Local syzygies of multiplier ideals

In recent years, multiplier ideals have found many applications in local and global algebraic geometry. Because of their importance, there has been some interest in the question of which ideals on a smooth complex variety can be realized as multiplier ideals. Other than integral closure no local obstructions have been known up to now, and in dimension two it was established by Favre-Jonsson and Lipman-Watanabe that any integrally closed ideal is locally a multiplier ideal. We prove the somewhat unexpected result that multiplier ideals in fact satisfy some rather strong algebraic properties involving higher syzygies. It follows that in dimensions three and higher, multiplier ideals are very special among all integrally closed ideals.Comment: 8 page

Number of comorbidities and their impact on perioperative outcome and costs - a single centre cohort study

AIMS OF THE STUDY: Multimorbidity is a growing global health problem, resulting in an increased perioperative risk for surgical patients. Data on both the prevalence of multimorbidity and its impact on perioperative outcome are limited. The American Society of Anesthesiologists (ASA) classification uses only the single most severe systemic disease to define the ASA class and ignores multimorbidity. This study aimed to assess the number and type of all anaesthesia-relevant comorbidities and to analyse their impact on outcome and hospital costs. METHODS: This cohort study is nested in the ClassIntra(R) validation study and includes only patients enrolled at the University Hospital of Basel. Approximately 30 patients per surgical discipline undergoing any type of in-hospital surgery were followed up until hospital discharge to record all intra- and postoperative adverse events. In addition, the type and severity of all perioperatively relevant comorbidities were extracted from the electronic medical record according to a predefined list. The primary endpoint was the number of all anaesthesia-relevant comorbidities by ASA class. Using structural equation models, the direct and indirect effects of comorbidities on costs were estimated after adjustment for the ASA class and further relevant confounders and mediators. RESULTS: Of 320 enrolled patients, 27 were ASA I (8%), 150 ASA II (47%), 116 ASA III (36%) and 27 ASA IV (8%). The median number of comorbidities per patient was 5 (range 0-18), this number significantly increasing with higher ASA class: 1 comorbidity (95% CI 0.0-2.0) in ASA I, 4 comorbidities (3.8-4.2) in ASA II, 9 (8.1-9.9) in ASA III and 12 (10-14) in ASA IV patients. Independent of ASA class, each additional comorbidity increased hospital costs by EUR 1,198 (95% CI 288-2108) with almost identical proportions of direct and indirect effects. The number of anaesthesia-relevant comorbidities also increased postoperative complications and postoperative length of hospital stay. CONCLUSIONS: Multimorbidity in perioperative patients is highly prevalent and has a relevant impact on hospital costs, independent of the ASA class. Incorporating multimorbidity into the ASA classification might be warranted to improve its predictive ability and support adequate reimbursement

Section Extension from Hyperbolic Geometry of Punctured Disk and Holomorphic Family of Flat Bundles

The construction of sections of bundles with prescribed jet values plays a fundamental role in problems of algebraic and complex geometry. When the jet values are prescribed on a positive dimensional subvariety, it is handled by theorems of Ohsawa-Takegoshi type which give extension of line bundle valued square-integrable top-degree holomorphic forms from the fiber at the origin of a family of complex manifolds over the open unit 1-disk when the curvature of the metric of line bundle is semipositive. We prove here an extension result when the curvature of the line bundle is only semipositive on each fiber with negativity on the total space assumed bounded from below and the connection of the metric locally bounded, if a square-integrable extension is known to be possible over a double point at the origin. It is a Hensel-lemma-type result analogous to Artin's application of the generalized implicit function theorem to the theory of obstruction in deformation theory. The motivation is the need in the abundance conjecture to construct pluricanonical sections from flatly twisted pluricanonical sections. We also give here a new approach to the original theorem of Ohsawa-Takegoshi by using the hyperbolic geometry of the punctured open unit 1-disk to reduce the original theorem of Ohsawa-Takegoshi to a simple application of the standard method of constructing holomorphic functions by solving the d-bar equation with cut-off functions and additional blowup weight functions

Challenges for Optimizing Real-World Evidence in Alzheimer’s Disease: The ROADMAP Project

ROADMAP is a public-private advisory partnership to evaluate the usability of multiple data sources, including real-world evidence, in the decision-making process for new treatments in Alzheimer’s disease, and to advance key concepts in disease and pharmacoeconomic modeling. ROADMAP identified key disease and patient outcomes for stakeholders to make informed funding and treatment decisions, provided advice on data integration methods and standards, and developed conceptual cost-effectiveness and disease models designed in part to assess whether early treatment provides long-term benefit

E-commerce transactions in a virtual environment: Virtual transactions

E-commerce is a fundamental method of doing business, such that for a firm to say it is trading at all in the modern market-place it must have some element of on-line presence. Coupled with this is the explosion of the "population" of Massively Multiplayer On-line Role Playing Games and other shared virtual environments. Many suggest this will lead to a further dimension of commerce: virtual commerce. We discuss here the issues, current roadblocks and present state of an e-commerce transaction carried out completely within a virtual environment; a virtual transaction. Although technically such transactions are in a sense trivial, they raise many other issues in complex ways thus making V-transactions a highly interesting cross-disciplinary issue. We also discuss the social, ethical and regulatory implications for the virtual communities in these environments of such v-transactions, how their implementation affects the nature and management of a virtual environment, and how they represent a fundamental merging of the real and virtual worlds for the purpose of commerce. We highlight the minimal set of features a v-transaction capable virtual environment requires and suggest a model of how in the medium term they could be carried out via a methodology we call click-through, and that the developers of such environments will need to take on the multi-modal behavior of their users, as well as elements of the economic and political sciences in order to fully realize the commercial potential of the v-transaction. © 2012 Springer Science+Business Media, LLC

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme

Doxycycline-controlled splicing modulation by regulated antisense U7 snRNA expression cassettes

Many diseases affect pre-mRNA splicing, and alternative splicing is a major source of proteome diversity and an important mechanism for modulating gene expression. The ability to regulate a specific splicing event is therefore desirable; for example, to understand splicing-associated pathologies. We have developed methods based on modified U7 snRNAs, which allow us to induce efficient skipping or inclusion of selected exons. Here, we have adapted these U7 tools to a regulatable system that relies on a doxycycline-sensitive version of the Kruppel-associated box (KRAB)/KAP1 transcriptional silencing. Co-transduction of target cells with two lentiviral vectors, one carrying the KRAB protein and the other the regulatable U7 cassette, allows a tight regulation of the modified U7 snRNA. No leakage is observed in the repressed state, whereas full induction can be obtained with doxycycline in ng ml(-1) concentrations. Only a few days are necessary for a full switch, and the induction/repression can be repeated over several cycles without noticeable loss of control. Importantly, the U7 expression correlates with splicing correction, as shown for the skipping of an aberrant beta-globin exon created by a thalassaemic mutation and the promotion of exon 7 inclusion in the human SMN2 gene, an important therapeutic target for spinal muscular atrophy