An arbitrary high-order discontinuous Galerkin method for elastic waves on unstructured meshes - II. The three-dimensional isotropic case

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Untersuchungen proteolytischer Prozesse in der Innen- und Außenmembran von Mitochondrien

Proteolytische Prozesse spielen eine wichtige Rolle während der Biogenese von Mitochondrien und bei der Qualitätskontrolle mitochondrialer Proteine. In der vorliegenden Arbeit wurde der Abbau von Proteinen in der Innen- und Außenmembran von Mitochondrien aus Saccharomyces cerevisiae untersucht. Ein erster Teil dieser Arbeit beschäftigt sich mit Mechanismen der Proteolyse in der mitochondrialen Innenmembran. Dazu wurde der Abbau einer mutanten Variante des polytopischen Membranproteins Oxa1 verfolgt. Es zeigte sich, dass die m-AAA-Protease den Abbau von Oxa1ts vermittelt, während keine Hinweise auf eine Beteiligung der i-AAAProtease erhalten wurden. In Abwesenheit der m-AAA-Protease wird Oxa1ts ebenfalls proteolytisch durch eine (oder mehrere) bislang nicht identifizierte Metallopeptidase(n) gespalten. Allerdings ist kein vollständiger Abbau von Oxa1ts durch diese Peptidase(n) zu beobachten. Vielmehr akkumulieren proteolytische Intermediate in den Mitochondrien. Nach den vorliegenden Untersuchungen kann die endoproteolytische Aktivität der Metallopeptidase(n) entweder eine Vorraussetzung für die Proteolyse durch die m-AAAProtease sein oder aber einen Bestandteil eines molekularen Ersatzsystems zum Abbau von mitochondrialen Innenmembranproteinen in Abwesenheit der m-AAAProtease darstellen. Während der Proteolyse durch AAA-Proteasen wird eine Dislokation von Membranproteinen beobachtet. Daher wurde eine mögliche Beteiligung von Translokationsporen der Innenmembran an Abbauvorgängen untersucht. Eine Rolle der TIM17/23-Translokase konnte ausgeschlossen werden. Des weiteren konnte auch für die OXA1-Pore keine essentielle Bedeutung für die Dislokation von Membranproteinen während der Proteolyse nachgewiesen werden. Eine Inaktivierung der Proteine Mba1 und Pnt1, die an Insertion von mitochondrialen Proteinen in die Innenmembran beteiligt sind, führte jedoch zu einer Beeinträchtigung von Abbauprozessen in der Innenmembran. Diese Befunde weisen auf eine Rezeptor- oder Chaperon-Funktion von Mba1 und Pnt1 während des Abbaus durch die AAA-Proteasen hin. In einem zweiten Teil der vorliegenden Arbeit wurde genetisch und biochemisch nach Komponenten gesucht, die den Abbau von Proteinen der mitochondrialen Außenmembran vermitteln. Ein Fusionsprotein, HA-DHFRWT-Tom6, das eine lösliche entfaltete Domäne in das Cytoplasma exponiert und im TOM-Komplex assembliert ist, wurde als Modellsubstrat verwendet. Während in isolierten Mitochondrien kein Abbau stattfindet, unterliegt das Protein in vivo deutlicher Proteolyse. Dieser Prozess wurde als ATP-abhängig charakterisiert. Eine Beteiligung des vakuolären Proteolyse-Systems, der i-AAA-Protease sowie des Ubiquitin- Proteasom-Abbauweges konnte unter den verwendeten experimentellen Bedingungen ausgeschlossen werden. Zur Identifizierung von Komponenten, die an der Proteolyse von Außenmembranproteinen beteiligt sind, wurde eine genetische Durchmusterung durchgeführt. Eine temperatursensitive Mutante des essentiellen Außenmembranproteins Tom40, das unter nicht-permissiven Bedingungen rasch abgebaut wird, wurde verwendet, um nach stabilisierenden Mutanten zu suchen. Die identifizierten Mutanten unterdrückten zwar den Wachstumsdefekt, führten aber zu keiner Stabilisierung von Tom40ts, weshalb keine am Abbau beteiligten Komponenten identifiziert werden konnten. Allerdings wurde durch die Isolierung eines Suppressors ein Bereich innerhalb des Proteins Tom40 beschrieben, der für die Assemblierung von Tom40 in den TOM-Komplex essentiell ist

An arbitrary high-order Discontinuous Galerkin method for elastic waves on unstructured meshes - V. Local time stepping and p-adaptivity

SUMMARY This article describes the extension of the arbitrary high-order Discontinuous Galerkin (ADER-DG) method to treat locally varying polynomial degress of the basis functions, so-called p-adaptivity, as well as locally varying time steps that may be different from one element to another. The p-adaptive version of the scheme is useful in complex 3-D models with small-scale features which have to be meshed with reasonably small elements to capture the necessary geometrical details of interest. Using a constant high polynomial degree of the basis functions in the whole computational domain can lead to an unreasonably high CPU effort since good spatial resolution at the surface may be already obtained by the fine mesh. Therefore, it can be more adequate in some cases to use a lower order method in the small elements to reduce the CPU effort without loosing much accuracy. To further increase computational efficiency, we present a new local time stepping (LTS) algorithm. For usual explicit time stepping schemes the element with the smallest time step resulting from the stability criterion of the method will dictate its time step to all the other elements of the computational domain. In contrast, by using local time stepping, each element can use its optimal time step given by the local stability condition. Our proposed LTS algorithm for ADER-DG is very general and does not need any temporal synchronization between the elements. Due to the ADER approach, accurate time interpolation is automatically provided at the element interfaces such that the computational overhead is very small and such that the method maintains the uniform high order of accuracy in space and time as in the usual ADER-DG schemes with a globally constant time step. However, the LTS ADER-DG method is computationally much more efficient for problems with strongly varying element size or material parameters since it allows to reduce the total number of element updates considerably. This holds especially for unstructured tetrahedral meshes that contain strongly degenerate elements, so-called slivers. We show numerical convergence results and CPU times for LTS ADER-DG schemes up to sixth order in space and time on irregular tetrahedral meshes containing elements of very different size and also on tetrahedral meshes containing slivers. Further validation of the algorithm is provided by results obtained for the layer over half-space (LOH.1) benchmark problem proposed by the Pacific Earthquake Engineering Research Center. Finally, we present a realistic application on earthquake modelling and ground motion prediction for the alpine valley of Grenoble

Description of a clinical decision support tool with integrated dose calculator for paediatrics

Medication errors, especially dosing errors are a leading cause of preventable harm in paediatric patients. The paediatric patient population is particularly vulnerable to dosing errors due to immaturity of metabolising organs and developmental changes. Moreover, the lack of clinical trial data or suitable drug forms, and the need for weight-based dosing, does not simplify drug dosing in paediatric or neonatal patients. Consequently, paediatric pharmacotherapy often requires unlicensed and off-label use including manipulation of adult dosage forms. In practice, this results in the need to calculate individual dosages which in turn increases the likelihood of dosing errors. In the age of digitalisation, clinical decision support (CDS) tools can support healthcare professionals in their daily work. CDS tools are currently amongst the gold standards in reducing preventable errors. In this publication, we describe the development and core functionalities of the CDS tool PEDeDose, a Class IIa medical device software certified according to the European Medical Device Regulation. The CDS tool provides a drug dosing formulary with an integrated calculator to determine individual dosages for paediatric, neonatal, and preterm patients. Even a technical interface is part of the CDS tool to facilitate integration into primary systems. This enables the support of the paediatrician directly during the prescribing process without changing the user interface. Conclusion: PEDeDose is a state-of-the-art CDS tool for individualised paediatric drug dosing that includes a certified calculator

Impact of a clinical decision support system on paediatric drug dose prescribing: a randomised within-subject simulation trial

BACKGROUND Drug dosing errors are among the most frequent causes of preventable harm in paediatrics. Due to the complexity of paediatric pharmacotherapy and the working conditions in healthcare, it is not surprising that human factor is a well-described source of error. Thus, a clinical decision support system (CDSS) that supports healthcare professionals (HCP) during the dose prescribing step provides a promising strategy for error prevention. METHODS The aim of the trial was to simulate the dose derivation step during the prescribing process. HCPs were asked to derive dosages for 18 hypothetical patient cases. We compared the CDSS PEDeDose, which provides a built-in dose calculator to the Summary of Product Characteristics (SmPC) used together with a pocket calculator in a randomised within-subject trial. We assessed the number of dose calculation errors and the time needed for calculation. Additionally, the effect of PEDeDose without using the built-in calculator but with a pocket calculator instead was assessed. RESULTS A total of 52 HCPs participated in the trial. The OR for an erroneous dosage using the CDSS as compared with the SmPC with pocket calculator was 0.08 (95% CI 0.02 to 0.36, p<0.001). Thus, the odds of an error were 12 times higher while using the SmPC. Furthermore, there was a 45% (95% CI 39% to 51%, p<0.001) time reduction when the dosage was derived using the CDSS. The exploratory analysis revealed that using only PEDeDose but without the built-in calculator did not substantially reduce errors. CONCLUSION Our results provide robust evidence that the use of the CDSS is safer and more efficient than manual dose derivation in paediatrics. Interestingly, only consulting a dosing database was not sufficient to substantially reduce errors. We are confident the CDSS PEDeDose ensures a higher safety and speeds up the prescribing process in practice

Evolution of two distinct phylogenetic lineages of the emerging human pathogen Mycobacterium ulcerans

<p>Abstract</p> <p>Background</p> <p>Comparative genomics has greatly improved our understanding of the evolution of pathogenic mycobacteria such as <it>Mycobacterium tuberculosis</it>. Here we have used data from a genome microarray analysis to explore insertion-deletion (InDel) polymorphism among a diverse strain collection of <it>Mycobacterium ulcerans</it>, the causative agent of the devastating skin disease, Buruli ulcer. Detailed analysis of large sequence polymorphisms in twelve regions of difference (RDs), comprising irreversible genetic markers, enabled us to refine the phylogenetic succession within <it>M. ulcerans</it>, to define features of a hypothetical <it>M. ulcerans </it>most recent common ancestor and to confirm its origin from <it>Mycobacterium marinum</it>.</p> <p>Results</p> <p><it> M. ulcerans </it>has evolved into five InDel haplotypes that separate into two distinct lineages: (i) the "classical" lineage including the most pathogenic genotypes – those that come from Africa, Australia and South East Asia; and (ii) an "ancestral" <it>M. ulcerans </it>lineage comprising strains from Asia (China/Japan), South America and Mexico. The ancestral lineage is genetically closer to the progenitor <it>M. marinum </it>in both RD composition and DNA sequence identity, whereas the classical lineage has undergone major genomic rearrangements.</p> <p>Conclusion</p> <p>Results of the InDel analysis are in complete accord with recent multi-locus sequence analysis and indicate that <it>M. ulcerans </it>has passed through at least two major evolutionary bottlenecks since divergence from <it>M. marinum</it>. The classical lineage shows more pronounced reductive evolution than the ancestral lineage, suggesting that there may be differences in the ecology between the two lineages. These findings improve the understanding of the adaptive evolution and virulence of <it>M. ulcerans </it>and pathogenic mycobacteria in general and will facilitate the development of new tools for improved diagnostics and molecular epidemiology.</p

Ongoing Genome Reduction in Mycobacterium ulcerans

M. ulcerans is adapting to a more stable environment

MR-guided beam gating: Residual motion, gating efficiency and dose reconstruction for stereotactic treatments of the liver and lung

PURPOSE This study aims to investigate the efficiency and the geometric as well as the dosimetric benefit of magnetic-resonance guided beam gating for stereotactic treatments in moving organs. METHOD Patients treated with MR-guided (MRIdian system) SBRT for lung (n = 10) and liver (n = 10) targets were analyzed. Breath-hold gating was performed based on lesion tracking in sagittal cine MRI images. The target offset from the geometric center of the gating window with and without gating was evaluated. A dose reconstruction workflow based on convolution of these 2D position-probability maps and the daily 3D dose distribution was used to estimate the daily delivered dose including motion. The dose to the clinical target volume (CTV) and to a 2-cm ring structure around the planning target volume were evaluated. RESULTS The applied gating protocol resulted in a mean (±standard deviation) gating efficiency of 55%±16%. Over all patients, the mean target offset (2D-root-mean-square error) was 8.3 ± 4.3 mm, which reduced to 2.4 ± 0.6 mm during gating. The dose reconstruction showed a mean deviation in CTV coverage (D95) from the static plans of -1.7%±1.8% with gating and -12.0%±8.4% if no gating would have been used. The mean dose (Dmean) in the ring structure, with respect to the static plans, showed mean deviations of -0.1%±0.3% with gating and -1.6%±1.8% without gating. CONCLUSION The MRIdian system enables gating based on the inner anatomy and the implemented dose reconstruction workflow demonstrated geometric robust delivery of the planned radiation doses

Peripheral neuropathy in patients with human immunodeficiency viral infection at a tertiary hospital in Ghana

Peripheral neuropathy (PN) is the most frequent neurological complication in people living with HIV/AIDS. Neurological damage was identified to not only be caused by the viral infection itself but also through neurotoxic antiretroviral therapy (ART). PN is associated with a variety of risk factors; however, detailed knowledge is scarce for sub-Saharan African populations, bearing among the highest HIV/AIDS infection burden.In a cross-sectional study, we assessed the prevalence of PN in 525 adult outpatients suffering from HIV/AIDS and admitted to the largest tertiary hospital in Ghana. Through a detailed questionnaire and clinical examination including neurologic assessment and laboratory blood sample testing, this study investigated associations of PN with demographic and health determinants and identified risk factors associated with sensory neuropathy.The prevalence of PN in the Ghanaian cohort was 17.7% and increased odd ratios (OR) when patients were taller (&gt; 1.57 m; OR = 3.84; 95% CI 1.38-10.66) or reached the age &gt; 34 years (p = 0.124). Respondents with longer education duration had significantly less PN (≥ 9 years of education; OR = 0.49; 95% CI 0.26-0.92). The study also identified significant association of PN to both waist and hip girth and neutrophil counts. Curiously, higher adjusted odd ratios (aOR) of PN of patients under ART treatment were observed when CD4 lymphocytes were elevated (aOR = 0.81; 95% CI 0.36-1.83 and aOR = 2.17; 95% CI 0.93-5.05, for 300 and 600 counts, respectively). For patients on ART, an increase of 10 CD4 cell count units increased their chance of developing PN by 1% (aOR = 1.01; 95% CI 1.00 to 1.03).Despite current drug application regulations, prevalence of PN is still unacceptably high in sub-Saharan African populations. Reduction in chronic morbidity through a health system with routine monitoring, early diagnosis and prompt intervention, and effective case management can improve people living with HIV/AIDS' quality of life