Testing the structural and cross-cultural validity of the KIDSCREEN-27 quality of life questionnaire

OBJECTIVES: The aim of this study is to assess the structural and cross-cultural validity of the KIDSCREEN-27 questionnaire. METHODS: The 27-item version of the KIDSCREEN instrument was derived from a longer 52-item version and was administered to young people aged 8-18 years in 13 European countries in a cross-sectional survey. Structural and cross-cultural validity were tested using multitrait multi-item analysis, exploratory and confirmatory factor analysis, and Rasch analyses. Zumbo's logistic regression method was applied to assess differential item functioning (DIF) across countries. Reliability was assessed using Cronbach's alpha. RESULTS: Responses were obtained from n = 22,827 respondents (response rate 68.9%). For the combined sample from all countries, exploratory factor analysis with procrustean rotations revealed a five-factor structure which explained 56.9% of the variance. Confirmatory factor analysis indicated an acceptable model fit (RMSEA = 0.068, CFI = 0.960). The unidimensionality of all dimensions was confirmed (INFIT: 0.81-1.15). Differential item functioning (DIF) results across the 13 countries showed that 5 items presented uniform DIF whereas 10 displayed non-uniform DIF. Reliability was acceptable (Cronbach's alpha = 0.78-0.84 for individual dimensions). CONCLUSIONS: There was substantial evidence for the cross-cultural equivalence of the KIDSCREEN-27 across the countries studied and the factor structure was highly replicable in individual countries. Further research is needed to correct scores based on DIF results. The KIDSCREEN-27 is a new short and promising tool for use in clinical and epidemiological studies.

Lake sediments as natural seismographs: A compiled record of Late Quaternary earthquakes in Central Switzerland and its implication for Alpine deformation

Central Switzerland lies tectonically in an intraplate area and recurrence rates of strong earthquakes exceed the time span covered by historic chronicles. However, many lakes are present in the area that act as natural seismographs: their continuous, datable and high-resolution sediment succession allows extension of the earthquake catalogue to pre-historic times. This study reviews and compiles available data sets and results from more than 10 years of lacustrine palaeoseismological research in lakes of northern and Central Switzerland. The concept of using lacustrine mass-movement event stratigraphy to identify palaeo-earthquakes is showcased by presenting new data and results from Lake Zurich. The Late Glacial to Holocene mass-movement units in this lake document a complex history of varying tectonic and environmental impacts. Results include sedimentary evidence of three major and three minor, simultaneously triggered basin-wide lateral slope failure events interpreted as the fingerprints of palaeoseismic activity. A refined earthquake catalogue, which includes results from previous lake studies, reveals a non-uniform temporal distribution of earthquakes in northern and Central Switzerland. A higher frequency of earthquakes in the Late Glacial and Late Holocene period documents two different phases of neotectonic activity; they are interpreted to be related to isostatic post-glacial rebound and relatively recent (re-)activation of seismogenic zones, respectively. Magnitudes and epicentre reconstructions for the largest identified earthquakes provide evidence for two possible earthquake sources: (i) a source area in the region of the Alpine or Sub-Alpine Front due to release of accumulated north-west/south-east compressional stress related to an active basal thrust beneath the Aar massif; and (ii) a source area beneath the Alpine foreland due to reactivation of deep-seated strike-slip faults. Such activity has been repeatedly observed instrumentally, for example, during the most recent magnitude 4.2 and 3.5 earthquakes of February 2012, near Zug. The combined lacustrine record from northern and Central Switzerland indicates that at least one of these potential sources has been capable of producing magnitude 6.2 to 6.7 events in the past.

CopywriteR: DNA copy number detection from off-target sequence data.

Current methods for detection of copy number variants (CNV) and aberrations (CNA) from targeted sequencing data are based on the depth of coverage of captured exons. Accurate CNA determination is complicated by uneven genomic distribution and non-uniform capture efficiency of targeted exons. Here we present CopywriteR, which eludes these problems by exploiting 'off-target' sequence reads. CopywriteR allows for extracting uniformly distributed copy number information, can be used without reference, and can be applied to sequencing data obtained from various techniques including chromatin immunoprecipitation and target enrichment on small gene panels. CopywriteR outperforms existing methods and constitutes a widely applicable alternative to available tools.

Retinal slit lamp video mosaicking

Purpose To this day, the slit lamp remains the first tool used by an ophthalmologist to examine patient eyes. Imaging of the retina poses, however, a variety of problems, namely a shallow depth of focus, reflections from the optical system, a small field of view and non-uniform illumination. For ophthalmologists, the use of slit lamp images for documentation and analysis purposes, however, remains extremely challenging due to large image artifacts. For this reason, we propose an automatic retinal slit lamp video mosaicking, which enlarges the field of view and reduces amount of noise and reflections, thus enhancing image quality. Methods Our method is composed of three parts: (i) viable content segmentation, (ii) global registration and (iii) image blending. Frame content is segmented using gradient boosting with custom pixel-wise features. Speeded-up robust features are used for finding pair-wise translations between frames with robust random sample consensus estimation and graph-based simultaneous localization and mapping for global bundle adjustment. Foreground-aware blending based on feathering merges video frames into comprehensive mosaics. Results Foreground is segmented successfully with an area under the curve of the receiver operating characteristic curve of 0.9557. Mosaicking results and state-of-the-art methods were compared and rated by ophthalmologists showing a strong preference for a large field of view provided by our method. Conclusions The proposed method for global registration of retinal slit lamp images of the retina into comprehensive mosaics improves over state-of-the-art methods and is preferred qualitatively.

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.

Detection of erythropoietin in exhaled breath condensate of nonhypoxic subjects using a multiplex bead array

As a noninvasive method, exhaled breath condensate (EBC) has gained importance to improve monitoring of lung diseases and to detect biomarkers. The aim of the study was to investigate, whether erythropoietin (EPO) is detectable in EBC. EBC was collected from 22 consecutive patients as well as from healthy individuals. Using a multiplex fluorescent bead immunoassay, we detected EPO in EBC, as well as tumour necrosis factor-alpha (TNF-alpha) in 13 out of 22 patients simultaneously (EPO 0.21 +/- 0.03 in U/mL and TNF-alpha 34.6 +/- 4.2 in pg/mL, mean +/- SEM). No significant differences for EPO levels or correlation between EPO and TNF-alpha were found but TNF-alpha was significantly higher in patients with chronic obstructive pulmonary disease (COPD) than in non-COPD (obstructive sleep apnoea, OSA, and lung healthy patients). This is the first report of detection of EPO in EBC. Due to the small study size more data is needed to clarify the role of EPO in EBC.

Varying expectancies and attention bias in phobic and non-phobic individuals.

Phobic individuals display an attention bias to phobia-related information and biased expectancies regarding the likelihood of being faced with such stimuli. Notably, although attention and expectancy biases are core features in phobia and anxiety disorders, these biases have mostly been investigated separately and their causal impact has not been examined. We hypothesized that these biases might be causally related. Spider phobic and low spider fearful control participants performed a visual search task in which they specified whether the deviant animal in a search array was a spider or a bird. Shorter reaction times (RTs) for spiders than for birds in this task reflect an attention bias toward spiders. Participants' expectancies regarding the likelihood of these animals being the deviant in the search array were manipulated by presenting verbal cues. Phobics were characterized by a pronounced and persistent attention bias toward spiders; controls displayed slower RTs for birds than for spiders only when spider cues had been presented. More important, we found RTs for spider detections to be virtually unaffected by the expectancy cues in both groups, whereas RTs for bird detections showed a clear influence of the cues. Our results speak to the possibility that evolution has formed attentional systems that are specific to the detection of phylogenetically salient stimuli such as threatening animals; these systems may not be as penetrable to variations in (experimentally induced) expectancies as those systems that are used for the detection of non-threatening stimuli. In sum, our findings highlight the relation between expectancies and attention engagement in general. However, expectancies may play a greater role in attention engagement in safe environments than in threatening environments.

Non-Contact Documentation of Physical Characteristics of Ecstasy Tablets, Hemp Coins, and Imprint Punches by using 3D Optical Surface Scanning

The description of seized illicit ecstasy tablets and other pressed drug products is an important step in casework. The physical and visual analysis and the description of the characteristics can be employed for intelligence purposes. Besides photography and manual measurements of dimensions, some optical instruments are employed for detailed measurements of physical characteristics. In this work, the method of 3D surface digitizing is introduced as a suitable tool for highly accurate documentation of small objects, especially for pressed drug products. The resulting detailed information about the geometry, and the results of an automatic comparison of apparently uniform tablets and coins with punches, can support drug intelligence.

Impact of Clinical Presentation (Stable Angina Pectoris vs Unstable Angina Pectoris or Non-ST-Elevation Myocardial Infarction vs ST-Elevation Myocardial Infarction) on Long-Term Outcomes in Women Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents

The long-term risk associated with different coronary artery disease (CAD) presentations in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is poorly characterized. We pooled patient-level data for women enrolled in 26 randomized clinical trials. Of 11,577 women included in the pooled database, 10,133 with known clinical presentation received a DES. Of them, 5,760 (57%) had stable angina pectoris (SAP), 3,594 (35%) had unstable angina pectoris (UAP) or non-ST-segment-elevation myocardial infarction (NSTEMI), and 779 (8%) had ST-segment-elevation myocardial infarction (STEMI) as clinical presentation. A stepwise increase in 3-year crude cumulative mortality was observed in the transition from SAP to STEMI (4.9% vs 6.1% vs 9.4%; p <0.01). Conversely, no differences in crude mortality rates were observed between 1 and 3 years across clinical presentations. After multivariable adjustment, STEMI was independently associated with greater risk of 3-year mortality (hazard ratio [HR] 3.45; 95% confidence interval [CI] 1.99 to 5.98; p <0.01), whereas no differences were observed between UAP or NSTEMI and SAP (HR 0.99; 95% CI 0.73 to 1.34; p = 0.94). In women with ACS, use of new-generation DES was associated with reduced risk of major adverse cardiac events (HR 0.58; 95% CI 0.34 to 0.98). The magnitude and direction of the effect with new-generation DES was uniform between women with or without ACS (pinteraction = 0.66). In conclusion, in women across the clinical spectrum of CAD, STEMI was associated with a greater risk of long-term mortality. Conversely, the adjusted risk of mortality between UAP or NSTEMI and SAP was similar. New-generation DESs provide improved long-term clinical outcomes irrespective of the clinical presentation in women.

Non-Viral Gene Therapy to Cells of the bovine Intervertebral Disc

Background. Low back pain is an increasing global health problem, which is associated with intervertebral disc (IVD) damage and degeneration. Major changes occur in the nucleus pulposus (NP), with the degradation of the extracellular matrix (ECM).1 Further studies showed that growth factors from transforming growth factor β (TGFβ) and bone morphogenic proteins (BMP) family may induce chondrogenic differentiation of mesenchymal stem cells (MSC).2 Focusing on non-viral gene therapies and their possible translation into the clinics, we investigated if GDF6 (syn. BMP13 or CDMP2) can induce regeneration of degraded NP. We hypothesized that IVD transfected with plasmid over-expressing GDF6 also up-regulates other NP- and chondrogenic cell markers and enhances ECM deposition. Methods. Bovine nucleus pulposus (bNPC) and annulus fibrosus cells (bAFC) were harvested from bovine coccygeal IVD. Primary cells were then electroporized with plasmid GDF6 (Origene, vector RG211366) by optimizing parameters using the Neon Transfection system (Life Technologies, Basel). After transfection, cells were cultured in 2D monolayer or 3D alginate beads for 7, 14 or 21 days. Transfection efficiency of pGDF6 was analyzed by immunohistochemistry and fluorescent microscopy. Cell phenotype was quantified by real-time RT-PCR. To test a non-viral gene therapy applied directly to 3D whole organ culture, coccygeal bovine IVDs were harvested as previously described. Bovine IVDs were transfected by injection of plasmid GDF6 into the center. Electroporation was performed with ECM830 Square Wave Electroporation System (Harvard Apparatus, MA) using 2-needle array electrode or tweezertrodes. 72 h after tranfection discs were fixed and cryosectioned and analyzed by immunofluorescence against GDF6. Results. RT-PCR and immunohistochemistry confirmed up-regulation of GFP and GDF6 in the primary bNPC/bAFC culture. The GFP-tagged GDF6 protein, however, was not visible, possibly due to failure of dimer formation as a result of fusion structure. Organ IVD culture transfection revealed GDF6 positive staining in the center of the disc using 2-needle array electrode. Results from tweezertrodes did not show any GDF6 positive cells. Conclusion. Non-viral transfection is an appealing approach for gene therapy as it fulfills the translational safety aspects of transiency and lacks the toxic effects of viral transduction. We identified novel parameters to successfully transfect primary bovine IVD cells. For transfection of whole IVD explants electroporation parameters need to be further optimized. Acknowledgements. This project was funded by the Lindenhof Foundation (Funds “Research & Teaching”) Project no. 13-02-F. The imaging part of this study was performed with the facility of the Microscopy Imaging Center (MIC), University of Bern. References. Roughly PJ (2004): Spine (Phila), 29:2691-2699 Clarke LE, McConell JC, Sherratt MJ, Derby B, Richardson SM, Hoyland JA (2014), Arthritis Research & Therapy, 16:R67