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Physics of plasmas 30(1), 013105 (2023). doi:10.1063/5.0124011, Published by American Institute of Physics

Magnetized plasma studies are necessary for many applied studies, including laser-driven inertial fusion, modeling astrophysically relevant phenomena, and innovative industrial and medical applications. An interesting method of generating highly magnetized plasma can be based on the interaction of a laser with spiral-shaped cavity (snail-like) targets. A target shaped in this way can represent the central area of a spherical pellet that is not irradiated radially, but rather through an entrance hole allowing the laser beam to almost impact its inner surface tangentially (Pisarczyk et al 2018 Sci. Rep. 8 17 895). In the reported experiment, snail targets of various diameters were irradiated by linearly or circularly polarized radiation of a Prague asterix laser system (PALS) iodine laser delivering ∼500 J, 350 ps and 1.315 μm pulses on targets. Three-frame complex interferometry demonstrated that plasma is generated on the entire inside and outside surfaces of the snail target, starting from the very beginning of the laser–target interaction. The time-resolved records of the magnetic field and the electron density distribution inside and outside the snail target characterize the changes in the structure of the magnetized plasma. Inside the target, the magnetic field survives long after the termination of the laser–matter interaction, namely longer than 10 ns. Compared to a circularly polarized laser pulse, the irradiation of targets with a p-polarized beam increases both the emission of hot electrons (HEs) and the intensity of the magnetic field. The emission of HEs is not isotropic, and their energy distribution cannot be characterized by a single temperature.

International audience; Investigating the potential benefits of the use of magnetic fields in inertial confinement fusion experiments has given rise to experimental platforms like the Magnetized Liner Inertial Fusion approach at the Z-machine (Sandia National Laboratories) or its laser-driven equivalent at OMEGA (Laboratory for Laser Energetics). Implementing these platforms at MegaJoule-scale laser facilities, such as the Laser MegaJoule (LMJ) or the National Ignition Facility (NIF), is crucial to reaching self-sustained nuclear fusion and enlarges the level of magnetization that can be achieved through a higher compression. In this paper, we present a complete design of an experimental platform for magnetized implosions using cylindrical targets at LMJ. A seed magnetic field is generated along the axis of the cylinder using laser-driven coil targets, minimizing debris and increasing diagnostic access compared with pulsed power field generators. We present a comprehensive simulation study of the initial B field generated with these coil targets, as well as two-dimensional extended magnetohydrodynamics simulations showing that a 5 T initial B field is compressed up to 25 kT during the implosion. Under these circumstances, the electrons become magnetized, which severely modifies the plasma conditions at stagnation. In particular, in the hot spot the electron temperature is increased (from 1 keV to 5 keV) while the density is reduced (from 40g/cm3 to 7g/cm3). We discuss how these changes can be diagnosed using x-ray imaging and spectroscopy, and particle diagnostics. We propose the simultaneous use of two dopants in the fuel (Ar and Kr) to act as spectroscopic tracers. We show that this introduces an effective spatial resolution in the plasma which permits an unambiguous observation of the B-field effects. Additionally, we present a plan for future experiments of this kind at LMJ.

BACKGROUND The prognosis of unresectable cutaneous squamous cell carcinomas is very poor. OBJECTIVE To evaluate the efficacy and safety of panitumumab alone or in association with radiotherapy in the treatment of unresectable cutaneous squamous cell carcinoma. METHODS This was a monocentre retrospective study of all consecutive patients having received at least two courses of panitumumab, alone or in association with radiotherapy, between 2016 and 2019. The primary endpoint was the rate of best overall response, evaluated according to the RECIST 1.1 criteria. The secondary endpoints were the response and disease control rates at 6 weeks and 6 months, progression-free survival, overall survival and safety. RESULTS A total of 25 patients were included; their median age was 86 years, and 17 (86%) had a WHO performance status over 2. The best overall response rate was 52%, including four complete responses (16%) and nine partial responses (36%). All patients with complete response and five out of nine patients with partial response had received concurrent radiotherapy, in most cases in moderate to low doses (

Resume Introduction Le granulome annulaire (GA) est une granulomatose cutanee benigne, generalisee (GAG) dans 15 % des cas. L’association a des maladies generales est rapportee mais peu de grandes series publiees. Nous avons effectue une etude anatomoclinique retrospective d’une serie de GAG afin d’en preciser les caracteristiques. Materiels et methodes Les cas classes en tant que GA au laboratoire d’histopathologie de Strasbourg ont ete inclus s’ils etaient generalises (plus de 10 lesions) et valides apres relecture histologique. Les renseignements cliniques ont ete collectes a partir des dossiers medicaux. Resultats Nous avions 35 cas de GAG, avec un sexe-ratio de 0,5 et un âge moyen de 54 ans. Les lesions etaient egalement reparties entre disposition annulaire et non annulaire, symptomatiques dans 25 % des cas. Une maladie systemique etait associee chez 77 % des patients, connue dans 60 % des cas : dyslipidemie (27 %), diabete (20 %), immunosuppression medicamenteuse (17 %), atopie (17 %), maladie auto-immune (17 %), hemopathie (14 %), cancer (9 %). Histologiquement, l’architecture etait plus souvent interstitielle (54 %) que palissadique (20 %), sans correlation avec la presentation clinique. Les eosinophiles etaient frequents (46 %), sans lien significatif avec une maladie systemique. Parmi les 40 % des patients traites, le GAG a ete resolu dans 50 % des cas par diverses therapeutiques, dont des dermocorticoides, cyclines, antipaludeens de synthese ou phototherapie. Discussion Le GAG est un tableau different du GA localise, frequemment associe a un etat pathologique connu, metabolique, infectieux, neoplasique ou immunodepression medicamenteuse, non correle a la presentation clinique ou histologique, dont le depistage est necessaire.

Optical generators of strong magnetic fields based on the laser-driven-coil target concept are considered to be useful tools for studies of magnetized plasmas in particular, for the study of implosion of magnetized fusion targets in inertial fusion research and astrophysical applications. This paper presents the results of the research directed at an investigation of the plasma properties in a laser-induced magnetic field. In the experiment carried out on the kilojoule PALS laser facility, a generator of the magnetic field was a disc-coil (DC) target composed of a Cu disk coupled to a single-turn coil irradiated by a 1ω laser beam with an energy of 500 J. The attention was focused on examining the influence of the magnetic field on properties of the hot electron (HE) flux emitted from the front surface of the irradiated target. The three-frame complex interferometry and four-frame x-ray camera combined with the measurements of the HE population and energy using a multi-channel magnetic electron spectrometer and 2D-resolved imaging of the induced Cu Kα line emission were applied to characterize the ablative plasma and the generated particles. Based on the measured angular distributions of the electron energy spectra, 3D simulations have been performed to visualize the effect of the magnetic field on the HE flux and to provide information on space-time distribution of the electron and current density both without and with the presence of an axial magnetic field. The obtained results confirmed the possibility of generating magnetic fields above 5 T using the proposed DC target design as well as the significant impact of these fields on properties of the ablative plasma and the HE emission.

Objective:Consumption of cow’s milk, which is associated with diet and health benefits, has decreased in the USA. The simultaneous increase in demand for more costly organic milk suggests consumer concern about exposure to production-related contaminants may be contributing to this decline. We sought to determine if contaminant levels differ by the production method used.Design:Half-gallon containers of organic and conventional milk (four each) were collected by volunteers in each of nine US regions and shipped on ice for analysis. Pesticide, antibiotic and hormone (bovine growth hormone (bGH), bGH-associated insulin-like growth factor 1 (IGF-1)) residues were measured using liquid or gas chromatography coupled to mass or tandem mass spectrometry. Levels were compared against established federal limits and by production method.Setting:Laboratory analysis of retail milk samples.Results:Current-use pesticides (5/15 tested) and antibiotics (5/13 tested) were detected in several conventional (26–60 %; n 35) but not in organic (n 34) samples. Among the conventional samples, residue levels exceeded federal limits for amoxicillin in one sample (3 %) and in multiple samples for sulfamethazine (37 %) and sulfathiazole (26 %). Median bGH and IGF-1 concentrations in conventional milk were 9·8 and 3·5 ng/ml, respectively, twenty and three times that in organic samples (P < 0·0001).Conclusions:Current-use antibiotics and pesticides were undetectable in organic but prevalent in conventionally produced milk samples, with multiple samples exceeding federal limits. Higher bGH and IGF-1 levels in conventional milk suggest the presence of synthetic growth hormone. Further research is needed to understand the impact of these differences, if any, on consumers.

We developed a robust analytical method for quantification of malondialdehyde (MDA) in exhaled breath condensate (EBC) via derivatization with 2,4-dinitrophenylhydrazine (DNPH). The target MDA-DNPH hydrazone was separated by ultra-performance liquid chromatography using two reversed-phase analytical columns (C18 and phenyl-hexyl) inter-connected via a two-position, six-port switching valve to a single-quadrupole mass spectrometer. The target derivative was analyzed under positive electrospray ionization using single ion monitoring mode (m/z = 235 for the target derivative, and m/z = 237 for its labeled isotopic analog). This pseudo two-dimensional chromatographic separation provided optimum separation conditions for the target derivative resulting in the limit of detection of 0.58 nM in EBC sample (or 36.2 pmol on-column amount), which is comparable to those reported previously using different techniques, including tandem mass spectrometry. Based on the calibration solutions, the method had a linear quantification range of 1.0–200 nM (r2 = 0.998). The method showed good relative recoveries (92.2–102.0%) and acceptable precisions (3.6–12.2% for inter-day precision, and 4.3–12.4% for intra-day precision for two quality control levels, prepared from 5 nM and 25 nM solutions). The derivative was found to be stable at room temperature for 48 h or during analysis. The method was used to analyze 205 exhaled breath condensate samples collected from individuals from a healthy population of student athletes. MDA was detected in approximately 95% of these samples, with concentrations ranging from 1.16 to 149.63 nM. The median concentration was 6.82 nM, (IQR 4.08–9.88). These data demonstrate that our method can be successfully used to measure MDA in population studies.

Air pollution has steadily increased for several decades, with widely studied effects on human health, including increased mortality, incidence of stroke, respiratory and allergic disease. However, the effects of pollution on the ocular surface, in direct contact with the outside world, have been less precisely studied.We conducted a literature review of articles on the subject published from 1966 to October 2020. Among the 661 articles identified, 33 were retained. Ocular surface disease associated with pollution included non-specific conjunctivitis, dry eye disease, blepharitis, and allergic conjunctivitis. The studied pollutants were particulate matter less than 2.5μm and 10μm (PM2.5, PM10), ozone (OAmong the markers of air pollution possibly associated with ophthalmic disease, NOAir pollution control would appear essential, as well as the development of new studies based on reliable methods of studying the environmental and its clinical effects.

Few studies have evaluated the role of digital dermoscopy (DD) in the surveillance of pigmented lesions in real-life practice.Patients followed with DD by 4 hospital dermatologists (group 1) and 4 private dermatologists (group 2) were retrospectively included if they had had at least 2 DD examinations for a minimum of 4 pigmented lesions. Their characteristics, risk factors, history of excision of benign nevi and melanomas prior to and during the DD follow-up, and characteristics of detected melanomas, were recorded.One hundred and ninety-six patients were included in group 1 and 205 in groups 2. A family history of melanoma (25% vs. 12%, p0.01), a personal history of melanoma before DD follow-up (47% vs. 15%, p0.01), and a family (3% vs. 0%, p=0.01) and personal (8% vs. 1%, p0.01) germline CDKN2a mutation were more frequent in group 1 than in group 2. In both groups, the number of excisions of benign lesions was higher before DD follow-up (380 and 347, respectively) than during DD follow-up (194 and 132). During follow-up, 29 melanomas were detected in group 1, with a median Breslow thickness of 0.4mm, versus 1.3mm for melanomas diagnosed before DD follow-up (p0.02). In group 2, 4 melanoma and 5 superficial atypical melanocytic proliferations of unknown significance were detected. The median Breslow thickness of newly diagnosed melanomas was 0.35mm vs. 0.6mm before DD follow-up (p=0.1).In both populations in real-life practice, DD seemed to allow the detection of thin melanomas and to decrease the rate of "futile" resections.

Allergic conjunctivitis affects 15 to 20% of the general population. It is currently evaluated by the Conjunctival Provocation Test (CPT), which is considered as the gold standard. In the investigation of allergic rhinitis and asthma, environmental exposure chambers (EEC) are increasingly utilised. For allergic conjunctivitis, EEC might be a valid alternative to the CPT. However, evaluation of the allergen response in individual provocation tests or in EECs is still in discussion due to the multiplicity of symptom scores. Indeed, there are many scores used to evaluate allergic conjunctivitis. The main criteria used were described by Abelson in 1990 and include redness, itching, tearing, and swelling. In clinical studies, the specifically ocular score most used is the Total Ocular Symptom Score (TOSS). Few treatments have been evaluated by EEC, including cold compresses, epinastine and N-acetyl aspartyl glutamic acid. Moreover, early data shows good correlation between ocular symptoms induced in an EEC and those assessed during natural exposure. EEC might be a valid alternative to CPT and correlate with natural seasonal allergen exposure. Finally, EEC might be useful in other fields as well, such as in the study of dry eye disease.

Allergic conjunctivitis affects 15 to 20% of the general population. It is currently evaluated by the Conjunctival Provocation Test (CPT), which is considered as the gold standard. In the investigation of allergic rhinitis and asthma, environmental exposure chambers (EEC) are increasingly utilised. For allergic conjunctivitis, EEC might be a valid alternative to the CPT. However, evaluation of the allergen response in individual provocation tests or in EECs is still in discussion due to the multiplicity of symptom scores. Indeed, there are many scores used to evaluate allergic conjunctivitis. The main criteria used were described by Abelson in 1990 and include redness, itching, tearing, and swelling. In clinical studies, the specifically ocular score most used is the Total Ocular Symptom Score (TOSS). Few treatments have been evaluated by EEC, including cold compresses, epinastine and N-acetyl aspartyl glutamic acid. Moreover, early data shows good correlation between ocular symptoms induced in an EEC and those assessed during natural exposure. EEC might be a valid alternative to CPT and correlate with natural seasonal allergen exposure. Finally, EEC might be useful in other fields as well, such as in the study of dry eye disease.

A developing application of laser-driven currents is the generation of magnetic fields of picosecond–nanosecond duration with magnitudes exceeding $B=10~\text{T}$ . Single-loop and helical coil targets can direct laser-driven discharge currents along wires to generate spatially uniform, quasi-static magnetic fields on the millimetre scale. Here, we present proton deflectometry across two axes of a single-loop coil ranging from 1 to 2 mm in diameter. Comparison with proton tracking simulations shows that measured magnetic fields are the result of kiloampere currents in the coil and electric charges distributed around the coil target. Using this dual-axis platform for proton deflectometry, robust measurements can be made of the evolution of magnetic fields in a capacitor coil target.

Laser plasma created by intense light interaction with matter plays an important role in high-energy density fundamental studies and many prospective applications. Terawatt laser-produced plasma related to the low collisional and relativistic domain may form supersonic flows and is prone to the generation of strong spontaneous magnetic fields. The comprehensive experimental study presented in this work provides a reference point for the theoretical description of laser-plasma interaction, focusing on the hot electron generation. It experimentally quantifies the phenomenon of hot electron retention, which serves as a boundary condition for most plasma expansion models. Hot electrons, being responsible for nonlocal thermal and electric conductivities, are important for a large variety of processes in such plasmas. The multiple-frame complex-interferometric data providing information on time resolved spontaneous magnetic fields and electron density distribution, complemented by particle spectra and x-ray measurements, were obtained under irradiation of the planar massive Cu and plastic-coated targets by the iodine laser pulse with an intensity of above 1016 W cm−2. The data shows that the hot electron emission from the interaction region outside the target is strongly suppressed, while the electron flow inside the target, i.e. in the direction of the incident laser beam, is a dominant process and contains almost the whole hot electron population. The obtained quantitative characterization of this phenomenon is of primary importance for plasma applications spanning from ICF to laser-driven discharge magnetic field generators.

Resume Introduction Le mebutate d’ingenol est un traitement medical des keratoses actiniques (KA) qui agit par un double mecanisme : induction rapide de mort cellulaire et reaction inflammatoire intense. Observation Nous rapportons le cas d’un patient de 75 ans qui a developpe une tumeur de croissance rapide 5 semaines apres l’application de mebutate d’ingenol sur des KA. L’analyse histologique apres exerese chirurgicale revelait un carcinome epidermoide (CE) invasif avec des signes d’agressivite (infiltration peri-nerveuse et permeation vasculaire). Discussion Les effets secondaires constants du mebutate d’ingenol sont benins et regressifs spontanement en 2 a 4 semaines : erytheme, œdeme, croutes, ulcerations/erosions, pustules. La survenue d’un CE est rare. Nous avons cherche d’autres cas dans la litterature et dans les centres de pharmacovigilance francais et europeens. Trois observations ont ete rapportees dans la litterature, 21 cas ont ete signales a l’agence europeenne du medicament et l’interrogation des centres de pharmacovigilance francais a permis de trouver cinq cas de CE apres application de mebutate d’ingenol. Le role du mebutate d’ingenol dans le developpement de CE n’est pas connu. L’inflammation induite par la molecule pourrait jouer un role dans le developpement de ces tumeurs, par analogie a d’autres evenements, de type traumatisme cutane (prise de greffe cutanee, incision chirurgicale). Le suivi au long cours de patients traites permettra de mieux connaitre la frequence des cas.

International audience; For most laser-driven ion acceleration applications, a well-characterized intense ion beam with a low divergence and a controllable energy spectrum produced at a high repetition rate is needed. Gas-jet targets have given promising results in simulations, and they have several technical advantages for high-repetition-rate lasers. In this work, we report on proton acceleration to energies up to 6 MeV using a supersonic H2 gas-jet target at the LULI PICO2000 laser facility. The experimental results are compared with the plasma hydrodynamics and the particle-in-cell simulations to identify the acceleration mechanisms at play.

Introduction Le mogamulizumab (MOGA) est un anticorps antiCCR4, indique dans le mycosis fongoide (MF) ou le syndrome de Sezary (SS). De 27 % a 62 % des patients ont sous MOGA une toxicite cutanee mal decrite : prurit, rash maculopapuleux,1 Steven–Johnson, 1 phenomene de rappel apres radiotherapie. Nous rapportons chez 3 patients une toxicite cutanee particuliere et discutons sa valeur pronostique. Observations Une femme de 62 ans, en echec de photopherese, interferon et bexarotene pour un SS de stade T4N0M0B1b, etait traitee par MOGA, avec une excellente reponse des 1 mois. A 6 mois, elle restait en reponse cutanee et sanguine subtotale, mais on notait des lesions squameuses en casque du cuir chevelu et des plaques infiltrees pre-auriculaires, bilaterales et symetriques. L’examen histologique montrait un infiltrat granulomateux dermique profond sans cellules residuelles de lymphome. Une femme de 65 ans etait traitee par MOGA pour un SS T4N3M0B2 apres echec du methotrexate, avec une reponse quasi complete. A 5 mois, apparaissaient un casque psoriasiforme du cuir chevelu et des plaques infiltrees pre-auriculaires bilaterales. L’examen histologique montrait le meme aspect de granulomes gigantocellulaires avec infiltrat histiocytaire et eosinophilique, sans lymphome residuel. Un homme de 56 ans, en echec de plusieurs lignes therapeutiques (interferon-photopherese, gemcitabine, doxorubicine) pour un SS T4N3M0B2, etait traite par MOGA. A 3 mois, on notait une reponse cutanee > 90 % et une remission sanguine complete. A 5 mois, apparaissaient des plaques infiltrees pre-auriculaires et un casque squameux. Les patientes 1 et 2 avaient aussi des plaques du tronc dont l’histologie montrait un aspect granulomateux (P1) ou inflammatoire riche en eosinophiles (P2) Discussion Ces 3 patients ont developpe sous MOGA une eruption cutanee cliniquement stereotypee et histologiquement granulomateuse, associee a une excellente reponse. Dans la litterature, 6 patients issus de l’essai princeps MAVORIC ont developpe apres un delai comparable a celui de notre serie (4,6 mois), parallelement a une bonne reponse au MOGA, une dermatose nommee par les auteurs « CGDE » (cutaneous granulomatous drug eruption),constituee de plaques erythemato-squameuses du tronc, des bras, du visage et du cuir chevelu. Histologiquement, l’infiltrat etait granulomateux, compose d’histiocytes, lymphocytes, eosinophiles et/ou cellules geantes multinucleees. Nous rapportons 3 cas histologiquement similaires a cette nouvelle entite, avec un aspect clinique tres particulier et facilement reconnaissable, caracterise par des lesions erythemato-squameuses en casque et des plaques inflammatoires pre-auriculaires, et parfois des plaques du tronc mal distinguables cliniquement de plaques de MF. La valeur pronostique favorable de cette eruption devra etre confirmee par des etudes prospectives.

Introduction Les anticorps anti-PD1 (anti-PD1) sont indiques pour les melanomes (M) de stade III inoperables ou de stade IV. Exceptionnellement, des M de stade I ou II ne sont pas accessibles a la chirurgie en raison de leur siege (souvent muqueux ou acral) et/ou de leur surface d’extension (visage), celle-ci etant non realisable ou inacceptable par son caractere mutilant ou delabrant. Nous rapportons 11 patients traites dans cette situation par un anti-PD1. Materiel et methodes Ont ete inclus tous les patients traites par un anti-PD1 entre janvier 2018 et avril 2020 pour un M de stade I ou II (AJCC8) pour lequel la reunion de concertation pluridisciplinaire avait exclu une intervention chirurgicale. Le critere de jugement principal etait le taux de reponse. Les criteres secondaires la survie globale, la survie sans progression et la toxicite. La date de point etait le 30/05/2020. Resultats Onze patients (8 femmes et 3 hommes), d’âge moyen 72 ans (extremes (E) : 49–90), ont ete inclus. Cinq ont recu du nivolumab, 5 du pembrolizumab, 1 du cemiplimab en raison d’un carcinome epidermoide cutane inoperable d’un membre qui constituait l’indication premiere. Le M etait cervico-facial dans 6 cas, plantaire dans 1 cas, muqueux dans 4 cas (endo-nasal : 2 ; pharynge : 1 ; vulvaire : 1). La surface lesionnelle variait de 5 a 44 cm2 (mediane :15). Un M etait in situ (femme jeune avec recidive tres etendue de la joue et du pourtour de l’oeil de part d’autre d’une greffe), les 10 autres invasifs, d’epaisseur 0,35 a 13 mm (mediane : 3 mm) mesuree sur des biopsies partielles (7 cas) ou une IRM (1 cas) (non evaluable : 2 cas). Tous les M etaient BRAF sauvage et exprimaient faiblement PDL1 en immunohistochimie ( Discussion Les anti-PD1 sont une alternative therapeutique interessante pour des M de stade I–II inoperables, incluant les M muqueux, pourtant moins sensibles a ces traitements au stade metastatique que les M cutanes. Le taux de reponse complete parait superieur a celui obtenu aux stades plus avances, independamment de l’expression de PDL1. Une etude prospective avec des criteres stricts de non operabilite pourrait etre proposee.

Introduction La radiotherapie dans les carcinomes a cellules de Merkel metastatiques n’est indiquee qu’a visee palliative. L’avelumab a transforme la survie de certains patients, avec un taux de reponse global modere a 33 %, mais une survie prolongee chez les repondeurs. De nouveaux schemas therapeutiques semblent necessaires afin d’augmenter les taux de reponse. Nous rapportons l’observation d’un carcinome de Merkel en hyper-progression locoregionale initiale sous avelumab pour lequel une reponse spectaculaire a ete obtenue apres adjonction de radiotherapie. Observations Un patient de 59 ans, opere avec des marges non saines d’un carcinome de Merkel du bras gauche, developpait une recidive locale rapide avec extension ganglionnaire axillaire (stade T4N1M0). La progression tres rapide se poursuivait sous chimiotherapie (carboplatine + etoposide : 2 cures) puis avelumab (4 cures), et se compliquait d’une anemie par saignement tumoral requerant des transfusions iteratives. Une radiotherapie a visee hemostatique etait alors proposee. Le patient recevait sur la tumeur une dose totale de 20 Gy en 5 fractions de 4 Gy. Au decours survenait une regression tumorale rapide. A 3 mois de la radiotherapie, on notait une reponse clinique et metabolique complete de la tumeur primitive et une regression partielle des adenopathies axillaires. Cette reponse se maintenait a 6 mois sous avelumab, avec une poursuite de la diminution en taille des adenopathies. Discussion L’avelumab est une immunotherapie anti-PD-L1 dont le mode d’action est de supprimer les effets inhibiteurs du PD-L1 sur les lymphocytes T CD8+ cytotoxiques, retablissant ainsi la reponse anti-tumorale. Il a obtenu une AMM en 2e ligne apres chimiotherapie suite a un essai de phase 2. L’effet abscopal est le phenomene de regression d’une metastase a distance du volume irradie. Il a ete initialement decrit de maniere sporadique avec la radiotherapie en monotherapie, mais sa frequence semble augmenter lorsque la radiotherapie est combinee a l’immunotherapie (effet synergique), la liberation d’antigenes tumoraux augmentant alors l’identification des cellules tumorales par les lymphocytes T qui, actives, peuvent induire une reponse anti-tumorale a distance du site irradie. Notre observation suggere une potentialisation de l’avelumab par la radiotherapie, avec une reponse spectaculaire de la lesion primitive apres une faible dose, associee a une regression de sites ganglionnaires non irradies. Cette observation de carcinome a cellules de Merkel de stade III en hyper-progression sous avelumab, suivie d’une reponse quasi complete apres adjonction d’une radiotherapie palliative suggere l’interet et la synergie de l’association avelumab–radiotherapie.

Introduction L’incidence des carcinomes cutanes et lesions pre-cancereuses ne cesse d’augmenter en raison notamment de l’esperance de vie et de l’exposition solaire. Les carcinomes basocellulaires et keratoses actiniques representent respectivement 1 et 5 % des consultations de dermatologie. Differents traitements existent dont la phototherapie dynamique (PDT), utilisant l’activation d’un photosensibilisant par la lumiere pour induire une necrose tumorale. Le laser CO2 permet une destruction cellulaire en agissant sur l’eau intracellulaire, potentialisant ainsi la PDT. Le laser CO2 associe a la PDT a ete etudie dans differents essais suggerant une augmentation d’efficacite, mais aucune etude francaise en vie reelle n’a ete rapportee a notre connaissance. Materiel et methodes Etude retrospective monocentrique des patients traites par laser CO2 et PDT pour un carcinome basocellulaire (CBC), un carcinome epidermoide micro-invasif (CSC), une maladie de Bowen (MB) ou des keratoses actiniques/champs de cancerisations (KA/CC). Chaque lesion a ete traitee par laser CO2 suivi de l’application de methyl amino levulinate sous occlusion pendant 3 heures, puis d’une seance d’illumination avec la lampe Aktilite CL 128®. Selon l’appreciation du medecin 1 a 3 sessions etaient realisees. Un traitement antalgique adapte etait propose (paracetamol, meopa, tramadol). La douleur etait evaluee sur une echelle visuelle analogique (EVA). L’efficacite clinique etait evaluee lors de la consultation de suivi a 3 mois, si necessaire une biopsie etait realisee. Le critere principal etait le taux de reponse complete (RC : avec disparition des lesions). Une reponse partielle (RP) etait definie par une diminution de 25 a 99 %, et un echec par une diminution Resultats 42 patients (30 hommes et 12 femmes) d’âge moyen 79 ans (extremes : 54–92) ont ete inclus et 71 lesions traitees. 5 patients ont ete perdus de vue, le plus souvent en raison d’un âge tres avance ou du deces. Les lesions traitees etaient 2 CSC, 13 MB, 24 KA/CC, 25 CBC. Du fait de l’inclusion jusqu’en mai 2020, le critere principal n’a pu etre evalue a la date de soumission de l’abstract que pour 40 lesions. Une RC a 3 mois etait obtenue pour 11/13 CBC superficiels (1 RP et 1 echec en zone irradiee), 2/4 CBC nodulaires (2 echecs), 8/13 KA/CC (5 RP et 2 echecs avec biopsie montrant un CSC micro infiltrant), 9/10 MB (1 RP). L’EVA de douleur etait disponible pour 20 patients avec une moyenne de 5,4, plus elevee pour les lesions du visage. Discussion Malgre des donnees partielles, on note de bons resultats pour l’association laser CO2–PDT, concordant avec ceux de la litterature, mais incluant aussi des reponses totales pour des carcinomes parfois tres etendus ou plus epais que ceux recommandes par l’AMM. Cette association parait etre plus efficace que la PDT classique et plus simple dans certaines situations que la chirurgie.

Introduction Depuis 2005, la microscopie confocale in vivo (MC) aide le dermatologue a ameliorer son diagnostic et a guider des gestes chirurgicaux en permettant de visualiser les lesions a l’echelle cellulaire, plus precisement que la dermoscopie. Cependant, aucune etude n’a realise un etat des lieux de l’utilisation de la MC dans les centres hospitalo-universitaires francais (CHU). L’objectif principal est de decrire l’activite de la MC en France. Les objectifs secondaires sont d’evaluer son utilite ainsi que la correlation MC et histologie. Materiel et methodes Cette evaluation des pratiques professionnelles prospective et multicentrique a ete realisee dans 10 CHU. Tous les patients adultes adresses dans ces centres pour une consultation de MC etaient inclus. Le dermatologue qui effectuait la MC remplissait un questionnaire standardise descriptif de la consultation de MC incluant l’histologie. L’etude a commence en fevrier 2020 et terminera fin de l’annee 2020. Nous rapportons ici les resultats preliminaires. Resultats 66 % (10/15) des CHU possedant un MC ont participe a l’etude. 78 lesions ont eu une indication a la MC et ont ete incluses. Les lesions localisees au visage representaient 50 % (39/78) des indications. Les principales indications etaient : diagnostic de lesions melanocytaires (63/78 ; 80,8 %), evaluation des marges de melanome de Dubreuilh (12/78 ; 15,4 %), suivi des muqueuses genitales (9/78 ; 11,5 %). 76/78 (97,4 %) lesions ont ete analysees en MC (2 examens de MC n’ont pu etre realises). Le Vivascope 3000® etait le plus utilise pour 61/76 cas (80 %), par rapport au Vivascope 1500® (7/76 ; 9,2 %). La duree de realisation de MC etait variable ; 50 % des examens etaient realises en moins de 10 minutes. Le confocaliste etait experimente (> 5 ans d’experience) dans 50 % (39/76) des cas. Les principaux diagnostics etaient le melanome de Dubreuilh dans 20/76 cas (74,1 %) et le carcinome basocellulaire (14/76 ; 21,9 %). Le diagnostic de lesion infectieuse/inflammatoire 1/76 cas (3,4 %) restait rare. Discussion D’apres les publications d’autres pays relatives a la pratique dermatologique de la MC, le temps moyen de l’examen est similaire a notre etude, d’environ 10 minutes. Il est egalement decrit, comme dans notre etude, l’interet de la MC pour les lesions du visage afin de limiter la rancon cicatricielle (50 % des indications). Notre etude demontre, en accord avec la litterature, l’interet de la MC dans la pratique quotidienne du dermatologue en France malgre un cout eleve du dispositif, le non-remboursement des actes et la formation longue des praticiens. Conclusion Les resultats preliminaires de cette etude francaise descriptive sur l’activite de la MC, sous reserve de confirmation sur un plus grand nombre de cas, pourraient justifier une plus grande diffusion de cette technologie en France, une formation accrue des dermatologues ainsi qu’une prise en charge de l’acte par l’assurance maladie.

By driving hot electrons between two metal plates connected by a wire loop, high power lasers can generate multi-tesla, quasi-static magnetic fields in miniature coil targets. Many experiments involving laser-coil targets rely on proton deflectometry directed perpendicular to the coil axis to extract a measurement of the magnetic field. In this paper, we show that quantitative measurements using perpendicular probing are complicated by the presence of GV m−1 electric fields in the target that develop on sub-ns timescales. Probing parallel to the coil axis with fiducial grids is shown to reliably separate the electric and magnetic field measurements, giving current estimates of I ≈ 5 kA in 1 mm- and 2 mm-diameter wire loops. An analytic model of proton deflection in electric and magnetic fields is used to benchmark results from the particle-in-cell code and help deconvolve the magnetic and electric field deflections. Results are used to motivate a new experimental scheme that combines a single-plate target with axial proton probing and direct current measurements. This scheme has several important advantages over the traditional target and diagnostic set-up, enabling the robust measurement of coil magnetic fields and plasma properties, as well as making it easier to validate different theoretical models at a range of laser intensities.

Background Alcohol use disorder and depression occur commonly in the community. Even though this high-prevalence comorbidity is associated with poorer posttreatment outcomes and greater utilization of costly treatment services, existing treatment trials often exclude patients with comorbid depressive and alcohol use disorders. Past research suggests that symptoms such as craving and anhedonia might be associated with alterations within the reward circuit, while emotion regulation deficits are related to disruptions within the default mode network. The aim of this clinical neuroimaging study is to transfer previous research about the reward circuit and default mode network underlying alcohol use disorder and depression to achieve a better understanding of neural signatures characterizing their comorbidity. In addition, the neurobiological results will be used to test whether two psychotherapeutic intervention programs, mindfulness-based training and behavioral activation training, are able to positively influence the identified pathomechanisms. Methods By means of functional magnetic resonance imaging (fMRI), 60 comorbid alcohol dependent and depressed patients are compared to 30 patients with depression only, 30 patients with alcohol use disorder only and 30 healthy control participants. Comorbid patients are randomized to either receive a behavioral activation or mindfulness based training and asked to participate in a second fMRI session and 3 month follow-up assessment. Thereby, we plan to explore whether these brief group psychotherapeutic intervention programs are able to positively influence the identified neurobiological pathomechanisms. The primary outcomes are reward and default mode network activity and connectivity evoked by paradigms measuring different facets of reward and emotion processing. Secondary outcome measures include craving and depression scores, as well as relapse rates. Predictors include participants’ characteristics, personality traits and indicators of mental health. Discussion The objective of the project is to identify common and/or distinct neural signatures underlying the comorbidity of alcohol dependence and depression. If the neurobiological understanding of alcohol addiction and depression is improved, this could potentially serve as a key predictor of treatment response to specific types of behavioral or mindfulness therapies hypothesized to alter reward and resting state systems. Trial registration German Clinical Trial Register DRKS00010249 . The trial was registered January 23th 2017.

Magnetic reconnection in a relativistic electron magnetization regime was observed in a laboratory plasma produced by a high-intensity, large energy, picoseconds laser pulse. Magnetic reconnection conditions realized with a laser-driven several kilotesla magnetic field is comparable to that in the accretion disk corona of black hole systems, i.e., Cygnus X-1. We observed particle energy distributions of reconnection outflow jets, which possess a power-law component in a high-energy range. The hardness of the observed spectra could explain the hard-state x-ray emission from accreting black hole systems.

The paper presents the general challenges of diagnostics for laser-produced plasmas related to their small dimensions and short duration but also to the presence of very strong temperature and density gradient in the plasma. In particular, we focus on more detailed examples related to optical diagnostics for the undercritical region of the plasma: shadowgraphy, schlieren, interferometry, polarimetry.

The double laser pulse approach to relativistic electron beam (REB) collimation in solid targets has been investigated at the LULI-ELFIE facility. In this scheme two collinear laser pulses are focused onto a solid target with a given intensity ratio and time delay to generate REBs. The magnetic field generated by the first laser-driven REB is used to guide the REB generated by a second delayed laser pulse. We show how electron beam collimation can be controlled by properly adjusting the ratio of focus size and the delay time between the two pulses. We found that the maximum of electron beam collimation is clearly dependent on the laser focal spot size ratio and related to the magnetic field dynamics. Cu-Kα and CTR imaging diagnostics were implemented to evaluate the collimation effects on the respectively low energy (≤100 keV) and high energy (≥MeV) components of the REB.

International audience; For most applications of laser driven ion beams, a well-characterized high repetition rate intense ion beam with low divergence and a controllable energy spectrum is needed. High power laser-solid targets interactions are usually used, in which the main acceleration mechanism is the so-called Target Normal Sheath Acceleration (TNSA). Changing solid targets for overcritical gas jet targets has given interesting results in theoretical simulations and these later have several technical advantages for high repetition rate lasers. In this work protons and helium ions are accelerated from a near-critical supersonic gas jet. The production of such targets is very challenging for near infrared lasers. We present recent results concerning the design and characterization of supersonic gas nozzles able to deliver such high densities and the first results obtained during the first experiment on PICO2000 facility at LULI. We succeeded to accelerate ions up to several MeV with a H2 and He gas jet target. The number of accelerated ions is comparable to the one usually obtained with solid targets.

International audience; Computational fluid dynamics simulations are performed to design gas nozzles, associated with a 1000 bars backing pressure system, capable of generating supersonic gas jet targets with densities close to the critical density for 1053 nm laser radiation (1021 cm−3). Such targets should be suitable for laser-driven ion acceleration at a high repetition rate. The simulation results are compared to the density profiles measured by interferometry, and characterization of the gas jet dynamics is performed using strioscopy. Proton beams with maximum energies up to 2 MeV have been produced from diatomic hydrogen gas jet targets in a first experiment.

Intense lasers interacting with dense targets accelerate relativistic electron beams, which transport part of the laser energy into the target depth. However, the overall laser-to-target energy coupling efficiency is impaired by the large divergence of the electron beam, intrinsic to the laser–plasma interaction. Here we demonstrate that an efficient guiding of MeV electrons with about 30 MA current in solid matter is obtained by imposing a laser-driven longitudinal magnetostatic field of 600 T. In the magnetized conditions the transported energy density and the peak background electron temperature at the 60-μm-thick target's rear surface rise by about a factor of five, as unfolded from benchmarked simulations. Such an improvement of energy-density flux through dense matter paves the ground for advances in laser-driven intense sources of energetic particles and radiation, driving matter to extreme temperatures, reaching states relevant for planetary or stellar science as yet inaccessible at the laboratory scale and achieving high-gain laser-driven thermonuclear fusion., Efficient energy transport by laser-driven relativistic electron beams is crucial in many applications including inertial confinement fusion, and particle acceleration. Here the authors demonstrate relativistic electron beam guiding in dense plasma with an externally imposed high magnetic field.

Introduction L’association encorafenib et binimetinib (ENCO/BINI) est autorisee depuis juin 2019 pour le traitement du melanome non resecable ou metastatique mute BRAF V600. Les toxicites, notamment renales, sont peu decrites. Materiel et methodes Il s’agit d’une etude retrospective, monocentrique, incluant tous les patients traites par ENCO/BINI dans un service de dermatologie oncologique entre octobre 2019 et juin 2020 pour un melanome. Resultats Douze patients, dont 8 femmes, ont ete traites par ENCO/BINI pour un melanome de stade III inoperable ou IV. L’âge moyen etait de 57 ans, 4 avaient une hypertension arterielle, dont 3 sous antihypertenseur nephrotoxique ou diuretique, 1 etait diabetique, aucun n’avait d’insuffisance renale chronique. Une insuffisance renale aigue (IRA) apparaissait chez 7 patients (58 %), apres un delai median de 13 jours (4 a 30), de grade 2 (3 cas), 3 (3 cas) ou 4 (1 cas). Ce dernier patient necessitait une hospitalisation en reanimation pour fievre, rhabdomyolyse et choc hypovolemique associes. Il s’agissait dans 3 cas d’une IRA organique avec une proteinurie moderee entre 27 et 330 mg/mmol de creatinine, de profil tubulaire associe a une composante fonctionnelle. L’IRA etait uniquement fonctionnelle dans un cas. On notait un cas d’IRA progressive sur 4 mois, sans proteinurie. Il n’y avait pas d’hematurie ni de leucocyturie. Deux cas rapidement resolutifs n’ont pas ete explores. Aucun patient n’a eu de biopsie renale. La resolution de l’IRA sans sequelles a ete obtenue par la suspension d’ENCO/BINI dans 6 cas, associee a une hydratation par voie IV dans 4 cas. La poursuite a la meme posologie ou une reprise a dose reduite ont ete possibles pour 2 patients sans recidive de l’IRA. Cinq patients ont eu un changement de therapie ciblee sans recidive de l’IRA. Discussion Les toxicites renales sont peu decrites avec les inhibiteurs de BRAF et MEK. Nous rapportons une frequence elevee de toxicite renale sous ENCO/BINI, chez environ 60 % de nos patients, necessitant une prise en charge hospitaliere dans les 2/3 des cas, ce qui n’avait pas ete rapporte dans les etudes de phase 2 et 3 (COLOMBUS), une IRA de grade 3 ou 4 n’etant notee que dans 0,7 % des cas de la population COMBO450. Une etude retrospective sur 57 patients a en revanche revele une IRA dans 26 % des cas, dont 3 de toxicite tubulaire, sans proteinurie superieure a 0,3 g/24 h, toujours resolutive. Comparativement aux autres associations anti-BRAK/MEK, la toxicite renale semble etre plus frequente sous ENCO/BINI et vemurafenib/cobimetinib (12 a 14 %) que sous dabrafenib/trametinib (4 %). Conclusion La frequence de la toxicite renale sous ENCO/BINI apparait elevee dans notre experience en vie reelle, atteignant deux tiers des patients sur un faible effectif. Une surveillance renale etroite et un controle strict des facteurs nephrotoxiques associes paraissent importants.

Introduction Le pronostic des carcinomes epidermoides cutanes (CEC) inoperables est sombre. Le but de cette etude est d’evaluer l’efficacite et la tolerance de l’anticorps anti-EGFR panitumumab, peu utilise en France, seul ou associe a la radiotherapie dans les CEC inoperables. Materiel et methodes Il s’agissait d’une etude retrospective et monocentrique de tous les patients consecutifs ayant recus au moins 2 cures de panitumumab seul ou en association avec la radiotherapie, entre 2016 et 2019, quels que soient les traitements anterieurs recus a l’exclusion d’anti-EGFR en monotherapie. Le critere de jugement principal etait le taux de meilleure reponse globale selon RECIST 1.1. Les criteres de jugement secondaires etaient les taux de reponse et de controle a 6 semaines et 6 mois, la survie sans progression, la survie globale et la tolerance. Resultats Vingt-cinq patients d’âge median 86 ans (extremes : 48–97) etaient inclus. Dix-sept (68 %) avaient un indice OMS ≥ 2. Le taux de meilleure reponse globale etait de 52 % avec 4 reponses completes (16 %) et 9 reponses partielles (36 %). Tous les patients en reponse complete et 5 sur 9 en reponse partielle avaient recu un traitement concomitant par radiotherapie, dans la plupart des cas a des doses moderees a faibles ( Discussion Malgre ses limites liees a son caractere monocentrique et retrospectif et a un nombre limite de patients, notre etude fournit pour la premiere fois des donnees « en vie reelle » sur l’efficacite et la securite du panitumumab dans le traitement des CEC inoperables. Ces resultats suggerent que le traitement des CEC inoperables par panitumumab reste pertinent, en particulier en association avec la radiotherapie, malgre l’apport recent des anticorps anti-PD1. Il presente plusieurs avantages : il peut etre utilise chez des patients tres âges ou fragiles comme dans notre serie ; il ne provoque pas de risque anaphylaxique comme le cetuximab, ni effets secondaires potentiellement irreversibles ou menacant le pronostic vital ; des reponses a long terme ont ete observees dans notre etude. Des etudes prospectives evaluant les anti-EGFR en association avec les anticorps anti-PD1 et/ou la chimiotherapie seraient utiles.

Introduction Le brentuximab vedotin (BV) est un conjugue anticorps monoclonal anti-CD30–medicament, liberant un poison du fuseau de facon selective dans les cellules CD30+. Son utilisation dans certains lymphomes T cutanes (LTC) exprimant le CD30 est validee par l’etude de phase III ALCANZA. Nous rapportons 2 observations exceptionnelles de LTC CD30+ a grandes cellules anaplasiques (LTCGCA) monomeliques, a tres forte masse tumorale, traites avec succes par BV. Observations Cas 1 : un homme de 84 ans etait hospitalise pour d’innombrables nodules et tumeurs ulcerees d’apparition rapide sur la jambe droite. L’examen histologique montrait un infiltrat dermique massif de grandes cellules CD4+/CD30+/ALK−/CD3−/CD20−/Ki67 a 100 %. Le bilan d’extension etait negatif. Le diagnostic de LTCGCA monomelique de stade T2cN0M0 etait retenu. Devant cette cinetique et un etat pulmonaire precaire, le BV 1,8 mg/kg/21 jours etait administre en 1ere ligne, permettant une remission complete (RC) des la 4e cure. L’apparition au TEP scanner d’un ganglion iliaque moderement hypermetabolique justifiait d’une radiotherapie a ce niveau, le BV etant arrete pour des paresthesies. La reponse clinique se maintenait a 6 mois. Cas 2 : une femme de 76 ans etait traitee en 2e ligne par BV, dans le cadre de l’essai therapeutique ALCANZA, pour un LTCGCA monomelique du membre inferieur droit a tres forte masse tumorale et cinetique rapide, de stade T2cN0M0. Une RC etait obtenue apres 3 cures. Le BV etait arrete apres 12 cures en raison d’une neuropathie peripherique (NP) de grade III, regressive en 8 mois. La RC se maintenait sans traitement avec 5 ans de recul. Discussion Ces 2 observations sont exceptionnelles par : 1) Cette presentation monomelique tres extensive et agressive tres rarement decrite au cours des LTCGCA et faisant craindre une dissemination rapide. 2) La reponse spectaculaire au BV. La litterature rapporte une observation analogue, chez un patient bulgare dont le LTCGCA monomelique progressait apres radiotherapie et methotrexate. Une regression tumorale > 80 % etait obtenue apres 4 cures. La duree optimale du traitement chez les patients repondeurs au BV pour une LTCGCA n’a pas ete evaluee. La limite principale de son utilisation prolongee est l’apparition de NP chez environ deux tiers des patients, regressive apres arret dans 82 % des cas. L’absence de recidive a tres long terme dans notre second cas suggere qu’un traitement de quelques mois pourrait suffire a assurer une reponse complete et durable. Conclusion Les formes monomeliques agressives de LTCGCA peuvent simuler cliniquement un lymphome B de type jambe. Leur agressivite contraste avec le resultat remarquable du BV chez ces 3 patients, faisant discuter sa place en 1ere ligne dans ces formes rares.

The VI International Conference on Laser&Plasma researches and technologies – LaPlas-2020, Moscow, Russia, 11 Feb 2020 - 14 Feb 2020; Journal of physics / Conference series 1686, 012004 (2020). doi:10.1088/1742-6596/1686/1/012004, Proton radiography is a common diagnostic technique in laser-driven magnetic field generation studies. It is based on measuring proton beam deflection in electromagnetic fields induced around the target with the help of radiochromic film stacks. Unraveling information recorded in experimental radiographs and extracting the field profiles is not always a straightforward task. In this paper, some aspects of data analysis by reproducing experimental radiographs in numerical simulations are described. The approach allows determining the field strength and structure in the target area for various target geometries., Published by IOP Publ.39969, Bristol

Alley cropping multi-rows of shrub willow hybrids and grassland is a promising temperate agroforestry practice for an environmentally sound provision of bioenergy feedstock. The effect of willows, aged 2–3 years, on two grassland mixtures (clover-grass, diversity oriented mixture) was determined at three positions along the tree-crop interface at a study site in Central Germany. Willows modified the incident light on understory along the interface. Biennial mean daily light integral at position south-west (SW) was 22 mol m−2 w−1, in the center of the alley 30 mol m−2 w−1 and at position north-east (NE) 26 mol m−2 w−1. Accordingly, soil temperature was lower at the positions SW and NE being adjacent to the willows. There was no clear pattern of the distribution of volumetric soil moisture content along the tree-crop interface in 15 cm depth, except that moisture content was highest in 35 cm depth at SW position in both years. In the early establishment phase, the diameter at breast height (DBH) of pooled inner willow rows (17 mm) was significantly different from pooled outer rows (21 mm). Direction had a significant influence on DBH in 2012, but not in 2013. The impact of willows on productivity of the two grassland mixtures was not confirmed until the third year after establishment. Dry matter yield was on par with those reported for single-cropped grassland adjacent to the agroforestry system. Sward composition of clover-grass changed along the tree-crop interface. Dry matter contribution of legumes was lower at the position SW. No remarkable impact of trees on quality parameters of grassland mixtures were found along the interface. Horizontal and vertical growth of the trees may modify the microclimate during the life-span of the alley cropping system consisting of willows and grassland. More research is needed on long-term monitoring of competitive, complementary and facilitative effects along the tree-crop interface.

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally we investigate the extent to which AL is genetically determined. We included 803 participants (52 women mean age 48±16years) from a population and family based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular metabolic lipidic oxidative hypothalamus pituitary adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status stress alcohol intake smoking dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99 95CI [1.22;13.05]) while the opposite was observed for men (middle vs. high OR=0.48 95CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54 95CI [1.69;7.4]/OR=1.59 95CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5 ±7.9. Our results suggest that generalized physiological dysregulation as measured by AL is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component which explains approximately 70 of the phenotypic variance.