people in precarious situations, often without health insurance coverage. All associated costs, for biology, radiology, and drugs, are free of charge for the patients.

Today, we can count 400 PASS in France, with 49 PASS located in Paris and its suburbs where many recently arrived migrants seek free health care. In 2015, they provided primary care to 57,613 patients, 60% of which were first time consultations. In 2018, the Hôtel-Dieu PASS delivered 9,893 primary care consultations.

The inclusion criteria for our study were being a migrant (person born abroad and arriving to France from a foreign country, regardless the length of stay in France) without French citizenship, ≥18 years old and no written proof of vaccination against tetanus. Patients with significant language barriers, complex medical consultations, or a vaccine catch-up already performed or in progress (recorded in our medical database), were excluded.

Medical consultations were conducted by general practitioners and residents in French or

English, or sometimes with the help of a companion speaking French or English. Every included patient was duly informed of the study's aim and asked to sign a written consent form. The following information was collected from our medical database used in PASS (ORBIS software):

-Age and sex, -Country of origin and urban or rural environment in the country of origin, -Spoken language, literacy, level of education, -Professional occupation in the country of origin (if yes, socio-occupational category), -Children, -Date of arrival in France, -Housing status (homeless, hosted by someone, specific reception structure, camp, tenant).

-Regarding their administrative situation, we separate the undocumented migrants (foreigner who does not have any permit of residence and does not apply for an asylum), refugees (obtained asylum in France), applicants for asylum, holders of a residence permit (temporary authorization to stay in France, renewable), Europeans, tourist visa holders, and those in a Dublin Procedure. It applies to migrants who have applied for asylum in another European country; the procedure is for a single asylum application to be made across Europe; thus a patient requesting asylum in France but having already filed a previous request in another country should be sent back to this country.

-There are different types of health insurance in France. The French health system, named Health Insurance (HI), is based on a social security system to guarantee health access for all. The basic assurance of the HI is destined for French citizens and foreign people living legally in France and working. Each person contracts a private insurance that covers the health care the basic HI does not cover. The Universal Health Insurance Coverage (UHC), created in 1999, is intented for people who live legally in France with low resources and/or who not supported by the basic HI (for example, people who do not work). The State Medical Assistance (SMA) was created for the undocumented migrants who have stably resided in France for at least 3 months and have low financial resources. These two special coverages allow free access to medical consultations, pharmacy, radiology, and biology exams.

All the above information was part of the regular anamnesis asked at the PASS. Patients were asked if they recall being vaccinated during childhood, adolescence and/or adulthood.

During the medical consultation, a TQS® test was performed on the patient (the TQS® test was not usually realized at the PASS); the presence or not of a Bacillus Calmette-Guérin (BCG) scar was also verified. The TQS® test's result and the presence or not of a BCG scar were recorded in the medical database.

Tétanos Quick Stick® (TQS®)

The Tétanos Quick Stick®, distributed by the INGEN laboratory, was the rapid test used for the evaluation of immunity status against tetanus. The test is made up of a solid phase coated with tetanus toxoid and colloidal gold. Blood obtained by finger prick was taken with a micropipette and applied in the test sample well in which diluent is added. The sample then runs to the windows. If antibodies against tetanus are present in the sample, they form a complex with the conjugate of the solid phase and a pink stripe appears in the T window.

The pink stripe, which appears in the C window, is for quality control. The test was interpreted after 10 minutes according to the manufacturer's recommendations. It is an immunochromatographic semi-quantitative test based on the ELISA method: the limits of detection were concentrations of tetanus antibodies of 0.2 UI/ml in whole blood and 0.1 UI/ml in serum, thresholds in which below it the test result is negative. TQS® positive means protective immune status because the threshold is above the level of antibodies considered protective by the WHO, which is 0.01 UI/ml, using neutralization tests. A negative test demonstrates, in most cases, a true level below 0.01 UI/ml of neutralizing antibodies, which is not protective.

Vaccines

Vaccines used for the catch-up were:

-dTacp-IPV for the first dose: a quadrivalent vaccine for diphtheria, tetanus, pertussis, and poliomyelitis, with reduced concentrations of diphtheria anatoxin and Bordetella pertussis antigens and antitoxin, -dT-IPV for the two other doses, if needed: a trivalent vaccine for diphtheria, tetanus, and poliomyelitis, with reduced concentrations of diphtheria anatoxin.

Catch-up procedure

Depending on the result of the TQS®, the catch-up procedure varied. If the TQS® test was negative, a complete catch-up with three doses of dT(acp)-IPV (the first with pertussis valence) at M0, M2 and M8-12 was proposed. If the TQS® test was positive, only one dose of dTacp-IPV was administered. Although a person with a positive test result has a protective antibody level, it was not possible to know the duration of this protection, thus a single additional injection provides long-term immunity.

Biology

In addition to the above, each patient consulting PASS for the first time had a blood test for a "health check-up", which included the hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency virus (HIV) serologies.

Statistical analysis

Prior to the study, a sample size calculation estimated that a number of 300 subjects was needed in order to estimate the prevalence rate of patients with a protective immunization status against tetanus with an error in precision of less than 5% and to study factors potentially associated with a protective immunization status.

Characteristics of patients with positive TQS® test were compared to those of patients with a negative TQS® test using the Chi-squared test or the Fischer exact test when needed for qualitative variables. A value of p <0.05 was considered significant. Factors associated with TQS® positivity were studied using univariable and multivariable logistic regression models.

All the factors that could influence vaccination status (socio-demographic characteristics, factors related to life in the country of origin and factors related to life in France) were tested in the univariable model. For the multivariable logistic regression model, only variables for which p was <0.10 in univariable analysis were included in the model.

The statistical analyses were performed with the SAS 9.4 software.

Cost analysis

The cost analysis relied on the price of the vaccines at the Hotel-Dieu's pharmacy at the time of the study. The price of the rapid TQS® test was 3.3 US$, while dTacp-IPV was 17.65 US$/per dose, dT-IPV was 8.44 US$/per dose, and the price of the outpatient consultation was 27.75 US$. We compared two catch-up strategies: the "immediate vaccine catch-up" with three doses of dT-IPV (the first one with pertussis valence "dTacp-IPV") delivered at three different consultations for all patients, and the "TQS® strategy" that depended on the result of a TQS®. In this TQS® strategy, when the test was positive, patients were to receive one dose of dTacp-IPV during the same consultation, and when the test was negative, the patient received three doses for the catch-up. By applying these two strategies to our included patients, and by considering the percentage of the patients with a TQS® positive test, we evaluated the cost of each strategy.

Ethics

The Institutional Review board "Comité de Protection des Personnes" (CPP) of Bron (France) approved the study on the 12 th of October in 2018. We also declared the study at the National Commission for Information Technology and Civil Liberties (CNIL).

RESULTS

Selection of the population

Between December 2018 and February 2019, 310 patients were included among 843 consecutive patients who came at the Hôtel-Dieu PASS for an outpatient consultation (figure 1). There were 298 patients excluded, mainly because they already had a vaccine catch-up or were minors. Eleven patients refused to take part in the study. There were 14 errors of inclusion because of medical records that were not complete. Finally, 221 patients could not be included because investigators did not offer to take part in the study.

Characteristics of the studied population (tables 1, 2, 3 & 4)

Among the 310 included patients, the majority were male (n = 216, 69.7%), median age was 31 years (IQR: 25-37) and 56.8% came for the first time at the Hôtel-Dieu PASS. The average length of stay in France was 18 months. Most of the patients came from Africa (70%).

Concerning their lives in the country of origin, 63.9% (n=198) lived in an urban area, 77.4% (n= 240) were literate and 27.4% (n=85) went to university. In their country of origin, 30.3% were unemployed, 7.4% were students; traders and craftsmen were the most represented socio-occupational category. In France, 55.5% (n=172) were undocumented migrants, 19.7% (n=61) were asylum seekers and 5.8% (n=18) were in possession of a residence permit. Most of them were hosted by a third party (n=122), while 27.4% (n=85) were homeless, and 20.6% (n=64) lived in a migrant reception facility. Most of them spoke French, followed by English (12.3%), Pashto-Afghan dialect-(5.2%), Arabic (4.8%) and Dari -Afghan dialect-(4.5%) for the most spoken languages. More than half of the patients did not have any health coverage (n=209).

The BCG scar was verified for 218 patients with 105 patients having had a BCG scar.

Serologies were available for 266 patients: six were HIV positive, 7 were HCV positive and 26 were antigen HBs positive.

Regarding vaccination declarations, 73.2% declared having previous vaccination(s) during their childhood. This number decreased for vaccinations reported in adolescence (35.5%) and adulthood (41%); 33.5% reported receiving vaccines at all ages. As a reminder, only patients without proof of vaccination were included: patients having a vaccination report seen by the investigator or already vaccinated in the service (catch-up done or in progress and recorded in the medical database) were not included.

Prevalence of a positive TQS® test and factors associated with a positive TQS® test

Among the 310 patients without written proof of previous vaccination, only 32% (95% CI [START_REF] Roye | Etude de la couverture vaccinale des migrants originaires d'Europe de l'Est consultant à la PASS[END_REF][START_REF] Sylvain | Intérêt de l'utilisation du Tétanos Quick Stick comme aide au rattrapage vaccinal chez les migrants arrivant en France[END_REF][START_REF] Orimadegun | Immunity Against Tetanus Infection, Risk Factors for Non-Protection, and Validation of a Rapid Immunotest Kit among Hospitalized Children in Nigeria[END_REF][30][START_REF] Awoh | Immunisation coverage in rural-urban migrant children in low and middle-income countries (LMICs): a systematic review and meta-analysis[END_REF][START_REF] Nicolaï | Tetanus risk assessment in the older outpatients: Usefulness of the « Tétanos Quick Stick ® »?[END_REF][START_REF] Stubbe | Improving tetanus prophylaxis in the emergency department: a prospective, double-blind cost-effectiveness study[END_REF][START_REF] Weinberger | Protection against Tetanus and Diphtheria in Europe: The impact of age, gender and country of origin based on data from the MARK-AGE Study[END_REF][START_REF] Wu | Decline of tetanus antitoxin level with age in taiwan[END_REF][START_REF] Sahan | Epidemiological Study of Tetanus Seropositivity Levels in Different Age Groups in Ankara Province, Turkey, 2017[END_REF][START_REF] Razzaghi | Tetanus immunity in individuals aged 50 years or older in Kashan, Iran[END_REF]) had a positive TQS® test.

Two variables were significantly associated with a positive TQS® test: gender, and the patient living in an urban area in their country of origin (table 5). Women had a higher chance to have a positive TQS® compared to men with an odds ratio (OR) of 1.69 (95% CI [1.02-2.8]).

Urban living was significantly associated with a positive TQS® compared to rural living with an OR of 1.79 (95% CI [1.07-3.02]).

Having a stable administrative situation was almost a significant variable. To study this variable, we separated the administrative situations in three categories: those who were undocumented migrants, the legally residents (including Europeans, refugees, residence permit holders, VISA's holders) and those who were asylum seekers or engaged in a Dublin procedure. 43.5% of the legally residents had a positive TQS®, against 29.7% of the undocumented migrants and 27.5% of the asylum seekers and those in Dublin procedure (p = 0.0795).

The following variables were not studied because of the small size of the subcategories or the large number of missing data: presence or absence of a BCG scar, type of sociooccupational category, result of the HBV's serology, and housing status.

A multivariable analysis (table 5) including all variables for which a p-value <0.10 was found in the univariable analysis (sex, administrative situation and living environment) was then performed. Although there was some tendencies, none of the variables were associated to a positive TQS®: female sex: p = 0.1014; ), urban life: p = 0.0738; ), legally residency: p= 0.1009; ).

Absence of correlation with the anamnesis

None of the declarations of vaccination were associated with a positive TQS® test as only 26% of the patients who declared vaccination at all the ages had a positive TQS® test and it was 25% among patients who declared no vaccination at all. There was no correlation between the anamnesis and the result of the TQS® test.

Delivery of post-test vaccinations

We returned to each medical file one month after the end of the study to verify if the patients were vaccinated with a first dose according to the protocol recommendations.

Overall, 47% (n=47) of the positive TQS® test group were vaccinated after one month, and 72.4% (n=152) were in the negative TQS® test group.

Costs analysis

By applying the two strategies to our 310 included patients, and by considering that 32% of the patients had a TQS® positive test, we evaluated the cost of each strategy:

• The immediate catch-up vaccine strategy would cost 36,511.8 US$.

• The strategy of using the TQS® would cost 29,989.8 US$.

The strategy of using the TQS® test in the vaccine catch-up could save 6,522 US$ or 20% for 310 patients. An extrapolation of our results over a year by taking into account that 8.7% of the population may have a proof of vaccination, 32% of the migrants may have a positive TQS®, and that 2010 new patients came the Hôtel-Dieu PASS in 2018, allowed us to demonstrate that the use of the TQS® test strategy would have saved 36,466.86 US$ yearly and have avoided 2496 useless vaccinations.

DISCUSSION

This prospective study was performed in 2019 at the PASS of the Hôtel-Dieu (Paris, France) to evaluate immunization status against tetanus using the Tétanos Quick Stick® in migrants having no evidence of prior vaccination against tetanus. We found that 32% of patients were correctly immunized against tetanus even though they had no evidence of vaccination.

Two factors were associated with the presence of a positive TQS® in univariable analysis: female sex (OR 1.69 (95% CI [1.02-2.8]), and urban living in the country of origin (OR 1.79 (95% CI [1.07-3.02])). However, self-report of previous history of vaccination was not correlated with a positive TQS® test result. We estimated that its use would result in costs savings as compared to the catch-up strategy currently in use.

Although all studies included migrants without proof of vaccination against tetanus, the rate of immunization against tetanus in migrants is lower in our study population than previous studies carried out in France:

-In 2014 at the Amiens vaccination centre [START_REF] Sylvain | Intérêt de l'utilisation du Tétanos Quick Stick comme aide au rattrapage vaccinal chez les migrants arrivant en France[END_REF], 64% of patients had a positive TQS® test.

-In 2015, at Orleans vaccination centre [START_REF] Seve | Quel schéma vaccinal pour la population migrante en France : schéma complet ou rappel ? Intérêt du tétanos quick test[END_REF], 72% of patients had a positive TQS® test, in a population of adults born outside Europe.

-In 2011, at the PASS Grenoble University Hospital for adults from Eastern Europe [START_REF] Roye | Etude de la couverture vaccinale des migrants originaires d'Europe de l'Est consultant à la PASS[END_REF], 57.5% of patients had a positive TQS® test.

Similarly, European studies about vaccination status of migrants using serologies also did find higher seroprotection rates (>50%). These studies included minors, which can explain the difference in the seroprotection rates.

Moreover, most studies did not mention the length of stay in France: patients who had lived for a long time in the host country were able to benefit from a catch-up vaccination in a general practitioner or in another vaccination centre before inclusion in studies.

Among variables associated with a positive TQS® test, female sex was already reported in studies in the countries of origin of migrants [START_REF] Orimadegun | Immunity Against Tetanus Infection, Risk Factors for Non-Protection, and Validation of a Rapid Immunotest Kit among Hospitalized Children in Nigeria[END_REF][30]. This difference between the sexes is inversed compared to Western countries, due to the vaccination policy targeted mainly at women of childbearing age for the prevention of maternal and neonatal tetanus.

The higher density of health care centres offered in cities could explain the link with life in urban areas. In 2017, a study performed in pregnant women and new-borns in Nigeria [30] showed that women with seroprotection against tetanus lived mainly in urban areas (80.7% versus 62.4% in rural areas). A literature review of Nigeria, China, and India found less immunization among children from rural areas as compared to those from urban areas [START_REF] Awoh | Immunisation coverage in rural-urban migrant children in low and middle-income countries (LMICs): a systematic review and meta-analysis[END_REF].

None of the other variables were significantly associated with a positive TQS® test. We hypothesized that the language spoken and/or the administrative situation might be associated with a positive TQS® by helping with access to health care, but no association was found.

Several studies have shown that the probability of being protected against tetanus decreases with age in developed countries [START_REF] Nicolaï | Tetanus risk assessment in the older outpatients: Usefulness of the « Tétanos Quick Stick ® »?[END_REF][START_REF] Stubbe | Improving tetanus prophylaxis in the emergency department: a prospective, double-blind cost-effectiveness study[END_REF][START_REF] Weinberger | Protection against Tetanus and Diphtheria in Europe: The impact of age, gender and country of origin based on data from the MARK-AGE Study[END_REF] and in developing countries [START_REF] Wu | Decline of tetanus antitoxin level with age in taiwan[END_REF][START_REF] Sahan | Epidemiological Study of Tetanus Seropositivity Levels in Different Age Groups in Ankara Province, Turkey, 2017[END_REF][START_REF] Razzaghi | Tetanus immunity in individuals aged 50 years or older in Kashan, Iran[END_REF] as boosters in adult age are not often administered. In our study, our population was young (average age 33.5 years) and only 27 patients had an age ≥50 years old; of these, only 18.5% had a positive TQS®, which is lower than the coverage rate in other age groups. However, age did not show up in our analysis as a factor significantly associated with the TQS® result.

There was no correlation between self-reported history of previous vaccination (at all three stages of life) and the result of the TQS® test (table 4). We could think of language as a barrier to vaccination's access. However, the sensitivity of the interview is also poor among French people [START_REF] Hatamabadi | Tetanus Quick Stick as an applicable and cost-effective test in assessment of immunity status[END_REF][START_REF] Stubbe | Seroprotection against tetanus in patients attending an emergency department in Belgium and evaluation of a bedside immunotest[END_REF][START_REF]Evaluation du statut vaccinal antitétanique des patients consultant dans les services d'urgences de notre département[END_REF]. A French study conducted in an emergency room has also shown that the TQS® test was a better tool than the interview to appreciate vaccination status [START_REF]Evaluation du statut vaccinal antitétanique des patients consultant dans les services d'urgences de notre département[END_REF].

Furthermore, during the study, type of vaccine was not specified when asking for previous vaccinations. However, most of the vaccines administered during adolescence and adulthood due to the need for boosters are the dt-IPV.

Missed opportunities were high in our study after one month. Each medical visit must be an occasion of vaccine catch-up, which should be started as soon as possible. To prevent these missed opportunities, a special section specific to vaccinations is present in the medical database with each vaccination noted as well as the date of the next booster, serving as a reminder for the practitioner. A regular supply of vaccine must be ensured to avoid a shortage of stocks (which happened during our study). Most of the time, medical consultations are long and complex, and vaccination is not the priority. The creation of a nursing post in the PASS would allow testing and vaccination to be carried out in parallel with medical consultations. We must also not forget that the implication of the patient himself in the catch-up program. A study published in 2019 showed that the implication of refugees in the vaccination program is suitable for better results [START_REF] Louka | Asylum seekers' perspectives on vaccination and screening policies after their arrival in Greece and The Netherlands[END_REF]. For this purpose, an explanation of the catch-up procedure in the language of the patient should proceed with use of a telephonic interpreter if needed. We could also give patients an appointment specially for the vaccination (generally, consultations are with no appointment). A copy of the medical file must be given to each migrant after the first vaccination in which the number of administered doses and which strategy was adopted are noted in order for catchup to be continued elsewhere if needed.

Overall, multiple actions need to be taken in order to improve the vaccination coverage of migrants, especially in Europe. First, there is a lack of specific catch-up recommendations targeting migrants in European countries as explained by the ECDC report (2018) [START_REF] Controle | Public health guidance on screening and vaccination for infectious diseases in newly arrived migrants within the EU/EEA[END_REF]. A review of the literature on the European strategies put in place to improve immunization among migrants showed that communication campaigns, education and targeted vaccination programs, improved vaccination coverage [START_REF] Hui | Interventions to Improve Vaccination Uptake and Cost Effectiveness of Vaccination Strategies in Newly Arrived Migrants in the EU/EEA : A Systematic Review[END_REF]. Also, many other actions remain to be taken, in particular, concerning free access to health care for all migrants, language barriers and education on the importance of vaccination (by using interpreters and cultural mediators) [START_REF] Vito | evidence on equitable delivery, access and utilization of immunization services for migrants and refugees in the WHO European Region[END_REF].

The use of the TQS® test in our population allowed us not only to increase the catch-up of people in need but also resulted in savings as compared to the current recommendations.

TQS® testing did permit to avoid a useless complete revaccination in a third of the patients, and to reduce the risk of a possible hyperimmunization and occurrence of undesirable effects. Many studies have demonstrated that this test had a good sensibility (85.3-86%), specificity (94-100%) and a good positive predictive value (92.1%-100%), using serology as the reference test; in France, the use of TQS® test is recommended in the emergency rooms.

The test is simple and fast and is easily accepted by patients as compared to serology because it is less invasive. Moreover, in our study, only one test was invalid (no appearance of a control band C). The test makes it possible to verify and initiate vaccination, if necessary, within the same consultation, and thus decreases the risk of missed opportunities. Indeed, our study showed that the main reason explaining the non-realization of vaccination was the non-presentation of patient to the next consultation. The economic interest of the TQS® test has been demonstrated in our study. If the TQS® test is positive, complete revaccination is avoided, saving at least 2 out of 3 vaccines and two consultations. TQS® testing is also cheaper than serology. The use of the TQS® test in the catch-up vaccination allowed savings of approximately 20% for 310 patients in comparison with the catch-up strategy without prior verification. This number depends, of course, on the percentage of individuals correctly vaccinated in the study population. In December 2019, new recommendations on the vaccine catch-up of migrants were published in France [START_REF] Has | Rattrapage vaccinal chez les migrants primo-arrivants en cas de statut vaccinal inconnu, incomplet ou incomplètement connu[END_REF]. Regarding tetanus, serology is recommended two months after a first dose. If the rate of antibodies against tetanus is low, catch-up will be pursued with two supplementary doses. If not, the patient is considered as protected and no other dose is administered. The addition of the TQS® test in this new strategy could be interesting.

The principal limitation of this test is its impossibility to distinguish a long-term protection (≥ 1 UI/ml) of a short-term protection (0.1-1 UI/ml). However, our protocol, which recommends one dose of DTP-IPV if the TQS® test is positive, allows patients with a shortterm protection against tetanus to reach a long-term protection if it was not the case beforehand.

Our study was monocentric and subject to several bias. Firstly, we performed the study on a short period (two months), which did not allow all countries of migration to be represented.

Secondly, the language barrier may have led to a collection bias. The physicians may have avoided recruiting patients having difficulties understanding or having multiple medical reasons to consult. Memory and suggestion biases might have occurred as well. Also, questions about vaccinations were approximate, while age of vaccination and type of vaccine received were not specifically asked. However, few patients usually remember the type of vaccines received, and this whether they are migrants or not.

However, our study had some forces. The number of included patients was important and the acceptability of the test by the patients was good (only 11 out of 622 patients refused to participate to the study). Our population was also representative of the migrants who came to France in 2018 according to OFPRA's report [44] ("Office Français pour les Réfugiés et Apatrides", French Office for the Refugees and Stateless people). Finally, the conditions of the medical consultation were similar to those in "real life" (without an interpreter and help for the realization of the TQS® test).

In conclusion, the use of the TQS® test in the vaccine catch-up of migrants is interesting in several ways. It is easy to use, rapid and economic in comparison to serology. To validate its use in the vaccine catch-up of migrants, other studies are needed, especially to compare the TQS® test and serology.

We hypothesize that this test might also be useful for all patients, especially the elderly who are the most affected by tetanus in developed countries.

  2), and model testing(external validation) was not performed. The decision of using all the data for training of these models aims to bring robustness to the model, because the larger the training sample is, the lower the risk of overfitting and chance correlation is. The most effective LASSO model (R 2 = 0.77, adjusted R 2 = 0.73, RMSE = 0.47, and Q 2 = 0.70) adopted three descriptive variables, and the equation is as follows: log10k = -12.401 + 32.295 × chi + 0.064 × log10VP -2.590 × BELm2[START_REF] Hübschen | IgG antibody prevalence suggests high immunization needs in newcomers to Luxembourg[END_REF]

3

 3 Molecular dipole moment (µ) debye Quadrupole moment tensor along the x axis (Qxx) debye Quadrupole moment tensor along the y axis (Qyy) debye Quadrupole moment tensor along the z axis (Qzz) debye Energy of the highest occupied molecular orbital (EHOMO) hartree Energy of the lowest unoccupied molecular orbital (ELUMO) hartree Octanol/water partition coefficient of the compound (Kow) -Boiling point of the compound (BP) °C Vapor pressure of the compound (VP) Pa Water solubility of the compound (WS) mg/l Henry's law constant of the compound (HC) Pa•m 3 /mol Octanol/air partition coefficient of the compound (Koa) -629

FIGURESFigure 1 .Figure 2 .Figure 3 .

 123 FIGURES

FIGURE 1 :

 1 FIGURE 1: Flow Chart

  VP, temperature and relative humidity were identified as the most relevant descriptive variables for predicting SVOC reactivity. The models developed in the present work can be used to predict the second-order reaction rate constant for SVOCs with OH, NO3 and O3 in air, for which measurement data are not available.

reactivity. The EHOMO, polarizability, Qzz, molar mass, nH, nN, chi, BELm2, BIC1, boiling point,

TABLES 627 Table 1 . Descriptors used in the present study 628

 6271

	Descriptor

Table 2 . Predicting the log10k for SVOC/OH reactions in the gas phase 630

 2

	Model	No. of preselected Model settings	Training	Testing

Table 3 . Predicting the log10k for SVOC/OH reactions in the particle phase 633 Model No. of preselected variables Model settings Training R² Adjusted R² RMSE Q²LOO

 3

		Lasso	15		3 variables selected		0.76	0.72	0.48	0.67
			5 *		3 variables selected		0.77	0.73	0.47	0.70
		Random Forest 15		150 bootstrap samples, 5 variables	0.90	0.52	0.31	0.46
					selected per iteration
			5 *		150 bootstrap samples, 2 variables	0.87	0.82	0.36	0.52
					selected per iteration
	634	*	The	most	effective	and		selected	models.

Table 4 . Predicting the log10k for SVOC/ozone reactions in the particle phase 635 Model No. of preselected variables Model settings Training R² Adjusted R² RMSE Q²LOO

 4

	Lasso	18	9 variables selected	0.73	0.62	0.60	0.38
		3	3 variables selected	0.57	0.54	0.76	0.40
	Random Forest 18 *	200 bootstrap samples, 6 variables	0.92	0.82	0.32	0.64
			selected per iteration
		3 *	100 bootstrap samples, 1 variable	0.85	0.84	0.45	0.58
			selected per iteration

Table 1 : Description of the sociodemographics characteristics of the study population

 1

	Sociodemographics characteristics	total	positive TQS®	negative TQS®
		N (%)	N (%)	N (%)	p-value
		310	100	210
	Sex				0.0479
	male	216 (6.7%)	62 (28.7%)	154 (71.3%)
	female	94 (30.3%)	38 (40.4%)	(59.6%)
	Age range				0.3328
	18-24	58 (18.7%)	19 (32.8%)	(18.6%)
	25-29	78 (25.2%)	27 (34.6%)	(65.4%)
	30-34	67 (21.6%)	26 (38.8%)	(61.2%)
	> or = 35	107 (34.5%)	28 (26.2%)	(73.8%)
	Geographics origins (WHO zones)				0.5389
	African region	217 (70%)	66 (30.4%)	151 (69.6%)
	Eastern Mediterranean region	67 (21.6%)	25 (37.3%)	(62.7%)
	European region	12 (3.9%)	6 (50%)	6 (50%)
	South-East Asia region	9 (2.9%)	2 (22.2%)	7 (77.8%)
	Region of the Americas	4 (1.3%)	1 (25%)	3 (75%)
	Western Pacific region	1 (0.3%)	0 (0%)	1 (100%)
	Language spoken				0.1893
	French	196 (63.2%)	62 (31.6%)	134 (68.4%)
	English	38(12.3%)	17 (44.7%)	(55.3%)
	others languages	76 (24.5%)	21 (27.6%)	(72.4%)

Table 2 : Description of living conditions in France of the study populationTable 3 : Characteristics of life in the country of origin of the study population Characteristics of life in France total

 23

		positive TQS®	negative TQS®
	N (%)	N (%)	N (%)	p-value

Table 4 : declarations of vaccinations, BCG scar and serologies in the study populationTable 5 : Factors associated with a positive TQS®. Results of univariable and multivariable logistic regression analysis Vaccination declarations, BCG scar and serologies

 45

		total	positive TQS®	negative TQS®
		N (%)		N (%)	N (%)	p-value
	Vaccination declarations					0.2424
	during childhood (before the age of ten years old)	227 (73.2%)		75 (33%)	152 (67%)	0.9137
	during adolescence	110 (35.5%)		34 (30.9%)	76 (69.1%)	0.1076
	during adulthood	127 (41.1%)		49 (38.6%)	78 (61.4%)	0.9137
	only in the childood	92 (29.7%)		25 (27.2%)	67 (72.8%)	0.127
	only in the childhood and/or adolescence	202( 65.2%)		59 (29.2%)	143 (70.8%)	0.324
	only in the adulthood	19 (6.1%)		4 (21.1%)	15 (78.9%)
	during all three stages in life	104 (33.5%)		24 (26%)	77 (74%)
	BCG scar
	BCG scar	105 (33.9%)		36 (34.2%)	69 (65.7%)
	no BCG scar	113 (36.5%)		30 (26.5%)	83 (73.5%)
	not verified	92 (29.7%)		34 (37%)	58 (63%)
	HBV serology
	not performed	44 (14.2%)		12 (27.3%)	32 (72.7%)
	seronegative	113 (36.5%)		37 (32.7%)	76 (67.3%)
	post-vaccination immunity acquired	24 (7.7%)		10 (41.7%)	14 (58.3%)
	acquired natural immunity	77 (24.8%)		29 (37.7%)	48 (62.3%)
	progressive infection	26 (8.4%)		2 (7.7%)	24 (92.3%)
	anti HbC antibodies isolated	26 (8.4%)		10 (38.5%)	16 (61.5%)
	HCV serology					0.4319
	negative	258 (83.2%)		86 (33.3%)	172 (66.7%)
	positive	7 (2.3%)		1 (14.3%)	6 (85.7%)
	not performed	45 (14.5%)		13 (28.9%)	32 (71.1%)
	HIV serology					0.6671
	negative	259 (83.5%)		86 (33.2%)	173 (66.8%)
	positive	6 (1.9%)		1 (16.7%)	5 (83.3%)
	not performed	45 (14.5%)		13 (28.9%)	32 (71.1%)
				OR (IC95%)	p	OR (IC 95%)	p
	female sex (vs male sex)		94	1

,69 [1,02-2,80] 0,0434

	Factors	N	Univariable analysis	Multivariable
					1,55 [0,92-2,62]	0,1014
	age range 18-24 (vs age range ≥35)	58	1,37 [0,68-2,76]	0,3467
	refugees, Europeans, VISA or resident permit's holders VS undocumented migrants	69	1,83 [1,02-3,25]		1,77 [0,98-3,18]	0,1009
	Africa VS others geogaphic origins	217	1,21 [0,51-2,86]	0,5535
	French VS others languages	196	0,83 [0,46-1,48]	0,1809
	literates VS illiterates	240	1,44 [0,79-2,63]	0,2331
	urban life VS rural life	198 1,79 [1,07-3,02] 0,0279	1,64 [0,95-2,81]	0,0738
	Vaccination reports
	vaccination before age 10 and / or during adolescence VS absence of vaccination during these two periods	202	1,48 [0,91-2,43]	0,117

analysis Sex Age Administrative situation Geographic origin Spoken language Literacy Living environment

* The most effective and selected models.

ACKNOWLEDGMENTS

This work received research funding from the Scientific and Technical Center for Building (CSTB) program on Health and Comfort in Buildings (Grant SEC21).

Acknowledgements

We thank INGEN® laboratory who freely provided all the TQS® tests needed for the study.

We also like to acknowledge all members of the medical team of the Hôtel-Dieu's PASS who participate in the study as investigators: Dr. de Champs Léger, Dr. Rieutord, Dr. Lelong, Dr. Giorno, Dr. Hass, Dr. Boyer, Dr. Lamache, Dr. Durel, Dr. Chicheportiche, Dr. Bouzouita, Dr. Renier, Dr. Paul Petit, Dr. de Willencourt, Dr. Blaes, Dr. Olivier and Dr. Bu. Also we would like to thank Mrs. PIETRI Marie-Pierre and ALABA Marie, who helped with setting up the study and following up with the study.