Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Pegfilgrastim to accelerate neutrophil engraftment following peripheral blood stem cell transplant and reduce the duration of neutropenia, hospitalization, and use of intravenous antibiotics: a phase II study in multiple myeloma and lymphoma and comparison with filgrastim-treated matched controls.

This trial was aimed to explore the efficacy of pegfilgrastim to accelerate neutrophil engraftment after stem cell autotransplant. Twenty patients with multiple myeloma and 20 with lymphoma received pegfilgrastim 6 mg on day +1. Forty cases treated with daily filgrastim starting at median day +7 (5-7), matched by age, sex, diagnosis, high-dose chemotherapy schedule, CD34 +  cell-dose, and prior therapy lines, were used for comparison. Median time to neutrophil engraftment was 9.5 vs. 11 days for pegfilgrastim and filgrastim, respectively (p < 0.0001). Likewise, duration of neutropenia, intravenous antibiotic use, and hospitalization favored pegfilgrastim, while platelet engraftment, transfusion requirement, and fever duration were equivalent in both groups. No grade  ≥ 3 toxicities were observed. Patients with lymphoma performed similarly to the entire cohort, while patients with myeloma showed faster neutrophil engraftment and shorter neutropenia but not shorter hospitalization and antibiotic use. The possibility of different outcomes for lymphoma and myeloma suggests that stratification by diagnosis may be useful in future phase III studies.

Inversion of multiple intersecting high-resolution crosshole GPR profiles for hydrological characterization at the Boise Hydrogeophysical Research Site

The integration of geophysical data into the subsurface characterization problem has been shown in many cases to significantly improve hydrological knowledge by providing information at spatial scales and locations that is unattainable using conventional hydrological measurement techniques. In particular, crosshole ground-penetrating radar (GPR) tomography has shown much promise in hydrology because of its ability to provide highly detailed images of subsurface radar wave velocity, which is strongly linked to soil water content. Here, we develop and demonstrate a procedure for inverting together multiple crosshole GPR data sets in order to characterize the spatial distribution of radar wave velocity below the water table at the Boise Hydrogeophysical Research Site (BHRS) near Boise, Idaho, USA. Specifically, we jointly invert 31 intersecting crosshole GPR profiles to obtain a highly resolved and consistent radar velocity model along the various profile directions. The model is found to be strongly correlated with complementary neutron porosity-log data and is further corroborated by larger-scale structural information at the BHRS. This work is an important prerequisite to using crosshole GPR data together with existing hydrological measurements for improved groundwater flow and contaminant transport modeling.

Bortezomib(Velcade®)-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting.

A pipeline approach with spatial information for segmenting multiple sclerosis lesions on brain magnetic resonance imaging

Background: Conventional magnetic resonance imaging (MRI) techniques are highly sensitive to detect multiple sclerosis (MS) plaques, enabling a quantitative assessment of inflammatory activity and lesion load. In quantitative analyses of focal lesions, manual or semi-automated segmentations have been widely used to compute the total number of lesions and the total lesion volume. These techniques, however, are both challenging and time-consuming, being also prone to intra-observer and inter-observer variability.Aim: To develop an automated approach to segment brain tissues and MS lesions from brain MRI images. The goal is to reduce the user interaction and to provide an objective tool that eliminates the inter- and intra-observer variability.Methods: Based on the recent methods developed by Souplet et al. and de Boer et al., we propose a novel pipeline which includes the following steps: bias correction, skull stripping, atlas registration, tissue classification, and lesion segmentation. After the initial pre-processing steps, a MRI scan is automatically segmented into 4 classes: white matter (WM), grey matter (GM), cerebrospinal fluid (CSF) and partial volume. An expectation maximisation method which fits a multivariate Gaussian mixture model to T1-w, T2-w and PD-w images is used for this purpose. Based on the obtained tissue masks and using the estimated GM mean and variance, we apply an intensity threshold to the FLAIR image, which provides the lesion segmentation. With the aim of improving this initial result, spatial information coming from the neighbouring tissue labels is used to refine the final lesion segmentation.Results:The experimental evaluation was performed using real data sets of 1.5T and the corresponding ground truth annotations provided by expert radiologists. The following values were obtained: 64% of true positive (TP) fraction, 80% of false positive (FP) fraction, and an average surface distance of 7.89 mm. The results of our approach were quantitatively compared to our implementations of the works of Souplet et al. and de Boer et al., obtaining higher TP and lower FP values.Conclusion: Promising MS lesion segmentation results have been obtained in terms of TP. However, the high number of FP which is still a well-known problem of all the automated MS lesion segmentation approaches has to be improved in order to use them for the standard clinical practice. Our future work will focus on tackling this issue.

Neutralizing antibodies in Multiple Sclerosis a model-based analysis of Interferon beta signaling pathway in macrophages

Multiple Sclerosis is the most common non-traumatic cause of neurologicaldisability in young people. There is no cure yet, and until recently, few long-termtherapies existed. Interferon beta (IFNβ) was the first treatment, and remains the mostcommonly prescribed. One of the most significant problems of IFNβ therapy is theproduction of drug specific antibodies. Up to 45% of patients develop neutralizingantibodies (NAbs) to IFNβ products. The neutralizing antibody binds to the biologicalagent preventing its interaction with its receptor, inhibiting the biological action of theprotein, which abrogates the clinical efficacy of IFNβ treatment. Interferon-betamediates its response by binding to its high affinity cell surface receptor and initiatingthe JAK/STAT signalling cascade. In this project we have analyzed the IFNβ signalingpathway in macrophages when neutralizing antibodies are present. The response tothis pathway after IFNβ stimulation shows a transient oscillatory rhythm of STAT1phosphorylation, which varies as NAbs concentration increases. To improve ourunderstanding of that behavior, we extended an existing mathematical model based onnonlinear ordinary differential equations of JAK/STAT pathway by including IFN-NAbassociation and IFN-activation receptor. Combining our theoretical model withexperimental data we could study the role of neutralizing antibodies on the molecularresponse and determine its lifetime after cytokine stimulation.

Internal arsenite bioassay calibration using multiple reporter cell lines

Bioassays with bioreporter bacteria are usually calibrated with analyte solutions of known concentrations that are analysed along with the samples of interest. This is done as bioreporter output (the intensity of light, fluorescence or colour) does not only depend on the target concentration, but also on the incubation time and physiological activity of the cells in the assay. Comparing the bioreporter output with standardized colour tables in the field seems rather difficult and error-prone. A new approach to control assay variations and improve application ease could be an internal calibration based on the use of multiple bioreporter cell lines with drastically different reporter protein outputs at a given analyte concentration. To test this concept, different Escherichia coli-based bioreporter strains expressing either cytochrome c peroxidase (CCP, or CCP mutants) or β-galactosidase upon induction with arsenite were constructed. The reporter strains differed either in the catalytic activity of the reporter protein (for CCP) or in the rates of reporter protein synthesis (for β-galactosidase), which, indeed, resulted in output signals with different intensities at the same arsenite concentration. Hence, it was possible to use combinations of these cell lines to define arsenite concentration ranges at which none, one or more cell lines gave qualitative (yes/no) visible signals that were relatively independent of incubation time or bioreporter activity. The discriminated concentration ranges would fit very well with the current permissive (e.g. World Health Organization) levels of arsenite in drinking water (10 µg l−1).

Paper 5: Surveillance of multiple congenital anomalies: implementation of a computer algorithm in European registers for classification of cases.

BACKGROUND: Surveillance of multiple congenital anomalies is considered to be more sensitive for the detection of new teratogens than surveillance of all or isolated congenital anomalies. Current literature proposes the manual review of all cases for classification into isolated or multiple congenital anomalies. METHODS: Multiple anomalies were defined as two or more major congenital anomalies, excluding sequences and syndromes. A computer algorithm for classification of major congenital anomaly cases in the EUROCAT database according to International Classification of Diseases (ICD)v10 codes was programmed, further developed, and implemented for 1 year's data (2004) from 25 registries. The group of cases classified with potential multiple congenital anomalies were manually reviewed by three geneticists to reach a final agreement of classification as "multiple congenital anomaly" cases. RESULTS: A total of 17,733 cases with major congenital anomalies were reported giving an overall prevalence of major congenital anomalies at 2.17%. The computer algorithm classified 10.5% of all cases as "potentially multiple congenital anomalies". After manual review of these cases, 7% were agreed to have true multiple congenital anomalies. Furthermore, the algorithm classified 15% of all cases as having chromosomal anomalies, 2% as monogenic syndromes, and 76% as isolated congenital anomalies. The proportion of multiple anomalies varies by congenital anomaly subgroup with up to 35% of cases with bilateral renal agenesis. CONCLUSIONS: The implementation of the EUROCAT computer algorithm is a feasible, efficient, and transparent way to improve classification of congenital anomalies for surveillance and research.

Magnetoencephalography demonstrates multiple asynchronous generators during human sleep spindles.

Sleep spindles are approximately 1 s bursts of 10-16 Hz activity that occur during stage 2 sleep. Spindles are highly synchronous across the cortex and thalamus in animals, and across the scalp in humans, implying correspondingly widespread and synchronized cortical generators. However, prior studies have noted occasional dissociations of the magnetoencephalogram (MEG) from the EEG during spindles, although detailed studies of this phenomenon have been lacking. We systematically compared high-density MEG and EEG recordings during naturally occurring spindles in healthy humans. As expected, EEG was highly coherent across the scalp, with consistent topography across spindles. In contrast, the simultaneously recorded MEG was not synchronous, but varied strongly in amplitude and phase across locations and spindles. Overall, average coherence between pairs of EEG sensors was approximately 0.7, whereas MEG coherence was approximately 0.3 during spindles. Whereas 2 principle components explained approximately 50% of EEG spindle variance, >15 were required for MEG. Each PCA component for MEG typically involved several widely distributed locations, which were relatively coherent with each other. These results show that, in contrast to current models based on animal experiments, multiple asynchronous neural generators are active during normal human sleep spindles and are visible to MEG. It is possible that these multiple sources may overlap sufficiently in different EEG sensors to appear synchronous. Alternatively, EEG recordings may reflect diffusely distributed synchronous generators that are less visible to MEG. An intriguing possibility is that MEG preferentially records from the focal core thalamocortical system during spindles, and EEG from the distributed matrix system.

Corporate responsibility in the postnational constellation : a multiple-case study

In my thesis I present the findings of a multiple-case study on the CSR approach of three multinational companies, applying Basu and Palazzo's (2008) CSR-character as a process model of sensemaking, Suchman's (1995) framework on legitimation strategies, and Habermas (1996) concept of deliberative democracy. The theoretical framework is based on the assumption of a postnational constellation (Habermas, 2001) which sends multinational companies onto a process of sensemaking (Weick, 1995) with regards to their responsibilities in a globalizing world. The major reason is that mainstream CSR-concepts are based on the assumption of a liberal market economy embedded in a nation state that do not fit the changing conditions for legitimation of corporate behavior in a globalizing world. For the purpose of this study, I primarily looked at two research questions: (i) How can the CSR approach of a multinational corporation be systematized empirically? (ii) What is the impact of the changing conditions in the postnational constellation on the CSR approach of the studied multinational corporations? For the analysis, I adopted a holistic approach (Patton, 1980), combining elements of a deductive and inductive theory building methodology (Eisenhardt, 1989b; Eisenhardt & Graebner, 2007; Glaser & Strauss, 1967; Van de Ven, 1992) and rigorous qualitative data analysis. Primary data was collected through 90 semi-structured interviews in two rounds with executives and managers in three multinational companies and their respective stakeholders. Raw data originating from interview tapes, field notes, and contact sheets was processed, stored, and managed using the software program QSR NVIVO 7. In the analysis, I applied qualitative methods to strengthen the interpretative part as well as quantitative methods to identify dominating dimensions and patterns. I found three different coping behaviors that provide insights into the corporate mindset. The results suggest that multinational corporations increasingly turn towards relational approaches of CSR to achieve moral legitimacy in formalized dialogical exchanges with their stakeholders since legitimacy can no longer be derived only from a national framework. I also looked at the degree to which they have reacted to the postnational constellation by the assumption of former state duties and the underlying reasoning. The findings indicate that CSR approaches become increasingly comprehensive through integrating political strategies that reflect the growing (self-) perception of multinational companies as political actors. Based on the results, I developed a model which relates the different dimensions of corporate responsibility to the discussion on deliberative democracy, global governance and social innovation to provide guidance for multinational companies in a postnational world. With my thesis, I contribute to management research by (i) delivering a comprehensive critique of the mainstream CSR-literature and (ii) filling the gap of thorough qualitative research on CSR in a globalizing world using the CSR-character as an empirical device, and (iii) to organizational studies by further advancing a deliberative view of the firm proposed by Scherer and Palazzo (2008).

Influence of multiple injections of human chorionic gonadotropin (hCG) on urine and serum endogenous steroids concentrations.

Since it is established that human chorionic gonadotropin (hCG) affects testosterone production and release in the human body, the use of this hormone as a performance enhancing drug has been prohibited by the World Anti-Doping Agency. Nowadays, the only validated biomarker of a hCG doping is its direct quantification in urine. However, this specific parameter is subjected to large inter-individual variability and its determination is directly dependent on the reliability of hCG immunoassays used. In order to counteract these weaknesses, new biomarkers need to be evidenced. To address this issue, a pilot clinical study was performed on 10 volunteers submitted to 3 subsequent hCG injections. Blood and urine samples were collected during two weeks in order to follow the physiological effects on related compounds such as the steroid profile or hormones involved in the hypothalamo-pituitary axis. The hCG pharmacokinetic observed in all subjects was, as expected, prone to important inter-individual variations. Using ROC plots, level of testosterone and testosterone on luteinizing hormone ratio in both blood and urine were found to be the most relevant biomarker of a hCG abuse, regardless of inter-individual variations. In conclusion, this study showed the crucial importance of reliable quantification methods to assess low differences in hormonal patterns. In regard to these results and to anti-doping requirements and constraints, blood together with urine matrix should be included in the anti-doping testing program. Together with a longitudinal follow-up approach it could constitute a new strategy to detect a hCG abuse, applicable to further forms of steroid or other forbidden drug manipulation.

An efficient algorithm to perform multiple testing in epistasis screening

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown over the last few years. It has been marked by promising methodological developments, improved translation efforts of statistical epistasis to biological epistasis and attempts to integrate different omics information sources into the epistasis screening to enhance power. The quest for gene-gene interactions poses severe multiple-testing problems. In this context, the maxT algorithm is one technique to control the false-positive rate. However, the memory needed by this algorithm rises linearly with the amount of hypothesis tests. Gene-gene interaction studies will require a memory proportional to the squared number of SNPs. A genome-wide epistasis search would therefore require terabytes of memory. Hence, cache problems are likely to occur, increasing the computation time. In this work we present a new version of maxT, requiring an amount of memory independent from the number of genetic effects to be investigated. This algorithm was implemented in C++ in our epistasis screening software MBMDR-3.0.3. We evaluate the new implementation in terms of memory efficiency and speed using simulated data. The software is illustrated on real-life data for Crohn’s disease. Results: In the case of a binary (affected/unaffected) trait, the parallel workflow of MBMDR-3.0.3 analyzes all gene-gene interactions with a dataset of 100,000 SNPs typed on 1000 individuals within 4 days and 9 hours, using 999 permutations of the trait to assess statistical significance, on a cluster composed of 10 blades, containing each four Quad-Core AMD Opteron(tm) Processor 2352 2.1 GHz. In the case of a continuous trait, a similar run takes 9 days. Our program found 14 SNP-SNP interactions with a multiple-testing corrected p-value of less than 0.05 on real-life Crohn’s disease (CD) data. Conclusions: Our software is the first implementation of the MB-MDR methodology able to solve large-scale SNP-SNP interactions problems within a few days, without using much memory, while adequately controlling the type I error rates. A new implementation to reach genome-wide epistasis screening is under construction. In the context of Crohn’s disease, MBMDR-3.0.3 could identify epistasis involving regions that are well known in the field and could be explained from a biological point of view. This demonstrates the power of our software to find relevant phenotype-genotype higher-order associations.