Localization and electrical characterization of interconnect open defects

A technique for extracting the electrical and topological parameters of open defects in process monitor lines is presented. The procedure is based on frequency-domain measurements performed at both end points of the line. The location as well as the resistive value of the open defect are derived from attenuation and phase shift measurements. The characteristic defect-free impedance of the line and its propagation constant are considered to be unknowns, and their values are also derived from the above measurements. In this way, the impact of process parameter variations on the proposed model is diminished. The experimental setup required to perform the characterization measurements and a simple graphical procedure to determine the defect and line parameters are presented. Experimental results show a good agreement between the predicted location of the open and its real location, found by optical beam induced resistance change inspection. Errors smaller than 2% of the total length of the line have been observed in the experiments.Postprint (published version

Identification of Damage Associated Molecular Patterns and Extracellular Matrix Proteins as Major Constituents of the Surface Proteome of Lung Implantable Silicone/Nitinol Devices

Lung implantable devices have been widely adopted as mechanical interventions for a wide variety of pulmonary pathologies. Despite successful initial treatment, long-term efficacy can often be impacted by fibrotic or granulation tissue formation at the implant sites. This study aimed to explore the lung-device interface by identifying the adhered proteome on lung devices explanted from patients with severe emphysema. In this study, scanning electron microscopy is used to visualize the adhesion of cells and proteins to silicone and nitinol surfaces of explanted endobronchial valves. By applying high-resolution mass-spectrometry, the surface proteome of eight explanted valves is characterized, identifying 263 unique protein species to be mutually adsorbed on the valves. This subset is subjected to gene enrichment analysis, matched with known databases and further validated using immunohistochemistry. Enrichment analyses reveal dominant clusters of functionally-related ontology terms associated with coagulation, pattern recognition receptor signaling, immune responses, cytoskeleton organization, cell adhesion and migration. Matching results show that extracellular matrix proteins and damage-associated molecular patterns are cardinal in the formation of the surface proteome. This is the first study investigating the composition of the adhered proteome on explanted lung devices, setting the groundwork for hypothesis generation and further exploration. STATEMENT OF SIGNIFICANCE: This is the first study investigating the composition of the adhered proteome on explanted lung devices. Lung implantable devices have been widely adopted as mechanical interventions for pulmonary pathologies. Despite successful initial treatment, long-term efficacy can often be impacted by fibrotic or granulation tissue formation around the implant sites. We identified the adhered proteome on explanted lung devices using several techniques. We identified 263 unique protein species to be mutually adsorbed on explanted lung devices. Pathway analyses revealed that these proteins are associated with coagulation, pattern recognition receptor signaling, immune responses, cytoskeleton organization, cell adhesion and migration. Furthermore, we identified that especially extracellular matrix proteins and damage-associated molecular patterns were cardinal in the formation of the surface proteome

Genetic Association Analysis of the Functional c.714T>G Polymorphism and Mucosal Expression of Dectin-1 in Inflammatory Bowel Disease

Contains fulltext : 80614.pdf (publisher's version ) (Open Access)BACKGROUND: Dectin-1 is a pattern recognition receptor (PRR) expressed by myeloid cells that specifically recognizes beta-1,3 glucan, a polysaccharide and major component of the fungal cell wall. Upon activation, dectin-1 signaling converges, similar to NOD2, on the adaptor molecule CARD9 which is associated with inflammatory bowel disease (IBD). An early stop codon polymorphism (c.714T>G) in DECTIN-1 results in a loss-of-function (p.Y238X) and impaired cytokine responses, including TNF-alpha, interleukin (IL)-1beta and IL-17 upon in vitro stimulation with Candida albicans or beta-glucan. The aim of the present study was to test the hypothesis that the DECTIN-1 c.714T>G (p.Y238X) polymorphism is associated with lower disease susceptibility or severity in IBD and to investigate the level of dectin-1 expression in inflamed and non-inflamed colon tissue of IBD patients. METHODOLOGY: Paraffin embedded tissue samples from non-inflamed and inflamed colon of IBD patients and from diverticulitis patients were immunohistochemically stained for dectin-1 and related to CD68 macrophage staining. Genomic DNA of IBD patients (778 patients with Crohn's disease and 759 patients with ulcerative colitis) and healthy controls (n = 772) was genotyped for the c.714T>G polymorphism and genotype-phenotype interactions were investigated. PRINCIPAL FINDINGS: Increased expression of dectin-1 was observed in actively inflamed colon tissue, as compared to non-inflamed tissue of the same patients. Also an increase in dectin-1 expression was apparent in diverticulitis tissue. No statistically significant difference in DECTIN-1 c.714T>G allele frequencies was observed between IBD patients and healthy controls. Furthermore, no differences in clinical characteristics could be observed related to DECTIN-1 genotype, neither alone, nor stratified for NOD2 genotype. CONCLUSIONS: Our data demonstrate that dectin-1 expression is elevated on macrophages, neutrophils, and other immune cells involved in the inflammatory reaction in IBD. The DECTIN-1 c.714T>G polymorphism however, is not a major susceptibility factor for developing IBD

Vedolizumab for Inflammatory Bowel Disease:Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, A Nationwide Prospective Observational Cohort Study: ICC Registry - Vedolizumab

Contains fulltext : 220028.pdf (Publisher’s version ) (Open Access)Prospective data of vedolizumab treatment for patients with inflammatory bowel disease (IBD) beyond 1 year of treatment is scarce but needed for clinical decision making. We prospectively enrolled 310 patients with IBD (191 with Crohn's disease (CD) and 119 patients with ulcerative colitis (UC)) with a follow-up period of 104 weeks (interquartile range: 103-104) in a nationwide registry. The corticosteroid-free clinical remission rate (Harvey Bradshaw Index ≤ 4, Short Clinical Colitis Activity index ≤ 2) at weeks 52 and 104 were 28% and 19% for CD and 27% and 28% for UC, respectively. Fifty-nine percent maintained corticosteroid-free clinical remission between weeks 52 and 104. Vedolizumab with concomitant immunosuppression showed comparable effectiveness outcomes compared with vedolizumab monotherapy (week 104: 21% vs. 23%; P = 0.77), whereas 8 of 13 severe infections occurred in patients treated with concomitant immunosuppression. To conclude, the clinical effect was 19% for CD and 28% for UC after 2 years of follow-up regardless of concomitant immunosuppression

Molecular characteristics of circulating tumor cells resemble the liver metastasis more closely than the primary tumor in metastatic colorectal cancer

Background: CTCs are a promising alternative for metastatic tissue biopsies for use in precision medicine approaches. We investigated to what extent the molecular characteristics of circula

Observation of High-Energy Astrophysical Neutrinos in Three Years of IceCube Data

A search for high-energy neutrinos interacting within the IceCube detector between 2010 and 2012 provided the first evidence for a high-energy neutrino flux of extraterrestrial origin. Results from an analysis using the same methods with a third year (2012-2013) of data from the complete IceCube detector are consistent with the previously reported astrophysical flux in the 100 TeV - PeV range at the level of $10^{-8}\, \mathrm{GeV}\, \mathrm{cm}^{-2}\, \mathrm{s}^{-1}\, \mathrm{sr}^{-1}$ per flavor and reject a purely atmospheric explanation for the combined 3-year data at $5.7 \sigma$. The data are consistent with expectations for equal fluxes of all three neutrino flavors and with isotropic arrival directions, suggesting either numerous or spatially extended sources. The three-year dataset, with a livetime of 988 days, contains a total of 37 neutrino candidate events with deposited energies ranging from 30 to 2000 TeV. The 2000 TeV event is the highest-energy neutrino interaction ever observed.Comment: 8 pages, 5 figures. Accepted by PRL. The event catalog, event displays, and other data tables are included after the final page of the article. Changed from the initial submission to reflect referee comments, expanding the section on atmospheric backgrounds, and fixes offsets of up to 0.9 seconds in reported event times. Address correspondence to: J. Feintzeig, C. Kopper, N. Whitehor

Ethical issues at the interface of clinical care and research practice in pediatric oncology: a narrative review of parents' and physicians' experiences

Contains fulltext : 97879.pdf (publisher's version ) (Open Access)BACKGROUND: Pediatric oncology has a strong research culture. Most pediatric oncologists are investigators, involved in clinical care as well as research. As a result, a remarkable proportion of children with cancer enrolls in a trial during treatment. This paper discusses the ethical consequences of the unprecedented integration of research and care in pediatric oncology from the perspective of parents and physicians. METHODOLOGY: An empirical ethical approach, combining (1) a narrative review of (primarily) qualitative studies on parents' and physicians' experiences of the pediatric oncology research practice, and (2) comparison of these experiences with existing theoretical ethical concepts about (pediatric) research. The use of empirical evidence enriches these concepts by taking into account the peculiarities that ethical challenges pose in practice. RESULTS: Analysis of the 22 studies reviewed revealed that the integration of research and care has consequences for the informed consent process, the promotion of the child's best interests, and the role of the physician (doctor vs. scientist). True consent to research is difficult to achieve due to the complexity of research protocols, emotional stress and parents' dependency on their child's physician. Parents' role is to promote their child's best interests, also when they are asked to consider enrolling their child in a trial. Parents are almost never in equipoise on trial participation, which leaves them with the agonizing situation of wanting to do what is best for their child, while being fearful of making the wrong decision. Furthermore, a therapeutic misconception endangers correct assessment of participation, making parents inaccurately attribute therapeutic intent to research procedures. Physicians prefer the perspective of a therapist over a researcher. Consequently they may truly believe that in the research setting they promote the child's best interests, which maintains the existence of a therapeutic misconception between them and parents. CONCLUSION: Due to the integration of research and care, their different ethical perspectives become intertwined in the daily practice of pediatric oncology. Increasing awareness of what this means for the communication between parents and physicians is essential. Future research should focus on efforts that overcome the problems that the synchronicity of research and care evokes

Machine learning used to compare the diagnostic accuracy of risk factors, clinical signs and biomarkers and to develop a new prediction model for neonatal early-onset sepsis

Background: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. Study Design: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. Results: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random. Conclusions: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics

The Functional −765G→C Polymorphism of the COX-2 Gene May Reduce the Risk of Developing Crohn's Disease

Contains fulltext : 87827.pdf (publisher's version ) (Open Access)BACKGROUND: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the conversion of arachidonic acid into prostaglandins. COX-2 is mainly induced at sites of inflammation in response to proinflammatory cytokines such as interleukin-1alpha/beta, interferon-gamma and tumor necrosis factor-alpha produced by inflammatory cells. AIM: The aim of this study was to investigate the possible modulating effect of the functional COX-2 polymorphisms -1195 A-->G and -765G-->C on the risk for development of inflammatory bowel disease (IBD) in a Dutch population. METHODS: Genomic DNA of 525 patients with Crohn's disease (CD), 211 patients with ulcerative colitis (UC) and 973 healthy controls was genotyped for the -1195 A-->G (rs689466) and -765G-->C (rs20417) polymorphisms. Distribution of genotypes in patients and controls were compared and genotype-phenotype interactions were investigated. RESULTS: The genotype distribution of the -1195A-->G polymorphism was not different between the patients with CD or UC and the control group. The -765GG genotype was more prevalent in CD patients compared to controls with an OR of 1.33 (95%CI 1.04-1.69, pC polymorphism was associated with a reduced risk for developing Crohn's disease in a Dutch population

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant – a historical prospective study

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2/FiO2 ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized