Model Based Analysis and Test Generation for Flight Software

We describe a framework for model-based analysis and test case generation in the context of a heterogeneous model-based development paradigm that uses and combines Math- Works and UML 2.0 models and the associated code generation tools. This paradigm poses novel challenges to analysis and test case generation that, to the best of our knowledge, have not been addressed before. The framework is based on a common intermediate representation for different modeling formalisms and leverages and extends model checking and symbolic execution tools for model analysis and test case generation, respectively. We discuss the application of our framework to software models for a NASA flight mission

Therapeutic prospects of exon skipping for epidermolysis bullosa

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes

Preimplantation Genetic Testing for Monogenic Kidney Disease

BACKGROUND AND OBJECTIVES: A genetic cause can be identified for an increasing number of pediatric and adult-onset kidney diseases. Preimplantation genetic testing (formerly known as preimplantation genetic diagnostics) is a reproductive technology that helps prospective parents to prevent passing on (a) disease-causing mutation(s) to their offspring. Here, we provide a clinical overview of 25 years of preimplantation genetic testing for monogenic kidney disease in The Netherlands. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective cohort study of couples counseled on preimplantation genetic testing for monogenic kidney disease in the national preimplantation genetic testing expert center (Maastricht University Medical Center+) from January 1995 to June 2019. Statistical analysis was performed through chi-squared tests. RESULTS: In total, 98 couples were counseled regarding preimplantation genetic testing, of whom 53% opted for preimplantation genetic testing. The most frequent indications for referral were autosomal dominant polycystic kidney disease (38%), Alport syndrome (26%), and autosomal recessive polycystic kidney disease (9%). Of couples with at least one preimplantation genetic testing cycle with oocyte retrieval, 65% experienced one or more live births of an unaffected child. Of couples counseled, 38% declined preimplantation genetic testing for various personal and technical reasons. CONCLUSIONS: Referrals, including for adult-onset disease, have increased steadily over the past decade. Though some couples decline preimplantation genetic testing, in the couples who proceed with at least one preimplantation genetic testing cycle, almost two thirds experienced at least one live birth rate

Strategies in Rapid Genetic Diagnostics of Critically Ill Children:Experiences From a Dutch University Hospital

Background: Genetic disorders are a substantial cause of infant morbidity and mortality and are frequently suspected in neonatal intensive care units. Non-specific clinical presentation or limitations to physical examination can result in a plethora of genetic testing techniques, without clear strategies on test ordering. Here, we review our 2-years experiences of rapid genetic testing of NICU patients in order to provide such recommendations. Methods: We retrospectively included all patients admitted to the NICU who received clinical genetic consultation and genetic testing in our University hospital. We documented reasons for referral for genetic consultation, presenting phenotypes, differential diagnoses, genetic testing requested and their outcomes, as well as the consequences of each (rapid) genetic diagnostic approach. We calculated diagnostic yield and turnaround times (TATs). Results: Of 171 included infants that received genetic consultation 140 underwent genetic testing. As a result of testing as first tier, 13/14 patients received a genetic diagnosis from QF-PCR; 14/115 from SNP-array; 12/89 from NGS testing, of whom 4/46 were diagnosed with a small gene panel and 8/43 with a large OMIM-morbid based gene panel. Subsequent secondary or tertiary analysis and/or additional testing resulted in five more diagnoses. TATs ranged from 1 day (QF-PCR) to a median of 14 for NGS and SNP-array testing, with increasing TAT in particular when many consecutive tests were performed. Incidental findings were detected in 5/140 tested patients (3.6%). Conclusion: We recommend implementing a broad NGS gene panel in combination with CNV calling as the first tier of genetic testing for NICU patients given the often unspecific phenotypes of ill infants and the high yield of this large panel

Characterization of the gene encoding human sarcolipin (SLN), a proteolipid associated with SERCA1: Absence of structural mutations in five patients with brody disease

Sarcolipin (SLN) is a low-molecular-weight protein that copurifies with the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase (SERCA1). Genomic DNA and cDNA encoding human sarcolipin (SLN) were isolated and characterized and the SLN gene was mapped to chromosome 11q22-q23. Human, rabbit, and mouse cDNAs encode a protein of 31 amino acids. Homology of SLN with phospholamban (PLN) suggests that the first 7 hydrophilic amino acids are cytoplasmic, the next 19 hydrophobic amino acids form a single transmembrane helix, and the last 5 hydrophilic amino acids are lumenal. The cytoplasmic and transmembrane sequences are not well conserved among the three species, but the lumenal sequence is highly conserved. Like SERCA1, SLN is highly expressed in rabbit fast-twitch skeletal muscle, but it is expressed to a lower extent in slow-twitch muscle and to an even lower extent in cardiac muscle, where SERCA2a and PLN are highly expressed. It is expressed in only trace amounts in pancreas and prostate. SLN and PLN genes resemble each other in having two small exons, with their entire coding sequences lying in exon 2 and a large intron separating the two segments. Brody disease is an inherited disorder of skeletal muscle function, characterized by exercise-induced impairment of muscle relaxation. Mutations in the ATP2A1 gene encoding SERCA1 have been associated with the autosomal recessive inheritance of Brody disease in three families, but not with autosomal dominant inheritance of the disease. A search for mutations in the SLN gene in five Brody families, four of which were not linked to ATP2A1, did not reveal any alterations in coding, splice junction or promoter sequences. The homozygous deletion of C438 in the coding sequence of ATP2A1 in Brody disease family 3, leading to a frameshift and truncation following Pro147 in SERCA1, is the fourth ATP2A1 mutation to be associated with autosomal recessive Brody disease

Experimental study on glass and polymers: determining the optimal material for potential use in terahertz technology

The optical properties of polymers and glasses useful for terahertz applications are experimentally characterized using terahertz time-domain spectroscopy (THz-TDS). A standard system setup utilizing transmission spectroscopy is used to measure different optical properties of materials including refractive index, relative permittivity, loss tangent, absorption coefficient, and transmittance. The thermal and chemical dependencies of materials are also studied to identify the appropriate materials for given terahertz applications. The selected materials can then be utilized for applications such as in waveguides, filters, lenses, polarization preserving devices, metamaterials and metasurfaces, absorbers, and sensors in the terahertz frequency range.MD Saiful Islam, Cristiano M. B. Cordeiro, Md J. Nine, Jakeya Sultana, Alice L. S. Cruz, Alex Dinovitser … et al

Gitelman syndrome

Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia

International differences in the selection and outcome of minimally invasive and open distal pancreatectomy:A transatlantic analysis

Background: The efficacy and safety of minimally invasive distal pancreatectomy have been confirmed by randomized trials, but current patient selection and outcome of minimally invasive distal pancreatectomy in large international cohorts is unknown. This study aimed to compare the use and outcome of minimally invasive distal pancreatectomy in North America, the Netherlands, Germany, and Sweden. Methods: All patients in the 4 Global Audits on Pancreatic Surgery Group (GAPASURG) registries who underwent minimally invasive distal pancreatectomy or open distal pancreatectomy during 2014–2020 were included. Results: Overall, 20,158 distal pancreatectomies were included, of which 7,316 (36%) were minimally invasive distal pancreatectomies. Use of minimally invasive distal pancreatectomy varied from 29% to 54% among registries, of which 13% to 35% were performed robotically. Both the use of minimally invasive distal pancreatectomy and robotic surgery were the highest in the Netherlands. Patients undergoing minimally invasive distal pancreatectomy tended to have a younger age (Germany and Sweden), female sex (North America, Germany), higher body mass index (North America, the Netherlands, Germany), lower comorbidity classification (North America, Germany, Sweden), lower performance status (Germany), and lower rate of pancreatic adenocarcinoma (all). The minimally invasive distal pancreatectomy group had fewer vascular resections (all) and lower rates of severe complications and mortality (North America, Germany). In the multivariable regression analysis, country was associated with severe complications but not with 30-day mortality. Minimally invasive distal pancreatectomy was associated with a lower risk of 30-day mortality compared with open distal pancreatectomy (odds ratio 1.633, 95% CI 1.159–2.300, P = .005). Conclusions: Considerable disparities were seen in the use of minimally invasive distal pancreatectomy among 4 transatlantic registries of pancreatic surgery. Overall, minimally invasive distal pancreatectomy was associated with decreased mortality as compared with open distal pancreatectomy. Differences in patient selection among countries could imply that countries are in different stages of the learning curve.</p

An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International

Approval of the vasopressin V2 receptor antagonist tolvaptan-based on the landmark TEMPO 3:4 trial-marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use