Rarely selected distractors in high stakes medical multiple-choice examinations and their recognition by item authors: A simulation and survey

Background Many medical exams use 5 options for multiple choice questions (MCQs), although the literature suggests that 3 options are optimal. Previous studies on this topic have often been based on non-medical examinations, so we sought to analyse rarely selected, 'non-functional' distractors (NF-D) in high stakes medical examinations, and their detection by item authors as well as psychometric changes resulting from a reduction in the number of options. Methods Based on Swiss Federal MCQ examinations from 2005-2007, the frequency of NF-D (selected by <1% or <5% of the candidates) was calculated. Distractors that were chosen the least or second least were identified and candidates who chose them were allocated to the remaining options using two extreme assumptions about their hypothetical behaviour: In case rarely selected distractors were eliminated, candidates could randomly choose another option - or purposively choose the correct answer, from which they had originally been distracted. In a second step, 37 experts were asked to mark the least plausible options. The consequences of a reduction from 4 to 3 or 2 distractors - based on item statistics or on the experts' ratings - with respect to difficulty, discrimination and reliability were modelled. Results About 70% of the 5-option-items had at least 1 NF-D selected by <1% of the candidates (97% for NF-Ds selected by <5%). Only a reduction to 2 distractors and assuming that candidates would switch to the correct answer in the absence of a 'non-functional' distractor led to relevant differences in reliability and difficulty (and to a lesser degree discrimination). The experts' ratings resulted in slightly greater changes compared to the statistical approach. Conclusions Based on item statistics and/or an expert panel's recommendation, the choice of a varying number of 3-4 (or partly 2) plausible distractors could be performed without marked deteriorations in psychometric characteristics.

Finite element analysis of aortic root dilation: a new procedure to reproduce pathology based on experimental data

Sinotubular junction dilation is one of the most frequent pathologies associated with aortic root incompetence. Hence, we create a finite element model considering the whole root geometry; then, starting from healthy valve models and referring to measures of pathological valves reported in the literature, we reproduce the pathology of the aortic root by imposing appropriate boundary conditions. After evaluating the virtual pathological process, we are able to correlate dimensions of non-functional valves with dimensions of competent valves. Such a relation could be helpful in recreating a competent aortic root and, in particular, it could provide useful information in advance in aortic valve sparing surgery.

Phenotype-genotype correlation in eight Polish patients with inherited Factor XIII deficiency: identification of three novel mutations

Inherited factor XIII (FXIII) deficiency is known as one of the most rare blood coagulation disorder in humans. In the present study, phenotype and genotype of eight FXIII deficient Polish patients from five unrelated families were compared. The patients presented with a severe phenotype demonstrated by a high incidence of intracerebral haemorrhages (seven of eight patients), haemarthrosis (six patients) and bleeding due to trauma (five patients). Introduction of regular substitution with FXIII concentrate prevented spontaneous bleeding in seven patients. In all patients, mutations within the F13A gene have been identified revealing four missense mutations (Arg77Cys, Arg260Cys, Ala378Pro, Gly420Ser), one nonsense mutation (Arg661X), one splice site mutation (IVS5-1 G>A) and one small deletion (c.499-512del). One homozygous large deletion involving exon 15 was detected by failure of PCR product. The corresponding mutations resulted in severely reduced FXIII activity and FXIII A-subunit antigen concentration, while FXIII B-subunit antigen remained normal or mildly decreased. Structural analysis demonstrated that the novel Ala378Pro mutation may cause a disruption of the FXIII catalytic triad leading to a non-functional protein which presumably undergoes premature degradation. In conclusion, the severe phenotype with high incidence of intracranial bleeding and haemarthrosis was in accordance with laboratory findings on FXIII and with severe molecular defects of the F13A gene.

Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas

BACKGROUND: The aim was to assess the clinical relevance of the World Health Organization and tumour node metastasis (TNM) classifications in patients with pancreatic neuroendocrine tumours (pNETs). METHODS: Prospectively collected data from 118 consecutive patients with a pNET receiving surgical intervention were analysed. RESULTS: Forty-one patients had well differentiated neuroendocrine tumours, 64 had well differentiated neuroendocrine carcinomas and 13 had poorly differentiated neuroendocrine carcinomas. Five-year survival rates were 95, 44 and 0 per cent respectively (P < 0.001). There was no difference in survival after R0 and R1/R2 resections in patients with neuroendocrine carcinomas (P = 0.905). In those with well differentiated neuroendocrine carcinomas, any resection and having a clinically non-functional tumour significantly increased survival (P = 0.003 and P = 0.037 respectively). The TNM stage was I in 37 patients, II in 15 patients, III in 32 patients and IV in 34 patients. There were significant differences in 5-year survival between stage I and II (88 and 85 per cent respectively) and stage III and IV (31 and 42 per cent respectively) (P = 0.010). CONCLUSION: Both classifications accurately reflect the clinical outcome of patients with pNET. The resection status may not be critical for long-term survival in patients with pNET.

Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2

Sustained growth of solid tumours can rely on both the formation of new and the co-option of existing blood vessels. Current models suggest that binding of angiopoietin-2 (Ang-2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes. Despite the intense research to decipher the role of angiopoietins during physiological neovascularization and tumour angiogenesis, a mechanistic understanding of angiopoietin function on vascular integrity and remodelling is still incomplete. We therefore assessed the vascular morphology of two mouse mammary carcinoma xenotransplants (M6378 and M6363) which differ in their natural angiopoietin expression. M6378 displayed Ang-1 in tumour cells but no Ang-2 in tumour endothelial cells in vivo. In contrast, M6363 tumours expressed Ang-2 in the tumour vasculature, whereas no Ang-1 expression was present in tumour cells. We stably transfected M6378 mouse mammary carcinoma cells with human Ang-1 or Ang-2 and investigated the consequences on the host vasculature, including ultrastructural morphology. Interestingly, M6378/Ang-2 and M6363 tumours displayed a similar vascular morphology, with intratumoural haemorrhage and non-functional and abnormal blood vessels. Pericyte loss was prominent in these tumours and was accompanied by increased endothelial cell apoptosis. Thus, overexpression of Ang-2 converted the vascular phenotype of M6378 tumours into a phenotype similar to M6363 tumours. Our results support the hypothesis that Ang-1/Tie2 signalling is essential for vessel stabilization and endothelial cell/pericyte interaction, and suggest that Ang-2 is able to induce a switch of vascular phenotypes within tumours.

CompAS: A new approach to commonality and variability analysis with applications in computer assisted orthopaedic surgery

In rapidly evolving domains such as Computer Assisted Orthopaedic Surgery (CAOS) emphasis is often put first on innovation and new functionality, rather than in developing the common infrastructure needed to support integration and reuse of these innovations. In fact, developing such an infrastructure is often considered to be a high-risk venture given the volatility of such a domain. We present CompAS, a method that exploits the very evolution of innovations in the domain to carry out the necessary quantitative and qualitative commonality and variability analysis, especially in the case of scarce system documentation. We show how our technique applies to the CAOS domain by using conference proceedings as a key source of information about the evolution of features in CAOS systems over a period of several years. We detect and classify evolution patterns to determine functional commonality and variability. We also identify non-functional requirements to help capture domain variability. We have validated our approach by evaluating the degree to which representative test systems can be covered by the common and variable features produced by our analysis.

A conceptual model of compensation/decompensation in lumbar segmental instability

Lumbar spinal instability (LSI) is a common spinal disorder and can be associated with substantial disability. The concept of defining clinically relevant classifications of disease or 'target condition' is used in diagnostic research. Applying this concept to LSI we hypothesize that a set of clinical and radiological criteria can be developed to identify patients with this target condition who are at high risk of 'irreversible' decompensated LSI for whom surgery becomes the treatment of choice. In LSI, structural deterioration of the lumbar disc initiates a degenerative cascade of segmental instability. Over time, radiographic signs become visible: traction spurs, facet joint degeneration, misalignment, stenosis, olisthesis and de novo scoliosis. Ligaments, joint capsules, local and distant musculature are the functional elements of the lumbar motion segment. Influenced by non-functional factors, these functional elements allow a compensation of degeneration of the motion segment. Compensation may happen on each step of the degenerative cascade but cannot reverse it. However, compensation of LSI may lead to an alleviation or resolution of clinical symptoms. In return, the target condition of decompensation of LSI may cause the new occurrence of symptoms and pain. Functional compensation and decompensation are subject to numerous factors that can change which makes estimation of an individual's long-term prognosis difficult. Compensation and decompensation may influence radiographic signs of degeneration, e.g. the degree of misalignment and segmental angulation caused by LSI is influenced by the tonus of the local musculature. This conceptual model of compensation/decompensation may help solve the debate on functional and psychosocial factors that influence low back pain and to establish a new definition of non-specific low back pain. Individual differences of identical structural disorders could be explained by compensated or decompensated LSI leading to changes in clinical symptoms and pain. Future spine surgery will have to carefully define and measure functional aspects of LSI, e.g. to identify a point of no return where multidisciplinary interventions do not allow a re-compensation and surgery becomes the treatment of choice.

How Do Software Architects Specify and Validate Quality Requirements?

Software architecture is the result of a design effort aimed at ensuring a certain set of quality attributes. As we show, quality requirements are commonly specified in practice but are rarely validated using automated techniques. In this paper we analyze and classify commonly specified quality requirements after interviewing professionals and running a survey. We report on tools used to validate those requirements and comment on the obstacles encountered by practitioners when performing such activity (e.g., insufficient tool-support; poor understanding of users needs). Finally we discuss opportunities for increasing the adoption of automated tools based on the information we collected during our study (e.g., using a business-readable notation for expressing quality requirements; increasing awareness by monitoring non-functional aspects of a system).

Dicto: A Unified DSL for Testing Architectural Rules

Software architecture consists of a set of design choices that can be partially expressed in form of rules that the implementation must conform to. Architectural rules are intended to ensure properties that fulfill fundamental non-functional requirements. Verifying architectural rules is often a non- trivial activity: available tools are often not very usable and support only a narrow subset of the rules that are commonly specified by practitioners. In this paper we present a new highly-readable declarative language for specifying architectural rules. With our approach, users can specify a wide variety of rules using a single uniform notation. Rules can get tested by third-party tools by conforming to pre-defined specification templates. Practitioners can take advantage of the capabilities of a growing number of testing tools without dealing with them directly.

Delegation Proxies: The Power of Propagation

Scoping behavioral variations to dynamic extents is useful to support non-functional requirements that otherwise result in cross-cutting code. Unfortunately, such variations are difficult to achieve with traditional reflection or aspects. We show that with a modification of dynamic proxies, called delegation proxies, it becomes possible to reflectively implement variations that propagate to all objects accessed in the dynamic extent of a message send. We demonstrate our approach with examples of variations scoped to dynamic extents that help simplify code related to safety, reliability, and monitoring.

Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation

BACKGROUND Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high inter-individual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients. METHODS Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped and clinical data were retrieved from patient charts. RESULTS While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (P = 0.031). ERL dose requirement was 0.02 mg/kg/day higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (P = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 ml/min/1.73m(2) ) in patients with baseline kidney dysfunction. CONCLUSION ERL pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability. This article is protected by copyright. All rights reserved.

Towards a new balance of trade in agriculture

Trade in agriculture is linked to a whole range of economic, environmental, societal and future interests. For this reason, international regulation of trade in agricultural goods is highly contentious. While mainly directed towards an opening of markets, the WTO Agreement on Agriculture also has some entry points for ‘non trade concerns’. However, the agreement still looks like a casual patchwork that allows rather unsystematic ally for exemptions, without explicitly exposing the grounds that allow for them. The question arises of how the agreement could be drafted in a more structured way, in order to make sure that the economic objectives are efficiently pursued, and at the same time that human rights and environmental concerns are adequately taken account of? The concept of sustainable development provides for a methodical ‘seven step’ framework that gives guidance on integrated decision making processes. In this paper, this framework is partially applied to the Agreement on Agriculture. This working paper served as an introductory note to a brainstorming workshop on the subject that took place on 27 March 2009 at the World Trade Institute, University of Bern.

Assembly, nuclear import and function of U7 snRNPs studied by microinjection of synthetic U7 RNA into Xenopus oocytes.

In Xenopus oocytes in vitro transcribed mouse U7 RNA is assembled into small nuclear ribonucleoproteins (snRNPs) that are functional in histone RNA 3' processing. If the special Sm binding site of U7 (AAUUUGUCUAG, U7 Sm WT) is converted into the canonical Sm sequence derived from the major snRNAs (AAUUUUUGGAG, U7 Sm OPT) the RNA assembles into a particle which accumulates more efficiently in the nucleus, but which is non-functional. U7 RNA with a heavily mutated Sm binding site (AACGCGUCAUG, U7 Sm MUT) is deficient in nuclear accumulation and function. By UV cross-linking U7 Sm WT RNA can be linked to three proteins, i.e. the common snRNP proteins G and B/B' and an apparently U7-specific protein of 40 kDa. As a result of altering the Sm binding site, U7 Sm OPT RNA cannot be cross-linked to the 40 kDa protein and no cross-links are obtained with U7 Sm MUT RNA. The fact that the Sm site also interacts with at least one U7-specific protein is so far unique to U7 RNA and may provide an explanation for the atypical sequence of this site. All described RNA-protein interactions, including that with the 40 kDa protein, already occur in the cytoplasm. An additional cytoplasmic photoadduct obtained with U7 Sm WT and U7 Sm OPT, but not U7 Sm MUT, RNAs is indicative of a protein of 60-80 kDa. The m7G cap structure of U7 Sm WT and U7 Sm OPT RNA becomes hypermethylated. However, the 3mG cap enhances, but is not required for, nuclear accumulation. Finally, U7 Sm WT RNA is functional in histone RNA processing even when bearing an ApppG cap.

The low abundance of U7 snRNA is partly determined by its Sm binding site.

In transient expression studies after DNA transfection of HeLa cells, the mouse U7 gene produces only approximately 30% of the RNA produced by a mouse U1b gene. This difference persists even when the transfected genes have all their 5' and 3' flanking sequences exchanged suggesting a post-transcriptional effect. When the special U7 Sm binding site is mutated to a consensus derived from the major snRNAs (Sm-opt), the U7 RNA level increases 4- to 5-fold, whereas no RNA is detected from a U7 gene with a non-functional Sm binding site (Sm-mut). Moreover, U1b genes with the U7 Sm binding site yield reduced RNA levels. The Sm-opt site also alters the cellular behaviour of the corresponding U7 snRNA. It accumulates to a higher level in the nucleus than wild type U7 RNA, and is better immunoprecipitable with anti-Sm antibodies. Injection experiments in Xenopus oocytes indicate that the U7 genes with either Sm-opt or Sm-mut sites produce similar amounts of RNA as wild type U7, but that they differ in opposing ways in the processing of precursors to mature size U7 snRNA and in nuclear accumulation. However, in reconstitution experiments using Xenopus oocytes, we show that U7 Sm-opt RNA, despite its efficient nuclear accumulation, is not active in 3' processing of histone pre-mRNA, whereas wild type U7 RNA is assembled into functional snRNPs, which correctly process histone pre-mRNA substrate. This suggests a functional importance of the special U7 Sm sequence.

Analysis of Lim1 LIM domains in mouse development

Transcriptional regulation is fundamental for the precise development of all organisms. Through tight regulation, necessary genes are activated at proper spatial and temporal patterns, while unnecessary genes are repressed. A large family of regulator proteins that have been demonstrated to be involved in various developmental processes by activation and repression of target genes is the homeodomain family of proteins. To date, the function of many of these homeoproteins has been elucidated in diverse species. However, the molecular mechanism underlying the function of these proteins has not been fully understood. In this study, the molecular mechanism of the function of a LIM-homeoprotein, Lim1, was examined. In addition to the homeodomain, Lim1 contains two LIM domains that are highly conserved among species. This high conservation along with data from in vitro studies on Xenopus Lim1 suggests that the LIM domains might be important for the function of Lim1 as a transcriptional regulator. Here, the functional importance of the LIM domains of Lim1 was determined by using a novel gene-targeting strategy in mouse embryonic stem (ES) cells. A cre-loxP system was used in conjunction with the unique genomic organization of Lim1 to obtain four types of mutant ES cell lines that would allow for the in vivo analysis of the function of both the LIM domains of Lim1 together and also singularly. These four mutant Lim1 alleles either contained base-pair changes at the LIM encoding exons that alters zinc-binding amino acids of the LIM domains or contained only exogenous loxP sequences in the first intron of Lim1, which serves as the control allele. These mutations in the LIM domains would presumably abolish the zinc-finger tertiary structure of the domain and thus render the domain non-functional. Mice carrying mutations at both the LIM domains of Lim1, L1L2, die around E10 without anterior head structures anterior to rhombomere 3, identical in phenotype to the Lim1 null mutants in spite of the presence of mutant Lim1 RNA. This result demonstrates that the integrity of both the LIM domains are essential for the function of Lim1. This is further supported by the phenotype of mice carrying mutation at only the second LIM domain of Lim1, L2. The L2 mice although still carrying one intact Lim1 LIM domain, also die in utero. The L2 mice die at varying times, from around E8 to E10 with anterior defects in addition to other axial defects which have yet to be fully characterized. The results of this study so far demonstrates that the integrity of both LIM domains are required for the function of Lim1. ^