Source-wavelet estimation during full-waveform inversion of ground-penetrating radar data

A major issue in the application of waveform inversion methods to crosshole ground-penetrating radar (GPR) data is the accurate estimation of the source wavelet. Here, we explore the viability and robustness of incorporating this step into a recently published time-domain inversion procedure through an iterative deconvolution approach. Our results indicate that, at least in non-dispersive electrical environments, such an approach provides remarkably accurate and robust estimates of the source wavelet even in the presence of strong heterogeneity of both the dielectric permittivity and electrical conductivity. Our results also indicate that the proposed source wavelet estimation approach is relatively insensitive to ambient noise and to the phase characteristics of the starting wavelet. Finally, there appears to be little to no trade-off between the wavelet estimation and the tomographic imaging procedures.

Estimating vadose zone hydraulic properties using ground penetrating radar: The impact of prior information

A number of geophysical methods, such as ground-penetrating radar (GPR), have the potential to provide valuable information on hydrological properties in the unsaturated zone. In particular, the stochastic inversion of such data within a coupled geophysical-hydrological framework may allow for the effective estimation of vadose zone hydraulic parameters and their corresponding uncertainties. A critical issue in stochastic inversion is choosing prior parameter probability distributions from which potential model configurations are drawn and tested against observed data. A well chosen prior should reflect as honestly as possible the initial state of knowledge regarding the parameters and be neither overly specific nor too conservative. In a Bayesian context, combining the prior with available data yields a posterior state of knowledge about the parameters, which can then be used statistically for predictions and risk assessment. Here we investigate the influence of prior information regarding the van Genuchten-Mualem (VGM) parameters, which describe vadose zone hydraulic properties, on the stochastic inversion of crosshole GPR data collected under steady state, natural-loading conditions. We do this using a Bayesian Markov chain Monte Carlo (MCMC) inversion approach, considering first noninformative uniform prior distributions and then more informative priors derived from soil property databases. For the informative priors, we further explore the effect of including information regarding parameter correlation. Analysis of both synthetic and field data indicates that the geophysical data alone contain valuable information regarding the VGM parameters. However, significantly better results are obtained when we combine these data with a realistic, informative prior.

Which change talk dimensions are associated with subsequent drinking among young men receiving a brief motivational intervention in a non-clinical setting?

Background: Patient change talk (CT) during brief motivational interventions (BMI) has been linked with subsequent changes in drinking in clinical settings but this link has not been clearly established among young people in non-clinical populations. Objective: To determine which of several CT dimensions assessed during an effective BMI delivered in a non-clinical setting to 20-year old men are associated with drinking 6 months later. Methods: Of 125 individuals receiving a face-to-face BMI session (15.8 ± 5.4 minutes), we recorded and coded a subsample of 42 sessions using the Motivational Interviewing Skill Code 2.1. Each patient change talk utterance was categorized as `Reason´, `Ability´, `Desire´, `Need´, `Commitment´, `Taking steps´, or `Other´. Each utterance was graded according to its strength (absolute value from 1 to 3) and direction (i.e. towards (positive sign) or away (negative sign) from change/in favor of status quo). `Ability´, `Desire´, and `Need´ to change (`ADN´) were grouped together since these codes were too scarce to conduct analyses. Mean strength scores over the entire session were computed for each dimension and later dichotomized in towards change (i.e. mean core > 0) and away from change/in favor of status quo. Negative binomial regression models were used to assess the relationship between CT dimensions and drinking 6 months later, adjusting for drinking at baseline. Results: Compared to subjects with a `Taking steps´ score away from change/in favor of status quo, subjects with a positive `Taking steps´ score reported significantly less drinking 6 months later (Incidence Rate Ration [IRR] for drinks per week: 0.56, 95% Confidence Interval [CI] 0.31, 1.00). IRR (95%CI) for subjects with a positive `ADN´ score was 0.58, (0.32, 1.03). For subjects with a positive `Reason´, `Commitment´, and `Other´ scores, IRR (95%CI) were 1.28 (0.77; 2.12) 1.63 (0.85; 3.14) and 1.03 (0.61; 1.72), respectively. Conclusion: A change talk dimension reflecting steps taken towards change (`Taking steps´) is associated with less drinking 6 months later among young men receiving a BMI in a non-clinical setting. Encouraging patients to take steps towa change may be a worthy objective for clinicians and may explain BMI efficacy.

Full-waveform inversion of cross-hole ground-penetrating radar data to characterize a gravel aquifer close to the Thur River, Switzerland

Cross-hole radar tomography is a useful tool for mapping shallow subsurface electrical properties viz. dielectric permittivity and electrical conductivity. Common practice is to invert cross-hole radar data with ray-based tomographic algorithms using first arrival traveltimes and first cycle amplitudes. However, the resolution of conventional standard ray-based inversion schemes for cross-hole ground-penetrating radar (GPR) is limited because only a fraction of the information contained in the radar data is used. The resolution can be improved significantly by using a full-waveform inversion that considers the entire waveform, or significant parts thereof. A recently developed 2D time-domain vectorial full-waveform crosshole radar inversion code has been modified in the present study by allowing optimized acquisition setups that reduce the acquisition time and computational costs significantly. This is achieved by minimizing the number of transmitter points and maximizing the number of receiver positions. The improved algorithm was employed to invert cross-hole GPR data acquired within a gravel aquifer (4-10 m depth) in the Thur valley, Switzerland. The simulated traces of the final model obtained by the full-waveform inversion fit the observed traces very well in the lower part of the section and reasonably well in the upper part of the section. Compared to the ray-based inversion, the results from the full-waveform inversion show significantly higher resolution images. At either side, 2.5 m distance away from the cross-hole plane, borehole logs were acquired. There is a good correspondence between the conductivity tomograms and the natural gamma logs at the boundary of the gravel layer and the underlying lacustrine clay deposits. Using existing petrophysical models, the inversion results and neutron-neutron logs are converted to porosity. Without any additional calibration, the values obtained for the converted neutron-neutron logs and permittivity results are very close and similar vertical variations can be observed. The full-waveform inversion provides in both cases additional information about the subsurface. Due to the presence of the water table and associated refracted/reflected waves, the upper traces are not well fitted and the upper 2 m in the permittivity and conductivity tomograms are not reliably reconstructed because the unsaturated zone is not incorporated into the inversion domain.

Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy.

INTRODUCTION: Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis. METHODS: Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course. RESULTS: 1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p<0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p<0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p<0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02-229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03-2.06), with no differences in major bleeding rate. CONCLUSION: Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations.

Randomized trial of a computerized coronary heart disease risk assessment tool in HIV-infected patients receiving combination antiretroviral therapy.

BACKGROUND: Exposure to combination antiretroviral therapy (cART) can lead to important metabolic changes and increased risk of coronary heart disease (CHD). Computerized clinical decision support systems have been advocated to improve the management of patients at risk for CHD but it is unclear whether such systems reduce patients' risk for CHD. METHODS: We conducted a cluster trial within the Swiss HIV Cohort Study (SHCS) of HIV-infected patients, aged 18 years or older, not pregnant and receiving cART for >3 months. We randomized 165 physicians to either guidelines for CHD risk factor management alone or guidelines plus CHD risk profiles. Risk profiles included the Framingham risk score, CHD drug prescriptions and CHD events based on biannual assessments, and were continuously updated by the SHCS data centre and integrated into patient charts by study nurses. Outcome measures were total cholesterol, systolic and diastolic blood pressure and Framingham risk score. RESULTS: A total of 3,266 patients (80% of those eligible) had a final assessment of the primary outcome at least 12 months after the start of the trial. Mean (95% confidence interval) patient differences where physicians received CHD risk profiles and guidelines, rather than guidelines alone, were total cholesterol -0.02 mmol/l (-0.09-0.06), systolic blood pressure -0.4 mmHg (-1.6-0.8), diastolic blood pressure -0.4 mmHg (-1.5-0.7) and Framingham 10-year risk score -0.2% (-0.5-0.1). CONCLUSIONS: Systemic computerized routine provision of CHD risk profiles in addition to guidelines does not significantly improve risk factors for CHD in patients on cART.

Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS: In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS: Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS: In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.

Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions

A series of 4 experiments examined the performance of rats with retrohippocampal lesions on a spatial water-maze task. The animals were trained to find and escape onto a hidden platform after swimming in a large pool of opaque water. The platform was invisible and could not be located using olfactory cues. Successful escape performance required the rats to develop strategies of approaching the correct location with reference solely to distal extramaze cues. The lesions encompassed the entire rostro-caudal extent of the lateral and medial entorhinal cortex, and included parts of the pre- and para-subiculum, angular bundle and subiculum. Groups ECR 1 and 2 sustained only partial damage of the subiculum, while Group ECR+S sustained extensive damage. These groups were compared with sham-lesion and unoperated control groups. In Expt 1A, a profound deficit in spatial localisation was found in groups ECR 1 and ECR+S, the rats receiving all training postoperatively. In Expt 1B, these two groups showed hyperactivity in an open-field. In Expt 2, extensive preoperative training caused a transitory saving in performance of the spatial task by group ECR 2, but comparisons with the groups of Expt 1A revealed no sustained improvement, except on one measure of performance in a post-training transfer test. All rats were then given (Expt 3) training on a cueing procedure using a visible platform. The spatial deficit disappeared but, on returning to the normal hidden platform procedure, it reappeared. Nevertheless, a final transfer test, during which the platform was removed from the apparatus, revealed a dissociation between two independent measures of performance: the rats with ECR lesions failed to search for the hidden platform but repeatedly crossed its correct location accurately during traverses of the entire pool. This partial recovery of performance was not (Expt 4) associated with any ability to discriminate between two locations in the pool. The apparently selective recovery of aspects of spatial memory is discussed in relation to O'Keefe and Nadel's (1978) spatial mapping theory of hippocampal function. We propose a modification of the theory in terms of a dissociation between procedural and declarative subcomponents of spatial memory. The declarative component is a flexible access system in which information is stored in a form independent of action. It is permanently lost after the lesion. The procedural component is "unmasked" by the retrohippocampal lesion giving rise to the partial recovery of spatial localisation performance.

Predictive value of the MGMT promoter methylation status in metastatic melanoma patients receiving first-line temozolomide plus bevacizumab in the trial SAKK 50/07.

The O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical trials with temozolomide plus bevacizumab therapy in metastatic melanoma patients are ongoing, although the predictive value of the MGMT promoter methylation status in this setting remains unclear. We assessed MGMT promoter methylation in formalin-fixed, primary tumor tissue of metastatic melanoma patients treated with first-line temozolomide and bevacizumab from the trial SAKK 50/07 by methylation-specific polymerase chain reaction. In addition, the MGMT expression levels were also analyzed by MGMT immunohistochemistry. Eleven of 42 primary melanomas (26%) revealed a methylated MGMT promoter. Promoter methylation was significantly associated with response rates CR + PR versus SD + PD according to RECIST (response evaluation criteria in solid tumors) (p<0.05) with a trend to prolonged median progression-free survival (8.1 versus 3.4 months, p>0.05). Immunohistochemically different protein expression patterns with heterogeneous and homogeneous nuclear MGMT expression were identified. Negative MGMT expression levels were associated with overall disease stabilization CR + PR + SD versus PD (p=0.05). There was only a poor correlation between MGMT methylation and lack of MGMT expression. A significant proportion of melanomas have a methylated MGMT promoter. The MGMT promoter methylation status may be a promising predictive marker for temozolomide therapy in metastatic melanoma patients. Larger sample sizes may help to validate significant differences in survival type endpoints.

Bayesian Markov-chain-Monte-Carlo inversion of time-lapse cross hole ground-penetrating radar data to characterize the vadose zone at the Arrenaes field site, Denmark

The ground-penetrating radar (GPR) geophysical method has the potential to provide valuable information on the hydraulic properties of the vadose zone because of its strong sensitivity to soil water content. In particular, recent evidence has suggested that the stochastic inversion of crosshole GPR traveltime data can allow for a significant reduction in uncertainty regarding subsurface van Genuchten-Mualem (VGM) parameters. Much of the previous work on the stochastic estimation of VGM parameters from crosshole GPR data has considered the case of steady-state infiltration conditions, which represent only a small fraction of practically relevant scenarios. We explored in detail the dynamic infiltration case, specifically examining to what extent time-lapse crosshole GPR traveltimes, measured during a forced infiltration experiment at the Arreneas field site in Denmark, could help to quantify VGM parameters and their uncertainties in a layered medium, as well as the corresponding soil hydraulic properties. We used a Bayesian Markov-chain-Monte-Carlo inversion approach. We first explored the advantages and limitations of this approach with regard to a realistic synthetic example before applying it to field measurements. In our analysis, we also considered different degrees of prior information. Our findings indicate that the stochastic inversion of the time-lapse GPR data does indeed allow for a substantial refinement in the inferred posterior VGM parameter distributions compared with the corresponding priors, which in turn significantly improves knowledge of soil hydraulic properties. Overall, the results obtained clearly demonstrate the value of the information contained in time-lapse GPR data for characterizing vadose zone dynamics.

Incidence of Infectious Complications in Kidney Transplant Recipients Receiving Induction with Basiliximab, Thymoglobulin or Both

Background: The possible additional risk of infection in patients receiving induction with both basiliximab (Ba) and thymoglobulin (Th) is unclear. We assessed the 1-year incidence of infectious complications in 3 groups of kidney transplant recipients according to the type of induction therapy received.Methods: We compared the incidence of infection at 1 year in 3 groups of patients at our institution: fi rst transplant recipients received Ba 20mg at days 0 and 4 (Group Ba); in case of retransplantation or if PRA was >20% patients received Th 1 mg/kg for 3-5 days (Group Th); in case of delayed graft function (DGF), Ba was discontinued and Th was initiated (Group Ba+Th) or prolonged in Group Th. Kaplan-Meier curves were used to calculate the incidence of infection. A Cox analysis was used to identify risk factors for the development of infection.Results: Over 5 years, 170 consecutive kidney transplant recipients were performed:n=113 in Group Ba, n=39 in Group Th and n=18 in Group Ba+Th. As expected, more patients in Group Th received a second transplant (p<0.001). No differences in CMV serostatus were observed between groups (p=0.9). Incidences of CMV infection, CMV disease, BK viremia, BK nephropathy and urinary tract infection (UTI) is shown in Table 1. Table 1 Group Ba (n=113) Group Th (n=38) Group Ba+Th (n=18) CMV infection 31 (27%) 20 (51%) 8 (44%) CMV disease 7 (6%) 4 (10%) 0 BK viremia 11 (8%) 5 (13%) 4 (22%) BK nephropathy 5 (4%) 1 (2%) 2 (11%) UTI 43 (38%) 23 (59%) 6 (33%) Incidences of infection according to type of induction In a multivariate model taking into account CMV serostatus, age, pretransplant dialysis, type of organ transplanted, number of transplants and type of induction, Group Ba carried a lower risk of CMV infection (OR 0.45, p=0.006), and UTI (OR=0.6, p=0.05), but there were no differences in CMV disease (p=0.38). There was a trend towards higher incidence of BK viremia, but not nephropathy in Group Ba+Th (OR 2.2, p=0.23). There were no signifi cant differences in kidney function or graft loss at 1 year between groups.Conclusion: By multivariate analysis, we observed a lower risk of CMV infection andUTI in patients receiving Ba. The group Ba+Th had a similar risk for infection than the group receiving Th alone. Larger studies are needed to clarify whether combining Ba+Th in the setting of DGF may increase the risk of infectious complications, in particular BK infection.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.