Circulating microRNA profiling in patients with advanced non-squamous NSCLC receiving bevacizumab/erlotinib followed by platinum-based chemotherapy at progression (SAKK 19/05).

OBJECTIVES Molecular subclassification of non small-cell lung cancer (NSCLC) is essential to improve clinical outcome. This study assessed the prognostic and predictive value of circulating micro-RNA (miRNA) in patients with non-squamous NSCLC enrolled in the phase II SAKK (Swiss Group for Clinical Cancer Research) trial 19/05, receiving uniform treatment with first-line bevacizumab and erlotinib followed by platinum-based chemotherapy at progression. MATERIALS AND METHODS Fifty patients with baseline and 24 h blood samples were included from SAKK 19/05. The primary study endpoint was to identify prognostic (overall survival, OS) miRNA's. Patient samples were analyzed with Agilent human miRNA 8x60K microarrays, each glass slide formatted with eight high-definition 60K arrays. Each array contained 40 probes targeting each of the 1347 miRNA. Data preprocessing included quantile normalization using robust multi-array average (RMA) algorithm. Prognostic and predictive miRNA expression profiles were identified by Spearman's rank correlation test (percentage tumor shrinkage) or log-rank testing (for time-to-event endpoints). RESULTS Data preprocessing kept 49 patients and 424 miRNA for further analysis. Ten miRNA's were significantly associated with OS, with hsa-miR-29a being the strongest prognostic marker (HR=6.44, 95%-CI 2.39-17.33). Patients with high has-miR-29a expression had a significantly lower survival at 10 months compared to patients with a low expression (54% versus 83%). Six out of the 10 miRNA's (hsa-miRN-29a, hsa-miR-542-5p, hsa-miR-502-3p, hsa-miR-376a, hsa-miR-500a, hsa-miR-424) were insensitive to perturbations according to jackknife cross-validation on their HR for OS. The respective principal component analysis (PCA) defined a meta-miRNA signature including the same 6 miRNA's, resulting in a HR of 0.66 (95%-CI 0.53-0.82). CONCLUSION Cell-free circulating miRNA-profiling successfully identified a highly prognostic 6-gene signature in patients with advanced non-squamous NSCLC. Circulating miRNA profiling should further be validated in external cohorts for the selection and monitoring of systemic treatment in patients with advanced NSCLC.

Hope as a resource for career exploration: Examining incremental and cross-lagged effects

Hope is believed to be beneficial for vocational pursuits, but the question of how and why hope is related to pivotal career development variables remains largely unaddressed. In a series of three studies, we investigated the relationship between hope and career exploration. Study 1 examined at-risk adolescents (N = 228) in Switzerland and showed that hope explains variance in career exploration beyond the significant effects of generalized self-efficacy beliefs and perceived social support. Study 2 found the same result among a group (N = 223) of first-year students at a Swiss university with a measure of state hope. Study 3 applied a one-year cross-lagged design with a diverse group of students (N = 266) at a German university to investigate the mutual effects of dispositional hope and career exploration over time. Although both variables were found to be related within and over time, we could not confirm lagged effects in either direction. The results suggest that hope is significantly correlated with career exploration because both are related to personality and social–contextual variables.

Prognostic and diagnostic value of EEG signal coupling measures in coma.

OBJECTIVE Our aim was to assess the diagnostic and predictive value of several quantitative EEG (qEEG) analysis methods in comatose patients. METHODS In 79 patients, coupling between EEG signals on the left-right (inter-hemispheric) axis and on the anterior-posterior (intra-hemispheric) axis was measured with four synchronization measures: relative delta power asymmetry, cross-correlation, symbolic mutual information and transfer entropy directionality. Results were compared with etiology of coma and clinical outcome. Using cross-validation, the predictive value of measure combinations was assessed with a Bayes classifier with mixture of Gaussians. RESULTS Five of eight measures showed a statistically significant difference between patients grouped according to outcome; one measure revealed differences in patients grouped according to the etiology. Interestingly, a high level of synchrony between the left and right hemisphere was associated with mortality on intensive care unit, whereas higher synchrony between anterior and posterior brain regions was associated with survival. The combination with the best predictive value reached an area-under the curve of 0.875 (for patients with post anoxic encephalopathy: 0.946). CONCLUSIONS EEG synchronization measures can contribute to clinical assessment, and provide new approaches for understanding the pathophysiology of coma. SIGNIFICANCE Prognostication in coma remains a challenging task. qEEG could improve current multi-modal approaches.

Assessment of total uncertainty in cocaine and benzoylecgonine wastewater load measurements

To check the effectiveness of campaigns preventing drug abuse or indicating local effects of efforts against drug trafficking, it is beneficial to know consumed amounts of substances in a high spatial and temporal resolution. The analysis of drugs of abuse in wastewater (WW) has the potential to provide this information. In this study, the reliability of WW drug consumption estimates is assessed and a novel method presented to calculate the total uncertainty in observed WW cocaine (COC) and benzoylecgonine (BE) loads. Specifically, uncertainties resulting from discharge measurements, chemical analysis and the applied sampling scheme were addressed and three approaches presented. These consist of (i) a generic model-based procedure to investigate the influence of the sampling scheme on the uncertainty of observed or expected drug loads, (ii) a comparative analysis of two analytical methods (high performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry), including an extended cross-validation by influent profiling over several days, and (iii) monitoring COC and BE concentrations in WW of the largest Swiss sewage treatment plants. In addition, the COC and BE loads observed in the sewage treatment plant of the city of Berne were used to back-calculate the COC consumption. The estimated mean daily consumed amount was 107 ± 21 g of pure COC, corresponding to 321 g of street-grade COC.

Application and comparison of classification algorithms for recognition of Alzheimer's disease in electrical brain activity (EEG)

The early detection of subjects with probable Alzheimer's disease (AD) is crucial for effective appliance of treatment strategies. Here we explored the ability of a multitude of linear and non-linear classification algorithms to discriminate between the electroencephalograms (EEGs) of patients with varying degree of AD and their age-matched control subjects. Absolute and relative spectral power, distribution of spectral power, and measures of spatial synchronization were calculated from recordings of resting eyes-closed continuous EEGs of 45 healthy controls, 116 patients with mild AD and 81 patients with moderate AD, recruited in two different centers (Stockholm, New York). The applied classification algorithms were: principal component linear discriminant analysis (PC LDA), partial least squares LDA (PLS LDA), principal component logistic regression (PC LR), partial least squares logistic regression (PLS LR), bagging, random forest, support vector machines (SVM) and feed-forward neural network. Based on 10-fold cross-validation runs it could be demonstrated that even tough modern computer-intensive classification algorithms such as random forests, SVM and neural networks show a slight superiority, more classical classification algorithms performed nearly equally well. Using random forests classification a considerable sensitivity of up to 85% and a specificity of 78%, respectively for the test of even only mild AD patients has been reached, whereas for the comparison of moderate AD vs. controls, using SVM and neural networks, values of 89% and 88% for sensitivity and specificity were achieved. Such a remarkable performance proves the value of these classification algorithms for clinical diagnostics.

A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men

BACKGROUND: Many HIV-infected patients on highly active antiretroviral therapy (HAART) experience metabolic complications including dyslipidaemia and insulin resistance, which may increase their coronary heart disease (CHD) risk. We developed a prognostic model for CHD tailored to the changes in risk factors observed in patients starting HAART. METHODS: Data from five cohort studies (British Regional Heart Study, Caerphilly and Speedwell Studies, Framingham Offspring Study, Whitehall II) on 13,100 men aged 40-70 and 114,443 years of follow up were used. CHD was defined as myocardial infarction or death from CHD. Model fit was assessed using the Akaike Information Criterion; generalizability across cohorts was examined using internal-external cross-validation. RESULTS: A parametric model based on the Gompertz distribution generalized best. Variables included in the model were systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, diabetes mellitus, body mass index and smoking status. Compared with patients not on HAART, the estimated CHD hazard ratio (HR) for patients on HAART was 1.46 (95% CI 1.15-1.86) for moderate and 2.48 (95% CI 1.76-3.51) for severe metabolic complications. CONCLUSIONS: The change in the risk of CHD in HIV-infected men starting HAART can be estimated based on typical changes in risk factors, assuming that HRs estimated using data from non-infected men are applicable to HIV-infected men. Based on this model the risk of CHD is likely to increase, but increases may often be modest, and could be offset by lifestyle changes.

Oral purified bacterial extracts in acute respiratory tract infections in childhood: a systematic quantitative review

BACKGROUND: Recurrent acute respiratory tract infections (ARTI) are a common problem in childhood. Some evidence suggests a benefit regarding the prevention of ARTI in children treated with the immunomodulator OM-85 BV (Bronchovaxom). METHODS: We summarised the evidence on the effectiveness of the immunomodulator OM-85 BV in the prevention of ARTI in children. We searched randomised comparisons of oral purified bacterial extracts against inactive controls in children with respiratory tract diseases in nine electronic databases and reference lists of included studies. We extracted salient features of each study, calculated relative risks (RR) or weighted mean differences (WMD) and performed meta-analyses using random-effects models. RESULTS: Thirteen studies (2,721 patients) of low to moderate quality tested OM-85 BV. Patients and outcomes differed substantially, which impeded pooling results of more than two trials. Two studies (240 patients) reporting on the number of patients with less than three infections over 6 month of follow-up in children not in day care showed a trend for benefit RR 0.82 (95% CI, 0.65-1.02). One out of two studies examining the number of children not in day care without infections over 4-6 month reported a significant RR of 0.42 (95% CI, 0.21-0.82) whereas the smaller, second study did not [RR 0.92 (95% CI, 0.58-1.46)]. Two studies reporting the number of antibiotic courses indicated a benefit for the intervention arm [WMD 2.0 (95% CI, 1.7-2.3)]. Two out of the three studies showed a reduction of length of episodes of 4-6 days whereas a third study showed no difference between the two groups. CONCLUSION: Evidence in favour of OM-85 BV in the prevention of ARTI in children is weak. There is a trend for fewer and shorter infections and a reduction of antibiotic use.

An efficient framework for photon Monte Carlo treatment planning

Currently photon Monte Carlo treatment planning (MCTP) for a patient stored in the patient database of a treatment planning system (TPS) can usually only be performed using a cumbersome multi-step procedure where many user interactions are needed. This means automation is needed for usage in clinical routine. In addition, because of the long computing time in MCTP, optimization of the MC calculations is essential. For these purposes a new graphical user interface (GUI)-based photon MC environment has been developed resulting in a very flexible framework. By this means appropriate MC transport methods are assigned to different geometric regions by still benefiting from the features included in the TPS. In order to provide a flexible MC environment, the MC particle transport has been divided into different parts: the source, beam modifiers and the patient. The source part includes the phase-space source, source models and full MC transport through the treatment head. The beam modifier part consists of one module for each beam modifier. To simulate the radiation transport through each individual beam modifier, one out of three full MC transport codes can be selected independently. Additionally, for each beam modifier a simple or an exact geometry can be chosen. Thereby, different complexity levels of radiation transport are applied during the simulation. For the patient dose calculation, two different MC codes are available. A special plug-in in Eclipse providing all necessary information by means of Dicom streams was used to start the developed MC GUI. The implementation of this framework separates the MC transport from the geometry and the modules pass the particles in memory; hence, no files are used as the interface. The implementation is realized for 6 and 15 MV beams of a Varian Clinac 2300 C/D. Several applications demonstrate the usefulness of the framework. Apart from applications dealing with the beam modifiers, two patient cases are shown. Thereby, comparisons are performed between MC calculated dose distributions and those calculated by a pencil beam or the AAA algorithm. Interfacing this flexible and efficient MC environment with Eclipse allows a widespread use for all kinds of investigations from timing and benchmarking studies to clinical patient studies. Additionally, it is possible to add modules keeping the system highly flexible and efficient.

Practice and perception--a nationwide survey of therapy habits in sepsis

OBJECTIVE: To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock. DESIGN: One-day cross-sectional survey. SETTING: Representative sample of German intensive care units stratified by hospital size. PATIENTS: Adult patients with severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Practice recommendations were selected by German Sepsis Competence Network (SepNet) investigators. External intensivists visited intensive care units randomly chosen and asked the responsible intensive care unit director how often these recommendations were used. Responses "always" and "frequently" were combined to depict perceived adherence. Thereafter patient files were audited. Three hundred sixty-six patients on 214 intensive care units fulfilled the criteria and received full support. One hundred fifty-two patients had acute lung injury or acute respiratory distress syndrome. Low-tidal volume ventilation < or = 6 mL/kg/predicted body weight was documented in 2.6% of these patients. A total of 17.1% patients had tidal volume between 6 and 8 mL/kg predicted body weight and 80.3% > 8 mL/kg predicted body weight. Mean tidal volume was 10.0 +/- 2.4 mL/kg predicted body weight. Perceived adherence to low-tidal volume ventilation was 79.9%. Euglycemia (4.4-6.1 mmol/L) was documented in 6.2% of 355 patients. A total of 33.8% of patients had blood glucose levels < or = 8.3 mmol/L and 66.2% were hyperglycemic (blood glucose > 8.3 mmol/L). Among 207 patients receiving insulin therapy, 1.9% were euglycemic, 20.8% had blood glucose levels < or = 8.3 mmol/L, and 1.0% were hypoglycemic. Overall, mean maximal glucose level was 10.0 +/- 3.6 mmol/L. Perceived adherence to strict glycemic control was 65.9%. Although perceived adherence to recommendations was higher in academic and larger hospitals, actual practice was not significantly influenced by hospital size or university affiliation. CONCLUSIONS: This representative survey shows that current therapy of severe sepsis in German intensive care units complies poorly with practice recommendations. Intensive care unit directors perceive adherence to be higher than it actually is. Implementation strategies involving all intensive care unit staff are needed to overcome this gap between current evidence-based knowledge, practice, and perception.

Extracorporeal membrane oxygenation (ECMO): extended indications for artificial support of both heart and lungs

Extracorporeal membrane oxygenation (ECMO) was used to achieve temporary artificial support in cardiac and pulmonary function in 22 patients from 1987 to September 1990. Standard indications were postcardiotomy cardiogenic shock (n = 4), neonatal (n = 1) and adult respiratory distress syndrome (n = 4). ECMO was also used for extended indications, such as graft failure following heart (n = 11) or lung transplantation (n = 2). In six of these cases ECMO was instituted as a bridge device to subsequent retransplantation of either the heart (n = 4) or one lung (n = 2). One out of nine patients supported by ECMO for standard indications, and two out of 13 patients supported for extended indications are long-term survivors. This series illustrates the results with ECMO in emergency situations, in patients under immunosuppressive protocols, or in patients with advanced lung failure requiring almost complete artificial gas exchange. In such complex situations, ECMO does provide stabilization until additional therapeutic measures are in effect. ECMO cannot be recommended for postoperative cardiogenic shock but short-term ECMO support is an accepted method in most cases with graft failure or pulmonary failure or other origin.

[New insights into diagnosis and management of gestational diabetes mellitus: recommendations of the Swiss Society for Endocrinology and Diabetes]

Physiology and current knowledge about gestational diabetes which led to the adoption of new diagnostic criterias and blood glucose target levels during pregnancy by the Swiss Society for Endocrinology and Diabetes are reviewed. The 6th International Workshop Conference on Gestational Diabetes mellitus in Pasedena (2008) defined new diagnostic criteria based on the results of the HAPO-Trial. These criteria were during the ADA congress in New Orleans in 2009 presented. According to the new criteria there is no need for screening, but all pregnant women have to be tested with a 75 g oral glucose tolerance test between the 24th and 28th week of pregnancy. The new diagnostic values are very similar to the ones previously adopted by the ADA with the exception that only one out of three values has to be elevated in order to make the diagnosis of gestational diabetes. Due to this important difference it is very likely that gestational diabetes will be diagnosed more frequently in the future. The diagnostic criteria are: Fasting plasma glucose > or = 5.1 mmol/l, 1-hour value > or = 10.0 mmol/l or 2-hour value > or = 8.5 mmol/l. Based on current knowledge and randomized trials it is much more difficult to define glucose target levels during pregnancy. This difficulty has led to many different recommendations issued by diabetes societies. The Swiss Society of Endocrinology and Diabetes follows the arguments of the International Diabetes Federation (IDF) that self-blood glucose monitoring itself lacks precision and that there are very few randomized trials. Therefore, the target levels have to be easy to remember and might be slightly different in mmol/l or mg/dl. The Swiss Society for Endocrinology and Diabetes adopts the tentative target values of the IDF with fasting plasma glucose values < 5.3 mM and 1- and 2-hour postprandial (after the end of the meal) values of < 8.0 and 7.0 mmol/l, respectively. The last part of these recommendations deals with the therapeutic options during pregnancy (nutrition, physical exercise and pharmaceutical treatment). If despite lifestyle changes the target values are not met, approximately 25 % of patients have to be treated pharmaceutically. Insulin therapy is still the preferred treatment option, but metformin (and as an exception glibenclamide) can be used, if there are major hurdles for the initiation of insulin therapy.

Age modeling of young non-varved lake sediments: methods and limits. Examples from two lakes in Central Chile

High-resolution and highly precise age models for recent lake sediments (last 100–150 years) are essential for quantitative paleoclimate research. These are particularly important for sedimentological and geochemical proxies, where transfer functions cannot be established and calibration must be based upon the relation of sedimentary records to instrumental data. High-precision dating for the calibration period is most critical as it determines directly the quality of the calibration statistics. Here, as an example, we compare radionuclide age models obtained on two high-elevation glacial lakes in the Central Chilean Andes (Laguna Negra: 33°38′S/70°08′W, 2,680 m a.s.l. and Laguna El Ocho: 34°02′S/70°19′W, 3,250 m a.s.l.). We show the different numerical models that produce accurate age-depth chronologies based on 210Pb profiles, and we explain how to obtain reduced age-error bars at the bottom part of the profiles, i.e., typically around the end of the 19th century. In order to constrain the age models, we propose a method with five steps: (i) sampling at irregularly-spaced intervals for 226Ra, 210Pb and 137Cs depending on the stratigraphy and microfacies, (ii) a systematic comparison of numerical models for the calculation of 210Pb-based age models: constant flux constant sedimentation (CFCS), constant initial concentration (CIC), constant rate of supply (CRS) and sediment isotope tomography (SIT), (iii) numerical constraining of the CRS and SIT models with the 137Cs chronomarker of AD 1964 and, (iv) step-wise cross-validation with independent diagnostic environmental stratigraphic markers of known age (e.g., volcanic ash layer, historical flood and earthquakes). In both examples, we also use airborne pollutants such as spheroidal carbonaceous particles (reflecting the history of fossil fuel emissions), excess atmospheric Cu deposition (reflecting the production history of a large local Cu mine), and turbidites related to historical earthquakes. Our results show that the SIT model constrained with the 137Cs AD 1964 peak performs best over the entire chronological profile (last 100–150 years) and yields the smallest standard deviations for the sediment ages. Such precision is critical for the calibration statistics, and ultimately, for the quality of the quantitative paleoclimate reconstruction. The systematic comparison of CRS and SIT models also helps to validate the robustness of the chronologies in different sections of the profile. Although surprisingly poorly known and under-explored in paleolimnological research, the SIT model has a great potential in paleoclimatological reconstructions based on lake sediments

The performance of single- and multi-proxy transfer functions (testate amoebae, bryophytes, vascular plants) for reconstructing mire surface wetness and pH

Peatlands are widely exploited archives of paleoenvironmental change. We developed and compared multiple transfer functions to infer peatland depth to the water table (DWT) and pH based on testate amoeba (percentages, or presence/absence), bryophyte presence/absence, and vascular plant presence/absence data from sub-alpine peatlands in the SE Swiss Alps in order to 1) compare the performance of single-proxy vs. multi-proxy models and 2) assess the performance of presence/absence models. Bootstrapping cross-validation showing the best performing single-proxy transfer functions for both DWT and pH were those based on bryophytes. The best performing transfer functions overall for DWT were those based on combined testate amoebae percentages, bryophytes and vascular plants; and, for pH, those based on testate amoebae and bryophytes. The comparison of DWT and pH inferred from testate amoeba percentages and presence/absence data showed similar general patterns but differences in the magnitude and timing of some shifts. These results show new directions for paleoenvironmental research, 1) suggesting that it is possible to build good-performing transfer functions using presence/absence data, although with some loss of accuracy, and 2) supporting the idea that multi-proxy inference models may improve paleoecological reconstruction. The performance of multi-proxy and single-proxy transfer functions should be further compared in paleoecological data.

A tutorial on data-driven methods for statistically assessing ERP topographies

Dynamic changes in ERP topographies can be conveniently analyzed by means of microstates, the so-called "atoms of thoughts", that represent brief periods of quasi-stable synchronized network activation. Comparing temporal microstate features such as on- and offset or duration between groups and conditions therefore allows a precise assessment of the timing of cognitive processes. So far, this has been achieved by assigning the individual time-varying ERP maps to spatially defined microstate templates obtained from clustering the grand mean data into predetermined numbers of topographies (microstate prototypes). Features obtained from these individual assignments were then statistically compared. This has the problem that the individual noise dilutes the match between individual topographies and templates leading to lower statistical power. We therefore propose a randomization-based procedure that works without assigning grand-mean microstate prototypes to individual data. In addition, we propose a new criterion to select the optimal number of microstate prototypes based on cross-validation across subjects. After a formal introduction, the method is applied to a sample data set of an N400 experiment and to simulated data with varying signal-to-noise ratios, and the results are compared to existing methods. In a first comparison with previously employed statistical procedures, the new method showed an increased robustness to noise, and a higher sensitivity for more subtle effects of microstate timing. We conclude that the proposed method is well-suited for the assessment of timing differences in cognitive processes. The increased statistical power allows identifying more subtle effects, which is particularly important in small and scarce patient populations.

Prediction of soil organic carbon for Ethiopian highlands using soil spectroscopy

Soil spectroscopy was applied for predicting soil organic carbon (SOC) in the highlands of Ethiopia. Soil samples were acquired from Ethiopia’s National Soil Testing Centre and direct field sampling. The reflectance of samples was measured using a FieldSpec 3 diffuse reflectance spectrometer. Outliers and sample relation were evaluated using principal component analysis (PCA) and models were developed through partial least square regression (PLSR). For nine watersheds sampled, 20% of the samples were set aside to test prediction and 80% were used to develop calibration models. Depending on the number of samples per watershed, cross validation or independent validation were used.The stability of models was evaluated using coefficient of determination (R2), root mean square error (RMSE), and the ratio performance deviation (RPD). The R2 (%), RMSE (%), and RPD, respectively, for validation were Anjeni (88, 0.44, 3.05), Bale (86, 0.52, 2.7), Basketo (89, 0.57, 3.0), Benishangul (91, 0.30, 3.4), Kersa (82, 0.44, 2.4), Kola tembien (75, 0.44, 1.9),Maybar (84. 0.57, 2.5),Megech (85, 0.15, 2.6), andWondoGenet (86, 0.52, 2.7) indicating that themodels were stable. Models performed better for areas with high SOC values than areas with lower SOC values. Overall, soil spectroscopy performance ranged from very good to good.