Approximative Verfahren auf erweiterten Fork/Join-Warteschlangennetzen zur Analyse von Logistiknetzen

Die Modellierung und Analyse Diskreter Ereignisorientierter Dynamischer Systeme (DEDS) ist in der Informatik seit langer Zeit ein wichtiger Themenschwerpunkt. In diesem Kontext haben sich Warteschlangennetze insbesondere im Anwendungsgebiet Computer und Kommunikationssysteme aufgrund der Verfügbarkeit sehr zeit– und platzeffizienter analytisch–algebraischer Analyseverfahren als adäquater Modellformalismus bewährt. Die Verfügbarkeit dieser Methoden in integrierten Modellierungs– und Analysewerkzeugen einerseits und die Interpretation alternativer Anwendungsfäalle als DEDS andererseits legen den Wunsch nahe, das Warteschlangeninstrumentarium auf weitere Anwendungsgebiete anzupassen. Speziell in der Logistik kommt der optimalen Planung, Steuerung und Optimierung von Systemen und damit deren Modellierung und Analyse eine entscheidende Bedeutung zu, da der Erfolg vieler Industrieunternehmen in zunehmendem Maße von der optimalen Auslegung ihrer Logistik beeinflußt wird. Das Warteschlangeninstrumentarium läßt sich häufig zur Analyse sehr grober logistischer Prozeßketten einsetzen, es versagt jedoch für detaillierte Modelle, da die effizienten algebraischen Analyseverfahren einigen typischen Eigenschaften logistischer Systeme nicht zugänglich sind. Mit dieser Motivation liegt das Ziel der vorliegenden Dissertation darin, einen Beitrag hinsichtlich der Anpassung der effizienten Analyseverfahren für Warteschlangennetze auf Prozeßketten zu leisten. Spezielles Augenmerk wird auf den Aspekt der Synchronisation komplexer paralleler Abläufe gelegt, der essentieller Bestandteil vieler logistischer Systeme ist. Aufgrund seiner hohen Flexibilität wird zur Analyse von Prozeßketten das Dekompositionsverfahren nach Kühn/Whitt herangezogen. Diese Methode ist ein approximatives Verfahren zur stationären Analyse einer recht allgemeinen Klasse offener Warteschlangennetze. Die Idee dieses Verfahrens liegt in der Zerlegung eines Warteschlangennetzes in Teilnetze, die isoliert voneinander analysiert werden. Die Interaktion der Teilnetze untereinander wird über das Input/Output–Verhalten hergestellt. Durch die Beschreibung der Netzlast durch sog. Phasenverteilungen wird die Analyse der isolierten Stationen auf die Betrachtung sog. Quasi–Birth–and–Death Prozesse zurückgeführt, die sich anhand Matrix–geometrischer Methoden effizient analysieren lassen. Zur Berücksichtigung paralleler Abläufe wird das Dekompositionsverfahren zunächst um die Analyse eines sehr einfachen Typs sog. Fork/Join–Netze angereichert. Die isolierte Analyse einfacher Fork/Join–Netze basiert auf einem von Balsamo vorgestellten approximativen Modell (Upper-Bound Modell). Im Zentrum der Arbeit steht die Entwicklung einer neuen umgebungsabhägigen Aggregierungstechnik, die es erlaubt, die Analyse komplexer, erweiterter Fork/Join–Netze auf die Analyse einfacher Fork/Join–Netze zurückzuführen. Die Aggregate haben die Eigenschaft, daß sie komplexe Warteschlangennetze hinsichtlich der ersten beiden Momente der Durchlaufzeitverteilung exakt durch FCFS–Single-Server Stationen ersetzen. Die erarbeitete Technik zur Analyse erweiterter Fork/Join–Warteschlangennetze wird anhand zweier Beispiele aus dem Anwendungskontext Logistik und anhand einer Internet–basierten Meta–Suchmaschine erprobt. Zur Beurteilung der Approximationsgüte werden die erzielten Analyseresultate mit Simulationsergebnissen verglichen. Dabei werden fallweise sehr zufriedenstellende Approximationsgüten erreicht

Impact of daclizumab, low-dose cyclosporine, mycophenolate mofetil and steroids on renal function after kidney transplantation

Background. Early and long-term use of cyclosporine A (CsA) leads to increased risks of renal toxicity. We hypothesized that administration of daclizumab in combination with mycophenolate mofetil (MMF) allows a relevant reduction in the dose of CsA. Methods. We carried out a 3-year, prospective, randomized, controlled clinical multi-centre trial in 156 patients. The patients were randomized to standard treatment (CsA, MMF, steroids) or to high-dose daclizumab (first dose: 2 mg/kg), in combination with low-dose CsA, MMF and steroids. We maintained the mean CsA levels of daclizumab patients at 57% of standard patients (132 versus 216 ng/ml) on Day 7 post-transplant, and 84% by 6 months. Results. Primary outcome, creatinine clearance (with imputation of informative dropouts) at 12 months, was significantly better in daclizumab-treated (34 ± 17) than standard patients (29 ± 17; P = 0.028, two sided). Only 5 cases of BPAR were recorded in the daclizumab compared to 22 in the standard group (P = 0.0016). Daclizumab patients had 91% event-free survival after 1 year compared to 66% in standard patients (P = 0.00017). Conclusion. We demonstrate here that high-dose daclizumab in combination with lower CsA levels in adult renal transplant recipients is as or more effective than standard regimen (CsA, MMF, steroids) and may result in better outcomes at 12 months post-transplant with no increase in adverse reaction

Forward and backward diffraction radiation of relativistic electrons in a dielectric targets

BACKGROUND: Early and long-term use of cyclosporine A (CsA) leads to increased risks of renal toxicity. We hypothesized that administration of daclizumab in combination with mycophenolate mofetil (MMF) allows a relevant reduction in the dose of CsA. METHODS: We carried out a 3-year, prospective, randomized, controlled clinical multi-centre trial in 156 patients. The patients were randomized to standard treatment (CsA, MMF, steroids) or to high-dose daclizumab (first dose: 2 mg/kg), in combination with low-dose CsA, MMF and steroids. We maintained the mean CsA levels of daclizumab patients at 57% of standard patients (132 versus 216 ng/ml) on Day 7 post-transplant, and 84% by 6 months. RESULTS: Primary outcome, creatinine clearance (with imputation of informative dropouts) at 12 months, was significantly better in daclizumab-treated (34 +/- 17) than standard patients (29 +/- 17; P = 0.028, two sided). Only 5 cases of BPAR were recorded in the daclizumab compared to 22 in the standard group (P = 0.0016). Daclizumab patients had 91% event-free survival after 1 year compared to 66% in standard patients (P = 0.00017). CONCLUSION: We demonstrate here that high-dose daclizumab in combination with lower CsA levels in adult renal transplant recipients is as or more effective than standard regimen (CsA, MMF, steroids) and may result in better outcomes at 12 months post-transplant with no increase in adverse reactions

Onset and progression of diabetes in kidney transplant patients receiving everolimus or cyclosporine therapy: an analysis of two randomized, multicenter trials

Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes. Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497). Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes). Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes. Trial registration: clinicaltrials.gov , NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT ( 2006-007021-32 and 2004-004346-40 )

Stress hormone signalling inhibits Th1 polarization in a CD4 T-cell-intrinsic manner via mTORC1 and the circadian gene PER1

Stress hormones are believed to skew the CD4 T-cell differentiation towards a Th2 response via a T-cell-extrinsic mechanism. Using isolated primary human naïve and memory CD4 T cells, here we show that both adrenergic- and glucocorticoid-mediated stress signalling pathways play a CD4 naïve T-cell-intrinsic role in regulating the Th1/Th2 differentiation balance. Both stress hormones reduced the Th1 programme and cytokine production by inhibiting mTORC1 signalling via two parallel mechanisms. Stress hormone signalling inhibited mTORC1 in naïve CD4 T cells (1) by affecting the PI3K/AKT pathway and (2) by regulating the expression of the circadian rhythm gene, period circadian regulator 1 (PER1). Both stress hormones induced the expression of PER1, which inhibited mTORC1 signalling, thus reducing Th1 differentiation. This previously unrecognized cell-autonomous mechanism connects stress hormone signalling with CD4 T-cell differentiation via mTORC1 and a specific circadian clock gene, namely PER1

Mesocrystalline Architecture in Hyaline Foraminifer Shells Indicates a Non-Classical Crystallisation Pathway

Calcareous foraminifer shells (tests) represent one of the most important archives for paleoenvironmental and paleoclimatic reconstruction. To develop a mechanistic understanding of the relationship between environmental parameters and proxy signals, knowledge of the fundamental processes operating during foraminiferal biomineralization is essential. Here, we apply microscopic and diffraction-based methods to address the crystallographic and hierarchical structure of the test wall of different hyaline foraminifer species. Our results show that the tests are constructed from micrometer-scale oriented mesocrystals built of nanometer-scale entities. Based on these observations, we propose a mechanistic extension to the biomineralization model for hyaline foraminifers, centered on the formation and assembly of units of metastable carbonate phases to the final mesocrystal via a non-classical particle attachment process, possibly facilitated by organic matter. This implies the presence of metastable precursors such as vaterite or amorphous calcium carbonate, along with phase transitions to calcite, which is relevant for the mechanistic understanding of proxy incorporation in the hyaline foraminifers.ISSN:1525-202

Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy.

HERAKLES was a 1-year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine-based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low-exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4-year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively. Adjusted estimated GFR at year 5 was significantly higher in the CNI-free group versus standard CNI (difference 7.2 mL/min/1.73 m , P < .001) or low CNI (difference 7.6 mL/min/1.73 m , P < .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m  and 10.1 mL/min/1.73 m , respectively. Biopsy-proven acute rejection occurred during the 4-year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively (P = .927). In conclusion, conversion to a CNI-free everolimus regimen 3 months after kidney transplantation improved long-term graft function, particularly in patients who continued the CNI-free regimen. Low CNI with everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account