Explicit Substitutions for Contextual Type Theory

In this paper, we present an explicit substitution calculus which distinguishes between ordinary bound variables and meta-variables. Its typing discipline is derived from contextual modal type theory. We first present a dependently typed lambda calculus with explicit substitutions for ordinary variables and explicit meta-substitutions for meta-variables. We then present a weak head normalization procedure which performs both substitutions lazily and in a single pass thereby combining substitution walks for the two different classes of variables. Finally, we describe a bidirectional type checking algorithm which uses weak head normalization and prove soundness.Comment: In Proceedings LFMTP 2010, arXiv:1009.218

Transparenz bei der Managervergütung - ist die Akzeptanz des Corporate Governance Kodex in Gefahr?

Mit der Weigerung, die Vergütung ihres Vorstandes einzeln offen zu legen, verstoßen vieler DAX-Unternehmen gegen eine Empfehlung des Deutschen Corporate Governance Kodex. Brigitte Zypries, Bundesjustizministerin, plädiert zwar für die Offenlegung der Vorstandsgehälter: "Damit Aktionäre ihr Kontrollrecht im Rahmen von Hauptversammlungen wirksam ausüben können, ist Transparenz für Anleger unverzichtbar. Dieses Kontrollrecht der Aktionäre umfasst auch die Höhe der Vorstandsbezüge. Sie müssen als "Eigentümer" einer börsennotierten Aktiengesellschaft darüber entscheiden können, ob sie das Gehalt ihrer Spitzenmanager für angemessen halten. Deshalb müssen Vorstandsgehälter individuell offen gelegt werden." Aber trotz der Weigerung vieler Unternehmen, dieser Empfehlung nachzukommen, ist für sie der Deutsche Corporate Governance Kodex als Ganzes eine "Erfolgsgeschichte". Sie geht davon aus, dass gesetzgeberisches Handeln nicht notwendig wird. Denn: "Die Kritiker der Offenlegung werden sich Entwicklungen auf EU-Ebene nicht verschließen können, die ein Zeichen dafür sind, dass international kein Weg an mehr Transparenz bei den Vorstandsbezügen vorbeiführt." Max Dietrich Kley, Präsident des Deutschen Aktieninstituts, möchte am Prinzip "Comply or Expain" festhalten, das den Unternehmen die Wahl lässt, sich für den Codex zu entscheiden oder ihn ganz oder teilweise abzulehnen. Seiner Meinung nach sollte sich an der Börse entscheiden, "ob und in welchem Grade Abweichungen oder die Ablehnung in Euro und Cent von den Marktteilnehmern gewertet" werden. Für Prof. Dr. Michael Adams, Universität Hamburg, ist vor allen Dingen die Vollständigkeit der Angabe des Wertes aus allen Vergütungsquellen für die Kontrolle der Integrität der Unternehmensleitung entscheidend. Dann könne, seiner Ansicht nach, auf die Individualisierung der Angaben verzichtet werden. Prof. Dr. Dres h.c. Marcus Lutter, Universität Bonn, unterstreicht, dass sich der Deutsche Corporate Governance Kodex bereits bewährt habCorporate Governance, Führungskräfte, Unternehmen, Gehalt, Deutschland

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020)

Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype

Although guidelines are available for hereditary hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles

Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents

BACKGROUND: In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non-Western and Western patients on dialysis. METHODS: All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included in the study. Non-Western patients were defined as children of whom one or both parents were born in non-Western countries. RESULTS: Seventy-nine of the 179 included patients (44%) were non-Western children. Compared to Western patients, non-Western patients more often were treated with hemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52 vs. 37%, p = 0.046). Before renal transplantation, non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p = 0.007). Renal osteodystrophy was diagnosed in 34% of non-Western vs. 18% of Western patients (p = 0.028). The incidence rate ratio [95% confidence interval] for acute peritonitis was 2.44 [1.43-4.17] (p = 0.032) for non-Western compared to Western patients. CONCLUSIONS: There are important disparities between children on chronic dialysis with parents from Western European origin and those from non-Western European origin in the choice of modality, duration, and outcomes of dialysis therapy

Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum

Purpose PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. Methods Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. Results Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. Conclusion This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1. yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS

Constructing the eastern european other: The horsemeat scandal and the migrant other

The Horsemeat scandal in the UK in 2013 ignited a furore about consumer deception and the bodily transgression of consuming something so alien to the British psyche. The imagination of the horse as a noble and mythic figure in British history and sociological imagination was invoked to construct the consumption of horsemeat as a social taboo and an immoral proposition in the British media debates. This paper traces the horsemeat scandal and its media framing in the UK. Much of the aversion to horsemeat was intertextually bound with discourses of immigration, the expansion of the EU and the threat in tandem to the UK. Food as a social and cultural artefact laden with symbolic meaning and national pride became a platform to construct the ‘Other’ – in this case the Eastern European Other. The media debates on the horsemeat scandal interwove the opening up of the EU and particularly UK to the influx of Eastern European migration. The horsemeat controversy in implicating the Eastern Europeans for the contamination of the supply chain became a means to not just construct the ‘Other’ but also to entwine contemporary policy debates about immigration. This temporal framing of contemporary debates enables a nation to renew and contemporise its notions of ‘otherness’ while sustaining an historic social imaginary of itself