Relationship of Genotype, Phenotype, and Treatment in Dopa-Responsive Dystonia: MDSGene Review

Background Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa-responsive dystonia (DRD). Diagnosis and treatment are often delayed due to high between- and within-group variability. Objectives Comprehensively analyzed individual genotype, phenotype, treatment response, and biochemistry information. Methods 734 DRD patients and 151 asymptomatic GCH1 mutation carriers were included using an MDSGene systematic literature review and an automated classification approach to distinguish between different forms of monogenic DRDs. Results Whereas dystonia, L-Dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags, parkinsonism without dystonia was rarely reported (11%) and combined with dystonia in only 18% of patients. While sex was equally distributed in autosomal recessive DRD, there was female predominance in autosomal dominant DYT/PARK-GCH1 patients accompanied by a lower median age at onset and more dystonia in females compared to males. Accordingly, the majority of asymptomatic heterozygous GCH1 mutation carriers (>8 years of age) were males. Multiple other subgroup-specific characteristics were identified, showing high accuracy in the automated classification approach: Seizures and microcephaly were mostly seen in DYT/PARK-PTS, autonomic symptoms appeared commonly in DYT/PARK-TH and DYT/PARK-PTS, and sleep disorders and oculogyric crises in DYT/PARK-SPR. Biochemically, homovanillic acid and 5-hydroxyindoleacetic acid in CSF were reduced in most DRDs, but neopterin and biopterin were increased only in DYT/PARK-PTS and DYT/PARK-SPR. Hyperphenylalaninemia was seen in DYT/PARK-PTS, DYT/PARK-QDPR, and rarely reported in autosomal recessive DYT/PARK-GCH1. Conclusions Our indicators will help to specify diagnosis and accelerate start of treatment. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Incremental Reconfiguration of Product Specific Use Case Models for Evolving Configuration Decisions

[Context and motivation] Product Line Engineering (PLE) is increasingly common practice in industry to develop complex systems for multiple customers with varying needs. In many business contexts, use cases are central development artifacts for requirements engineering and system testing. In such contexts, use case configurators can play a significant role to capture variable and common requirements in Product Line (PL) use case models and to generate Product Specific (PS) use case models for each new customer in a product family. [Question/Problem] Although considerable research has been devoted to use case configurators, little attention has been paid to supporting the incremental reconfiguration of use case models with evolving configuration decisions. [Principal ideas/results] We propose, apply, and assess an incremental reconfiguration approach to support evolving configuration decisions in PL use case models. PS use case models are incrementally reconfigured by focusing only on the changed decisions and their side effects. In our prior work, we proposed and applied Product line Use case modeling Method (PUM) to support variability modeling in PL use case diagrams and specifications. We also developed a use case configurator, PUMConf, which interactively collects configuration decisions from analysts to generate PS use case models from PL models. Our approach is built on top of PUM and PUMConf. [Contributions] We provide fully automated tool support for incremental configuration as an extension of PUMConf. Our approach has been evaluated in an industrial case study in the automotive domain, which provided evidence it is practical and beneficial

Septorhinoplasty and Septoplasty: Outcomes of a Large Cohort Using Autologous Versus Homologous Cartilage, 1999-2019

This study describes the complication rate and use of autologous and/or homologous cartilage in a large 20-year cohort of septo(rhino)plasty surgeries in a Dutch hospital, in relation to postoperative complications of septo(rhino)plasty surgery described in previous studies. A retrospective medical chart review was conducted. 2606 patients, mean age 34.7 (+/- 13.2) and 59.9% male, underwent primary or revision septo(rhino)plasty surgery from 01/01/1999 to 01/09/2019. Follow-up was known in 1384 of 2606 patients (53.1%) with a mean duration of 47.5 months. Complication registration was complete for 1774 patients. The overall complication rate was 270 out of 1774 (15.2%). The use of autologous costal cartilage (ACC) was a risk factor for overall complication with an odds ratio (OR) of 11.1 (95% CI 0.03-0.30;P < 0.01) as compared to 5.9 (95% CI 0.06-0.45;P < 0.01) when using homologous costal cartilage (HCC). Infections were more likely when ACC (5/26 [19.2%]) was used than when HCC (1/28 [3.6%]) was used. Notable resorption of cartilage was more likely when HCC (9/28 [32.1%]) was used than when ACC (1/26 [3.8%]) was used. Both the use of autologous costal cartilage grafts (OR 11.1) and homologous costal cartilage grafts (OR 5.9) lead to an increased risk of complications. When choosing cartilage type for reconstruction in septo(rhino)plasty, it should be taken into account that both ACC and HCC are associated with a higher risk of complications.Development and application of statistical models for medical scientific researc

Software product line engineering with the UML: Deriving products

Software product line engineering introduces two new dimensions into the traditional engineering of software-based systems: the variability modeling and the product derivation. The variability gathers characteristics that differ from one product to another, while the product derivation is defined as a complete process of building products from the product line. Software Product Line Engineering with the UML has received a lot of attention in recent years. However most of these works only concern variability modeling in UML static models and few works concern behavioral models. In addition, there is very little research on product derivation. This chapter investigates the product derivation in the context of the product line engineering with the UML. First, a set of extensions are proposed to model product line variability in two types of UML models: class diagrams (the static aspect) and sequence diagrams (the behavioral aspect). Then we formalize product derivation using a UML model transformation. An algorithm is given to derive a static model for a product and an algebraic approach is proposed to derive product specific statecharts from the sequence diagrams of the product line. Two simple case studies are presented, based on a Mercure product line and the banking product line, to illustrate the overall process, from the modeling of the produc

From conceptual modeling to requirements engineering

International audienc

Model-Driven Enterprise Systems Configuration

Enterprise Systems potentially lead to significant efficiency gains but require a well-conducted configuration process. A promising idea to manage and simplify the configuration process is based on the premise of using reference models for this task. Our paper continues along this idea and delivers a two-fold contribution: first, we present a generic process for the task of model-driven Enterprise Systems configuration including the steps of (a) Specification of configurable reference models, (b) Configuration of configurable reference models, (c) Transformation of configured reference models to regular build time models, (d) Deployment of the generated build time models, (e) Controlling of implementation models to provide input to the configuration, and (f) Consolidation of implementation models to provide input to reference model specification. We discuss inputs and outputs as well as the involvement of different roles and validation mechanisms. Second, we present an instantiation case of this generic process for Enterprise Systems configuration base

A Model-Checking Tool for Families of Services

International audienceWe propose a model-checking tool for on-the-fly verification of properties expressed in a branching-time temporal logic based on a deontic interpretation of classical modal and temporal operators over modal transition systems. We apply this tool to the analysis of variability in behavioural descriptions of families of services

Challenges and industry practices for managing software variability in small and medium sized enterprises

Software variability is an ability to change (configure, customize, extend) software artefacts (e.g. code, product, domain requirements, models, design, documentation, test cases) for a specific context. Optimized variability management can lead a software company to 1) shorter development lead time, 2) improved customer and improved user satisfaction, 3) reduced complexity of product management (more variability, same $) and 4) reduced costs (same variability, less$). However, it is not easy for software companies, especially small and medium size of enterprises to deal with variability. In this paper we present variability challenges and used practices collected from five SMEs. Our study indicates that increased product complexity can lead growing SMEs to the time-consuming decision-making. Many of the analyzed medium size of companies also expect improved tool support to help them to boost their productivity when managing increasingly complex products and increasing amount of variants In fact, in many of the analysed SMEs, a high level of automation in design, release management and testing are or become a key factor for market success By introducing the challenges and used practices related to variability the paper deepens understanding of this highly relevant but relatively under-researched phenomenon and contributes to the literature on software product line engineering