Anthony Chapel
email: anthony.chapel@insa-cvl.fr

Jérôme Fortineau

Nicolas Porcher

Simon Malandain

Séverine Boucaud-Gauchet

Séverine Boucaud Gauchet

Effect of thermo-mechanical ageing on materials and interface properties in flexible microelectronic devices

Keywords: Flexible microelectronics, thermo-mechanical ageing, epoxy resin, durability, encapsulation

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The development of flexible microelectronic devices has led to a blossoming of new applications. Flexible microelectronics allows lightweight and conformable devices to be developed and used as biomedical implants, smart textile, or sensors for the internet of things. Münzenrieder et al developed flexible and stretchable oxide-based electronic sensors for skin and smart-implant uses [START_REF] Münzenrieder | Stretchable and Conformable Oxide Thin-Film Electronics[END_REF]. Carta et al. designed flexible sensors for monitoring biomedical parameters such as heartbeat, temperature, humidity, and respiratory rate. Most commonly, such sensors were designed and embedded in smart textiles [START_REF] Carta | Design and implementation of advanced systems in a flexible-stretchable technology for biomedical applications[END_REF].

To achieve such flexibility, however, micro-electronic components have to be interconnected to conformable flexible substrates. Thin, light, conformable, and flexible substrates offer a reliable alternative to rigid printed circuit boards (PCB). Several studies have presented polymers such as polyethylene terephthalate (PET), polyethylene naphthalate (PEN), and polyimide (PI) as suitable candidates to use as flexible substrates [START_REF] Rim | Recent Progress in Materials and Devices toward Printable and Flexible Sensors[END_REF][START_REF] Zardetto | Substrates for flexible electronics: A practical investigation on the electrical, film flexibility, optical, temperature, and solvent resistance properties[END_REF][START_REF] Macdonald | Latest advances in substrates for flexible electronics[END_REF].

Today, the development of flexible, stretchable, and reliable electronic circuits is an important research area. Gonzalez et al. used finite element modeling to determine the geometrical stresses in the metallic connection [START_REF] Gonzalez | Design and implementation of flexible and stretchable systems[END_REF] and arrived at the horseshoe as the optimal geometry. In their review, Rim et al. demonstrated that conductive nanoparticles, deposited via inkjet printing, can offer a suitable solution for processing flexible electronics [START_REF] Rim | Recent Progress in Materials and Devices toward Printable and Flexible Sensors[END_REF].

Like classical rigid electronic systems, flexible microelectronic devices are susceptible to physical conditions in their working environment. Both electrical circuits and silicon chips are subject to attack by humidity and oxygen from the air. To better prolong the lifetime of these devices, their microelectronic systems require protection by a conformable encapsulant. Here, the encapsulant protects against physical and chemical attacks from the external environment and mechanical impacts. In particular, it ensures water-tightness of the system [START_REF] Salem | Thin-film flexible barriers for PV applications and OLED lighting[END_REF]. Lewis has outlined the permeability requirement for flexible electronics [START_REF] Lewis | Material challenge for flexible organic devices[END_REF]. Although inorganic encapsulants such as glass readily meet these requirements, they are particularly impractical as flexible devices.

Several studies have dealt with the development of flexible encapsulation systems, especially those in the field of organic photovoltaics. For example, Gaume et al. developed an ultra-multilayer barrier based on polyvinyl alcohol (PVA) and clay for such applications [START_REF] Gaume | Optimization of PVA clay nanocomposite for ultra-barrier multilayer encapsulation of organic solar cells, 9[END_REF]. However, the durability of this multi-layer depends on the long-term stability of their composite materials and interfaces. Topolniak et al. studied the ageing of ethylene vinyl alcohol (EVOH)/zeolite composites for the encapsulation of flexible photovoltaics [START_REF] Topolniak | Applications of polymer nanocomposites as encapsulants for solar cells and LEDs: Impact of photodegradation on barrier and optical properties[END_REF] and it was later shown that the photo-oxidation of such composites could lead to a weakening of the barrier properties.

Bossuyt et al. studied the stability of flexible microelectronic devices under cyclic mechanical stretching [START_REF] Bossuyt | Cyclic endurance reliability of stretchable electronic substrates[END_REF]. They focused on the mechanical cycling effects on the electrical properties of microelectronic devices.

Fatigue rupture in electrical copper traces was observable after several hundred thousand cycles.

Although the combined effects of thermal ageing of materials and mechanical stress can occur in many flexible systems and lead to early failure, to our knowledge, only a few papers have dealt with this phenomenon.

In this paper, a flexible epoxy formulation based on ECC and EA is studied as a potential candidate for encapsulation of microelectronic devices. Despite the large number of papers dealing with epoxy resin durability, most have focused on bisphenol A diglycidyl ether (DGEBA) and epoxy amine-based resins [START_REF] Ernault | Origin of epoxies embrittlement during oxidative ageing[END_REF][START_REF] Ernault | Thermal-oxidation of epoxy/amine followed by glass transition temperature changes[END_REF][START_REF] Delor-Jestin | Thermal and photochemical ageing of epoxy resin -Influence of curing agents[END_REF][START_REF] Bondzic | Chemistry of thermal ageing in aerospace epoxy composites[END_REF]. Delor-Jestin et al. [START_REF] Delor-Jestin | Thermal and photochemical ageing of epoxy resin -Influence of curing agents[END_REF] showed that t the thermal and photochemical stability of DGEBA-based epoxy were both affected by the chemical nature of the curing agent used. Ernault et al. linked the embrittlement of such epoxies upon thermal ageing to changes in their glass transition temperature [START_REF] Ernault | Thermal-oxidation of epoxy/amine followed by glass transition temperature changes[END_REF], and β-transitions [START_REF] Ernault | Origin of epoxies embrittlement during oxidative ageing[END_REF]. The β-transitions are attributable to local motions of hydroxyether groups present in DGEBA [START_REF] Heux | Dynamic mechanical and 13C n.m.r. investigations of molecular motions involved in the β relaxation of epoxy networks based on DGEBA and aliphatic amines[END_REF]. Embrittlement of DGEBA-based epoxy resin is associated with changes in the transitiontemperature and intensity upon oxidative ageing [START_REF] Ernault | Origin of epoxies embrittlement during oxidative ageing[END_REF].

To be flexible and conformable requires that the chemical structure of the epoxy resins be linear and saturated. Few articles have dealt with saturated epoxy ageing or used mechanical criteria to characterize ageing. Dupuis et al. [START_REF] Dupuis | Photo-oxidative degradation behavior of linseed oil based epoxy resin[END_REF] presented the photo-oxidative degradation mechanism of linseed-based epoxy resin and its effects on the surface and mechanical properties. Their results showed that for shorter irradiation times (<150h), crosslinking reactions induced an increase in nano-hardness, while scission reactions become more competitive at longer irradiations, resulting in a decrease in hardness. The chemical structure of the resin studied mainly consisted of aliphatic chains. In our study, the chemical structure is quite different, with the monomers used based on cyclohexene oxide derivatives. Thus, the main chain segment consisted of a cyclohexane ring linked to an oxygen bridge. The degradation mechanisms also differ from the ones reported in previous publications [START_REF] Delor-Jestin | Thermal and photochemical ageing of epoxy resin -Influence of curing agents[END_REF][START_REF] Bondzic | Chemistry of thermal ageing in aerospace epoxy composites[END_REF]. This paper aimed to identify and understand the destruction mechanisms induced in flexible smartcards by environmental conditions via temperature and mechanical fatigue during their use. The effects of the encapsulant and substrate ageing on the electrical performance and durability of flexible microelectronic devices are presented. This work primarily focused on the polymer material behaviors as the encapsulant and substrate; and the interfacial integrity between the encapsulant/substrate bilayer systems.

Materials and Methods

Materials

The epoxy resin formulation used as encapsulant (named PNE) was developed and supplied by Protavic International.

The formulation comprised a mixture of two monomers:

3,4-epoxycyclohexylmethyl-3',4'-epoxy-cyclohexene carboxylate (ECC) and 3,4-epoxycyclohexyl adipate (EA). Their chemical structures are shown in Figure 1. A weight ratio of 1.5 for the ECC monomer to 1 for the EA monomer was employed. Bis [4-(diphenylsulfonio)phenyl]sulfide bis(hexafluoroantimonate) at (0.25-0.50 wt%), also presented in Figure 1, was used as a photo-initiator. The resin was filled with amorphous silicon oxide (30-40 wt%) and cured under UV radiation.

Sample preparation

Commercial PET films with a thickness of 120 µm were selected for their flexibility and used as the substrate.

A silver electrical circuit was deposited on the substrate and a silicon chip glued to it (Figure 2 Multilayer samples were prepared and used to study the interfacial quality of encapsulant/substrate bilayers using the peeling test (Figure 2 c). Epoxy resin films (17 mm width, 100 µm thick) were deposited on PET substrate film (120 µm thick) and cured under the same conditions as the free-standing films.

DSC analysis was employed to verify that the epoxy resin was 100% cured. No residual precursor was detected.

Ageing conditions

A total of six ageing conditions were performed based on industrial requirements for smartcard applications.

Thermal ageing was carried out in a ventilated oven at 120°C for up to 500 hours. Since there is no ageing temperature definition in the ISO10373 standard, the project partner STMicroelectronics proposed conducting thermal ageing at 120°C as recommended for microelectronics devices. This temperature also allowed the simulation of localized heating points that often appear in materials and interfaces during long-term mechanical fatigue tests.

Mechanical fatigue involved the imposition of bending cycles on the test samples by winding them around a roller at a constant frequency of 24 cycles per min, at room temperature. Ageing involved using a homemade bending bench (Figure 3 All ageing conditions performed on the samples are reported in Table 1. The results presented in this paper were obtained by analyzing up to 7 samples and 4 TVs per condition. 30°C to 250°C at a rate of 10°C/min. DSC analyses allowed us to ascertain curing completion and to monitor changes in the microstructure after ageing. The crystallinity rate (χc) for the PET substrate was calculated using a melting enthalpy for 100% crystalline PET of 140 J/g, in line with the literature [START_REF] Brandrup | Polymer handbook[END_REF].

Dynamic mechanical thermal analyses were done on a TA Instruments DMA Q800 under air. Rectangular shaped (18 mm x 9 mm) and 100 µm thick samples were analyzed. A tensile dynamic strain of 0.1% was imposed on the samples at a frequency of 1Hz. The samples were heated from -100°C to +100°C at a rate of 3°C/min. The glass transition temperature (Tg) and the β-transition were determined using the loss modulus thermograms. The full width at half maximum (FWHM) of the peaks was also determined.

Tensile tests were carried out on an Instron Microtester 5948 equipped with a 2 kN force cell. Three 100 µm thick rectangular samples (1.7 cm*10 cm) cut from free standing films were analyzed at room temperature, under NF ISO527-3 standard. The preload was 0.5 N and the tensile speed 5 mm.min -1 . Three specimen for each ageing condition were analyzed.

Thermo-gravimetric analyses (TGA) were performed on a Setaram Setsys 16/18 apparatus under an air atmosphere. Sample masses of 5 mg were heated from 25°C to 700°C at a rate of 10°C/min. TGA analyses were employed to determine and monitor the degradation temperature corresponding to a mass loss of 5%.

Fourier transform infrared analyses (FTIR) were performed on 20 µm thick films in transmission mode with a JASCO FT/IR-6800 spectrophotometer. FTIR spectra used 32 scan summations at a 4 cm -1 resolution.

Determination of epoxy resin adhesion strengths on the PET substrate involved peeling tests performed at a peeling angle of 90° at room temperature. The peeling strengths were directly measured using an Instron

Microtester 5948 mechanical testing machine equipped with a 2 kN force cell and a specifically designed peeling bench. The applied load was monitored continuously during epoxy film peeling, at a constant displacement rate of 5 mm/s. The peeling force was determined using:

= × 1 -cos /
where G is the peeling force (in N/cm), F is the applied load in the stationary domain (in N), θ is the peeling angle (here 90°), and w is the epoxy resin band width (in cm). Three samples for each ageing condition were measured.

Optical microscopy was performed on A Keyence VHX-1000 microscope and employed a 100X optical magnification. The magnification used enabled delamination or formation of cracks to be detected.

Confocal Raman spectroscopy allowed for the in depth chemical structural changes during ageing to be studied.

The depth profiles of TV were performed starting from the substrate down to the encapsulating resin. The recorded Raman spectra with an InVia Renishaw microscope used the 633 nm laser line. To allow for analysis of the substrate and then the epoxy resin, samples were placed with the substrate on top. The spectra were recorded at room temperature with various focalizations, from 10 µm for the surface to 200 µm for deep inner sample visualizations at 10 µm intervals.

To detect TV functional failures, electrical tests that involved measuring the electrical resistance between the terminals of the chip (Figure 2 d) were performed. A Fluke 175 true RMS multimeter was used. An increase in the value measured corresponded to device failure and thus defined as the end of life criteria for TV in our study.

Results and discussion

Epoxy resin characterization

Ageing-induced changes of the PNE epoxy resin were determined through thermal and mechanical properties using DMTA, tensile tests and TGA. DMTA thermograms of the epoxy resin are presented in Figure 4. The main peak of the loss modulus thermogram (Figure 4 a) is centered at +13°C. This peak is attributable to the glass transition of the PNE resin.

A secondary maximum at -67°C is attributable to the β-transition of the resin. Udagawa et al. studied the dynamic mechanical properties of UV-cured ECC and EA [START_REF] Udagawa | Dynamic mechanical properties of cycloaliphatic epoxy resins cured by ultra-violet-and heat-initiated cationic polymerizations[END_REF] and attributed the presence of β transition in both polymers to molecular motions of the cyclohexyl rings. As the same chemical structures are present in PNE resin, its β-transition is attributable to the same molecular motions.

Mechanical properties were determined at room temperature using tensile test measurements. Figure 5 a presents a stress-strain curve for the PNE epoxy resin. Epoxy resin films exhibited a brittle break. Both Young's modulus and strain at break were determined. The resin films presented Young's modulus (E) of 33 ± 1 MPa and a strain at break (εB) of 22.9 ± 1.1 %. Thermal degradation occurred in two stages. At the end of the experiment, 42.5 % of the original weight remained, corresponding to the silicon oxide fillers that do not degrade at these temperatures. Thus, suggesting that the filler content in the studied samples was 42.5 wt%.

Thermal ageing

Below, the effects of thermal ageing on the encapsulant and the substrate are discussed. Chemical and mechanical analyses for each specimen type are presented.

Epoxy resin ageing

It is important to note that the resin films presented yellowing upon ageing, indicating an alteration of their chemical structure. The evolution of the FTIR spectra with thermal ageing conditions is presented in Figure 6.

The spectral differences (x hours -reference) in the carbonyl domain (1850-1650 cm -1 ) are also presented. A white box hides a saturated part of the spectra to facilitate reading. Spectral band formation (upwards) and disappearance (downwards) were detectable on difference spectra.

The main change visible on the original spectra was the decrease in the broad band for wavelengths over 3 000 cm -1 . This band is attributed to O-H bonds from adsorbed water or alcohol present in the film. Amid the carbonyl domain, was observed the formation of bands at 1814, 1780 and 1764 cm -1 . Whereas the vibration band at 1780 cm -1 corresponds to lactones formations [START_REF] Morlat-Therias | Polymer/carbon nanotube nanocomposites: Influence of carbon nanotubes on EVA photodegradation[END_REF], the bands at 1814 and 1764 cm -1 were attributed to anhydride acids formation.

A decrease in intensity of the band at 1710 cm -1 was noticeable. This band signaled the presence of ketones that degrade during thermal ageing.

Although these attributions relied on a reference table and previous literature findings, they should be confirmed by complementary analysis such as chemical derivatization treatments with NH3 SF4 or 2,4-dinitrophénylhydrazine (2,4-DNPH) [START_REF] Carlsson | Identification of Products from Polyolefin Oxidation by Derivatization Reactions[END_REF][START_REF] Wilhelm | Infrared identification of carboxylic acids formed in polymer photooxidation[END_REF]. Based on their specific reactivity with the different carbonyl functional groups, these treatments used together with FTIR analysis can identify contributions to the carbonyl band. NH3 is reactive with esters, carboxylic acids and anhydrides; SF4 with carboxylic acids; and the 2,4-DNPH with aldehydes and ketones. Table 2 summarizes changes in the thermo-mechanical properties of the resin upon thermal ageing. The Tg and the β-transition were determined using DMTA. The FWHM of the peaks was also calculated. Whereas the Tg increased following thermal ageing, its FWHM remained unchanged. The β-transitions were unaffected by the thermal ageing.

The Young's modulus was four times higher after thermal ageing while the strain at break decreased by a third. This change was well reflected through observed stiffening and embrittlement of the resin films.

The decomposition temperature of the resin increased from 294°C to 307°C. reactions. These reactions are antagonistic and their kinetics are not identical and can vary according to the degree of degradation, ageing conditions and the nature of the polymer. Crosslinking reactions are usually linked to increases in both Young's modulus and Tg [START_REF] Sindt | Molecular architecture-mechanical behaviour relationships in epoxy networks[END_REF][START_REF] Rasoldier | Model systems for thermo-oxidised epoxy composite matrices[END_REF], whereas chain scission reactions have the opposite effect.

The marked stiffening of the resin studied, coupled with the increase in its glass transition temperature during thermal ageing, could be explained by the dominance of crosslinking reactions over chain scissions in the thermal oxidation mechanism. This result is verifiable by the observed increase in the decomposition temperature, as observed by TGA. It is shown that crosslinking reactions during ageing significantly increase the polymer degradation temperature [START_REF] Patel | Durability of hygrothermally aged graphite/epoxy woven composite under combined hygrothermal conditions[END_REF]. Dupuis et al. reported similar result from a study on the photo-degradation mechanism of linseed-based epoxy resin [START_REF] Dupuis | Photo-oxidative degradation behavior of linseed oil based epoxy resin[END_REF]. They showed that crosslinking reactions control degradation for shorter ageing times (200h) and are associated with marked increases in the modulus.

Ernault et al. linked the embrittlement of DGEBA/TTDA and DGEBA/IPDA during thermal-oxidative degradation to crosslinking reactions and β-transition intensity decrease [START_REF] Ernault | Origin of epoxies embrittlement during oxidative ageing[END_REF]. They attributed intensity decreases in the β-transition to the oxidation of the hydroxypropylether groups of DGEBA since their local motions corresponds to this transition. In the present study, β-transitions for the PNE resin were not affected by thermal ageing at 120°C for 500h. As this transition corresponds to the cyclohexyl ring motions, the molecular mobility of this moiety should be exempt from the thermal-oxidative degradation of the epoxy resin. To better decipher the events that underpin the ageing of the bilayer assembly, PET substrate films were aged using the same conditions.

PET substrate ageing

The mechanical and thermal properties of PET films both before and after 500h at 120°C are summarized in Table 3. The Young's modulus, the strain at break and the melting temperature (Tm) remained unchanged after thermal ageing. PET crystallinity increased slightly, presumably as a result of thermal annealing. The Raman spectra of the PET substrate before and after 500h at 120°C are presented in Figure 7. The initial spectrum exhibits the conventional vibration bands of PET [START_REF] Lin | Chemical depth profiling of photovoltaic backsheets after accelerated laboratory weathering[END_REF][START_REF] Rebollar | Physicochemical modifications accompanying UV laser induced surface structures on poly(ethylene terephthalate) and their effect on adhesion of mesenchymal cells[END_REF]. There was no spectral modification after thermal ageing. Instead, a broad peak covering the entire scan range appeared. However, the chemical structure of the PET substrate film should not be modified by thermal ageing under these thermal ageing conditions. Thus, the observed peak broadening is probably due to the fluorescence that emanates from the adjacent PNE layer (see description in the next part).

After thermal ageing at 120°C for 500h, the chemical structure and mechanical properties of the PET substrate films were conserved. The parameter change of note was an increase in PET crystallinity, possibly due to the annealing process.

Bilayer and test vehicle ageing

PET/PNE bilayer systems and TV were all thermally aged under the same conditions. The bilayer systems were employed to characterize thermal ageing on the interface quality between encapsulant and substrate. TVs were used to determine the effects of thermal ageing on their functional properties (i.e. electrical properties).

The results of the peeling tests performed on bilayer systems are presented in Table 4. An adhesive rupture was observed both before and after ageing. The value of the peeling force G increased after thermal ageing at 120°C for 500h. The changes observed followed the same trend as both the Tg and mechanical properties of the epoxy resin while the substrate properties remained unchanged. The crosslinking reactions occurring in the epoxy resin during thermal ageing led to an increased peeling strength, although the exact mechanism that underlies this phenomenon remains unclear. Accordingly, complementary experiments are needed to decipher this mechanism and those will be the subject of a separate study. 5).

After thermal ageing, the epoxy resin deposited on TV presented marked yellowing (Figure 8), whereas the PET substrate was unchanged. Similar results were obtained after free films ageing. Two areas are distinguishable on the reference TV. Intense vibration bands attributed to the PET substrate were detected for depths from 0 to approximatively 100 µm. There were no identifiable vibration bands for depths over 100 µm. The Raman signal of the studied epoxy resin was very low compared to that of PET.

A broader vibration band for depths greater than 100 µm (i.e. in the epoxy resin area) for thermally aged TV was evident. This band presumably arises from fluorescent groups derived from the chemical degradation of the epoxy resin. Indeed, samples undergoing yellowing were also the ones that exhibited Raman spectra modified by fluorescence due to the thermal oxidation of the polymer. The yellowing of polymers during oxidative ageing has already been described [START_REF] Yang | Thermally resistant UV-curable epoxysiloxane hybrid materials for light emitting diode (LED) encapsulation[END_REF][START_REF] Allen | Aspects of the thermal oxidation, yellowing and stabilisation of ethylene vinyl acetate copolymer[END_REF][START_REF] Gardette | Fundamental and technical aspects of the photooxidation of polymers[END_REF]. Moreover, fluorescent oxidation products can form in polymer materials during oxidative ageing [START_REF] Peike | Indoor vs. outdoor aging: polymer degradation in PV modules investigated by Raman spectroscopy[END_REF][START_REF] Allen | Thermal and photo-chemical degradation of nylon 6,6 polymer: Part 1-Influence of amine-carboxyl end group balance on luminescent species[END_REF]. Accordingly, the fluorescence serves as an indicator of the formation of oxidation products during thermo-oxidative ageing. These results are verifiable through FTIR analytical results obtained on aged PNE films. The force needed to peel the epoxy resin from the substrate increased due to the crosslinking reactions occurring during thermal ageing. TV functional properties were not affected by this reinforcement because the intensity of the increase was not sufficient.

Mechanical fatigue

Epoxy resin fatigue

The thermal and mechanical properties of the epoxy resins, following fatigue ageing under F2 conditions were determined using DMTA, tensile tests and TGA. The corresponding results are presented in Table 2.

The Young's modulus increased from a reference value 33 ± 1 MPa to 50 ± 6 MPa after fatigue ageing under F1 conditions, indicating a stiffening of the films. However, the stiffening recorded under F1 condition remained modest upon comparison, with the 133 ± 32 MPa recorded for thermal ageing at 120°C for 500h.

Between F1 and F2 fatigue ageing conditions, PNE films stiffening increased further. Fatigue ageing under F2 conditions did not affect the glass transition (Tg), β-transition (Tβ) or decomposition (Td) temperatures.

Additionally, the thermo-mechanical properties of PNE resin films were not significantly affected by fatigue at room temperature. In order to confirm these trends, fatigue experiments should be either continued under the same or harsher conditions.

PET substrate fatigue

The evolution of the PET substrate films properties subjected to mechanical fatigue appears in Table 3.

After fatigue ageing, the PET Young's modulus increased reflecting a stiffening of the substrate. The crystallinity ratio was modified, whereas the melting temperature was unchanged.

Micro-Raman spectra, obtained for PET substrates before and after mechanical fatigue under F1 and F2 conditions, are presented in Figure 10. Raman spectra after fatigue testing at ambient temperature remained unchanged, suggesting that the PET chemical structure was stable under these conditions. The observed stiffening of PET after F1 is well explained by the increase in crystallinity in the polymer.

However, the additional increase of stiffening, indicated by an increase in Young's modulus after F2, is nonetheless accompanied by a marked decrease in crystallinity back to its initial value. Another stiffening mechanism is involved in this case. The additional stiffening mechanism is presumably due to the presence of crosslinking reactions. For both F1 and F2 fatigue conditions, there was no sign of a modification of the chemical structure of PET. However, the chemical bond formed by the crosslinking reaction might not be active in Raman spectroscopy. Accordingly, complementary analyses are required to confirm the presence of crosslinking reactions.

Bilayer and test vehicle fatigue

The change in peeling force G between the PET substrate and PNE resin with fatigue ageing is reported in Table 4. The peeling force G remained stable after mechanical ageing, and adhesive ruptures were observed for each condition and each sample tested. The interface quality was unaffected under the fatigue conditions of the study.

TVs electrical testing after fatigue in condition F1 was positive. However, the tests were negative after condition F2 (Table 5), indicating a discontinuity in the electrical circuit. Under these harsher conditions, TV failure was observed even earlier, after 5 000 cycles on the 50 mm diameter roll followed by 3 000 additional cycles on the 25 mm diameter roll. Optical microscopy was performed on TVs to determine the origin of these failures. Figure 11 presents a microscopic image of a chip on a TV that failed the electrical test. This micrograph was captured through the transparent PET substrate to examine the electrical circuit under the chip.

For this micrograph, cracks (denoted as red lines) formed within the glue layer at the substrate and the chip interface, under the harshest condition during mechanical ageing. These cracks are probably due to the marked differences in stiffness between the silicon chip and the PET film. Under these conditions, stress accumulates in the glue layer leading to cracking. The chemical structure of both substrate and encapsulant layer presented no detectable chemical modification.

After mechanical fatigue, the studied epoxy resin presented slight stiffening while its other properties remained unchanged. A stiffening of the PET substrate was similarly accompanied by increases in its crystallinity but with no change in its chemical structure. These microstructure modifications are probably due to mechanical effects only. The frequency of mechanical cycles used was probably too low to induce a substantial rise in the internal temperature by the friction of polymer macromolecules. The chemical structure of both PET and epoxy resin was also stable under these ageing conditions.

TV succumbed to electrical failure under the harshest ageing condition following the formation of cracks in the glue layer.

Thermo-mechanical coupling

All sample types were thermo-mechanical aged. Samples were first aged for 500h at 120°C under air, followed by mechanical bending for 5 000 cycles on a 50 mm diameter roll (TM1) and finally to 5 000 cycles on a 25 mm diameter roll (TM2). Mechanical bending cycle experiments were performed at ambient temperature. Samples characterization used the same techniques as previously described.

Epoxy resin TM coupling

Analytical characterization of PNE resin was by DMTA, tensile tests and TGA. The results are summarized in Table 2.

After ageing under condition TM1, Tg, Td, and Young's modulus increased. Tβ was unchanged. Visual inspection of the samples revealed a yellowing of the resin. The effect of thermo-mechanical ageing under TM1 condition was the combination of both thermal ageing for at 120°C for 500h and mechanical fatigue under F1 condition. As previously explained for thermal ageing, the simultaneous increase in these parameters reveals that crosslinking reactions were predominant. Based on the phenomenon of intensity difference between thermal ageing and mechanical fatigue as previously described, most of the changes observed under the combined regimen were due to thermal ageing. Yellowing of the resin observed after 500h at 120°C did not change during the subsequent fatigue.

Both Tg and Young's modulus decreased under the harshest (TM2) ageing conditions. An increase in the effectiveness of chain scission reactions explains this effect.

As for thermal ageing and fatigue, the β-transition was not affected by thermo-mechanical ageing under either condition.

A two steps system is identified as underpinning the thermo-mechanical ageing of epoxy resins. The first step TM1 is the direct addition of thermal ageing and fatigue F1. During this step, the crosslinking reactions proved dominant as evidenced by the stiffening of the films and increasing of their glass transition temperature.

Yellowing of the resins due to thermal ageing was similarly recorded.

The second step TM2 presented different mechanisms, evidenced by a softening of the films and a decrease in Tg. During this step, chain scission reactions became more competitive.

PET substrate TM coupling

The changes in thermal and mechanical properties of PET substrates with thermo-mechanical ageing are presented in Table 3. The Young's modulus, strain at break and melting temperature for the PET substrate, after thermo-mechanical ageing, were not significantly modified under either condition. However, the PET substrate crystallinity ratio increased slightly. As for the recorded increase in crystallinity after thermal ageing, this is probably the result of a thermal annealing effect on the film.

The Raman spectra of PET films after thermo-mechanical ageing are presented in Figure 12. Both the peak positions and their width were unchanged after ageing, suggesting that the chemical structure of PET was stable during ageing under these conditions.

Bilayer and test vehicle TM coupling

The PET/PNE bilayer and TV were all subjected to thermo-mechanical ageing. The values of the peeling force G recorded after ageing are reported in Table 4. After ageing under TM1 conditions, the peeling force increased from 1.74 ± 0.15 N/cm to 2.61 ± 0.19 N/cm. However, this value is of the same magnitude as that recorded after thermal ageing at 120°C for 500h (2.70 ± 0.14 N/cm), suggests that the recorded increase during thermos-mechanical ageing TM1 was mainly due to the thermal ageing step. After ageing under condition TM2, a slight decrease in G was detected. This observation is consistent with the increase in chain-scission efficiency, evidenced for the epoxy resin ageing under this condition.

The results of the electrical tests performed on TV are presented in Table 5. These tests were positive for all the chips tested after thermo-mechanical ageing under both conditions. However, the TV aged under the harshest condition (TM2) presented some delamination between the PET substrate and the encapsulating resin.

Illustrated by the micrograph shown in Figure 13, delamination occurred on each side of the silicon chip and parallel to the bending direction. This is also explained by the stiffening of the resin measured after thermo-mechanical ageing. Thus conformability of the resin is reduced by this significant stiffening. Stresses then accumulate at the interface during the bending function of the TV. These observations are different from those observed for mechanical fatigue under F2 conditions. Here stresses are released when cracks form in the glue layer. Changes of both polymer materials during the thermo-mechanical ageing lead to modifications in the distribution of internal stresses that, in turn, results in different release modes.

Delamination between resin and substrate enabled water and oxygen to diffuse into the system.

Accordingly, the encapsulation layer ceases to play its protective role. Functional properties would be degraded with longer ageing periods. Although yellowing of the epoxy resin developed during the thermal ageing stage, there was no recorded change during the subsequent mechanical ageing stage.

Conclusion

The durability and functional performances of microelectronic test vehicles comprising epoxy resin encapsulant and PET substrates have been thoroughly assessed after thermal, mechanical fatigue and thermo-mechanical ageing. Under moderate (TM1) ageing conditions, the changes observed resulted directly from combined thermal ageing and mechanical fatigue. Under these ageing conditions, oxidation of the epoxy resin resulting from the thermal ageing coupled with a stiffening of the films induces an increase of the peeling force, and reinforcement of the encapsulant/substrate interface. Whereas crosslinking reactions dominated under moderate ageing TM1 conditions, no further oxidation was detected under harsher TM2 conditions.

Instead, chain scission reactions induced by fatigue stress following thermal ageing (TM2) were dominant. A softening of the epoxy resin coupled with a decrease in Tg was evidenced. The peeling force required to decouple the encapsulant from the substrate decreased, and delamination between the encapsulant and the substrate was observed in TV. While delamination does not always necessarily cause electrical failure, it probably induces damage to the barrier properties.

The peeling tests show that adhesion between the encapsulant and substrate is governed by degradation mechanisms occurring within the epoxy resin. The failure mechanism of TV as delamination or cracks in the glue layer is influenced by mechanical changes of all the constituting materials.

To that end, if the thermo-mechanical ageing remains inadequately controlled, a variety of reliability issues, circuit failure, performance degradation, ultimately leading to possible devices damage, will be the results.

Figure 1 .

 1 Figure 1. Chemical structures of the two monomers (ECC and EA) constituting the PNE encapsulant and the photo-initiator

  a). These systems, called Test Vehicles (TV), were supplied by STMicroelectronics. TVs were encapsulated using a glob top of the PNE resin (Figure 2 b). The glob top architecture, chosen because it advantageously minimizes the amount of protective polymer, also reduced delamination damage by ensuring a lower interfacial surface contact with the substrate. Resin deposition was conducted in a clean room and employed an industrial Asymtek C-341 automatic dispenser. Curing used a 365 nm UV LED for 30 seconds at room temperature under an air atmosphere.

Figure 2 .

 2 Figure 2. (a) Schematic side view of the glob top encapsulated TV showing the architectural ensemble, (b) TV encapsulated within the PNE resin, (c) multilayered PET and PNE ensemble for the peeling test, and (d) schematic top-view illustrating the experimental assembly of the resistance measurements

  a). The principle of the mechanical tests is shown in Figure 3 b. Samples were rolled (5 000 cycles) around a 50 mm diameter roller (F1) and then subjected to optical microscopy or electrical testing. If no degradation was noticeable, the samples were again rolled ( 5 000 cycles) around a 25 mm diameter roller (F2).

Figure 3 .

 3 Figure 3. (a) Photograph and (b) schematic illustration of the functional principle of the bending bench

Figure 4 .

 4 Figure 4. DMTA thermograms of unaged PNE epoxy resin showing, (a) storage and loss modulus; and(b) tanδ a) b) -100 -75 -50 -25 0 25 50 75 100

Figure 5 .

 5 Figure 5. (a) Stress-strain curve and (b) TGA thermogram of unaged PNE resin film

Figure 6 .

 6 Figure 6. Changes in the epoxy resin films with thermal ageing time (a) full FTIR spectra and (b) FTIR difference (xhours-reference) spectra for the carbonyl domain (1650-1850 cm -1 )

Figure 7 .

 7 Figure 7. Raman spectra of PET substrate TV before (Reference) and after thermal ageing at 120°C for 500h

Figure 8 .

 8 Figure 8. (a) Photographic image of a TV and (b) optical micrograph of on encapsulated chip before (Reference) and after thermal ageing (500h 120°C)

Figure 9 .

 9 Figure 9. Raman depth profiles of TVs a) before; and after ageing under b) 500h, c) F1, d) F2, e) TM1 and f) TM2 conditions

Figure 10 .

 10 Figure 10. Changes in micro-Raman spectra of PET substrate in TVs before and after mechanical ageing under F1 and F2 conditions

Figure 11 .Figure 9

 119 Figure 11. Optical micrograph of a TV after it was subjected to fatigue ageing under F2 conditions

Figure 12 .

 12 Figure 12. Changes in micro-Raman spectra of PET substrate in TVs before and after thermo-mechanical ageing under TM1 and TM2 conditions

Figure 13 .

 13 Figure 13. Optical micrograph of a TV after it was subjected to thermo-mechanically ageing under TM2 conditions

Table 1 . Ageing conditions and the number of samples used in this study AGEING TYPE REFERENCE THERMAL FATIGUE THERMO-MECHANICAL

 1

	CONDITION	Pristine	Up to 500h	5000cy ⌀50 5000cy ⌀50 +	500h 120°C +	500h 120°C
			at 120°C		5000cy ⌀25	5000cy ⌀50	+ 5000cy
							⌀50 +
							5000cy ⌀25
	NOTATION	Ref	Xh*	F1	F2	TM1	TM2
	Total number	4 TV	4 TV	4 TV	4 TV	4 TV	4 TV
	of sample	7 film samples	7 film	6 film	7 film	7 film samples	7 film
			samples	samples	samples		samples

* X is the ageing time in hours

2.4. Characterization methods

DSC measurements were performed on a Mettler Toledo DSC 1 apparatus under an air atmosphere. Sample masses of 10 mg were placed in aluminum DSC crucibles and subjected to two heating-cooling cycles from

Table 2 .

 2 Changes in PNE resin characteristics (Tg, Tβ, E, εB, Td) induced by the different ageing

	conditions
	Ageing	Tg	FWHM of Tg	Tβ	FWHM of Tβ	E (MPa)	εB (%)	Td
	Reference	13°C	23.1°C	-67°C	36°C	33 ± 1	22.9 ± 1.1	294°C
	500h 120°C	26°C	24.2°C	-67°C	38°C	133 ± 32	15.1 ± 1.2	307°C
	F1					50 ± 6
	F2	14°C	23.1°C	-71°C	49°C	56 ± 11	15.7 ± 2.2	295°C
	TM1	28°C	31.4°C	-67°C	42°C	153 ± 21	17.8 ± 3.7	301°C
	TM2	20°C	21.5°C	-69°C	50°C	126 ± 20	20.2 ± 1.0	306°C
	Polymer degradation mechanisms in the presence of oxygen involve both crosslinking and chain scissions

Table 3 .

 3 Changes in mechanical and thermal properties of PET films induced by the different ageing

	conditions
	Ageing	E (MPa)	εB (%)	Tm	χc (%)
	Reference	5049 ± 42	72.7 ± 5.7	258°C	28%
	500h 120°C	5116 ± 289	71.0 ± 17.6	256°C	32%
	F1	5212 ± 177	71.8 ± 2.1	257°C	35%
	F2	5538 ± 42	74.4 ± 8.6	257°C	30%
	TM1	4932 ± 250	61.1 ± 20.2	256°C	33%
	TM2	4828 ± 312	72.0 ± 11.3	256°C	34%

Table 4 .

 4 Changes in the peeling force between PET and PNE films induced by the different ageing thermally aged TV successfully passed the electrical test (Table

	conditions
	Ageing	(N/cm) G	(N/cm) ∆G	Rupture
	Reference	1.74	0.15	Adhesive
	500h 120°C	2.70	0.14	Adhesive
	F1	1.63	0.11	Adhesive
	F2	1.72	0.05	Adhesive
	TM1	2.61	0.19	Adhesive
	TM2	2.50	0.16	Adhesive
	Both unaged and

Table 5 .

 5 Results of electrical tests performed on TV devices after each ageing condition

	Ageing type		Thermal		Fatigue	Thermo-mechanical
	Ageing condition	Reference	500h	F1	F2	TM1	TM2
	Electrical test	Positive	Positive	Positive	Negative	Positive	Positive

Funding: This work was supported by Région Centre-Val de Loire through Regional project APR2015.

Acknowledgement:

The authors would like to thank STMicroelectronics and Protavic International, the technical platforms of CERTeM located in Tours and of the IUT located in Blois.

Conflicts of Interest:

The authors declare no conflict of interest.


Thibaut Caltabellotta

Julien Magne

Baptiste Salerno

Valerie Pradel

Pierre-Bernard Petitcolin

Gilles Auzemery

Patrice Virot

Victor Aboyans
email: victor.aboyans@unilim.fr

Characteristics associated with patient delay during the management of ST-segment elevated myocardial infarction, and the influence of awareness campaigns

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

Objectifs. -Nous avons évalué les facteurs liés au délai patient et les effets d'une campagne régionale de sensibilisation.

Méthodes. -Les données provenaient du registre régional des SCA ST+ du Limousin (France) et nous avons de plus recueilli par questionnaire les antécédents, les signes cliniques, le contexte, les conditions socioéconomiques, la perception et comportement des patients. Des groupes "appel précoce" (1 e et 2 e tertile, < 154 minutes) et "appel tardifs" (3 e tertile > 154 minutes) ont été comparés par analyse univariée puis multivariée. L'influence de la sensibilisation a été étudiée en comparant les délais avant et après ces campagnes régionales.

Résultats. -Sur 481 patients, le délai d'appel médian était de 87 minutes. Les facteurs indépendamment liés au délai tardif étaient : l'âge (OR 1,02, IC95 % 1,00 à 1,03), l'horaire entre 0h et 6h (OR 1,86, IC95 % 1,10 à 3,12), le recours à un médecin généraliste (OR 2,58, IC95 % 1,66 à 4,04) ou au service des urgences (OR 4,10, IC95 % 2,04 à 8,32). Le symptôme «sueurs» et le sentiment de gravité étaient associés à un délai précoce. Après les campagnes de sensibilisation, le délai patient n'était pas modifié mais la part d'appel au 15 est passée de 55 % à 62 % (P < 0,001).

Conclusions. -L'allongement du délai patient est multifactoriel. L'impact des campagnes de sensibilisions est mitigé. Les aspects psychologiques et comportementaux semblent déterminants et devraient être pris en considération pour adresser des messages ciblés vers des publics spécifiques.

KEYWORDS

Background

Ischaemic heart disease is the main cause of death worldwide [1]; its most serious form is ST-segment elevation myocardial infarction (STEMI), which requires urgent intervention to restore myocardial perfusion. The organization of care is essential for timely management, because reperfusion delay is prognostic [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF]. The initial care provider (Emergency Medical Services [EMS]/emergency telephone number, general practitioner, emergency service, etc.) largely determines the patient's path. Indeed, in case of severe chest pain or suspicion of myocardial infarction, the current recommendation is to call the national emergency number ("112", "911" or similar numbers in different countries).

To minimize patient delay and to increase public awareness of how to recognize the common symptoms of STEMI and to call the emergency number, two public campaigns were conducted in our region in 2013 and 2015 to alert the public to call 112 quickly in case of chest pain.

The purpose of this study was to highlight the characteristics (epidemiological, socioeconomic and clinical) of patients who do not request assistance quickly when experiencing a STEMI, to better target the populations requiring the most adapted education to decrease the delay. A second objective was to assess the efficacy of a regional campaign encouraging the public to call the EMS rapidly in case of chest pain.

Methods

The SCALIM registry

Our first data source was SCALIM, which contains data on all STEMI cases occurring in Limousin < 24 hours after the onset of symptoms. Initiated on June 2011, this registry has as its main objective to assess the patients' paths and the delays of all patients presenting STEMI in the region of Limousin, France. The "patient delay" was calculated from the onset of symptoms to the time of contact, seeking assistance. The distance (in minutes) between the patient's home and our centre was calculated using Google Maps for the fastest route.

For the present analysis, patients included were adults from the SCALIM registry who had initially been treated at Limoges University Hospital for STEMI onset between 01 June 2011 and 31 December 2012 (Period A) or between 01 January 2016 and 31 December 2017 (Period B). These periods were used to assess the evolution of patient delays and paths before and after a public campaign advertised in the same area between the two periods.

Telephone survey

The telephone survey aimed to obtain additional information on socioeconomic status, as well as the circumstances in which the STEMI had started. A questionnaire was submitted by telephone.

Public awareness campaigns

Two public campaigns were conducted in our region in November 2013 and November 2015, to raise public awareness about the necessity to call the EMS rapidly when experiencing chest pain. The campaigns comprised newspaper, radio and television advertisements and billboard posters in the main cities in the region, as well as newsletters to general practitioners and other healthcare providers, including pharmacists.

Statistical analysis

The "patient delay", expressed in minutes, was defined according to the recommendations of the European Society of Cardiology as the delay that elapsed between the onset of symptoms and, depending on the patient's path, the call to the EMS or admission to a hospital centre (Fig. 1) [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF]. The patient delay and the medical delay (related to health system efficiency) are the two components of the overall time elapsing between the first onset of symptoms and the recanalization of the culprit coronary artery. Patient characteristics were compared between the two periods of study (2011-2012 versus 2016-2017). Based on the distribution of patient delay, all cases were categorized as "early callers" or "late callers". The "early callers" group corresponded to the first and second tertiles of the distribution of patient delay, and the "late callers" group included those in the third tertile of patient delay.

Continuous variables are expressed as means ± standard deviations, and qualitative variables are expressed as numbers and percentages. All time periods are reported as means with their corresponding 95% confidence intervals (CIs). The normality of distributions of quantitative variables was tested using Shapiro's test. The comparison between "early callers" and "late callers" was performed using the unpaired Student's t test, Fisher's test or the χ 2 test, as appropriate. For quantitative variables that did not have a normal distribution, the Wilcoxon-Mann-Whitney test was used. The level of significance was P < 0.05. To compare a continuous variable, with skewed distribution, with a categorical variable of more than two levels, we applied a Kruskal-Wallis test followed by multiple paired tests. In this case, the P values were adjusted using the Bonferonni correction. A multivariable analysis of the variables of the entire study population was performed by logistic regression, and odds ratios (ORs) and 95% CIs were reported. We selected for an initial model variables with a P value in univariate analysis > 0.25; then, we established the final model by a backward stepwise selection. In addition, another model that included the variables collected through the survey was performed by the same method. The evolution between the two periods ( 2011

Results

During the two study periods, 545 patients were enrolled in SCALIM, of whom 481 actually had a confirmed diagnosis of STEMI without initial cardiopulmonary arrest, and were therefore included in the analysis. Of these, 208 (43.2%) were from period A, 273 (56.8%) were from period B, 37 had died at the time of administration of the questionnaire, 32 were unable to answer reliably and 141 refused to participate or could not be reached by telephone or post (Fig. 2). A subset of 271 (56.3%) patients took part in the survey. There was no significant difference in sex, age, medical history, cardiovascular risk factors, dates, times or locations between patients in period A compared with those in period B.

The comparison of patients participating in the survey versus those who did not answer showed significant differences in terms of age (62.9 ± 24.5 vs 65.9 ± 33.5 years, respectively; P = 0.02), male sex (77.9% vs 66.7%; P < 0.01), proportion of "late callers" (28.8% vs 40.0%; P = 0.01) and family history of cardiovascular disease (25.1% vs 11.4%; P < 0.001).

Patient delay

The patient delay ranged from 0 to 1397 minutes, with a global median value of 87 minutes (Q1 36; Q3 216). Median (Q1; Q3) delays for patients calling and not calling the EMS were 62 minutes (25; 149) and 138.5 minutes (68.75; 328.5), respectively. Fig. 3 shows the distribution of patient delay. The "early callers" and "late callers" were separated at the threshold of 154 minutes (2 hours 34 minutes, i.e. the third tertile). In the "early callers" group, the median patient delay was 50 (24.5; 86.5) minutes, whereas it was 309 (215.25; 493.25) minutes in the "late callers" group.

Univariate analysis

Table 1 compares "early callers" and "late callers" for each of the variables collected via the SCALIM registry, and Table 2 compares the groups for additional variables collected from the survey. The proportion of women and mean age were significantly higher in the "late callers" group.

Regarding the time of onset of symptoms, the patient delay was on average shorter when this occurred between noon and 6 p.m. The highest rates of "late callers" were found when symptoms occurred between midnight and 6 a.m.

In the "late callers" group, initial care by the emergency department or a general practitioner was more frequent than initial care by the EMS.

Rates of "no" or "mild" pain and "progressive-onset" pain were significantly more frequent in the "late callers" group. Similarly, retired or non-active patients were more frequent among the "late callers". The comparison with other socioprofessional categories did not show any significant difference. The proportions of patients who self medicated and patients who were alone during symptom onset were higher in the "late callers" group. Conversely, considering the situation to be severe, a heart issue or related to a heart attack, anxiety and sweating were more frequent among "early callers".

The study of the other variables did not show a statistically significant difference between the two groups.

Multivariable analysis

A first multivariable analysis included all the data in the registry available for the whole study group.

The final model (Fig. 4) highlighted older age, time of symptom onset between 0:00 and 5:59 a.m. and the initial care provider as factors significantly associated with a longer patient delay.

In a second model, including data from the survey (Fig. 4), the significant factor associated with "late callers" was initial caregiver other than the EMS, with the presence of sweats and the patient feeling that the situation was severe being associated with a shorter delay.

Effects of the regional campaign

Table 3 presents the comparison between patients in periods A (2011-2012) and B (2016-2017); between these periods, the two awareness campaigns were undertaken in our region.

There was no difference between the two periods regarding patient delay and proportion of "late callers". The initial care provider was more often the EMS and the emergency department, and less often the general practitioner during period B (P < 0.001). The proportion of patients planning to call the EMS (emergency telephone number 112) in the event of a recurrence did not change significantly (from 86% to 87%; P = 0.97).

Discussion

The present study shows that in patients with STEMI, patient delay was > 50 minutes for two-thirds of cases, almost > 90 minutes for half of the cases and 2.5 hours for the last third of the cases (the "late callers" group). This is a long period compared with that optimally recommended for the management of STEMI [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF]. The distribution of this variable was similar to that in other studies of prehospital delays [START_REF] Benamer | Longer pre-hospital delays and higher mortality in women with STEMI: the e-MUST Registry[END_REF][START_REF] Lucas | Factors associated with delay in calling Emergency Medical Services ("15") for patients with ST-elevation myocardial infarction in southern Isere][END_REF].

Older patients are more likely to have an increased patient delay. Several studies have also highlighted the influence of age on patient delay [START_REF] Benamer | Longer pre-hospital delays and higher mortality in women with STEMI: the e-MUST Registry[END_REF][START_REF] Lucas | Factors associated with delay in calling Emergency Medical Services ("15") for patients with ST-elevation myocardial infarction in southern Isere][END_REF][START_REF] Callahan | Facteurs influençant le délai avant la prise en charge médicale dans les syndromes coronariens aigus ST+[END_REF][START_REF] Goldberg | Duration of, and temporal trends (1994-1997) in, prehospital delay in patients with acute myocardial infarction: the second National Registry of Myocardial Infarction[END_REF][START_REF] Goldberg | Prehospital Delay in Patients With Acute Coronary Syndromes (from the Global Registry of Acute Coronary Events [GRACE])[END_REF]. Clinical manifestations are less typical in the older population [START_REF] Bayer | Changing presentation of myocardial infarction with increasing old age[END_REF][START_REF] Solomon | Comparison of clinical presentation of acute myocardial infarction in patients older than 65 years of age to younger patients: the Multicenter Chest Pain Study experience[END_REF]. Care seeking may be delayed in the elderly because of cognitive impairment, motor and sensory disorders, frailty, social isolation or frequency of chronic pain that minimizes the event.

Our univariate analysis showed higher rates of females in the "late callers" group, but this association was no longer significant after further adjustments. Others studies have shown that women are more likely to have prolonged prehospitalization delay [START_REF] Benamer | Longer pre-hospital delays and higher mortality in women with STEMI: the e-MUST Registry[END_REF][START_REF] Lucas | Factors associated with delay in calling Emergency Medical Services ("15") for patients with ST-elevation myocardial infarction in southern Isere][END_REF][START_REF] Goldberg | Duration of, and temporal trends (1994-1997) in, prehospital delay in patients with acute myocardial infarction: the second National Registry of Myocardial Infarction[END_REF][START_REF] Goldberg | Prehospital Delay in Patients With Acute Coronary Syndromes (from the Global Registry of Acute Coronary Events [GRACE])[END_REF]. In 2015, a review [START_REF] Chen | Gender differences in symptoms associated with acute myocardial infarction: a review of the research[END_REF] showed that women were more likely to experience atypical symptoms during the onset of STEMI.

Data from the French FAST-MI programme also showed that women and patients admitted to hospital through an emergency department were associated with higher case-fatality rates [START_REF] Gabet | Early and late case fatality after hospitalization for acute coronary syndrome in France, 2010-2015[END_REF] (especially in the early stage of hospitalization), which could be consistent with our results. The prolonged delay between onset of pain and first medical contact could explain this observation, besides a particular risk profile in women [START_REF] Isorni | Temporal trends in clinical characteristics and management according to sex in patients with cardiogenic shock after acute myocardial infarction: The FAST-MI programme[END_REF].

Socioeconomic factors do not appear to be independently associated with patient delay, whereas retirement was trending towards being more frequent among "late callers", but was confounded by the age factor. This result is consistent with another French study that focused on the delay between pain onset and electrocardiography [START_REF] Callahan | Facteurs influençant le délai avant la prise en charge médicale dans les syndromes coronariens aigus ST+[END_REF]. Ageing is known to be associated with delay, and is a confounding factor, explaining this result in retired patients. Furthermore, another study has shown an association between a low level of education and prehospital delay [START_REF] Fournier | Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention[END_REF].

We did not show any statistical relationship between patient delay and the variable "living alone", which is not consistent with some previous papers [START_REF] Callahan | Facteurs influençant le délai avant la prise en charge médicale dans les syndromes coronariens aigus ST+[END_REF][START_REF] Perkins-Porras | Pre-hospital delay in patients with acute coronary syndrome: factors associated with patient decision time and home-to-hospital delay[END_REF]. One study [START_REF] Atzema | Effect of marriage on duration of chest pain associated with acute myocardial infarction before seeking care[END_REF] suggested that the favourable association of marriage with prehospital delay is more complex, and would not apply to women.

The associated symptom "sweating" is another determinant acting independently to reduce the care-seeking delay. This factor has been found in other studies [START_REF] Herlitz | Factors of importance for patients' decision time in acute coronary syndrome[END_REF][START_REF] Johansson | Factors related to delay times in patients with suspected acute myocardial infarction[END_REF], but its association independent of other factors should be confirmed.

The feeling that the situation was severe was independently associated with the "early callers" group, and is an important determinant of prehospital delay [START_REF] Burnett | Distinguishing between early and late responders to symptoms of acute myocardial infarction[END_REF], but other psychological mechanisms may exist [START_REF] O'carroll | Psychological factors associated with delay in attending hospital following a myocardial infarction[END_REF]. The psychological factors influencing patient delay in STEMI have also been studied according to various theoretical frameworks [START_REF] Dracup | Causes of delay in seeking treatment for heart attack symptoms[END_REF]: the Health Belief model, models inspired by symbolic interactionism and the model of self-regulation of behaviour [START_REF] Dracup | Causes of delay in seeking treatment for heart attack symptoms[END_REF][START_REF] Walsh | Factors influencing the decision to seek treatment for symptoms of acute myocardial infarction: an evaluation of the Self-Regulatory Model of illness behaviour[END_REF]. These models are conceptual frames to help us to understand a patient's reactions in case of health problems. For example, a qualitative study [START_REF] Dempsey | Women's decision to seek care for symptoms of acute myocardial infarction[END_REF] presented a model of reaction to an acute phase of a myocardial infarction in women, highlighting "maintaining control" factors that can lengthen the delay (attribution to benign cause; beliefs about acute myocardial infarction in general and acute myocardial infarction in women in particular; denial; concern for others ["fear of disturbing"]) and "relinquishing control" factors pushing women to seek help (persistence of symptoms and anxiety). More generally, among the strategies initially adopted by those who experience a myocardial infarction, waiting or ignorance of the symptoms are found in > 75% of them [START_REF] Meischke | Utilization of emergency medical services for symptoms of acute myocardial infarction[END_REF].

Major cardiovascular risk factors did not appear to be significantly influential in our study, whereas another study reported hypertension and diabetes as factors associated with prolonged patient delay [START_REF] Solomon | Comparison of clinical presentation of acute myocardial infarction in patients older than 65 years of age to younger patients: the Multicenter Chest Pain Study experience[END_REF].

Surprisingly, patients with a history of cardiovascular disease did not call for help more quickly than others. Some studies provided similar results [START_REF] Lucas | Factors associated with delay in calling Emergency Medical Services ("15") for patients with ST-elevation myocardial infarction in southern Isere][END_REF][START_REF] Johansson | Factors related to delay times in patients with suspected acute myocardial infarction[END_REF][START_REF] Puymirat | Patient education after acute myocardial infarction: cardiologists should adapt their message--French registry of acute ST-elevation or non-STelevation myocardial infarction 2010 registry[END_REF], although others found shorter delays in patients with a history of myocardial infarction or angioplasty [START_REF] Goldberg | Duration of, and temporal trends (1994-1997) in, prehospital delay in patients with acute myocardial infarction: the second National Registry of Myocardial Infarction[END_REF][START_REF] Goldberg | Prehospital Delay in Patients With Acute Coronary Syndromes (from the Global Registry of Acute Coronary Events [GRACE])[END_REF]. One of the hypotheses is that patients who have already experienced a myocardial infarction expect to have similar symptoms in case of recurrence, whereas this is not always the case.

We found that the period between midnight and 6 a.m. was a significant and independent factor associated with delayed call; this result is supported by other studies [START_REF] Goldberg | Prehospital Delay in Patients With Acute Coronary Syndromes (from the Global Registry of Acute Coronary Events [GRACE])[END_REF][START_REF] Pereira | Factors influencing patient delay before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: The Stent for life initiative in Portugal[END_REF].

Experimental studies evaluated the impact, in case of recurrence, of personalized prevention measures in patients with a history of myocardial infarction. In 2012, a study including 1944 patients randomized between a control group and an experimental group showed a significant reduction in prehospital delay in the experimental group [START_REF] Mooney | A randomized controlled trial to reduce prehospital delay time in patients with acute coronary syndrome (ACS)[END_REF]. By comparison, in 2009, a similar study design including 3522 patients did not show a significant difference [START_REF] Dracup | A randomized clinical trial to reduce patient prehospital delay to treatment in acute coronary syndrome[END_REF].

A choice other than EMS as the initial care provider is a patient delay lengthening factor. This result has been found in other French [START_REF] Lucas | Factors associated with delay in calling Emergency Medical Services ("15") for patients with ST-elevation myocardial infarction in southern Isere][END_REF] and European [START_REF] Johansson | Factors related to delay times in patients with suspected acute myocardial infarction[END_REF][START_REF] Pereira | Factors influencing patient delay before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: The Stent for life initiative in Portugal[END_REF] studies. Also, a study on factors associated with delay in transfer of patients with STEMI showed that, even after the first medical contact, patients who did not call EMS (15/112) and those with prolonged patient delay have, in addition, an increased transfer delay in reaching the catheterization laboratory [START_REF] Range | Factors associated with delay in transfer of patients with ST-segment elevation myocardial infarction from first medical contact to catheterization laboratory: Lessons from CRAC, a French prospective multicentre registry[END_REF]. In another words, patients who have a delayed call have a "double-penalty" as they are those seeking suboptimal assistance, so that both delays, before and after the call until angioplasty, could be increased. This supports the importance of the initial care provider in the patient pathway. The probability of being a "late caller" is higher in patients who directly go to the emergency room compared with those who call their general practitioner because, in the former case, the time to go to the emergency room is added to the delay to decision to seek medical assistance. Another reason could be that the longer patients wait, the more severe the symptoms are, and the more likely it is that patients will to choose to directly go to the emergency room rather than to a general practitioner. Furthermore, this result should be interpreted with caution because of the small sample size, resulting in obvious 95% CI overlap.

Self medication during the first symptoms of STEMI was more common in the "late callers" group, but this association did not persist in the multivariable analysis.

Our study did not show any significant reduction in the delay after the regional campaign. However, we found an increase in first contact with the EMS. The lack of efficacy of the campaign in decreasing the patient delay is probably multifactorial, including the lack of sufficient coverage to sensitize the whole population, the need for more repetitive advertising to change patient behaviour and the fact that the campaign had two messages: "call fast, call 112", and it is plausible that the second message was better retained than the first. New campaigns focusing on the necessity to call quickly should take our results into consideration. The evaluation of a public campaign carried out in Spain in 2012-2013 identified increased use of the EMS number and an increase in treated patients, but did not observe any significant effect on time delays [START_REF] Regueiro | Impact of the "ACT NOW. SAVE A LIFE" public awareness campaign on the performance of a European STEMI network[END_REF]. By comparison, a campaign carried out in Switzerland for a long period between 2005 and 2008 significantly reduced prehospital time in STEMI and non-STEMI. However, this decrease was not significant in the subgroups of women, those aged > 75 years and patients with atypical symptoms [START_REF] Naegeli | Impact of a nationwide public campaign on delays and outcome in Swiss patients with acute coronary syndrome[END_REF].

Practical implications

The awareness campaigns could be improved by targeting specific patient profiles at high risk of STEMI and making late calls. According to our data, the campaigns could mostly focus on elderly patients, those who already have experienced a myocardial infarction and those with cardiovascular risk factors. It could be useful to refine the prevention messages: reiterate the value of a call to the EMS at any time, including at night, especially for the older patients; and inform about typical and atypical symptoms, especially in women. The patient and their relatives should be encouraged to call the EMS if the symptoms persist beyond 15 minutes.

Study limitation

Our study has limitations. First, it was a single-centre study, and our findings need further confirmation in other geographical areas, as cultural dimensions may also affect results. We were unable to know if the patients studied had been hit directly by the campaigns, so the effect of the campaigns on patient delay is difficult to address directly. The intermediate (56%) rate of responders to our survey is also a limitation, as it may generate a selection bias. Some characteristics of "late callers" match with those of "non-responders" -mostly demographic and socioeconomic variables. In particular, the probability of being a "late caller" was higher in elderly patients. It is likely that elderly patients are also most difficult to be reached (by telephone or mail) for reasons of social isolation, cognitive and sensory impairment or physical disability. Hence, the results of our survey should be interpreted with caution.

Conclusions

At the occurrence of signs of STEMI, several factors might influence the delay for in seeking assistance. Psychological and behavioural factors seem to be determining and complex. Other main factors are age, the time period of symptom onset and the choice of initial care provider. The impact of previous public awareness campaigns is mixed. We propose to target awareness messages to specific groups of patients, such as elderly people, and with a special educational emphasis on those who already have risk factors or a cardiovascular history. The awareness campaigns should also highlight atypical presentations and stress that the best option is to call the emergency telephone number (112/911).

Sources of funding

This research received no specific grant from any funding agency in the public, commercial or not-forprofit sectors. The SCALIM registry was funded by the Agence Régionale de Santé du Limousin during the period of this study. a In France, in more remote/rural areas, firefighters can be called for health issues; they can make the connection with the EMS to reduce transport delays.

Disclosure of interest

b Ambulance used to get to hospital or patient already hospitalized because of an issue other than STEMI.

  Abbreviations: CI, confidence interval; EMS, Emergency Medical Services; OR, odds ratio; STEMI, ST-segment elevation myocardial infarction.

  Questions submitted in 2012-2013 to patients from period A (2011-2012) were included in the questionnaire submitted in 2018 to patients from period B (2016-2017), but the latter also contained questions about the awareness campaigns. The questionnaire covered various topics (medical history, clinical data, context, socioeconomic factors and perception and behaviour of the patient). In May 2018, the questionnaire was also sent via post with a reply envelope to patients inaccessible by telephone. Socioprofessional categories were based on French National Institute for Statistical and Economic Studies (INSEE) nomenclature of occupations and socioprofessional categories [3]. The following cases from the SCALIM registry were excluded from the survey: deceased patients; those who might have difficulty answering the telephone questionnaire (patients aged > 90 years, those with cognitive impairment and those who did not speak French fluently); and those who declined to participate. Data collection was done after informing the patient of the study objectives, and as part of the Cardiology Department of the University Hospital of Limoges, which declares its research activities to the French National Commission for Data Protection and Liberties (CNIL). Data were anonymized after collection.

  -12 and 2016-17) was assessed by comparing patient delay and choice of initial caregiver. Statistical analyses and diagrams were performed using R software, version 3.4.4. (R Foundation for Statistical Computing, Vienna, Austria).

Figure 1 .

 1 Figure 1. Definition of patient delay and study goal. EMS: Emergency Medical Services; STEMI: STsegment elevation myocardial infarction.

Figure 2 .

 2 Figure 2. Flow diagram of inclusion and exclusion of patients. STEMI: ST-segment elevation myocardial infarction.

Figure 3 .

 3 Figure 3. A. Patient distribution. B. Box plot of patient delay.

Figure 4 .

 4 Figure 4. Results of multivariable logistic regression models of the factors associated with patient delay. A. Whole population; variables included sex, age, history of hypertension, symptom onset time slot and initial care provider. B. Subgroup responding to the survey; variables included sex, age, history of hypertension, symptom onset time slot, initial care provider, history of depression, psychotropic treatment, no or mild pain, progressive-onset pain, retrosternal chest pain, epigastric pain, upper limb pain, associated symptoms (nausea/vomiting, sweats, anxiety), alone during symptom onset, retirement, interpretation of symptoms as severe, cardiac or MI, and self medication. CI: confidence interval; EMS: Emergency Medical Services; OR: odds ratio.

Table 1

 1 Comparison of "early callers" and "late callers".

	No. with available	All patients	Early callers Late callers P
	variable
		(n = 481)	(n = 319)	(n = 162)

Data are expressed as % or mean ± standard deviation. ACS: acute coronary syndrome; CABG: coronary artery bypass grafting; CV: cardiovascular; CVD: cardiovascular disease; EMS: Emergency Medical Services; No.: number of patients; PCI: percutaneous coronary intervention; PAD: peripheral arterial disease; STEMI: ST-segment elevation myocardial infarction.

Table 2

 2 Comparison of additional characteristics from the survey. Data are expressed as %. MI: myocardial infarction; No.: number of patients; NRS: numeric rating scale.

	No. with available	All patients Early callers Late callers P
	variable
		(n = 271)	(n = 193)	(n = 78)

Figure 4