Once-daily saquinavir (SAQ)/ritonavir (RTV) (2000/100 mg) with abacavir/lamivudine (600/300 mg) or tenofovir/emtricitabine (245/300 mg) in naïve patients

Poster presentation: Background In the past years, once-daily (QD) dosing of antiretroviral combination therapy has become an increasingly available treatment option for HIV-1+ patients. Methods Open label study in which HIV-1+ patients treated with SAQ/RTV (1000/100 mg BID) and two NRTIs with HIV-RNA-PCR < 50 copies/ml were switched to SAQ/RTV(2000/100 mg QD) with unchanged NRTI-backbone. CD4-cells, HIV-RNA-PCR, SAQ and RTV drug-levels and metabolic parameters were compared. Summary of results 17 patients (15 male, 42 years), median CD4 456 ± 139/micro l were included so far. The median follow-up time is 4 months. The HIV-RNA-PCR remained <50 copies/ml for all patients. Fasting metabolic parameters remained unchanged. The SAQ AUC 0–12 h were significantly higher when given QD vs. BID (median 29,400 vs. 18,500 ng*h/ml; p = 0.009), whereas the Cmin, Cmax and AUC was lower for RTV when given QD vs. BID (7,400 vs. 11,700 ng*h/ml; p = 0.02). Conclusion In this ongoing study SAQ/RTV (2000/100 mg QD) was well tolerated and demonstrated higher SAQ and lower RTV drug levels as compared to the BID dosing schedule. (Table 1 and Figure 1.

Effect of population stratification analysis on false-positive rates for common and rare variants

Principal components analysis (PCA) has been successfully used to correct for population stratification in genome-wide association studies of common variants. However, rare variants also have a role in common disease etiology. Whether PCA successfully controls population stratification for rare variants has not been addressed. Thus we evaluate the effect of population stratification analysis on false-positive rates for common and rare variants at the single-nucleotide polymorphism (SNP) and gene level. We use the simulation data from Genetic Analysis Workshop 17 and compare false-positive rates with and without PCA at the SNP and gene level. We found that SNPs’ minor allele frequency (MAF) influenced the ability of PCA to effectively control false discovery. Specifically, PCA reduced false-positive rates more effectively in common SNPs (MAF > 0.05) than in rare SNPs (MAF < 0.01). Furthermore, at the gene level, although false-positive rates were reduced, power to detect true associations was also reduced using PCA. Taken together, these results suggest that sequence-level data should be interpreted with caution, because extremely rare SNPs may exhibit sporadic association that is not controlled using PCA

Pattern formation in directional solidification under shear flow. I: Linear stability analysis and basic patterns

An asymptotic interface equation for directional solidification near the absolute stabiliy limit is extended by a nonlocal term describing a shear flow parallel to the interface. In the long-wave limit considered, the flow acts destabilizing on a planar interface. Moreover, linear stability analysis suggests that the morphology diagram is modified by the flow near the onset of the Mullins-Sekerka instability. Via numerical analysis, the bifurcation structure of the system is shown to change. Besides the known hexagonal cells, structures consisting of stripes arise. Due to its symmetry-breaking properties, the flow term induces a lateral drift of the whole pattern, once the instability has become active. The drift velocity is measured numerically and described analytically in the framework of a linear analysis. At large flow strength, the linear description breaks down, which is accompanied by a transition to flow-dominated morphologies, described in a companion paper. Small and intermediate flows lead to increased order in the lattice structure of the pattern, facilitating the elimination of defects. Locally oscillating structures appear closer to the instability threshold with flow than without.Comment: 20 pages, Latex, accepted for Physical Review

Structural and functional analysis of the MutS C-terminal tetramerization domain

The Escherichia coli DNA mismatch repair (MMR) protein MutS is essential for the correction of DNA replication errors. In vitro, MutS exists in a dimer/tetramer equilibrium that is converted into a monomer/dimer equilibrium upon deletion of the C-terminal 53 amino acids. In vivo and in vitro data have shown that this C-terminal domain (CTD, residues 801–853) is critical for tetramerization and the function of MutS in MMR and anti-recombination. We report the expression, purification and analysis of the E.coli MutS-CTD. Secondary structure prediction and circular dichroism suggest that the CTD is folded, with an α-helical content of 30%. Based on sedimentation equilibrium and velocity analyses, MutS-CTD forms a tetramer of asymmetric shape. A single point mutation (D835R) abolishes tetramerization but not dimerization of both MutS-CTD and full-length MutS. Interestingly, the in vivo and in vitro MMR activity of MutS(CF/D835R) is diminished to a similar extent as a truncated MutS variant (MutS800, residues 1–800), which lacks the CTD. Moreover, the dimer-forming MutS(CF/D835R) has comparable DNA binding affinity with the tetramer-forming MutS, but is impaired in mismatch-dependent activation of MutH. Our data support the hypothesis that tetramerization of MutS is important but not essential for MutS function in MMR

Data accuracy, consistency and completeness of the national Swiss cystic fibrosis patient registry: Lessons from an ECFSPR data quality project.

BACKGROUND Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research. METHODS All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed. RESULTS The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with 5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved. CONCLUSIONS Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research

Heme Oxygenase-1 Accelerates Cutaneous Wound Healing in Mice

Heme oxygenase-1 (HO-1), a cytoprotective, pro-angiogenic and anti-inflammatory enzyme, is strongly induced in injured tissues. Our aim was to clarify its role in cutaneous wound healing. In wild type mice, maximal expression of HO-1 in the skin was observed on the 2nd and 3rd days after wounding. Inhibition of HO-1 by tin protoporphyrin-IX resulted in retardation of wound closure. Healing was also delayed in HO-1 deficient mice, where lack of HO-1 could lead to complete suppression of reepithelialization and to formation of extensive skin lesions, accompanied by impaired neovascularization. Experiments performed in transgenic mice bearing HO-1 under control of keratin 14 promoter showed that increased level of HO-1 in keratinocytes is enough to improve the neovascularization and hasten the closure of wounds. Importantly, induction of HO-1 in wounded skin was relatively weak and delayed in diabetic (db/db) mice, in which also angiogenesis and wound closure were impaired. In such animals local delivery of HO-1 transgene using adenoviral vectors accelerated the wound healing and increased the vascularization. In summary, induction of HO-1 is necessary for efficient wound closure and neovascularization. Impaired wound healing in diabetic mice may be associated with delayed HO-1 upregulation and can be improved by HO-1 gene transfer

Mobility in a Globalised World

The term mobility has different meanings in the following academic disciplines. In economics, mobility is the ability of an individual or a group to improve their economic status in relation to income and wealth within their lifetime or between generations. In information systems and computer science, mobility is used for the concept of mobile computing, in which a computer is transported by a person during normal use. Logistics creates, by the design of logistics networks, the infrastructure for the mobility of people and goods. Electric mobility is one of today’s solutions from engineering perspective to reduce the need of energy resources and environmental impact. Moreover, for urban planning, mobility is the crunch question about how to optimize the different needs for mobility and how to link different transportation systems. The conference “Mobility in a Globalised World” took place in Iserlohn, Germany, on September 14th – 15th, 2011. The aim of this conference was to provide an interdisciplinary forum for the exchange of ideas among practitioners, researchers, and government officials regarding the different modes of mobility in a globalised world, focusing on both domestic and international issues. The proceedings at hand document the results of the presentations and ensuing discussions at the conference

Mobility in a Globalised World 2012

The term mobility has different meanings in the following science disciplines. In economics, mobility is the ability of an individual or a group to improve their economic status in relation to income and wealth within their lifetime or between generations. In information systems and computer science, mobility is used for the concept of mobile computing, in which a computer is transported by a person during normal use. By designing logistics networks, logistics creates the infrastructure for the mobility of people and goods. Electric mobility is one of today’s solutions from an engineering perspective to the problem of reducing the need for energy resources and environmental impact. Finally, for urban planning, mobility is the crunch question as to how to optimise the different needs for mobility and how to link different transportation systems. In this publication we have collected the ideas of practitioners, researchers, and government officials about the different modes of mobility in a globalised world, focusing on both domestic and international issues

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR