Anne Brédart
email: anne.bredart@curie.fr

Julia Dick

Alejandra Cano

Robieux Léonore

Antoine De Pauw

Rita K Schmutzler

Dominique Stoppa-Lyonnet

Sylvie Dolbeault

Jean-Luc Kop

Léonore Robieux

How to facilitate psychosocial adjustment in women tested for hereditary breast or ovarian cancer susceptibility? Insights from network analysis

Keywords: Psychosocial difficulties, coping strategies, hereditary breast and ovarian cancer, genetic counselling, network analysis

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The discovery of new cancer susceptibility genes has led to the implementation of multigene testing in clinical practice. In the context of the hereditary breast or ovarian cancer (HBOC) syndrome, testing a panel of genes increases the complexity of counselling especially because of the addition of cancer genes at moderate risk and the identification of an increased number of variants of uncertain significance (VUS) [START_REF] Hiraki | Cancer risk assessment using genetic panel testing: considerations for clinical application[END_REF], both with unclear clinical recommendations (actionability) [START_REF] Easton | Genepanel sequencing and the prediction of breast-cancer risk[END_REF].

Gene panel testing is generally proposed to index cases, often affected with breast cancer and who are tested first in the family. In HBOC index case testing, possible results include a pathogenic variant (PV) on BRCA1/2 or other high/moderate-risk gene, an uninformative negative (UN) or a VUS result. An index case with a PV result may then inform her blood relatives that they present a possible genetic susceptibility to cancer. They may thus be offered single gene targeted testing, leading to a PV or true negative (TN) result.

Carriers of a BRCA1 or a BRCA2 pathogenic variant face up to 72% and 69% risk of breast cancer (BC) by age 80 years, and 44% and 17% risk of ovarian cancer (OC), respectively [START_REF] Kuchenbaecker | Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers[END_REF]. When affected with BC, the risk is of 40% (BRCA1) and 26% (BRCA2) of developing a contralateral BC [START_REF] Singer | Genetic counselling and testing of susceptibility genes for therapeutic decision-making in breast cancer-an European consensus statement and expert recommendations[END_REF]. Pathogenic variants identified in other genes from the panel, such as ATM, CHEK2, PALB2, BARD1 or RAD51D, are associated to moderate risk of BC [START_REF] Couch | Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer[END_REF]. Clinical recommendations for BC or OC genetic risk management follow specific guidelines, which may comprise intensive surveillance or preventive surgeries [START_REF] Rutgers | European Breast Cancer Council manifesto 2018: Genetic risk prediction testing in breast cancer[END_REF].

In that context, women undergoing genetic testing for HBOC susceptibility experience a stressful situation due to the perceived threat to themselves and their families. A wide range of specific psychosocial difficulties is elicited in relation to the personal or familial cancer vulnerability, management of the hereditary predisposition or communication about cancer risk within the family [START_REF] Farrelly | Unmet support needs and distress among women with a BRCA1/2 mutation[END_REF][START_REF] Vos | The counselees' self-reported request for psychological help in genetic counseling for hereditary breast/ovarian cancer: not only psychopathology matters[END_REF][START_REF] Eijzenga | Psychosocial Aspects of Hereditary Cancer (PAHC) questionnaire: development and testing of a screening questionnaire for use in clinical cancer genetics[END_REF]. These difficulties may solicit various coping strategies [START_REF] Gooding | Genetic susceptibility testing from a stress and coping perspective[END_REF][START_REF] Roussi | Identification of cognitive profiles among women considering BRCA1/2 testing through the utilisation of cluster analytic techniques[END_REF][START_REF] Bennett | Concerns and coping during cancer genetic risk assessment[END_REF].

How individuals cope with stressful events is broadly characterized as increased efforts or giving-up responses [START_REF] Kvillemo | Coping with breast cancer: a meta-analysis[END_REF]. According to Lazarus and Folkman [START_REF] Folkman | Appraisal, coping, health status, and psychological symptoms[END_REF], coping consists of a process of "constantly changing cognitive and behavioural efforts to manage specific external and/or internal demands that are appraised as taxing or exceeding the resources of the person". Coping responses may thus be thought to vary specifically according to individuals' appraisals interacting with the characteristics of the situation. In the HBOC context, empirical research has shown that coping strategies could differ according to BC risk perception or worry [START_REF] Roussi | Identification of cognitive profiles among women considering BRCA1/2 testing through the utilisation of cluster analytic techniques[END_REF][START_REF] Den Heijer | Long-term psychological distress in women at risk for hereditary breast cancer adhering to regular surveillance: a risk profile[END_REF][START_REF] Molina | Perceived breast cancer risk and breast cancer worry among women with a family history of breast cancer: a new perspective on coping as a mediator[END_REF], and clinical features, such as the BC diagnosis status [START_REF] Dougall | Coping with genetic testing for breast cancer susceptibility[END_REF][START_REF] Mattei | Coping Mechanisms, Psychological Distress, and Quality of Life Prior to Cancer Genetic Counseling[END_REF] or test result [START_REF] Dougall | Coping with genetic testing for breast cancer susceptibility[END_REF][START_REF] Fantini-Hauwel | Genetic testing for hereditary cancer: effects of alexithymia and coping strategies on variations in anxiety before and after result disclosure[END_REF].

Little research has focused on the role of different coping strategies in relation to the various psychosocial difficulties that arise in cancer genetics [START_REF] Bennett | Concerns and coping during cancer genetic risk assessment[END_REF]. Coping strategies such as avoidance [START_REF] Dougall | Coping with genetic testing for breast cancer susceptibility[END_REF], distraction or helplessness [START_REF] Molina | Perceived breast cancer risk and breast cancer worry among women with a family history of breast cancer: a new perspective on coping as a mediator[END_REF][START_REF] Hirschberg | Psychiatric implications of cancer genetic testing[END_REF], self-controlling (e.g., excessive breast self-examination) [START_REF] Den Heijer | Long-term psychological distress in women at risk for hereditary breast cancer adhering to regular surveillance: a risk profile[END_REF] or reliance on others [START_REF] Hirschberg | Psychiatric implications of cancer genetic testing[END_REF] have been shown to predict increased worry and psychological distress. While most women at high genetic risk of BC do not evidence severe, enduring distress following genetic testing [START_REF] Hirschberg | Psychiatric implications of cancer genetic testing[END_REF][START_REF] Hamilton | Emotional distress following genetic testing for hereditary breast and ovarian cancer: a meta-analytic review[END_REF], those with increased psychosocial difficulties may need further help to minimize their distress [START_REF] Farrelly | Unmet support needs and distress among women with a BRCA1/2 mutation[END_REF][START_REF] Hirschberg | Psychiatric implications of cancer genetic testing[END_REF]. Psychosocial difficulties may be inter-related to coping strategies in possible feed-back loops. For example, more intense worries may elicit (in)appropriate coping strategies which in turn may cause more (or less) worrying. Identifying these possible vicious/virtuous cycles of mutual relationships may guide counselling as intervention on one element can have an impact on another.

Network analysis (NA) is a useful statistical approach to analyse the inter-relationships among elements of complex psychological phenomena [START_REF] Costantini | Stability and variability of personality networks. A tutorial on recent developments in network psychometrics[END_REF][START_REF] Kossakowski | The application of a network approach to Health-Related Quality of Life (HRQoL): introducing a new method for assessing HRQoL in healthy adults and cancer patients[END_REF]. To our knowledge, this approach, recently applied in psychology [START_REF] Cramer | Comorbidity: a network perspective[END_REF], has never been used in the psychosocial field in cancer genetics. In contrast to statistical approaches such as regression analyses, which explain a specific outcome by a number of independent factors, or psychometric analyses which reveal latent unobservable variables, NA summarizes complex patterns of associations by computing conjoint inter-relationships among elements of phenomena [START_REF] Costantini | Stability and variability of personality networks. A tutorial on recent developments in network psychometrics[END_REF]. This analysis statistically determines the unique association between two elements, controlling for their associations with all the other elements (i.e., conditional dependence relationships). Moreover, NA may also be used to investigate inter-individual variability comparing networks according to the characteristics of the situation.

Hence, the main objective of this study was to estimate networks of inter-relationships among coping strategies and specific psychosocial difficulties in women undergoing testing for HBOC susceptibility. We also descriptively compared these networks according to the type of genetic testing, the test result, and the assessment timing.

Methods

This is a prospective, multicentre study was undertaken within BRIDGES research program (https://bridges-research.eu). The protocol was approved in France by the Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé (CCTIRS: Consultative committee for information management in health research -N°16.314), in Germany by the Ethics Committee of the University Hospital of Cologne (N°16-098) and, in Spain by the Ethics Committee of the Instituto Catalán de Oncología of Barcelona (N° -PR111/16).

Counselees

From November 2016 to April 2018, women over the age of 18 years, eligible for BC risk testing according to national criteria, unaffected or affected by a non-metastatic BC were recruited at the Cancer genetic unit of Institut Curie (IC, France), Breast cancer clinic of Cologne University Hospital (CUH, Germany) and Cancer genetic unit of Barcelona Institute of Oncology (ICO, Spain). Women with a BC recurrence, a personal history of OC or a major psychiatric disorder were not included. All recruited women provided written informed consent. Researchers explained the study objectives to the women on the day of the initial cancer genetic counselling visit and, when they agreed to participate, they were given questionnaires to fill in at home and return within two weeks (T1). Two months after the test result notification visit, they received another set of questionnaires to be filled in at home and returned within two weeks (T2). When necessary, a reminder call was made at both time-points. A sample size of 500 counselees was targeted in order to compare groups of at least 50 counselees by main genetic test results (i.e., positive, negative or VUS). Online questionnaire completion was also possible through CleanWeb TM software.

Questionnaires and data collection

Socio-demographic and clinical data were collected from counselees after the initial genetic consultation or from medical records.

Psychosocial assessment

Genetic-specific psychosocial difficulties were assessed at T1 and T2 using the 26-item 'Psychosocial Aspects of Hereditary Cancer' (PAHC) questionnaire ( 9) translated and empirically validated in French, German and Spanish cancer genetics settings (Brédart et al, The 'Psychosocial Aspects in Hereditary Cancer' questionnaire in women attending breast cancer genetic clinics: reliability, validity, responsiveness and interpretability across French-, German-and Spanish versions. Under review). It provides scores of increasing difficulties on a 0 to 100 scale for six domains addressing concerns about hereditary predisposition (e.g., worrying about the choice of possible preventive options), family and social issues (e.g., feelings of responsibility towards family members related to genetic testing), negative emotions (e.g., insecure about the future), familial cancer (e.g., worry that family member has cancer), personal cancer (e.g., worry about chance of getting cancer again), and children-related issues (e.g., guilt about passing genetic alteration).

Adequate internal consistencies with Cronbach's alpha > 0.70 were found for these scales in the three language versions .

Coping was measured at T1 and T2 using the Brief-COPE abbreviated inventory of coping responses [START_REF] Carver | You want to measure coping but your protocol's too long: consider the brief COPE[END_REF]. Available in French- [START_REF] Muller | Multidimensional assessment of coping: validation of the Brief COPE among French population[END_REF], German-( 27) and Spanish-( 28) language, this 28-item measure presents fourteen 2-item scales. Following a higher order empirical validation [START_REF] Doron | Examination of the hierarchical structure of the brief COPE in a French sample: empirical and theoretical convergences[END_REF], to allow a more parsimonious assessment, these scales were aggregated into five dimensions: 1) avoidance, 2) cognitive restructuring, 3) problem solving, 4) distraction and 5) support seeking. Instructions asked about the counselee's usual strategies to respond to difficult events such as the risk of cancer.

All but two of the five scales and three languages (avoidance: Cronbach's alpha=0.57 in Spanish; Distraction: Cronbach's alpha=0.58 in French) exceeded Cronbach's alpha 0.60, which is above the value of 0.50 regarded as minimally acceptable.

Statistical analyses

Statistical analyses were performed with R software (R Core Team, 2017). Network analyses were carried out with the qgraph statistical package of R software [START_REF] Seaacalwavsad | qgraph: Network Visualizations of Relationships in Psychometric Data[END_REF]. Socio-demographic, clinical and psychosocial univariate and bivariate statistics has been described previously [START_REF] Brédart | Sylvie Dolbeault Psychosocial problems in women attending French, German and Spanish genetics clinics before and after targeted or multigene testing results: an observational prospective study[END_REF].

Network analyses provide graphs which consist of two elements: nodes (circles; observed variables corresponding to the Brief-COPE and PAHC domains in orange and blue, respectively) and edges (lines; links or inter-relationships between these variables) [START_REF] Seaacalwavsad | qgraph: Network Visualizations of Relationships in Psychometric Data[END_REF][START_REF] Epskamp | Estimating psychological networks and their accuracy: A tutorial paper[END_REF]. The links between variables are estimated using partial correlation coefficients, controlling for all other variables. The thickness of the edge represents the strength of the inter-relationship and is proportional in absolute value to the size of the partial correlation coefficient. The stronger the link between two nodes, the thicker the edge. Positive and negative links are denoted by blue and red edges, respectively. Networks were regularized using an algorithm called graphical LASSO ('Least Absolute Shrinkage and Selection Operator'). Graphical LASSO removes network links to obtain the simplest network that best reproduces the partial correlations matrix (fewer links and therefore easier interpretation) while losing as little information as possible [START_REF] Friedman | Sparse inverse covariance estimation with the graphical lasso[END_REF]. The regularization severity parameter was set at 0.5 to obtain highly regularized networks. Whereas potential information may be lost, the remaining links are expected to be found in another sample of observations. Nodes are organized in such a way that the variables with the most intense inter-relationships to the other variables are closer to each other and often at the centre of the network [START_REF] Fruchterman | Graph drawing by forced-directed placement[END_REF]. For graphs readability, only edges greater than 0.10 in absolute value (partial r) were displayed.

Network comparisons: we compared networks estimated according to the type of genetic testing (i.e., single gene-targeted or multigene panel), the test result received (i.e., PV, UN, or VUS) and, the assessment time, T1 and T2, for either PV or UN. We investigated whether the basic structures of the networks were similar by calculating the linear correlation between the strength of interrelationships among variables in a network and those in another network. A high correlation (r > 0.70) between networks reflects that if the strength of a relationship between two variables is high in a network, this relationship is also strong in the other network.

Note that analyses did not comprise the PAHC children-related domains as items applied to fewer women. Besides, the TN result sample was too small (N=44, 9.6%) to allow for estimating networks in women receiving that test result.

Results

Sample characteristics

Socio-demographic and clinical characteristics of the sample are provided in Supplementary online material S1. Among 752 counselees consecutively approached, 646 (86%) and 460 (61%) returned the questionnaires at T1 and T2, respectively. Eligible counselees and respondents did not differ on age, parental and BC diagnosis status. Overall eligible counselees' and respondents' mean (standard deviation) age was 47.8 (11.5) and 47.7 (11.4), respectively.

Multigene panel and single gene targeted testing was performed in 508 (78.6%) and 138 (21.4%) respondents, respectively. Counselees undergoing multigene panel differed as expected to those undergoing targeted testing, in that they were older (p < 0.001), reported having children more frequently (p < 0.05), were more frequently affected by BC (p < 0.001), lost a family member more frequently (p < 0.001) and had a longer time to wait for the test result receipt (p < 0.001).

Among respondents at T2, networks were estimated for 98 (21.3%), 259 (56.3%), and 59 (12.8%) women who received a PV, UN and VUS result, respectively.

Psychological characteristics

The mean (standard deviation) levels of genetic-specific psychosocial difficulties (PAHC) and coping strategies (Brief-COPE) by test result and at T1 and T2 are provided in Supplementary material 2. Less than 10% item omission was present in psychosocial assessments.

Network description

Figures 1a, 1b, 2a, 2b, 2c and, provided in Supplementary material S4, figures 3a, 3b, 3c and 3d show networks of inter-relationships between coping strategies and psychosocial difficulties in women undergoing targeted or panel testing, those receiving a PV, UN or VUS result, and at T1 and at T2 in women receiving a PV or UN result, respectively.

The conceptual distinction between psychosocial difficulties and coping strategies is reflected in the global structure of all networks, as domains of each concept, represented by nodes in blue (psychosocial difficulties) or in orange (coping strategies), were more closely connected to each other.

Insert figure 1a and 1b, 2a, 2b, and 2c about here Across networks, a striking feature was the centrality of the 'emotions' node, connected to other psychosocial difficulties and to specific coping strategies. Concentrating on inter-relationships between coping strategies and difficulties (partial r > 0.10), the strongest links were observed between avoidance (e.g., giving up trying to deal with it) and higher negative emotions (e.g., anxious) in seven over nine networks. Avoidance was also linked to familial and social difficulties (e.g., contacting family members about genetic testing) in five of the networks. Cognitive restructuring (e.g., seeing in a different light) was the only coping strategy related to lower psychosocial difficulties, i.e. negative emotions (partial r = -0.12 to -0.25), concerns about familial (e.g., worried about the chance that family members will get cancer) (partial r = -0.13 & -0.14) or personal (e.g., worried about getting cancer again) cancer (partial r = -0.12 to -0.19). Problem solving, distraction and seeking support were to a lesser extent linked to psychosocial difficulties. Partial correlations coefficients > 0.10 between coping strategies and psychosocial difficulties in Network Analyses are provided in Supplementary material S3.

Network comparison

In the following, examples of differences among networks are presented.

In women offered multigene testing, a relatively strong connection emerged between avoidance and negative emotions (partial r = 0.21), while in women offered targeted testing, avoidance was strongly linked to familial/social difficulties (partial r = 0.20). In these women, a relatively strong link was also observed between cognitive restructuring and lower negative emotions (partial r = -0.25) which appeared to a lesser degree in women offered panel testing (partial r = -0.14).

Avoidance and emotions (partial r = 0.29) and familial/social difficulties (partial r = 0.26), were strongly connected in women who received a PV result. In women who received a VUS result, avoidance was linked to difficulties about personal cancer (partial r = 0.19) and hereditary predisposition (e.g., worry about the choice of possible preventive options) (partial r = 0.15). In women receiving a UN result, avoidance was also connected to emotions (partial r = 0.26) which, to a lesser degree, was also linked to cognitive restructuring (partial r = -0.17).

When comparing networks over T1 and T2 (Figures 3a, 3b, 3c and3d shown in Supplementary material S4), we noted, for example, in PV carriers, a strong connection between avoidance and difficulties with familial/social issues, absent at T1, was revealed at T2 (partial r = 0.24), while the same strong link in women with uninformative negative test result (UN) present at T1 (partial r = 0.20), was no longer present at T2.

Discussion

In this study, we applied NA among coping strategies and specific psychosocial difficulties in women undergoing genetic testing for HBOC susceptibility, and contrasted networks by clinical features to suggest specific further counselling needs. Extending previous studies that assessed coping strategies in relation to distress as a specific outcome [START_REF] Den Heijer | Long-term psychological distress in women at risk for hereditary breast cancer adhering to regular surveillance: a risk profile[END_REF][START_REF] Molina | Perceived breast cancer risk and breast cancer worry among women with a family history of breast cancer: a new perspective on coping as a mediator[END_REF][START_REF] Dougall | Coping with genetic testing for breast cancer susceptibility[END_REF][START_REF] Mattei | Coping Mechanisms, Psychological Distress, and Quality of Life Prior to Cancer Genetic Counseling[END_REF][START_REF] Fantini-Hauwel | Genetic testing for hereditary cancer: effects of alexithymia and coping strategies on variations in anxiety before and after result disclosure[END_REF], NA evidenced unique inter-relationships among various coping strategies and a comprehensive range of psychosocial difficulties relevant to the cancer genetics context [START_REF] Eijzenga | Psychosocial Aspects of Hereditary Cancer (PAHC) questionnaire: development and testing of a screening questionnaire for use in clinical cancer genetics[END_REF].

Among networks drawn in this study, the 'negative emotions' node was central. This PAHC questionnaire domain evidenced high correlation to psychological distress [START_REF] Brédart | Sylvie Dolbeault Psychosocial problems in women attending French, German and Spanish genetics clinics before and after targeted or multigene testing results: an observational prospective study[END_REF] and so, among nodes which were positively correlated to negative emotions, specific coping strategies may reveal unhelpful.

Prominent inter-relationships between avoidance (e.g., giving up trying to deal with it) and, negative emotions (e.g., anxious) as well as familial/social difficulties (e.g., worried about contact with family members; feelings of responsibility; lack of support) were revealed. Although a 'distraction' coping strategy may be useful while waiting for the genetic test result [START_REF] Phelps | The development of a distraction-based coping intervention for women waiting for genetic risk information: a phase 1 qualitative study[END_REF], avoidance has been recognised as an unhelpful strategy in women affected with BC generally [START_REF] Kvillemo | Coping with breast cancer: a meta-analysis[END_REF] and in those facing HBOC susceptibility specifically [START_REF] Den Heijer | Long-term psychological distress in women at risk for hereditary breast cancer adhering to regular surveillance: a risk profile[END_REF][START_REF] Molina | Perceived breast cancer risk and breast cancer worry among women with a family history of breast cancer: a new perspective on coping as a mediator[END_REF][START_REF] Dougall | Coping with genetic testing for breast cancer susceptibility[END_REF]. In contrast, cognitive restructuring (e.g., seeing in a different light, looking at something good in what is happening, learning to live with it) was the only coping strategy that inter-related to lower psychosocial difficulties. This is in line with a decreased long-term distress in relation to coping by fostering reassuring thoughts in women from HBOC syndrome [START_REF] Den Heijer | Long-term psychological distress in women at risk for hereditary breast cancer adhering to regular surveillance: a risk profile[END_REF]. Network structures proved similar across clinical features, especially over time. However, depending on the clinical situation, specific variations could be observed. For example, a relative strong link between avoidance and familial/social difficulties was revealed in women undergoing targeted testing. These women often unaffected with BC and surrounded by familial losses due to cancer [START_REF] Roussi | Identification of cognitive profiles among women considering BRCA1/2 testing through the utilisation of cluster analytic techniques[END_REF] may have difficulty soliciting genetic information and support from relatives already affected with cancer.

Besides, we also evidenced relatively strong connections between avoidance and familial/social difficulties in women who received a PV result, which suggests that among PV carriers, those who use avoidance to cope may need further help to address their difficulties in communicating about the genetic cancer predisposition with concerned family members [START_REF] Bowen | Effects of a web-based intervention on women's breast health behaviors[END_REF].

Moreover, links between avoidance and, hereditary predisposition difficulties (e.g., worried about coping with the test result) or personal cancer (e.g., worried about getting cancer again) emerged in women who received a VUS result. The disclosure of an ambiguous test result with a lack of actionability may be difficult to understand, maintain uncertainty and distress [START_REF] Esteban | Psychological impact of multigene cancer panel testing in patients with a clinical suspicion of hereditary cancer across Spain[END_REF] and require further counselling to interpret the significance of this result in the context of personal or familial cancer history [START_REF] Reuter | Understanding variants of uncertain significance in the era of multigene panels: Through the eyes of the patient[END_REF].

Referring to coping flexibility [START_REF] Cheng | Coping flexibility and psychological adjustment to stressful life changes: a meta-analytic review[END_REF] or the ability to modulate the choice of coping strategies according to the situation, Bennett [START_REF] Bennett | Concerns and coping during cancer genetic risk assessment[END_REF] observed that individuals attending cancer genetic counselling generally used cognitive restructuring in response to concerns they could not change, and support seeking to gain information. Similarly, we observed an inter-relationship between cognitive restructuring and negative emotions in women who learn that they did not carry a pathogenic variant whereas this link was not present in these women before obtaining their test result. The information gained from the test result, i.e. the absence of an identified pathogenic variant explaining their personal or familial cancer history, also means that the cancer risk estimated by the family pedigree has not been clarified by genetic testing and therefore the medical recommendation remains unchanged. This situation may have prompted an acceptance mode of coping in facing one's personal cancer concerns.

A relatively smaller link between the problem solving strategy and difficulties related to hereditary predisposition was evidenced in women who received a PV. This test result may raise concerns about the choice of possible cancer risk management strategies and thus efforts to actively manage the stress associated to the confirmed high cancer risk.

Limitations and strengths

This study is the first to use NA in the psychosocial field in cancer genetics, providing nuanced information on the link between coping strategies and genetic-specific psychosocial difficulties. It comprises a relatively large sample with a high initial response rate and absence of statistical difference between respondents and non-respondents on available characteristics. However, findings are only valid to women opting for genetic testing and who were mainly affected with breast cancer. While causal relationships between strongly inter-related variables may be advocated, the direction in the relationships among coping strategies and difficulties may not be ascertained by cross-sectional analyses.

Conclusions

NA was fruitful to highlight prominent mutual relationships among coping strategies and specific psychosocial difficulties in women tested for HBOC susceptibility. These findings suggest further areas for counselling. In particular, women undergoing single gene-targeted testing, and in those with a PV test result -regardless of the genetic test type (single gene-targeted or multigene panel test), may need help to overcome avoidance and their difficulties in contacting family members. Women carriers of a PV may also need further support to make a decision about their cancer risk management. Cognitive restructuring should be facilitated, especially since as it was related to less negative emotions, personal and familial cancer worries. Linear correlation between networks' coefficients for women having received a pathogenic variant or a negative uninformative result: r=0.60; linear correlation between networks' coefficients for women having received a pathogenic variant or a variant of uncertain significance result: r=0.59; linear correlation between networks' coefficients for women having received a negative uninformative or a variant of uncertain significance result: r=0.71.

Figure 1a &

 1a Figure 1a & 1b. Networks of relationships among coping strategies and psychosocial difficulties in women undergoing targeted or gene panel testing for high breast cancer risk

Figure 2a .

 2a Figure 2a. 2b & 2c. Networks of relationships among coping strategies and psychosocial difficulties in women receiving a pathogenic variant, an uninformative negative or a variant of uncertain significance

Figure 1a .

 1a Figure 1a. Targeted tesing

Funding and acknowledgment: Project funded by the European Union Horizon 2020 research and innovation programme under grant agreement No 634935 (BRIDGES). Partly funded in France through the SiRIC label and Institut Curie integrated cancer research site and a grant from Ile-de-France Cancer Pole N° 2015-1-EMERG-14-ICH-1.

Competing interests

Peter Devilee reports grants from EU Horizon2020 during the conduct of the study


Gabriel Pedroza
email: gabriel.pedroza@cea.fr

Towards safety and security co-engineering Challenging aspects for a consistent intertwining

Keywords: safety, security, development cycle, co-engineering, MDE, safety-security metrics

HAL is

Introduction

Safety and security are topics often referred in the literature as major concerns to be addressed in systems engineering. Along with the difficulties found in the practice of safety and security in their usual standalone mode, research and industry should also face new challenges arisen from the need of a common practice. The referred need does not only obey to a mere optimization of resources, but it is essentially generated by the emergence -or evolution -of application domains which are identified as both safety and security critical. Indeed, the observed dependencies between safety and security aspects in different use cases, the potential conflicts between proposed solutions, the variety of development and analysis methods, and the growing number of exigencies to improve systems' trustworthiness lead to a singular problematics. Structuring the aspects for a seamless co-engineering process is a vast, complex and, thus, very tough task. This short paper aims to describe, in a non-exhaustive manner, some aspects to move forward, highlight identified issues and perspectives for solutions, and, finally, address some questions that may enrich the ongoing discussions. In particular, it aims to raise attention on the need for a common practice of safety and security via the consistent integration of known techniques. The rest of the paper is structured as follows. The section 2 presents a conceptual positioning of safety and security. The section 3 gives an overview of the standards ecosystem. A MDE approach that can be leveraged for safety-security co-engineering is explained in section 4. Some difficulties to achieve integration and adoption of safety and security development cycles comes in section 5. A discussion on the consistent integration of safety and security techniques is given in section 6. Finally, the overall perspectives come in section 7.

Positioning safety and security

This section introduces a minimal background to make explicit what safety and security stand for in this paper. To do so, some application domains are recalled including representative use cases which are recognized by the community as both safety and security critical. Afterwards, a conceptual positioning of safety w.r.t. security (or conversely) is given. This positioning helps to highlight commonalities and also specificities of both areas.

Application domains positioning w.r.t. safety and security

Industry application domains are defined by categories of problematics and by the technology applied/developed to tackle them. A wide variety of systems are developed within each application domain. They include software and hardware artifacts structured by an architecture which is often networked. Despite there is no consensus on metrics to assess criticality, the systems are labeled as critical regarding the goals and missions they should/must accomplish and the potential unwanted impacts of not succeeding in doing so. Several instances of critical systems can be found in aerospace, railway, automotive, health, and nuclear domains but also in other sectors like e-commerce, e-voting, and social-network based systems. The operation of systems in the different domains has been impacted by the evolution of Information and Communication Technology (ICT), and by the progress in autonomy, automation and -more recently -in artificial intelligence techniques. Despite these evolutions, it is likely that the emerging systems will lead to a few new relevant risks, i.e., risks that have not been foreseen nor already faced by human-beings. If that occurs, our current paradigms to perceive systems' criticality will remain valid across time irrespective of the type of concern. However, what is changing for sure is the increasing gain in (1) usage of ICT over formerly manual works and missions, (2) systems automation, smartness, and complexity, and (3) physical and virtual accessibility of systems. All in all, the main stake is the trustworthiness that human-beings have on those systems, i.e., the proved reliability, safety, security, etc. of those highly automated-networkedcomplex systems. By definition, catastrophic risks related to a safety critical system endanger human-being lives [START_REF]ARP4754A -Guidelines for Development of Civil Aircraft and Systems[END_REF]. As long as those systems exhibit the three features previously listed, they will also become security critical. Thus for instance, a railway system including ICT artifacts, mostly automated, and physically and virtually accessible will certainly face critical security risks. On the contrary, certain security critical systems will be in no way safety-related, e.g., e-voting, e-commerce, social network, mobile-communication systems (see Figure 1). This implies that safety and security depend upon technical specificities of application domains. The identification, assessment and management of risks may demand a clear understanding of them.

Conceptual positioning of safety and security

The current standalone practices of safety and security consists in separately integrate them into an engineering development cycle. The outcome is a couple of concern-oriented cycles that allow engineers to separately perform the different development phases up to the system disposal. Figure 2 roughly depicts the current state of safety and security engineering processes and their fundamental elements. Regarding the intersection between safety and security engineering processes, we can highlight the existence of commonalities between both processes. More specifically, there are conceptually similar terms and notions in both areas, like for instance, risk, severity, likelihood, etc. As long as those terms and notions are proven to be semantically related, they constitute a basis for a common safety-security engineering process. But constitute such common basis is rather bulky, in particular, due to the variability of terms and notions found in standards, methods, guides and other technical documents. Some aspects to consider when determining notions similarity are:

Syntactically similar terms with different meanings. It refers to syntactically similar terms used in both safety and security having different meanings. For instance, even if the term Feared Event is used in both safety and security risks analyses, it does not necessarily have the same meaning nor structural form. A Feared Event in safety can be considered as a combination of a hazard and an Syntactically different terms with equivalent meanings. In this case, two different terms respectively used in safety and security stand for the same notion. For instance, the term Threat Condition introduced in the standards ED202 [START_REF]ED202 -Airworthiness Security Process Specification[END_REF], ED-203 [START_REF]ED203 -Airworthiness Security Methods and Considerations[END_REF] mostly correspond to the notion of Feared Event found in standards like ISO-27005 [3] and also in methods like EBIOS [START_REF]des Systèmes d'Information: EBIOS -Expression des Besoins et Identification des Objectifs de Sécurité. ANSSI[END_REF].

It is expected that a common engineering process shall include metrics useful to evaluate both safety and security risks. Referred metrics are necessary when paths to risks combine both safety and security events, and their likelihood of occurrence and severity of impact need to be evaluated. Along with previous commonalities, several specificities have been already identified:

Specific criteria for evaluation. The technical criteria for evaluation of safety and security are almost specific to each area. Known security criteria are for instance authenticity, integrity, confidentiality, non-repudiation, freshness, controlled access, etc. On the other side, relevant safety criteria are for instance reliability, availability, maintainability, etc. Even if for some cases certain criteria are common to both areas, for instance availability), to our knowledge, most of the criteria remain specific either to security or to safety.

Different nature of events. Safety and security analyses aim to asses the robustness of a system w.r.t. certain unwanted events. However, the nature of those events is rather different for each analysis. As for safety events, we can mention accidents, system failures and functions faults. As for security events, we can mention cyber or physical attacks, e.g., intrusions, and intentional damages and failures. Therefore, the physics of components, the system usage and its exposure to an environment are the root causes of safety events. On the contrary, security events are mostly determined by human-related factors like the motivations, gains and opportunities of attackers. In addition, successful events may require for an attacker to acquire certain knowledge, skills, and resources.

Standards, development cycles and methods

Standards ecosystem

A wide variety of standards have been published targeting safety or security aspects. The Figure 3 shows some of them. Most standards are elaborated not only targeting a given problematics but also considering the specificities of an application domain. In the safety area, the standard IEC-61508 [START_REF]-Functional safety of electrical/electronic/programmable electronic safety-related systems. IEC[END_REF] is a generic reference to conduct functional safety analyses of so called Electrical-Electronic-Electronically Programmable (E/E/EP) systems. This generic standard has been taken as a reference in order to adapt and specialize the safety analyses for different application domains. An analogous pattern can be found in the development of standards pertaining to the security area (e.g., considering ISO-27005 [3] as a generic standard). However, the level of maturity, consensus and/or adoption of security standards is still limited and many discussions and work are in progress. This disparity can be partially explained by the late identification of security as a strategic topic in the industry-research landscape. In addition, the analysis of security introduces specificities and new elements which raise questions and increase the complexity of discussions. Standards not only provide a conceptual basis but also guidelines for the integration of concerns in the development cycle. Thus, development cycles can be accordingly completed via the integration of safety and security aspects. A representative instance of such integrated process can be found in the ISO-26262 standard [START_REF]International Organization for Standardization: ISO 26262 -Road vehicles -Functional safety. ISO[END_REF] (safety of road vehicles). A common practice of safety and security engineering will demand and integration of both safety and security aspects.

Towards an unified development cycle

If a development process integrating safety and security aspects is required, such integration does not suffice to achieve an effective safety-security co-engineering. For instance, typical standalone instances of safety and security development cycles include a requirements elicitation phase. A naive integration can consist in first elicit safety requirements and afterwards the security requirements (or conversely). This sequential integration may result inefficient and may even be ineffective, since it does not address potential conflicts between requirements. In addition, conflicts may not only appear during the problem definition phases but also during the solution phases in the development cycle, e.g., a cypher mechanism deployed to protect frames confidentiality may impact system's performance and violate real-time safety constraints. Therefore, a unified development cycle should not only consider the integration of development processes and phases, but also the specific methods and techniques used in safety and security -in addition to the specificities of the application domains. The achievement of such unified development cycle shall be a milestone of industry-research working groups. However its definition is limited by: (1) the observed disparity between security and safety standards (maturity, consensus and adoption), and (2) the complexity of ensuring coherence between safety and security methods and techniques.

Model-driven approaches for co-engineering

The importance of integrating not only processes but also methods for safety and security analyses was highlighted in previous section. This section provides insights on model-driven engineering (MDE) techniques for achieving coengineering of safety and security.

Safety and security engineering commonalities

The current state of practice shows that safety and security engineering are conducted in standalone mode and guided by independent processes and methods. Figure 4 shows an overview of two instances of processes to conduct safety and security activities in the development cycle. To tackle the structural complexity and integrate both processes into a single one, the following high level commonalities are observed:

-The usage of evaluation criteria is present in both processes and some criteria rely upon discrete evaluation scales (qualitative and quantitative). -Both processes demand the definition of metrics or scales to evaluate risks, likelihood, and severity.

-Both processes are risk oriented and the evaluation of risks is based upon likelihood and severity scales. -A function to evaluate the acceptability of risks exists in both processes.

-The elicitation of Feared Events is targeted in both processes.

Regarding the last item, notice that Feared Events identified during the safety analysis might be also targeted by attackers. Conversely, some Feared Events, unveiled during the security analysis, might also be caused by purely accidental functional failures. In such cases, common or interdependent Feared Events can be the basis to conduct the expected co-engineering.

Model-driven approaches for multi-concern analyses

It is assumed that the reader is familiar with Model Driven Engineering (MDE) principles and techniques. Non-savvy readers can consult these references [START_REF]Object Management Group[END_REF], [START_REF]The Eclipse Foundation: Papyrus[END_REF]. MDE has been applied to support engineers during several phases of the development cycle, e.g., design and verification [START_REF] Pedroza | A Formal Methodology Applied to Secure Over-the-Air Automotive Applications[END_REF], [START_REF] Hamid | Security patterns modeling and formalization for pattern-based development of secure software systems[END_REF]. In particular, during the design phases a model of the target system is usually constructed. The model is based upon standardized languages like UML [START_REF]Object Management Group: Unified Modeling Language specification[END_REF] and SysML [START_REF]Object Management Group: System Modeling Language specification[END_REF] which facilitate typical design tasks like system structuring, refinement, decomposition, extension, and/or transformation. MDE languages are flexible enough to be extended and specialized so as to capture the elements necessary to conduct safety and security analyses. Indeed, fundamental concepts, the relationships between them, and analyses steps can also be represented and implemented. Following typical MDE approaches, the system model can be enriched either with the elements related to safety or security. Annotating finally yields two models suitable to -separately-conduct safety or security analyses (see Figure 5); the annotated models are insufficient to support joint safety-security analyses. However, they provide a basis to construct the co-engineering framework as explained in next subsection.

Joint safety-security engineering

To support joint safety-security analyses (co-engineering), the MDE framework can be leveraged in the following way:

Integration of meta-models. Safety and security annotations are defined in separated meta-models. The meta-models allow to capture the fundamental notions, principles associated to the concern and also capture their relationships. The conceptual alignment, necessary to achieve joint safety-security analyses, can be initiated by identifying common elements, prior to a first integration of meta-models. The Figure 6 shows an excerpt of a diagram used to associate concepts pertaining to different standards. Solving conflicts. Once meta-models are aligned by linking common parts, the dependencies can be observed and the potential conflicts along methods phases can be better identified and solved. Recall that conflicts can appear from the application of safety and security methods and techniques and also between their outcomes. In particular, when a technique is applied over modeling instances that are out of common parts in the integrated metamodel.

Integration of processes and phases. Once method phases are supposed to be "free of conflicts", the processes can be integrated. Notice that certain conflicts can not be identified in advance at method level. For instance, conflicts between safety and security requirements -elicited at different phases -can appear after a first architecture design is made. A safety-security development cycle should consider this kind of issues. Framework implementation. The framework supporting joint safety-security analyses can be implemented following typical MDE development steps: metamodel implementation via a UML/SysML profile, generation of profile code, implementation of safety and security algorithms, customization of the framework front-end, and building the tool product.

5 Difficulties to achieve integration of safety and security processes and their adoption

In previous section, a generic, coarse description was provided about leveraging MDE techniques in order to achieve safety-security co-engineering. Our involvement in several academy-industry projects (AMASS, SESNA, ModSécAéro) allows us to ensure the effectiveness of those MDE techniques. By doing so, several technical and non technical difficulties have been identified which may limit the progress of ongoing work. First, regarding the current state of standalone safety and security development processes, they are in general complex, costly and mostly human based: few support for tasks automation exists. Despite there exist development processes that show certain integration of safety and security aspects (e.g., [START_REF]ED202 -Airworthiness Security Process Specification[END_REF]), they are rather specific to an application domain. In general, a low level of maturity is observed in aspects like integration, tool support and automation. Other aspects impacting the dissemination and progress of safetysecurity co-engineering are related to current engineering practices. Globally, conduct joint safety-security analyses is a quite recent research and engineering area. To our knowledge, information about case studies showing co-engineering in practice are rare. In addition, there is almost no published feedback from industry on the effectiveness of applied methods and techniques. It is reasonable to believe that some years are still necessary to consolidate our understanding on the topic. For many industry sectors and several application domains, cyber-security is almost an emerging concern. In those cases, an a posteriori reaction to cyber-security threats is observed: the lack of awarness on cybersecurity risks/culture often leads to underestimate, misunderstand or believe not concerned by the potential threats. Some market, organizational and engineers practices may facilitate the adoption of safety-security engineering processes. In particular, certification is a powerful mechanism to align technical criteria and ensure trustworthiness what finally shapes markets. However today, no certification process for safety-security critical systems exists so far. Last but not least, the impact of safety and security concerns in current organizations and engineer practices should be better identified in order to facilitate the adoption of an integrated development cycle.

Integration of safety and security techniques

This section is dedicated to explain an instance of techniques integration. The chosen techniques are usually applied in safety and security. The instance is relevant since it helps to highlight some challenges for a consistent safety-security intertwining.

Combined attack-fault trees

Fault and attack trees are known techniques respectively used in safety and security areas. They are means to structure and evaluate unwanted events impacting a target system. On one side, fault trees are often composed by nodes representing system failures as boolean variables. The fault nodes are linked by logical gates AND, OR and can be assigned with a probability of occurrence. On the other side attack trees can be composed by nodes representing vulnerable states of the system, attacker actions, or conditions for attack progression. They are also linked by logical gates AND, OR. Despite the assignation of probabilities to attack nodes has been suggested, the estimation and interpretation of outcomes are still arguable (more details in subsection 6.4). Several approaches have been proposed to integrate (merge) fault and attack trees, e.g., [START_REF] Nai Fovino | Integrating cyber attacks within fault trees[END_REF]. However, the integration is mostly structural and, in general, several issues still remain unsolved. Some pros and cons observed in approaches for tree merging are described in the following items:

Pros: Most algorithms for integration of fault and attack trees have a polynomial complexity on the number of nodes. Those algorithms can be implemented thus providing support for automatically merging trees. In certain cases, the attack tree is transformed towards a fault tree yielding a merged tree with a simpler structure. It is also observed that safety metrics and functions are often reused for evaluating certain properties of attacks. In particular, the failure rate and the Mean Time to Failure inspire their security counterparts, namely, Attack rate, and Mean Time to Attack. These metrics and functions are useful to estimate the probability of attacks occurrence. Cons: The variety of attack tree nodes semantics seems broader than their safety counterparts. Indeed, irrespective of the reference considered, the definition of fault trees remains mostly equivalent. On the contrary, there is no common definition for attack trees and consequently a rather heterogeneous variety of definitions exist. No common semantic for attack tree nodes can be identified so far. As a consequence, nodes describing attack steps or actions, can be specified at different levels of abstraction and granularity. Since vulnerabilities can be present at different system levels (HW/SW) and caused by different types of flaws, the tree nodes representing them are also heterogeneous. Attack nodes representing the conditions for attack progression show similar characteristics. Referred specificities suggest that, to keep consistency, fault and attack trees merging shall mostly remain a human-based task. Since the semantics and nature of nodes (safety and security events) are different, reusing safety metrics and functions to evaluate security aspects should be more thoroughly considered.

Discussion on metrics for safety assessment

The so called Mean Time Before Failure (MTBF) is a central metrics applied in safety to estimate systems life and other related features. The MTBF is computed by obtaining the mathematical mean of a probability distribution function (pdf ) with exponential basis (see Figure 7). The exponential pdf measures the probability of failures occurrence and is characterized by its λ: λ is a failure rate which measures the failures of a component (or system) per time unit. However, as shown in Figure 7, the exponential-based pdf is not the only probability distribution available. The exponential pdf is currently adopted as a valid metric thanks to (1) the experiments that can be conducted to compute λ and (2) the effectiveness of MTBF predictions w.r.t. systems life observed at field. These facts imply that a suitable correspondence between the mathematical model and the physical phenomenon (systems ageing) has been settled. One of the main hypothesis for the estimation of the MTBF is that the failure rate λ remains constant. However, the validity of this hypothesis is limited. The Figure 8 depicts the actual evolution of components failure rate across their life time. It is observed that the failure rate is mostly constant during a life interval (called normal), but rapidly changes during youth and ageing stages. All in all, even if the mathematical model reflects the essence of a phenomenon, it remains constrained by the validity of hypotheses. Recent experimental results show that certain MTBF predictions may differ from real life time of systems observed at field [START_REF]Experimentation of the new Reliability prediction method FIDES[END_REF]. According to this study, the failure rate λ is not only determined by the physics of components, their nominal usage, and the exposure to a given environment. It also depends upon the quality of the process for components (and subcomponents) development. Moreover, accidental damages, occurred during manufacturing, may over-stress the components and finally increase their failure rate. A more precise calculation of λ shall require to consider previous factors. 6.3 Discussion on metrics for security assessment Many approaches found in the literature rely upon variants of the exponentialbased pdf to estimate the probability of an attack. However, not many address the question about the adequacy of this mathematical model w.r.t. the phenomenon, i.e., the attack progression. The work in [START_REF] Holm | A Large-Scale Study of the Time Required to Compromise a Computer System[END_REF] provides experimental results on the time to compromise a large informatics system. The proposed metrics is named Mean Time to First Attack (MTFA) and is calculated from data gathered from intrusions at field. The collected data are used to compute attacks frequency and afterwards to calculate parameters of several pdf 's (and in particular λ). The predictions of the MTFA relying upon different pdf 's are then compared to the real periods of attacks' occurrence. The results of the comparison show that the best fitted model is not the exponential but the Pareto based pdf [START_REF] Holm | A Large-Scale Study of the Time Required to Compromise a Computer System[END_REF]. Thus, it is reasonable to question about other potential mismatches like the one just identified for the safety assessment metrics. In particular, whether the attack rate remains constant along a given period during the systems life. Or even whether the use of the attack rate suffices to characterize the whole phenomenon which involves threats and vulnerabilities. A first element to answer these questions is that, along with factors affecting elements manufacturing (quality of development process, accidental damages), the attack rate is likely also impacted by other factors appearing before and during attack execution. Those factors could be identified and analyzed by considering the phases of attack preparation and deployment. The so called intrusion kill chain [START_REF]and Transportation: A "Kill Chain" Analysis of the 2013 Target Data Breach[END_REF] (see Figure 9) defines several attack phases which can be useful for that purpose.

Perspectives for consistent assessment of safety and security

The use of field data to validate a mathematical model for attack prediction seems a consistent approach. However, the metrics used for security assessment may need to be validated in larger case studies and for other kind of systems. The pdf 's for predicting security (and also safety) events occurrence might be better rely upon other basis than the exponential. Further studies may help to identify the accuracy of predictions already obtained with the exponential model. To gain representativeness in the security assessment, larger and more diversified field data are necessary, for instance, data from different attack categories, known vulnerabilities, and application domains. To improve the computation of attack rates, factors related to attack preparation and deployment phases need to be introduced, for instance, attacker resources, skills, smartness, and motivations. Nonetheless, increasing the accuracy of a mathematical model also increases its complexity, and the cost and complexity of the prediction method. Consequently, more guidance and support will be necessary to bring forward these suggestions.

Overall perspectives

Safety and security co-engineering is rather a young area and further works and progress are expected to gain in maturity. Regarding the conceptual and processes integration, certain engineering techniques (like MDE) will contribute to consolidate the the co-engineering of safety and security. However, certain specificities of each area will remain and it is likely that standalone development practices will prevail for a while. The choice of a unified safety-security development cycle seems feasible but its deployment and adoption remains, for now, complex and costly to achieve. Further methodological and tool support are needed to help concerned communities to overcome these issues. Regarding the metrics for safety-security assessment, the consistency and validity of metrics need to be ensured in order to achieve more accurate predictions. The application of mathematical models in security assessment still needs further validations.

Fig. 1 .

 1 Fig. 1. Relationship between safety and security critical systems

Fig. 2 .

 2 Fig. 2. Conceptual positioning of safety and security elements

Fig. 3 .

 3 Fig. 3. Overview of some relevant standards for safety and security

Fig. 4 .

 4 Fig. 4. Overview of standalone safety and security development processes

Fig. 5 .

 5 Fig. 5. View of safety and security models obtained after annotations

Fig. 6 .

 6 Fig. 6. Excerpt of a diagram showing meta-models integration

Fig. 7 .

 7 Fig. 7. Some metrics and functions used for systems safety assessment

Fig. 8 .

 8 Fig.8. Typical evolution of failure rate across time. The graph is borrowed from[START_REF]Experimentation of the new Reliability prediction method FIDES[END_REF]

Fig. 9 .

 9 Fig.9. Phases of the so named intrusion kill chain. Image borrowed from[START_REF]and Transportation: A "Kill Chain" Analysis of the 2013 Target Data Breach[END_REF]


Teodosio Vicente Parra

Del Caño

María L Rodríguez-Méndez

José A De Saja

Marcel Bouvet

Yasuhiko Shirota

Teodosio Del Caño

Electroactivity of a starburst hole-transport material in Langmuir-Blodgett films. Solid state effects and intervalence charge transfer

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Graphical abstract

The fundamental electrochemical properties of unprecedented Langmuir-Blodgett films of m-MTDATA are analyzed to support why it is one of the most efficient hole-transport materials in OLEDs applications.

Introduction

Organic semiconductors have emerged in the last decade as main active components in practical thin films devices as photovoltaic cells, light emitting displays, field-effect transistors, sensors and other electronic devices1-3. Within the large variety of organic semiconductors, amorphous molecular materials or "molecular glasses" have found successful application for use in organic electroluminescent devices (OLEDs) and other applications as photovoltaic, photochromic and resist materials4. The reason of this rich variety of applications is their facility to form smooth, uniform, isotropic, and in certain cases transparent thin films by evaporation or spincoating from solution. In particular, 4,4´,4´´tris [3-methylphenyl(phenyl)amino] triphenylamine (m-MTDATA) is widely known to be an excellent hole-transport material that has been extensively and successfully used in OLEDs designing5, 6.

Recently, one of the authors of the present work has studied the influence of the method of thin film preparation in the performance of OLEDs using m-MTDATA as hole injector7. Thus, it is motivating to study the properties of thin films fabricated using alternative techniques such as Langmuir-Blodgett, focusing in their electrochemical and spectroelectrochemical behavior.

The LB technique has been mainly used in the fabrication of thin films of molecular materials of amphiphilic nature or with high planarity that can easily form ordered films8. However, few attempts have been carried out to prepare LB films of non-amphiphilic polymers9, characterized by the absence of molecular order, or non-planar molecules as fullerene10, coordination complexes11, etc. Thus, in this line, although m-MTDATA results to be a nonamphiphilic starburst molecule, its extended πconjugated system might allow a high enough intermolecular coupling compatible with the LB technique. In addition, the fabrication of this kind of molecular films is useful in applications 100 where the film thickness should be controlled at a nanometric level or in devices where the physicochemical process takes place at the film surface, as for instance, in sensor units12.

Therefore, the reasons of using the LB 105 technique are, on one hand, the skills offered by this approach when one wants to attain homogeneous and controlled films. On the other hand, we contributed on the fundamental research on LB films, regarding the particular 110 structural features of m-MTDATA.

In addition, the application of fundamental electrochemical methods to survey the oxidative behavior of materials with inherent hole-transport properties can be extremely 115 useful13. Using voltammetric techniques such as CV, it is feasible to elucidate features such as the number of electron transfer processes involved in the redox steps, the active sites present in the skeleton's molecule, and their kinetic and 120 thermodynamic properties, among other practical information as the estimation of optical bandgaps14,15. Indeed, the electrochemical characterization of m-MTDATA has been carried out yet in solution16. However, since the 125 practical applications in devices take place in the solid state, it would be of great interest to exploit the CV behavior in molecular films as LB multilayers, which are closely related to the functionality of molecular materials in Organic 130 Electronics purposes.

Finally, and according to the important role played by this starburst triphenylamine molecules in OLEDs applications4,17-19, we studied the spectroelectrochemical behavior of 135 the films, which, by integration with the results from the electrochemical experiments, can provide a powerful source of information in order to analyze the electroactive properties of m-MTDATA in thin films, as it does when playing the role of hole-transport material in molecular electronic devices.

Triarylamine derivatives bringing a number of linked π-bridged phenylamine groups are materials that lead to mixed-valence states once oxidized. Studies dealing with mixedvalence organic materials have not been traditionally performed if we compare with those of metal-bonded or metal-conjugated compounds20. Thus, in particular, the analysis of the spectroelectrochemical behavior of m-MTDATA in LB thin films state constitutes a profitable experiment to support its usage as functional material in electroluminescent devices. Moreover, this kind of experiments are likely to be integrated with the electrochemical analysis previously discussed, and then leading to a valuable source of information regarding the electroactive properties of this molecule in thin films, i.e. the state used in Organic Electronics applications.

There are a very scarce literature devoted to spectroelectrochemical studies of this sort of materials in solid state, and those existing deal with electropolymerized films18,21. However, 165 none study has been performed in films built using electroless approaches as the LB technique, that is, in films built by pure solid state intermolecular interactions.

Experimental 2.1 Materials.

m-MTDATA was synthesized according to the reported procedure16. Dichloromethane (CH2Cl2, HPLC grade, purchased from Aldrich), 175 KCl, KClO4, tetrabutylammonium perchlorate (TBAP, 99% Aldrich) and ferrocene (Fluka) were used as received. For solid state electrochemistry, water solvent was distilled and subsequently passed through a Millipore Milli-Q 180 system to attain ultrapure quality (18.2 MΩ.cm resistivity).

LB films and LB electrodes fabrication.

The thin films were fabricated using a KSV 5000 LB trough equipped with a Wilhelmy plate to measure the surface pressure changes. The m-MTDATA was dissolved in CH2Cl2 at a concentration of 1.1x10-4 mol.L-1. A total volume of 350 l was spread with a Hamilton 190 microsyringe onto ultrapure distilled Millipore Milli-Q water, maintained at 18 ºC. Monolayer characterization and isotherm stability tests were carried out. After evaporation of the solvent (20 minutes), the floating molecules were 195 compressed at 10 mm.min-1 speed. The layers were then transferred to glass, gold mirrors and ITO/glass substrates at 5 mm.min-1 speed when a target surface pressure of 18 mN.m-1 was reached (within the solid phase of the Langmuir 200 film). The thin films were fabricated using Zdeposition (i.e. transferred only during substrate's upstroke). 18 Monolayers were transferred to the different substrates. This entails the accomplishment of a practical film 205 thickness, representative of that used in device's designing.

For the fabrication of the m-MTDATA LB-based electrodes used in the electrochemical and spectroelectrochemical experiments, glass 210 slides (2.5 x 1 cm2) coated with ITO (150 Ω/sq sheet resistance) were used as substrates, being initially cleaned in pure acetone and ultrasonicated in Millipore MilliQ water for 5 minutes. The metallic contacts were ensured with 215 silver paste and fixed by adding an epoxy resin on top of them.

The gold films (50 nm thick) used as substrates for Reflection-Absorption Infrared Spectroscopy (RAIRS) measurements were 220 prepared by high vacuum deposition (BALZERS SCD004) over microscope glass slides.

2.3

Thin film characterization and electrochemical measurements.

225

The UV/Vis/NIR spectra of films were recorded using a double beam SHIMADZU 1603 spectrophotometer (wavelength range 300-1100 nm). RAIRS spectra were recorded using a Nicolet Magna IR 760 Spectrometer equipped 230 with a DTGS detector. The RAIRS spectra were recorded at an incident angle of 80º. The material was also dispersed in KBr powder to produce a pellet which transmission infrared provides a random spatial distribution of dynamic dipoles. 235 Therefore, it can be considered as reference in molecular organization studies. All spectra were collected using a resolution of 4 cm-1, and the mean of 256 scans was obtained. The sample chamber was systematically purged using dry N2 before data collection, to minimize the atmospheric interferences.

Cyclic voltammetry (CV) of LB films were performed using a potentiostat/galvanostat EG&G PARC mod. 263 at controlled temperature (20 ºC). We employed a three electrode-cell configuration consisting of a Pt plate (surface: 1.5 x 1 cm) as the auxiliary electrode, an Ag/AgCl|KCl saturated as reference electrode, and LB thin films of m-MTDATA coating ITO/glass substrates (surface: 2.5 x 1 cm) as working electrodes. To avoid a possible effect of oxidization of m-MTDATA in presence of oxygen16, all solutions were previously purged using dry N2. For CV experiments in organic solution, the potentials were measured against the same aqueous-based reference electrode, but the peaks were calibrated with an external standard, the ferrocene/ferrocenium (Fc/Fc+) redox system, at analogous conditions (0.1 mol.L-1 TBAP in CH2Cl2). The working electrode was a Pt disk (1 mm diameter) and the auxiliary electrode, a Pt wire.

The potential scans were applied in oxidative sense, from negative potentials (-0.75 or -0.20 V, corresponding to voltages separated from the m-MTDATA's electroactivity) to 1.3 V, and finishing at the original potential values. The sweep rates ranged from 20 to 500 mV.s-1 depending on the aim of each experiment.

The spectroelectrochemistry was carried out by oxidizing the films at fixed potentials by both CV and chronoamperometry, then recording the subsequent UV/Vis/NIR spectra independently.

Results and discussion

Langmuir and Langmuir-Blodgett Films.

Reproducible surface pressure (Π)-area isotherms of the m-MTDATA floating monolayers were obtained, being characterized by the formation of a well-defined solid phase as shown in Figure 1. As it is observed, the surface pressure starts to raise at area-per-molecule values of ca. 110 Å2. Then, a monotonous stiff rising in Π starts near 8 mN.m-1. This part of the isotherm can be attributed to the liquid-solid phase transition due to the increasing π-π intermolecular interaction in the floating film. The area-per-molecule value extrapolated to Π = 290 0 for the Langmuir film -the "mean molecular" area -extracted from the sharpest portion of the isotherm results to be 76 Å2. Finally, at a pressure of ca. 25 mN.m-1 (molecular area of 45 Å2), a slight slope change occurs, which is 295 ascribed to the beginning of the Langmuir film's collapse. monomolecular film at the air-water interface. In any case, one can observe that the extended πconjugated electronic system allows high enough stacking between adjacent molecules, leading to the formation of the clear solid phase in the isotherm. Moreover, in order to study the degree of reversibility of the interactions between the film-forming molecules, some compressionexpansion studies were carried out at Π = 35 mN.m-1 (from 0 to Π mN.m-1, then the inverse process), over the collapse point. As it is also noticed in Figure 1, the corresponding first expansion cycle shows an extrapolated molecular area to zero surface pressure of 62 Å2 indicating certain, but not severe, degree of hysteresis. In summary, although the m-MTDATA floating layer on pure water might not be a true monomolecular layer, the extracted area-permolecule value, and the moderate hysteresis, indicates that this starburst molecule accommodates well-enough in a floating layer structure, forming a non-monomolecular layer but permitting the transfer onto solid substrates. Regarding this process, the transfer ratios varied from 1.2 from the first upstroke to 0.6 for the last layer transferred, in agreement with the nonamphiphilic character of the compound.

Fourier Transform Infrared (FTIR) analysis.

In this study, Polarization IR spectroscopy was used to determine the molecular arrangement within the m-MTDATA LB film. Reflectionabsorption Infrared spectroscopy (RAIRS) profits from the perpendicular polarization of the electrical field at the nodal point on the reflecting surface plane. Therefore, the intensity of the vibrational modes with dynamic dipole components perpendicular to the surface will be enhanced, while those parallel to the surface will be suppressed23,24 (i. e., a "surface selection rule"). Pellet (bulk) transmission spectrum, where the material is dispersed in a KBr matrix, i.e. random spatial distribution of dynamic dipoles, is used as reference. Thus, by comparison of the relative intensity of the vibrational modes in transmission KBr and RAIRS spectra, information about the molecular organization over the substrate can be extracted25. In Figure 2, the LB film RAIRS and KBr 380 pellet spectra of the m-MTDATA are shown. Table 1 also collects some quantitative data regarding the relative intensities and assignments of the bands. The main vibrational components of the KBr infrared transmission spectrum are 385 closely related to the triphenylamine spectral patterns and can be summarized as follows: C-H wagging modes centered at 696 and 751 cm-1, the C-N stretching modes observed at 1273 and 1309 cm-1, the C=C stretching modes at 1503 390 cm-1, the C-C stretching mode at 1583 and 1592 cm-1. In this spectrum, the most intense vibrational band results to be the C=C stretching mode at 1503 cm-1, followed by the C-N stretching mode observed at 1273 cm-1. At first 395 glance, the thin film m-MTDATA RAIRS spectrum shows a similar profile that could be ascribed to an random distribution of dipoles, and thereby, the absence of a preferential molecular alignment, in agreement with the 400 amorphous nature of m-MTDATA.

However, a detailed analysis of the relative intensities highlights certain differences between spectra. In the RAIRS, the C=C and C-C stretching modes become more prominent,

CV of LB films in

Current / uA

Current / uA reported in Figure 4. Figure 4a shows the two first cycles of an 18-layer LB film, which display an oxidation process defined by a unique redox couple. It is observed the appearance of an anodic peak from the second cycle, accompanied to the corresponding cathodic couple, which is slightly shifted with respect to the first one. The anodic potential locates at 0.95 V and the cathodic at 0.49 V, which means E1/2 = 0.77 V.

510

This well-defined redox couple, with an icathodic/ianodic ratio near 1, suggests that the electrochemical step is quasireversible. In Figure 4b, the subsequent three cycles after the initial two cycled scanning are presented to allow the stability of the film in KCl to be checked. As is observed, consecutive scanning produces evident changes in the CV, 530 which mainly occur in the cathodic waves.Herein, the peak shifts to lower potentials and current values vary, besides the occurrence of a clear loss of shape.

CV of LB films in KClO4 solution.

It can be expected that during the films' oxidization, the electrolytic anions will diffuse into the film to maintain the electroneutrality of 540 the system. For this reason, the use of different counteranions should help to elucidate the nature of the oxidization's mechanism. In order to evaluate the role of the electrolytic solution in the electrochemical properties of the 545 films of m-MTDATA, they were immersed in 0.1 mol.L-1 KClO4 and the results were compared to those obtained by using KCl. In case of ClO4-, the hydrated energy of this counteranion is markedly lower (i.e. more 550 hydrophobic) than that of Cl-(-ΔGsolvation = 214 KJ.mol-1 vs. 347 KJ.mol-1, respectively)28. Thus, it is possible to acquire useful information regarding the affinity of the film to both anions during the oxidization. Figure 4c illustrates the 555 CV diagrams of a LB film in a 0.1 mol.L-1 KClO4 solution. Here, the oxidation and reduction processes at the second cycle appeared at 0.79 V and 0.40 V (i.e. E1/2 = 0.59 V). These values, together with the almost found 100% 560 peak currents ratio are also indicative of a quasireversible redox reaction. However, the response of a LB film polarized in KClO4 differed noticeably to that in KCl. On one hand, films immersed in KClO4 are much more easily 565 oxidized (there is a cathodic shift of 180 mV). On the other hand, the electrolyte also plays an important role in the reproducibility of the successive cycles. Figure 4d Regarding the cathodic waves, values of r2= 0.998 vs. v1/2, and r2= 0.958 vs. v were found. Thus, these trends support the envisaged slow redox kinetics, being the process mainly 620 governed by the diffusion of the electrolyte into the film, more than a mechanism typical of surface-confined species.

Solid state (LB) electrochemical

625 behavior. Discussion Some interesting features are revealed after analyzing the voltammetric behavior of m-MTDATA in LB films, namely i) the appearance of an unique, broad and non-Nernstian 630 oxidization process in LB films instead of the two well defined redox activities observed in solution; ii) a diffusion-controlled, then rather slow redox mechanism and iii) a noticeable influence of electrolyte's anions in the 635 oxidization process. First, to explain such outcomes, issues as the solid state effects in the thin solid film, the different solvent-based solutions and sizes of the hydrated electrolyte's anions are key factors.

640

As it was introduced above, it is expected that the electrooxidation of m-MTDATA occurs in the sites with the highest density of charge of the starburst skeleton, namely the nitrogen atoms of the triphenylamine groups. The molecule 645 owns four of them (cf. inset of Figure 1), but the fact that only one and broad peak was observed may indicate a noticeable influence of the adjacent molecules, suggesting the creation of an equivalent charged state in the stacked molecular 650 film. This unique process, according to their features, namely potential values comparable to the two monoelectronic peaks observed in solution, its fashion (large separation of peaks and width) and the slow kinetics behavior, could 655 be related to the formation of not only aminyl radical cations, but also dications29,30. Besides, the electrochemically p-doped film would be somehow stabilized by delocalization of the electron density as a result of solid state original film; M: structurally modified film; F: final film.

In order to compare the voltammetric behavior in both molecular environments (solution and LB film) and taking into consideration the known hole-hopping charge transport properties phenomenon of m-690 MTDATA, one can allude to the Marcus theory for the charge transfer30. According to this semiclassical theory, the kinetics of the charge transfer is related to the molecule's reorganization energy after formation of radical 695 cations and geometric relaxation. This parameter is defined as the sum of an intramolecular (vibronic) factor -structural changes in the equilibrium structures during the self-exchange charge transfer process Molecule+ + Molecule 700 ↔ Molecule + Molecule+ -and other attributed to environmental effects (solvent polarity, aggregation state, etc.). As a result, it is obvious that these two terms will contrast manifestly between the CH2Cl2 solution and LB thin film state, either by the oxidization process depending on the solvent-based electrolyte solution or by the relaxation phenomenon after formation of the radical cations in the π-π interacting molecular film.

On the other hand, it should be also pointed out the effect of the anion's electrolyte in the oxidization mechanism of m-MTDATA LB films, according to the different redox behavior observed, in terms of stability and reversibility, depending on the presence of the hydrated chloride (Cl-aq) or perchlorate counterions (ClO4-aq) in the diffusion-layer near the electrode. In both cases, in the first electrooxidative potential scan, there is evidence of no (or rather weak, in case of perchlorate) oxidization peak of the m-MTDATA's multilayer. This indicates that the surface of the film needs to be unlocked to allow the ingress of the counterions to electroneutralize the locally created positive charges (process supported by the prominent cathodic peak in the corresponding reverse scan). In particular, when Cl-aq takes action, there is a sensible variation, i.e. different current values and peak shifting at lower anodic 730 potentials, in the electroactivity during the reverse reduction scans. This behavior is likely to be associated to a strong ion-pair formation of chlorides at the film surface (Figure 6).

In contrast, this trend is not followed in 735 case of ClO4-aq, anion that makes the electron transfer more reversible and stable. This is likely to be explained in terms of its larger hydrophobicity (i.e. lower hydration energy), which allows it to diffuse (ingress and egress) 740 easily into the film26. Nonetheless, herein, the slightly loss in the peak currents ratio (icathodic/ianodic) during consecutive cycling (Figure . 4d), such an outcome also exhibited in the CV diagrams at different sweep rates (Figure. The diffusion of charged mass is suggested to be associated to the efficient 750 interconnection between the starburst molecules into the packed film, which permits the renewal of the oxidized surface in a simultaneous way to that of the ion's entrance.

Spectroelectrochemistry

The spectroelectrochemical properties were examined by analyzing the UV/Vis/NIR spectra of films treated at different oxidization conditions. These experiments were carried out 760 by both CV and chronoamperometry, using the KClO4 solution. The results are shown as a series of electronic spectra correlated to films electrochemically treated (Figure 7).

Thus, prior to anodic treatment, the 765 white-yellowish films showed an intense band at 335 nm, with lack of additional absorptions all along the visible region (Figure 7A). A negligible absorbance increasing between 400 and 600 nm was observed after multicycling the 770 LB film (3 times) up to 0.7 V (Figure 7B), potential value ascribed to the anodic wave rising previous to peaking (i.e. earlier than complete oxidization of m-MTDATA). On the other hand, by further increasing the applied potential to 1.3 775 V and 1.6 V, the film turned greenish and displayed new absorption patterns near 450 nm, such a band ascribed to the formation of radical species, besides a wide-ranging band growing from ca. 760 nm, which is markedly extended over NIR region (Figures 7C-D). At 1.3 V, this band shows a maximum at 910 nm, which is more intense and slightly red-shifted when oxidizing up to 1.6 V. These emerging bands are due to the formation of new species at the film's surface during its oxidization, namely aminyl radical cations. Afterwards, and as a stronger oxidization method, chronoamperometry was applied to overoxidize the filmsubmitting it to 2.5 V during a period of 15 s -. Then, it was 790 observed how the NIR absorption even increased noticeably, further modifying its shape. Moreover, the band emerging at 448 nm, related to the radical nature of the film-forming material, diminished drastically (Figure 7E), whereas that with maximum at 335 nm showed no change.

Overall, the appearance of this intense and wellseparated band located at NIR is in agreement with the occurrence of Intervalence Charge Transfer (IVCT) between two redox centers in 800 the film-forming molecule18,25,33. By monitoring the NIR's absorption upon each oxidization, it can be deduced that the IVCT excitation changes (figures 7C to 7E) both in energy, intensity and shape (bandwidth). This 805 trend suggests that the molecule's reorganization energy and coupling between redox centers25 are modified, then varying the transition's features between ground and excited states in the material. According to the proposed oxidization mechanism, after oxidization, we are creating positive charges (i. e. holes, p-doping by electrochemistry) that are supposed to diffuse all 835 along the packed film, a process favored by the insertion of electrolyte's couteranions, which stabilize the formed radical species (by chemical reaction). The electrolyte's stabilization was supported by the irreversible tendency of the 840 optical features when performing the electrorreduction of the films. The concurrent formation of "polymeric" structures from m-MTDATA cannot be discarded, taking into consideration the known affinity between radical 845 species and the trend followed by the band at ca. 450 nm throughout the progressive oxidization process showed in Figure 7 (a transient process from neutral to radical, and then polymeric species). 850 Thus, this particular phenomenon is integrated with the fact that π-bridged triphenylamine derivatives are very functional hole carrier systems, since the showed coupling of redox centers over π-conjugated channels in 855 thin molecular films is a key factor on the design of new optoelectronic materials34.

Conclusions

The fabrication of Langmuir and Langmuir-860 Blodgett films of a non-amphiphilic starburst molecule as m-MTDATA has been attained for first time ever. The Π-A isotherms of the floating layer of m-MTDATA indicated the formation of an extended solid phase, and the successive 865 compression-expansion cycles revealed that despite the fact that it is not a monomolecular floating layer, the Langmuir film presented strong cohesion, not high film rigidity and a good stability. These characteristics allowed the 870 transfer onto solid substrates, accomplishing uniform films. The FT-IR analysis showed that the films exhibit an isotropic nature but with an enhanced molecular planarity due to the induced packing by the use of the LB technique. On the 875 other hand, the solid state electrochemistry and spectroelectrochemistry highlighted the strong electron donating character of m-MTDATA. Meanwhile in solution two oxidation processes involving one-electron releasing took place ascribed to interacting triphenylamine centers, but in LB solid state only one peak is observed, suggesting the formation of an equivalent radical cationic derivative stabilized by delocalization all along the packed film. The electrolyte's anions influence markedly the redox mechanism. It is believed to consist of a local ion-pair formation at the surface, being stronger in case of Cl-aq. For ClO4-aq, due to its lower hydration energy (i.e. hydrophobicity) its diffusion into the film is facilitated. The spectroelectrochemical measurements showed that the oxidized species exhibit new absorption features, being of special interest the emerging bands in the NIR region. The features of this band (energy, intensity and shape) depended on the extent of the oxidization performed. According to the mixed-valence nature of m-MTDATA, this excitation is attributed to an intermolecular intervalence charge transfer (IVCT) between the formed aminyl radical cations. The charge transfer is believed to be assisted by the molecular thin film state (pure intermolecular interactions; electroless formed film). The stabilization of the oxidized material is favored by the aboveconcluded insertion of counterions, then making irreversible the electrorreduction process. Finally, the transient formation of polymeric species at higher potentials cannot be completely discarded.

Fig. 1 .

 1 Fig.1.-Π-A Isotherm compression-expansion cycle of the m-MTDATA Langmuir film registered at 18 °C. Upper inset: molecular 300

Fig. 2 .

 2 Fig.2.-FT-IR transmission spectrum of a KBr pellet and RAIRS spectrum of the m-MTDATA LB film.

  405whereas the C-N stretching modes and the C-H wagging modes show lower intensities if we compare with the pellet spectrum. These changes in relative intensities might be correlated with a close packing of the triphenylamine groups of 410 adjacent m-MTDATA molecules, which is enhanced due to the LB technique. It is known that this starburst molecule owns a non-planar shape, and the introduction of the methyl meta-position of the phenyl group favors the amorphous glassy state16. Then, despite one can deduce the absence of a neat preferential molecular orientation in thin films, and according to the relative intensities of the C-N stretching and C-H wagging modes in the LB film RAIRS spectrum with respect to the randomly arranged KBr pellet, this particular solid state supports the reorganization of the m-MTDATA molecules in a more planar conformation, a practical fact that would entail 425 an improvement of the electron conjugation all along the starburst skeleton.

Fig. 3 .

 3 Fig.3.-Cyclic voltammogram of m-MTDATA (10 mM) in CH2Cl2 with TBAP as the supporting electrolyte (sweep rate: 100 mV.s-1). Inset: Square Wave Voltammogram. Conditions: 495

  KCl aqueous solution.The electrochemical response of the m-500 MTDATA LB electrode in KCl and in KClO4 is

Fig. 4 .

 4 Fig.4.-Cyclic voltammograms of a 18-layer LB film immersed in a 0.1 mol.L-1 aqueous KCl solution; a) First two cycles starting from 0 V; b) first three scans in the subsequent experiment. Cyclic voltammograms of several molecular 520

Fig. 5 .

 5 Fig.5.-Cyclic voltammograms registered at 20, 50, 100, 150, 200, 250 and 500 mV.s-1 of a m-MTDATA LB film immersed in a 0.1 mol.L-1 aqueous KClO4 solution.

3. 3 . 4

 34 Redox reaction rate. The dynamics of the oxidization of the m-MTDATA films was examined by analyzing the influence of the sweep rate (20, 50, 100, 150, 250, 500 mV/s) in the peak features of the LB films (Figure 5, perchlorate-based solution). As a result, when sweep rate increases, besides the expected increasing of peak's currents, the appearance of raising diffusion tails in both anodic and cathodic signals agrees with the 610 occurrence a slow electron transfer electrode reaction. Likewise, in case of the anodic process, there is a highly fitted linear relation between the peak's current and the square root of the sweep rate (v1/2), giving a coefficient of regression of 615 r2= 0.999 (r2= 0.970 for current vs. v).

Fig. 6 .

 6 Fig.6.Schema illustrating a general mechanism 675

745 5 )

 5 , agrees well with the occurrence of a fairly rapid chemical reaction following the oxidization of m-MTDATA molecules.

  755

Fig. 7 .

 7 Fig.7.-Spectroelectrochemical behavior of m-MTDATA LB films at different oxidization 825

  830

Table 1 .

 1 -Wavenumbers of characteristic vibrational modes of m-MTDATA observed in the FT-IR spectra in thin film (RAIRS) and KBr pellet. The relative absorbance's intensities are referred to the strongest peak in the pellet spectrum.

	435
		Vibrational	KBr	RAIRS
		modes	pellet	LB film
		Wavenumber	Irelative	Irelative	Assignments
		/ cm-1
		1584	0.29	0.38	C-C phenyl stretching
		1503	1	1	C=C phenyl stretching
		1309	0.35	0.24	C-N stretching
		1271	0.46	0.38	C-N stretching
		696	0.3	0.2	C-H wagging
		3.3 Electrochemical studies.
		3.3.1 CV of m-MTDATA in solution.
		A 10-3 mol.L-1 CH2Cl2 solution of m-
	440	MTDATA was examined by CV in order to
		study its oxidation properties. Since the reference
		electrode was Ag/AgCl|KCl saturated and we
		used CH2Cl2 as organic solvent, the ferrocene
		(Fc) electroactivity was measured at equal
	445	conditions, in order to have an external reference
		(E1/2 vs. Ag/AgCl = 0.57 V). Figure 3 represents
		the voltammograms of m-MTDATA in a
		CH2Cl2 solution. In agreement with the
		electrochemical behavior of m-MTDATA
	450	previously found in solution but in other
		conditions16, two reversible processes can be
		observed at E1/21 = 0.43 V and E1/22 = 0.79 V

Acknowledgements

The GOODFOOD program (FP6-1-508774-IP) is grateful acknowledged for the financial support.