Romain Schneckenburger
email: schneckenburger-r@chu-caen.fr

Hainselin Mathieu

Fausto Viader

Francis Eustache

Peggy Quinette

Serum cortisol level in patients with a transient global amnesia

Keywords: Transient Global Amnesia, Cortisol, Stress, Memory

Transient Global Amnesia (TGA) could be triggered by a high level of blood cortisol. We assessed whether patients had a higher level of cortisol during the TGA than shortly after. We included 52 patients 21 with blood collected during the TGA and 31 shortly after. We compared these two groups after adjustment on time of blood collection. The cortisol's level was significantly higher in the perictal group (p= 0.03) and negatively correlated with the time elapsed from the onset of symptoms (p= 0.005). The results are consistent with of the hypothesis of a hyperreactivity of the hypothalamicpituitary-adrenal axis.

Introduction

Transient global amnesia (TGA) is a benign neurological condition that occurs principally in people between 50 and 70 years and is characterized by a profound memory impairment of sudden onset which lasts up to 24h. The clinical syndrome is now well described. It combines a profound anterograde amnesia, retrograde amnesia, disorientation in time and repetitive questioning, contrasting with spared consciousness and other cognitive functions [1].

The cause of TGA remains unclear, even though the diffusion-weighted magnetic resonance data point to an acute impairment of the CA1 field of the hippocampus [2]. However, the pathophysiology of this impairment is still unknown. One theory assumes the role of stressrelated factors in the emergence of TGA. According to this hypothesis [START_REF] Döhring | Stress-related factors in the emergence of transient global amnesia with hippocampal lesions[END_REF], the metabolic stress could induce a high blood level of cortisol which, in return, might trigger an impairment of hippocampal functioning. This assumption is backed by several facts: the high prevalence of stressing events occurring before TGA shown by epidemiological studies [START_REF] Quinette | What does transient global amnesia really mean? Review of the literature and thorough study of 142 cases[END_REF], the high density of glucocorticoid receptors in the hippocampus -especially in the CA1 subfield -, the rise in serum cortisol level in stress situations and the deleterious effect of acute stress or cortisol injection on declarative memory [START_REF] Bartsch | Transient global amnesia: functional anatomy and clinical implications[END_REF]. A recent study in 14 patients, seen during and after TGA [START_REF] Griebe | Enhanced cortisol secretion in acute transient global amnesia[END_REF], found that the salivary cortisol levels were higher during the TGA than after. The aim of our study is to replicate these results on a larger sample of patients with an assessment of serum cortisol levels during the TGA or in the following 24 hours.

Patients, material and methods.

The patients included in this study are part of an ongoing cohort of TGA patients seen at Caen University Hospital between 2000 and 2012. All subjects included in the present study fulfilled the Hodges and Warlow criteria and were enrolled in the emergency department.

They had a blood sample collected either during the TGA or the first following twenty-four hours to assess the level of cortisol. The study design was accepted by a local ethics committee and each participant gave written informed consent. The main objective of this study was to determine whether the level of cortisol was higher during the acute stage of TGA than after it. The secondary objectives were to estimate if this level was associated with stress as trigger factors of TGA or with its severity defined as its total duration. A stress factor was defined either as a physical stress (strengthening exercises, cleaning of the house…) or as an emotional stress (fight with a relative, hospitalization of a granddaughter).

We applied a Student t test to compare quantitative data between groups and categorical comparisons were made by the Pearson χ 2 test. All statistical analyses were conducted using R software 3.4.0. Results were considered significant at a 2-sided α-level of 0.05.

Fifty-three patients met the inclusion criteria, but one of them was excluded from analysis because the time of blood sampling was missing. Twenty-one patients had a blood sample taken during the acute phase (per-TGA group) and thirty-one after the TGA (post-TGA group).

Results

The main characteristics of each group are summarised in Table 1. The two groups were similar in age (63.6 years vs 62.5, p = 0.62), gender (Males = 36.5% vs 35%, p = 1) and presence of stress as a trigger factor (38% vs 32%, p = 0.4) but the duration was longer in the per-ictal than in the post-ictal group (5.6 hours vs 4.7 hours, p = 0.02). They also differed by the time of blood sampling (p < 0.001), as a higher proportion of patients in the post-TGA group was tested between 08:00 and 12:00 military time (18 vs 1).

There was no significant difference between the cortisol levels of the two groups (168.5 ng/l vs 163.5ng/l, t= -0.27 p = 0.8). However, after adjustment on time of blood sampling in a multiple linear regression model, the difference in cortisol levels became significant (p = 0.03, Fig. 1): with a similar time of blood collection, cortisol levels were significantly higher in the per-TGA group than in the post-TGA group. Moreover, in the per-TGA group, cortisol levels were negatively correlated with duration between TGA onset and blood sampling (Pearson's R= -0.6, CI95%: -0.8, -0.2; p = 0.005, Fig. 2). On the contrary, cortisol levels were associated neither with the duration of TGA (cor = 0.08; CI95%: -0.2, 0.3; p = 0.6) nor with the presence of stress as an identified trigger factor (155ng/l vs 169ng/l; p = 0.07). These results were not modified by the adjustment for time of blood sampling.

Discussion

The results presented above are coherent with the metabolic hypothesis as, after adjustment for the time of blood collection, the level of cortisol was higher during the TGA than shortly after. They are also coherent with previous data in the literature. Besides, the levels of cortisol were negatively correlated with the elapsed time since the TGA's beginning, backing the hypothesis that there is a threshold of serum cortisol above which the risk of TGA is increased and under which it is more likely to end. Moreover, the cortisol level during the TGA is not related to the stress as a causative factor, so it seems that the high cortisol level is not only an expression of the level of stress that has triggered the TGA, but could be itself involved in the pathogenesis. As glucocorticoids are highly responsive to stressful events [START_REF] Munck | Physiological functions of glucocorticoids in stress and their relation to pharmacological actions[END_REF], it may be argued that the high level of cortisol during the TGA is only a physiological response that reflects the severe anxiety that is common during it. But it has been shown that patients who recently suffered from TGA had a stronger dexamethasone feedback than healthy controls and a higher cortisol level in anticipation of experimental stress. The results seem to indicate a hyperreactivity of the hypothalamic-pituitary-adrenal axis (HPPAA) [START_REF] Griebe | Stronger pharmacological cortisol suppression and anticipatory cortisol stress response in transient global amnesia[END_REF]. They are in favor of the hypothesis that the high cortisol level is not associated with the anxiety induced by the TGA but could result, at least in part, from a primary disorder of the HPAA and explain why a stress event could trigger it.

But the HPAA could also play a key part in the psychopathology of TGA. A recent review stressed that the psychiatric symptoms during TGA -such as anxiety and depressive moodshould be considered as a core feature of TGA and are uncommon in other situations of acute anterograde amnesia like transient epileptic amnesia. [START_REF] Noël | The Still Enigmatic syndrome of Transient Global Amnesia: Interactions of Neurological and Psychopathological Factors[END_REF]. It has been shown that cortisol is involved in the pathogenesis of anxiety disorders especially in older adults [START_REF] Hek | Anxiety disorders and salivary cortisol levels in older adults: a population-based study[END_REF]. A high cortisol level during TGA could trigger both the neuropsychological and the psychiatric symptoms of TGA. Consequently, one of the strengths of the metabolic hypothesis is that it can explain both neurological and neuropsychological symptoms through a common pathophysiological pathway.

New studies are needed to better understand the pathophysiology of TGA, especially to establish correlation between cortisol levels and psychological features at baseline and during the episode.

  Hodges JR, Warlow CP. Syndromes of transient amnesia: towards a classification. A study of 153 cases. Journal of Neurology, Neurosurgery & Psychiatry, 1990; 53, 834-843. [2] Bartsch T, Alfke K, Stingele R, Rohr A, Freitag-Wolf, S, Jansen, O, Deuschl, G. Selective affection of hippocampal CA-1 neurons in patients with transient global amnesia without long-term sequelae. Brain 2006; 129, 2874-2884. doi.org/10.1093/brain/awl248

Figure 1 :

 1 Figure 1: Boxplots of cortisol level after or during transient global amnesia (TGA) by time of blood sampling. With a similartime of blood collection, cortisol levels were significantly higher during TGA than after it was over.

Figure 2 :

 2 Figure 2: Correlations between cortisol level after or during transient global amnesia (TGA) and time between beginning of the episode and blood collection.

Table 1 :

 1 Main characteristics of TGA patients. ‡ Missing data for 6 patients; * t. tests for quantitative variable, Fischer test or Chi-Square for qualitative data between the per-ictal and post-ictal groups. ♣ Examples of stress factor in our cohort: medical procedure, fight with a relative…


Clémence Lacroix

Michel Mallaret

Annie-Pierre Jonville-Bera
email: jonville-bera@chu-tours.fr

DRUG AND ORPHAN DISEASES Pharmacovigilance and drug-induced rare diseases: strengths of the French Network of Regional Pharmacovigilance Centres Pharmacovigilance and drug-induced rare diseases

Keywords: Pharmacovigilance, Rare disease, Adverse drug reactions, Drug-induced disease, Collaboration, Network adverse drug reaction

The French-style organization in the field of rare diseases allows a close contact between reference centres and regional pharmacovigilance centres thanks to their implementation within the French university hospital. This collaboration leads to highlight more and more drug-induced rare diseases.

Through several historical examples (eosinophilia-myalgia syndrome due to L-tryptophan, type 1 narcolepsy with H1N1 pandemic influenza vaccine, capillary leak syndrome, acquired von Willebrand syndrome), it remains clear that pharmacovigilance is the cornerstone of the alert system. Clinicians from the rare disease reference centres can easily report adverse drug reactions (ADRs) to pharmacologists from their regional pharmacovigilance centre. Through experience, collaboration between countries, large database, and sometimes pharmacoepidemiological studies, an alert can then be raised. This collaboration underlines also similarities between the two disciplines, through the frequency of ADRs and diseases, the difficulty of the diagnosis in front of scarce data, and through the unusual worsening symptoms. Patients and associations of patients play also a proactive role as research partners at different steps, to quantify and qualify symptoms and ADRs, and also to develop orphan drugs. These several collaborations are a precious tool to improve patients' outcomes. These close contacts between the different actors are important to make earlier diagnosis of rare diseases and severe ADRs. Rare disease does not have to mean overlooked diseases.

Introduction

Pharmacovigilance plays a key role in assessing, monitoring and preventing adverse drug reactions (ADRs). Among the available methods, the reporting of suspected ADR in clinical practice is the cornerstone of pharmacovigilance monitoring. Its main purpose is the early detection of new, rare and serious ADRs with the advantage to cover the entire population without any selection. The French pharmacovigilance monitoring is among the best in the World, ranking in the first countries about the quantity of ADRs reports and also its quality linked to its informativeness [1].

In the same way, as demonstrated by the orphaned registry and the French national plans for rare disease for more than 20 years, France has had a leadership role in initiatives in the field of rare disease [START_REF] Micallef | Pharmacology and drug development in rare diseases: the attractiveness and expertise of the French medical pharmacology[END_REF].

In the past two decades, epidemiologic, molecular, and other research that takes advantage of scientific and technological advances in the biological sciences has greatly increased the number of rare diseases that have an identified cause-usually, although not invariably, genetic. In the present paper, we will present the organization of the French pharmacovigilance system and its link to healthcare for rare diseases, the illustration of such organization to detect earlier warnings on drug-induced rare disease, the similarities between rare diseases reference centres and pharmacovigilance activities, and the importance of a collaboration between all involved actors.

The French system of pharmacovigilance and its link to healthcare for rare diseases

The French pharmacovigilance network has been first established in 1973 and consists in 31 regional pharmacovigilance centres [START_REF] Vial | Pharmacovigilance française : missions, organisation et perspectives[END_REF]. These are part of French medical pharmacology centres exclusively implemented within the French university hospitals, public hospitals linked to a medical school, a pharmacy school and research units. In these centres, pharmacologists make evaluation of safety and surveys for post-marketing drugs via collecting and analyzing pharmacologically, clinically and biologically spontaneous reports of ADRs. Spontaneous reports come from patients and healthcare professionals who solicit pharmacovigilance clinicians to help them making a druginduced disease diagnosis. They play a major role in the diagnosis of these under-recognized and overlooked diseases for example heart disease and benfluorex [START_REF] Noize | Valvular heart disease in a patient taking benfluorex[END_REF], psychiatric disorders and dolutegravir [START_REF] Kheloufi | Psychiatric disorders after starting dolutegravir: report of four cases[END_REF], central nervous system disorders and cephalosporins [START_REF] Lacroix | Serious central nervous system side effects of cephalosporins: A national analysis of serious reports registered in the French Pharmacovigilance Database[END_REF]. By its implementation through the public hospital, pharmacovigilance centres have privileged relationship with medical excellence units such as rare diseases care and research units [START_REF] Micallef | Pharmacology and drug development in rare diseases: the attractiveness and expertise of the French medical pharmacology[END_REF]. Thanks to the pharmacovigilance clinician's expertise and their large and detailed fulfilled database, several drug-induced rare diseases had also been highlighted such as pulmonary arterial hypertension associated with protein kinase inhibitors [START_REF] Chaumais | Pharmacovigilance in a rare disease: example of the VIGIAPATH program in pulmonary arterial hypertension[END_REF][START_REF] Cornet | Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilancepharmacodynamic study[END_REF]. Detecting, understanding and preventing are the three key words of this original and unique organization. Due to their specialized and advanced expertise (reflection on pharmacological mechanisms in front of unexpected ADRs, accurate reading of literature, management of specific studies and national medications follow-ups), pharmacologists are able to detect early warning signals and launch alerts to raise clinicians' awareness. This multidimensional way of thinking is possible thanks to their specialization in fundamental and clinical pharmacology. This French-style organization aims to improve patient's outcome and contribute to warn healthcare professional, especially in case of rare diseases for which only scarce data are available. Indeed, the French pharmacovigilance network is the first in Europe to contribute to report serious pharmacological signals. French pharmacovigilance centres are certainly the most active in the world because of their structuration.

Practical implementation: illustration and lessons learned with several warnings on drugsinduced rare disease

Rare diseases affect a limited number of individuals, defined as no more than 2000 individuals in the European Union, and consequently lead to specific difficulties [9]. With more than 7000 discovered ones, rare diseases are numerous and new ones are steadily discovered and published.

Drug-induced rare diseases can be split into 2 different categories: specific drug-induced diseases, for whom drug exposition is the solely etiology (for example the fetal valproate syndrome, the eosinophilia-myalgia syndrome due to L-tryptophan …), and diseases for whom drug is one of the possible etiologies (in most of cases). For the first category of disease, clinicians often react quickly. For the second category, it can lead to serious outcomes because of a late recognition of the drug involved. Moreover, new drug-induced rare diseases are regularly reported to the pharmacovigilance network of clinical pharmacologists (such as narcolepsy induced by H1N1 vaccines). For these rare diseases, only European and even international pharmacoepidemiological studies can confirm the link with the drug and sometimes, can describe the clinical and biological specificities to further better understand the pathology. Beside the publication as case reports, notification of cases of drug-induced rare disease to the regional pharmacovigilance centres is mandatory and helpful. First, better describing their particularities and understanding their pathophysiology can lead to therapeutic hypothesis for these rare diseases (as for example for interleukine-2-induced capillary leak syndrome). Secondly, the notification allows a validation of the case, which can lead to a signal emit by the regional pharmacovigilance centre, and if validated (search for similar cases and pharmacoepidemiology studies), will launch the alert and trigger health measures.

The following historical examples have been selected to illustrate the phenomenon because of specific highlighting modalities or specific characteristics. These examples are not exhaustive, all drugs can induce all diseases (or so). That's why pharmacovigilance clinicians play a major role.

They first help clinicians to make a drug-induced disease diagnosis, then they raise a signal and lead to an alert.

Eosinophilia-myalgia syndrome due to L-tryptophan

This syndrome is an excellent illustration of a drug-induced rare disease. L-tryptophan is an aminoacid normally present in dietary proteins, as a serotonin precursor. L-tryptophan has been commercialized for depressive syndrome or insomnia without proof of efficacy, at a daily dose of 3 to 9 grams. Its main adverse drug reactions were dizziness, headache, nausea and digestive disorders in a dose-dependent manner. In 1989, in New Mexico, several patients exhibited a couple of symptoms associating severe myalgia and hyper eosinophilia. Other similar cases were then reported to the Centre for Disease Control. The Centre then described this new syndrome as "eosinophilia-myalgia syndrome" when eosinophilia >1000/mm3 and generalized and disabled myalgia were associated, and when a parasitological etiology (in particular trichinosis) or even infectious and neoplastic conditions were excluded [START_REF] Centers | Eosinophilia-myalgia syndrome and L-tryptophancontaining products--New Mexico, Minnesota, Oregon, and New York[END_REF][START_REF]From the Centers for Disease Control. Eosinophilia-myalgia syndrome--New Mexico[END_REF]. To elucidate the apparent association between L-tryptophan-containing products (medications and dietary supplements) and eosinophilia-myalgia syndrome, a case-control study was done with 11 case reports. This pharmacoepidemiological study led to a recall of all L-tryptophan-containing products in January 1990 and to their end of commercialization by the Food and Drug Administration [START_REF] Eidson | L-tryptophan and eosinophilia-myalgia syndrome in New Mexico[END_REF]. This "epidemic syndrome", with a multiplication of case reported since July 1989, has led to evoke a contamination of the amino acid by a toxic compound when manufactured [START_REF] Slutsker | Eosinophiliamyalgia syndrome associated with exposure to tryptophan from a single manufacturer[END_REF]. Another hypothesis was of a tryptophan metabolism abnormality revealed or triggered by the ingestion of L-tryptophancontaining products and its contaminant because one of the manufacturers had recently changed the fermentation process (with another bacteria strain) and purification system [START_REF] Silver | Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan[END_REF]. In France, 24 cases of eosinophilia-myalgia syndrome were reported to the 31 regional pharmacovigilance centres [START_REF] Castot | Eosinophilia-myalgia" syndrome due to L-tryptophan containing products. Cooperative evaluation of French Regional Centers of Pharmacovigilance. Analysis of 24 cases[END_REF].

Thanks to these reports, specific clinical manifestations could be defined: generalized myalgia sufficiently severe to affect a patient's ability to pursue daily activities, hypereosinophilia (sometimes major), asthenia, early and fleeting cutaneous manifestations (cutaneous induration) and most rarely fever, loss of weight, arthralgia, digestive disorders, pulmonary disorders (cough, dyspnea) or neurological ones (paresthesia, neuropathy) [START_REF] Castot | Eosinophilia-myalgia" syndrome due to L-tryptophan containing products. Cooperative evaluation of French Regional Centers of Pharmacovigilance. Analysis of 24 cases[END_REF]. One third of patients were hospitalized with a corticosteroid treatment and one third suffered from sequelae. In January 1990, the French Ministry of Health quickly stopped the manufacture, the importation and the commercialization authorization of L-tryptophan-containing products, after the reports of the first two cases in France in December 1989 (more than 15 products were commercialized at that time) [START_REF] Legifrance | Arrêté du 4 janvier 1990 portant suspension de la fabrication, de l'importation[END_REF]. As this new syndrome has been quickly recognized by the American health regulatory authorities and rapidly linked to a drug, it is a good example of pharmacoepidemiologic studies early set up to confirm the hypothesis and to establish quick health measures.

Type 1 narcolepsy with H1N1 pandemic influenza vaccine

Narcolepsy following pandemic H1N1 vaccination is another example of drug-induced rare disease.

Narcolepsy is a consequence of a loss of hypocretin production by specialized hypothalamic neurons. It is a chronic affection characterized by excessive daytime sleepiness with irresistible sleep attacks, abrupt loss of muscle tone and sleep disturbances. Pediatric incidence is three times rarer than in adults. Narcolepsy etiology has probably a genetic origin and before 2010, no cases of drug-induced narcolepsy has been yet reported. Nevertheless, a relationship between narcolepsy and Pandemrix ® vaccination was evoked in Finland in August 2010 after 15 cases were reported to the National Institute for Health and Welfare. The same year, 12 cases were also reported to the Medical Products Agency of Sweden [START_REF] Nihw | National Institute for Health and Welfare recommands discontinuation of Pandemrix vaccination[END_REF][START_REF]Current information on the investigation of cases of narcolepsy after vaccination with Pandemrix[END_REF]. In September 2010, the three major centres of reference for narcolepsy (Montpellier, France; Montreal, Canada; and Stanford University, United States) collaborated to publish a case series of 16 reports of narcolepsy following H1N1 influenza vaccination [START_REF] Dauvilliers | Post-H1N1 narcolepsy-cataplexy[END_REF]. The median time to onset was 7.4 weeks. The most striking features of the reports were the abrupt onset and the unusual severity of both sleepiness and cataplexy. During the same time, Finland and Sweden continued to report an increase of type 1 narcolepsy cases [START_REF] Wijnans | The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns[END_REF]. The increase of narcolepsy incidence during the H1N1 pandemic influenza vaccination campaign with a similar chronology between the different case reports, 1 to 2 months after Pandemrix ® injection in children and adolescents, led to suspect a relationship between the two events. Four different vaccines had been used in Europe: Pandemrix ® , Panenza ® , Focetria ® and Celvapan ® . About 650 cases of narcolepsy were reported to the European pharmacovigilance after the vaccination campaign for more than 19 million people vaccinated. In France, 4.1 million people were vaccinated with 59 reports of narcolepsy identified on 21 adults and 38 children (from 4 to 17 years old); 54 were vaccinated by Pandemrix ® and 3 with Panenza ® . After the emergence of this signal, the European Medical Agency asked for a reevaluation of the benefit/risk balance of this vaccine. In Finland, a pharmacoepidemiological study concluded that the use of Pandemrix ® was associated with an increase narcolepsy incidence factor of 12.7 for children and young adults who received the vaccine. The incidence of narcolepsy was 9.0 in the vaccinated as compared to 0.7/100,000 personyears in the unvaccinated individuals [START_REF] Nohynek | AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland[END_REF][START_REF] Partinen | Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland[END_REF]. This association between narcolepsy and Pandemrix ® use was quickly confirmed by other countries data using the same product such as Ireland, Great-Britain and France [START_REF] Dauvilliers | Post-H1N1 narcolepsy-cataplexy[END_REF][START_REF] O'flanagan | Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010[END_REF][START_REF] Winstone | Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England[END_REF]. In a specific and complete analysis of the French data through a case-control study called "NarcoFlu-VF", H1N1 vaccination was strongly associated with an increased risk of narcolepsy-cataplexy in both children and adults in France [START_REF] Dauvilliers | Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France[END_REF]. This case-control study managed in 15 expert centres (83 cases and 202 control subjects) also showed an association between H1N1 vaccination (Pandemrix ® for 90%) including adults, with an Odds Ratio of 4.6 [2.3-8.9]. The vaccinated patients more often exhibited cataplexy (91% vs 57%).

A homology in sequences of virus proteins and hypocretin-producing neurons is among the different hypothesis raised to explain this unknown ADR and the possible association with the Pandemrix ® vaccine [START_REF] Jacob | Narcolepsy with cataplexy: an autoimmune disease?[END_REF]. In fact, type I narcolepsy is a rare cause of hypersomnia which is characterized by the destruction of hypocretin-producing neurons in genetically predisposed patients. It is an auto-immune, multi factorial pathology involving genetic and environmental factors. Because among cases reported, narcolepsy occurred almost exclusively with Pandemrix®, the involvement of a specific adjuvant in Pandemrix ® (ASO3) was questioned. This hypothesis is also supported by another observation: in other countries such as United States, Australia or China, no narcolepsy had been reported after the H1N1 vaccination using vaccine without this adjuvant.

The role of a genetic predisposition was also raised in front of a majority of patient vaccinated who also exhibited a particular genetic mutation [START_REF] Singh | Genetic association, seasonal infections and autoimmune basis of narcolepsy[END_REF]. The lonely mutation could not be sufficient to express the disease but it could be revealed by a vaccination or an infectious condition and lead to narcolepsy [START_REF] Tafti | DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe[END_REF].

Even if the number of case reports was not very high, a relationship with the vaccination was established. Nevertheless, numerous interrogations about vaccine-induced narcolepsy etiology subsist. Since then, Pandemrix ® has no longer been commercialized and the French health authorities now preconizes the manufacture of vaccines without that adjuvant [29].

Capillary leak syndrome

The capillary leak syndrome was first described in the 60s, characterized by weight gain with edema, oliguria, hypotension which could lead to a shock condition. These clinical symptoms were also associated with biological features like hemoconcentration and hypoalbuminemia [START_REF] Gousseff | The Systemic Capillary Leak Syndrome: A Case Series of 28 Patients From a European Registry[END_REF]. Several types of the syndrome are described. The idiopathic capillary leak syndrome or Clarkson syndrome is mostly caused by malignant hemopathy and viral infections, rarely drug-induced. Numerous drugs, especially oncologic ones, are involved in secondary capillary leak syndrome such as interleukin-2 with more than 75 case reports published [START_REF] Gousseff | The Systemic Capillary Leak Syndrome: A Case Series of 28 Patients From a European Registry[END_REF]. Studies concerning the pathophysiology of the interleukin-2-induced capillary leak syndrome showed alterations of the post-capillary endothelium promoting the adhesion and extravasation of activated leukocytes [START_REF] Samlowski | Endothelial nitric oxide synthase is a key mediator of interleukin-2-induced hypotension and vascular leak syndrome[END_REF].

Endothelium could be then damaged by leukocytes, attracting inflammatory cells and increasing capillary permeability thanks to a cytokines release. Moreover, studies in mice showed that recombinant interleukin-2-induced capillary leak syndrome were enhanced by TNF-alpha blockade [START_REF] Puri | Combined effects of interferon alpha and interleukin 2 on the induction of a vascular leak syndrome in mice[END_REF]. Hematopoietic growth factors are in the second position in providing capillary leak syndrome, which is not surprising because the endogenous granulocyte-colony-stimulating factor seems to be involved in the pathology [START_REF] Dagdemir | G-CSF related capillary leak syndrome in a child with leukemia[END_REF]. In France, the Agence nationale de sécurité du médicament et des produits de santé (ANSM) had raised an alert concerning hematopoietic growth factors and capillary leak syndrome several times [START_REF]de-sante[END_REF][START_REF] Ansm | Risque de syndrome de fuite capillaire associé au lenograstim (Granocyte®) chez les patients atteints d'un cancer et chez les donneurs sains -Lettre aux professionnels de santé[END_REF]. In the literature, cases are more often published with the use of oncology drugs such as gemcitabine, bortezomib, taxanes (docetaxel, paclitaxel), ciclosporin, doxorubicin, clofarabine and trastuzumab [START_REF] Duron | Idiopathic and secondary capillary leak syndromes: A systematic review of the literature[END_REF]. Nevertheless, beside these sporadic case reports, pharmacovigilance plays a major role in detecting new drugs involved in capillary leak syndrome to alert healthcare professionals. Indeed, a recent French publication has reported 576 cases of capillary leak syndrome collected by national drug authorities of 29 countries using data from the international pharmacovigilance [START_REF] Mertz | Characterizing drug-induced capillary leak syndromes using the World Health Organization VigiBase[END_REF]. The median age was 57 years old and the most frequent clinical manifestations were edema, hypotension or shock, renal failure, pulmonary edema and pleural effusion. Compared to the idiopathic form, hypoalbuminemia was less severe in the drug-induced syndrome but pulmonary edema was frequent. The mean time of onset was 8 days, and 27% led to fatal outcomes. Concerning drugs, oncology or immunomodulatory drugs were involved at 86% with mostly gemcitabine and clofarabine. A disproportionality analysis highlighted an increased risk of capillary leak syndrome with 52 drugs, which was a new adverse drug effect for32 drugs (not yet published nor listed) [START_REF] Bate | A Bayesian neural network method for adverse drug reaction signal generation[END_REF].

This study underlines the importance of notification to the regional pharmacovigilance centres, especially in drug-induced rare diseases. All these data contribute to feed the international pharmacovigilance database allowing international pharmacoepidemiolgic studies. Indeed, with only a few French cases, specific analysis can then be performed on the international database to highlight an association and raise an alert.

Acquired von Willebrand syndrome

Acquired von Willebrand syndrome is a rare hemorrhagic disorder, which is similar to congenital von Willebrand disease regarding the clinical and laboratory features. It is found in individuals without hemorrhagic or family history [START_REF] Shetty | Pathophysiology of acquired von Willebrand disease: a concise review[END_REF]. Three major pathogenic mechanisms are suggested to explain this syndrome: auto-immune disorder with auto-antibodies and von Willebrand factor (vWF) complexes (like in auto-immune pathologies and in monoclonal gammopathies); absorption of vWF by malignant cells clones (link in neoplasia); excessive proteolysis of high molecular weight vWF multimers in congenital heart defects (like aortic stenosis). Hereditary Willebrand disease is a well-known disease, it is the most frequent constitutional hemorrhagic disease with a prevalence of 1% in the whole population whereas acquired von Willebrand syndrome is a rare disease (almost 300 case reports in the literature) probably underdiagnosed. This pathology is mostly reported in case of auto-immune disorder and lymphoproliferative or myeloproliferative syndromes. Nevertheless, a drug etiology can also be involved [START_REF] Mingot-Castellano | Hemofilia adquirida: epidemiología, clínica, diagnóstico y tratamiento[END_REF] and the most frequently ones are interferon alpha, penicillin derivatives, paclitaxel, fludarabine, phenytoin, clopidogrel, alphamethyldopa, levodopa but also more common medications like for example sulfonamide antimicrobial agents, fluoroquinolones or griseofulvin [START_REF] Mingot-Castellano | Hemofilia adquirida: epidemiología, clínica, diagnóstico y tratamiento[END_REF][START_REF] El-Osta | Acquired factor VIII inhibitors: case reports of paclitaxel and penicillin-induced entities[END_REF][START_REF] Paul | Acquired factor VIII inhibitor in an HIVinfected patient after treatment with pegylated interferon-alpha 2a and ribavirin[END_REF][START_REF] Franchini | Drug-induced antifactor VIII antibodies: a systematic review[END_REF]. In some reports with a drug etiology, mechanism could be different, without antibodies anti-FVIII or anti-vWF. Then Conrad and al. described a case of an acquired von Willebrand syndrome in a 51-years-old-male treated by griseofulvine for 2 months. His biological results showed a severe deficit of FVIIIc (10%) and vWF (8%). Clinical and biological manifestations disappeared a few days after stopping the griseofulvine treatment [START_REF] Conrad | Acquired von Willebrand's disease, IgE polyclonal gammopathy and griseofulvin therapy[END_REF]. Another author described two cases of ciprofloxacin-induced acquired von Willebrand syndrome. Abnormalities disappeared during the follow-up, without any specific therapy. No inhibition of FVIIIc or vWF was detected but a proteolysis mechanism was among hypothesis [START_REF] Castaman | Characterization of two cases of acquired transitory von Willebrand syndrome with ciprofloxacin: evidence for heightened proteolysis of von Willebrand factor[END_REF].

More interesting is that the pharmacological and physicochemical characteristics of a colloid, named hydroxyethyl starch (HES), explain the occurrence or not of a vWF deficiency.

Colloids can lead to two consequences on the homeostasis: non-specific ones linked to hemodilution (provoked by the perfusion of high volumes), and specific ones due to macromolecular solutes effect on coagulation and/or fibrinolysis. At the beginning of the 60s, studies showed that first generation high-molecular-weight HES had an impact on homeostasis, independent of the hemodilution. Because their high-molecular-weight was associated with a longer life time, this observation led to a decrease of the recommended dose [START_REF] Garzon | Hydroxyethyl starch (HES) and bleeding. An experimental investigation of its effect on hemostasis[END_REF]. Medium-molecularweight HES were then manufactured. Nonetheless, a dozen of years after their commercialization, a case series of acquired von Willebrand syndrome was reported by a French pharmacovigilance team [START_REF] Jonville-Béra | Acquired type I von Willebrand's disease associated with highly substituted hydroxyethyl starch[END_REF], with twelve reports of hemostatic disorders. All patients were treated with Elohes® as hemodilution therapy (for vasospasm secondary to subarachnoid hemorrhage). Eight patients exhibited an acquired von Willebrand disease, 6 with neurological complications, and 3 fatal outcomes. They had no medical history and biological parameters were normal at the admission day. Patients exhibited symptoms after a more than 4 day therapy. HES are natural polysaccharides which substitution slows hydrolysis by alpha-amylase, thus it increases the effect duration, as the high-molecular-weight and the elevated substitution ratio. The more the HES hydrolysis is slowed, the more the drug can accumulate. Yet an absorption of the vWF on the HES exists, the complex is thus eliminated through urines which induces a quantitative vWF decrease; this phenomenon leads to a type I-like von Willebrand syndrome. Studies showed that first and second HES generations decreased circulating FVIII and vWF for more than 80%, even for doses from 25 to 50 ml/kg [START_REF] De Jonge | Decreased circulating levels of von Willebrand factor after intravenous administration of a rapidly degradable hydroxyethyl starch (HES 200/0.5/6) in healthy human subjects[END_REF][START_REF] Jones | The influence of crystalloid and colloid replacement solutions in acute normovolemic hemodilution: a preliminary survey of hemostatic markers[END_REF]. When there were commercialized, low-molecular-weight HES were presented without any risk of hemorrhage, because their use was only perioperative and very short. The structure modifications realized to increase their effectiveness were associated with an increase of accumulation explaining that during prolonged used, the risk of hemorrhage was the same as highmolecular-weight HES. Treib and al. demonstrates that after 10 days of hemodilution, vWF activity decreased for almost 45% at day 5 and for 60% at day 10 with a long-time elimination HES like Elohes ® , whereas with a short-time elimination HES, vWF activity was the same [START_REF] Treib | An international view of hydroxyethyl starches[END_REF]. Thus, in April 1999, the Agence française de sécurité sanitaire des produits de santé (AFSSaPS) informed healthcare professionals about the risk of serious hematological disorders reported after prolonged Elohes ® administration due to its physico-chemical properties leading to an accumulation of the product. AFSSaPS made also a contraindication of the HES when acquired or constitutional hemostatic disorders are known or suspected. The daily dose was limited to 33 mL/kg/d and the duration to 4 days with a maximal dose at 80 ml/kg. A specific hemostatic monitoring was also recommended [51].

This last example highlights the necessity of a quickly declaration to the Regional Centre of Pharmacovigilance, of any suspicion of adverse effect, even if the link with the drug is not certain.

In that example, the alert was raised after collecting cases by asking all neuro-anesthetists about the hemorrhagic adverse effect observed with this product. Several of them had noticed some hemorrhagic syndrome with prolonged use of the infusion of this HES and had changed their practices (decreased duration of use), but very few had thought to declare them to a CRPV, which would have allowed earlier health measures.

Similarities between rare diseases reference centres and pharmacovigilance activities, importance of a collaboration between all involved actors

Through these different examples, we can easily recognize similarities between rare diseases reference centres and pharmacovigilance activities. Most of the time, severe ADRs are as rare as rare diseases, even if many drug side effects are unfortunately frequent. Clinical trials usually concern a restricted number of people and that is why all ADRs are not detected. Indeed, ADRs occur in only one patient over 1 million treated patients, or even less.

The second similarity concerns difficulties among diagnosis. Some new rare diseases or ADRs are discovered through an unknown symptom or syndrome. To discover the etiology and the pathophysiology in these cases, it can be time spending before confirmation. A small or a big percentage of rare disease causes may be due to a sole pharmacological substance.

The third similarity is the frequent occurrence of unusual worsening symptoms. For example, Charcot-Marie-Tooth disease may be worsened by sleep disorders or by neurotoxic drugs.

An estimated innocuous drug in a country population may worsen the syndrome in a rare disease patient.

In the future, we may find new rare diseases or new ADRs as we have found new syndromes in the recent past. Anti-NMDA receptor encephalitis, a rare case of encephalitis was diagnosed only in 2007 with immunology progress. Frequently used anesthetic ketamine was synthesized in 1956 but ketamine induced bladder fibrosis in ketamine abusers has only been recently discovered and confirmed by experimental studies on a mouse model [START_REF] Shen | Ketamine-induced bladder dysfunction is associated with extracellular matrix accumulation and impairment of calcium signaling in a mouse model[END_REF]. Bladder effects of ketamine have not been detected by experimental preclinical and clinical studies. Pharmacovigilance and addictovigilance are useful in new and also in old substances surveys. We may ask the crucial question: in the past decades, was the association of ketamine use and bladder fibrosis underdiagnosed? Early detection of ADRs will always need more collaborations between patients and different caregivers.

There is still an important lack of information in the field of rare diseases and ADRs, even if there are great (but rare) specialists and even if the internet provides a large choice of data. In both cases, there is a need of informed clinicians, pharmacists, nurses and helping families.

Rare diseases need a multi-disciplinary expertise. Pharmacologists of the French pharmacovigilance centres network could increase their collaboration with rare disease organization to help in the evaluation of the association of drugs and rare diseases. The pharmacologists may try to discover the potential mechanism of drug effect on rare diseases. It could be useful to improve the knowledge of rare diseases, and to prevent ADRs.

In 2014-2015, an experiment was conducted thanks to the collaboration of the association "maladies rares info service", the French pharmacovigilance network and the ANSM. This experiment has permitted to elaborate a close contact between patients and clinicians from the Regional Pharmacovigilance centres. It may be pursued in order to answer to most of the patient's questions. It is important to maintain a regional and a national organization to provide the best expertise to patients.

Patients may directly contact the nearest regional pharmacovigilance centre or indirectly through the "portail national de signalement des evènements indésirables". This close contact with the patient, his/her family or friends remains useful and may be associated with the different caregivers. A close collaboration is important to gather accurate informations about the disease and its evolution. The French pharmacovigilance network provides a practical and a close help for patients and their families. Nevertheless, there is also an increasing need of a close relationship between pharmacologists of this network and rare diseases centres clinicians to manage specialized cooperative works.

Rare disease patients are particularly concerned by an early warning system at the national level, like the French-style organization. Rare disease reference centres are an important link to give decompartementalized informations. These useful warnings are identified and shared at national, European (European Medicinal Agency) and at an international level (World Health Organization).

Conclusion

In order to reach a better knowledge of rare diseases, pharmacologists from the regional pharmacovigilance centres, clinicians from the reference centres of rare diseases, patients and French drug agency have to pursue their collaboration. Through the previous examples, it remains clear that this close relationship allows to raise signals, make an alert and to improve patients' outcomes but it offers also a proposed mechanism for the new and potential scientific hypothesis for the rare diseases.

Disclosure of interest

Authors have no competing interest to declare


Boubou Thiam Niang
email: boubou-thiam.niang@univ-lyon2.fr

Giacomo Kahn
email: giacomo.kahn@univ-lyon2.fr

Nawel Amokrane
email: nawel.amokrane@berger-levrault.com

Yacine Ouzrout
email: yacine.ouzrout@univ-lyon2.fr

Hamza Sahli
email: hamza.sahli@berger-levrault.com

Mustapha Derras
email: mustapha.derras@berger-levrault.com

Jannik Laval
email: jannik.laval@univ-lyon2.fr

Automatic Generation of Interoperability Connectors using Software Product Lines Engineering

Keywords: Code Generation, Information System, Interoperability, Model-Driven Engineering, Software Product Line Engineering

Information Systems (ISs) of modern companies must be reactive and capable to communicate with third-party IS. It is, therefore, necessary to establish agile interoperability between information systems. For this purpose, connectors are used to ensure interactions between IS components. However, components are independently designed and conform to different technical and domain standards that are continuously evolving. Given that the connectors are often developed manually and are not reusable in most cases, establishing and maintaining interoperability becomes a major challenge. In this paper we propose an approach to automatically generate connectors, using software product line engineering to reuse common features and better manage variability. A metamodel of the connector is proposed to show that they can be considered as first-class entities. An industrial case study followed by a discussion is proposed to demonstrate the feasibility of our approach.

INTRODUCTION

Companies have to interact with many partners, which are structurally diverse and operate in various business sectors. In addition, companies have to evolve from a technical and organizational point of view through mergers, acquisition of subsidiaries or technological migrations. Despite their diversities, frequent changes, and independent development, the Information Systems (ISs) of different stakeholders and their components must remain compatible with each other in order to work together at all times. Connectors [START_REF] Mehta | Towards a taxonomy of software connectors[END_REF] are used for this purpose to enable a successful interaction between component.

Some works have been carried out on the effective implementation of interoperability connectors. In [START_REF] Aldrich | Archjava: Connecting software architecture to implementation[END_REF][START_REF] Arellanes | Exogenous connectors for hierarchical service composition[END_REF][START_REF] Garcés | Software mediators as first-class entities of systems-ofsystems software architectures[END_REF] the authors focuse on the notion of exogenous connectors i.e., connectors separated from business logic components to increase decoupling and flexibility. However, this approach do not address the automation of connectors implementation.Other proposals such as [START_REF] Seinturier | A componentbased middleware platform for reconfigurable serviceoriented architectures[END_REF][START_REF] Roth | Xware-a customizable interoperability framework for pervasive computing systems[END_REF] are interested in automatic recon-figuration for services orchestration, but the notion of connectors remains implicit. Then, some approaches have addressed the automatic synthesis of the connectors as first-class entities like [START_REF] Bencomo | The role of models@ run. time in supporting on-the-fly interoperability[END_REF][START_REF] Bennaceur | Automated synthesis of mediators to support component interoperability[END_REF][START_REF] Bouloukakis | Automated synthesis of mediators for middleware-layer protocol interoperability in the iot[END_REF][START_REF] Autili | Automated synthesis of application-layer connectors from automata-based specifications[END_REF]. These solutions generally target a specific type of connector to be synthesized as a peer-to-peer exchange, without offering more flexibility to generate other types of connectors.

Having identified that the cited approaches do not take into account all the interesting points mentioned in the cited works, and the shortcomings identified for each of the listed works, we raised two research questions (RQ):

RQ1: To what extent it is possible to decouple the connector by separating the interaction-specific code from the business code? The objective of this RQ is to clearly identify what falls under interaction codes and and what falls under business logic in order to generate the connector.

RQ2: How to facilitate the connectors implementation despite their variability? The objective of this RQ is to show that different types of connectors can be generated regardless of its variability by minimizing the effort and reusing the connectors features. This paper consider connectors as first class-entity and the set of connectors is considered as a Software Product Line (SPL) [START_REF] Clements | Salion, inc.: A software product line case study[END_REF] in order to exploit the commonalities of the connectors and easily manage their variability. The main contributions of this article are the following:

• Analysis of connectors commonalities and variability to consider them as a software product line,

• Design of a feature model (FM) that represents commonalities and variability of connectors,

• Proposal of a connector metamodel with reusable artifacts,

• Proposal of a software product line approach for generating interoperability connectors.

Based on an industrial case study where two connectors have to be implemented between different applications in various domains, we discussed the approach and gave feedback on the lessons learned. The metamodels, the feature models and the implementation example of the study discussed in the article are available on a public git repository.1 . The paper is organized as follows: in Section 2, we discuss the state of the art. The proposed software product lines approach for connector generation is presented in Section 3. Section 4 presents a case study that illustrates a concrete problem to be solved. Finally, in Section 5 we discuss the approach and present feedback on the lessons learned.

STATE OF THE ART

Different approaches have been developed to facilitate implementation of connectors, seen in several aspects: exogenous connectors, dynamic orchestrations, and automatic synthesis.

The first aspect focuses on the separation of connectors and business logic components to increase decoupling and flexibility. Approaches such as [START_REF] Aldrich | Archjava: Connecting software architecture to implementation[END_REF][START_REF] Arellanes | Exogenous connectors for hierarchical service composition[END_REF][START_REF] Garcés | Software mediators as first-class entities of systems-ofsystems software architectures[END_REF] go in this direction by considering connectors as first-class entities that aim to guarantee the technical, geographical, and life cycle management independence of the connectors.

The second aspect concerns the dynamic implementation of connectors via reconfiguration for component orchestration. Thus, studies such as [START_REF] Seinturier | A componentbased middleware platform for reconfigurable serviceoriented architectures[END_REF] and [START_REF] Roth | Xware-a customizable interoperability framework for pervasive computing systems[END_REF] propose a way of composing connectors by simplifying the development of connectors. These approaches are design-time or at runtime with the possibility of reconfiguration of the interactions between the entities.

The third aspect deals with the generation of connectors. Inverardi, Tivoli and Autili [START_REF] Inverardi | Automatic synthesis of modular connectors via composition of protocol mediation patterns[END_REF][START_REF] Autili | Choreography realizability enforcement through the automatic synthesis of distributed coordination delegates[END_REF] propose a method for automatic synthesis of modular connectors, a composition of independent primitive sub-connectors called mediators, which realize a mediation pattern. Proposition like [START_REF] Bencomo | The role of models@ run. time in supporting on-the-fly interoperability[END_REF] or [START_REF] Bennaceur | Automated synthesis of mediators to support component interoperability[END_REF] go further by focusing on functionality discovery and automatic generation of connectors onthe-fly. To this end, both combine machine learning techniques and ontological reasoning. Bouloukakis et al. [START_REF] Bouloukakis | Automated synthesis of mediators for middleware-layer protocol interoperability in the iot[END_REF] introduce a solution for the automated synthesis of mediators that ensure the interoperability of heterogeneous things, Data eXchange (DeX) connector model. This solution aims to devise a generic connector that comprehensively abstracts and represents the semantics of the various middleware protocols. [START_REF] Autili | Automated synthesis of application-layer connectors from automata-based specifications[END_REF] define a model-based framework for mediators and an automated approach to mediator synthesis. the model takes as input an interaction process, a choreography specification and its ontology to produce what is called coordination delegate.

The state of the art show some limitations that may constraint open and evolving interoperability. Studies that address the notion of exogenous connectors do not explain how to implement them. Solutions that allow the dynamic reconfiguration of services are highly focused on orchestration where the connector is centralized. The notion of exogenous connector is not put forward for these types of approaches. It is therefore difficult to change a single connector without impacting other connector's combination. Approaches that deal with automatic connector synthesis for creating connectors are mainly focused on choreography and does not address the orchestration. Our approach aims to overcome some of the limitations mentioned in the state of the art.

THE CONNECTORS PRODUCT LINE

3.1 Proposed Software Product Line Engineering approach

In accordance of the software product line engineering, the proposed approach follow two sub-process: Domain Engineering (DE) and Application Engineering (AE). Each of the sub-processes can be divided into two parts, the problem space and the solution space as illustrated in Fig. 1.

In both sub-processes, we rely on model-driven engineering (MDE) [START_REF] Schmidt | Model-driven engineering[END_REF]. For the DE subprocess, the architecture of the software product line is represented by the connector metamodel. In AE sub-process, the expected connector model is used for code generation, instead of directly generating the connector source code. This allows for a higher level of abstraction and flexibility. Indeed, without MDE, the SPL would have to directly implement a main class, in a target programming language, representing the connectors commonalities and variability. Thus, operations such as adding, deleting or removing can be made to this main class to vary it, and then generate the connector directly in the pretargeted language. This kind of implementation can be achieved through delta-oriented programming with tools like DeltaJ [START_REF] Koscielny | Deltaj 1.5: deltaoriented programming for java 1.5[END_REF]. However, this would be a major constraint in terms of openness and scalability, as some technical choices such as the target language have to be made upstream. To avoid this, MDE provides platform independence and allows source code to be generated a posteriori using model-to-code transformation techniques to generate source code in a desired language.

Description of the approach

Analysis of commonalities and variability of connectors

The first step of the DE sub-process corresponds to the top leftmost box in Fig. 1. This step consists of identifying the commonalities and variability of the connectors. To this end, software product line engineering offers three approaches [START_REF] Bakar | Feature extraction approaches from natural language requirements for reuse in software product lines: A systematic literature review[END_REF]: proactive, reactive, and extractive. This work is produced with an industrial partner Berger-Levrault (BL)2 , which already operates various interoperability connectors: REST API call, Enterprise Service Bus, event-driven connectors, etc. Since we are not starting from scratch and are given the existing connectors, we opted for the extractive approach. We combine the extractive approach with the iterative approach for a variability analysis that goes beyond the existing connectors, and for future scalability of the connectors product line. The extractive approach itself can be carried out according to several extraction strategies according to Assunc ¸ão et al. [START_REF] Assunc ¸ão | Reengineering legacy applications into software product lines: a systematic mapping[END_REF]. This paper relies on Static Analysis and Expert-Driven strategy extraction strategies.

Static analysis consists of analyzing the structural information of static artifacts such as source code, or textual technical and functional specification documents. To do this, we considered a repository of twenty connector projects from our industrial partner BL implementing different communication mechanisms. For most existing connectors, there is a strong coupling between the communication and the business logic source code. It was therefore necessary to first carry out a manual separation of concerns by isolating the connectors codes as much as possible. This separation of concerns addresses one of our research questions on separating interaction-specific source code from business logic (RQ1). Once this separation is made, we analyzed connectors specification documents, even for connectors that are not yet in use or have not been effectively implemented by the company. Finally, we collect additional characteristics from the literature such as the EIPs [START_REF] Hohpe | Enterprise integration patterns: Designing, building, and deploying messaging solutions[END_REF] book. These three sources allowed us to define the required features for the connectors. Thus, we have identified that the connector as a first-class entity is mainly decomposed into three sub-components: source, sink, and processor which are common to all connectors. The source is the entry point of the connector which receives the message from an externe component, the sink is the output of the connector, it sends the message to a component, the processor is a sub-component which can transform the information that passes through the connector such as filtering or aggregation. Each of these subcomponents can vary depending on the need for interoperability. For example, you may have a rabbitMQ or an http source, a kafka or ftp sink and an aggregator or message sequencer processor. These commonalities and variability make it easier to choose the SPL for connectors and therefore the positioning of our paper.

The Expert-Driven strategy relies on the expertise of specialists e.g. software engineers, architects, developers, and stakeholders, etc. Experts knowledge allows us to complete, adjust and validate the extracted features.

Modeling connector variability

The second step of the DE sub-process corresponds to the second box from the left at the top in Fig. 1. This step allows to represent the previously analyzed connectors features by highlighting commonalities and variability. For this purpose, we use a feature model (FM) [START_REF] Kang | Feature-oriented domain analysis (foda) feasibility study[END_REF], which present all possible features to create a connector. For reasons of space

The Connectors software product line architecture

This is the last step of the DE sub-process, the last box on top from the left. It is broken down into two phases.

• The first phase concerns the implementation of the connector software product line architecture, the connector metamodel shown in Fig. 3, which is one of the contributions of this paper. The proposal of a metamodel allows us to assert that connectors are first-class entities rather than an implicit mechanism for interaction between components. The connector metamodel is designed ac-cording to the domain FM. The transition from the domain FM to the connector metamodel is done manually. Indeed, the features present in the feature model become the entities of the metamodel, and different constraints and relationships must be maintained. The common features, which have a mandatory constraint, are transformed into an entity whose life cycle depends on that of the connector. This results in a composition relationship between the connector and these common entities, with the minimum cardinality equal to one. As far as the optional features are concerned, they are transformed into non-mandatory entities, which results in a composition relation with no minimal cardinality. The other constraints are represented by simple associations between entities. Features that can take a simple value becomes attributes, for example message format can be JSON or Avro. Due to space limitations and to stay readable, a portion of the metamodel is presented in Fig. 3. The complete connector metamodel is provided via public access on the provided git repository, and remains expandable to ensures evolving of the connector product line by adding new functionalities to the connector feature model and the corresponding entities in the metamodel. This extension is done manually.

• The second phase focuses on the creation of reusable operations that specify the modifications that could be applied to the connector architecture, it metamodel in this case. Indeed, these operations is due to our implementation choice which is based on Delta-Oriented Programming (DOP) [START_REF] Schulze | Refactoring delta-oriented software product lines[END_REF]. The connectors product lines is represented by a core model, and a set of delta modules. The core model provides an implementation of a valid base connec- tor. It is here about the connector metamodel. Delta modules specify the changes to be applied to the core module to create an expected connector by adding, modifying and deleting entities or their attributes. This phase consists in creating a number of delta modules, each of them is created for a valid configuration of the connector feature model. Then, for each delta module, the difference with the metamodel is evaluated that constitute so-called delta actions for later use. It should be noted that delta actions can be calculated between two delta modules, i.e., one delta module is considered as a core model to create another delta module. In this case, constraints on the order of application of the module deltas are created. The industrial case study proposed in Sec. 4 will illustrate the application and use of delta actions through a concrete case. To create delta modules and delta actions, we use SiPL [START_REF] Pietsch | Sipl-a delta-based modeling framework for software product line engineering[END_REF], a model-driven delta-oriented tool offered on top of the Eclipse modeling framework (EMF) [START_REF] Steinberg | EMF: eclipse modeling framework[END_REF].

Application Engineering

The AE sub-process leverages the domain engineering one to create a connector. It consists in four steps. The first step, the leftmost box at the bottom in Fig. 1 is to specify the desired connector. In the second step, a stakeholder configures the domain feature model by selecting the required feature for the connector specification. The third step, second to last box from the left, is the synthesis of the expected connector model. This is done on the basis of the connector product line architecture, delta modules and constraints created in the problem space of the DE sub-process, and the desired connector configuration based on the domain feature model. Delta actions are created with different constraints in the DE sub-process. Each delta action is created for a given configuration. Thus, in the current step, all delta actions corresponding to the configuration of the feature model are automatically proposed, while respecting constraints such as the order of application. The application of these delta actions allows to automatically obtain the expected connector model. The connector model is then instantiated to generate the source code of the connector in the desired language. The last step, last box from the left at the bottom in Fig. 1 is a sub-process that involves the use of certain Eclipse-based tools. To transform the model into code, the Eclipse GenModel tool is used to generate the model code which then instantiates the expected connector with property values provided by a end user. An example of an application showing concretely how each step of the entire process works is presented in the section. 4.

INDUSTRIAL CASE STUDY

Scenario presentation

To illustrate our approach, we consider a concrete case study from our industrial partner BL as shown in Fig. 4. It concerns a part of an information system where some internal components have to interact: SaaS-Console, Legibase, and Helios Analyzer and Helios Scraper. For this purpose, two variable connectors are needed to answer the research question (RQ2).

1. The SaaS-Console is an administration console that allows the clients to autonomously manage their accounts and access rights related to the Software as a Service (SaaS) they use.

2. Legibase is an application that manages practical fact sheets, articles on the latest legislation and case law developments in several areas. Legibase is used by professionals who need access to the latest versions of often evolving legislation.

3. The Helios analyzer gathers data from different information sources such as social network, scientific and political report and integrate these information in the Helios scrapper database. Helios Analyzer allows to make a weather forecast of the latest news.

Fig. 4 shows two connectors that allow the described application to interact: an event-driven connector based on publish-subscribe [START_REF] Tarkoma | Publish/subscribe systems: design and principles[END_REF] communication pattern, and an hybrid connector that combine one event-driven consumer and one synchronous http endpoint.

The objectives of the first connector are to synchronize user access between the SaaS-Console, the Helios scraper, and the Helios analyzer applications, and to data between the Helios scraper database and the Helios analyzer database. This connector accomplish event-driven communication using the publish-subscribe pattern. We identify interactions performed by the same connector: SaaS-Console ↔ Helios scrapper, SaaS-Console ↔ Helios analyzer, and Helios scrapper database → Helios analyzer database. The directions of the arrows indicate in which direction the exchanges are made.

From SaaS-Console to Helios Scraper and Helios Analyzer and conversely, when the status of a user account changes in the UserAccessTopic in which the SaaS-Console has beforehand pushed. An event is then sent to Helios Scraper and Helios Analyzer through the connector. Events are then delivered to consumers subscribed to the topic, in this case Helios scraper and Helios analyzer. In this study case, connectors source consume the event from SaaS-Console. Upon receiving the event, components subscribed to the topic can consume the message from the sink of the connector. This is partly the same as for the flow SaaS-Console to Legibase. The difference is that for the communication from the connector to Legibase, the connector sink calls the API exposed by Legibase, upon receiving the event. The flow from Helios scraper and Helios analyzer operates in the same way, with the difference that the communication is between databases and not between business applications.

A first effort has been made by our industrial partner BL with the creation of BL-MOM, a messagingbased API (Application Platform Interface) that aims to support implementing a new connector according to the publish-subscribe communication pattern and based on the RabbitMQ broker. However, to date, BL-MOM only supports the development of asynchronous connectors. Another problem with BL-MOM is that backwards compatibility is not obvious. Indeed, our industry partner BL has found that adapting the BL-MOM API to create connectors based on a Kafka broker, for example, instead of a RabbitMQ broker requires an important development cost. In this specific case, our approach overcomes these limitations in terms of backwards compatibility, connector type and development time.

The present exchange flow case study is about a new need to connect the SaaS-Console to Legibase for access contract management, connect the SaaS-Console to Helios Scrapper and Helios analyzer for user access creation and update purpose, and connecting Helios Scrapper and Helios analyzer database for synchronization.

Implementation of the use case

we consider one of the connectors presented in Fig. 4 to prove the feasibility of our approach, the connector that enable communication between SaaS-Console and Legibase components.

1. We need first the specification of the connectors.

For this, we consider the connector that enable interoperability between SaaS-Console and Legibase. The objective is to generate a connector that receives an event concerning user access to which it is subscribed via a topic and to make a HTTP call to the Legibase component. It is possible for the connector to filter some information thanks to the filter processor as shown in Fig. 4 2. Once the connector specified, the domain feature model must be configured by selecting the required features. The configuration is realized using SiPL tool as explained in Section 3 and Fig. 1.

3. As reminder, in the DE sub-process shown in Sec. 1, several delta modules have been created for different configurations. For each delta module the difference with the connector metamodel is calculated to obtain the delta actions, that must be applied to obtain the model of the expected connector. The resulting connector model is shown in Fig. 3, when only the entities with the bold border are considered. In other words, the model of the expected connector corresponds to the metamodel of the connector presented in Fig. 3, from which several entities have been removed such as: ftp sources, rabbit sink, and all processors except filter.

4. The last step focuses on the sub-process of transforming the resulting model of the expected con- To move on to the automatic generation of the connector code itself, we created a code generator module with our industrial partner BL. This module requires a JSON file as input and generate a connector code in java. Simply convert the XMI file to JSON and run the automatic code generation add-on. An example of an automatic end-to-end connector generation project based on the proposed approach is available on the indicated gitlab repository. The project contains four sub-projects: feature modeling, ecore modeling, delta modeling with SiPL, and eclipse fragment project.

Discussion and Lessons learned

The proposed approach helps to reduce the effort required for the development of connectors by reusing their commonalities.

We made sure that the analysis of variability was as complete as possible. For this purpose, we considered concrete connectors used in the industry, or open source tools such as Spring Cloud Data Flow (SCDF)3 , and Kafka Connect4 . We also retrieved features found in the literature, such as from the EIPs. This rigorous analysis of commonalities and variability has provided us a feature model that cover a wide range of connector types. The paper also explains the transition from a feature model to a software product line architecture manually and following rules we described. We have also shown how to use the feature model and the product line architecture to easily create a desired connector. For this purpose, deltaoriented programming was exploited using the SiPL tool and other Eclipse tools such as GenModel.

The DE sub-process being set up only once with punctual evolution, by considering the steps of AE only, we noted with the presented example that the generation of source code process based on our approach take less than one hour. This is very encouraging in terms of time saving, as according to feedback from BL developers and experts, it takes about a week for a novice to develop a connector for a single exchange flow. Although feedback from our industrial partner, BL confirms that an experienced developer takes less time, about three hours, it is always advantageous to start with an existing base project, this reduces, for example, the number of copy/paste operations that need to be performed without forgetting anything. Moreover, the fact of having a common core codes makes it possible to reduce the number of tests to be carried out, in fact the base of the product is tested only once.

Conclusion

We have adopted model-driven engineering to be platform independent, and have gone as far as possible with the code generated in Java. In the future we need to prove the code generation in other languages. We will also need to be able to manage the life cycle of connectors. Indeed, once the connector is generated, we must be able to make it evolve without having to regenerate all its source code. Considering life cycle management, the proposed approach can also be used for low-coding purposes in component-based connectors such as the SCDF connectors. In this case, we have a catalog of components sources, sinks, and processors to create connectors. The approach could thus be used to generate configurations allowing the creation of complex connectors through the composition of various sub-components.

Figure 1 :

 1 Figure1: Overview of the software product line approach to generate connectors. The process presents the domain engineering (top) and the application engineering sub-process (bottom). For each sub-process the problem space (left) and the solution space (right) are identified.

Figure 2 :

 2 Figure 2: The domain feature model of the connectors that represents all possible features to create a connector.

Figure 3 :

 3 Figure 3: The metamodel of the connector representing the connectors software product line architecture. The entities with a bold border correspond to the expected connector model.

Figure 4 :

 4 Figure 4: Overview of the industrial use case showing several components that must interact through two variable connectors based on interoperability requirements.

https://cvs.disp-lab.fr/demo-approach-spl-dopconnector

Berger-Levrault is a software provider specialized in the fields of education, health, sanitary, social and territorial management.

https://spring.io/projects/spring-cloud-dataflow

https://docs.confluent.io/platform/current/connect/index.html


Teddy Novais
email: teddy.novais@chu-lyon.fr

PhD Mélanie Chomel

PharmD Virginie Dauphinot

PhD Christelle Mouchoux

Caregiver in Alzheimer's disease, pharmacist, and pharmacy technician attitudes and knowledge about caregiver

Keywords: Aidants, Fardeau, Pharmacie d'officine, maladie d'Alzheimer et maladies apparentées Caregivers, Burden, Community pharmacy, Alzheimer's disease and related disorders

et préparateurs en pharmacie concernant le repérage du fardeau des aidants de patients atteints de la maladie d'Alzheimer en pharmacie d'officine.

Introduction

Cognitive impairment, functional autonomy loss and behavioral disorders caused by Alzheimer's Disease (AD) may lead to an increase in caregiver burden [START_REF] Vellas | Progression of Alzheimer disease in Europe: data from the European ICTUS study[END_REF][START_REF] Dauphinot | Risk Factors of Caregiver Burden Evolution, for Patients With Subjective Cognitive Decline or Neurocognitive Disorders: A Longitudinal Analysis[END_REF]. The caregiver burden is the burden felt by the caregiver in relation to the accompaniment and assistance in the daily living activities provided to their illness relative. The caregiver is often a spouse or an adult child providing assistance with daily living activities, managing the relative's behavioural symptoms, coordinating supportive services, facilitating healthcare visits, and making financial and healthcare decisions [START_REF] Black | Unmet needs of community-residing persons with dementia and their informal caregivers: findings from the maximizing independence at home study[END_REF]. Caregivers thus play a central role in the care of people with AD. Therefore, the burden of care may have physical, psychological, emotional, social and financial consequences [START_REF] Zarit | Relatives of the impaired elderly: correlates of feelings of burden[END_REF]. Caregivers are exposed to higher risk of hypertension, heart disease, and mortality, sleep disorders, mood disorders with a greater use of psychotropic drugs, and lower quality of life [START_REF] Pinquart | Differences between caregivers and noncaregivers in psychological health and physical health: a meta-analysis[END_REF][START_REF] Mccurry | Sleep disturbances in caregivers of persons with dementia: contributing factors and treatment implications[END_REF][START_REF] Cooper | A systematic review of the prevalence and covariates of anxiety in caregivers of people with dementia[END_REF][START_REF] Von Känel | Increased Framingham Coronary Heart Disease Risk Score in dementia caregivers relative to non-caregiving controls[END_REF][START_REF] Schulz | Psychiatric and physical morbidity effects of dementia caregiving: prevalence, correlates, and causes[END_REF][START_REF] Thomas | Vulnerability of caregivers for demented patients. The Pixel study[END_REF]. In the PIXEL study focusing on family caregivers of patients with Alzheimer's disease, one in three caregivers had to postpone or give up a medical appointment, a hospitalization or medical care for themselves to stay with their relative [START_REF] Thomas | Vulnerability of caregivers for demented patients. The Pixel study[END_REF]. This decline in care is more marked when the caregiver is a spouse. Yaffe et al. showed that a higher caregiver burden was associated with an early institutionalization of the patient [START_REF] Yaffe | Patient and caregiver characteristics and nursing home placement in patients with dementia[END_REF].

The APhA (American Pharmacists Association) Foundation's White Paper on Expanding the Role of Pharmacist in Caring for Individuals with AD concluded that increased pharmacist involvement in the care of individuals with AD and their caregivers could improve clinical outcomes and their quality of life [START_REF] Skelton | White paper on expanding the role of pharmacists in caring for individuals with Alzheimer's disease: APhA Foundation Coordinating Council to Improve Collaboration in Supporting Patients with Alzheimer's Disease[END_REF]. According to the APhA Foundation, the pharmacist could support caregivers to manage their own chronic health conditions, provide them with medication consultation and education to ensure medication compliance, provide them with support and information about community resources including information about respite care.

In 2010, the French Health Authority published guidelines regarding the screening of caregiver burden by general practitioners (GPs) or community pharmacists in order to improve the caregiver support in primary care [START_REF]Maladie d'Alzheimer et maladies apparentées: suivi médical des aidants naturels[END_REF]. However, these guidelines are not well known and not implemented in practice. In France as in most countries, community pharmacists are on the frontline to screen caregiver burden. In France, pharmacists and pharmacy technicians are in contact with patients and their caregivers and can deliver drugs.

The activities of the pharmacy technicians are under the responsibility of the pharmacists. To our knowledge only one observational study in the community pharmacy setting in Spain has been conducted to quantify caregiver burden and to identify any signs of psychopathology (e.g. anxiety and depression) [START_REF] Cotelo | Burden and associated pathologies in family caregivers of Alzheimer's disease patients in Spain[END_REF].

This study was conducted to (1) explore caregiver, pharmacist and pharmacy technician attitudes toward burden screening in community pharmacies and (2) to assess the burden in caregivers of patients with AD in community pharmacies.

Methods

Study Design, Population, and Setting

This cross-sectional study was conducted in 10 community pharmacies between November 2016 and February 2017 in Lyon, France. Community pharmacies in Lyon were recruited on random, practicality and voluntary basis. In each community pharmacy, pharmacists and pharmacy technicians (P/PT) willing to participate in this study were included. The selection criteria for the caregivers were: non-professional caregivers who provided consent and managing patients with known AD or patients with AD treated by antidementia drug (cholinesterase inhibitor and/or memantine). Caregivers were excluded if they could not speak, read or write French.

The study was introduced to caregivers during the community pharmacy drug dispensing process. Oral consent was obtained among caregivers and health professionals for their participation in the study. They could decline to participate in the study. Before the distribution of the questionnaire, a verbal comprehensive description about this study was introduced to caregivers by the P/PT and supplemented with an information letter explaining that caregiver burden screening in primary care is recommended by the French Health Authority [START_REF]Maladie d'Alzheimer et maladies apparentées: suivi médical des aidants naturels[END_REF]. Caregivers could decline to answer the questionnaire or withdraw at any time after inclusion. They were assured that the answers were kept confidential and the questionnaires would be anonymous with the assignation of a code to each one.

Data collection

A self-reported questionnaire developed for the study by the authors was distributed during the community pharmacy drug dispensing process to caregivers by P/PT (table 1). Caregivers could directly complete the questionnaire in the community pharmacy or complete the questionnaire at home and return it to the pharmacy during the study period (the next month during medication refill). This questionnaire included: (i) the scale to assess caregiver burden (validated instrument); and (ii) items about caregiver attitudes toward support and burden screening in the community pharmacy practice setting (yes/no questions). The scale used to assess caregiver burden was the validated short version of the Zarit Burden Interview (ZBI), which was previously developed for routine medical care [START_REF] Zarit | Subjective burden of husbands and wives as caregivers: a longitudinal study[END_REF][START_REF] Revel | Construction of a simplified scale for general medicine in detection of caregiver burden of a dependent elderly person[END_REF]. The 7-item scale consists of an interval score ranged from 0 to 7. This score represents the sum of the answers to 7 questions to which the caregivers answered "never" (0 point), "sometimes" (0.5 point) or "nearly always" (1 point). Caregiver burden can be classified as no or mild burden ([0-1]), mild to moderate ([1.5-3]), moderate to severe ([3.5-5]), and severe ( [5.5-7]).

Another self-reported questionnaire developed for the study by the authors was used for P/PT to assess P/PT attitudes regarding caregiver burden before the caregiver recruitment (table 1). This 8-item questionnaire (yes/no questions) included items about: (i) P/PT knowledge and skills about caregiver support, and caregiver burden; (ii) P/PT knowledge and attitudes toward caregiver support, and caregiver burden screening in the community pharmacy practice setting.

Demographic variables were also collected: gender for P/PT; age, gender, relation with the patient, duration of caregiving and time spent per day, professional status (retired or with a job) for caregivers.

Statistical Analysis

Descriptive statistics were performed using means ± standard deviations (SD) for continuous variables and frequencies (percentages) for categorical variables. The data of the two populations (P/PT and caregivers) were analyzed separately.

Results

A total of 20 caregivers (12/20 women) with a mean (±SD) age of 61.8 ± 13.7 years (range 40-84) were included to the caregiver burden screening and responded to the survey (table 2).

Sixty per cent of included caregivers were adult children of patients with AD (12/20) and 30% were spouses (6/20). No caregiver was excluded from the study. Twenty-two community pharmacists and thirty pharmacy technicians participated in the study. Of the 20 included caregivers, 90% (18/20) had a perception of burden: 15% (3/20) a perception of mild to moderate burden, 50% (10/20) moderate to severe burden, and 25% (5/20) severe burden (table 2). The mean caregiver burden score detected in this pilot study was 4.0 ± 1.7 (range 0-7), corresponding to a moderate to severe burden.

Table 3 presents the P/PT and caregiver attitudes regarding support and burden screening in the community pharmacy. Sixty-five per cent of caregivers reported their caregiver status to their pharmacist. In comparison, fifty-six per cent of P/PT indicated that caregivers easily confide their caregiving status. Eighty-four per cent of P/PT knew the meaning of caregiver burden. Regarding the burden screening, 70% of caregivers and 96% of P/PT stated that it should be assessed in the community pharmacy. However, only 26% of P/PT claimed to be able to assess the caregiver burden. Eighty-two per cent of P/PT thought they had to inform the caregiver's GPs about the detected burden level in the community pharmacy.

Discussion

This study demonstrated the prevalence of caregiver burden and the pharmacy staff's knowledge and perceived ability to screen for caregiver burden in the community pharmacy setting. Ninety per cent of caregivers reported experiencing a burden with 25% of which25% experienced a severe level of burden. The majority of caregivers and P/PT stated that the caregiver burden screening should be implemented in community pharmacies. For P/PT, the burden level detected should be communicated and referred to the caregiver's GP to optimize the caregiver's and patient's support (i.e. use of appropriate services).

Only one other published study conducted in community pharmacy assessing caregiver burden was found in the literature [START_REF] Cotelo | Burden and associated pathologies in family caregivers of Alzheimer's disease patients in Spain[END_REF]. Of the 25 included caregivers (55 ± 12.8 years) in this study, 28% had a perception of severe burden, 28% a perception of mild burden and 48% had no burden. The proportion of caregivers with severe burden was similar to the results of this present study (28% vs. 25%). However, the proportion of caregivers with no burden was different (48% vs. 10%).

The ZBI developed by Zarit et al. (22 items), Translated and validated in several languages, is the most widely used scale in the world in research and in clinical practice [START_REF] Zarit | Relatives of the impaired elderly: correlates of feelings of burden[END_REF][START_REF] Zarit | The Hidden Victims of Alzheimer's Disease: Families Under Stress[END_REF]. Short versions of ZBI have been published in different countries for clinical practice [START_REF] Revel | Construction of a simplified scale for general medicine in detection of caregiver burden of a dependent elderly person[END_REF][START_REF] Bédard | The Zarit Burden Interview: a new short version and screening version[END_REF][START_REF] O'rourke | Psychometric properties of an abridged version of The Zarit Burden Interview within a representative Canadian caregiver sample[END_REF][START_REF] Arai | The short version of the Japanese version of the Zarit Caregiver Burden Interview (J-ZBI_8): its reliability and validity[END_REF].

However, other tools assessing the caregiver burden have been validated such as the Caregiver Burden Inventory and the Screen for caregiver Burden [START_REF] Novak | Application of a multidimensional caregiver burden inventory[END_REF][START_REF] Vitaliano | The screen for caregiver burden[END_REF]. In this study, the short version of ZBI was chosen given its convenient use in clinical practice and its recommended use by the French Health Authority during the annual medical consultation of the caregiver [START_REF]Maladie d'Alzheimer et maladies apparentées: suivi médical des aidants naturels[END_REF].

Pharmacist-initiated screening in cognitive disorders

In the area of cognitive disorders, other screening services, such as memory screening, have been evaluated in community pharmacies. A study conducted by Breslow described patient attitudes toward pharmacist-administered memory screening and assessed patient satisfaction [START_REF] Breslow | Patient attitudes regarding pharmacist-administered memory screening in community pharmacies[END_REF]. Most participants responded to having community pharmacies offer memory screening because of their convenient locations (100%) and willingness to have an annual screening (92%) performed by a trained pharmacist (80%). A second study conducted by Rickles et al. assessed the impact of a pharmacy-based cognitive memory screening using the Mini-cog (combination of the three-Word Recall and the Clock Draw Test) and the Animal Fluency Test [START_REF] Rickles | Cognitive memory screening and referral program in community pharmacies in the United States[END_REF]. Of the 161 included participants, 44.1% experienced at least one cognitive deficiency that required referral to a physician.

The results of the memory screening studies combined with the results of this present study highlight the need to involve the community pharmacists in memory and caregiver burden screening. The purpose of identifying caregivers with a high level of burden is to optimize and to provide appropriate human, material and financial support. However, the implementation of these new services in a community pharmacy practice setting will require close collaboration with GPs and an assessment of the GPs' satisfaction with a referral program. Currently, there is no threshold or guidelines indicating when caregivers should be referred to their GP. Further research could be conducted to propose guidelines regarding this threshold and the means to communicate burden level and to refer caregivers to GPs. Several limitations for the implementation of this new clinical service in community pharmacy have been identified in this study. Indeed, nearly half of P/PT reported that caregivers did not easily confide their caregiving status. Only ten P/PT reported knowing how to measure the caregiver burden (without verification), thus requiring prior training of professionals.

Limitations

Among the limitations of this pilot study, we emphasize the small sample of P/PT and caregivers. The number of caregivers who refused to complete the questionnaire was not collected. The time required to complete the survey -which forced the caregiver to be away from home longer than usual -may have contributed to limiting the sample size.

The narrow selection criteria also prevented the inclusion of caregivers whose relatives were not treated by antidementia drugs or who had not communicated with the P/PT about the patients' AD. The study also did not include caregivers who could not speak, read, or write French. These selection biases potentially excluded caregivers and patients with reduced access to care. In this study, the burden scale (short version of the ZBI) was self-reported by the caregivers. P/PT will require training and qualifications to administer the scale during an interview with the caregiver.

Conclusion

Caregiver burden screenings performed in a community pharmacy by pharmacists and pharmacy technicians provides a valuable opportunity to identify caregivers with a significant burden level. However, larger studies are needed to measure the pharmacists' and pharmacy technicians' ability to assess the caregiver burden, to assess the costs of this new clinical service, and to confirm the benefits of burden screening in community pharmacy (on the burden evolution, the improvement of the caregiver medical follow-up and the implementation of health and social services).

  my caregiver status to my pharmacist 13 (65) I am disclosing my caregiver status to my GP 17 (85) I think that pharmacist must be able to screen caregiver burden in community pharmacy 14 (70) GP: General Practitioner; P: Pharmacists; PT: pharmacy Technicians; P/PT: Pharmacists and pharmacy Technicians. *missing data for one pharmacist/pharmacy technician; ** missing data for four pharmacist(s)/pharmacy technician(s); *** missing data for two pharmacist(s)/pharmacy technician(s).

Table 1 . Items of the questionnaire for caregivers and questionnaire for pharmacists/pharmacy technicians Tableau 1. Thèmes du questionnaire à destination des pharmaciens et préparateurs en pharmacie.

 1

	Questionnaire for caregivers

Table 3 . Pharmacists, pharmacy technicians and caregivers attitudes regarding support and burden screening in the community pharmacy practice setting. Tableau 3. Représentation et connaissances des pharmaciens et préparateurs en officine concernant le soutien et le repérage du fardeau de l'aidant en pharmacie d'officine.

 3

	Items

I think we must inform the caregiver's GP about their burden level (score to the burden scale)