Off-time Treatment Options for Parkinson’s Disease

Funding Information: Margherita Fabbri declares the following conflicts of interest: honoraria to speak: BIAL and AbbVie; Consultancy/ LVL Médicale. Raquel Barbosa declares the following conflicts of interest: financial support by Fundação para a Ciência e Tecnologia (FCT) through a Ph.D. Scholarship (SFRH/BD/143797/2019) and Prémio João Lobo Antunes by Santa Casa da Misericórdia de Lisboa. Olivier Rascol declares the following conficts of interest: advisory board and consultancy: BIAL; advisory boards and consultancy: AbbVie, Adamas, Acorda, Addex, AlzProtect, Apopharma, Astrazeneca, Axovant, Biogen, Britannia, Buckwang, Cerespir, Clevexel, Denali, INC Reasearch, Lundbeck, Lupin, Merck, MundiPharma, Neuratris, Neuroderm, Novartis, ONO Pharma, Osmotica, Parexel, Pfzer, Prexton Therapeutics, Quintiles, Roche, Sanof, Servier, Sunovion, Théranexus, Takeda, Teva, UCB, Vectura, Watermark Research, XenoPort, XO, and Zambon; grant: Agence Nationale de la Recherche (ANR), CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJFox Foundation, Programme Hospitalier de Recherche Clinique, European Commission (FP7, H2020), and Cure Parkinson IK; other: grant to participate in a symposium and contribute to the review of an IPMDS article . Publisher Copyright: © 2023, The Author(s).Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor – Opicapone-, two MAO-B inhibitors plus channel blocker – Zonisamide and Safinamide and one amantadine extended-release formulation – ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients’ preference, caregiver’s availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.publishersversionepub_ahead_of_prin

Relationships between magmatism and extension along the Autun-La Serre fault system in the Variscan Belt of the eastern French Massif Central

International audienceThe ENE-WSW Autun Shear Zone in the northeastern part of the French Massif Central has been interpreted previously as a dextral wrench fault. New field observations and microstructural analyses document a NE-SW stretching lineation that indicates normal dextral motions along this shear zone. Further east, similar structures are observed along the La Serre Shear Zone. In both areas, a strain gradient from leucogranites with a weak preferred orientation to highly sheared mylonites supports a continuous Autun-La Serre fault system. Microstructural observations, and shape and lattice-preferred orientation document high-temperature deformation and magmatic fabrics in the Autun and La Serre granites, whereas low- to intermediate-temperature fabrics characterize the mylonitic granite. Electron microprobe monazite geochronology of the Autun and La Serre granites yields a ca. 320 Ma age for pluton emplacement, while mica 40Ar-39Ar datings of the Autun granite yield plateau ages from 305 to 300 Ma. The ca. 300 Ma 40Ar-39Ar ages, obtained on micas from Autun and La Serre mylonites, indicate the time of the mylonitization. The ca. 15-Ma time gap between pluton emplacement and deformation along the Autun-La Serre fault system argue against a synkinematic pluton emplacement during late orogenic to postorogenic extension of the Variscan Belt. A ductile to brittle continuum of deformation is observed along the shear zone, with Lower Permian brittle faults controlling the development of sedimentary basins. These results suggest a two-stage Late Carboniferous extension in the northeastern French Massif Central, with regional crustal melting and emplacement of the Autun and La Serre leucogranites around 320 Ma, followed, at 305-295 Ma, by ductile shearing, normal brittle faulting, and subsequent exhumation along the Autun-La Serre transtensional fault system

Are Deicing Salts Necessary to Promote Scaling in Concrete?

International audienceThe main purpose of the present study is to investigate the role of the material parameters such as permeability, thermal diffusivity, and pore size distribution on the mechanical behavior of cementitious structures submitted to frost action, such as surface scaling. An experimental device, in which a cement paste specimen is exposed to freezing-thawing cycles under a thermal gradient, has been developed. The experimental results show that under high thermal gradient (up to 1.5°C/mm), skin damage can occur without a saline layer in contact with the frozen surface. This can be explained and quantified in the framework of poromechanics. The model is based on the coupling between liquid-ice crystal thermodynamic equilibrium, liquid water transport, thermal conduction, and elastic properties of the different phases that form the saturated porous material. It eventually predicts that a less permeable sample is more susceptible to damage by surface defacement, which explains the observed experimental result

Comment on "Aptian faulting in the Haushi-Huqf (Oman) and the tectonic evolution of the southeast Arabian platform-margin" by C. Montenat, P. Barrier and H.J. Soudet

International audienceOn the basis of field observations in the Huqf area in eastern Oman, Montenat et al. (2003) defined an extensional phase of faulting of Aptian age in the Arabian platform (see also Montenat and Barrier, 2002). We recently revisited the fault exposures of the Wadi Sha'bat al Tawraq from which this conclusion has been drawn (location in Figure 1a). Our observations contradict those of Montenat et al. (2003), and consequently our conclusions are opposite from theirs. Here we review the conflicting observations and discuss the different interpretations

Feedback between erosion and active deformation: geomorphic constraints from the frontal Jura fold-and-thrust belt (eastern France)

A regional tectono-geomorphic analysis indicates a Pliocene to recent rock uplift of the outermost segment of the Jura fold-and-thrust belt, which spatially coincides with the intra-continental Rhine-Bresse Transfer Zone. Elevated remnants of the partly eroded Middle Pliocene Sundgau-Forêt de Chaux Gravels identified by heavy mineral analyses allow for a paleo-topographic reconstruction that yields minimum regional Latest Pliocene to recent rock uplift rates of 0.05±0.02mm/year. This uplift also affected the Pleistocene evolution of the Ognon and Doubs drainage basins and is interpreted as being tectonically controlled. While the Ognon River was deflected from the uplifted region the Doubs deeply incised into it. Focused incision of the Doubs possibly sustained ongoing deformation along anticlines which were initiated during the Neogene evolution of the thin-skinned Jura fold-and-thrust belt. At present, this erosion-related active deformation is taking place synchronously with thick-skinned tectonics, controlling the inversion of the Rhine-Bresse Transfer Zone. This suggests local decoupling between seismogenic basement faulting and erosion-related deformation of the Mesozoic cover sequence

Structural evolution of the Nojima fault (Awaji Island, Japan) revisited from the GSJdrill hole at Hirabayashi.

International audienceFollowing the Hyogoken Nanbu earthquake (Januray 17, 1995, Mw = 7.2), three drillholes were sunk through the Nojima Fault (Awaji Island, Japan). Textural andpetrographic studies of the Geological Survey of Japan (GSJ) drill cores allow recognition of two deformation episodes. The first one is older than the deposition of the Middle to LateEocene Kobe Group, corresponds to a left-lateral movement on the Nojima fault and is expressed by pseudotachylytes, kinking of biotite crystals in the low-strain rocks and anintense laumontite hydrothermal alteration. The second one displaces the basal unconformity of the Kobe group, corresponds to a right-lateral reverse displacement and is expressed atleast by carbonate-filled hydraulic fractures and thin gouge zones. Different important deformation mechanisms are recorded by the fault rocks, but questions relating to theattribution of deformation and alteration features to one or other deformation episodes remain unresolved

Comportement au gel-dégel d'une structure en ciment

Ce travail vise à l'étude du comportement au gel-dégel des matériaux cimentaires. Le model poromécanique développé dans cette optique permet d'étudier l'influence sur la mécanique du couplage entre le changement de phase eau/glace, les transports en milieu poreux, la conduction thermique et le comportement de chacune des phases en présence. Nous pouvons ainsi prédire une pression de pore maximale au voisinage de la surface soumise au gel-dégel pouvant induire un endommagement localisé superficiel. Par la suite, l'influence relative des différents phénomènes physiques responsables de l'endommagement au gel-dégel est étudiée, permettant d'identifier les pressions hydrauliques de Powers comme prépondérantes

Patient-perceived progression in multiple system atrophy: natural history of quality of life

Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improving patient care, and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients, and identify informative items using a four-step statistical strategy.We leveraged the data of the French MSA cohort comprising annual assessments with the MSA-QoL questionnaire for more than 500 patients over up to 11 years. The four-step strategy (1) determined the subdimensions of Hr-QoL in MSA; (2) modelled the subdimension trajectories over time, accounting for the risk of death; (3) mapped the sequence of item impairments with disease stages; and (4) identified the most informative items specific to each disease stage.Among the 536 patients included, 50% were women and they were aged on average 65.1 years old at entry. Among them, 63.1% died during the follow-up. Four dimensions were identified. In addition to the original motor, nonmotor, and emotional domains, an oropharyngeal component was highlighted. While the motor and oropharyngeal domains deteriorated rapidly, the nonmotor and emotional aspects were already slightly to moderately impaired at cohort entry and deteriorated slowly over the course of the disease. Impairments were associated with sex, diagnosis subtype, and delay since symptom onset. Except for the emotional domain, each dimension was driven by key identified items.Hr-QoL is a multidimensional concept that deteriorates progressively over the course of MSA and brings essential knowledge for improving patient care. As exemplified with MSA, the thorough description of Hr-QoL using the 4-step original analysis can provide new perspectives on neurodegenerative diseases' management to ultimately deliver better support focused on the patient's perspective