Monitoring Programmes, Multiple Stress Analysis and Decision Support for River Basin Management

The identification of plausible causes for water body status deterioration will be much easier if it can build on available, reliable, extensive and comprehensive biogeochemical monitoring data (preferably aggregated in a database). A plausible identification of such causes is a prerequisite for well-informed decisions on which mitigation or remediation measures to take. In this chapter, first a rationale for an extended monitoring programme is provided; it is then compared to the one required by the Water Framework Directive (WFD). This proposal includes a list of relevant parameters that are needed for an integrated, a priori status assessment. Secondly, a few sophisticated statistical tools are described that subsequently allow for the estiation of the magnitude of impairment as well as the likely relative importance of different stressors in a multiple stressed environment. The advantages and restrictions of these rather complicated analytical methods are discussed. Finally, the use of Decision Support Systems (DSS) is advocated with regard to the specific WFD implementation requirements.

Comprehensive analysis of CpG island methylator phenotype (CIMP)-high, -low, and -negative colorectal cancers based on protein marker expression and molecular features

CpG island methylator phenotype (CIMP) is being investigated for its role in the molecular and prognostic classification of colorectal cancer patients but is also emerging as a factor with the potential to influence clinical decision-making. We report a comprehensive analysis of clinico-pathological and molecular features (KRAS, BRAF and microsatellite instability, MSI) as well as of selected tumour- and host-related protein markers characterizing CIMP-high (CIMP-H), -low, and -negative colorectal cancers. Immunohistochemical analysis for 48 protein markers and molecular analysis of CIMP (CIMP-H: ? 4/5 methylated genes), MSI (MSI-H: ? 2 instable genes), KRAS, and BRAF were performed on 337 colorectal cancers. Simple and multiple regression analysis and receiver operating characteristic (ROC) curve analysis were performed. CIMP-H was found in 24 cases (7.1%) and linked (p < 0.0001) to more proximal tumour location, BRAF mutation, MSI-H, MGMT methylation (p = 0.022), advanced pT classification (p = 0.03), mucinous histology (p = 0.069), and less frequent KRAS mutation (p = 0.067) compared to CIMP-low or -negative cases. Of the 48 protein markers, decreased levels of RKIP (p = 0.0056), EphB2 (p = 0.0045), CK20 (p = 0.002), and Cdx2 (p < 0.0001) and increased numbers of CD8+ intra-epithelial lymphocytes (p < 0.0001) were related to CIMP-H, independently of MSI status. In addition to the expected clinico-pathological and molecular associations, CIMP-H colorectal cancers are characterized by a loss of protein markers associated with differentiation, and metastasis suppression, and have increased CD8+ T-lymphocytes regardless of MSI status. In particular, Cdx2 loss seems to strongly predict CIMP-H in both microsatellite-stable (MSS) and MSI-H colorectal cancers. Cdx2 is proposed as a surrogate marker for CIMP-H.

How does spatial extent of fMRI datasets affect independent component analysis decomposition?

Spatial independent component analysis (sICA) of functional magnetic resonance imaging (fMRI) time series can generate meaningful activation maps and associated descriptive signals, which are useful to evaluate datasets of the entire brain or selected portions of it. Besides computational implications, variations in the input dataset combined with the multivariate nature of ICA may lead to different spatial or temporal readouts of brain activation phenomena. By reducing and increasing a volume of interest (VOI), we applied sICA to different datasets from real activation experiments with multislice acquisition and single or multiple sensory-motor task-induced blood oxygenation level-dependent (BOLD) signal sources with different spatial and temporal structure. Using receiver operating characteristics (ROC) methodology for accuracy evaluation and multiple regression analysis as benchmark, we compared sICA decompositions of reduced and increased VOI fMRI time-series containing auditory, motor and hemifield visual activation occurring separately or simultaneously in time. Both approaches yielded valid results; however, the results of the increased VOI approach were spatially more accurate compared to the results of the decreased VOI approach. This is consistent with the capability of sICA to take advantage of extended samples of statistical observations and suggests that sICA is more powerful with extended rather than reduced VOI datasets to delineate brain activity.

The role of admission blood glucose in outcome prediction of surviving patients with multiple injuries

BACKGROUND: Recent literature demonstrates hyperglycemia to be common in patients with trauma and associated with poor outcome in patients with traumatic brain injury and critically ill patients. The goal of this study was to analyze the impact of admission blood glucose on the outcome of surviving patients with multiple injuries. METHODS: Patients' charts (age >16) admitted to the emergency room of the University Hospital of Berne, Switzerland, between January 1, 2002, and December 31, 2004, with an Injury Severity Score >or=17 and more than one severely injured organ system were reviewed retrospectively. Outcome measurements included morbidity, intensive care unit, and hospital length of stay. RESULTS: The inclusion criteria were met by 555 patients, of which 108 (19.5%) patients died. After multiple regression analysis, admission blood glucose proved to be an independent predictor of posttraumatic morbidity (p < 0.0001), intensive care unit, and hospital length of stay (p < 0.0001), despite intensified insulin therapy on the intensive care unit. CONCLUSIONS: In this population of patients with multiple injuries, hyperglycemia on admission was strongly associated with increased morbidity, especially infections, prolonged intensive care unit, and hospital length of stay independent of injury severity, gender, age, and various biochemical parameters.

Social Meets Molecular: Combining Phylogenetic and Latent Class Analyses to Understand HIV-1 Transmission in Switzerland

Switzerland has a complex human immunodeficiency virus (HIV) epidemic involving several populations. We examined transmission of HIV type 1 (HIV-1) in a national cohort study. Latent class analysis was used to identify socioeconomic and behavioral groups among 6,027 patients enrolled in the Swiss HIV Cohort Study between 2000 and 2011. Phylogenetic analysis of sequence data, available for 4,013 patients, was used to identify transmission clusters. Concordance between sociobehavioral groups and transmission clusters was assessed in correlation and multiple correspondence analyses. A total of 2,696 patients were infected with subtype B, 203 with subtype C, 196 with subtype A, and 733 with recombinant subtypes (mainly CRF02_AG and CRF01_AE). Latent class analysis identified 8 patient groups. Most transmission clusters of subtype B were shared between groups of gay men (groups 1-3) or between the heterosexual groups "heterosexual people of lower socioeconomic position" (group 4) and "injection drug users" (group 8). Clusters linking homosexual and heterosexual groups were associated with "older heterosexual and gay people on welfare" (group 5). "Migrant women in heterosexual partnerships" (group 6) and "heterosexual migrants on welfare" (group 7) shared non-B clusters with groups 4 and 5. Combining approaches from social and molecular epidemiology can provide insights into HIV-1 transmission and inform the design of prevention strategies.

The Coin Rotation Task: A Valid Test for Manual Dexterity in Multiple Sclerosis

BACKGROUND: Impaired manual dexterity is frequent and disabling in patients with multiple sclerosis (MS). Therefore, convenient, quick and validated tests for manual dexterity in MS patients are needed. OBJECTIVE: The aim of this study was to validate the Coin Rotation task (CRT) to examine manual dexterity in patients with MS. DESIGN: Cross-sectional study. METHODS: 101 outpatients with MS were assessed with the CRT, the Expanded Disability Status Scale (EDSS), the Scale for the assessment and rating of ataxia (SARA), the Modified Ashworth Scale (MAS), and their muscle strength and sensory deficits of the hands were noted. Concurrent validity and diagnostic accuracy of the CRT were determined by comparison with the Nine Hole Peg Test (9HPT). Construct validity was determined by comparison with a valid dexterity questionnaire. Multiple regression analysis was done to explore correlations of the CRT with the EDSS, SARA, MAS, muscle strength and sensory deficits. RESULTS: The CRT correlated significantly with the 9HPT (r=.73, p<.0001) indicating good concurrent validity. The cut-off values for the CRT relative to the 9HPT were 18.75 seconds for the dominant (sensitivity: 81.5%; specificity 80.0%) and 19.25 seconds for the non-dominant hand (sensitivity: 90.3%; specificity: 81.8%) demonstrating good diagnostic accuracy. Furthermore, the CRT correlated significantly with the dexterity questionnaire (r=-.49, p<.0001) indicating moderate construct validity. Multiple regression analyses revealed that the EDSS was the strongest predictor for impaired dexterity. LIMITATIONS: Mostly relapsing-remitting MS patients with an EDSS up to 7 were examined. CONCLUSIONS: This study validates the CRT as a test that can be used easily and quickly to evaluate manual dexterity in patients with MS.

Effect of pulsatility on the mathematical modeling of rotary blood pumps

In this study, the effect of time derivatives of flow rate and rotational speed was investigated on the mathematical modeling of a rotary blood pump (RBP). The basic model estimates the pressure head of the pump as a dependent variable using measured flow and speed as predictive variables. Performance of the model was evaluated by adding time derivative terms for flow and speed. First, to create a realistic working condition, the Levitronix CentriMag RBP was implanted in a sheep. All parameters from the model were physically measured and digitally acquired over a wide range of conditions, including pulsatile speed. Second, a statistical analysis of the different variables (flow, speed, and their time derivatives) based on multiple regression analysis was performed to determine the significant variables for pressure head estimation. Finally, different mathematical models were used to show the effect of time derivative terms on the performance of the models. In order to evaluate how well the estimated pressure head using different models fits the measured pressure head, root mean square error and correlation coefficient were used. The results indicate that inclusion of time derivatives of flow and speed can improve model accuracy, but only minimally.

Vitrectomy for juvenile uveitis: prognostic factors for the long-term functional outcome

PURPOSE: This study evaluated the long-term effect of pars plana vitrectomy (PPV) in children and adolescents with chronic uveitis on visual function, anatomical outcome, and the requirement of systemic treatment. Further, predictive preoperative factors associated with a beneficial visual outcome were assessed. METHODS: Retrospective review of 29 eyes of 23 consecutive paediatric and juvenile patients below 20 years of age with chronic uveitis who underwent a PPV for visually significant opacities in 25 eyes, vitreous haemorrhage in three eyes, and retinal detachment in one eye. The clinical diagnosis was chronic intermediate uveitis in 22 eyes and retinal vasculitis of different origin in seven eyes. RESULTS: LogMAR visual acuity improved from an average of 0.91 to 0.33 (P<0.001). Cystoid macular oedema (CME) was significantly reduced in eight of 10 eyes postoperatively (P=0.021). In the multiple regression analysis, a low preoperative logMAR visual acuity and the presence of a CME had a negative influence on the final logMAR visual acuity. Furthermore, the appearance of chronic uveitis relapses was significantly reduced from 15 eyes before to seven eyes after surgery (P=0.042). CONCLUSIONS: PPV has a beneficial effect on the course and the complications of chronic uveitis in paediatric and juvenile patients with respect to the anatomical and visual outcome. Preoperative logMAR visual acuity and clinically significant CME were the most accurate predictors for the functional outcome.

Comparison of intraarterial and intravenous thrombolysis for ischemic stroke with hyperdense middle cerebral artery sign

BACKGROUND AND PURPOSE: It is unclear whether intraarterial (IAT) or intravenous (IVT) thrombolysis is more effective for ischemic stroke with hyperdense middle cerebral artery sign (HMCAS) on computed tomography (CT). The aim of this study was to compare IAT and IVT in stroke patients with HMCAS. METHODS: Comparison of data from 2 stroke units with similar management of stroke associated with HMCAS, except that 1 unit performed IAT with urokinase and the other IVT with plasminogen activator. Time to treatment was up to 6 hours for IAT and up to 3 hours for IVT. Outcome was measured by mortality and the modified Rankin Scale (mRS), dichotomized at 3 months into favorable (mRS 0 to 2) and unfavorable (mRS 3 to 6). RESULTS: One hundred twelve patients exhibited a HMCAS, 55 of 268 patients treated with IAT and 57 of 249 patients who underwent IVT. Stroke severity at baseline and patient age were similar in both groups. Mean time to treatment was longer in the IAT group (244+/-63 minutes) than in the IVT group (156+/-21 minutes; P=0.0001). However, favorable outcome was more frequent after IAT (n=29, 53%) than after IVT (n=13, 23%; P=0.001), and mortality was lower after IAT (n=4, 7%) than after IVT (n=13, 23%; P=0.022). After multiple regression analysis IAT was associated with a more favorable outcome than IVT (P=0.003) but similar mortality (P=0.192). CONCLUSIONS: In this observational study intraarterial thrombolysis was more beneficial than IVT in the specific group of stroke patients presenting with HMCAS on CT, even though IAT was started later. Our results indicate that a randomized trial comparing both thrombolytic treatments in patients with middle cerebral artery occlusion is warranted.

Intravascular US-guided direct intrahepatic portocaval shunt with an expanded polytetrafluoroethylene-covered stent-graft

PURPOSE: To retrospectively evaluate the midterm patency rate of the nitinol (Viatorr, W.L. Gore and Associates, Flagstaff, Ariz) stent-graft for direct intrahepatic portacaval shunt (DIPS) creation. MATERIALS AND METHODS: Institutional Review Board approval for this retrospective HIPAA-compliant study was obtained with waiver of informed consent. DIPS was created in 18 men and one woman (median age, 54 years; range, 45-65 years) by using nitinol polytetrafluoroethylene (PTFE)-covered stent-grafts. The primary indications were intractable ascites (n = 14), acute variceal bleeding (n = 3), and hydrothorax (n = 2). Follow-up included Doppler ultrasonography at 1, 6, and 12 months and venography with manometry at 6-month intervals after the procedure. Shunt patency and cumulative survival were evaluated by using the Kaplan-Meier method and survival curves were plotted. Differences in mean portosystemic gradients (PSGs) were evaluated by using the Student t test. Multiple regression analysis for survival and DIPS patency were performed for the following parameters: Child-Pugh class, model of end-stage liver disease score, pre- and post-DIPS PSGs, pre-DIPS liver function tests, and pre-DIPS creatinine levels. RESULTS: DIPS creation was successful in all patients. Effective portal decompression and free antegrade shunt flow was achieved in all patients. Intraperitoneal bleeding occurred in one patient during the procedure and was controlled during the same procedure by placing a second nitinol stent-graft. The primary patency rate was 100% at all times during the follow-up period (range, 2 days to 30 months; mean, 256 days; median, 160 days). Flow restrictors were deployed in two (11%) of 19 patients. The 1-year mortality rate was 37% (seven of 19). CONCLUSION: Patency after DIPS creation with the nitinol PTFE-covered stent-graft was superior to that after TIPS with the nitinol stent-graft.

Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C

BACKGROUND/AIM: Both steatosis and insulin resistance have been linked to accelerated fibrosis in chronic hepatitis C. Connective tissue growth factor (CTGF) plays a major role in extracellular matrix production in fibrotic disorders including cirrhosis, and its expression is stimulated in vitro by insulin and glucose. We hypothesized that CTGF may link steatosis, insulin resistance and fibrosis. METHODS: We included 153 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study and for whom a liver biopsy and plasma samples were available. CTGF expression was assessed quantitatively by immunohistochemistry. In 94 patients (57 with genotypes non-3), plasma levels of glucose, insulin and leptin were also measured. CTGF synthesis was investigated by immunoblotting on LX-2 stellate cells. RESULTS: Connective tissue growth factor expression was higher in patients with steatosis (P=0.039) and in patients with fibrosis (P=0.008) than those without these features. CTGF levels were neither associated with insulinaemia or with glycaemia, nor with inflammation. By multiple regression analysis, CTGF levels were independently associated with steatosis, a past history of alcohol abuse, plasma leptin and HCV RNA levels; when only patients with genotypes non-3 were considered, CTGF levels were independently associated with a past history of alcohol abuse, plasma leptin levels and steatosis. Leptin stimulated CTGF synthesis in LX-2 cells. CONCLUSIONS: In patients with chronic hepatitis C and steatosis, CTGF may promote fibrosis independently of inflammation. CTGF may link steatosis and fibrosis via increased leptin levels.

Effects of gender and dementia severity on Alzheimer's disease caregivers' sleep and biomarkers of coagulation and inflammation

BACKGROUND: Being a caregiver for a spouse with Alzheimer's disease is associated with increased risk for cardiovascular illness, particularly for males. This study examined the effects of caregiver gender and severity of the spouse's dementia on sleep, coagulation, and inflammation in the caregiver. METHODS: Eighty-one male and female spousal caregivers and 41 non-caregivers participated (mean age of all participants 70.2 years). Full-night polysomnography (PSG) was recorded in each participants home. Severity of the Alzheimer's disease patient's dementia was determined by the Clinical Dementia Rating (CDR) scale. The Role Overload scale was completed as an assessment of caregiving stress. Blood was drawn to assess circulating levels of D-dimer and Interleukin-6 (IL-6). RESULTS: Male caregivers who were caring for a spouse with moderate to severe dementia spent significantly more time awake after sleep onset than female caregivers caring for spouses with moderate to severe dementia (p=.011), who spent a similar amount of time awake after sleep onset to caregivers of low dementia spouses and to non-caregivers. Similarly, male caregivers caring for spouses with worse dementia had significantly higher circulating levels of D-dimer (p=.034) than females caring for spouses with worse dementia. In multiple regression analysis (adjusted R(2)=.270, p<.001), elevated D-dimer levels were predicted by a combination of the CDR rating of the patient (p=.047) as well as greater time awake after sleep onset (p=.046). DISCUSSION: The findings suggest that males caring for spouses with more severe dementia experience more disturbed sleep and have greater coagulation, the latter being associated with the disturbed sleep. These findings may provide insight into why male caregivers of spouses with Alzheimer's disease are at increased risk for illness, particularly cardiovascular disease.

Predictors of inflammation in response to anthracycline-based chemotherapy for breast cancer

Although chemotherapy for breast cancer can increase inflammation, few studies have examined predictors of this phenomenon. This study examined potential contributions of demographics, disease characteristics, and treatment regimens to markers of inflammation in response to chemotherapy for breast cancer. Thirty-five women with stage I-III-A breast cancer (mean age 50 years) were studied prior to cycle 1 and prior to cycle 4 of anthracycline-based chemotherapy. Circulating levels of inflammatory markers with high relevance to breast cancer were examined, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), Interleukin-1 receptor antagonist (IL1-RA), vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), Interleukin- (IL-6), soluble P-selectin (sP-selectin), and von Willebrand factor (vWf). Chemotherapy was associated with elevations in VEGF (p < or = 0.01), sICAM-1 (p < or = 0.01), sP-selectin (p < or = 0.02) and vWf (p < or = 0.05). Multiple regression analysis controlling for age and body mass index (BMI) showed that higher post-chemotherapy levels of inflammation were consistently related to higher pre-chemotherapy levels of inflammation (ps < or =0.05) as well as to certain disease characteristics. Post-chemotherapy IL-6 levels were higher in patients who had larger tumors (p < or = 0.05) while post-chemotherapy VEGF levels were higher in patients who had smaller tumors (p < or = 0.05). Post-chemotherapy sP-selectin levels were highest in women who had received epirubicin, cytoxan, 5-fluorouracil chemotherapy (p < or = 0.01). These findings indicate that chemotherapy treatment can be associated with elevations in certain markers of inflammation, particularly markers of endothelial and platelet activation. Inflammation in response to chemotherapy is most significantly related to inflammation that existed prior to chemotherapy but also potentially to treatment regimen and to certain disease characteristics.

Benchmarking with Spine Tango: potentials and pitfalls

The newly released online statistics function of Spine Tango allows comparison of own data against the aggregated results of the data pool that all other participants generate. This comparison can be considered a very simple way of benchmarking, which means that the quality of what one organization does is compared with other similar organizations. The goal is to make changes towards better practice if benchmarking shows inferior results compared with the pool. There are, however, pitfalls in this simplified way of comparing data that can result in confounding. This means that important influential factors can make results appear better or worse than they are in reality and these factors can only be identified and neutralized in a multiple regression analysis performed by a statistical expert. Comparing input variables, confounding is less of a problem than comparing outcome variables. Therefore, the potentials and limitations of automated online comparisons need to be considered when interpreting the results of the benchmarking procedure.

A prediction model for personal radio frequency electromagnetic field exposure

Radio frequency electromagnetic fields (RF-EMF) in our daily life are caused by numerous sources such as fixed site transmitters (e.g. mobile phone base stations) or indoor devices (e.g. cordless phones). The objective of this study was to develop a prediction model which can be used to predict mean RF-EMF exposure from different sources for a large study population in epidemiological research. We collected personal RF-EMF exposure measurements of 166 volunteers from Basel, Switzerland, by means of portable exposure meters, which were carried during one week. For a validation study we repeated exposure measurements of 31 study participants 21 weeks after the measurements of the first week on average. These second measurements were not used for the model development. We used two data sources as exposure predictors: 1) a questionnaire on potentially exposure relevant characteristics and behaviors and 2) modeled RF-EMF from fixed site transmitters (mobile phone base stations, broadcast transmitters) at the participants' place of residence using a geospatial propagation model. Relevant exposure predictors, which were identified by means of multiple regression analysis, were the modeled RF-EMF at the participants' home from the propagation model, housing characteristics, ownership of communication devices (wireless LAN, mobile and cordless phones) and behavioral aspects such as amount of time spent in public transports. The proportion of variance explained (R2) by the final model was 0.52. The analysis of the agreement between calculated and measured RF-EMF showed a sensitivity of 0.56 and a specificity of 0.95 (cut-off: 90th percentile). In the validation study, the sensitivity and specificity of the model were 0.67 and 0.96, respectively. We could demonstrate that it is feasible to model personal RF-EMF exposure. Most importantly, our validation study suggests that the model can be used to assess average exposure over several months.