Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment guidelines. These consensus recommendations are intended to provide guidance for the treatment and monitoring of patients with Fabry disease receiving migalastat. Methods: A modified Delphi process was conducted to determine consensus on treatment decisions and monitoring of patients with Fabry disease receiving migalastat. The multidisciplinary panel comprised 14 expert physicians across nine specialties and two patients with Fabry disease. Two rounds of Delphi surveys were completed and recommendations on the use of biomarkers, multidisciplinary monitoring, and treatment decisions were generated based on statements that reached consensus. Results: The expert panel reached consensus agreement on 49 of 54 statements, including 16 that reached consensus in round 1. Statements that reached consensus agreement are summarized in recommendations for migalastat treatment and monitoring, including baseline and follow-up assessments and frequency. All patients with Fabry disease and an amenable mutation may initiate migalastat treatment if they have evidence of Fabry-related symptoms and/or organ involvement. Treatment decisions should include holistic assessment of the patient, considering clinical symptoms and organ involvement as well as patient-reported outcomes and patient preference. The reliability of α-Gal A and globotriaosylsphingosine as pharmacodynamic response biomarkers remains unclear. Conclusion: These recommendations build on previously published guidelines to highlight the importance of holistic, multidisciplinary monitoring for patients with Fabry disease receiving migalastat, in addition to shared decision-making regarding treatments and monitoring throughout the patient journey. (Figure presented.)

Party finance reform as constitutional engineering? The effectiveness and unintended consequences of party finance reform in France and Britain

In both Britain and France, party funding was traditionally characterized by a laissez faire approach and a conspicuous lack of regulation. In France, this was tantamount to a 'legislative vacuum'. In the last two decades, however, both countries have sought to fundamentally reform their political finance regulation regimes. This prompted, in Britain, the Political Parties, Elections and Referendums Act 2000, and in France a bout of 'legislative incontinence' — profoundly transforming the political finance regime between 1988 and 1995. This article seeks to explore and compare the impacts of the reforms in each country in a bid to explain the unintended consequences of the alternative paths taken and the effectiveness of the new party finance regime in each country. It finds that constitutional engineering through party finance reform is a singularly inexact science, largely due to the imperfect nature of information, the limited predictability of cause and effect, and the constraining influence of non-party actors, such as the Constitutional Council in France, and the Electoral Commission in Britain

Morphometry of the Cranial Base in Subjects with Class III Malocclusion

The significance of the cranial base in the development of Class III malocclusion remains uncertain. The purpose of this study was to determine whether the form of the cranial base differs between prepubertal Class I and Class III subjects. Lateral cephalographs of 73 children of European-American descent aged between 5 and 11 years with Class III malocclusion were compared with those of their counterparts with a normal, Class I molar occlusion. The cephalographs were traced, checked, and subdivided into seven age- and sex-matched groups. Average geometries, scaled to an equivalent size, were generated based on 13 craniofacial landmarks by means of Procrustes analysis, and these configurations were statistically tested for equivalence. Bivariate and multivariate analyses utilizing 5 linear and angular measurements were undertaken to corroborate the Procrustes analysis. Graphical analysis, utilizing thin-plate spline and finite element methods, was performed for localization of differences in cranial base morphology. Results indicated that cranial base morphology differed statistically for all age-wise comparisons. Graphical analysis revealed that the greatest differences in morphology occurred in the posterior cranial base region, which generally consisted of horizontal compression, vertical expansion, and size contraction. The sphenoidal region displayed expansion, while the anterior regions showed shearing and local increases in size. It is concluded that the shape of the cranial base differs in subjects with Class III malocclusion compared with the normal Class I configuration, due in part to deficient orthocephalization, or failure of the cranial base to flatten during development.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67377/2/10.1177_00220345970760021101.pd

The role of glacier mice in the invertebrate colonisation of glacial surfaces: the moss balls of the Falljökull, Iceland

Glacier surfaces have a surprisingly complex ecology. Cryoconite holes contain diverse invertebrate communities while other invertebrates, such as Collembola often graze on algae and windblown dead organic on the glacier surface. Glacier mice (ovoid unattached moss balls) occur on some glaciers worldwide. Studies of these glacier mice have concentrated on their occurrence and mode of formation. There are no reports of the invertebrate communities. But, such glacier mice may provide a suitable favourable habitat and refuge for a variety of invertebrate groups to colonise the glacier surface. Here we describe the invertebrate fauna of the glacier mice (moss balls) of the Falljökull, Iceland. The glacier mice were composed of Racomitrium sp. and varied in size from 8.0 to 10.0 cm in length. All glacier mice studied contained invertebrates. Two species of Collembola were present. Pseudisotoma sensibilis (Tullberg, 1876) was numerically dominant with between 12 and 73 individuals per glacier mouse while Desoria olivacea (Tullberg, 1871) occurred but in far lower numbers. Tardigrada and Nematoda had mean densities of approximately 200 and 1,000 respectively. No Acari, Arachnida or Enchytraeidae were observed which may be related to the difficulty these groups have in colonizing the glacier mice. We suggest that glacier mice provide an unusual environmentally ameliorated microhabitat for an invertebrate community dwelling on a glacial surface. The glacier mice thereby enable an invertebrate fauna to colonise an otherwise largely inhospitable location with implications for carbon flow in the system

Together forever? Explaining exclusivity in party-firm relations

Parties and firms are the key actors of representative democracy and capitalism respectively and the dynamic of attachment between them is a central feature of any political economy. This is the first article to systematically analyse the exclusivity of party-firm relations. We consider exclusivity at a point in time and exclusivity over time. Does a firm have a relationship with only one party at a given point in time, or is it close to more than one party? Does a firm maintain a relationship with only one party over time, or does it switch between parties? Most important, how do patterns of exclusivity impact on a firm’s ability to lobby successfully? We propose a general theory, which explains patterns of party-firm relations by reference to the division of institutions and the type of party competition in a political system. A preliminary test of our theory with Polish survey data confirms our predictions, establishing a promising hypothesis for future research

Controls on gut phosphatisation : the trilobites from the Weeks Formation Lagerstätte (Cambrian; Utah)

Despite being internal organs, digestive structures are frequently preserved in Cambrian Lagerstätten. However, the reasons for their fossilisation and their biological implications remain to be thoroughly explored. This is particularly true with arthropods--typically the most diverse fossilised organisms in Cambrian ecosystems--where digestive structures represent an as-yet underexploited alternative to appendage morphology for inferences on their biology. Here we describe the phosphatised digestive structures of three trilobite species from the Cambrian Weeks Formation Lagerstätte (Utah). Their exquisite, three-dimensional preservation reveals unique details on trilobite internal anatomy, such as the position of the mouth and the absence of a differentiated crop. In addition, the presence of paired pygidial organs of an unknown function is reported for the first time. This exceptional material enables exploration of the relationships between gut phosphatisation and the biology of organisms. Indeed, soft-tissue preservation is unusual in these fossils as it is restricted to the digestive structures, which indicates that the gut played a central role in its own phosphatisation. We hypothesize that the gut provided a microenvironment where special conditions could develop and harboured a source of phosphorus. The fact that gut phosphatization has almost exclusively been observed in arthropods could be explained by their uncommon ability to store ions (including phosphorous) in their digestive tissues. However, in some specimens from the Weeks Formation, the phosphatisation extends to the entire digestive system, suggesting that trilobites might have had some biological particularities not observed in modern arthropods. We speculate that one of them might have been an increased capacity for ion storage in the gut tissues, related to the moulting of their heavily-mineralised carapace

Intonation and Compensation of Fretted String Instruments

In this paper we present mathematical and physical models to be used in the analysis of the problem of intonation of musical instruments such as guitars, mandolins and the like, i.e., we study how to improve the tuning on these instruments. This analysis begins by designing the placement of frets on the fingerboard according to mathematical rules and the assumption of an ideal string, but becomes more complicated when one includes the effects of deformation of the string and inharmonicity due to other string characteristics. As a consequence of these factors, perfect intonation of all the notes on the instrument can never be achieved, but complex compensation procedures are introduced and studied to minimize the problem. To test the validity of these compensation procedures, we have performed extensive measurements using standard monochord sonometers and other basic acoustical devices, confirming the correctness of our theoretical models. In particular, these experimental activities can be easily integrated into standard acoustics courses and labs, and can become a more advanced version of basic experiments with monochords and sonometers.Comment: Improved version, with minor changes. 25 pages, including 6 figures and 2 tables. Accepted for publication in the American Journal of Physics (AJP

Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: Findings from the Fabry Registry

Purpose: To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease. Methods: the SF-36 (R) Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/2 weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline. Results: Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease. Conclusion: Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men. Genet Med 2010:12(11):703 712.Genzyme CorporationGenzymeNatl Univ Hosp, Dept Endocrinol, DK-2100 Copenhagen, DenmarkSan Bassano Hosp, Dept Neurol, Bassano Del Grappa, ItalyUniv Padua, Dept Neurosci, Padua, ItalyUniv Wurzburg, Dept Med, Wurzburg, GermanyColumbia Univ, Dept Pediat, Div Clin Genet, Coll Phys & Surg, New York, NY 10027 USACincinnati Childrens Hosp, Div Human Genet, Cincinnati, OH USAUniversidade Federal de São Paulo, Inatos Metab CREIM, São Paulo, BrazilMassachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USAGenzyme Corp, Dept Biomed Data Sci & Informat, Cambridge, MA USAUniversidade Federal de São Paulo, Inatos Metab CREIM, São Paulo, BrazilWeb of Scienc