Corinne Jegat
email: corinne.jegat@univ-st-etienne.fr

Nathalie Mignard
email: nathalie.mignard@univ-st-etienne.fr

Effect of the polymer matrix on the thermal behaviour of a furan-maleimide type adduct in the molten state

Keywords: Diels-Alder, retro Diels-Alder, N-phenylmaleileimide, furfuryl alcohol, adduct thermal stability, polymer matrix, molten state

The effect of three different polymer matrices on the stability of the exo-adduct formed from N-Phenylmaleimide (PM) and furfuryl alcohol (FAl) toward retro Diels-Alder reaction was studied. First, a stereospecific synthesis of the exo-adduct was carried out at the condensed state and for a best understanding, its thermal properties was reported. The temperature of the rDA reaction of the exo-adduct in polyolefins (a low density polyethylene and a random copolymer of ethylene and glycidyl methacrylate) was found similar to the pure exo-adduct rDA reaction temperature. In a poly(vinylacetate)-g-polycaprolactone matrix this temperature was distinctly lower. In this last matrix, the reversibility of the rDA reaction was proved by the formation of the endo-adduct FAlPM during cooling.

Introduction

Diels-Alder (DA) and retro Diels-Alder (rDA) reactions have been widely used in organic synthesis. Diels-Alder reaction is a reversible 4+2-cycloaddition which involves a diene and a dienophile. It produces an adduct able to convert into reagents at higher temperature. The furan/maleimide couple is one of the most used diene/dienophile pairs due to the low temperature required for the DA and rDA and the high yield of products. Characterization of adducts, stereoisomers endo/exo structure, kinetic studies of DA and rDA reactions, solvent effect have been reported [1][START_REF] Goussé | D Thesis INP Grenoble[END_REF][START_REF] Tobia | [END_REF][4][5][6]. The temperature at which the rDA reactions occur depends on the specific nature of the reagents in terms of both electronic and steric effects, on the synthesis conditions and reaction mixture for a diene/dienophile pair. The reversibility of DA has interested the macromolecular field for two or three decades. In order to develop well defined life cycle materials, preparation of reworkable polymers using the DA/rDA reactions becomes more and more investigated. Watanabe et al [6], Teramoto et al [7] obtained linear polymers from bisfunctional diene and dienophile. Liu YL [8], Gandini et al [9], Goiti et al [10][11], Chang BTA et al [START_REF] Chang | Electronic Components and Technology Conference[END_REF], Jen AKY and coworkers [START_REF] Kim | [END_REF] reported the synthesis of thermally reversible crosslinked polymers. Chen X [14-15] Liu and Hsieh [16] prepared dendrimers from multifunctional diene and dienophile. Organic-inorganic hybrid materials using DA and rDA reactions were synthesized by Adachi et al [17]. More recently Durmaz et al [18] used DA reaction for one pot synthesis of ABC triblocks type macromolecules in mild condition and Costanzo [19] to control dispersion and migration of nanoparticules in polymer matrices. In all cases, diene and dienophile functions are linked to the macromolecules backbone and most of these synthesis are carried out in solvents. To the best of our knowledge no study was found on the thermal stability of the adducts dispersed or dissolved in a polymer matrix at the molten state. In the absence of solvent, rDA reaction temperature of solid adduct corresponds to adduct melting temperature. Moreover the reaction occurs with best yield in solid state [5]. So, it seemed interesting to study the polymer matrix effect on adduct rDA reaction in the melt. This article deals with the furan/maleimide type adduct synthesis from furfuryl alcohol and N-phenylmaleimide without solvent and its thermal behaviour in melt polymer matrices with different polarity groups (apolar, semi-polar and polar).

Experimental

Materials

N-phenylmaleimide (PM) (mp : 87-89°C) and furfuryl alcohol (FAl) purchased from Acros were used without purification. Low density polyethylene, LDPE, PBD 2000 (Tm = 108°C, Mw = 470000 g.mol -1 ) was supplied by BP, copolymer of ethylene and glycidyl methacrylate Lotader AX8840 (Tm = 103°C ; Mw = 105000 g.mol -1 ) with 8% wt of glycidyl methacrylate was supplied by Arkema. (PVA-Ac)-g-PCL is a polycaprolactone grafted with a polyvinylalcohol prepared by the partial hydrolysis of acetoxy groups of a poly(vinylacetate) (Tg = 62 °C ) [20][21] Synthesis of furfuryl alcohol/ N-phenylmaleimide endo/exo-adduct (scheme 1) N-phenylmaleimide (2.5g, 0.014mol) and furfuryl alcohol (1.4g, 0.014mol) were stirred under refluxing at room temperature for 12h. The obtained solid was washed with diethyl ether to afford white powder in endo/exo 71/29 ratio (confirmed by 1 H-NMR) with a 66% yield, mp: 118°C (endo), 156°C (exo).

Synthesis of furfuryl alcohol/ N-phenylmaleimide exo-adduct

N-phenylmaleimide and furfuryl alcohol were mixed together in equimolar quantity at 95°C until a homogen mixture was obtained. Then, the resulting viscous liquid was introduced in an oil bath at 140°C for 8 min. White powder was obtained after washing with diethyl ether with a 82% yield. mp: 156°C.

(O-H), 3450w (O-H), 3150vw (C=C), 3084-3010 (=C-H), 1772m (C=O)sym, 1705vs (C=O)asym, 1592m (C-C phenyl), 1575vw (C=C), 1497s (C-C phenyl), 1393s (C-N-C)sym, 1212s (C-N-C)asym, 1042m (C-O).

Preparation of polymer and exo-adduct blends

All blends were carried out from polymer (87%wt) and exo-adduct (13%wt) in a batch mixer Haake Rheomix model 600 equipped with two counter-rotating blades and a 50 cm 3 mixing chamber. The rotation speed of the rotors was set to 50 rpm and the temperature to 130°C. The polymer was introduced first in the mixing chamber. Then, the adduct was added when torque and temperature were stabilized. After 5 min of mixing, the blend was cooled down at room temperature.

Characterization

Differential scanning calorimetry (DSC) was carried out on a TA instrument Q10 at a heating or cooling rate of 2 to 10°.min -1 under N 2 atmosphere. Powder adducts sample of 2 mg were sealed in an aluminium pan. The analysis of polymer samples was started off with heating and cooling scans at 10°.min -1 between 0 and 160°C. Dynamic thermogravimetric runs were made using a Setaram G70 thermal analyser under a dry Helium atmosphere at flow rate of 3L.h -1 . Initial weight of the sample was about 60 mg and the heating rate of 10°.min -1 . FT-IR spectra of KBr pellets or polymer films obtained at 120°C under 180 bars for 10 min were recorded on a Nicolet Nexus FT-IR spectrometer in the wave range of 4000-500 cm -1 . 1 H-NMR spectroscopy measurements were performed on a Bruker Avance spectrometer at 250 MHz with 50% solutions in TCE/C 6 D 6 at 80°C for polyolefins and in d 6 -DMSO at 25°C for adducts and (PVA-Ac)-g-PCL with tetramethylsilane as internal reference.

Two cycles of heating and cooling between 25°C and 160°C at 1°.min -1 were conducted in a well-sealed tube from PM and FAl (1:1) mixture to observe changes in state of the adducts and the addends.

Results and discussion

The main objective of this work is to study the thermal behaviour of the adducts in dispersed or dissolved state in a polymer matrix. For a best understanding, we first study the thermal behaviour of adducts without polymer matrix.

Thermal behaviour of endo/exo-adduct without polymer matrix

As known, the synthesis of furan-phenylmaleimide type adduct at room temperature leads to a stereoisomers mixture with an excess of the endo-adduct (71%). For the first time, the stereospecific synthesis in condensed state of 100% exo-adduct is reported. This DA reaction was obtained in a short time at 140°C and with a good yield (82%). Figure 1 represents the 1 H-NMR spectra of endo/exo-adduct in d 6 -DMSO solution at 25°C, 50°C, 90°C and 120°C. At 90°C, furfuryl alcohol (FAl) and Nphenylmaleimide (PM) characteristics peaks can be observed and prove that rDA reaction occurred. The yield of rDA reaction calculated by NMR results is about 53% at 90°C and 81% at 120°C. The ratio of endo/exo stereoisomers in adduct mixture has changed depending on the temperature. At 50°C the proportion of endo/exo is always 71/29, 29/71 at 90°C and 18.5/81.5 at 120°C. It can be due to possible isomerization of endo-adduct in exo-adduct [1]. However, the percentage of exo stereoisomer adduct in the FAl, PM, exo and endoadduct mixture decreases with increasing temperature proving that rDA reaction in d 6 -DMSO occurred with both stereoisomers.

Adducts samples studied by DSC analysis were heated from 0 to 160°C at 2°.min -1 , followed by cooling to 0°C at 10°.min -1 for several cycles. Figures 2 and3 show the DSC thermograms of endo/exo and pure exo adducts when heating. In Figure 2 during the 1 st heating, two endothermic peaks and an exothermic peak were observed respectively at 118°C, 156°C and 119°C. The peaks observed at 118°C and 119°C in Figure 2 are not present on the DSC thermograms of pure exo-adduct. They may be attributed to the melting of endo-adduct at 118°C and to the endo-exo isomerization and exo-adduct crystallization at 119°C in accordance with Gandini and al [1][START_REF] Goussé | D Thesis INP Grenoble[END_REF] and Mironov [22]. Peak at 156°C is attributed to exo-adduct melting as we observed change of state in sealed tube at this temperature. During the following heating cycles (Figure 2), an exothermic peak around 84°C was appeared and the endothermic peak at 156°C was observed again. Both of these peaks decrease with successive scans. During the cooling, no peaks were observed. Pure exo-adduct has the same comportment at similar temperature (Figure 3). The decrease of exothermic and endothermic peaks may be explicated by a possibly decomposition of exo-adduct at temperature higher than 156°C with time. In order to understand the phenomena observed between 115°C and 119°C with the endo/exo-adduct, isothermal run of the endo/exo-adduct at 113°C, 114°C, 116°C and 118°C were carried out (Figure 4). At 113°C, no peak was observed. At 114°C, a broad exothermic peak was observed after about 6 min. At 116°C, the exothermic peak area increases and appears after 2 min. At 118°C, an endothermic peak was appeared before the exothermic peak. This results suggest that the isomerization can begin near 114°C without endo-adduct melting. At 118°C, adduct melting occurs and seems to catalyse the endo-to-exo isomerization. Endo/exo-adduct behaviour with increasing temperature was followed by FT-IR in a solid sample cell by keeping the powder between two KBr plates and by increasing temperature from room temperature to 130°C at an average rate of 6°.min -1 . Figure 5 represents the FT-IR spectra of adduct recorded at 25°C, 115°C, and 122°C The examination of the spectra shows significantly changes between 115°C and 122°C: intensity of peaks at 3450, 3146, 1180, 1064 cm -1 decreases leading to a spectrum comparable to the exo-adduct spectrum. No characteristic peak from FAl and PM was found. To test the hypothesis that rDA reaction occurs with melting [5] TGA analysis on adducts were performed. Thermogram recorded in Figure 6 shows the thermal degradation in dynamic run of endo/exo and exo adduct. The first step of endo/exoadduct thermal degradation begins at 115°C while the thermal degradation in dynamic run of exo-adduct begins near 150°C. These degradation temperatures are similar to the melting endothermic peaks of every adduct. These results confirm that melting and rDA reaction are indivisible in our studies conditions. Our main results on adduct without polymer matrix are represented by Scheme 2. The indicated temperatures correspond to the DSC peaks temperatures.

Scheme 2. DA and rDA reactions and isomerization of adducts.

Thermal behaviour of exo-adduct with polymer matrix

To study the influence of the polymer matrix on the rDA reaction temperature we focused on the exo-adduct for its higher thermal stability at blend temperature and to avoid the isomerization.

DSC thermograms of the exo-adduct blended with polymers are shown in Figure 7.

With Lotader AX8840 and PBD 2000 blends, two endothermic peaks were observed at 108°C and 152°C for PBD 2000, at 103°C and 152°C for Lotader AX8840. With (PVA-Ac)-g-PCL matrix no significant peak was observed. The endothermic peak at 152°C may be attributed to the melting or/and rDA reaction of the exo-adduct. The polymers melting peaks at 103°C for Lotader AX8840 and 108°C for PBD 2000 appeared with a small shoulder near 85°C. This shoulder may correspond to the PM melting temperature formed by rDA reaction during the first heating cycle. The result with (PVA-Ac)-g-PCL suggests that the exo-adduct disappeared or is miscible in polymer. Exo-adduct blended with (PVA-Ac)-g-PCL acts differently. Figure 10 shows a degradation beginning near 100°C with a weight loss of 5% at the end of the stage. As (PVA-Ac)-g-PCL includes 1% of water, the right weight loss is of 4% in the blend. If this weight loss is attributed to rDA reaction, then the rDA reaction occurres before the pure exo-adduct rDA reaction and by analogy with our 1 H-NMR results (Figure 1), we can conclude that the exo-adduct, and its rDA products FAl and PM, were totally soluble in (PVA-Ac)-g-PCL matrix at the mixing temperature. Therefore, we can suppose that rDA reaction occurred at 130°C during mixing of (PVA-Ac)-g-PCL and pure exo-adduct, leading to formation and volatilization of FAl and PM. The presence of endo-adduct in polymer matrix is a conclusive evidence of the rDA reaction occurring and its reversibility during cooling. The endo-adduct was formed during the cooling from PM and FAl not volatilized.

Conclusions

Stereospecific DA reaction between N-phenylmaleimide and furfuryl alcohol is realized at condensed state. If at room temperature, a mixture of endo/exo adduct is obtained, pure exo stereoisomer is formed easily at temperature over 118°C. Its thermal behaviour, like decomposition by rDA reaction is closed to melting temperature.

In a polymer matrix in molten state the behaviour of exo-adduct depends strongly on its solubility in the matrix at the mixing temperature. Thus, with miscibility conditions, rDA reaction occurs at temperature lower than exo-adduct melting temperature and leads to endo-adduct formation by DA reaction according to the DA reactions reversibility property. With non miscibility conditions, rDA reaction occurs at exo-adduct melting temperature. So, below this temperature exo-adduct thermal properties are preserved. Further experiments will be performed to verify the reversibility over several cycles of DA reaction with dispersed adduct in a polymer matrix.

  Scheme 1. FAlMP adduct

  1 H-NMR [d 6 -DMSO, ppm)]: 7.5-7.18 (5H ar , m); 6.58 (2H c,d , s); 5.2 (1H b , s); 4.98 (1H f , t); 3.75-4.14 (2H e , m); 3.2 (1H g , d); 3.04 (1H a , d). FT-IR (KBr pellet, cm -1 ): 3504s

Figure 1 :

 1 Figure 1: 1 H-NMR spectra of endo/exo-adduct in d 6 -DMSO at 25°C (a), 50°C (b), 90°C (c), 120°C (d).

Figure 2 .Figure 3 .

 23 Figure 2. DSC thermograms of the endo/exoadduct heating cycles Figure 3. DSC thermograms of the exo-adduct heating cycles

Figure 4 .

 4 Figure 4. DSC thermograms of the endo/exo-adduct in isothermal runs

Figure 5 .

 5 Figure 5. FT-IR spectra of endo/exo-adduct at 25°C, 115°C, 122°C

Figure 6a .

 6a Figure 6a. Dynamic thermogravimetric curves for exo-adduct (○) and endo/exo-adduct () Figure 6b. view of Figure 6a between 100°C and 200°C

Figure 7 .

 7 Figure 7. DSC thermograms of FAlMP exo-adduct in several polymer matrices 2 nd heating cycle at 2°.min -1 .

Figure 8 .Figure 9 .Figure 10 .

 8910 Figure 8. Dynamic thermogravimetric curves of PBD 2000 (○) and PBD 2000/ exo-adduct () Figure 9. Dynamic thermogravimetric curves of Lotader AX8840 (○) and Lotader AX8840/exo-adduct ()

Figure 11 .

 11 Figure 11. 1 H-NMR spectra in d 6 -DMSO at 25°C. exo-adduct (a), (PVA-Ac)-g-PCL (b), (PVA-Ac)-g-PCL /exo-adduct (c)


MD Christine Fardeau
email: christine.fardeau@aphp.

Marie-Adélaïde Ferchaud

MD Caroline Besnard

MD Miguel Hié

CBL mutation retinopathy mimicking uveitis

Two unrelated young patients, with complex medical histories, were initially treated for chronic bilateral uveitis. In following their ophthalmological responses to immunosuppressants, with no improvement in the ophthalmological alterations being observed in response to successive treatments, a diagnosis of retinal dystrophy was made. Known cone-rod dystrophy variants were excluded. Whole exome sequencing revealed mutations in the Casitas B-lineage Lymphoma (CBL) gene.

The ocular phenotype associated with each mutation was accurately described, including the clinical aspects, colour fundus photographs, autofluorescence photographs, optic nerve head and macular optical coherence tomography (OCT), visual fields (VF), fluorescein angiography (FA), electroretinography (ERG) and the clinical course. The ocular phenotype described in detail in this article, associated with the various systemic disorders presented by our patients, could pave the way for a new description of syndromic retinal dystrophy associated with a mutation in the CBL gene.

Retinal dystrophies are a clinically heterogeneous group of inherited degenerative disorders characterised by damage to the retinal photoreceptors. [START_REF] Hartong | Retinitis pigmentosa[END_REF] All modes of genetic transmission may be involved. The aim of this study was to describe two unrelated cases with atypical retinal dystrophy with a mutation identified in the Casitas B-lineage Lymphoma (CBL) gene. [START_REF] Niemeyer | Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia[END_REF] The patients underwent a comprehensive eye examination with multimodal retinal imaging, including FA and OCT, VF, ERG, repeated systemic work-up, and genetic analyses. One patient and the second minor patient's parents signed informed consents, and the study was approved by our local Ethics Committee. The study was conducted in compliance with good clinical practice and the tenets of the Declaration of Helsinki.

Two young patients showed ophthalmological and systemic similarities: presence of a chronic macular oedema (MO), vascular and papillary leakage on FA unchanged on successive immunosuppressive treatments, progressive VF worsening, progressive visual field worsening and a severe bilateral and symmetrical alteration of the retinal function seen on ERG. They also had a history of hepatosplenomegaly since childhood and severe primary infection with Epstein-Barr Virus (EBV). Aqueous humour sampling was negative for Herpes virus, including EBV, by polymerase chain reaction. Successive immunosuppressive therapies did not change retinal fluorescein leakage and failed to prevent retinal damage and VF constriction.

Case 1 was a 24-year-old female patient, complaining since the age of 17 years of sporadic decreases in vision in both eyes, with episodes of retrobulbar optic neuritis.

The visual acuity (VA) was 20/32 in both eyes with night blindness. There were no signs of inflammation in the anterior segment. Anterior vitreous showed 1+ cells in both eyes. Fundus, OCT and FA are shown in figure 1. VF testing found bilateral constriction.

At the systemic level, a history of hepatosplenomegaly since childhood, a history of fibrosing interstitial lung disease due to primary infection with EBV at the age of 19, a nephrotic syndrome, a lupus profile and a right parietal pilocytic astrocytoma were found. The diagnoses of lysosomal disease and congenital immune deficiency were ruled out. Mother and maternal grandmother had normal ophthalmological examinations.

Whole exome sequencing identified a mutation with a loss of heterozygosity in the CBL gene: Exon 8 c.1149 A>G; p. I383M, known to be related to the RASopathy family of disorders.

Case 2 was a 13-year-old male patient who presented with a progressive decrease in vision in both eyes since the age of 6 years. The VA was 20/32 in the right eye and 20/63 in the left eye. There were no signs of cell inflammation in the anterior segment, and 1+ cells in the anterior vitreous. OCT showed bilateral MO. VF showed slight peripheral constriction in both eyes (figure 2). ERG performed 3 years later showed scotopic alterations. Six years later, rod-cone dystrophy was diagnosed on clinical examination, autofluorescence retinography, OCT, FA, tubular VF and altered ERG.

At the systemic level, there was a history of severe EBV infection at the age of 3 years, with a hepatosplenic and peripheral lymph node tumour syndrome, and encephalitis that had responded to corticosteroid treatment.

Panel next generation sequencing identified a mutation with a loss of heterozygosity in the CBL gene: Exon 8 c.1141T>G; p.C381G.

Clinical features of retinal dystrophy had been described in chronic posterior uveitis.

However, VF constriction and ERG abnormalities were present at admission or in the few years following the admission of the current cases. Moreover, FA leakage did not respond to successive immunosuppressive treatments. Several elements, including chronic MO, fluorescein leakage, and cells in the anterior vitreous may have lead to the initial diagnosis of autoimmune uveitis, although these three elements are compatible with the diagnosis of typical retinitis pigmentosa (RP). [START_REF] Hartong | Retinitis pigmentosa[END_REF][START_REF] Strong | Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention[END_REF] Inflammatory mechanisms have been shown in typical RP, such as proinflammatory cytokines and chemokines detected in intraocular fluids that could participate in photoreceptor apoptosis via the activation of the microglia, and antiretinal antibodies detected in the serum of patients with typical RP and MO. [START_REF] Hartong | Retinitis pigmentosa[END_REF][START_REF] Strong | Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention[END_REF] These findings suggest a sustained chronic inflammatory reaction that may mediate multiple events such as the recruitment of leukocytes. [START_REF] Yoshida | Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa[END_REF] However, a high level of immunosuppression achieved by various immunosuppressive regimens over multiple years failed to prevent photoreceptor damage and loss of visual field. Thus, MO and fluorescein leakage could be linked to several mechanisms, including the effects of cytokines on the expression of occludin and claudin in the tight junctions, and the dysregulation of dynamic neuro-glio-vascular cross-talk. [START_REF] Strong | Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention[END_REF][START_REF] Daruich | Mechanisms of macular edema: Beyond the surface[END_REF]

Figure 1 :

 1 Figure 1: 24-year-old woman complaining of visual loss. Fundus appeared similar in both eyes . Right fundoscopy showed pigmentary changes while autofluorescence retinography did not show any hyperautofluorescent ring. Late phase fluorescein angiography showed vascular leakage at the posterior pole, while optic coherence tomography showed macular oedema with cysts in the inner nuclear layer.

Figure 2 :

 2 Figure 2: 13-year-old boy complaining of progressive visual loss. Fundus appeared similar in both eyes. Right infrared fundus imaging showed thin vessels. Late phase fluorescein angiography showed posterior pole leakage, and optical coherence tomography showed cysts located mainly in the inner nuclear layer. Goldmann visual field testing showed slight constriction.

The CBL gene encodes an E3 ubiquitin ligase that negatively regulates the Ras/MAPK pathway. The newly described CBL syndrome is characterized by constitutional and late-onset vascular disorders overlapping with Noonan syndrome and type 1 neurofibromatosis, and may be associated with juvenile myelomonocytic leukaemia. 2 The combination of whole-exome sequencing and clinical analysis allows for more accurate diagnosis of rare syndromic retinal dystrophies.

The local Ethics Committee in Pitié-Salpétrière Hospital approved the current retrospective study.


M Borja-Lloret

A Etxebeste

G Llosá

Enrique Muñoz

Ana Ros

Etienne Testa

Efficiency

Efficiency enhancement studies in a scintillator-based Compton camera for hadrontherapy

teaching and research institutions in France or abroad, or from public or private research centers.

• Gate v9.0 [5,6] with CCMod, a dedicated module for Compton camera simulations [7]. • Detected hits in the whole crystal are added into a single, that reproduces the detector response.

➔ Energy of the single: sum of the deposited energy by the hits.

➔ Position: energy weighted centroid position.

• No randoms included.

• Coincidence requirement: at least one single in a parallel plane.

• Sequence coincidence: singles within coincidences were ordered by increasing axial distance to the source (assuming forward scattering).

The proposed Compton camera design with four additional lateral scintillator planes shows a gain in total efficiency of a factor 4 with respect to the standard configuration made of three parallel planes.

Compton cameras have been proposed as an alternative to collimated cameras in hadron therapy monitoring due to the potential efficiency gain of electronic collimation with respect to mechanically collimated cameras [1,2,3].

In this simulation study, the efficiency enhancement of a LaBr 3 -based Compton camera with an alternative design in which 4 lateral planes were added to the standard configuration.

This design has been compared with the IBA knife-edge slit camera prototype described in [4] through the simulation of a prompt gamma distribution generated by a proton beam of 150 MeV in a PMMA phantom.

Illustration adapted from [4]

Efficiency comparison

Source in both systems: PG with E γ >1 MeV emitted in the FoV of the gamma camera (10 cm along the beam path).

This gain is observed throughout the whole studied range of energies, where the most abundant type of coincidences corresponds to events with one interaction in parallel planes and one interaction in lateral planes. Compared to the knife-edge slit camera, the Compton camera in the studied configuration presents an increase of total efficiency by a factor of 8.8 and a factor of 4 for the effective efficiency. Further work will focus on the impact of the design with enhanced efficiency on the image reconstruction process in order to evaluate its improvement in terms of beam range determination.

Effective coincidence • Forward Compton scattering followed by an interaction of the scattered photon in a different detector layer.

Effective coincidence • Forward Compton scattering followed by an interaction of the scattered photon in a different detector layer. Background events • Backscattering.

• Forward Compton scattering where electrons escape from the crystals. • First interaction other than Compton such as, multiple Compton scattering (within the same layer) and gamma conversion into e -e + pair.

Effective events in gamma camera: detected events when the collimator is ideal (100% absorption).

•

  Initial design: parallel monolithic scintillator crystals of LaBr 3 . ➔ Crystal surface: 200 × 200 mm 2 • Proposed design: parallel planes surrounded by four rectangular-shaped planes of LaBr 3 . • Thickness of the crystals: ➔ Parallel planes (P): 5 mm except for the last parallel plane. ➔ Lateral planes (L) and last parallel plane: 10 mm. Classification P i L j 0: no singles 1: one single m: multiple singles P 1 L 1 , P 1 L m , P m L 1 , P m L m , P m L 0 According to the number of pulses in the set of parallel planes (P) and lateral planes (L), there are 5 categories defined: Dashed lines: design with lateral planes Continuous lines: design with only parallel planes Corresponding author: Marina.Borja@ific.uv.es Aknowledgements Proposed designType of events (total)

P 1 L

 1 1 and P m L 0 are the predominant types. They are the categories with the highest percentage of effective coincidences: At 4.4 MeV, 21% of P 1 L 1 coincidences are effective coincidences whereas 19.9% of P m L 0 coincidences are effective.

This work was performed within the framework of the Labex PRIMES (ANR-11-LABX-0063) and from Spanish Ministerio de Ciencia e Innovación (PID2019-110657RB-I00). The project has received funding from PIC 2018 programme under the reference CSIC 2018FR0032 and CNRS PICS08272. Authors are supported by Ramón y Cajal, SEJIGENT programmes and Spanish Ministerio de Universidades FPU predoctoral contract.


Isabelle Pr
email: isabelle.arnulf@aphp.fr

Arnulf

NREM parasomnia as a dream enacting behavior

Keywords: sleepwalking, sleep terror, parasomnia, dream-enacting behavior

Introduction

In contrast to REM sleep behavior disorder, NREM parasomnias have often been considered as non-dreaming states, as they emerge from N3 sleep (a sleep stage with minimal dream recall), and are frequently amnestic, especially in children [1]. However, recent studies challenge this view, as up to 80% of adult patients with sleepwalking/sleep terrors occasionally remember a short dreamlike mentation associated with the parasomniac episode [START_REF] Oudiette | Dreamlike mentations during sleepwalking and sleep terrors in adults[END_REF][START_REF] Haridi | Is there a common motor dysregulation in sleepwalking and REM sleep behaviour disorder?[END_REF][START_REF] Zadra | Somnambulism: clinical aspects and pathophysiological hypotheses[END_REF]: mostly an unpleasant visual scene containing immediate danger, associated with apprehension and projected in the bedroom setting [START_REF] Uguccioni | Fight or flight? Dream content during sleepwalking/sleep terrors vs rapid eye movement sleep behavior disorder[END_REF]. However, direct evidences of isomorphism between behaviors and dreamlike mentation are exceptional. Plus, little is known about the overt presence of content from daily experiences in N3 dreams.

Case report

A 37 year-old woman, trainer in activity, who practiced sailing as a hobby, was referred for agitated nightmares. After falling at 3 months of age, she had a skull fracture, secondary meningitis and coma. Nevertheless, she presented a normal development. She described nightmares since childhood, containing hospital lights and smells, which disappeared during adolescence. At age 17 years-old, she started to leave her bed during the night, with amnesia of the behavior. She once opened the bedroom window and was awakened by the cold air. Her husband reported that she frequently sat on her bed and sleep talked. She did not take any drug or substance. She benefit from a video-polysomnography on two successive nights. The 13 sudden awakenings from N3 sleep included sleep talking (mumbles or "What, what is it ? Why are you making this face ? What ? Ah !"; "I sleep like a baby"; "Oh damn, it's crazy !"), gestures and surprised face. In one of the N3 interruptions (Video-clip #1) she opened the eyes, saying "Slowly!", then screamed while protecting her head and throwing herself to the right side. She then slowly raised her head again (still holding her protected), looking up and down cautiously, while saying "Oh damned, what is it? Oh boy !", looking up, down and around. Motor activity, rapid eye movements, EEG slow waves of reduced amplitude and tachycardia were observed in the concomitant recording (Figure).

The nurse entered the room 26 sec after the beginning of the parasomniac event, and the patient immediately reported: "I don't know what I've done. It's super bizarre. That's scaring. It is super-hot here (showing her chest, saying it was painful). It was a nightmare." She later reported to the nurse that she was dreaming to be on a boat sailing with the wind astern, and that the boom was slowly moving and suddenly gybed, which was about to smash her head (as illustrated in Video-clip #2). There was a normal muscle atonia and no movements during REM sleep, and no EEG epileptiform waves. The patient was successfully treated with carbamazepine 200 mg taken 1 h before bedtime and hypnosis.

Discussion

The patient had obviously sleep terrors and somnambulism, thanks to her medical history and the observation of confusional arousals, sleep talking and complex non stereotyped behaviors emerging from N3 sleep. REM sleep behavior disorder and post-traumatic stress disorder (which are associated with dream-enacting behaviors), as well as epilepsy were ruled out (Table ). This case illustrates a brief, scenic behavior, which includes surprise, head protection, examination of the bedroom and semi-rapid recover of consciousness, followed by the report of a nightmare (a gybing boom, which is an imminent threat) congruent with the behavior observed before the full awakening, followed by a prolonged feeling of painful heat. She dreamt of normal sailing, a condition that she experienced several times in real life before, suggesting some incorporation of episodic memory. In contrast, many adult sleepwalkers rather report being buried alive, facing a collapsing roof or a tsunami, or seeing snakes in the bed (conditions that they never experienced before), which do not suggest incorporation of episodic memory [START_REF] Oudiette | Dreamlike mentations during sleepwalking and sleep terrors in adults[END_REF]. Here, the dream-behavior isomorphism is a direct evidence that NREM parasomnias can be dream-enacting behaviors. A similar case has been previously displayed [START_REF] Bhat | Dream-enacting behavior in non-rapid eye movement sleep[END_REF]: a patient sleeping in N3 sleep suddenly stood up on the bed and raised his right arm. He later remembered dreaming that the roof was collapsing and he was trying to hold it up. Such dream-enacting behaviors followed by congruent dream recall are exceptionally monitored in the sleep laboratory, but more frequently reported at home [START_REF] Pillmann | Complex dream-enacting behavior in sleepwalking[END_REF][START_REF] Mwenge | Sleepwalking: long-term home video monitoring[END_REF], where they usually last longer. They are precious illustrations indicating that not only REM sleep behavior disorder, but also NREM parasomnias can be dream-enacting behaviors.

Table -Frequency and characteristics of dream-enacted behaviors in the context

Legend of the video-clip #1:

Time is 11 showed her chest, and then her left leg, saying it was painful). The doctor says that it is some dreams, but there it was a nightmare." She later reported to the nurse that she was dreaming to be on a boat sailing with the wind astern, and that the boom was slowly moving and suddenly gybed, threatening to smash her head.

Legend of the video-clip #2: An animator placed a fictive boom moving above the patient's bed to illustrate the content of the dream.

The patient gave her written consent for the video to be displayed in a medical journal.

Figure: 30 -

 30 Figure: 30-sec epoch of the videopolysomnography during the NREM parasomniac episode,

Figure

  Figure

of NREM parasomnia, REM sleep behavior disorder, post-traumatic stress disorder and sleep- related frontal lobe epilepsy

	Subjective experiences and dreams associated with the behavior Legend of the figure:
	Recall of	Infrequent recall	Frequent	Frequent recall	Frequent recall
	associated	(occasional in	recall	(but startling	of the seizure,
	mentation	70%)		may occur in	but no
				absence of	associated
				dream recall	dreams
	Disorder	NREM N3	RBD	Acute PTSD [9] except fear)	Sleep-related
		parasomnia			frontal lobe
	Complexity	Brief visual scenes	More complex	Complex	epilepsy [10] No dreams
			dreams and	nightmare
	Sleep stage	N3	R nightmares	N2, R	N1, N2
	Behaviors during the episode Content Misfortune or	Threat or	Replays of prior	No dreams
		aggression	aggression,	combat or
	Eyes	Open	Closed rarely related to personal history	Open traumatic experiences	Open
	Ambulation the dreamer Response of	Frequent rarely attacks the from danger, Tends to flee	Exceptional the bed partner back, may attack Tends to fight	Rarely jumping out of bed and walking behaviors, may offensive Defensive or	Rare running wandering and nocturnal No dreams
	Interaction with	Frequent bed partner	Less frequent	Frequent attack the bed partner	Frequent
	environment Emotions	Frequently fear,	More variable,	Intense fear	Possible fear
	Movements	Similar to wake apprehension	Various, varying can laugh too	Frequent,	Stereotyped
		movements:	from jerky	explosive,	paroxysmal
		confusional	simple	violent	arousals, tonic
	arousals with orientation behavior or complex, purposeful, prolonged behaviors NREM : non rapid eye movement sleep; PTSD: post-traumatic stress disorder; RBD: Rapid movements to movements; posturing, focal complex, usually rubbing bradykinesia bicycling, hand and absent automatisms; Absent tremor startling purposeful behavior. shaking, gestures, semi-brief purposeful thrashing, clonic activity, eye movement sleep behavior disorder.
	Vocalizations	Moaning,	Moaning,	Frequent	Moaning,
		sentences,	sentences,	vocalizations,	palilalic speech
		swearing	insults	grunting,	comprehensible
		Interrogative tone	Imperative tone	screaming yelling,	words

  PM, one hour after the patient fell asleep. She is in N3 stage at the beginning of the video-clip, then she opens her eyes, saying "slowly, slowly, slowly !". Then she screamed (two brief acute screams) while protecting her head with her hands and throwing herself to her side, as if ducking to avoid something dangerous. She says "is it OK ?" then slowly raised her head (still cautiously holding her protected), and looked up and down several time cautiously, while saying "Oh damned, what is it? Oh boy! What is it? Oh boy !", looking back, up and then around. The nurse entered the room 26 sec after the beginning of the parasomniac event, and the patient immediately reported: "I don't know what I've done. It's super bizarre. That's scaring. I had the feeling of… I don't know how it is. I feel hot here (she


Ane Etxebeste

Enrique Muñoz

Denis Dauvergne

J M Letang

M Borja-Lloret

G Llosá

Voichita Maxim

David Sarrut

Etienne Testa

J M Létang

É Testa

Comparison of efficiency and activity recovery coefficients of Compton and Anger cameras in Nuclear Medicine

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

The application of Compton cameras (CCs) in Nuclear Medicine, in particular in therapy monitoring, has received significant attention in the recent years. Due to the electronic collimation these systems can outperform Anger cameras (ACs) in some aspects (e.g. efficiency)

Illustration of a conventional CC based on a scatterer and an absorber working in time coincidence

Main goal

Introduction

Monte Carlo simulations were performed with GATE/Geant4 [4] version 9.0. Perfect detection (100% detection efficiency and perfect energy and spatial resolution) was considered in the AC as well as in the absorber of the CC by using a phase-space actor. Physics list (em-opt4) with Doppler broadening was selected. Mono-energetic gamma sources emitting in [140,511] keV range were employed.

• layers based on CLaRyS CC prototype [2] • 9x9x0.

Tomographic data: Activity Recovery Coefficients (ARCs)

Better ARC values were obtained for t-AC for energies below 245 keV for higher energies, better ARC values were obtained for t-CC Tomographic acquisitions for CC (t-CC) and AC (t-AC): 180 views, step of 2 degrees 0.5 s/view at 100 mm from rotation center

Results showed an increase of the detection efficiency of CC up to a factor 74 in the studied energy range as compared to standard AC. For energies above 245 keV, a better angular resolution and ARC were obtained for t-CC, whereas for energies below 245 keV the quality of the reconstructed image in terms of ARC, under the studied conditions, was better for t-AC.

In the future, we plan to include realistic conditions in absorber detectors and compare the performance of this CC design with commercial SPECT AC system designs.

In addition, we plan to evaluate in more detail the quality of the different types of coincidences detected in the CC system.

t-AC t-CC 364 keV 364 keV

Reconstruction, ML-EM algorithm : RTK toolkit [5] for t-AC in-house code [6] for t-CC FoV 46×46×46 voxels of 4. Scatter detector (composed of 9 parallel layers using GATE CCMod [3]).

Results: point-like sources at 100 mm from first scatterer layer (CC) / collimator surface (AC)

Future work

Coincidences sorted by event identification (no randoms)

Perfect coincidence sequence reconstruction:

Singles within a coincidence are ordered by increasing time-stamp value

+

  High efficiency (electronic collimation) + May provide higher spatial resolution + Wider energy acceptance + 3D capability -Based on time coincidences -Complex image reconstruction algorithms CCs with respect to ACs

2 cm 3 2 source E 0 E 1 (

 3201 silicon strip detectors (double sided 2x64 strips, 1.4 mm pitch) • grid discretization module + first neighbour policy • depth of interaction set to the centre of the layer • energy resolution of 2.5% at 200 keV, inverse square root energy law • 5 keV energy threshold 70-80% of coincidences: one single in scatterer and one in absorber Lead (𝞺=11.34 g/cm 3 ) hexagonal holes (d=4 mm) septal thickness (t=1.8 mm) Previous studies [1,2] have shown electronic collimation allows a gain in detection efficiency of a factor 20 with respect to standard ACs. In this work, we present ongoing MC simulation studies for further enhancing detection efficiency through a CC design with high angular coverage over the scattered photons. The performance of the CC is compared with a standard AC in terms of detection efficiency and activity recovery coefficients. distribution rms of the angular distribution (source position known) of energy selected events fraction of events that produce a detected coincidence (at least a single in the scatterer with the scattered photon traversing the absorber) fraction of events (after energy selection around the incident photon energy) exiting the collimator surface towards ideal detector E 1 energy deposited in the Compton scattering m e mass of the electron E 𝜃 !"#$ -𝜃 "%"&!' )

4 mm 3

 3 ARCs (t-CC and t-AC) as a function of the sphere volume for different energies.Source distribution (NEMA IEC body phantom config): 6 spheres of 10/13/17/22/28/37 mm diameters distributed along a circumference of D=114.4 mm Constant activity concentration: 20.5 kBq/mL mono-energetic gamma sources[140, 245, 364, 511] keVReconstructed transversal central slice for t-AC and t-CCQuality of images has been quantified through ARC defined as the ratio between the fraction of activity reconstructed in each simulated source volume and the ground truth Detection Efficiency (DE) Angular resolution (RMS)

Acknowledgements

This work was performed within the framework of the Labex PRIMES (ANR-11-LABX-0063). This project has received funding from PIC 2018 programme under the reference CSIC 2018FR0032 and CNRS PICS08272

Corresponding author: ane.etxebeste@creatis.insa-lyon.fr