Medication adherence in patients with myotonic dystrophy and facioscapulohumeral muscular dystrophy

Myotonic dystrophy (DM) and facioscapulohumeral muscular dystrophy (FSHD) are the two most common adult muscular dystrophies and have progressive and often disabling manifestations. Higher levels of medication adherence lead to better health outcomes, especially important to patients with DM and FSHD because of their multisystem manifestations and complexity of care. However, medication adherence has not previously been studied in a large cohort of DM type 1 (DM1), DM type 2 (DM2), and FSHD patients. The purpose of our study was to survey medication adherence and disease manifestations in patients enrolled in the NIH-supported National DM and FSHD Registry. The study was completed by 110 DM1, 49 DM2, and 193 FSHD patients. Notable comorbidities were hypertension in FSHD (44 %) and DM2 (37 %), gastroesophageal reflux disease in DM1 (24 %) and DM2 (31 %) and arrhythmias (29 %) and thyroid disease (20 %) in DM1. Each group reported high levels of adherence based on regimen complexity, medication costs, health literacy, side effect profile, and their beliefs about treatment. Only dysphagia in DM1 was reported to significantly impact medication adherence. Approximately 35 % of study patients reported polypharmacy (taking 6 or more medications). Of the patients with polypharmacy, the DM1 cohort was significantly younger (mean 55.0 years) compared to DM2 (59.0 years) and FSHD (63.2 years), and had shorter disease duration (mean 26 years) compared to FSHD (26.8 years) and DM2 (34.8 years). Future research is needed to assess techniques to ease pill swallowing in DM1 and to monitor polypharmacy and potential drug interactions in DM and FSHD

The Epsilon Calculus and Herbrand Complexity

Hilbert's epsilon-calculus is based on an extension of the language of predicate logic by a term-forming operator $\epsilon_{x}$. Two fundamental results about the epsilon-calculus, the first and second epsilon theorem, play a role similar to that which the cut-elimination theorem plays in sequent calculus. In particular, Herbrand's Theorem is a consequence of the epsilon theorems. The paper investigates the epsilon theorems and the complexity of the elimination procedure underlying their proof, as well as the length of Herbrand disjunctions of existential theorems obtained by this elimination procedure.Comment: 23 p

Acoustic Analog to Quantum Mechanical Level Splitting

A simple physical system is discussed that mirrors the quantum mechanical infinite square well with a central delta well potential. The physical realization consists of a continuous sound wave traveling in a pair of tubes separated by an adjustable diaphragm. The equivalence between the quantum system and the acoustic system is explored. The analytic solution to the quantum system exhibits level splitting as does the acoustic system

On the alleged simplicity of impure proof

Roughly, a proof of a theorem, is “pure” if it draws only on what is “close” or “intrinsic” to that theorem. Mathematicians employ a variety of terms to identify pure proofs, saying that a pure proof is one that avoids what is “extrinsic,” “extraneous,” “distant,” “remote,” “alien,” or “foreign” to the problem or theorem under investigation. In the background of these attributions is the view that there is a distance measure (or a variety of such measures) between mathematical statements and proofs. Mathematicians have paid little attention to specifying such distance measures precisely because in practice certain methods of proof have seemed self- evidently impure by design: think for instance of analytic geometry and analytic number theory. By contrast, mathematicians have paid considerable attention to whether such impurities are a good thing or to be avoided, and some have claimed that they are valuable because generally impure proofs are simpler than pure proofs. This article is an investigation of this claim, formulated more precisely by proof- theoretic means. After assembling evidence from proof theory that may be thought to support this claim, we will argue that on the contrary this evidence does not support the claim

A multiscale model of virus pandemic: Heterogeneous interactive entities in a globally connected world

This paper is devoted to the multidisciplinary modelling of a pandemic initiated by an aggressive virus, specifically the so-called SARS–CoV–2 Severe Acute Respiratory Syndrome, corona virus n.2. The study is developed within a multiscale framework accounting for the interaction of different spatial scales, from the small scale of the virus itself and cells, to the large scale of individuals and further up to the collective behaviour of populations. An interdisciplinary vision is developed thanks to the contributions of epidemiologists, immunologists and economists as well as those of mathematical modellers. The first part of the contents is devoted to understanding the complex features of the system and to the design of a modelling rationale. The modelling approach is treated in the second part of the paper by showing both how the virus propagates into infected individuals, successfully and not successfully recovered, and also the spatial patterns, which are subsequently studied by kinetic and lattice models. The third part reports the contribution of research in the fields of virology, epidemiology, immune competition, and economy focussed also on social behaviours. Finally, a critical analysis is proposed looking ahead to research perspectives.publishedVersionFil: Bellomo, Nicola. Universidad de Granada. Departamento de Matemática Aplicada; España.Fil: Bingham, Richard. University of York. Departments of Mathematics and Biology. Cross-disciplinary Centre for Systems Analysis; United Kingdom.Fil: Chaplain, Mark A. J. University of St Andrews. School of Mathematics and Statistics; Scotland.Fil: Dosi, Giovanni. Scuola Superiore Sant’Anna. Institute of Economics and EMbeDS; Italia.Fil: Forni, Guido. Accademia Nazionale dei Lincei; Italia.Fil: Knopoff, Damian A. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía, Física y Computación; Argentina.Fil: Knopoff, Damian A. Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Centro de Investigacion y Estudios de Matematica; Argentina.Fil: Lowengrub, John. University California Irvine. Department of Mathematics; United States.Fil: Twarock, Reidun. University of York. Departments of Mathematics and Biology. Cross-disciplinary Centre for Systems Analysis; United Kingdom.Fil: Virgillito, Maria Enrica.Scuola Superiore Sant’Anna. Institute of Economics and EMbeDS; Italia

H0LiCOW X: Spectroscopic/imaging survey and galaxy-group identification around the strong gravitational lens system WFI2033-4723

Galaxies and galaxy groups located along the line of sight towards gravitationally lensed quasars produce high-order perturbations of the gravitational potential at the lens position. When these perturbation are too large, they can induce a systematic error on $H_0$ of a few-percent if the lens system is used for cosmological inference and the perturbers are not explicitly accounted for in the lens model. In this work, we present a detailed characterization of the environment of the lens system WFI2033-4723 ($z_{\rm src} = 1.662$, $z_{\rm lens}$ = 0.6575), one of the core targets of the H0LICOW project for which we present cosmological inferences in a companion paper (Rusu et al. 2019). We use the Gemini and ESO-Very Large telescopes to measure the spectroscopic redshifts of the brightest galaxies towards the lens, and use the ESO-MUSE integral field spectrograph to measure the velocity-dispersion of the lens ($\sigma_{\rm {los}}= 250^{+15}_{-21}$ km/s) and of several nearby galaxies. In addition, we measure photometric redshifts and stellar masses of all galaxies down to $i < 23$ mag, mainly based on Dark Energy Survey imaging (DR1). Our new catalog, complemented with literature data, more than doubles the number of known galaxy spectroscopic redshifts in the direct vicinity of the lens, expanding to 116 (64) the number of spectroscopic redshifts for galaxies separated by less than 3 arcmin (2 arcmin) from the lens. Using the flexion-shift as a measure of the amplitude of the gravitational perturbation, we identify 2 galaxy groups and 3 galaxies that require specific attention in the lens models. The ESO MUSE data enable us to measure the velocity-dispersions of three of these galaxies. These results are essential for the cosmological inference analysis presented in Rusu et al. (2019).Comment: Matches the version accepted for publication by MNRAS. Note that this paper previously appeared as H0LICOW X

Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

Background Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania). Results The registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact. Conclusions The community should consider how to maximise this collective resource in future therapeutic programmes

Repenser le management des ressources humaines et des relations de travail

Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral β-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open β-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties